Antiemetics for adults for prevention of nausea and vomiting caused by moderately or highly emetogenic chemotherapy: a network meta‐analysis

Abstract

Background

About 70% to 80% of adults with cancer experience chemotherapy‐induced nausea and vomiting (CINV). CINV remains one of the most distressing symptoms associated with cancer therapy and is associated with decreased adherence to chemotherapy. Combining 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists with corticosteroids or additionally with neurokinin‐1 (NK₁) receptor antagonists is effective in preventing CINV among adults receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). Various treatment options are available, but direct head‐to‐head comparisons do not allow comparison of all treatments versus another. 

Objectives

• In adults with solid cancer or haematological malignancy receiving HEC

‐ To compare the effects of antiemetic treatment combinations including NK₁ receptor antagonists, 5‐HT₃ receptor antagonists, and corticosteroids on prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy‐induced nausea and vomiting in network meta‐analysis (NMA)

‐ To generate a clinically meaningful treatment ranking according to treatment safety and efficacy

• In adults with solid cancer or haematological malignancy receiving MEC

‐ To compare whether antiemetic treatment combinations including NK₁ receptor antagonists, 5‐HT₃ receptor antagonists, and corticosteroids are superior for prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy‐induced nausea and vomiting to treatment combinations including 5‐HT₃ receptor antagonists and corticosteroids solely, in network meta‐analysis

‐ To generate a clinically meaningful treatment ranking according to treatment safety and efficacy

Search methods

We searched CENTRAL, MEDLINE, Embase, conference proceedings, and study registries from 1988 to February 2021 for randomised controlled trials (RCTs).

Selection criteria

We included RCTs including adults with any cancer receiving HEC or MEC (according to the latest definition) and comparing combination therapies of NK₁ and 5‐HT₃ inhibitors and corticosteroids for prevention of CINV.

Data collection and analysis

We used standard methodological procedures expected by Cochrane.

We expressed treatment effects as risk ratios (RRs). Prioritised outcomes were complete control of vomiting during delayed and overall phases, complete control of nausea during the overall phase, quality of life, serious adverse events (SAEs), and on‐study mortality. We assessed GRADE and developed 12 'Summary of findings' tables. We report results of most crucial outcomes in the abstract, that is, complete control of vomiting during the overall phase and SAEs. For a comprehensive illustration of results, we randomly chose aprepitant plus granisetron as exemplary reference treatment for HEC, and granisetron as exemplary reference treatment for MEC.

Main results

Highly emetogenic chemotherapy (HEC)

We included 73 studies reporting on 25,275 participants and comparing 14 treatment combinations with NK₁ and 5‐HT₃ inhibitors. All treatment combinations included corticosteroids.

Complete control of vomiting during the overall phase

We estimated that 704 of 1000 participants achieve complete control of vomiting in the overall treatment phase (one to five days) when treated with aprepitant + granisetron. Evidence from NMA (39 RCTs, 21,642 participants; 12 treatment combinations with NK₁ and 5‐HT₃ inhibitors) suggests that the following drug combinations are more efficacious than aprepitant + granisetron for completely controlling vomiting during the overall treatment phase (one to five days): fosnetupitant + palonosetron (810 of 1000; RR 1.15, 95% confidence interval (CI) 0.97 to 1.37; moderate certainty), aprepitant + palonosetron (753 of 1000; RR 1.07, 95% CI 1.98  to 1.18; low‐certainty), aprepitant + ramosetron (753 of 1000; RR 1.07, 95% CI 0.95 to 1.21; low certainty), and fosaprepitant + palonosetron (746 of 1000; RR 1.06, 95% CI 0.96 to 1.19; low certainty). 

Netupitant + palonosetron (704 of 1000; RR 1.00, 95% CI 0.93 to 1.08; high‐certainty) and fosaprepitant + granisetron (697 of 1000; RR 0.99, 95% CI 0.93 to 1.06; high‐certainty) have little to no impact on complete control of vomiting during the overall treatment phase (one to five days) when compared to aprepitant + granisetron, respectively. 

Evidence further suggests that the following drug combinations are less efficacious than aprepitant + granisetron in completely controlling vomiting during the overall treatment phase (one to five days) (ordered by decreasing efficacy): aprepitant + ondansetron (676 of 1000; RR 0.96, 95% CI 0.88 to 1.05; low certainty), fosaprepitant + ondansetron (662 of 1000; RR 0.94, 95% CI 0.85 to 1.04; low certainty), casopitant + ondansetron (634 of 1000; RR 0.90, 95% CI 0.79 to 1.03; low certainty), rolapitant + granisetron (627 of 1000; RR 0.89, 95% CI 0.78 to 1.01; moderate certainty), and rolapitant + ondansetron (598 of 1000; RR 0.85, 95% CI 0.65 to 1.12; low certainty).

We could not include two treatment combinations (ezlopitant + granisetron, aprepitant + tropisetron) in NMA for this outcome because of missing direct comparisons. 

Serious adverse events

We estimated that 35 of 1000 participants experience any SAEs when treated with aprepitant + granisetron. Evidence from NMA (23 RCTs, 16,065 participants; 11 treatment combinations) suggests that fewer participants may experience SAEs when treated with the following drug combinations than with aprepitant + granisetron: fosaprepitant + ondansetron (8 of 1000; RR 0.23, 95% CI 0.05 to 1.07; low certainty), casopitant + ondansetron (8 of 1000; RR 0.24, 95% CI 0.04 to 1.39; low certainty), netupitant + palonosetron (9 of 1000; RR 0.27, 95% CI 0.05 to 1.58; low certainty), fosaprepitant + granisetron (13 of 1000; RR 0.37, 95% CI 0.09 to 1.50; low certainty), and rolapitant + granisetron (20 of 1000; RR 0.57, 95% CI 0.19 to 1.70; low certainty).

Evidence is very uncertain about the effects of aprepitant + ondansetron (8 of 1000; RR 0.22, 95% CI 0.04 to 1.14; very low certainty), aprepitant + ramosetron (11 of 1000; RR 0.31, 95% CI 0.05 to 1.90; very low certainty), fosaprepitant + palonosetron (12 of 1000; RR 0.35, 95% CI 0.04 to 2.95; very low certainty), fosnetupitant + palonosetron (13 of 1000; RR 0.36, 95% CI 0.06 to 2.16; very low certainty), and aprepitant + palonosetron (17 of 1000; RR 0.48, 95% CI 0.05 to 4.78; very low certainty) on the risk of SAEs when compared to aprepitant + granisetron, respectively. 

We could not include three treatment combinations (ezlopitant + granisetron, aprepitant + tropisetron, rolapitant + ondansetron) in NMA for this outcome because of missing direct comparisons. 

Moderately emetogenic chemotherapy (MEC)

We included 38 studies reporting on 12,038 participants and comparing 15 treatment combinations with NK₁ and 5‐HT₃ inhibitors, or 5‐HT₃ inhibitors solely. All treatment combinations included corticosteroids.

Complete control of vomiting during the overall phase

We estimated that 555 of 1000 participants achieve complete control of vomiting in the overall treatment phase (one to five days) when treated with granisetron. Evidence from NMA (22 RCTs, 7800 participants; 11 treatment combinations) suggests that the following drug combinations are more efficacious than granisetron in completely controlling vomiting during the overall treatment phase (one to five days): aprepitant + palonosetron (716 of 1000; RR 1.29, 95% CI 1.00 to 1.66; low certainty), netupitant + palonosetron (694 of 1000; RR 1.25, 95% CI 0.92 to 1.70; low certainty), and rolapitant + granisetron (660 of 1000; RR 1.19, 95% CI 1.06 to 1.33; high certainty). 

Palonosetron (588 of 1000; RR 1.06, 95% CI 0.85 to 1.32; low certainty) and aprepitant + granisetron (577 of 1000; RR 1.06, 95% CI 0.85 to 1.32; low certainty) may or may not increase complete response in the overall treatment phase (one to five days) when compared to granisetron, respectively. Azasetron (560 of 1000; RR 1.01, 95% CI 0.76 to 1.34; low certainty) may result in little to no difference in complete response in the overall treatment phase (one to five days) when compared to granisetron.

Evidence further suggests that the following drug combinations are less efficacious than granisetron in completely controlling vomiting during the overall treatment phase (one to five days) (ordered by decreasing efficacy): fosaprepitant + ondansetron (500 of 1000; RR 0.90, 95% CI 0.66 to 1.22; low certainty), aprepitant + ondansetron (477 of 1000; RR 0.86, 95% CI 0.64 to 1.17; low certainty), casopitant + ondansetron (461 of 1000; RR 0.83, 95% CI 0.62 to 1.12; low certainty), and ondansetron (433 of 1000; RR 0.78, 95% CI 0.59 to 1.04; low certainty).

We could not include five treatment combinations (fosaprepitant + granisetron, azasetron, dolasetron, ramosetron, tropisetron) in NMA for this outcome because of missing direct comparisons. 

Serious adverse events

We estimated that 153 of 1000 participants experience any SAEs when treated with granisetron. Evidence from pair‐wise comparison (1 RCT, 1344 participants) suggests that more participants may experience SAEs when treated with rolapitant + granisetron (176 of 1000; RR 1.15, 95% CI 0.88 to 1.50; low certainty). NMA was not feasible for this outcome because of missing direct comparisons. 

Certainty of evidence

Our main reason for downgrading was serious or very serious imprecision (e.g. due to wide 95% CIs crossing or including unity, few events leading to wide 95% CIs, or small information size). Additional reasons for downgrading some comparisons or whole networks were serious study limitations due to high risk of bias or moderate inconsistency within networks.

Authors' conclusions

This field of supportive cancer care is very well researched. However, new drugs or drug combinations are continuously emerging and need to be systematically researched and assessed.

For people receiving HEC, synthesised evidence does not suggest one superior treatment for prevention and control of chemotherapy‐induced nausea and vomiting. 

For people receiving MEC, synthesised evidence does not suggest superiority for treatments including both NK₁ and 5‐HT₃ inhibitors when compared to treatments including 5‐HT₃ inhibitors only. Rather, the results of our NMA suggest that the choice of 5‐HT₃ inhibitor may have an impact on treatment efficacy in preventing CINV. 

When interpreting the results of this systematic review, it is important for the reader to understand that NMAs are no substitute for direct head‐to‐head comparisons, and that results of our NMA do not necessarily rule out differences that could be clinically relevant for some individuals.

Plain language summary

Which drug combinations are best for prevention of nausea and vomiting caused by chemotherapy in adults with cancer?

The burden of nausea and vomiting caused by chemotherapy and what helps to prevent it?

In about 70% to 80% of adults with cancer, chemotherapy induces nausea and vomiting (CINV). Depending on the type of chemotherapy, treatment can cause strong or moderate sickness (hereafter referred to as HEC (highly emetogenic chemotherapy) and MEC (moderately emetogenic chemotherapy)). Multiple drug combinations have showed high benefit for CINV among adults receiving HEC or MEC.

What was the aim of our review?

Using a network meta‐analysis, we aimed to compare the benefits and harms of different drug combinations for prevention of CINV among people receiving HEC or MEC, and to identify treatment ranking. A network meta‐analysis is a technique used to compare different treatments described in already published trials, even when the original individual trial does not describe such comparisons.

What studies did we look at?

We searched selected medical databases and trial registries until February 2021. We included studies comparing multiple drug combinations for prevention of CINV among adults with any type of cancer receiving HEC or MEC that is commonly used in clinical practice. In particular, we looked at drugs inhibiting two specific biochemical receptors (neurokinin receptor and serotonin receptor) that trigger nausea and vomiting after chemotherapy. We looked at the preventative effects of these treatments over five days. This is the period during which the maximum intensity of CINV and further peaks of intensity are expected, after the start of chemotherapy. 

Our key results...

...for people receiving HEC

We found 73 studies that reported on the experience of 25,275 participants and compared 14 treatment combinations of our interest. 

Benefits. Over five days, investigated treatments helped to prevent any vomiting in 60% to 81% of people on average. Those individuals also had no need for rescue medicines, which are used in case nausea and vomiting occur even though prophylactic treatment has been given. The results of our analysis suggest some differences in effectiveness of different treatments, but overall we had little confidence that those differences would be reflected in real‐world observations. 

Harms. We estimated that 1% to 4% of people experience serious side effects. The differences between treatments were small. 

...for people receiving MEC

We found 38 studies that reported on the experience of 12,038 participants and compared 15 treatment combinations of our interest.

Benefits. Over five days, investigated treatments helped prevent any vomiting in 43% to 72% of people on average. Those individuals also had no need for rescue medicines. The results of our analysis suggest some differences in the effectiveness of different treatments, but overall, we had little confidence that those differences would be reflected in real‐world observations. 

Harms. Few studies reported serious side effects. The ones that did suggest that on average 15% to 18% of people experience such events. Differences between treatments were small. However, we think that future research is needed to rule out potential differences between treatments. 

Our confidence in the findings

We assessed how confident we were that there are differences between compared treatments. We had low or very low confidence that one treatment is better or worse than another in preventing CINV. Our confidence in differences between statistical results was mainly limited because measures of variation were wide apart and included both potential advantages and disadvantages, although measures of precision showed no or little effect. We also identified limitations in some of the included studies, which further limited our confidence in the effects. This was mainly the case when study personnel and participants knew which treatments were given and therefore may not adhere to the planned intervention, or may perceive or report effects differently. 

Our conclusions

The results of our analysis suggest that there is no superior drug combination for prevention of CINV for people receiving HEC or MEC. However, results suggest that the choice of drugs targeting the serotonin receptor may impact effectiveness, irrespective of whether given with or without a drug targeting the neurokinin receptor. However, when interpreting these results, it is important for the reader to understand that these kinds of multiple‐comparison analyses are no substitute for head‐to‐head comparisons, and that the results do not necessarily rule out differences that could be clinically relevant for some individuals.

How up‐to‐date is this evidence?

Evidence is up‐to‐date to 2 February 2021.

Background

Description of the condition

Many cancer patients, both with solid tumours and with haematological malignancies, suffer from chemotherapy‐induced nausea and vomiting (CINV), which is an important contributor to morbidity, poor performance status, and decreased quality of life (Feyer 2011; Jordan 2015). The reported age‐adjusted incidence rate of cancer in the USA in 2010 was 464.6 per 100,000, and the mortality rate was 199.8 per 100,000 persons per year (Howlader 2013). Without appropriate antiemetic therapy, 70% to 80% of cancer patients receiving chemotherapy develop CINV (Feyer 2011). This condition is classified into five categories, depending on the start of CINV in relation to the start of chemotherapy and patients’ negative previous experiences (Navari 2016; Tageja 2016).

• Acute: nausea and vomiting occurring within the first 24 hours of treatment with chemotherapy, with maximal intensity after five to six hours; activated through a peripheral pathway in which 5‐hydroxytryptamine‐3 (5‐HT₃) receptor activation plays a role.

• Delayed: nausea and vomiting occurring from 24 hours to 120 hours of treatment with chemotherapy, with peaks of intensity between 48 and 72 hours; activated through a central pathway in which neurokinin‐1 (NK₁) receptor activation is involved.

• Breakthrough: nausea and vomiting occurring although appropriate prophylaxis has been administered.

• Anticipatory: conditioned response to the occurrence of CINV in previous chemotherapy cycles resulting in nausea and vomiting.

• Refractory: nausea and vomiting recurring in subsequent cycles of chemotherapy, excluding anticipatory CINV.

In this review, we will focus on prevention of acute and delayed CINV.

Several prognostic factors such as younger age, female sex, previous hyperemesis gravidarum or history of vomiting in pregnancy, and motion sickness have been found to increase the likelihood of CINV (Di Mattei 2016; Dranitsaris 2017; Furukawa 2014; Hu 2016; Warr 2014); regular alcohol consumption has been found to reduce the risk of CINV (Hesketh 2010; Hu 2016).

CINV remains one of the most distressing symptoms associated with cancer therapy and can lead to dehydration, electrolyte imbalances, malnutrition, and metabolic disturbances (Viale 2012). Moreover, CINV is associated with decreased adherence to chemotherapy, which could lead to a decreased response resulting in increased risk of death among cancer patients (Wozniak 1998). Therefore, preventing CINV is an important goal for cancer patients.

According to the Multinational Association of Supportive Care in Cancer (MASCC)/European Society of Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO), practice focuses on the emetogenicity of chemotherapeutic agents (minimal, low, moderate, high) and the relative doses of antineoplastic agents used (Basch 2012; Jordan 2017; Roila 2016).

Highly emetogenic chemotherapy includes the following agents or combinations of agents (Basch 2012).

• Anthracycline/cyclophosphamide combination.

• Carmustine.

• Cisplatin.

• Cyclophosphamide ≥ 1500 mg/m².

• Dacarbazine.

• Hexamethylmelamine.

• Mechlorethamine.

• Procarbazine.

• Streptozocin.

Moderately emetogenic chemotherapy includes the following agents (Basch 2012).

• Alemtuzumab.

• Azacitidine.

• Bendamustine.

• Bosutinib.

• Carboplatin.

• Ceritinib.

• Clofarabine.

• Crizotinib.

• Cyclophosphamide 1000 mg/m².

• Daunorubicin.

• Doxorubicin.

• Epirubicin.

• Idarubicin.

• Ifosfamide.

• Imatinib.

• Irinotecan.

• Oxaliplatin.

• Romidepsin.

• Temozolomide.

• Thiotepa.

• Trabectedin.

• Vinorelbine.

According to the latest MASCC/ESMO guidelines, carboplatin has higher emetogenic potential compared to the other moderately emetogenic agents; patients receiving this drug should receive the same prophylaxis as described for patients with highly emetogenic potential (Jordan 2017; Roila 2016).

With appropriate antiemetic prophylaxis, acute CINV and delayed CINV are clinically significantly reduced. In a recent systematic review, Yuan and colleagues found that the complete response rate of patients receiving an NK₁ receptor antagonist was significantly higher compared to that seen in patients given various control regimens (like 5‐HT₃ receptor antagonists + dexamethasone), with complete response in the acute phase of 85.1% versus 79.6% and complete response in the delayed phase of 71.4% versus 58.2%. According to review authors, the safety profile of NK₁ receptor antagonists was comparable to that of other regimens, with less insomnia but more diarrhoea and hiccups (Yuan 2016).

Description of the intervention

Options for prevention of CINV are 5‐HT₃ receptor antagonists (e.g. ondansetron, granisetron, palonosetron) in combination with corticosteroids (e.g. dexamethasone), or additionally combined with NK₁ receptor antagonists (e.g. aprepitant, fosaprepitant, netupitant, rolapitant). Although antiemetic therapy is common among cancer patients at risk for CINV, recommendations provided in current guidelines are inconsistent. According to ASCO, practice focuses on the emetogenicity of chemotherapeutic agents (minimal, low, moderate, high) and the relative dose of antineoplastic agents used. This guideline recommends 5‐HT₃ receptor antagonists plus dexamethasone for patients administered moderately emetogenic chemotherapy (Basch 2012). The latest update of this guideline for patients receiving highly emetogenic chemotherapy (including anthracycline + cyclophosphamide) recommends a combination of an NK₁ receptor antagonist, a 5‐HT₃ receptor antagonist, and dexamethasone. The oral combination of palonosetron, netupitant, and dexamethasone is one of the specific treatments recommended for these patients (Hesketh 2016). The recommendation in the moderately emetogenic setting is less clear. In the latest MASCC/ESMO guideline report, it was acknowledged that carboplatin‐based chemotherapy might have higher risk of nausea and vomiting compared to other drugs in the category moderately emetogenic chemotherapy (Roila 2016). The MASCC/ESMO guideline recommends the same three‐drug combination as the ASCO guideline for patients receiving highly emetogenic chemotherapy (including anthracycline plus cyclophosphamide) but points out that no published comparative studies have identified differences in efficacy and toxicity between available NK₁ receptor antagonists to recommend one specific drug over another (Roila 2016). In the so called other moderate emetogenic risk group, a 5‐HT₃ receptor antagonist + dexamethasone is still standard of care, although National Comprehensive Cancer Network (NCCN) guidelines broaden the indication for an NK₁ receptor antagonist in this risk category (Ettinger 2017).

Another option for prevention and treatment of CINV‐ or radiotherapy‐induced nausea and vomiting is olanzapine. However, evidence for efficacy and safety of this drug is not yet clear and is being evaluated in a Cochrane Review (Cochrane protocol already published: Sutherland 2017).

How the intervention might work

For 5‐HT₃ receptor antagonists and dexamethasone, solely or in combination with NK₁ receptor antagonists, systematic reviews and meta‐analyses have shown that they improve CINV in cancer patients administered especially highly emetogenic chemotherapy including anthracycline‐cyclophosphamide‐based chemotherapy, with inconclusive evidence on effectiveness and rates of adverse events for one drug compared to another (Celio 2013; dos Santos 2013; Hocking 2014; Jin 2012; Jordan 2016b; Lee 2013; Popovic 2014).

As the central nervous system, the neurotransmitter, and their receptors play a critical role in CINV, both 5‐HT₃ receptor antagonists and NK₁ receptor antagonists inhibit processing of antiemetic signals from the gut to the central nervous system (Janelsins 2013). Both drugs are usually combined with dexamethasone to improve efficacy. A pilot randomised controlled trial (RCT) including 31 patients receiving cisplatin chemotherapy has shown first improved efficacy of ondansetron when combined with dexamethasone and a good safety profile (Smith 1991). Another RCT conducted between 1992 and 1994 for patients receiving moderately emetogenic chemotherapy has shown highest efficacy in terms of complete protection of vomiting and nausea and less delayed vomiting and nausea with the combination of granisetron and dexamethasone compared to granisetron or dexamethasone. No severe adverse events were reported, but constipation and hot flushes were more often found in the granisetron + dexamethasone arm compared to single‐drug arms (Italian Group for Antiemetic Research 1995). Granisetron + dexamethasone has also shown improved efficacy compared to both single drugs only among patients receiving cisplatin chemotherapy (Heron 1994). Thereafter, a 5‐HT₃ receptor antagonist combined with dexamethasone became standard prophylaxis for preventing CINV (Gralla 1999).

As NK₁ receptor antagonists inhibit another receptor in the emetic signal activation, they are combined with 5‐HT₃ receptor antagonists and dexamethasone for patients receiving cisplatin or other highly emetogenic chemotherapeutic agents (Hesketh 2003; Poli‐Bigelli 2003). 

Why it is important to do this review

As mentioned above, the decision‐making process for prevention of CINV is usually confusing for patients and physicians, as there are no clear recommendations in international guidelines for a consistent approach to the use of antiemetic agents (Hesketh 2016; Roila 2016). Economic arguments are introduced in discussions on the best strategy, as direct and indirect costs differ enormously for various treatment options, and this could lead to increased healthcare costs (Avritscher 2010; Humphreys 2013). In addition, direct head‐to‐head comparisons of prophylactic options are too sparse to favour one drug or a combined drug regimen over another.

The aim of our systematic review and network analysis is to provide a comprehensive overview on the benefits and harms of antiemetic agents for CINV. By systematically identifying all relevant RCTs conducted to date and critically reviewing their reliability and validity while considering similar trials in the network analysis, we will overcome statistical limitations of individual studies. The network meta‐analysis will allow a hierarchy of therapeutic options, in particular, if the benefits of one option compared to another will translate into a clinically important difference. This comprehensive overview is necessary for clinical decision‐making, and it has the potential to have a great impact on international guidelines and clinical pathways. Moreover, it may contribute to high‐grade decision support for effective therapeutic strategies for the individual person.

The results of this network meta‐analysis will be published in the Cochrane Library and presented at national and international expert meetings and conferences (e.g. American Society of Clinical Oncology, Multinational Association of Supportive Care in Cancer). Results of the network analysis have the potential to influence the design of new RCTs for antiemetic agents. As we have evaluated patient‐related outcomes, a direct impact on patient care and treatment might be expected.

Objectives

• In adults with solid cancer or haematological malignancy receiving highly emetogenic chemotherapy

  • To compare the effects of antiemetic treatment combinations including NK₁ receptor antagonists, 5‐HT₃ receptor antagonists, and corticosteroids on prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy‐induced nausea and vomiting in network meta‐analysis

  • To generate a clinically meaningful treatment ranking according to treatment safety and efficacy

• In adults with solid cancer or haematological malignancy receiving moderately emetogenic chemotherapy

  • To compare whether antiemetic treatment combinations including NK₁ receptor antagonists, 5‐HT₃ receptor antagonists, and corticosteroids are superior for prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy‐induced nausea and vomiting to treatment combinations including 5‐HT₃ receptor antagonists and corticosteroids solely, in network meta‐analysis

  • To generate a clinically meaningful treatment ranking according to treatment safety and efficacy

Methods

Criteria for considering studies for this review

Types of studies

The protocol for this review was previously published in the Cochrane Library (Skoetz 2017). Any differences to the protocol are described in Differences between protocol and review.

We included studies if they were randomised controlled trials (RCTs), which are best designed to minimise bias when evaluating the effectiveness of an intervention. We required full journal publication, with the exception of online clinical trial results and summaries of otherwise unpublished clinical trials and abstracts with sufficient data for analysis. We considered only results from the first cycle, regardless of potential cross‐over. We included blinded and non‐blinded studies, and we addressed the potential impact of blinding in our bias assessment and sensitivity analyses. We applied no limitations with respect to length of follow‐up. However, we considered only results from the first cycle. 

We excluded studies that were cluster‐randomised or non‐randomised, as well as case reports and clinical observations.

Types of participants

Studies included trials involving adult patients according to the definition provided in the studies (usually ≧ 18 years of age), with a confirmed diagnosis of cancer, irrespective of type and stage of cancer and gender. We included both patients with solid cancer and patients with haematological malignancies. We included trials that included patients receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) according to the latest Antineoplastic Agents Emetic Risk Classification (Jordan 2017; Roila 2016). As this classification has changed over the years (e.g. anthracycline and cyclophosphamide combination is nowadays classified as HEC instead of MEC), we used this classification to assess the emetogenic risk of one specific chemotherapeutic agent, irrespective of the emetogenic risk applied by study authors (see section Description of the condition). We performed separate analyses for populations receiving HEC and MEC, according to the definition provided by Multinational Association of Supportive Care in Cancer (MASCC)/European Society of Medical Oncology (ESMO) (Jordan 2017; Roila 2016). We assumed that patients who fulfil the inclusion criteria were equally eligible to be randomised to any of the interventions that we had planned to compare.

We excluded trials including participants not receiving emetogenic chemotherapies at the same level of risk, which did not provide subgroup data for each emetogenic risk group. We excluded trials evaluating participants at risk for radiotherapy‐induced nausea and vomiting. We excluded trials evaluating participants at risk of vomiting and nausea due to underlying disease.

Types of interventions

At the time this review was produced, recommended antiemetics for prophylaxis of chemotherapy‐induced nausea and vomiting (CINV) caused by highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) included the following drug combinations.

• 5‐Hydroxytryptamine‐3 (5‐HT₃) receptor antagonists and corticosteroids.

• Neurokinin‐1 (NK₁) receptor antagonists, 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists, and corticosteroids.

We compared combinations of these interventions at any dose and by any route versus each other in a full network. We included all RCTs comparing in at least two study arms the intervention of interest ‐ either 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroids, or neurokinin‐1 (NK₁) receptor antagonists in combination with 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroids. 

We included only trials that included patients on corticosteroids in both arms.

We analysed prophylaxis for cancer patients administered HEC or MEC separately. We assumed that any participant who met the inclusion criteria was, in principle, equally likely to be randomised to any of the eligible interventions. We grouped interventions by evaluating different drug doses together as one drug of interest, according to the product characteristics.

We excluded trials evaluating solely treatment of nausea and vomiting, meaning that the drug is not given before chemotherapeutic agents are administered to prevent CINV but rather once nausea or vomiting appears. Antiemetic agents to treat CINV might be the same agents used for prevention of CINV, but to include clinically homogenous trials to answer the research question, we focused on prophylaxis only.

Comparisons of direct interest

As mentioned above, current guidelines are highly uncertain about whether to recommend a double^a or triple^b drug combination for cancer patients receiving MEC, and which triple regimen should be administered to cancer patients receiving HEC (Basch 2012; Hesketh 2016; Roila 2016). Therefore the following comparisons are of direct interest.

^aDouble drug combination: treatments including a 5‐HT₃ receptor antagonist and corticosteroids.

^bTriple drug combination: treatments including an NK₁ receptor antagonist, a 5‐HT₃ receptor antagonist, and corticosteroids.

Comparisons in cancer patients receiving highly emetogenic chemotherapy (HEC)

• NK₁ receptor antagonist + 5‐HT₃ receptor antagonist + corticosteroid versus other specific combinations of these drug classes + corticosteroid

We additionally included the following comparisons to strengthen the network.

• NK₁ receptor antagonist + 5‐HT₃ receptor antagonist + corticosteroid versus 5‐HT₃ receptor antagonist + corticosteroid.

• 5‐HT₃ receptor antagonist + corticosteroid versus other specific combinations of this drug class + corticosteroid.

An overview of all included treatment regimens is provided in Table 5.

1. Overview of treatment regimens and treatment abbreviations.

Drug combinations	Treatment regimena	Abbreviation	Used in HECb setting	Used in MECc setting
NK₁ receptor antagonists and 5‐HT₃ receptor antagonists + corticosteroid	aprepitant with granisetron	apre_grani	X	X
	aprepitant with ondansetron	apre_ondan	X	X
	aprepitant with palonosetron	apre_palo	X	X
	aprepitant with ramosetron	apre_ramo	X
	aprepitant with tropisetron	apre_tropi	X
	casopitant with ondansetron	caso_ondan	X	X
	fosaprepitant with granisetron	fosa_grani	X	X
	ezlopitant with granisetron	ezlo_grani	X
	fosaprepitant with ondansetron	fosa_ondan	X	X
	fosaprepitant with palonosetron	fosa_palo	X
	fosnetupitant with palonosetron	fosnetu_palo	X
	netupitant with palonosetron	netu_palo	X	X
	rolapitant with granisetron	rola_grani	X	X
	rolapitant with ondansetron	rola_ondan	X
5‐HT₃ receptor antagonists+ corticosteroid	azasetron	aza	X	X
	dolasetron	dola		X
	granisetron	grani	X	X
	ondansetron	ondan	X	X
	palonosetron	palo	X	X
	ramosetron	ramo	X	X
	tropisetron	tropi	X	X

^aAll treatment regimens also include a corticosteroid.

^bHighly emetogenic chemotherapy.

^cModerately emetogenic chemotherapy.

Comparisons in cancer patients receiving moderately emetogenic chemotherapy (MEC)

• NK₁ receptor antagonist + 5‐HT₃ receptor antagonist + corticosteroid versus other specific drug combinations of this drug class + corticosteroid

• NK₁ receptor antagonist + 5‐HT₃ receptor antagonist + corticosteroid versus 5‐HT₃ receptor antagonist + corticosteroid

• 5‐HT₃ receptor antagonist + corticosteroid versus other specific combinations of this drug class + corticosteroid

An overview of all included treatment regimens is provided in Table 5.

We evaluated different intervention doses and different routes of administration together, and we had planned to assess differences in subgroup analyses. However, we were not able to perform these subgroup analyses because networks were not connected when doses and routes were considered separately. 

Additional interventions to supplement the analysis

In the HEC setting, we also included trials analysing the following comparisons in addition to the direct comparisons of interest, to increase the amount of available (indirect) information included in the analysis (Ades 2013; Chaimani 2017).

• NK₁ receptor antagonist + 5‐HT₃ receptor antagonist + corticosteroid versus 5‐HT₃ receptor antagonist + corticosteroid.

• 5‐HT₃ receptor antagonist + corticosteroid versus other specific combinations of this drug class + corticosteroid.

Included trials should have been comparable in terms of clinical and methodological criteria to hold for transitivity (Chaimani 2017). Therefore, we excluded trials evaluating in only one arm an intervention of interest but in the control arm different drug classes (e.g. metoclopramide). We excluded these trials, as they evaluated drugs that are no longer recommended for primary prophylaxis of CINV in moderately and highly emetogenic chemotherapy. As these trials might be outdated, the assumption that any participant who met the inclusion criteria was, in principle, equally likely to be randomised to any of the eligible interventions has not been sustained. The efficacy and safety of cannabinoids were evaluated in the Cochrane Review by Smith and colleagues (Smith 2015); cannabinoids are not evaluated in this review.

Types of outcome measures

We included all trials fitting the inclusion criteria mentioned above, irrespective of reported outcomes. We estimated the relative ranking of competing interventions according to each of the following outcomes.

Efficacy

• Complete control of nausea (no nausea and no significant nausea, as defined on a study level^a), determined from reports in participant diaries; in the Results section, we refer to this outcome as "no nausea"

  • in the acute phase (first 24 hours of treatment with chemotherapy)

  • in the delayed phase (after 24 to 120 hours of treatment with chemotherapy)

  • overall (after 0 to 120 hours of treatment with chemotherapy)

• Complete control of vomiting (no vomiting and no use of rescue medications), determined from reports in participant diaries; this outcome was usually referred to as "complete response" in the studies; we also refer to it in the Results section as "complete response"

  • in the acute phase (first 24 hours of treatment with chemotherapy)

  • in the delayed phase (after 24 to 120 hours of treatment with chemotherapy)

  • overall (after 0 to 120 hours of treatment with chemotherapy)

Quality of life

• No impairment of quality of life, up to longest follow‐up available, if measured by validated instruments

  • Functional Living Index–Emesis (FLIE) (Lindley 1992)

  • Modified Functional Living Index–Emesis (M‐FLIE) (Martin 2003; Martin 2003a)

Safety

• On‐study mortality (deaths occurring from randomisation up to 30 days)

• Adverse events

• Serious adverse events

• Neutropenia

• Febrile neutropenia

• Infections

• Local reactions at infusion site

• Hiccups

For outcome measurement of any adverse events, we used the longest follow‐up available. 

As there are different underlying mechanisms for anticipatory CINV, which do not respond to prophylactic antiemetics, we did not evaluate this outcome.

An overview of all outcomes and prioritisation of outcomes are provided in Table 6.

2. Overview of outcomes.

Outcome	Definition	Unit of outcome measurement	Referred to as/abbreviation	Prioritisation
Complete control of nausea	No nausea and no significant nausea, as defined on a study levela Assessed for: acute phase: first 24 h of treatment with chemotherapy delayed phase: after 24 to 120 h of treatment with chemotherapy overall: 0 to 120 h of treatment with chemotherapy	Binary; participants with complete control of nausea	No nausea	Overall phase prioritised for GRADE assessment
Complete control of vomiting	No vomiting and no use of rescue medications Assessed for: acute phase: first 24 h of treatment with chemotherapy delayed phase: after 24 to 120 h of treatment with chemotherapy overall: 0 to 120 h of treatment with chemotherapy	Binary; participants with complete control of vomiting	Complete response (CR)	Delayed and overall phases prioritised for GRADE assessment Overall phase chosen as most important efficacy outcome
Quality of life	No impairment in quality of life during active study period	Binary; participants with no impairment in quality of life	QoL	Prioritised for GRADE assessment
On‐study mortality	Deaths occurring from randomisation up to 30 days after the active study period	Binary; participants who died	OSM	Prioritised for GRADE assessment
Adverse events	As defined on a study level; during active study period	Binary; participants with at least 1 event	AEs	‐
Serious adverse events	As defined on a study level; during active study period	Binary; participants with at least 1 event	SAEs	Prioritised for GRADE assessment  Chosen as most crucial safety outcome
Neutropenia	As defined on a study level; during active study period	Binary; participants with at least 1 event	‐	‐
Febrile neutropenia	As defined on a study level; during active study period	Binary; participants with at least 1 event	‐	‐
Infection	As defined on a study level; during active study period	Binary; participants with at least 1 event	‐	‐
Local reaction at infusion site	As defined on a study level; during active study period	Binary; participants with at least 1 event	‐	Prioritised for GRADE assessment
Hiccup	As defined on a study level; during active study period	Binary; participants with at least 1 event	‐	‐

^aStandardised tools are typically used to assess degree of nausea and vomiting (Wood 2011). No nausea and no significant nausea were defined on a study level and typically refer to pre‐defined cutoffs, e.g. in Rapoport 2015 (a) or Schwartzberg 2015, nausea was assessed on a visual analogue scale (VAS; 0 to 100 mm; 0 = no nausea, 100 = severe nausea; < 5 mm = no nausea, < 25 mm = no significant nausea). No significant nausea is typically more subjective because of the wider range on the scale and is therefore less objective, especially in an open‐label study design. To increase comparability of studies and minimise biased results, we were therefore interested in patients with no nausea.

^aStandardised tools are typically used to assess degree of nausea and vomiting (Wood 2011). No nausea and no significant nausea were defined on a study level and typically referred to pre‐defined cutoffs (e.g. in Rapoport 2015 (a) or Schwartzberg 2015, nausea was assessed on a visual analogue scale (VAS; 0 to 100 mm; 0 = no nausea, 100 = severe nausea) as < 5 mm for no nausea and < 25 mm for no significant nausea). No significant nausea is typically more subjective because of the wider range on the scale and therefore is less objective, especially with an open‐label study design. To increase comparability of studies and to minimise biased results, we were interested in patients with no nausea.

Search methods for identification of studies

Electronic searches

We searched the following databases without language restrictions. As all intervention arms had to include at least one 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonist, which has been mentioned first in 1988 for treatment of chemotherapy‐induced emesis (Carmichael 1988), we restricted our search from 1988 to present. Only trials that compared at least two of the drug combinations mentioned above are eligible. We searched for all possible comparisons formed by interventions of interest.

• Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 2 of 12), in the Cochrane Library.

• Embase (Ovid, 1988 to 2 February 2021).

• MEDLINE (Ovid, 1988 to 2 February 2021).

We used medical subject headings (MeSH) or equivalent and text word terms. We did not apply any language restrictions, and we tailored searches to individual databases. The search strategies used can be found in Appendix 1.

Adverse effects

We did not perform a separate search for adverse effects of target interventions. We considered adverse effects only as described in included studies. 

Searching other resources

In addition, we searched the following databases/sources.

• Conference proceedings of annual meetings of the following societies if they were not included in CENTRAL (1988 to 2 February 2021).

  • American Society of Clinical Oncology (ASCO).

  • European Society of Medical Oncology (ESMO).

  • Multinational Association of Supportive Care in Cancer (MASCC).

• Databases of ongoing trials.

• clinicaltrials.gov (www.clinicaltrials.gov).

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/).

• Reference lists of reviews and retrieved articles for additional studies (we also performed citation searches on key articles).

We contacted experts in the field for unpublished and ongoing trials. We contacted study authors for additional information when necessary.

Data collection and analysis

Selection of studies

Two review authors independently screened results of the search strategies for eligibility for this review by reading the abstracts using Covidence software (Covidence systematic review software). We coded the abstracts as either 'retrieve' or 'do not retrieve'. In the case of disagreement, or if it was unclear whether we should have retrieved the abstract or not, we obtained the full‐text publication for further discussion. Independent review authors excluded records that clearly did not meet the inclusion criteria and obtained full‐text copies of the remaining records. Two review authors assessed these records independently against our pre‐defined eligibility criteria to identify relevant studies. In the event of disagreement, we adjudicated a third review author. We did not anonymise the studies before assessment. We included a Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow chart in the full review, which shows the status of identified studies (Figure 1; Moher 2009), as recommended in Part 2, Section 11.2.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011; Schünemann 2011). We included studies in the review irrespective of whether measured outcome data were reported in a ‘usable’ way.

1.

Study flow diagram.

Data extraction and management

Two review authors extracted data using a standardised data extraction form developed in Covidence (Covidence systematic review software). If these authors were unable to reach a consensus, we consulted a third review author for final decision. If required, we contacted the authors of specific studies for supplementary information (Higgins 2011a). After agreement had been reached, we entered data into Review Manager (RevMan 2014). We extracted the following information.

• General information: author, title, source, publication date, country, language, duplicate publications.

• Risk of bias assessment: sequence generation, allocation concealment, blinding (participants, personnel, outcome assessors), incomplete outcome data, selective outcome reporting, other sources (not pre‐specified) of bias.

Moreover, we extracted the following information, which may have acted as effect modifiers.

• Study characteristics: trial design, aims, setting and dates, source of participants, inclusion/exclusion criteria, comparability of groups, subgroup analysis, statistical methods, power calculations, treatment cross‐overs, compliance with assigned treatment, length of follow‐up, time point of randomisation.

• Participant characteristics: age, gender, ethnicity, number of participants recruited/allocated/evaluated, participants lost to follow‐up, cancer type and stage, additional diagnoses, type and intensity of antineoplastic therapy, emetogenic risk, other patient‐specific prognostic factors, e.g. pregnancy, motion sickness, alcohol intake.

• Interventions and comparators: type and dosage of antiemetic agents, duration of prophylaxis, duration of follow‐up.

• Outcomes: complete control of nausea (acute, delayed, and overall phases), complete control of vomiting (acute, delayed, and overall phases), on‐study mortality, quality of life, adverse events, and serious adverse events. When possible, we extracted data at arm level, not summary effects.

• Notes: sponsorship/funding for trial and notable conflicts of interest of review authors.

We collated multiple reports of the same study, so that each study rather than each report was the unit of interest in the review. We collected characteristics of the included studies in sufficient detail to populate a table of Characteristics of included studies.

Assessment of risk of bias in included studies

This section was taken from the PaPaS template for protocols and was amended to fit our analysis criteria.

Two review authors independently assessed risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions ‐ Higgins 2011c ‐ and adapted from those used by the Cochrane Pregnancy and Childbirth Group, with disagreements resolved by discussion. We completed a 'Risk of bias' table for each included study using the 'Risk of bias' tool in RevMan (RevMan 2014).

We assessed the following for each study.

• Random sequence generation (checking for possible selection bias). We assessed the method used to generate the allocation sequence as low risk of bias (any truly random process, e.g. random number table; computer random number generator) or unclear risk of bias (method used to generate sequence not clearly stated). We excluded studies using a non‐random process (e.g. odd or even date of birth; hospital or clinic record number).

• Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during, recruitment, or could have been changed after assignment. We assessed these methods as low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes) or unclear risk of bias (method not clearly stated). We excluded studies that did not conceal allocation (e.g. open list).

• Blinding of participants and personnel (checking for possible performance bias). We assessed the methods used to blind study participants and personnel from knowledge of which intervention a participant received. We assessed methods as low risk of bias (study stated that it was blinded and described the method used to achieve blinding, such as identical tablets matched in appearance or smell, or a double‐dummy technique) or unclear risk of bias (study stated that it was blinded but did not provide an adequate description of how this was achieved). We considered studies that were not double‐blinded to have high risk of bias. We assessed blinding separately for: 

  • participants; and

  • personnel.

• Blinding of outcome assessment (checking for possible detection bias). We assessed the methods used to blind study participants and outcome assessors from knowledge of which intervention a participant received. We assessed the methods as low risk of bias (study had a clear statement that outcome assessors were unaware of treatment allocation, and ideally described how this was achieved) or unclear risk of bias (study stated that outcome assessors were blind to treatment allocation but lacked a clear statement on how this was achieved). We considered studies for which outcome assessment was not blinded as having high risk of bias. We assessed the blinding of outcome assessment for two outcome categories.

  • Subjective outcomes (patient‐reported outcomes).

  • Objective outcomes (including mortality and safety).

• Incomplete outcome data (checking for possible attrition bias due to the quantity, nature, and handling of incomplete outcome data). We assessed the methods used to deal with incomplete data as low risk (< 10% of participants did not complete the study and/or used ‘baseline observation carried forward’ analysis), unclear risk of bias (used 'last observation carried forward' analysis), or high risk of bias (used 'completer' analysis). We assessed attrition bias for two outcome categories.

  • Subjective outcomes (patient‐reported outcomes).

  • Objective outcomes (including mortality and safety).

• Selective reporting (checking for reporting bias). We assessed whether primary and secondary outcome measures were pre‐specified, and whether these were consistent with those reported: low risk of bias (study protocol was available and all of the study’s pre‐specified (primary and secondary) outcomes that were of interest in the review have been reported in the pre‐specified way, or the study protocol was not available but it was clear that the published reports included all expected outcomes, including those that were pre‐specified); unclear risk of bias (insufficient information to permit judgement of ‘low risk’ or ‘high risk'); or high risk of bias (not all of the study’s pre‐specified primary outcomes have been reported, or one or more primary outcomes are reported using measurements, analysis methods, or subsets of data that were not pre‐specified, or one or more reported primary outcomes were not pre‐specified, or one or more outcomes of interest in the review are reported incompletely so that they could not be entered into a meta‐analysis, or the study report failed to include results for a key outcome that would have been expected to have been reported for such a study).

• Other sources of bias: we did not pre‐specify 'other sources of bias' that we were looking for in studies. This item provided us with freedom for potential causes of bias not listed otherwise, such as (but not limited to):

  • temporary halting of study;

  • midway protocol amendments, addition or removal of arms, treatment changes; and

  • additional medications provided based on subjective criteria.

We applied the following rule when making an overall risk of bias judgement per study.

Overall risk of bias judgement	Criteria
Low risk of bias	The study is judged to be at low risk of bias for all domains for this result Or The study is judged to be at low risk of bias for most domains and at unclear risk of bias for selection, performance, and/or detection bias
Unclear risk of bias	The study is judged to be at unclear risk of bias in at least 1 of the domains of incomplete outcome data, selective reporting, or other bias for this outcome, but not to be at high risk of bias for any domain
High risk of bias	The study is judged to be at high risk of bias in at least 1 domain for this result

Measures of treatment effect

Relative treatment effect

We used intention‐to‐treat data. For binary outcomes, we used risk ratios (RRs) with 95% confidence intervals (CIs) as the measure of treatment effect. We had planned to calculate continuous outcomes as mean differences (MDs) with 95% CIs, but we did not measure the effect of any outcome using continuous data. In case outcomes would have been reported as continuous data, and different instruments were used, we had planned to use standardised mean differences (SMDs) with 95% CIs to assess the extent of effects.

Relative treatment ranking

We obtained a treatment hierarchy using P scores (Rücker 2015). P scores allow ranking of treatments on a continuous zero to 1 scale in a frequentist network meta‐analysis.

Unit of analysis issues

We considered only results from the first treatment cycle. RCTs with a cross‐over design were eligible, as long as results had been reported after the first cycle, and therefore before cross‐over.

Studies with multiple treatment groups

As recommended in Chapter 16.5.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b), for studies with multiple treatment groups, we combined arms as long as they could be regarded as subtypes of the same intervention.

When arms could not be pooled this way, we compared each arm with the common comparator separately. For pair‐wise meta‐analysis, we split the ‘shared’ group into two or more groups with smaller sample sizes, and we included two or more (reasonably independent) comparisons. For this purpose, for dichotomous outcomes, we divided up both the number of events and the total number of participants, and for continuous outcomes, we divided up the total number of participants with unchanged means and standard deviations. For network meta‐analysis, instead of subdividing the common comparator, we used an approach that accounted for the within‐study correlation between effect sizes by re‐weighting all comparisons in each multi‐arm study (Rücker 2012; Rücker 2014).

Dealing with missing data

As suggested in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b), we took the following steps to deal with missing data.

Whenever possible, we contacted the original investigators to request relevant missing data. If the number of participants evaluated for a given outcome was not reported, we used the number of participants randomised per treatment arm as the denominator. If only percentages but no absolute numbers of events were reported for binary outcomes, we calculated numerators using percentages. If estimates for means and standard deviations were missing, we planned to calculate these statistics from reported data whenever possible, using approaches described in Chapter 7.7 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). If standard deviations were missing and we had not been able to calculate them from reported data, we planned to calculate values according to a validated imputation method (Furukawa 2006). If data were not reported numerically but were presented graphically, we estimated missing data from figures. We planned to perform sensitivity analyses to assess how sensitive results were to imputing data in some way. However, as we did not have continuous data, it was not necessary to impute potential missing data, and sensitivity analyses as described were unnecessary. We will apply this approach in future updates when necessary. We addressed in the Discussion the potential impact of missing data on review findings.

Assessment of heterogeneity

Pair‐wise meta‐analyses

For each direct comparison, we used visual inspection of forest plots as well as Cochran’s Q based on the Chi² statistic and the I² statistic to detect the presence of heterogeneity. We interpreted I² values according to Chapter 9.5.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). 

We used the following thresholds for interpretation of I².

• 0% to 40%: might not be important.

• 30% to 60%: may represent moderate heterogeneity.

• 50% to 90%: may represent substantial heterogeneity.

• 75% to 100%: considerable heterogeneity.

However, we also considered the magnitude and direction of effects and the strength of evidence for heterogeneity. We used the P value of the Chi² test only in describing the extent of heterogeneity ‐ not in determining statistical significance. In addition, we reported Ʈ² ‐ the between‐study variance in random‐effects meta‐analysis.

Network meta‐analysis

A very important pre‐supposition for using network meta‐analysis is to make sure that the network is consistent, meaning that direct evidence and indirect evidence on the same comparisons agree. Inconsistency could be caused by incomparable inclusion and exclusion criteria of trials in the network.

We evaluated the assumption of transitivity epidemiologically by comparing the distribution of potential effect modifiers across the different pair‐wise comparisons. We created a table of important clinical and methodological characteristics, and we assessed whether there were systematic differences between identified comparisons. In particular, we looked at the following potential effect modifiers.

• Clinical characteristics: gender, age, chemotherapy, tumour/cancer type.

• Methodological characteristics: cross‐over design, blinding, placebo‐controlled, study period, sample size, country, multi‐centre, number of treatment arms, country.

We visually inspected the similarity of these factors, including the inclusion and exclusion criteria of every trial in the network, and we discussed whether the transitivity assumption was met. 

To evaluate the presence of inconsistency locally, we used the Bucher method for single loops of evidence (Bucher 1997), as described, for example, in Dias 2013. For each closed loop, we calculated the difference between direct and indirect evidence, together with its 95% CI. We used loop‐specific z‐tests to infer about the presence of inconsistency in each loop. To assess inconsistency, we used graphical representations of direct and indirect estimates together with 95% CIs; we reported the percentage of inconsistent loops in the network and visually examined the forest plots and league tables to assess inconsistency. It should be noted that in a network of evidence, there may be many loops, and with multiple testing, the likelihood that we might find an inconsistent loop by chance was increased. Therefore, we have been cautious when deriving conclusions from the statistical approach and from preferred visual examination to assess inconsistency. 

To evaluate the presence of inconsistency in the entire network, we gave the generalised heterogeneity statistic Q_total and the generalised I² statistic, as described in Rücker 2019. We used the decomp.design command in the R package netmeta (R 2019; netmeta 2016) for decomposition of the heterogeneity statistic into a Q statistic for assessing heterogeneity between studies with the same design, and a Q statistic for assessing design inconsistency to identify the amount of heterogeneity/inconsistency within as well as between designs. Furthermore, we created a netheat plot (Krahn 2013) ‐ a graphical tool for locating inconsistency in network meta‐analysis, using the command netheat in the R package netmeta. We gave Q_total and its components as well as net heat plots based on fixed‐effect and random‐effects models to identify differences between these approaches (netheat plots and forest plots of fixed‐effect models not shown in the review). For random‐effects models, we reported Ʈ².

In case we identified substantive heterogeneity and/or inconsistency, we explored possible sources by performing pre‐specified sensitivity and subgroup analyses (see below). In addition, we reviewed the evidence base, reconsidered inclusion criteria, and discussed the potential role of unmeasured effect modifiers to identify further sources.

Assessment of reporting biases

In pair‐wise comparisons with at least 10 trials, we planned to examine the presence of small‐study effects graphically by generating funnel plots. We planned to use linear regression tests to test for funnel plot asymmetry (Egger 1997). A P value less than 0.1 would have been considered significant for this test (Sterne 2011). We planned to examine the presence of small‐study effects for the primary outcome only. As described above, we searched study registries to identify completed but not published trials.

Data synthesis

Methods for direct treatment comparisons

We performed analyses according to recommendations provided in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011), and we used the statistical software of Cochrane ‐ Review Manager (RevMan 2014) ‐ for analysis. We performed separate analyses for cancer patients receiving HEC or MEC. If applicable, we used R for additional analyses that could not be done with RevMan (R 2019).

Pair‐wise comparisons were part of the network meta‐analysis. However, to outline available direct evidence, we provided forest plots for pair‐wise comparisons with at least 10 trials if trials were clinically homogenous. We performed these standard pair‐wise meta‐analyses using a random‐effects model. We calculated corresponding 95% CIs for all analyses, and we graphically presented the results using forest plots. When trials would have been clinically too heterogenous to be combined, we would have performed only subgroup analyses without calculating an overall estimate.

Methods for indirect and mixed comparisons

If we considered the data sufficiently similar to be combined, we performed a network meta‐analysis using the frequentist weighted least squares approach described by Rücker 2012. We used a random‐effects model, taking into account the correlated treatment effects in multi‐arm studies. We assumed a common estimate for the heterogeneity variance across the different comparisons. To evaluate the extent to which treatments were connected, we gave a network plot for our primary and secondary outcomes. For each comparison, we gave the estimated treatment effect along with its 95% CI. We graphically presented the results using forest plots, with placebo as the reference. We used the R package netmeta for statistical analyses (R 2019; netmeta 2016).

Subgroup analysis and investigation of heterogeneity

We conducted the following subgroup analysis, if appropriate.

• Type of chemotherapy (carboplatin versus other moderately emetogenic chemotherapy, cisplatin versus other highly emetogenic chemotherapy, and anthracycline versus other highly emetogenic chemotherapy).

• Cancer type (solid tumours versus haematological malignancies, and breast cancer versus others).

We had planned to use the test for interactions to test for subgroup differences. However, this test is not yet available for network‐meta analysis in netmeta 2016. We will apply this in future updates when possible.

We had planned to conduct the following subgroup analysis but could not do so because of missing information or split networks.

• Drug dosage.

• Route of administration.

• Patient‐specific prognostic factors.

Sensitivity analysis

To test the robustness of the results, we conducted fixed‐effect pair‐wise and network meta‐analyses. We reported estimates of the fixed‐effect model only if they showed a difference from estimates of the random‐effects model. We explored the influence of risk of bias components by considering studies at low risk of bias when compared to all studies. Our rule for an overall risk of bias judgement is described under Assessment of risk of bias in included studies.

Summary of findings and assessment of the certainty of the evidence

'Summary of findings' table

According to Chapter 14 of the updated Cochrane Handbook for Systematic Reviews of Interventions, the “most critical and/or important health outcomes, both desirable and undesirable, limited to seven or fewer outcomes” should be included in the summary of findings table(s) (Schünemann 2019). Together with a clinical expert (KJ), we prioritised the most important and crucial (underlined) outcomes as follows.

• Complete control of nausea in the overall phase (Days 1 to 5).

• Complete control of vomiting.

  • Delayed phase (Days 2 to 5).

  • Overall phase (Days 1 to 5).

• No impairment of quality of life.

• On‐study mortality.

• Serious adverse events.

• Local reactions at infusion site.

We planned to include a 'Summary of findings' table for each outcome per emetogenic group (HEC and MEC) to present the main findings in a transparent and simple tabular format. Each table includes key information concerning the certainty of evidence and the magnitude of effect of interventions examined. For a comprehensive illustration of our results, we randomly chose aprepitant plus granisetron as exemplary reference treatment for HEC, and granisetron as exemplary reference treatment for MEC. However, theoretically, we could have used every treatment combination as a reference. The estimated absolute effects provided in the 'Summary of findings' table were based on actual event rates reported for the main comparators and summed across studies, and are provided for illustrative purposes only. 

We could not include a 'Summary of findings' table for the outcome local reactions at infusion site because in the HEC group, no study reported the outcome for our reference treatment (aprepitant plus granisetron), and in the MEC group, no study reported the outcome at all. 

Assessment of the certainty of the evidence

Two review authors independently rated the certainty of evidence of each prioritised outcome for both HEC and MEC groups. We used the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system to rank the certainty of evidence using the GRADEprofiler Guideline Development Tool software (GRADEpro GDT 2015), along with the guidelines provided in Chapter 12.2 of the CochraneHandbook for Systematic Reviews of Interventions (Schünemann 2011a), specifically for network meta‐analyses (Puhan 2014). The GRADE Working Group suggests assessment of the certainty of evidence for no more than seven outcomes, and for each outcome included in 'Summary of findings' tables ‐ therefore only for outcomes that are most critical or important for decision‐making (Guyatt 2013).

The GRADE approach used five considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess certainty of the body of evidence for each outcome. The GRADE system used the following criteria for assigning grade of evidence.

• High = we are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate = we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.

• Low = our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.

• Very low = we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

The GRADE system used the following criteria for assigning a certainty level to a body of evidence (Chapter 12, Schünemann 2011a).

• High: randomised trials; or double‐upgraded observational studies.

• Moderate: downgraded randomised trials; or upgraded observational studies.

• Low: double‐downgraded randomised trials; or observational studies.

• Very low: triple‐downgraded randomised trials; or downgraded observational studies; or case series/case reports.

We decreased grade if we noted:

• serious (‐1) or very serious (‐2) risk of bias;

• important inconsistency (‐1);

• some (‐1) or major (‐2) uncertainty about directness;

• imprecise or sparse data (‐1) or very imprecise or very sparse data (‐2); or

• high probability of reporting bias (‐1).

Results

Description of studies

For this systematic review, we identified 383 records for full‐text screening, of which 107 RCTs comprising 197 references, with approximately 37,313 participants, fulfilled the inclusion criteria.

Results of the search

We identified 5192 potentially relevant references through database searches and five additional references through handsearching. After full‐text screening, we concluded that 197 references representing 73 studies in the HEC group (Appendix 2), along with 38 studies in the MEC group (Appendix 3), met the pre‐defined eligibility criteria; thus we selected them for assessment. As some trials were reported in multiple full‐text reports, abstracts, and posters, we indexed these repeating references under the main publications. Four studies included people treated with both highly and moderately emetogenic chemotherapeutic regimens and reported results for both regimens separately; thus we included them in both HEC and MEC groups (Raftopoulos 2015; Ghosh 2010; Ho 2010; Tsubata 2019), resulting in a total of 107 included studies. Two studies in the HEC group were reported in the Korean language (Cho 1998; Lee 1997), and the remaining 105 studies were reported in the English language.

We documented the overall numbers of records screened, identified, selected, excluded, and included in a PRISMA flow diagram (Figure 1, Supplementary Figure 1). Supplementary figures are available from https://osf.io/dr2u7/ (Piechotta 2021).

Included studies

In the HEC group, we included 73 studies reporting on 25,275 participants. Studies were conducted between December 1992 ‐ Roila 1995 ‐ and February 2018 ‐ Li 2019. Stewart 1996 did not report the information that we sought. Sample sizes varied from 15 in Abdel‐Malek 2017 to 2322 participants in Grunberg 2011. In the MEC group, we included 38 studies reporting on 12,038 participants. Studies were conducted between July 1997 for Herrington 2000 and March 2017 for Xiong 2019. Sample sizes varied from 12 in Brohee 1995 to 1369 participants in Schwartzberg 2015.

In the HEC group, 45 studies (62%) included cisplatin > 50 mg/m² alone or in combination for treatment of solid malignancies. Eleven studies (15%) included only breast cancer patients and used the combination of anthracycline and cyclophosphamide in the chemotherapy regimen (Arce‐Salinas 2019; Herrstedt 2009; Kalaycio 1998; Li 2019; Matsumoto 2020; Nakamura 2012; Ohzawa 2015; Rugo 2017; Saito 2017; Warr 2005; Wenzell 2013). Schmitt 2014, Svanberg 2015, Mohammed 2019, and Egerer 2010 used melphalan or ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine) in the chemotherapy regimen for treatment of haematological malignancies. In the MEC group, 13 studies (35%) included patients treated with carboplatin for solid and haematological malignancies (Eisenberg 2003; Endo 2012; Herrington 2000; Ito 2014; Jordan 2016a; Kaushal 2010; Kaushal 2015; Kim 2017; Kusagaya 2015; Maehara 2015; Sugimori 2017; Tanioka 2013; Yahata 2016), eight studies (22%) included patients treated with cyclophosphamide ≤ 1500 mg/m² (Arpornwirat 2009; Brohee 1995; Ghosh 2010; Raftopoulos 2015; Rapoport 2010; Schwartzberg 2015; Song 2017; Yeo 2009), and four studies (11%) included patients treated with oxaliplatin for solid and haematological malignancies (Aridome 2016; Hesketh 2012; Ho 2010; Nishimura 2015). Yeo 2009 and Webb 2010 included patients with breast cancer.

A majority of studies (70%) in the HEC group were double‐blinded (typically reported in journal publication and referring to participants and investigators) or quadruple‐blinded (typically reported in trials registries and referring to participants, care providers, investigators, and outcome assessors), and 27 studies among them were placebo‐controlled. Eleven studies (15%) were open‐label and were not placebo‐controlled (Ando 2016; Arce‐Salinas 2019; Cho 1998; Chua 2000; Ishido 2016; Lee 1997; Mahrous 2020; NCT01640340; Ohzawa 2015; Tsubata 2019; Wenzell 2013). Abdel‐Malek 2017 Kang 2020, and Mohammed 2019 were single‐blinded studies. In the MEC group, 16 studies (43%) were double‐blind with 11 studies (30%) among them placebo‐controlled, and 14 studies (38%) were open‐label. Fifteen studies in the HEC group (Abdel‐Malek 2017; Aksu 2013; Albany 2012; Cho 1998; Chua 2000; Gao 2013; Innocent 2018; Ishido 2016; Kimura 2015; Koizumi 2003; Lee 1997; Nakamura 2012; Ohzawa 2015; Stewart 2000; Wit 2001), as well as four studies in the MEC group (Fujiwara 2015; Jantunen 1992; Kaushal 2015; Seol 2016), were cross‐over studies.

Forty‐nine studies in the HEC group and 26 studies in the MEC group included a triple‐drug combination, including a neurokinin‐1 (NK₁) receptor antagonist, a 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonist, and a corticosteroid, as experimental intervention. The most frequently used NK₁ receptor antagonist was aprepitant, followed by fosaprepitant, rolapitant, netupitant, casopitant, and ezlopitant. As 5‐HT₃ receptor antagonists, palonosetron, granisetron, ondansetron, ramosetron, tropisetron, and azasetron were used. As a corticosteroid, either dexamethasone or methylprednisolone was used. An overview of all included treatment regimens is provided in Table 5.

Nearly all of the studies included individuals ≥ 18 years of age with confirmed malignancy and naïve to emetogenic chemotherapy. Albany 2012, Kimura 2015, and Ghosh 2010 included participants ≥ 15 years of age. Data were not reported separately for participants ≥ 18 years and participants ≥ 15 years in any of these studies. As study authors considered the age of 15 as an appropriate cut‐off and provided no reason to separate the analysis, we assumed that the effects for 15‐ to 17‐year‐olds and ≥ 18‐year‐olds would not differ. Therefore, although the proportions of participants < 18 years old were not reported, we included them in the analysis.

The foremost causes of exclusion were symptomatic malignancy of the central nervous system (CNS) and participant had vomited within 24 hours before treatment Day 1, had an active infection, had an active systemic fungal infection, had any severe concurrent illness except for malignancy, or had abnormal laboratory values.

Seventeen studies from both HEC and MEC groups included participants from Asia, Europe, Africa, North America and South America, Australia, and the Pacific region (Aapro 2006; Arpornwirat 2009; Chawla 2003; Grunberg 2009; Grunberg 2011; Herrstedt 2009 Hesketh 2003; Hesketh 2012; Jordan 2016a; Rapoport 2010; Rapoport 2015 (a); Rugo 2017; Ruhlmann 2017; Warr 2005; Weinstein 2016; Schmoll 2006; Schwartzberg 2015); all were multi‐national and multi‐centred. Most studies were conducted in Asia, including Japan (23%). Other Asian sites were South Korea (Cho 1998; Kim 2015; Kim 2017; Lee 1997; Seol 2016), China (Chua 2000; Ho 2010; Hu 2014; Song 2017; Xiong 2019; Yang 2017; Yeo 2009), and India (Ghosh 2010; Kaushal 2010; Kaushal 2015). Precisely 12 studies included participants only from USA with different ethnicities (Albany 2012; Bubalo 2005; Bubalo 2018; Fox‐Geiman 2001; Herrington 2008; NCT01640340; Raftopoulos 2015; Rapoport 2015 (b); Rapoport 2015 (c); Schnadig 2016; Stiff 2013; Wenzell 2013), and eight studies included participants exclusively from Europe (Brohee 1995; Egerer 2010; Flenghi 2015; Hesketh 2014; Roila 1995; Schmitt 2014; Stewart 2000; Svanberg 2015).

We visually inspected the similarity of clinical and methodological characteristics that could act as potential effect modifiers and assessed whether there were systematic differences between identified comparisons (available from study authors upon request). We decided that for most studies (50 in the HEC group, 26 in the MEC group), it was hypothetically equally likely that any participant could have been randomised to any treatment.

We therefore included 50 studies from the HEC group in the network meta‐analysis (NMA). We could not include 23 HEC studies in the NMA for the following reasons.

• Different definitions of efficacy outcomes: Kimura 2015, Svanberg 2015, Fox‐Geiman 2001, Wit 2001, Koizumi 2003, Ghosh 2010, Lee 1997, Chua 2000, Mohammed 2019

• Different definitions of acute, delayed, and overall phases: Albany 2012, Ando 2016

• Efficacy outcomes reported as a score: Albany 2012, Ando 2016

• Results reported over multiple cycles including cross‐over: Abdel‐Malek 2017

• Only number of adverse events reported: Albany 2012, Kalaycio 1998

• Adverse events divided by severity grade: Kimura 2015, Svanberg 2015

• Only abstract with insufficient information available: Arce‐Salinas 2019 Cho 1998, Flenghi 2015, Forni 2000, Gao 2013, Mahrous 2020 Stewart 1996

• Full text with insufficient information or without any outcome of interest: Stewart 2000, Egerer 2010

• Part of the study population received additional irradiation and results for the subgroup without irradiation have not been separately reported: Bubalo 2018

• Adverse events for HEC and MEC reported together: Ghosh 2010.

We included 26 studies from the MEC group in the NMA. We could not include 12 MEC studies in the NMA for the following reasons.

• Missing specification of 5‐HT₃ inhibitor: Ito 2014, Maehara 2015, Yahata 2016

• Missing specification of 5‐HT₃ and NK₁ inhibitors: Nishimura 2015

• Results reported over multiple cycles including cross‐over: Fujiwara 2015, Kitayama 2015

• Results reported over multiple cycles: Brohee 1995

• Only number of treatment‐related adverse events reported: Seol 2016

• Different definitions of efficacy outcomes: Ghosh 2010, Jantunen 1992

• Adverse events for HEC and MEC reported together: Ghosh 2010

• Only abstract with insufficient information available: Webb 2010, Miyabayashi 2015, Schnadig 2014.

For detailed information regarding the characteristics of included studies, please refer to the Characteristics of included studies table.

Excluded studies

We excluded 140 records of assessed full texts for the following reasons. 

We excluded 89 records (63%) because of the antiemetic therapy.

• 69 used no corticosteroid or corticosteroids in only one arm (Audhuy 1996; Ballatori 1995; Bianchi 1996; Bonneterre 1995; Bubalo 2001; Campora 1994; Dong 2011; Fauser 1995; Fauser 1996; Fauser 1999; Feng 2000; Feng 2002; Fengyi 2002; Gebbia 1994; Goldschmidt 1997; Gralla 1998; Gralla 2003; Hesketh 1996; Huang 2013; Huc 1998; Iihara 2012; Jantunen 1993; Kang 2002; Kim 1998; Kim 2004; Leonardi 1996; Lofters 1995; Martoni 1996; Marty 1995; Matsuoka 2003; Micha 2016; Nasu 2013; Noble 1994; Noda 2002; Ogihara 1999; Park 1997; Pectasides 2007; Perez 1998 (a); Peterson 1996; Poon 1998; Qiu 2011; Ruff 1994; Sheng 2010; Shi 2007; Slabý 2000; Spector 1998; Stewart 1995; Sun 2014; Tang 2013; Tian 2011; Tominaga 1996; Tong 2014; Tremont‐Lukats 2017; Tsavaris 1996; Tsubata 2015; Tsukuda 1995; Weant 2017; Xie 2003; Yalçin 1999; Yang 2005; Yano 2005; Yu 2009; Zeng 2001; Zhang 1996; Zhang 1999; Zhang 2003; Zhang 2003 (a); Zhang 2007; Öge 2000).

• 9 used other antiemetics (metoclopramide (Italian Group for Antiemetic Research 1993; Italian Group for Antiemetic Research 1995 (a); Italian Group for Antiemetic Research 1995 (b); Van der Vorst 2021), lorazepam (Lacerda 2000; Mandanas 2005), prochlorperazine (Lindley 2005; Matsui 1996), dronabinol (Meiri 2007)).

• 5 used no 5‐HT₃ inhibitors or 5‐HT₃ inhibitors in only one arm (Belle 2002; Cocquyt 2001; Lavoie 2012; Ohta 1992; Van Belle 2002).

• 3 did not define which 5‐HT₃ inhibitors or NK₁ inhibitor was used (Nishimura 2015 (a); Nishimura 2015 (b); Yahata 2016 (a)).

• 1 used corticosteroids as pre‐therapy before chemotherapy (Perez 1998 (b)).

• 2 compared different preparations of the same drug (Huang 1998; NCT04636632).

We excluded 39 records (28%) because of the study design.

• 15 were non‐randomised studies of the intervention (Abali 2007; Albany 2014; Choi 2014; Craver 2011; Creed 1999; Huang 2001; Long 2002; Monda 1994; Pater 1997; Perez 1996; Plasencia‐Mota 1993; Rzepecki 2009; Takenaka 2007; Takeshima 2014; Zeidman 1998).

• 12 were pharmacokinetic studies (Bubalo 2012; Loos 2007; Ottoboni 2014; Suzuki 2015; Tsuji 2016; Vadhan‐Raj 2011; Vadhan‐Raj 2012; Vadhan‐Raj 2014; Vadhan‐Raj 2015; Walko 2012; Zhang 2002; Zhang 2012).

• 3 were cost‐effectiveness analyses (Barrajon 2000; Humphreys 2013; Moore 2007).

• 3 were letters or correspondences (Bonneterre 1994; Fedele 1995; Silvestris 2013).

• 2 were retrospective subset analyses of included studies (Hudis 2003; Uchino 2012).

• 2 were dose‐finding studies (Roila 2009; Tanimura 1998).

• 1 was a pooled analysis of different trials (Molassiotis 2013).

• 1 was a review (Navari 2016).

We excluded 12 records (9%) because of the underlying chemotherapy.

• 5 did not clearly define the chemotherapy, so it was unclear whether it was HEC or MEC (Chiou 2000; Kilickap 2013; Kim 2012; Lee 2014; Saito 2015).

• 3 used a concurrent chemoradiotherapy (Kawaguchi 2015; Ruhlmann 2016; Tong 2012).

• 2 did not provide individual data for HEC and MEC groups (Roscoe 2012; Tan 2004).

• 1 used a low emetogenic chemotherapy (Dandamudi 2011).

• 1 used an antiblastic therapy (Adamo 1994).

For further information, please check Characteristics of excluded studies.

Ongoing studies

Of the 12 ongoing studies, four studies are comparing different combinations of NK₁ and 5‐HT₃ inhibitors for prevention and control of nausea and vomiting for people receiving HEC (KTC0001495; UMIN000004021; UMIN000006773; UMIN000007882); three studies are comparing different combinations of NK₁ and 5‐HT₃ inhibitors for prevention and control of nausea and vomiting for people receiving MEC (UMIN000005317; UMIN000005494; UMIN000032860); four studies are comparing a 5‐HT₃ inhibitor versus a combination of NK₁ and 5‐HT₃ inhibitors for prevention and control of nausea and vomiting for people receiving MEC (ChiCTR1900025227; IRCT20191103045317N1; UMIN000012500; UMIN000041004); and one study is comparing different combinations of NK₁ and 5‐HT₃ inhibitors for prevention and control of nausea and vomiting for people receiving both HEC and MEC (NCT03606369).

Please refer to Characteristics of ongoing studies for more detailed information.

Studies awaiting classification

Of the 34 studies awaiting assessment, 10 studies are not recruiting and no results are available for these (four studies using HEC (EUCTR2004‐004956‐38; EUCTR2004‐000371‐34; EUCTR2007‐004043‐30; EUCTR2015‐001800‐74), five studies using MEC (EUCTR2006‐000781‐37; EUCTR2006‐003512‐22; EUCTR2007‐005169‐36; EUCTR2009‐016775‐30; EUCTR2009‐017603‐28), and one study using both HEC and MEC (EUCTR2010‐023297‐39)).

We classified nine further studies with HEC setting and without available results as awaiting assessment because the status is given as "pending" (ChiCTR‐INR‐17010779), "authorised recruitment may be ongoing or finished" (EUCTR2008‐001339‐37), "terminated per PI’s request" (NCT02732015), or "completed" (NCT01101529; NCT03403712; UMIN000004826; UMIN000004863; UMIN000008897), or because status is unknown (PER‐055‐12).

We classified ten further studies with MEC setting and without available results as awaiting assessment because the status is given as "authorised recruitment may be ongoing or finished" (EUCTR2004‐001020‐20), "completed" (CTRI/2017/10/010163; UMIN000004998; UMIN000008041; UMIN000008552; UMIN000010056; UMIN000010186; UMIN000019122), or "terminated" (insufficient accrual)“ (NCT02550119), or because status is unknown (NCT02407600).

Two records were abstracts with insufficient information (Mylonakis 1996; Spina 1995), and one study was completed with no available results and with no information with regard to chemotherapy (NCT00169572).

One study provided insufficient information on the antiemetic regimen in the trial registry (JapicCTI‐194691). 

Please refer to Characteristics of studies awaiting classification for more detailed information.

Risk of bias in included studies

Summaries of the risk of bias of included studies for all assessed domains across included studies and per included study are presented in Figure 2 and Figure 3 and in Supplementary Figure 2. Supplementary figures are available from https://osf.io/dr2u7/ (Piechotta 2021).

2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Among the 107 included studies, 55 (51%) reported a randomised allocation process using simple randomisation, a block randomisation method, computer‐generated randomisation, an interactive voice response system, or a telephone call; therefore we judged them as having low risk of bias for 'Random sequence generation'. The remaining 52 studies (49%) mentioned the random allocation process but did not provided information regarding the sequence generation; therefore, we judged these studies as having unclear risk of bias for 'Random sequence generation'.

Allocation is concealed to ensure that the group assignment of participants is not revealed before they are definitively allocated to their respective groups. We judged the risk of bias for allocation concealment to be low for 17 studies (16%), as these studies used methods such as sealed envelopes, central randomisation, or engaging unrelated personnel/organisations to determine group assignments (Albany 2012; Cheirsilpa 2005; Fox‐Geiman 2001; Grunberg 2011; Hu 2014; Koizumi 2003; Maehara 2015; Matsumoto 2020; Mohammed 2019; Rapoport 2010; Rapoport 2015 (b); Rapoport 2015 (c); Schwartzberg 2015; Sugawara 2019; Svanberg 2015; Weinstein 2016; Zhang 2020). We judged the remaining 90 studies (84%) as having unclear risk of bias, as they provided no sufficient information regarding concealment of allocation.

Blinding

Performance bias

Participants

Regarding blinding of participants towards treatment arms, 71 studies (66%) were reported to be single‐blind, double‐blind, or quadruple‐blind; therefore we judged them as having low risk of bias. We judged nine studies (8%) as having unclear risk of bias, as they provided no information concerning blinding of participants (Aksu 2013; Endo 2012; Forni 2000; Gao 2013; Li 2019; Matsuda 2014; Miyabayashi 2015; Ozaki 2013; Zhang 2018 (b)); we judged the remaining 27 studies (25%) as having high risk of bias because participants were not blinded (Ando 2016; Arce‐Salinas 2019; Aridome 2016; Badar 2015; Cho 1998; Chua 2000; Fujiwara 2015; Herrington 2000; Ishido 2016; Ito 2014; Jantunen 1992; Kaushal 2010; Kaushal 2015; Kusagaya 2015; Lee 1997; Maehara 2015; Mahrous 2020; Mattiuzzi 2007; NCT01640340; Nishimura 2015; Ohzawa 2015; Seol 2016; Song 2017; Sugimori 2017; Tsubata 2019; Wenzell 2013; Xiong 2019). 

Personnel

Sixty‐three studies (59%) reported blinding of personnel towards treatment arms; therefore we judged them as having low risk of bias for 'Blinding of personnel'. We judged 11 studies (10%) as having unclear risk of bias, as we found no suggestive information concerning blinding of personnel (Aksu 2013; Brohee 1995; Endo 2012; Forni 2000; Gao 2013; Li 2019; Matsuda 2014; Miyabayashi 2015; Ozaki 2013; Xiong 2019; Zhang 2018 (b)); we judged the remaining 33 studies (31%) as having high risk of bias because personnel were not blinded (Abdel‐Malek 2017; Ando 2016; Arce‐Salinas 2019; Aridome 2016; Badar 2015; Cho 1998; Chua 2000; Fujiwara 2015; Herrington 2000; Ishido 2016; Ito 2014; Jantunen 1992; Kang 2020; Kaushal 2010; Kaushal 2015; Kim 2015; Kimura 2015; Kitayama 2015; Kusagaya 2015; Lee 1997; Maehara 2015; Mahrous 2020; Mattiuzzi 2007; Mohammed 2019; Nakamura 2012; NCT01640340; Nishimura 2015; Ohzawa 2015; Seol 2016; Song 2017; Sugimori 2017; Tsubata 2019; Wenzell 2013).

Detection bias

We assessed blinding of outcome assessment for two outcome categories ‐ subjective and objective outcomes ‐ as previously described. 

Subjective outcomes

Assessment of subjective outcomes, such as complete control of nausea, complete control of vomiting, and quality of life, can be influenced by awareness of the intervention. We judged 65 studies (61%) as having low risk of bias because outcome assessors (i.e. participants) were blinded to the intervention. We judged ten studies (9%) as having unclear risk of bias for subjective outcomes, as they provided no information regarding blinding of participants (Aksu 2013; Brohee 1995; Endo 2012; Forni 2000; Gao 2013; Li 2019; Matsuda 2014; Miyabayashi 2015; Ozaki 2013; Zhang 2018 (b)). We judged 32 studies (30%) as having high risk of bias for subjective outcomes, as the unblinded study design might have influenced the outcome assessment (Abdel‐Malek 2017; Ando 2016; Arce‐Salinas 2019; Aridome 2016; Badar 2015; Cho 1998; Chua 2000; Fujiwara 2015; Herrington 2000; Ishido 2016; Ito 2014; Jantunen 1992; Kaushal 2010; Kaushal 2015; Kim 2015; Kimura 2015; Kitayama 2015; Kusagaya 2015; Lee 1997; Maehara 2015; Mahrous 2020; Mattiuzzi 2007; Nakamura 2012; NCT01640340; Nishimura 2015; Ohzawa 2015; Seol 2016; Song 2017; Sugimori 2017; Tsubata 2019; Wenzell 2013; Xiong 2019).

Objective outcomes

Assessment of objective outcomes, such as mortality and adverse events, should not be influenced by awareness of the intervention. We, therefore, judged the risk of detection bias to be low for all studies that assessed or reported objective outcomes. Assessment of detection bias for objective outcomes was not applicable for 41 studies (38%) because objective outcomes were not assessed or reported in those studies (Abdel‐Malek 2017; Aksu 2013; Albany 2012; Ando 2016; Brohee 1995; Bubalo 2005; Cho 1998; Chua 2000; Egerer 2010; Flenghi 2015; Forni 2000; Fox‐Geiman 2001; Fujiwara 2015; Gao 2013; Herrington 2000; Innocent 2018; Jantunen 1992; Jordan 2016a; Kaushal 2010; Kaushal 2015; Li 2019; Maehara 2015; Matsumoto 2020; Mattiuzzi 2007; Miyabayashi 2015; Mohammed 2019; NCT01640340; Ohzawa 2015; Ozaki 2013; Poli‐Bigelli 2003; Rugo 2017; Saito 2017; Schnadig 2014; Stewart 1996; Stewart 2000; Svanberg 2015; Tsubata 2019; Webb 2010; Wenzell 2013; Wit 2001; Zhang 2018 (b)). 

Incomplete outcome data

We assessed risk of attrition bias for both outcome categories ‐ subjective and objective outcomes ‐ as previously described. We judged 93 studies (87%) as having low risk of bias for subjective objectives and 60 studies (56%) as having low risk of bias for objective outcomes, as most of the randomised participants (92% to 100%) were included in the antiemetic efficacy and safety analyses in primary studies, and reported study discontinuations were balanced between arms.

Subjective outcomes

We judged 11 studies (10%) as having unclear risk of bias for subjective outcomes, as insufficient information was provided to make an explicit decision whether or not the intention‐to‐treat population was analysed (Aksu 2013; Arce‐Salinas 2019; Cho 1998; Forni 2000; Gao 2013; Lee 1997; Li 2019; Mahrous 2020; Mohammed 2019; Stewart 1996; Zhang 2018 (b)). We judged three studies (3%) as having high risk of bias for subjective outcomes because Kang 2020 used a modified ITT analysis and included only participants who received at least one treatment, because Ozaki 2013 excluded 15 participants (25% of the initial included population) from the efficacy analysis due to insufficient diary entries and protocol violations, and because Seol 2016 analysed the per‐protocol population. 

Objective outcomes

We judged five studies (5%) as having unclear risk of bias for objective outcomes because we were not able to evaluate completeness of safety data for Arce‐Salinas 2019 and Mahrous 2020, as only an abstract was available, because Herrington 2008 did not report whether or not serious adverse events occurred, because it was unclear for Matsumoto 2020 who was included in the safety population, and because we were not able to evaluate the completeness of safety data from Lee 1997 due to a language barrier (and we could not identify someone via Cochrane TaskExchange to translate those for us). We judged two studies (2%) as having high risk of bias for objective outcomes because Kang 2020 included the ITT population in safety analysis even though not all participants received at least one study drug, and because Yahata 2016 did only report antiemetic treatment‐related adverse events. We did not assess detection bias for objective outcomes for 40 studies (37%) because objective outcomes were not assessed or reported in those studies (Abdel‐Malek 2017; Aksu 2013; Albany 2012; Ando 2016; Brohee 1995; Bubalo 2005; Cho 1998; Chua 2000; Egerer 2010; Flenghi 2015; Forni 2000; Fox‐Geiman 2001; Fujiwara 2015; Gao 2013; Herrington 2000; Innocent 2018; Jantunen 1992; Jordan 2016a; Kaushal 2010; Kaushal 2015; Li 2019; Maehara 2015; Mattiuzzi 2007; Miyabayashi 2015; Mohammed 2019; NCT01640340; Ohzawa 2015; Ozaki 2013; Poli‐Bigelli 2003; Rugo 2017; Saito 2017; Schnadig 2014; Stewart 1996; Stewart 2000; Svanberg 2015; Tsubata 2019; Webb 2010; Wenzell 2013; Wit 2001; Zhang 2018 (b)). 

Selective reporting

We judged 85 studies (79%) as having low risk of bias for selective reporting because outcome reporting seemed to be complete in the study reports for all primary, secondary, and additional outcomes, and we identified no reasons for concern. 

We judged 18 studies (17%) as having unclear risk of bias for selective reporting for the following reasons. Ando 2016 reported the pre‐specified outcomes but not according to treatment arms. Herrstedt 2009 was completed and published in 2009. In 2017, the principal investigators (PIs) or Sponsors submitted the results to be published in the trials register. After quality control, results were resubmitted twice, then submission was cancelled at both times (please see https://clinicaltrials.gov/ct2/show/results/NCT00366834). We are not sure whether this means that the quality check revealed some issues with the data and the study authors did not want to resolve those, whether they were not able to resolve those, or whether after this long period of time, the data simply did not meet the quality standard of clinicaltrials.gov, and PIs and Sponsors did not have data needed for the revision because they had never been obtained. We contacted the study authors for clarification and did not receive a response. Svanberg 2015 mentioned that adverse events were not differing between groups but did not provide any supporting data. We could not evaluate selective reporting for Tsubata 2019, as the wrong study registration number was provided in the paper and the correct number was not retrievable. Further, we could not evaluate two studies because of language barriers and we could not identify someone via Cochrane TaskExchange to translate those for us (Cho 1998; Lee 1997). Twelve studies were conference abstracts with insufficient reporting (Arce‐Salinas 2019; Brohee 1995; Flenghi 2015; Forni 2000; Gao 2013; Mahrous 2020; Miyabayashi 2015; Ozaki 2013; Schnadig 2014; Stewart 1996; Webb 2010; Zhang 2018 (b))

We judged five studies (4%) as having high risk of bias for selective reporting. Bubalo 2005 did not provide any results for their pre‐specified secondary outcomes (effects on nausea, appetite and taste changes, and pharmacokinetic interactions). Egerer 2010 mentioned safety assessment in the introduction but did not provide any safety data. Kaushal 2015 and Maehara 2015 did not report any results for pre‐determined safety outcomes. Saito 2017 reported only complete response and quality of life. 

Other potential sources of bias

We judged 88 studies (82%) as having low risk for other potential sources of bias because we did not identify any information that would suggest other bias. 

We judged 19 studies (18%) as having unclear risk for other potential sources of bias because one study was temporarily halted and the protocol was amended with removal of one arm (Arm C) (Herrington 2008); descriptive statistics of participants in Arm C were not included in the report. Ito 2014 allowed additional antiemetic agents and other supportive treatments at the discretion of the treating physician. Kitayama 2015 did not record the incidence and severity of CINV daily but only on Days 2 and 5. We could not evaluate two studies because of language barriers and we could not identify someone via Cochrane TaskExchange to translate those for us (Cho 1998; Lee 1997). We could not find any full‐text publication for 14 studies and the abstracts did not contain sufficient  information to exclude other potential sources of bias (Arce‐Salinas 2019; Brohee 1995; Flenghi 2015; Forni 2000; Gao 2013; Mahrous 2020; Mattiuzzi 2007; Miyabayashi 2015; Ozaki 2013; Saito 2017; Schnadig 2014; Stewart 1996; Webb 2010; Zhang 2018 (b)).

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4

Summary of findings 1. Summary of findings: complete control of vomiting during the overall phase (HEC) when compared to treatment with aprepitant + granisetron.

Efficacy
Antiemetics for adults for prevention of nausea and vomiting caused by highly emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by highly emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: aprepitant (NK₁) combined with granisetron (5‐HT₃) + corticosteroid Outcome: complete control of  vomiting during the overall phase (0 to 120 h of treatment with chemotherapy) RR < 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)a	Illustrative comparative risks* (95% CI)		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with aprepitant + granisetron	Corresponding risk with the intervention
fosnetupitant + palonosetron	704 of 1000	810 of 1000 (683 to 944)	RR 1.15  (0.97 to 1.37)	21,642 (39)	⊕⊕⊕⊝ moderateb	Fosnetupitant + palonosetron probably increases complete response in the overall phase when compared with aprepitant + granisetron
aprepitant + palonosetron	704 of 1000	753 of 1000 (690 to 831)	RR 1.07  (0.98 to 1.18)	21,642 (39)	⊕⊕⊝⊝ lowb,c	Aprepitant + palonosetron may result in a slight increase in complete response in the overall phase when compared with aprepitant + granisetron
aprepitant + ramosetron	704 of 1000	753 of 1000 (669 to 852)	RR 1.07  (0.95 to 1.21)	21,642 (39)	⊕⊕⊝⊝ lowb,c	Aprepitant + ramosetron may result in a slight increase in complete response in the overall phase when compared with aprepitant + granisetron
fosaprepitant + palonosetron	704 of 1000	746 of 1000 (676 to 838)	RR 1.06  (0.96 to 1.19)	21,642 (39)	⊕⊕⊝⊝ lowb,c	Fosaprepitant + palonosetron may result in a slight increase in complete response in the overall phase when compared with aprepitant + granisetron
netupitant + palonosetron	704 of 1000	704 of 1000 (655 to 760)	RR 1.00  (0.93 to 1.08)	21,642 (39)	⊕⊕⊕⊕ high	Netupitant + palonosetron has little to no impact on complete response in the overall phase when compared with aprepitant + granisetron
fosaprepitant + granisetron	704 of 1000	697 of 1000 (655 to 746)	RR 0.99  (0.93 to 1.06)	21,642 (39)	⊕⊕⊕⊕ high	Fosaprepitant + granisetron has little to no impact on complete response in the overall phase when compared with aprepitant + granisetron
aprepitant + ondansetron	704 of 1000	676 of 1000 (620 to 739)	RR 0.96  (0.88 to 1.05)	21,642 (39)	⊕⊕⊝⊝ lowb,c	Aprepitant + ondansetron may result in a slight decrease in complete response in the overall phase when compared with aprepitant + granisetron
fosaprepitant + ondansetron	704 of 1000	662 of 1000 (598 to 732)	RR 0.94  (0.85 to 1.04)	21,642 (39)	⊕⊕⊝⊝ lowb,c	Fosaprepitant + ondansetron may result in a slight decrease in complete response in the overall phase when compared with aprepitant + granisetron
casopitant + ondansetron	704 of 1000	634 of 1000 (556 to 725)	RR 0.90  (0.79 to 1.03)	21,642 (39)	⊕⊕⊝⊝ lowb,c	Aprepitant + ondansetron may decrease complete response in the overall phase when compared with aprepitant + granisetron
rolapitant + granisetron	704 of 1000	627 of 1000 (549 to 711)	RR 0.89  (0.78 to 1.01)	21,642 (39)	⊕⊕⊕⊝ moderateb	Rolapitant + granisetron probably decreases complete response in the overall phase when compared with aprepitant + granisetron
rolapitant + ondansetron	704 of 1000	598 of 1000 (458 to 788)	RR 0.85 (0.65 to 1.12)	21,642 (39)	⊕⊕⊝⊝ lowc,d	Rolapitant + ondansetron may decrease complete response in the overall phase when compared with aprepitant + granisetron
*Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 1312 of 1863 (70.4%) participants treated with aprepitant + granisetron achieved complete response during the overall phase (aprepitant + granisetron was used in 7 studies reporting the outcome).  The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aEither dexamethasone or methylprednisolone was used in all treatment regimens. bDowngraded once for serious imprecision because 95% CIs cross unity. cDowngraded once for serious study limitations due to high risk of bias. dDowngraded once for serious imprecision due to wide confidence intervals.

Summary of findings 2. Summary of findings: serious adverse events (HEC) when compared to treatment with aprepitant + granisetron.

Safety
Antiemetics for adults for prevention of nausea and vomiting caused by highly emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by highly emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: aprepitant (NK₁) combined with granisetron (5‐HT₃) + corticosteroid Outcome: serious adverse events RR < 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)a	Illustrative comparative risks* (95% CI)		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with aprepitant + granisetron	Corresponding risk with the intervention
aprepitant + ondansetron	35 of 1000	8 of 1000 (1 to 40)	RR 0.22  (0.04 to 1.14)	16,065 (23)	⊕⊝⊝⊝ very lowb,c,d	Evidence is very uncertain about the effect of aprepitant + ondansetron on risk of serious adverse events when compared to aprepitant + granisetron
fosaprepitant + ondansetron	35 of 1000	8 of 1000 (2 to 37)	RR 0.23  (0.05 to 1.07)	16,065 (23)	⊕⊕⊝⊝ lowb,c	Fosaprepitant + ondansetron may decrease the risk of serious adverse events slightly when compared to aprepitant + granisetron
casopitant + ondansetron	35 of 1000	8 of 1000 (1 to 49)	RR 0.24  (0.04 to 1.39)	16,065 (23)	⊕⊕⊝⊝ lowb,c	Casopitant + ondansetron may decrease the risk of serious adverse events slightly when compared to aprepitant + granisetron
netupitant + palonosetron	35 of 1000	9 of 1000 (2 to 55)	RR 0.27  (0.05 to 1.58)	16,065 (23)	⊕⊕⊝⊝ lowb,c	Netupitant + palonosetron may decrease the risk of serious adverse events slightly when compared to aprepitant + granisetron
aprepitant + ramosetron	35 of 1000	11 of 1000 (2 to 67)	RR 0.31  (0.05 to 1.90)	16,065 (23)	⊕⊝⊝⊝ very lowb,c,d	Evidence is very uncertain about the effect of aprepitant plus ramosetron on risk of serious adverse events when compared to aprepitant + granisetron
fosaprepitant + palonosetron	35 of 1000	12 of 1000 (1 to 103)	RR 0.35  (0.04 to 2.95)	16,065 (23)	⊕⊝⊝⊝ very lowb,e	Evidence is very uncertain about the effect of fosaprepitant + palonosetron on risk of serious adverse events when compared to aprepitant + granisetron
fosnetupitant + palonosetron	35 of 1000	13 of 1000 (2 to 76)	RR 0.36  (0.06 to 2.16)	16,065 (23)	⊕⊝⊝⊝ very lowb,e	Evidence is very uncertain about the effect of fosnetupitant + palonosetron on risk of serious adverse events when compared to aprepitant + granisetron
fosaprepitant + granisetron	35 of 1000	13 of 1000 (3 to 53)	RR 0.37  (0.09 to 1.50)	16,065 (23)	⊕⊕⊝⊝ lowb,c	Fosaprepitant + granisetron may decrease the risk of serious adverse events slightly when compared to aprepitant + granisetron
aprepitant + palonosetron	35 of 1000	17 of 1000 (2 to 167)	RR 0.48  (0.05 to 4.78)	16,065 (23)	⊕⊝⊝⊝ very lowb,d,e	Evidence is very uncertain about the effect of aprepitant + palonosetron on risk of serious adverse events when compared to aprepitant + granisetron
rolapitant + granisetron	35 of 1000	20 of 1000 (7 to 60)	RR 0.57  (0.19 to 1.70)	16,065 (23)	⊕⊕⊝⊝ lowb,c	Rolapitant + granisetron may decrease the risk of serious adverse events slightly when compared to aprepitant + granisetron
*Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 20 of 573 (3.5%) participants treated with aprepitant + granisetron experienced at least 1 SAE (aprepitant + granisetron was used in 2 studies reporting the outcome, with follow‐up of up to 29 days). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aEither dexamethasone or methylprednisolone was used in all treatment regimens. bDowngraded once for moderate inconsistency. cDowngraded once for serious imprecision because 95% CIs cross unity and confidence intervals are wide. dDowngraded once for serious study limitations due to high risk of bias. eDowngraded twice for very serious imprecision because 95% CIs cross unity and confidence intervals are very wide, suggesting high possibility of harm.

Summary of findings 3. Summary of findings: complete control of vomiting during the overall phase (MEC) when compared to treatment with granisetron.

Efficacy
Antiemetics for adults for prevention of nausea and vomiting caused by moderately emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by moderately emetogenic chemotherapy Settings: inpatient and outpatient care Intervention neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid OR 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: granisetron (5‐HT₃) + corticosteroid Outcome: complete control of  vomiting during the overall phase (0 to 120 h of treatment with chemotherapy) RR < 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)a	Illustrative comparative risks* (95% CI)		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with granisetron	Corresponding risk with the intervention
aprepitant + palonosetron	555 of 1000	716 of 1000 (555 to 921)	RR 1.29  (1.00 to 1.66)	7800 (22)	⊕⊕⊝⊝ lowb,c	Aprepitant + palonosetron may increase complete response in the overall phase when compared to granisetron
netupitant + palonosetron	555 of 1000	694 of 1000 (510 to 944)	RR 1.25  (0.92 to 1.70)	7800 (22)	⊕⊕⊝⊝ lowb,d	Netupitant + palonosetron may increase complete response in the overall phase when compared to granisetron
rolapitant + granisetron	555 of 1000	660 of 1000 (588 to 738)	RR 1.19  (1.06 to 1.33)	7800 (22)	⊕⊕⊕⊕ high	Rolapitant + granisetron results in an increase in complete response in the overall phase when compared to granisetron
palonosetron	555 of 1000	588 of 1000 (472 to 733)	RR 1.06  (0.85 to 1.32)	7800 (22)	⊕⊕⊝⊝ lowb,d	Palonosetron may or may not increase complete response in the overall phase when compared to granisetron
aprepitant + granisetron	555 of 1000	577 of 1000 (483 to 694)	RR 1.06  (0.85 to 1.32)	7800 (22)	⊕⊕⊝⊝ lowb,d	Aprepitant + palonosetron may or may not increase complete response in the overall phase when compared to granisetron
azasetron	555 of 1000	561 of 1000 (422 to 738)	RR 1.01  (0.76 to 1.33)	7800 (22)	⊕⊕⊝⊝ lowb,e	Azasetron may result in little to no difference in complete response in the overall phase when compared to granisetron
fosaprepitant + ondansetron	555 of 1000	500 of 1000 (366 to 677)	RR 0.90  (0.66 to 1.22)	7800 (22)	⊕⊕⊝⊝ lowb,d	Fosaprepitant + ondansetron may decrease complete response in the overall phase when compared to granisetron
aprepitant + ondansetron	555 of 1000	477 of 1000 (355 to 649)	RR 0.86  (0.64 to 1.17)	7800 (22)	⊕⊕⊝⊝ lowb,d	Aprepitant + ondansetron may decrease complete response in the overall phase when compared to granisetron
casopitant + ondansetron	555 of 1000	461 of 1000 (344 to 622)	RR 0.83 (0.62 to 1.12)	7800 (22)	⊕⊕⊝⊝ lowb,d	Casopitant + ondansetron may decrease complete response in the overall phase when compared to granisetron
ondansetron	555 of 1000	433 of 1000 (327 to 577)	RR 0.78  (0.59 to 1.04)	7800 (22)	⊕⊕⊝⊝ lowb,d	Ondansetron may decrease complete response in the overall phase when compared to granisetron
*Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 623 of 1123 (55.5%) participants treated with granisetron achieved complete response during the overall phase (granisetron was used in 5 studies reporting the outcome). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aEither dexamethasone or methylprednisolone was used in all treatment regimens. bDowngraded once for serious study limitations due to high risk of bias. cDowngraded once for serious imprecision because 95% CIs included zero effect line. dDowngraded once for serious imprecision because 95% CIs cross unity. eDowngraded once for serious imprecision due to wide confidence intervals.

Summary of findings 4. Summary of findings: serious adverse events (MEC) when compared to treatment with granisetron.

Safety
Antiemetics for adults for prevention of nausea and vomiting caused by moderately emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by moderately emetogenic chemotherapy Settings: inpatient and outpatient care Intervention neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid OR 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: granisetron (5‐HT₃) + corticosteroid Outcome: serious adverse events RR < 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)a	Illustrative comparative risks* (95% CI)		Risk ratio (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk with granisetron	Corresponding risk with the intervention
rolapitant + granisetron	153 of 1000	176 of 1000 (135 to 230)	RR 1.15  (0.88 to 1.50)	1344 (1)	⊕⊕⊝⊝ lowb	Rolapitant + granisetron may increase the risk of serious adverse events slightly when compared to granisetron
*Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 103 of 674 (10.3%) participants treated with granisetron experienced at least 1 SAE (granisetron was used in 1 study reporting the outcome; time frame for reporting safety data was not described). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aEither dexamethasone or methylprednisolone was used in all treatment regimens. bDowngraded twice for very serious imprecision because 95% CIs cross unity, confidence intervals are wide, and information size is small.

An overview of all outcomes including prioritisation of outcomes is provided in Table 6. Supplementary figures are available from https://osf.io/dr2u7/ (Piechotta 2021).

Highly emetogenic chemotherapy (HEC)

Our objectives were to compare the effects of antiemetic treatment combinations including NK₁ receptor antagonists, 5‐HT₃ receptor antagonists, and corticosteroids on prevention of acute, delayed, and overall chemotherapy‐induced nausea and vomiting, and to generate a clinically meaningful treatment ranking according to their safety and efficacy. To strengthen the network, we also included treatment arms including 5‐HT₃ receptor antagonists and corticosteroids solely. However, we report outcomes only for comparisons including also NK₁ receptor antagonists.

We describe all comparisons that show evidence of a difference between treatment comparisons including NK₁ and 5‐HT₃ inhibitors and corticosteroids. All other comparisons are provided per outcome in a league table. We do not describe the ranking of treatments because P score rankings also include treatments that include 5‐HT₃ inhibitors and corticosteroids solely. For a comprehensive illustration of our results in forest plots and presentation in 'Summary of findings' tables, we randomly chose aprepitant plus granisetron and a corticosteroid as exemplary reference treatment for HEC. However, theoretically, we could have used every treatment combination as a reference. 

Efficacy

Complete control of nausea

We defined complete control of nausea as no nausea and no significant nausea, and we refer to it hereafter as "no nausea".

No nausea and no significant nausea were defined on a study level and typically refer to pre‐defined cutoffs (e.g. in Rapoport 2015 (a) or Schwartzberg 2015, nausea was assessed on a visual analogue scale (VAS; 0 to 100 mm; 0 = no nausea, 100 = severe nausea): < 5 mm for no nausea and < 25 mm for no significant nausea. No significant nausea is typically more subjective because of the wider range on the scale and therefore is less objective, especially in an open‐label study design. To increase comparability of studies and minimise biased results, we were therefore interested in patients with no nausea.

Acute phase (0 to 24 hours)

No nausea in the acute phase was reported in 22 studies including 11,225 participants and comparing a total of 17 treatment regimens. We could include all studies in network meta‐analysis (NMA), and the network was fully connected (see Supplementary Figure 3). Results for all network comparisons, including ranking of treatments, are shown in Supplementary Figures 4 and 5. We observed moderate heterogeneity (I² = 49.9%) between studies in the network. More participants treated with ezlopitant plus granisetron experienced no nausea in the acute phase than participants treated with netupitant plus palonosetron (risk ratio (RR) 1.58, 95% confidence interval (CI) 1.02 to 2.46), and than participants treated with aprepitant plus granisetron (RR 1.64, 95% CI 1.05 to 2.56), respectively. Evidence suggests no other differences between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid.

We identified no evidence of a difference between direct and indirect estimates in closed loops in the network (see Supplementary Figure 6). 

Delayed phase (24 to 120 hours)

No nausea in the delayed phase was reported in 19 studies including 10,545 participants and comparing a total of 15 treatment regimens. We could include all studies in NMA, and the network was fully connected (see Supplementary Figure 7). Results for all network comparisons, including ranking of treatments, are shown in Supplementary Figures 8 and 9. We observed serious heterogeneity (I² = 66.7%) between studies in the network. Evidence suggests no differences between treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid.

We identified no evidence of a difference between direct and indirect estimates in the only closed loop for aprepitant plus granisetron versus granisetron versus palonosetron (P = 0.7668 ) (see Supplementary Figure 10).

Overall phase (0 to 120 hours)

No nausea in the overall phase was reported in 22 studies including 14,588 participants and comparing a total of 14 treatment regimens. We could include all studies in NMA, and the network was fully connected (see Supplementary Figure 11). Results for all network comparisons, including ranking of treatments, are shown in Supplementary Figures 12 and 13. We observed no heterogeneity (I² = 0%) between studies in the network. More participants treated with fosaprepitant plus palonosetron experienced no nausea in the overall phase than participants treated with fosaprepitant plus granisetron (RR 1.43, 95% CI 1.10 to 1.85), aprepitant plus granisetron (RR 1.46, 95% CI 1.12 to 1.90), netupitant plus palonosetron (RR 1.52, 95% CI 1.13 to 2.05), fosaprepitant plus ondansetron (RR 1.62, 95% CI 1.20 to 2.19), aprepitant plus ondansetron (RR 1.68, 95% CI 1.23 to 2.30), and casopitant plus ondansetron (RR 1.83, 95% CI 1.29 to 2.60). Furthermore, evidence suggests that more participants treated with fosnetupitant plus granisetron experience no nausea in the overall phase than participants treated with casopitant plus ondansetron (RR 1.52, 95% CI 1.05 to 2.20); and that more participants treated with rolapitant plus granisetron (RR 1.40, 95% CI 1.02 to 1.93) and fosaprepitant plus granisetron (RR 1.28, 95% CI 1.01 to 1.62) achieve no nausea in the overall phase than participants treated with casopitant plus ondansetron, respectively. Evidence suggests no differences between treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid.

We rated the certainty of evidence for all treatments when compared to aprepitant plus granisetron according to the GRADE system. Using actual reported event rates, we estimated that 896 of 1000 participants achieve complete control of nausea in the overall phase when treated with aprepitant plus granisetron. When compared to treatment with aprepitant plus granisetron, treatment with fosaprepitant plus palonosetron (moderate certainty) probably results in a large increase in complete control of nausea in the overall phase (moderate certainty); treatment with fosnetupitant plus palonosetron (moderate certainty) or rolapitant plus granisetron (moderate certainty) probably increases complete control of nausea in the overall phase; and treatment with ezlopitant plus granisetron may increase complete control of nausea in the overall phase (low certainty). When compared to treatment with aprepitant plus granisetron, treatment with fosaprepitant plus granisetron (high certainty) or netupitant plus palonosetron (high certainty) has little to no effect on complete control of nausea in the overall phase, and treatment with rolapitant plus ondansetron (moderate certainty) likely results in little to no difference. When compared to treatment with aprepitant plus granisetron, treatment with fosaprepitant plus ondansetron (moderate certainty), aprepitant plus ondansetron (moderate certainty), or casopitant plus ondansetron (moderate certainty) probably decreases control of nausea in the overall phase. Our main reasons for downgrading were serious study limitations due to risk of bias and serious or very imprecision. We provide reasons for downgrading per assessment in Table 7. 

3. Summary of findings: complete control of nausea during the overall phase (HEC) when compared to treatment with aprepitant + granisetron.

Antiemetics for adults for prevention of nausea and vomiting caused by highly emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by highly emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: aprepitant (NK₁) combined with granisetron (5‐HT₃) + corticosteroid Outcome: complete control of nausea during the overall phase (0 to 120 h of treatment with chemotherapy) RR < 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)a	Illustrative comparative risks* (95% CI)		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with aprepitant + granisetron	Corresponding risk with the intervention
fosaprepitant + palonosetron	896 of 1000	NE of 1000 (NE to NE)	RR 1.46  (1.12 to 1.90)	14,588 (22)	⊕⊕⊕⊝ moderateb	Fosaprepitant + palonosetron probably results in a large increase in complete control of nausea in the overall phase when compared with aprepitant + granisetron
fosnetupitant + palonosetron	896 of 1000	NE of 1000 (851 to NE)	RR 1.21  (0.95 to 1.56)	14,588 (22)	⊕⊕⊕⊝ moderatec	Fosnetupitant + palonosetron probably increases complete control of nausea in the overall phase when compared with aprepitant + granisetron
ezlopitant + granisetron	896 of 1000	NE of 1000 (554 to NE)	RR 1.31  (0.62 to 2.80)	14,588 (22)	⊕⊕⊝⊝ lowd	Ezlopitant + granisetron may increase complete control of nausea in the overall phase when compared with aprepitant + granisetron
rolapitant + granisetron	896 of 1000	NE of 1000 (860 to NE)	RR 1.12  (0.96 to 1.31)	14,588 (22)	⊕⊕⊕⊝ moderatec	Rolapitant + granisetron probably increases complete control of nausea in the overall phase when compared with aprepitant + granisetron
fosaprepitant + granisetron	896 of 1000	914 of 1000 (780 to NE)	RR 1.02  (0.87 to 1.20)	14,588 (22)	⊕⊕⊕⊕ high	Fosaprepitant + granisetron has little to no effect on complete control of nausea in the overall phase when compared with aprepitant + granisetron
rolapitant + ondansetron	896 of 1000	860 of 1000 (591 to NE)	RR 0.96  (0.66 to 1.39)	14,588 (22)	⊕⊕⊕⊝ moderatec	Rolapitant + ondansetron probably decreases complete control of nausea slightly in the overall phase when compared with aprepitant + granisetron
netupitant + palonosetron	896 of 1000	860 of 1000 (753 to 986)	RR 0.96  (0.84 to 1.10)	14,588 (22)	⊕⊕⊕⊕ high	Netupitant + palonosetron has little to no effect on complete control of nausea in the overall phase when compared with aprepitant + granisetron
fosaprepitant + ondansetron	896 of 1000	806 of 1000 (645 to NE)	RR 0.90  (0.72 to 1.13)	14,588 (22)	⊕⊕⊕⊝ moderatec	Fosaprepitant + ondansetron probably decreases complete control of nausea slightly in the overall phase when compared with aprepitant + granisetron
aprepitant + ondansetron	896 of 1000	780 of 1000 (609 to NE)	RR 0.87  (0.68 to 1.10)	14,588 (22)	⊕⊕⊕⊝ moderatec	Aprepitant + ondansetron probably decreases complete control of nausea in the overall phase when compared with aprepitant + granisetron
casopitant + ondansetron	896 of 1000	717 of 1000 (538 to 950)	RR 0.80  (0.60 to 1.06)	14,588 (22)	⊕⊕⊕⊝ moderatec	Casopitant + ondansetron probably decreases complete control of nausea in the overall phase when compared with aprepitant + granisetron
*Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 412 of 460 (89.6%) participants treated with aprepitant + granisetron experienced no nausea during the overall phase (aprepitant + granisetron was used in 5 studies reporting the outcome). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; NE: not estimable; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aEither dexamethasone or methylprednisolone was used in all treatment regimens. bDowngraded once for serious study limitations due to high risk of bias. cDowngraded once for serious imprecision because 95% CIs cross unity and confidence intervals are wide. dDowngraded twice for very serious imprecision because wide confidence intervals suggest both a potentially substantial harm and benefit for the intervention.

We identified no evidence for a difference between direct and indirect estimates for both closed loops within this network (see Supplementary Figure 14).

Subgroup analyses

We were able to conduct the following two subgroup analyses.

Type of chemotherapy (cisplatin versus other HEC)

Cisplatin was used for chemotherapy in 16 trials including 9421 participants and comparing a total of 14 treatment regimens. Because of limited direct evidence, not all treatments in the network were connected through direct comparisons but treatments were split into two sub‐networks (figures available from study authors upon request). Sub‐network 1 included ten studies and compared nine treatments versus another. We observed no heterogeneity between studies in this sub‐network. Sub‐network 2 included six studies and compared five treatments versus another. We observed moderate heterogeneity (I² = 48%) between studies in this sub‐network. In subgroup analysis, including cisplatin chemotherapy only, evidence suggests no robust advantage for fosaprepitant plus palonosetron when compared to fosaprepitant plus granisetron (RR 1.49, 95% CI 0.89 to 2.50), aprepitant plus granisetron (RR 1.44, 95% CI 0.92 to 2.27), or netupitant plus palonosetron (RR 1.51, 95% CI 0.94 to 2.41), respectively. Confidence intervals of the effect estimates were widely overlapping, and we identified no evidence of a difference. Despite the split network, we did not identify any further differences in direction and extent of effect in subgroup analysis between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid.

Type of cancer (solid versus other)

Seventeen trials included only participants with solid tumours (n = 10,555) and compared 13 treatment regimens. We could include all studies in NMA, and the network was fully connected (figures available from study authors upon request). We observed no heterogeneity between studies in the network. In subgroup analysis, including participants with solid tumours only, evidence suggests no robust advantage for fosaprepitant plus palonosetron when compared with fosaprepitant plus granisetron (RR 1.40, 95% CI 0.85 to 2.31), aprepitant plus granisetron (RR 1.38, 95% CI 0.89 to 2.15), netupitant plus palonosetron (RR 1.44, 95% CI 0.91 to 2.29), fosaprepitant plus ondansetron (RR 1.59, 95% CI 0.95 to 2.68), casopitant plus ondansetron (RR 1.66, 95% CI 0.95 to 2.68), or aprepitant plus ondansetron (RR 1.66, 95% CI 0.98 to 2.81), respectively. Further, evidence from subgroup analysis suggests no robust advantage of fosnetupitant plus palonosetron (RR 1.30, 95% CI 0.79 to 2.15), rolapitant plus granisetron (RR 1.19, 95% CI 0.75 to 1.88), or fosaprepitant plus granisetron (RR 1.18, 95% CI 0.91 to 1.53), when compared with casopitant plus ondansetron, respectively. Confidence intervals of the effect estimates were widely overlapping, and we identified no evidence of a difference. We did not identify further differences in direction and extent of effect in subgroup analysis between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid. 

Sensitivity analyses

We included in risk of bias (RoB) sensitivity analysis 21 studies with low risk of bias including 13,942 participants and comparing a total of 14 treatment regimens. We could include all studies in NMA, and the network was fully connected (not shown). We observed low heterogeneity (I² = 4.3%) between studies in the network. We did not identify differences in direction and extent of effect in sensitivity analysis compared to the full analysis set. 

Complete control of vomiting

We defined complete control of vomiting as no vomiting and no use of rescue medicine. This outcome was usually referred to in the studies as complete response (CR); hereafter we refer to it as CR.

Acute phase (0 to 24 hours)

CR in the acute phase was reported in 41 studies (40 two‐arm studies, one three‐arm study) including 22,400 participants and comparing a total of 18 treatment regimens. The network was not fully connected and consists of two sub‐networks (see Supplementary Figure 15). We performed NMA only for Sub‐network 1, as Sub‐network 2 consisted of only one pair‐wise comparison (Li 2019). Briefly, Li 2019 included 100 participants and compared aprepitant plus tropisetron versus tropisetron. Evidence suggest higher CR in the acute phase for aprepitant plus tropisetron compared to tropisetron (RR 1.24, 95% CI 1.03 to 1.49).

We could include in NMA 40 studies reporting on 22,300 participants and comparing 16 treatment regimens. Results for all network comparisons within Sub‐network 1, including ranking of treatments, are shown in Supplementary Figures 16 and 17. We observed low heterogeneity (I² = 5.6%) between studies in the sub‐network. Fosnetupitant plus palonosetron (RR 1.15, 95% CI 1.05 to 1.27), fosaprepitant plus palonosetron (RR 1.14, 95% CI 1.06 to 1.24), aprepitant plus ramosetron (RR 1.13, 95% CI 1.05 to 1.20), fosaprepitant plus granisetron (RR 1.12, 95% CI 1.04 to 1.20), rolapitant plus granisetron (RR 1.12, 95% CI 1.02 to 1.23), aprepitant plus granisetron (RR 1.11, 95% CI 1.04 to 1.18), aprepitant plus palonosetron (RR 1.11, 95% CI 1.03 to 1.18), fosaprepitant plus ondansetron (RR 1.09, 95% CI 1.03 to 1.16), netupitant plus palonosetron (RR 1.09, 95% CI 1.02 to 1.16), and aprepitant plus ondansetron (RR 1.08, 95% CI 1.03 to 1.14) show higher CR in the acute phase than casopitant plus ondansetron, respectively. Evidence suggests no other differences between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid.

We identified no evidence of a difference between direct and indirect estimates (see Supplementary Figure 18).

Delayed phase (24 to 120 hours)

CR in the delayed phase was reported in 38 studies (37 two‐arm studies, one three‐arm study) including 21,663 participants and comparing a total of 17 treatment regimens. However, the network was not fully connected and consists of two sub‐networks (see Supplementary Figure 19). We performed NMA only for Sub‐network 1, as Sub‐network 2 consisted of only one pair‐wise comparison (Li 2019). Briefly, Li 2019 included 100 participants and compared aprepitant plus tropisetron versus tropisetron. Evidence suggests higher CR in the delayed phase for aprepitant plus tropisetron compared to tropisetron (RR 1.67, 95% CI 1.21 to 2.30).

We could include in NMA 37 studies reporting on 21,563 participants and comparing 15 treatment regimens. Results for all network comparisons within Sub‐network 1, including ranking of treatments, are shown in Supplementary Figures 20 and 21. We observed moderate heterogeneity (I² = 42.8%) between studies in the sub‐network. Evidence suggests no differences between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid.

We rated the certainty of evidence for all treatments when compared to aprepitant plus granisetron according to the GRADE system. Using actual reported event rates, we estimated that 694 of 1000 participants achieve complete control of vomiting (CR) in the delayed phase when treated with aprepitant plus granisetron. When compared to treatment with aprepitant plus granisetron, treatment with fosnetupitant plus palonosetron may increase CR in the delayed phase (low certainty). Fosaprepitant plus granisetron (moderate certainty) or netupitant plus palonosetron (moderate certainty) probably results in little to no difference in CR in the delayed phase when compared to aprepitant plus granisetron. Treatment with rolapitant plus granisetron (low certainty), fosaprepitant plus ondansetron (low certainty), or casopitant plus ondansetron (low certainty) may reduce CR in the delayed phase, when compared to aprepitant plus granisetron. Evidence is very uncertain about the effects of fosaprepitant plus palonosetron (very low certainty), aprepitant plus palonosetron (very low certainty), aprepitant plus ramosetron (very low certainty), aprepitant plus ondansetron (very low certainty), and rolapitant plus ondansetron (very low certainty) on CR in the delayed phase when compared to aprepitant plus granisetron. Our main reasons for downgrading were serious study limitations due to risk of bias, moderate inconsistency, and serious imprecision. We provide reasons for downgrading per assessment in Table 8.

4. Summary of findings: complete control of vomiting during the delayed phase (HEC) when compared to treatment with aprepitant + granisetron.

Antiemetics for adults for prevention of nausea and vomiting caused by highly emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by highly emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: aprepitant (NK₁) combined with granisetron (5‐HT₃) + corticosteroid Outcome: complete control of vomiting during the delayed phase (24 to 120 h of treatment with chemotherapy) RR > 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)a	Illustrative comparative risks* (95% CI)		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk aprepitant + granisetron	Corresponding risk with the intervention
fosnetupitant + palonosetron	694 of 1000	784 of 1000 (632 to 972)	RR 1.13 (0.91 to 1.40)	21,563 (37)	⊕⊕⊝⊝ lowb,c	Fosnetupitant + palonosetron may increase complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
fosaprepitant + palonosetron	694 of 1000	736 of 1000 (632 to 854)	RR 1.06 (0.91 to 1.23)	21,563 (37)	⊕⊝⊝⊝ very lowb,c,d	Evidence is very uncertain about the effect of fosaprepitant + palonosetron on complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
aprepitant + palonosetron	694 of 1000	722 of 1000 (652 to 798)	RR 1.04 (0.94 to 1.15)	21,563 (37)	⊕⊝⊝⊝ very lowb,c,d	Evidence is very uncertain about the effect of aprepitant + palonosetron on complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
aprepitant + ramosetron	694 of 1000	722 of 1000 (625 to 1.21)	RR 1.04 (0.90 to 1.21)	21,563 (37)	⊕⊝⊝⊝ very lowb,c,d	Evidence is very uncertain about the effect of aprepitant + ramosetron on complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
fosaprepitant + granisetron	694 of 1000	701 of 1000 (632 to 770)	RR 1.01 (0.91 to 1.11)	21,563 (37)	⊕⊕⊕⊝ moderateb	Fosaprepitant + granisetron probably has little to no effect on complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
netupitant + palonosetron	694 of 1000	687 of 1000 (618 to 763)	RR 0.99 (0.89 to 1.10)	21,563 (37)	⊕⊕⊕⊝ moderateb	Netupitant + palonosetron probably has little to no effect on complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
aprepitant + ondansetron	694 of 1000	645 of 1000 (576 to 722)	RR 0.93 (0.83 to 1.04)	21,563 (37)	⊕⊝⊝⊝ very lowb,c,d	Evidence is very uncertain about the effect of aprepitant + ondansetron on complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
rolapitant + granisetron	694 of 1000	632 of 1000 (541 to 736)	RR 0.91 (0.78 to 1.06)	21,563 (37)	⊕⊕⊝⊝ lowb,c	Rolapitant + granisetron may decrease complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
fosaprepitant + ondansetron	694 of 1000	632 of 1000 (548 to 722)	RR 0.91 (0.79 to 1.04)	21,563 (37)	⊕⊕⊝⊝ lowb,c	Fosaprepitant + ondansetron may decrease complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
casopitant + ondansetron	694 of 1000	618 of 1000 (507 to 756)	RR 0.89 (0.73 to 1.09)	21,563 (37)	⊕⊕⊝⊝ lowb,c	Casopitant + ondansetron may decrease complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
rolapitant + ondansetron	694 of 1000	583 of 1000 (437 to 784)	RR 0.84 (0.63 to 1.13)	21,563 (37)	⊕⊝⊝⊝ very lowb,c,d	Evidence is very uncertain about the effect of rolapitant + ondansetron on complete control of vomiting in the delayed phase when compared to aprepitant + granisetron
*Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 1537 of 2215 (69.4%) participants treated with aprepitant + granisetron achieved complete response during the delayed phase (aprepitant + granisetron was used in 10 studies reporting the outcome). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aEither dexamethasone or methylprednisolone was used in all treatment regimens. bDowngraded once for moderate inconsistency. cDowngraded once for serious imprecision because 95% CIs cross unity and confidence intervals are wide. dDowngraded once for serious study limitations due to high risk of bias.

We identified no evidence of a difference between direct and indirect estimates (see Supplementary Figure 22).

Overall phase (0 to 120 hours)

CR in the overall phase was reported in 39 studies (38 two‐arm studies, one three‐arm study) including 21,642 participants and comparing a total of 17 treatment regimens. However, the network was not fully connected and consists of two sub‐networks (Figure 4 and Supplementary Figure 23). We performed NMA only for Sub‐network 1, as Sub‐network 2 consisted of only one pair‐wise comparison (Li 2019). Briefly, Li 2019 included 100 participants and compared aprepitant plus tropisetron versus tropisetron. Evidence suggests higher CR in the overall phase for aprepitant plus tropisetron compared to tropisetron (RR 1.67, 95% CI 1.21 to 2.30).

4.

Network graph for the outcome complete control of vomiting in the overall phase (HEC).

A line connects any two treatments when there is at least one study comparing the two treatments. Line width: number of patients.

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

We included in NMA 38 studies comprising 21,542 participants and a total of 15 treatment regimens. Results for all network comparisons within Sub‐network 1, including ranking of treatments, are shown in Figure 5 and Figure 6 and in Supplementary Figures 24 and 25. We observed low heterogeneity (I² = 11.7%) between studies in the sub‐network. Evidence suggests that more people treated with fosnetupitant plus palonosetron achieve CR in the overall phase than people treated with aprepitant plus ondansetron (RR 1.20, 95% CI 1.01 to 1.43), fosaprepitant plus ondansetron (RR 1.23, 95% CI 1.02 to 1.47), casopitant plus ondansetron (RR 1.28, 95% CI 1.05 to 1.56), and rolapitant plus granisetron (RR 1.29, 95% CI 1.06 to 1.59), respectively. Aprepitant plus palonosetron shows higher CR in the overall phase than aprepitant plus ondansetron (RR 1.12, 95% CI 1.01 to 1.24), fosaprepitant plus ondansetron (RR 1.14, 95% CI 1.02 to 1.28), casopitant plus ondansetron (RR 1.19, 95% CI 1.03 to 1.37), and rolapitant plus granisetron (RR 1.20, 95% CI 1.03 to 1.40), respectively. Treatment with aprepitant plus ramosetron shows higher CR in the overall phase than treatment with casopitant plus ondansetron (RR 1.19, 95% CI 1.03 to 1.38) and rolapitant plus granisetron (RR 1.20, 95% CI 1.01 to 1.42). Treatment with fosaprepitant plus palonosetron shows higher CR in the overall phase than treatment with casopitant plus ondansetron (RR 1.18, 95% CI 1.01 to 1.38) and rolapitant plus granisetron (RR 1.20, 95% CI 1.02 to 1.40). Evidence suggests no other differences between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid.

5.

League table for the outcome complete control of vomiting in the overall phase (HEC). Network estimates with 95% CIs are given. Descending P score shows ranking of treatment options. Statistically significant results are marked in yellow. Global approach to check inconsistency/heterogeneity: Q‐statistics, I².

No. of studies: 34. No. of treatments: 14. No. of pair‐wise comparisons: 36. No. of designs: 21.

Q_total = 23.95, df = 22, P = 0.35/Q_within = 17.60, df = 13, P = 0.17/Q_between = 6.34, df = 9, P = 0.71; I² = 8.1%, Tau² = 0.0005.
Treatment effects + 95% CIs (risk ratios, random‐effects model).

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

6.

Exemplary network meta‐analysis forest plot for the outcome complete control of vomiting during the overall phase (HEC) (random‐effects model).

Aprepitant + granisetron was used as exemplary reference treatment. Ranking of treatments is ordered by P score (descending).

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

We rated the certainty of evidence for all treatments when compared to aprepitant plus granisetron according to the GRADE system. Using actual reported event rates, we estimated that 704 of 1000 participants achieve complete control of vomiting (CR) in the overall phase when treated with aprepitant plus granisetron. When compared to treatment with aprepitant plus granisetron, treatment with fosnetupitant plus palonosetron probably increases CR in the overall phase. When compared to treatment with aprepitant plus granisetron, treatment with aprepitant plus palonosetron (low certainty), aprepitant plus ramosetron (low certainty), and fosaprepitant plus palonosetron (low certainty) may result in a slight increase in CR in the overall phase. When compared to treatment with aprepitant plus granisetron, treatment with netupitant plus palonosetron (high certainty) or fosaprepitant plus granisetron (high certainty) results in little to no difference in CR in the overall phase. Treatment with aprepitant plus ondansetron (low certainty) or treatment with fosaprepitant plus ondansetron (low certainty) may result in a slight decrease in CR in the overall phase, when compared to treatment with aprepitant plus granisetron. Treatment with casopitant plus ondansetron (low certainty) or rolapitant plus ondansetron (low certainty) may decrease, and treatment with rolapitant plus granisetron (moderate certainty) probably decreases, CR in the overall phase when compared to aprepitant plus granisetron. Our main reasons for downgrading were serious study limitations due to risk of bias and serious imprecision. We provide reasons for downgrading per assessment in Table 1.

We identified no evidence of a difference between direct and indirect estimates (Figure 7 and Supplementary Figure 26).

7.

Comparison of direct and indirect evidence (in closed loops) for the outcome complete control of vomiting in the overall phase (HEC). CI: confidence interval; RR: risk ratio. 

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

Subgroup analyses

We were able to conduct the following three subgroup analyses.

Type of chemotherapy (cisplatin versus other HEC)

Cisplatin was used for chemotherapy in 19 trials including 11,637 participants and comparing a total of 12 treatment regimens. All trials could be included in NMA, and the network was fully connected (not shown). We observed low heterogeneity (I² = 10%) between studies in the network. In subgroup analysis including cisplatin‐based chemotherapy only, evidence suggests no robust advantage for fosnetupitant plus palonosetron when compared with aprepitant plus ondansetron (RR 1.29, 95% CI 0.99 to 1.44) or fosaprepitant plus ondansetron (RR 1.20, 95% CI 0.96 to 1.47), respectively. Evidence further suggests no robust advantage for fosaprepitant plus palonosetron when compared with casopitant plus ondansetron (RR 1.18, 95% CI 0.96 to 1.45); nor for aprepitant plus palonosetron when compared with aprepitant plus ondansetron (RR 1.07, 95% CI 0.92 to 1.25), fosaprepitant plus ondansetron (RR 1.08, 95% CI 0.91 to 1.28), or casopitant plus ondansetron (RR 1.16, 95% CI 0.95 to 1.42), respectively. Confidence intervals of the effect estimates were widely overlapping, and we identified no evidence of a difference. We did not identify further differences in direction and extent of effect in subgroup analysis between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid. 

Type of cancer (breast cancer versus other)

Eight trials included only participants with breast cancer (n = 5162) and compared ten treatment regimens. The network was not fully connected and consisted of three sub‐networks (figures available from study authors upon request). Sub‐network 1 included six studies and compared six treatments versus another. We observed no heterogeneity between studies in this sub‐network. Sub‐network 2 and Sub‐network 3 each included one study and, respectively, compared two treatments versus another. In comparison to the full analysis set, none of the comparisons of treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor demonstrated any evidence of a difference between comparisons. Confidence intervals of the effect estimates for both analyses were widely overlapping.

Type of cancer (solid (excluding breast cancer) versus other)

Twenty‐five trials included only participants with solid tumours (excluding breast cancer) (n = 13,716) and compared 14 treatment regimens. We could include all studies in NMA, and the network was fully connected (figures available from study authors upon request). We observed low heterogeneity (I² = 29.7%) between studies in the network. In comparison to the full analysis set, none of the comparisons of treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor demonstrated any evidence of a difference between comparisons. Confidence intervals of the effect estimates for both analyses were widely overlapping. 

Sensitivity analyses

We included 30 studies with low risk of bias including 20,137 participants and comparing a total of 14 treatment regimens in RoB sensitivity analysis. We could include all studies in NMA, and the network was fully connected (figures available from study authors upon request). We observed low heterogeneity (I² =  27.1%) between studies in the network. When only studies at low risk of bias are considered in NMA, evidence suggests no robust advantage of fosnetupitant plus palonosetron when compared with aprepitant plus ondansetron (RR 1.21, 95% CI 0.99 to 1.46) or fosaprepitant plus ondansetron (RR 1.23, 95% CI 1.00 to 1.51), respectively. Further, evidence suggests no robust advantage for aprepitant plus palonosetron when compared with aprepitant plus ondansetron (RR 1.12, 95% CI 0.97 to 1.30), fosaprepitant plus ondansetron (RR 1.14, 95% CI 0.98 to 1.33), or casopitant plus ondansetron (RR 1.19, 95% CI 1.00 to 1.43), respectively. Sensitivity analysis also suggests no robust advantage for fosaprepitant plus palonosetron when compared with casopitant plus ondansetron (RR 1.18, 95% CI 0.99 to 1.42). However, we identified no evidence of a difference in direction or estimates of effect between the full analysis set and studies with low risk of bias for treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid.

Quality of life

No impairment in quality of life

We reported and extracted this endpoint as number of participants with no impairment in quality of life (QoL).

QoL was reported in 16 studies (all two‐arm studies) including 8264 participants and comparing a total of 13 treatment regimens. All studies used the Functional Life Index‐Emesis (FLIE) to assess impairment in quality of life. The network was not fully connected and consisted of three sub‐networks (see Supplementary Figure 27). We performed NMA only for Sub‐network 1, as Sub‐networks 2 and 3 consisted of only one pair‐wise comparison (Kang 2020; Li 2019). Briefly, Li 2019 included 100 participants and compared aprepitant plus tropisetron versus tropisetron. Evidence suggests higher QoL for aprepitant plus tropisetron compared to tropisetron (RR 3.00, 95% CI 1.04 to 8.67). Kang 2020 included 270 participants and compared aprepitant plus palonosetron versus aprepitant plus ramosetron. Evidence suggests no differences between treatments (RR 1.01, 95% CI 0.88 to 1.17).

We could include in NMA 14 studies reporting on 7894 participants and comparing nine treatment regimens. Results for all network comparisons within Sub‐network 1, including ranking of treatments, are shown in Supplementary Figures 28 and 29. We observed substantial heterogeneity (I² = 78.1%) between studies in the sub‐network. Evidence suggests no differences in QoL between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid. 

We rated the certainty of evidence for all treatments when compared to aprepitant plus granisetron according to the GRADE system. Using actual reported event rates, we estimated that 714 of 1000 participants have no impairment in quality of life when treated with aprepitant plus granisetron. When compared to aprepitant plus granisetron, the evidence is very uncertain about the effects of rolapitant plus ondansetron (very low certainty), netupitant plus palonosetron (very low certainty), casopitant plus ondansetron (very low certainty), rolapitant plus granisetron (very low certainty), and aprepitant plus ondansetron (very low certainty) on QoL. Our main reasons for downgrading were serious study limitations due to risk of bias, inconsistency, and imprecision. We provide reasons for downgrading per assessment in Table 9. 

5. Summary of findings: quality of life (HEC) when compared to treatment with aprepitant + granisetron.

Antiemetics for adults for prevention of nausea and vomiting caused by highly emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by highly emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: aprepitant (NK₁) combined with granisetron (5‐HT₃) + corticosteroid Outcome: no impairment in quality of life RR <1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)a	Illustrative comparative risks* (95% CI)		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with aprepitant + granisetron	Corresponding risk with the intervention
rolapitant + ondansetron	714 of 1000	893 of 1000 (486 to 1649)	RR 1.25  (0.68 to 2.31)	7894 (14)	⊕⊝⊝⊝ very lowb,c	Evidence is uncertain about the effect of rolapitant + ondansetron on quality of life when compared to aprepitant + granisetron
netupitant + palonosetron	714 of 1000	764 of 1000 (585 to 1007)	RR 1.07  (0.82 to 1.41)	7894 (14)	⊕⊝⊝⊝ very lowb,d	Evidence is uncertain about the effect of netupitant + palonosetron on quality of life when compared to aprepitant + granisetron
casopitant + ondansetron	714 of 1000	743 of 1000 (421 to 1307)	RR 1.04  (0.59 to 1.83)	7894 (14)	⊕⊝⊝⊝ very lowb,c	Evidence is uncertain about the effect of casopitant + ondansetron on quality of life when compared to aprepitant + granisetron
rolapitant + granisetron	714 of 1000	693 of 1000 (521 to 921)	RR 0.97  (0.73 to 1.29)	7894 (14)	⊕⊝⊝⊝ very lowb,d	Evidence is uncertain about the effect of rolapitant + granisetron on quality of life when compared to aprepitant + granisetron
aprepitant + ondansetron	714 of 1000	657 of 1000 (393 to 1100)	RR 0.92  (0.55 to 1.54)	7894 (14)	⊕⊝⊝⊝ very lowb,c,e	Evidence is uncertain about the effect of aprepitant + ondansetron on quality of life when compared to aprepitant + granisetron
*Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 569 of 797 participants treated with aprepitant + granisetron experienced no impact on QoL (aprepitant + granisetron was used in 3 studies reporting the outcome, follow‐up on Day 6). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aEither dexamethasone or methylprednisolone was used in all treatment regimens. bDowngraded twice for high inconsistency within the network. cDowngraded twice for very serious imprecision because 95% CIs cross unity and confidence intervals are very wide, suggesting high benefit for the comparator. dDowngraded once for serious imprecision because 95% CIs cross unity and confidence intervals are wide. eDowngraded once for serious study limitations due to high risk of bias.

As presented in Figure 27 (supplementary material), there are no closed loops in the network. Therefore, we could not statistically or visually analyse inconsistencies between direct and indirect evidence.

Safety

Safety outcomes were not consistently reported across studies. To be able to meta‐analyse results, we could consider only those that reported the number of participants with at least one event. We could not consider cumulated events or breakdowns in degree of severity, nor further subgroups.

On‐study mortality

On‐study mortality was reported in 18 studies (17 two‐arm studies, one three‐arm study) including 10,392 participants and comparing a total of 11 treatment regimens (see Supplementary Figure 30). We had to exclude from the analysis two studies including a total of 2362 participants due to zero events because no indication is provided of the direction nor the magnitude of the relative treatment effect (Grunberg 2011; NCT01640340). Furthermore, for NMA, we broke down one study ‐ Hesketh 2014 ‐ into two independent studies, as this is a three‐arm study in which two arms did not report any events and therefore one of the three comparisons was not possible. We could include in NMA 16 studies including 8030 participants and nine treatment regimens, and the network was fully connected. Results for all network comparisons, including ranking of treatments, are shown in Supplementary Figures 31 and 32. We observed no heterogeneity (I² = 0.0%) between studies in the network. Evidence suggests no differences between treatments in on‐study mortality.

We rated the certainty of evidence for all treatments when compared to aprepitant plus granisetron according to the GRADE system. Using actual reported event rates, we estimated that 8 of 1000 participants died during the study when treated with aprepitant plus granisetron. When compared to treatment with aprepitant plus granisetron, treatment with netupitant plus palonosetron (low certainty), aprepitant plus ondansetron (low certainty), casopitant plus ondansetron (low certainty), or rolapitant plus granisetron (low certainty) may reduce on‐study mortality. When compared to treatment with aprepitant plus granisetron, treatment with rolapitant plus ondansetron may increase on‐study mortality (low certainty). Our reason for downgrading was very serious imprecision (please also see Table 10).

6. Summary of findings: on‐study mortality (HEC) when compared to treatment with aprepitant + granisetron.

Antiemetics for adults for prevention of nausea and vomiting caused by highly emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by highly emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: aprepitant (NK₁) combined with granisetron (5‐HT₃) + corticosteroid Outcome: on‐study mortality RR < 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)a	Illustrative comparative risks* (95% CI)		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with aprepitant + granisetron	Corresponding risk with the intervention
netupitant + palonosetron	8 of 1000	2 of 1000 (0 to 19)	RR 0.29  (0.04 to 2.34)	8030 (16)	⊕⊕⊝⊝ lowb	Netupitant + palonosetron may have little to no effect on on‐study mortality when compared with aprepitant + granisetron
aprepitant + ondansetron	8 of 1000	5 of 1000 (1 to 35)	RR 0.57  (0.07 to 4.39)	8030 (16)	⊕⊕⊝⊝ lowb	Aprepitant + ondansetron may have little to no effect on on‐study mortality when compared with aprepitant + granisetron
casopitant + ondansetron	8 of 1000	5 of 1000 (1 to 44)	RR 0.65  (0.08 to 5.53)	8030 (16)	⊕⊕⊝⊝ lowb	Casopitant + ondansetron may have little to no effect on on‐study mortality when compared with aprepitant + granisetron
rolapitant + granisetron	8 of 1000	5 of 1000 (1 to 33)	RR 0.66  (0.11 to 4.09)	8030 (16)	⊕⊕⊝⊝ lowb	Rolapitant + granisetron may have little to no effect on on‐study mortality when compared with aprepitant + granisetron
rolapitant + ondansetron	8 of 1000	12 of 1000 (1 to 216)	RR 1.56  (0.09 to 26.97)	8030 (16)	⊕⊕⊝⊝ lowb	Rolapitant + ondansetron may have little to no effect on on‐study mortality when compared with aprepitant + granisetron
*Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 7 of 844 (0.08%) participants treated with aprepitant + granisetron died during the study (aprepitant + granisetron was used in 4 studies reporting the outcome, with follow‐up of up to 29 days). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aEither dexamethasone or methylprednisolone was used in all treatment regimens. bDowngraded twice for very serious imprecision due to few events and very wide confidence intervals, suggesting potential benefit and harm for the comparator.

We identified no evidence of a difference between direct and indirect estimates within this network (see Supplementary Figure 33).

Adverse events

Participants with at least one adverse event (AE) were reported in 20 studies (19 two‐arm studies, one three‐arm study) including 13,036 participants and comparing a total of 13 treatment regimens. We could include all studies in NMA, and the network was fully connected (see Supplementary Figure 34). Results for all network comparisons, including ranking of treatments, are shown in Supplementary Figures 35 and 36. We observed no heterogeneity (I² =  0.0%) between studies in the network. Evidence suggests similar relative risks of an AE for all treatment comparisons. However, evidence also suggests that participants treated with aprepitant plus granisetron experienced fewer AEs than participants treated with fosaprepitant plus ondansetron (RR 0.93, 95% CI 0.88 to 0.99), fosnetupitant plus palonosetron (RR 0.92, 95% CI 0.88 to 0.97), and fosaprepitant plus granisetron (RR 0.92, 95% CI 0.88 to 0.96), respectively. Evidence suggests no other differences between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid.

We identified no evidence of a difference between direct and indirect estimates (see Supplementary Figure 37).

Serious adverse events

Participants with at least one serious AE (SAE) were reported in 23 studies (22 two‐arm studies, one three‐arm study) including 16,065 participants and comparing a total of 14 treatment regimens. We could not include in the analysis Cheirsilpa 2005, which included 73 participants, due to zero events. We could include 22 studies in NMA, and the network was fully connected (Figure 8 and Supplementary Figure 38). Results for all network comparisons, including ranking of treatments, are shown in Figure 9 and Figure 10 and in Supplementary Figures 39 and 40. We observed moderate heterogeneity (I² = 50.2%) between studies in the network. Evidence suggests no differences between treatment combinations.

8.

Network graph for the outcome serious adverse events (HEC).

A line connects any 2 treatments when there is at least 1 study comparing the 2 treatments. Line width: number of patients.

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

9.

League table for the outcome serious adverse events (HEC). Network estimates with 95% CIs are given. Descending P score shows ranking of treatment options. Statistically significant results are marked in yellow. Global approach to check inconsistency/heterogeneity: Q‐statistics, I².

No. of studies: 20. No. of treatments: 12. No. of pair‐wise comparisons: 22. No. of designs: 13.

Q_total = 20.26, df = 9, P = 0.016/Q_within = 16.39, df = 7, P = 0.022/Q_between = 3.87, df = 2, P = 0.14; I² = 55.6%, Tau² = 0.1057.
Treatment effects + 95% CIs (risk ratios, random‐effects model).

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

10.

Exemplary network meta‐analysis forest plot for the outcome serious adverse events (HEC) (random‐effects model).

Aprepitant + granisetron was used as exemplary reference treatment. Ranking of treatments is ordered by P score (descending). 

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

We rated the certainty of evidence for all treatments when compared to aprepitant plus granisetron according to the GRADE system. Using actual reported event rates, we estimated that 35 of 1000 participants experience SAEs when treated with aprepitant plus granisetron. When compared to treatment with aprepitant plus granisetron, treatment with fosaprepitant plus ondansetron (low certainty), casopitant plus ondansetron (low certainty), netupitant plus palonosetron (low certainty), fosaprepitant plus granisetron (low certainty), or rolapitant plus granisetron (low certainty) may slightly reduce the risk of SAEs. When compared to treatment with aprepitant plus granisetron, evidence is very uncertain about the effects of aprepitant plus ondansetron (very low certainty), aprepitant plus ramosetron (very low certainty), fosaprepitant plus palonosetron (very low certainty), fosnetupitant plus palonosetron (very low certainty), or aprepitant plus palonosetron (very low certainty) on SAEs. Our main reasons for downgrading were serious study limitations due to risk of bias, moderate inconsistency, and serious or very serious imprecision. We provide reasons for downgrading per assessment in Table 2.

We identified no evidence of a difference between direct and indirect estimates (Figure 11 and Supplementary Figure 41).

11.

Comparison of direct and indirect evidence (in closed loops) for the outcome serious adverse events (HEC). CI: confidence interval; RR: risk ratio.

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

Neutropenia

Neutropenia was reported in 13 studies (all two‐arm studies) including 10,585 participants and comparing a total of 13 treatment regimens. However, the network was not fully connected and consists of two sub‐networks (see Supplementary Figure 42). We performed NMA for Sub‐networks 1 and 2. Results of all network comparisons within Sub‐networks 1 and 2, including ranking of treatments, are shown in Supplementary Figures 43 and 44. 

We observed no heterogeneity (I² = 0.0%) between studies in Sub‐network 1. Evidence suggests that fewer participants treated with aprepitant plus ondansetron experienced neutropenia than participants treated with casopitant plus ondansetron (RR 0.35, 95% CI 0.15 to 0.84). Evidence suggests no other differences between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, within Sub‐network 1.

As presented in Supplementary Figure 42, there are no closed loops in the network. Therefore, we could not statistically or visually analyse inconsistencies between direct and indirect evidence.

We could not analyse generalised heterogeneity statistic Q_total and generalized I² statistic for Sub‐network 2. Evidence suggests no differences between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid, within Sub‐network 2.

As presented in Supplementary Figure 42, there are no closed loops in Sub‐network 2. Therefore, we could not visually nor statistically analyse inconsistencies between direct and indirect evidence.

Febrile neutropenia

Febrile neutropenia was reported in 19 studies (all two‐arm studies) including 13,873 participants and comparing a total of 14 treatment regimens. We could include all studies in NMA, and the network was fully connected (see Supplementary Figure 45). Results for all network comparisons, including ranking of treatments, are shown in Supplementary Figures 46 and 47. We observed no heterogeneity (I² = 0.0%) between studies in the network. Evidence suggests no differences between treatment combinations.

As presented in Supplementary Figure 45, there are no closed loops in the network. Therefore, we could not statistically or visually analyse inconsistencies between direct and indirect evidence.

Infection

The numbers of participants experiencing any infection were reported in two pair‐wise studies including 999 participants and comparing four treatment combinations (Ishido 2016; Schnadig 2016). Treatment combinations were not connected, and we could not perform NMA (see Supplementary Figure 48) for this outcome. Ishido 2016 included 84 participants and compared aprepitant plus granisetron versus palonosetron. Evidence suggests no differences between aprepitant plus granisetron versus palonosetron (RR 6.68, 95% CI 0.36 to 125.38). Schnadig 2016 included 915 participants and compared fosaprepitant plus granisetron versus fosaprepitant plus ondansetron. Evidence also suggests no differences between fosaprepitant plus granisetron and fosaprepitant plus ondansetron (RR 1.01, 95% CI 0.36 to 2.85).

Local reaction at infusion site

The numbers of participants experiencing any reaction at the infusion site were reported in seven pair‐wise studies including 6522 participants and comparing nine treatment combinations. The network was not fully connected and consisted of three sub‐networks (available from study authors upon request). We could perform NMA for Sub‐network 1 only, as Sub‐networks 2 and 3 consisted of only pair‐wise comparisons. Results for all treatment comparisons are available from study authors upon request, including ranking of treatments for comparisons included in Sub‐network 1. 

We could include four studies comparing five treatment combinations and data from 1491 participants in NMA for Sub‐network 1. We could not analyse generalised heterogeneity statistic Q_total and generalized I² statistic for Sub‐network 1. Evidence suggests no differences between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid, within Sub‐network 1.

We included data from two studies in Sub‐network 2. Grunberg 2009 and Herrstedt 2009 compared casopitant plus ondansetron versus ondansetron and included a total of 2719 participants. Results of pair‐wise meta‐analysis suggest no differences between casopitant plus ondansetron and ondansetron (RR 5.33, 95% CI 0.70 to 40.83). Sub‐network 3 consisted of only one study. Grunberg 2011 included 2312 participants and compared fosaprepitant plus ondansetron versus aprepitant plus ondansetron. Evidence suggests that participants treated with aprepitant plus ondansetron experienced fewer local reactions at the infusion site than participants treated with fosaprepitant plus ondansetron (RR 0.20, 95% CI 0.08 to 0.51).

We had planned to rate the certainty of evidence for local reactions at the infusion site according to the GRADE system for all treatment regimens compared to aprepitant plus granisetron, respectively. However, as no study reported the outcome for this treatment regimen, we could not rate the certainty of evidence for local reactions at the infusion site.

Hiccups

Hiccups were reported in 18 studies (17 two‐arm studies, one three‐arm study) including 9913 participants and comparing a total of 13 treatment regimens. The network was not fully connected and consisted of two sub‐networks (Supplementary Figure 49). We could perform NMA for Sub‐network 1 only, as Sub‐network 2 consisted of only one pair‐wise comparison. Briefly, Zhang 2020 included 646 participants and compared fosaprepitant plus palonosetron versus aprepitant plus palonosetron. Evidence suggests no differences between treatments (RR 1.17, 95% CI 0.69 to 2.0).

Results for all network comparisons included in Sub‐network 1, including ranking of treatments, are shown in Supplementary Figures 50 and 51. We observed no heterogeneity (I² = 0.0%) between studies in the network. Evidence suggests that participants treated with fosaprepitant plus granisetron (RR 0.44, 95% CI 0.24 to 0.81) and aprepitant plus granisetron (RR 0.52, 95% CI 0.29 to 0.92) experienced fewer hiccups than participants treated with rolapitant plus granisetron, respectively. Evidence suggests no other differences between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid.

We identified no evidence of a difference between direct and indirect estimates (Supplementary Figure 52).

Efficacy versus acceptability

Optimal treatment should be characterised by both high efficacy and acceptability. Figure 12 and Supplementary Figure 53 illustrate concurrently an exemplary ranking of treatment combinations for the outcome CR during the overall phase, for which we chose to represent efficacy, and the outcome SAEs, for which we chose to represent acceptability. We ordered treatments by P score. Treatment combinations with both high efficacy and high acceptability are located in the upper right corner of this graph. The related league table with all network estimates (RRs and 95% CIs) is given in Figure 13 and in Supplementary Figure 54. According to this ranking, we could not identify superior treatment within this comparison. We could include in this exemplary ranking plot only treatment combinations for which data were available for both outcomes (CR during the overall phase and SAEs).

12.

Exemplary ranking plot representing simultaneously the efficacy (x‐axis, CR during the overall phase) and the acceptability (y‐axis, SAEs) of all antiemetic regimens for patients receiving highly emetogenic chemotherapy.

Only antiemetic regimens for which data for both endpoints (CR during the overall phase and SAEs) were available are represented in the ranking plot.

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

13.

League table with network estimates (RR with 95% CIs) of all treatment combinations for efficacy (CR during the overall phase) and acceptability (SAEs) (HEC).

Treatments are presented in alphabetical order. For efficacy, RRs > 1 favour the first treatment in alphabetical order. For safety, RRs < 1 favour the first treatment in alphabetical order.

n.a.: no data were available for this comparison

Statistically significant results are marked bold.

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

Moderately emetogenic chemotherapy (MEC)

Our objectives were to compare whether antiemetic treatment combinations including NK₁ receptor antagonists, 5‐HT₃ receptor antagonists, and corticosteroids are superior for prevention of acute, delayed, and overall CINV to treatment combinations including 5‐HT₃ receptor antagonists and corticosteroids, and to generate a clinically meaningful treatment ranking according to their safety and efficacy. 

We describe all comparisons that show evidence of a difference between treatment combinations including 5‐HT₃ inhibitors and corticosteroids and treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and corticosteroids. All other comparisons are provided per outcome in league tables. We describe the ranking of treatments for those that appear to be most and least effective/safe. Additionally to the P score, we considered the distribution of P scores across rankings, estimated treatment effects, and confidence intervals. For a comprehensive illustration of our results in forest plots and presentation in 'Summary of findings' tables, we randomly chose granisetron as an exemplary reference treatment for MEC. However, theoretically, we could have used every treatment combination as a reference.

Efficacy

Complete control of nausea

We defined complete control of nausea as no nausea and no significant nausea, and we refer to it hereafter as "no nausea".

Acute phase (0 to 24 hours)

No nausea in the acute phase was reported in 13 studies including 4335 participants and comparing eight treatment regimens. We could include all studies in NMA, and the network was fully connected (see Supplementary Figure 55). Results for all network comparisons, including ranking of treatments, are shown in Supplementary Figures 56 and 57. We observed no heterogeneity (I² = 0.0%) between studies in the network. Evidence suggests no differences between treatment combinations including 5‐HT₃ inhibitors, and a corticosteroid versus treatment combination including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid. Ranking of treatments suggests aprepitant plus palonosetron to be most effective in preventing nausea during the acute phase (P score 0.90), and aprepitant plus granisetron (P score 0.11) to be least effective.

The test for incoherence and visual examination showed no evidence of a difference between direct and indirect estimates in the only closed loop in the network (see Supplementary Figure 58).

Delayed phase (24 to 120 hours)

No nausea in the delayed phase was reported in ten studies including 4136 participants and comparing eight treatment regimens. However, the network was not fully connected and consists of two sub‐networks (see Supplementary Figure 59). We performed NMA for Sub‐networks 1 and 2. Results for all network comparisons, including ranking of treatment combinations for both sub‐networks, are shown in Supplementary Figures 60 and 61. We observed substantial heterogeneity (I² = 64.2%) between studies in Sub‐network 1. Aprepitant plus palonosetron shows higher complete control of nausea in the delayed phase than ondansetron (RR 1.63, 95% CI 1.07 to 2.47). Evidence suggests no other differences between treatment combinations including 5‐HT₃ inhibitors and a corticosteroid versus treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid, within Sub‐network 1.

We identified no evidence of a difference between direct and indirect estimates in the only closed loop in Sub‐network 1 (see Supplementary Figure 62).

Generalised heterogeneity statistic Q_total and generalized I² statistic could not be analysed for Sub‐network 2. Evidence suggests no differences between treatment combinations including 5‐HT₃ inhibitors and a corticosteroid versus treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid, within Sub‐network 2.

As presented in Supplementary Figure 59, there are no closed loops in Sub‐network 2. Therefore, we could not visually nor statistically analyse inconsistencies between direct and indirect evidence.

Overall phase (0 to 120 hours)

No nausea in the overall phase was reported in ten studies including 5036 participants and comparing nine treatment regimens. However, the network was not fully connected and consists of two sub‐networks (see Supplementary Figure 63). We performed NMA for Sub‐networks 1 and 2. Results for all network comparisons, including ranking of treatment combinations for both sub‐networks, are shown in Supplementary Figures 64 and 65. We observed moderate heterogeneity (I² =  41.6%) between studies in Sub‐network 1. Aprepitant plus palonosetron shows higher complete control of nausea in the overall phase than palonosetron (RR 1.68, 95% CI 1.09 to 2.58) and ondansetron (RR 1.91, 95% CI 1.24 to 2.95), respectively. Evidence suggests no other differences between treatment combinations including 5‐HT₃ inhibitors, and a corticosteroid versus treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid, within Sub‐network 1.

We identified no evidence of a difference between direct and indirect estimates in the only closed loops in Sub‐network 1 (see Supplementary Figure 66).

We could not analyse generalised heterogeneity statistic Q_total and generalized I² statistic for Sub‐network 2. Evidence suggests no differences between treatment combinations including 5‐HT₃ inhibitors and a corticosteroid versus treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid, within Sub‐network 2.

As presented in Supplementary Figure 63, there are no closed loops in Sub‐network 2. Therefore, we could not visually nor statistically analyse inconsistencies between direct and indirect evidence.

We rated the certainty of evidence for all treatments when compared to granisetron according to the GRADE system. Using actual reported event rates, we estimated that 419 of 1000 participants achieve complete control of nausea in the overall phase when treated with granisetron. When compared to treatment with granisetron, treatment with aprepitant plus granisetron likely increases complete control of nausea in the delayed phase (low certainty); treatment with rolapitant plus granisetron likely slightly increases complete control of nausea in the delayed phase (low certainty). Our main reason for downgrading was very serious imprecision (please also see Table 11).

7. Summary of findings: complete control of nausea during the overall phase (MEC) when compared to treatment with granisetron.

Antiemetics for adults for prevention of nausea and vomiting caused by moderately emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by moderately emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid OR 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: granisetron (5‐HT₃) + corticosteroid Outcome: complete control of nausea during the overall phase (0 to 120 h of treatment with chemotherapy) RR < 1 indicates an advantage for the intervention. Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)a	Illustrative comparative risks* (95% CI)		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with granisetron	Corresponding risk with the intervention
aprepitant + granisetron	419 of 1000	570 of 1000 (365 to 897)	RR 1.36  (0.87 to 2.14)	1423 (2)	⊕⊕⊝⊝ lowb	Aprepitant + granisetron may increase complete control of nausea in the overall phase when compared with granisetron
rolapitant + granisetron	419 of 1000	453 of 1000 (402 to 511)	RR 1.08  (0.96 to 1.22)	1423 (2)	⊕⊕⊝⊝ lowc	Rolapitant + granisetron may increase complete control of nausea in the overall phase slightly when compared with granisetron
*Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 298 of 712 (41.9%) participants treated with granisetron experienced no nausea during the overall phase (granisetron was used in 2 studies reporting the outcome). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aEither dexamethasone or methylprednisolone was used in all treatment regimens. bDowngraded twice for very serious imprecision because 95% CIs cross unity, information size is small, and confidence intervals are very wide, suggesting benefit and harm for the comparator. cDowngraded twice for very serious imprecision because 95% CIs cross unity, confidence intervals are wide, and information size is small.

Subgroup analyses

We have been able to conduct the following subgroup analyses. 

Type of chemotherapy (carboplatin versus other MEC)

Carboplatin was used for chemotherapy in three trials including 211 participants and comparing five treatment regimens. Just as for the full analysis set, the network was not fully connected in subgroup analyses and likewise was divided into two sub‐networks (figure available from study authors upon request). Sub‐network 1 included two studies and compared three treatments versus another. We observed no heterogeneity between studies in this sub‐network. Sub‐network 2 included one study and compared two treatments versus another. In comparison to the overall analysis of Sub‐network 1, evidence from the subgroup analysis does not suggest a robust advantage for aprepitant plus palonosetron compared to palonosetron (RR 1.11, 95% CI 0.53 to 2.34). Confidence intervals of the effect estimates were widely overlapping, and we identified no evidence of a difference. The direction and extent of effect of the subgroup analysis for Sub‐network 2 do not deviate from the full analysis set of Sub‐network 2.

Type of cancer (solid versus other)

Nine trials included only participants with solid tumours (n = 4935) and compared nine treatment regimens. Just as for the full analysis set, the network was not fully connected in subgroup analyses and likewise was divided into two sub‐networks (figures available from study authors upon request). Sub‐network 1 included seven studies and compared six treatment regimens. We observed low heterogeneity (I² = 29%) between studies in this sub‐network. Sub‐network 2 included two trials and compared three treatment regimens. We observed no heterogeneity between studies in this sub‐network. In the overall analysis, evidence may suggest an advantage of aprepitant plus ondansetron compared to palonosetron (RR 1.03, 95% CI 0.58 to 1.81), fosaprepitant plus ondansetron (RR 1.11, 95% CI 0.75 to 1.564), ondansetron (RR 1.17, 95% CI 0.85 to 1.62), and casopitant plus ondansetron (RR 1.28, 95% CI 0.88 to 1.85). In subgroup analysis including solid tumours only, the direction of effect changes and evidence may suggest an advantage for palonosetron (RR 1.32, 95% CI 0.66 to 2.62), fosaprepitant plus ondansetron (RR 1.23, 95% CI 0.71 to 2.12), ondansetron (RR 1.16, 95% CI 0.69 to 1.95), and casopitant plus ondansetron (RR 1.05, 95% CI 0.62 to 1.82) compared to aprepitant plus ondansetron. Confidence intervals of the effect estimates were widely overlapping, and we identified no evidence of a difference. We identified no further differences in direction and extent of effects in subgroup analysis between treatments. 

Sensitivity analyses

We included six studies with low risk of bias including 3977 participants and comparing a total of seven treatment regimens in RoB sensitivity analysis. Just as for the full analysis set, the network was not fully connected in subgroup analyses and likewise was divided into two sub‐networks (figures available from study authors upon request). Sub‐network 1 included four studies and compared four treatment regimens. We observed low heterogeneity (I² = 13.1%) between studies in this sub‐network. Sub‐network 2 included two trials and compared three treatment regimens. In the overall analysis, evidence may suggest an advantage of aprepitant plus ondansetron compared to fosaprepitant plus ondansetron (RR 1.11, 95% CI 0.75 to 1.56), ondansetron (RR 1.17, 95% CI 0.85 to 1.62), and casopitant plus ondansetron (RR 1.28, 95% CI 0.88 to 1.85). In subgroup analysis including solid tumours only, the direction of effect changes and evidence may suggest an advantage for fosaprepitant plus ondansetron (RR 1.23, 95% CI 0.73 to 2.06), ondansetron (RR 1.16, 95% CI 0.70 to 1.92), and casopitant plus ondansetron (RR 1.05, 95% CI 0.63 to 1.75) compared to aprepitant plus ondansetron. Confidence intervals of the effect estimates were widely overlapping, and we identified no evidence of a difference.

Complete control of vomiting

We defined complete control of vomiting as no vomiting and no use of rescue medicine. This outcome was usually referred to in the studies as complete response (CR); hereafter we also refer to this as CR.

Acute phase (0 to 24 hours)

CR in the acute phase was reported in 21 studies (20 two‐arm studies, one three‐arm study) including 7783 participants and comparing 11 treatment regimens. We could include all studies in NMA, and the network was fully connected (see Supplementary Figure 67). Results for all network comparisons, including ranking of treatments, are shown in Supplementary Figures 68 and 69. We observed moderate heterogeneity (I² = 43.5%) between studies in the network. Aprepitant plus palonosetron showed higher CR in the acute phase than ondansetron (RR 1.19, 95% CI 1.08 to 1.31); and rolapitant plus granisetron showed higher CR in the acute phase than ondansetron (RR 1.14, 95% CI 1.01 to 1.29). However, palonosetron showed higher CR in the acute phase than fosaprepitant plus ondansetron (RR 1.14, 95% CI 1.01 to 1.27), aprepitant plus ondansetron (RR 1.14, 95% CI 1.03 to 1.25), and casopitant plus ondansetron (RR 1.15, 95% CI 1.04 to 1.27). Evidence suggests no other differences between treatment combinations including 5‐HT₃ inhibitors and a corticosteroid versus treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid. 

Ranking of treatments suggests that aprepitant plus palonosetron (P score 0.91) and palonosetron (P score 0.84) may be most effective in completely controlling vomiting during the acute phase, and ondansetron (P score 0.12) may be least effective.

We identified no evidence of a difference between direct and indirect estimates in closed loops in the network (see Supplementary Figure 70).

Delayed phase (24 to 120 hours)

CR in the delayed phase was reported in 21 studies (20 two‐arm studies, one three‐arm study) including 8421 participants and comparing ten treatment regimens. We could include all studies in NMA, and the network was fully connected (see Supplementary Figure 71). Results for all network comparisons, including ranking of treatments, are shown in Supplementary Figures 72 and 73. We observed low heterogeneity (I² = 6.5%) between studies in the network.

In the delayed phase, aprepitant plus palonosetron shows higher CR than palonosetron (RR 1.22, 95% CI1.08 to 1.37), granisetron (RR 1.29, 95% CI 1.11 to 1.50), and ondansetron (RR 1.51, 95% CI 1.30 to 1.76); rolapitant plus granisetron shows higher CR than granisetron (RR 1.16, 95% CI 1.06 to 1.27) and ondansetron (RR 1.35, 95% CI 1.17 to 1.56); fosaprepitant plus ondansetron shows higher CR than ondansetron (RR 1.15, 95% CI 1.05 to 1.26); and aprepitant plus ondansetron shows higher CR than ondansetron (RR 1.09, 95% CI 1.01 to 1.18). However, palonosetron shows higher CR than casopitant plus ondansetron (RR 1.18, 95% CI 1.04 to 1.34). Evidence suggests no other differences between treatment combinations including 5‐HT₃ inhibitors and a corticosteroid versus treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid. 

Ranking of treatments suggests aprepitant plus palonosetron (P score 0.98) and rolapitant plus granisetron (P score 0.85) may be most effective in completely controlling vomiting during the delayed phase, and ondansetron (P score 0.03) may be least effective.

We identified no evidence of a difference between direct and indirect estimates in closed loops in the network (see Supplementary Figure 74).

We rated the certainty of evidence for all treatments when compared to granisetron according to the GRADE system. Using actual reported event rates, we estimated that 641 of 1000 participants achieve complete control of vomiting (CR) in the delayed phase when treated with granisetron. When compared to granisetron, treatment with rolapitant plus granisetron increases CR in the delayed phase (high certainty); and treatment with aprepitant plus palonosetron likely results in a large increase in CR in the delayed phase (moderate certainty). When compared to granisetron, treatment with palonosetron may slightly increase CR in the delayed phase (low certainty); treatment with aprepitant plus granisetron may or may not slightly increase CR in the delayed phase (low certainty); treatment with azasetron may result in little to no difference in CR in the delayed phase (low certainty); treatment with fosaprepitant plus ondansetron probably results in little to no difference in CR in the delayed phase (moderate certainty); treatment with aprepitant plus ondansetron may slightly decrease CR in the delayed phase (low certainty); treatment with casopitant plus ondansetron may decrease CR in the delayed phase (low certainty); and treatment with ondansetron probably decreases CR in the delayed phase (moderate certainty). Our main reasons for downgrading were serious study limitations due to risk of bias and serious imprecision. We provide reasons for downgrading per assessment in Table 12.

8. Summary of findings: complete control of vomiting during the delayed phase (MEC) when compared to treatment with granisetron.

Antiemetics for adults for prevention of nausea and vomiting caused by moderately emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by moderately emetogenic chemotherapy Settings: inpatient and outpatient care Intervention: neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid OR 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: granisetron (5‐HT₃) + corticosteroid Outcome: complete control of vomiting during the delayed phase (24 to 120 h of treatment with chemotherapy) RR > 1 indicates an advantage for the intervention Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network
Interventions (corticosteroids included in all regimens)a	Illustrative comparative risks* (95% CI)		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with granisetron	Corresponding risk with the intervention
aprepitant + palonosetron	641 of 1000	823 of 1000 (712 to 962)	RR 1.29  (1.11 to 1.50)	8421 (21)	⊕⊕⊕⊝ moderateb	Aprepitant + palonosetron likely results in a large increase of complete control of vomiting during the delayed phase when compared to granisetron
rolapitant + granisetron	641 of 1000	744 of 1000 (679 to 814)	RR 1.16  (1.06 to 1.27)	8421 (21)	⊕⊕⊕⊕ high	Rolapitant + granisetron increases complete control of vomiting during the delayed phase when compared to granisetron
palonosetron	641 of 1000	679 of 1000 (622 to 750)	RR 1.06  (0.97 to 1.17)	8421 (21)	⊕⊕⊝⊝ lowb,c	Palonosetron may increase complete control of vomiting during the delayed phase slightly when compared to granisetron, but the evidence is uncertain
aprepitant + granisetron	641 of 1000	667 of 1000 (564 to 788)	RR 1.04  (0.88 to 1.23)	8421 (21)	⊕⊕⊝⊝ lowb,c	Palonosetron may or may not increase complete control of vomiting during the delayed phase slightly when compared to granisetron, but the evidence is uncertain
azasetron	641 of 1000	647 of 1000 (494 to 846)	RR 1.01  (0.77 to 1.32)	8421 (21)	⊕⊕⊝⊝ lowb,d	Azasetron may result in little to no difference in complete control of vomiting during the delayed phase slightly when compared to granisetron, but the evidence is uncertain
fosaprepitant + ondansetron	641 of 1000	596 of 1000 (551 to 718)	RR 0.98  (0.86 to 1.12)	8421 (21)	⊕⊕⊕⊝ moderateb	Fosaprepitant + ondansetron probably results in little to no difference in complete control of vomiting during the delayed phase slightly when compared to granisetron
aprepitant + ondansetron	641 of 1000	596 of 1000 (526 to 679)	RR 0.93  (0.82 to 1.06)	8421 (21)	⊕⊕⊝⊝ lowb,c	Aprepitant + ondansetron may decrease complete control of vomiting during the delayed phase slightly when compared to granisetron, but the evidence is uncertain
casopitant + ondansetron	641 of 1000	570 of 1000 (506 to 647)	RR 0.89  (0.79 to 1.01)	8421 (21)	⊕⊕⊝⊝ lowb,d	Casopitant + ondansetron may decrease complete control of vomiting during the delayed phase when compared to granisetron, but the evidence is uncertain
ondansetron	641 of 1000	551 of 1000 (493 to 609)	RR 0.86  (0.77 to 0.95)	8421 (21)	⊕⊕⊕⊝ moderateb	Ondansetron probably decreases complete control of vomiting during the delayed phase when compared to granisetron
*Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 953 of 1486 (64.1%) participants treated with granisetron achieved complete response during the delayed phase (granisetron was used in 7 studies reporting the outcome). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aEither dexamethasone or methylprednisolone was used in all treatment regimens. bDowngraded once for serious study limitations due to high risk of bias. cDowngraded once for serious imprecision because 95% CIs cross unity and include potential advantages and disadvantages. dDowngraded once for serious imprecision due to wide confidence intervals.

Overall phase (0 to 120 hours)

CR in the overall phase was reported in 22 studies including 7800 participants and comparing a total of 11 treatment regimens. We could include all studies in NMA, and the network was fully connected (Figure 14 and Supplementary Figure 75). Results for all network comparisons, including ranking of treatments, are shown in Figure 15 and Figure 16 and in Supplementary Figures 76 and 77. We observed low heterogeneity (I² = 13.7%) between studies in the network.

14.

Network graph for the outcome complete control of vomiting during the overall phase (MEC).

A line connects any 2 treatments when there is at least 1 study comparing the 2 treatments. Line width: number of patients.

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

15.

League table for the outcome complete control of vomiting during the overall phase (MEC). Network estimates with 95% CIs are given. Descending P score shows ranking of treatment options. Statistically significant results are marked in yellow. Global approach to check inconsistency/heterogeneity: Q‐statistics, I².

No. of studies: 22. No. of treatments: 11. No. of pair‐wise comparisons: 22. No. of designs: 11.

Q_total = 13.90, df = 12, P = 0.31/Q_within = 13.80, df = 11, P = 0.24/Q_between = 0.09, df = 1, P = 0.76; I² = 13.7%, Tau² = 0.0018.

Treatment effects + 95% CIs (risk ratios, random‐effects model); RR > 1 favours the upper treatment/treatment on the left.

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

16.

Exemplary network meta‐analysis forest plot for the outcome complete control of vomiting during the overall phase (MEC) (random‐effects model).

Granisetron was used as exemplary reference treatment. Ranking of treatments is ordered by P score (descending). 

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

In the overall phase, aprepitant plus palonosetron shows higher CR than palonosetron (RR 1.21, 95% CI 1.06 to 1.38) and ondansetron (RR 1.64, 95% CI 1.33 to 2.03); netupitant plus palonosetron shows higher CR than ondansetron (RR 1.60, 95% CI 1.22 to 2.10); rolapitant plus granisetron shows higher CR than granisetron (RR 1.19, 95% CI 1.06 to 1.33) and ondansetron (RR 1.52, 95% CI 1.11 to 2.07); fosaprepitant plus ondansetron shows higher CR than ondansetron (RR 1.15, 95% CI 1.03 to 1.29); and aprepitant plus ondansetron shows higher CR than ondansetron (RR 1.11, 95% CI 1.01 to 1.21). However, palonosetron shows higher CR than casopitant plus ondansetron (RR 1.28, 95% CI 1.04 to 1.57). Evidence suggests no other differences between treatment combinations including 5‐HT₃ inhibitors and a corticosteroid versus treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid. 

Ranking of treatments suggests aprepitant plus palonosetron (P score 0.91), netupitant plus palonosetron (P score 0.85), and rolapitant plus granisetron (P score 0.81) may be most effective in completely controlling vomiting during the overall phase, and ondansetron (P score 0.03) may be least effective.

We identified no evidence of a difference between direct and indirect estimates in the only closed loop in the network (Figure 17 and Supplementary Figure 78).

17.

Comparison of direct and indirect evidence (in closed loops) for the outcome complete control of vomiting during the overall phase (MEC). CI: confidence interval; RR: risk ratio. 

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

We rated the certainty of evidence for all treatments when compared to granisetron according to the GRADE system. Using actual reported event rates, we estimated that 555 of 1000 participants achieve complete control of vomiting (CR) in the overall phase when treated with granisetron. When compared to granisetron, treatment with rolapitant plus granisetron increases CR in the overall phase (high certainty); treatment with aprepitant plus palonosetron (low certainty) and netupitant plus palonosetron may increase CR in the overall phase (low certainty), and treatment with palonosetron (low certainty) or aprepitant plus granisetron (low certainty) may or may not increase CR in the overall phase. When compared to granisetron, treatment with azasetron may result in little to no difference in CR in the overall phase (low certainty). When compared to granisetron, fosaprepitant plus ondansetron (low certainty), aprepitant plus ondansetron (low certainty), casopitant plus ondansetron (low certainty), or ondansetron (low certainty) may reduce CR in the overall phase. Our main reasons for downgrading were serious study limitations due to risk of bias and serious imprecision. We provide reasons for downgrading per assessment in Table 3.

Subgroup analyses

We have been able to conduct the following subgroup analyses.

Type of chemotherapy (carboplatin versus other MEC)

Carboplatin was used for chemotherapy in eight trials including 1628 participants and comparing eight treatment regimens. The network was not fully connected and consisted of two sub‐networks (figures available from study authors upon request).  Sub‐network 1 included six studies and compared five treatments to another. No heterogeneity was observed between studies in this sub‐network. Sub‐network 2 included two studies and compared three treatments to another. No heterogeneity was observed between studies in this sub‐network. In comparison to the overall analysis, evidence from the subgroup analysis does not suggest a robust advantage for aprepitant plus palonosetron compared to palonosetron (RR 1.06, 95% CI 0.84 to 1.34) nor for aprepitant plus ondansetron compared to ondansetron (RR 1.04, 95% CI 0.93 to 1.17). However, evidence from subgroup analysis does suggest a robust advantage for palonosetron compared to aprepitant plus ondansetron (RR 1.34, 95% CI 1.08 to 1.67). Despite the split network, we identified no further differences in direction and extent of effects in subgroup analysis. Confidence intervals of the effect estimates were widely overlapping, and we identified no evidence of a difference.

Type of cancer (solid versus other)

Sixteen trials included only participants with solid tumours (n = 6082) and compared 11 treatment regimens. The network was not fully connected and consisted of two sub‐networks (figures available from study authors upon request). Sub‐network 1 included 12 studies and compared seven treatments to another. We observed moderate heterogeneity (I² = 44.1%) between studies in this sub‐network. Sub‐network 2 included four studies and compared four treatments to another. We observed no heterogeneity between studies in this sub‐network.  In comparison to the overall analysis, evidence from subgroup analysis does not suggest a robust advantage for netupitant plus palonosetron compared to fosaprepitant plus ondansetron (RR 1.41, 95% CI 0.97 to 2.05) nor for palonosetron compared to casopitant plus ondansetron (RR 1.26, 95% CI 0.98 to 1.60), fosaprepitant plus ondansetron compared to ondansetron (RR 1.15, 95% CI 0.97 to 1.36), or aprepitant plus ondansetron compared to ondansetron (RR 1.08, 95% CI 0.94 to 1.24). Despite the split network, we identified no further differences in direction and extent of effects in subgroup analysis. Confidence intervals of the effect estimates were widely overlapping, and we identified no evidence of a difference.

Sensitivity analyses

We included 11 studies with low risk of bias including 6074 participants and comparing a total of ten treatment regimens in RoB sensitivity analysis. The network was not fully connected and consisted of two sub‐networks (figures available from study authors upon request). Sub‐network 1 included ten studies and compared eight treatments to another. We observed moderate heterogeneity (I² = 38.7%) between studies in this sub‐network. Sub‐network 2 included one study only and compared two treatments to another. In comparison to the overall analysis, evidence from the sensitivity analysis does not suggest a robust advantage for rolapitant plus granisetron compared to casopitant plus ondansetron (RR 1.43, 95% CI 0.98 to 2.22), nor for palonosetron compared to casopitant plus ondansetron (RR 1.28, 95% CI 0.98 to 1.67) or aprepitant plus ondansetron compared to ondansetron (RR 1.08, 95% CI 0.97 to 1.21). Despite the split network, we identified no differences in direction and extent of effects in sensitivity analysis between treatments. Confidence intervals of the effect estimates were widely overlapping, and we identified no evidence of a difference.

Quality of life

No impairment in quality of life

We reported and extracted this outcome as number of participants without any impairment in quality of life (QoL).

QoL was reported in four studies including 2783 participants and comparing five treatment regimens. All studies used the Functional Life Index‐Emesis (FLIE) to assess impairment in quality of life. The network was not fully connected and consists of two sub‐networks (Supplementary Figure 79). We performed NMA only for Sub‐network 1, as Sub‐network 2 consisted of only one pair‐wise comparison (Schwartzberg 2015). Briefly, Schwartzberg 2015 included 1212 participants and compared rolapitant plus granisetron versus granisetron. Evidence suggests higher QoL for participants treated with rolapitant plus granisetron compared to participants treated with granisetron (RR 0.92, 95% CI 0.86 to 0.99).

We could include three studies comprising 1671 participants and three treatment regimens in NMA. Results for all network comparisons within Sub‐network 1, including ranking of treatments, are shown in Supplementary Figures 80 and 81. We observed substantial heterogeneity (I² = 78.5%) between studies in the sub‐network. Evidence suggests no differences between treatment combinations including 5‐HT₃ inhibitors and a corticosteroid versus treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid, within Sub‐network 1.

We rated the certainty of evidence for all treatments when compared to granisetron according to the GRADE system. Using actual reported event rates, we estimated that 674 of 1000 participants have no impairment in quality of life when treated with granisetron. When compared to granisetron, treatment with rolapitant plus granisetron likely results in a decrease in QoL (moderate certainty). Our main reason for downgrading was serious imprecision (please also see Table 13).

9. Summary of findings: quality of life (MEC) when compared to treatment with granisetron.

Antiemetics for adults for prevention of nausea and vomiting caused by moderately emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by moderately emetogenic chemotherapy Settings: inpatient and outpatient care Intervention neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid OR 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: granisetron (5‐HT₃) + corticosteroid Outcome: no impairment in quality of life RR < 1 indicates an advantage for the intervention. Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network.
Interventions (corticosteroids included in all regimens)a	Illustrative comparative risks* (95% CI)		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with granisetron	Corresponding risk with the intervention
rolapitant + granisetron	674 of 1000	620 of 1000 (580 to 667)	RR 0.92  (0.86 to 0.99)	1212 (1)	⊕⊕⊕⊝ moderateb	Rolapitant + granisetron probably decreases quality of life slightly when compared to granisetron
*Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 409 of 607 (67.4%) participants treated with granisetron experienced no impact on QoL (granisetron was used in 1 study reporting the outcome, follow‐up on Day 6). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aEither dexamethasone or methylprednisolone was used in all treatment regimens. bDowngraded once for serious imprecision for the small sample size.

As presented in Supplementary Figure 79, there are no closed loops in the network. Therefore, we could not visually nor statistically analyse inconsistencies between direct and indirect evidence.

Safety

Safety outcomes were not consistently reported across studies. To be able to meta‐analyse results, we could consider safety outcomes only when the number of participants with at least one event was reported. We could not consider cumulated events or breakdown in degree of severity, nor further subgroups.

On‐study mortality

On‐study mortality was reported in five studies including 4149 participants and comparing a total of seven treatment regimens. The network was not fully connected and consists of two sub‐networks (see Supplementary Figure 82). We performed NMA only for Sub‐network 1, as Sub‐network 2 consisted of only one pair‐wise comparison (Schwartzberg 2015). Briefly, Schwartzberg 2015 included 1369 participants and compared rolapitant plus granisetron to granisetron. In the rolapitant plus granisetron group, 12 out of 684 participants died; in the granisetron group, four out of 685 participants died (RR 3.00, 95% CI 0.97 to 9.27).

We could include in NMA four studies reporting on 2780 participants and comparing five treatment regimens. Results for all network comparisons, including ranking of treatments within Sub‐network 1, are shown in Supplementary Figures 83 and 84. We could not analyse generalised heterogeneity statistic Q_total and generalized I² statistic. Evidence suggests no differences between treatment comparison combinations including 5‐HT₃ inhibitors and a corticosteroid versus treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid, within Sub‐network 1.

As presented in Supplementary Figure 82, there are no closed loops in the network. Therefore, we could not visually nor statistically analyse inconsistencies between direct and indirect evidence.

We rated the certainty of evidence for all treatments when compared to granisetron according to the GRADE system. Using actual reported event rates, we estimated that 6 of 1000 participants died during the study when treated with granisetron. When compared to granisetron, treatment with rolapitant plus granisetron may result in a large increase in on‐study mortality (low certainty). Our main reason for downgrading was very serious imprecision (please also see Table 14).

10. Summary of findings: on‐study mortality (MEC) when compared to treatment with granisetron.

Antiemetics for adults for prevention of nausea and vomiting caused by moderately emetogenic chemotherapy
Patient or population: adult cancer patients at risk for CINV caused by moderately emetogenic chemotherapy Settings: inpatient and outpatient care Intervention neurokinin‐1 (NK₁) receptor antagonist and 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid OR 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists + corticosteroid Comparison: granisetron (5‐HT₃) + corticosteroid Outcome: on‐study mortality RR < 1 indicates an advantage for the intervention. Combinations of these interventions at any dose and by any route as mentioned above have been compared to one another in a full network.
Interventions (corticosteroids included in all regimens)a	Illustrative comparative risks* (95% CI)		Risk ratio (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk with granisetron	Corresponding risk with the intervention
rolapitant + granisetron	6 of 1000	18 of 1000 (6 to 56)	RR 3.00  (0.97 to 9.27)	1369 (1)	⊕⊕⊝⊝ lowb	Rolapitant + granisetron may make little to no difference in on‐study mortality when compared to granisetron
*Basis for the assumed risk is actual event rates reported for the main comparator summed across studies: 4 of 685 (0.6%) participants treated with granisetron died during the study (granisetron was used in 1 study reporting the outcome, time frame for reporting safety data was not described). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the risk ratio of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aEither dexamethasone or methylprednisolone was used in all treatment regimens. bDowngraded twice for very serious imprecision because 95% CIs cross unity and because of the small information size.

Adverse events

Participants with at least one adverse event (AE) were reported in seven studies including 4394 participants and comparing eight treatment regimens. The network was not fully connected and consists of two sub‐networks (see Supplementary Figure 85). We performed NMA only for Sub‐network 1, as Sub‐network 2 consisted of only one pair‐wise comparison (Kusagaya 2015). Briefly, Kusagaya 2015 included 80 participants and compared aprepitant plus palonosetron versus palonosetron. Of 41 participants who were treated with aprepitant plus palonosetron, 39 experienced at least one AE; of 39 participants who were treated with palonosetron, 37 experienced at least one AE (RR 1.00, 95% CI 0.91 to 1.11).

We could include in NMA six studies comprising 4314 participants and six treatment regimens. Results for all network comparisons within Sub‐network 1, including ranking of treatments, are shown in Supplementary Figures 86 and 87. We observed no heterogeneity (I² = 0.0%) between studies in the sub‐network. Evidence suggests lower risk of AEs for ondansetron compared to rolapitant plus granisetron (RR 0.61, 95% CI 0.41 to 0.91). However, evidence also suggests lower risk of AEs for fosaprepitant plus ondansetron (RR 0.60, 95% CI 0.40 to 0.90), casopitant plus ondansetron (RR 0.60, 95% CI 0.40 to 0.89), and aprepitant plus ondansetron (RR 0.62, 95% CI 0.41 to 0.95), when compared to granisetron. Evidence suggests no other differences between treatment combinations including 5‐HT₃ inhibitors and a corticosteroid versus treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid, within Sub‐network 1.

As presented in Supplementary Figure 85, there are no closed loops in the network. Therefore, we could not visually nor statistically analyse inconsistencies between direct and indirect evidence.

Serious adverse events

Participants with at least one serious AE (SAE) were reported in five studies including 4124 participants and comparing seven treatment regimens. The network was not fully connected and consists of two sub‐networks (Figure 18 and Supplementary Figure 88). We performed NMA only for Sub‐network 1, as Sub‐network 2 consisted of only one pair‐wise comparison (Schwartzberg 2015). Briefly, Schwartzberg 2015 included 1344 participants and compared rolapitant plus granisetron versus granisetron. Of 674 participants who were treated with granisetron, 103 experienced at least one SAE; of 670 participants who were treated with rolapitant plus granisetron, 89 experienced at least one SAE (RR 1.15, 95% CI 0.88 to 1.50).

18.

Network graph for the outcome serious adverse events (MEC).

A line connects any 2 treatments when there is at least 1 study comparing the 2 treatments. Line width: number of patients.

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

We could include in NMA four studies comprising 2780 participants and five treatment regimens. Results for all network comparisons within Sub‐network 1, including ranking of treatments, are shown in Figure 19 and Figure 20 and in Supplementary Figures 89 and 90. We could not analyse generalised heterogeneity statistic Q_total and generalized I² statistic. Evidence suggests no other differences between treatment combinations including 5‐HT₃ inhibitors and a corticosteroid versus treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid, within this sub‐network.

19.

League table for the outcome serious adverse events (MEC). Network estimates with 95% CIs are given. Descending P score shows ranking of treatment options. Statistically significant results are marked in yellow. Global approach to check inconsistency/heterogeneity: Q‐statistics, I².

No. of studies: 4. No. of treatments: 5. No. of pair‐wise comparisons: 4. No. of designs: 4.

Heterogeneity/inconsistency: Q = 0, df = 0, P = not available; I² = not available, Tau² = not available.

Treatment effects + 95% CIs (risk ratios, random‐effects model).

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

20.

Exemplary network meta‐analysis forest plot for the outcome serious adverse events (MEC) (random‐effects model).

Ondansetron was used as exemplary reference treatment. Ranking of treatments is ordered by P score (descending).

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

We rated the certainty of evidence for all treatments when compared to granisetron according to the GRADE system. Using actual reported event rates, we estimated that 153 of 1000  participants experienced serious adverse events (SAE) when treated with granisetron. When compared to granisetron, treatment with rolapitant plus granisetron may increase SAEs (low certainty). Our main reason for downgrading was very serious imprecision (please also see Table 4).

As presented in Figure 18 and in Supplementary Figure 88, there are no closed loops in the network. Therefore, we could not visually nor statistically analyse inconsistencies between direct and indirect evidence.

Neutropenia

Neutropenia was reported in seven studies including 4214 participants and comparing a total of 99 treatment regimens. However, the network was not fully connected and consists of three sub‐networks (Supplementary Figure 91). We performed NMA only for Sub‐networks 1 and 2, as Sub‐network 3 consisted of only one pair‐wise comparison (Kusagaya 2015). Briefly, Kusagaya 2015 included 80 participants and compared aprepitant plus palonosetron versus palonosetron. Of 41 participants who were treated with aprepitant plus palonosetron, 26 experienced neutropenia; of 39 participants who were treated with palonosetron, 19 experienced neutropenia (RR 1.30, 95% CI 0.88 to 1.94).

We could include in NMA of Sub‐network 1 four studies involving 2543 participants and four treatment regimens. Results for all network comparisons within Sub‐network 1, including ranking of treatments, are shown in Supplementary Figures 92 and 93. We observed no heterogeneity (I² = 0.0%) between studies in the sub‐network. Evidence suggests no differences between treatment combinations including 5‐HT₃ inhibitors and a corticosteroid versus treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid, within this sub‐network. 

We could include in NMA of Sub‐network 2 two studies involving 1591 participants and three treatment regimens. Results for all network comparisons within Sub‐network 2, including ranking of treatments, are shown in Supplementary Figures 92 and 93. We could not analyse generalised heterogeneity statistic Q_total and generalised I² statistic. Evidence suggests no differences between treatment comparison combinations including 5‐HT₃ inhibitors and a corticosteroid versus treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid, within this sub‐network. 

As presented in Supplementary Figure 91, there are no closed loops in the network. Therefore, we could not visually nor statistically analyse inconsistencies between direct and indirect evidence.

Febrile neutropenia

Participants with febrile neutropenia were reported in three studies including 2469 participants and comparing a total of five treatment regimens. The network was not fully connected and consists of two sub‐networks (see Supplementary Figure 94). We performed NMA only for Sub‐network 1, as Sub‐network 2 consisted of only one pair‐wise comparison (Schwartzberg 2015). Briefly, Schwartzberg 2015 included 1344 participants and compared rolapitant plus granisetron versus granisetron. Of 674 participants who were treated with granisetron, 25 experienced febrile neutropenia; of 670 participants who were treated with rolapitant plus granisetron, 14 experienced febrile neutropenia (RR 0.56, 95% CI 0.30 to 1.07).

We could include in NMA two studies comprising 1125 participants and a total of three treatment regimens. Results for all network comparisons within Sub‐network 1, including ranking of treatments, are shown in Supplementary Figures 95 and 96. We could not analyse generalised heterogeneity statistic Q_total and generalised I² statistic. Evidence suggests no differences between treatment combinations including 5‐HT₃ inhibitors and a corticosteroid versus treatment combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid, within this sub‐network. 

As presented in Supplementary Figure 94, there are no closed loops in the network. Therefore, we could not visually nor statistically analyse inconsistencies between direct and indirect evidence.

Infection

None of the included studies reported the number of participants with infection.

Local reaction at the infusion site

None of the included studies reported the number of participants with local reaction at the infusion site.

We had planned to rate the certainty of evidence for local reaction at the infusion site according to the GRADE system for all treatment regimens compared to granisetron, respectively. However, as no study reported this outcome, we could not rate the certainty of evidence for this outcome.

Hiccups

Hiccups were reported in five pair‐wise studies including 1061 participants and comparing six treatment combinations. The network was not fully connected and consisted of three sub‐networks (figures available from study authors upon request). We could not perform NMA, as all sub‐networks consisted of only one pair‐wise comparison. Briefly, Kim 2017 and Song 2017 compared aprepitant plus ondansetron to ondansetron and included a total of 591 participants. Results of pair‐wise meta‐analysis suggest no differences between aprepitant plus ondansetron versus ondansetron (RR 2.08, 95% CI 1.00 to 4.43). Kusagaya 2015 and Xiong 2019 compared aprepitant plus palonosetron versus palonosetron and included a total of 185 participants. Results of pair‐wise meta‐analysis suggest no differences between aprepitant plus palonosetron versus palonosetron (RR 0.77, 95% CI 0.30 to 1.97). Ho 2010 included 285 participants and compared ramosetron to granisetron. Of 144 participants treated with ramosetron, nine experienced hiccups; of 141 participants treated with granisetron, five experienced hiccups (RR 1.76, 95% CI 0.61 to 5.13).

Efficacy versus acceptability

Optimal treatment should be characterised by both high efficacy and acceptability. Figure 21 and Supplementary Figure 97 illustrate concurrently an exemplary ranking of treatment combinations for the outcome CR during the overall phase, which we chose to represent efficacy, and for the outcome SAEs, which we chose to represent acceptability. We ordered treatments by P score. Treatment combinations with both high efficacy and high acceptability are located in the upper right corner of this graph. The related league table with all network estimates (RRs and 95% CIs) is given in Figure 22 and in Supplementary Figure 98. According to this ranking, we considered palonosetron as the most efficacious and acceptable treatment within this comparison. We could include only treatment combinations for which data were available for both outcomes (CR during the overall phase and SAEs) in this exemplary ranking plot.

21.

Exemplary ranking plot representing simultaneously the efficacy (x‐axis, CR during overall phase) and the acceptability (y‐axis, SAEs) of all antiemetic regimens for patients receiving moderately emetogenic chemotherapy.

Only antiemetic regimens for which data for both endpoints (CR during the overall phase and SAEs) were available are represented in the ranking plot.

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

22.

League table with network estimates (RR with 95% CIs) of all treatment combinations for efficacy (CR during the overall phase) and acceptability (SAEs) (MEC).

Treatments are presented in alphabetical order. For efficacy, RRs > 1 favour the first treatment in alphabetical order. For safety, RRs < 1 favour the first treatment in alphabetical order.

n.a.: no data were available for this comparison.

Statistically significant results are marked bold.

A list of treatment abbreviations is provided in Table 5; all treatments included a corticosteroid. 

Discussion

Summary of main results

The aim of this systematic review and network meta‐analysis was to synthesise all available evidence on different treatment options for prevention and control of chemotherapy‐induced nausea and vomiting (CINV) in adults with cancer receiving highly or moderately emetogenic chemotherapy (HEC or MEC, respectively). We identified 107 randomised controlled trials (RCTs) that included 37,313 participants from high‐, middle‐, and low‐income countries. Four studies included both HEC and MEC; in total, 73 trials analysed treatment options for prevention of CINV caused by HEC, and 38 analysed treatment options for prevention of CINV caused by MEC.

We investigated 22 different treatment regimens in these studies. Treatment regimens included a 5‐hydroxytryptamine‐3 (5‐HT₃) inhibitor (azasetron, granisetron, ondansetron, palonosetron, ramosetron, or tropisetron) and dexamethasone, and could additionally include a neurokinin‐1 (NK₁) inhibitor (aprepitant, casopitant, ezlopitant, fosaprepitant, fosnetupitant, netupitant (the latter two so far are available only in combination with palonosetron), or rolapitant). All treatment combinations included corticosteroids.

We could include in network meta‐analyses 50 studies in the HEC group and 26 studies in the MEC group. Overall risk of bias was generally low across studies. Results and certainty of evidence for the main outcomes and comparisons are summarised in 'Summary of findings' tables (Table 1; Table 2; Table 3; Table 4; Table 7; Table 8; Table 9; Table 10; Table 11; Table 12; Table 13; Table 14), and the most crucial outcomes are summarised below. These include complete control of vomiting during the overall treatment phase (Days 1 to 5) and serious adverse events.

Highly emetogenic chemotherapy (HEC)

We included 73 studies reporting on 25,275 participants and comparing 14 treatment combinations with NK₁ and 5‐HT₃ inhibitors. All treatment combinations included corticosteroids.

Complete control of vomiting during the overall phase

We estimated that 704 of 1000 participants achieve complete control of vomiting in the overall treatment phase (one to five days) when treated with aprepitant + granisetron. Evidence from network meta‐analysis (NMA) (39 RCTs, 21,642 participants, 12 treatment combinations with NK₁ and 5‐HT₃ inhibitors) suggests that the following drug combinations are more efficacious than aprepitant + granisetron in completely controlling vomiting during the overall treatment phase (one to five days): fosnetupitant + palonosetron (810 of 1000, risk ratio (RR) 1.15, 95% confidence interval (CI) 0.97 to 1.37; moderate certainty), aprepitant + palonosetron (753 of 1000, RR 1.07, 95% CI 1.98  to 1.18; low certainty), aprepitant + ramosetron (753 of 1000, RR 1.07, 95% CI 0.95 to 1.21; low certainty), and fosaprepitant + palonosetron (746 of 1000, RR 1.06, 95% CI 0.96 to 1.19; low certainty). 

Netupitant + palonosetron (704 of 1000, RR 1.00, 95% CI 0.93 to 1.08; high certainty) and fosaprepitant + granisetron (697 of 1000, RR 0.99, 95% CI 0.93 to 1.06; high certainty) have little to no impact on complete control of vomiting during the overall treatment phase (one to five days) when compared to aprepitant + granisetron, respectively. 

Evidence further suggests that the following drug combinations are less efficacious than aprepitant + granisetron in completely controlling vomiting during the overall treatment phase (one to five days) (ordered by decreasing efficacy): aprepitant + ondansetron (676 of 1000, RR 0.96, 95% CI 0.88 to 1.05; low certainty), fosaprepitant + ondansetron (662 of 1000, RR 0.94, 95% CI 0.85 to 1.04; low certainty), casopitant + ondansetron (634 of 1000, RR 0.90, 95% CI 0.79 to 1.03; low certainty), rolapitant + granisetron (627 of 1000, RR 0.89, 95% CI 0.78 to 1.01; moderate certainty), and rolapitant + ondansetron (598 of 1000, RR 0.85, 95% CI 0.65 to 1.12; low certainty).

We could not include two treatment combinations (ezlopitant + granisetron, aprepitant + tropisetron) in NMA for this outcome because of missing direct comparisons. 

Serious adverse events

We estimated that 35 of 1000 participants experience any serious adverse events (SAEs) when treated with aprepitant + granisetron. Evidence from NMA (23 RCTs, 16,065 participants, 11 treatment combinations) suggests that fewer participants may experience SAEs when treated with the following drug combinations than with aprepitant + granisetron: fosaprepitant + ondansetron (8 of 1000, RR 0.23, 95% CI 0.05 to 1.07; low certainty), casopitant + ondansetron (8 of 1000, RR 0.24, 95% CI 0.04 to 1.39; low certainty), netupitant + palonosetron (9 of 1000, RR 0.27, 95% CI 0.05 to 1.58; low certainty), fosaprepitant + granisetron (13 of 1000, RR 0.37, 95% CI 0.09 to 1.50; low certainty), and rolapitant + granisetron (20 of 1000, RR 0.57, 95% CI 0.19 to 1.70; low certainty).

Evidence is very uncertain about the effects of aprepitant + ondansetron (8 of 1000, RR 0.22, 95% CI 0.04 to 1.14; very low certainty), aprepitant + ramosetron (11 of 1000, RR 0.31, 95% CI 0.05 to 1.90; very low certainty), fosaprepitant + palonosetron (12 of 1000, RR 0.35, 95% CI 0.04 to 2.95; very low certainty), fosnetupitant + palonosetron (13 of 1000, RR 0.36, 95% CI 0.06 to 2.16; very low certainty), and aprepitant + palonosetron (17 of 1000, RR 0.48, 95% CI 0.05 to 4.78; very low certainty) on risk of SAEs when compared to aprepitant + granisetron, respectively. 

We could not include three treatment combinations (ezlopitant + granisetron, aprepitant + tropisetron, rolapitant + ondansetron) in NMA for this outcome because of missing direct comparisons. 

Moderately emetogenic chemotherapy (MEC)

We included 38 studies reporting on 12,038 participants and comparing 15 treatment combinations with NK₁ and 5‐HT₃ inhibitors, or 5‐HT₃ inhibitors solely. All treatment combinations included corticosteroids.

Complete control of vomiting during the overall phase

We estimated that 555 of 1000 participants achieve complete control of vomiting in the overall treatment phase (one to five days) when treated with granisetron. Evidence from NMA (22 RCTs, 7800 participants, 11 treatment combinations) suggests that the following drug combinations are more efficacious than granisetron in completely controlling vomiting during the overall treatment phase (one to five days): aprepitant + palonosetron (716 of 1000, RR 1.29, 95% CI 1.00 to 1.66; low certainty), netupitant + palonosetron (694 of 1000, RR 1.25, 95% CI 0.92 to 1.70; low certainty), and rolapitant + granisetron (660 of 1000, RR 1.19, 95% CI 1.06 to 1.33; high certainty). 

Palonosetron (588 of 1000, RR 1.06, 95% CI 0.85 to 1.32; low certainty) and aprepitant + granisetron (577 of 1000, RR 1.06, 95% CI 0.85 to 1.32; low certainty) may or may not increase complete response in the overall treatment phase (one to five days) when compared to granisetron, respectively. Azasetron (560 of 1000, RR 1.01, 95% CI 0.76 to 1.34; low certainty) may result in little to no difference in complete response in the overall treatment phase (one to five days) when compared to granisetron.

Evidence further suggests that the following drug combinations are less efficacious than granisetron in completely controlling vomiting during the overall treatment phase (one to five days) (ordered by decreasing efficacy): fosaprepitant + ondansetron (500 of 100, RR 0.90, 95% CI 0.66 to 1.22; low certainty), aprepitant + ondansetron (477 of 1000, RR 0.86, 95% CI 0.64 to 1.17; low certainty), casopitant + ondansetron (461 of 1000, RR 0.83, 95% CI 0.62 to 1.12; low certainty), and ondansetron (433 of 1000, RR 0.78, 95% CI 0.59 to 1.04; low certainty).

We could not include five treatment combinations (fosaprepitant + granisetron, azasetron, dolasetron, ramosetron, tropisetron) in NMA for this outcome because of missing direct comparisons. 

Serious adverse events

We estimated that 153 of 1000 participants experience any SAEs when treated with granisetron. Evidence from pair‐wise comparison (1 RCT, 1344 participants) suggests that more participants may experience SAEs when treated with rolapitant + granisetron (176 of 1000, RR 1.15, 95% CI 0.88 to 1.50; low certainty). NMA was not feasible for this outcome because of missing direct comparisons. 

Overall completeness and applicability of evidence

Robustness of results in subgroup and sensitivity analyses

We were able to compare a total of 21 different treatments combining 5‐HT₃ inhibitors with corticosteroids or additionally an NK₁ inhibitor for prevention and control of CINV in adults with cancer receiving HEC; of these, 14 included both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid. We were able to compare 15 different treatment combinations for adults with cancer receiving MEC; of these, 8 included both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and a corticosteroid. We summarised different types of chemotherapies, drug dosages, routes of administration, cancer types, and patient‐specific prognostic factors, and we had planned to analyse subgroups, if possible. Because of missing information or disconnected networks, we have not been able to analyse subgroups of drug dosages, routes of administration, or patient‐specific prognostic factors. We have been able to conduct subgroup analyses for type of chemotherapy and type of cancer, as well as sensitivity analyses for risk of bias, for both HEC and MEC. We manually compared the results of our subgroup and sensitivity analyses to the results of the full analysis set and investigated whether there were deviations in direction of effects, extent of effects, or both. Most of the effect estimates have been robust in subgroup and sensitivity analyses.

In the HEC group, we noticed that confidence intervals of the effect estimates were widely overlapping, and we found no evidence of a difference between subgroup and sensitivity analyses when compared to the full analysis set, for the outcomes complete control of nausea in the overall phase and complete control of vomiting in the overall phase. The same applies for the outcomes complete control of nausea in the overall phase and complete control of vomiting in the overall phase, which we had investigated in subgroup and sensitivity analyses for the MEC group. However, we have not been able to test for subgroup differences because the test for interactions is not yet available in the software package we used.  

Usability of reported outcomes

Not all of the included studies reported the same outcomes. At protocol stage, we defined our efficacy outcomes with the assistance of a clinical expert. However, the definitions of efficacy outcomes used within the included trials did not always correspond with our definitions. For example, we defined the outcome complete control of vomiting as no vomiting and no use of rescue medicine. However, some trials reported the outcome total control of vomiting and defined it as no vomiting, no use of rescue medicine, and no or mild nausea. As a result, we were not able to include these outcomes in our analysis.

Reporting of safety outcomes also differed between studies and led to limited comparability. We decided at protocol stage to include the reported safety data in NMA, if the number of participants experiencing at least one event was reported. We were not able to consider cumulated events or breakdowns in degree of severity or further subgroups (e.g. types of local reactions) in NMA. Not all trials reported the number of participants with at least one event. Therefore, we were not able to compare all identified treatment combinations versus one other for all outcomes. Because of these differences in reporting, we split most safety networks into sub‐networks. Therefore, we could compare only treatments included in the same sub‐network versus each other, reducing the informative value of our results. For the MEC group, the outcomes infection and local reaction at the infusion site have not been reported in any trials; therefore, we could not compare any treatments for these outcomes. We attempted to generate a ranking of treatments comparing efficacy against acceptability; however we could include only a limited number of treatments in this ranking because of the absence of all necessary information.

Consistency of results across phases

We checked whether the ranking of treatments was consistent across acute, delayed, and overall phases. We noticed that for the outcome complete control of nausea in the HEC group, ranking of treatments widely varied across phases. These differences probably originate from the fact that we could include different studies in the analysis of different time periods. However, this indicates discrepancies across the results of different trials and should be further investigated. Until this is done, these findings should be considered with caution.

Consistency within networks per outcome

We detected moderate inconsistency within networks for the outcomes complete control of nausea in the acute phase, complete control of vomiting in the delayed phase, and serious adverse events in the HEC group, and complete control of nausea in delayed and overall phases in the MEC group. We detected substantial inconsistency for the outcome quality of life (QoL) in both HEC and MEC groups. This inconsistency could not be statistically explained nor solved by sensitivity and subgroup analyses and probably originates from the interplay of some effect modifiers, in which our included trials differ slightly (e.g. cancer types, individuals' perceptions of nausea and quality of life, overall morbidity, study start date, study region). These are only minor differences. From a clinical point of view, our included studies therefore remain largely comparable. All trials reporting QoL used the Functional Life Index‐Emesis (FLIE) score to assess any impairments on QoL. We defined at protocol stage that we will compare the numbers of participants without any impairment in QoL. Therefore we did not consider or compare median scores. This may be a reason for inconsistency within networks and may explain why we could not identify differences between treatments. 

Entirety of conducted research

In addition to the studies included in this review, we are aware of 46 additional trials that may be eligible for inclusion in our review. Of these, 34 trials are still awaiting assessment, as no results are yet available, and 12 trials are still ongoing. These studies may alter our results, if included in our analysis.

However, despite all these limitations, we were able to identify an extensive number of trials comparing many treatment combinations for multiple outcomes versus one another. We were able to consider the experience of more than 25,000 individuals in the HEC analyses and more than 12,000 individuals in the MEC analyses, emphasising the overall completeness and applicability of our findings.

Quality of the evidence

Rating the certainty of evidence in network meta‐analysis

The advantage and likewise a major challenge of NMA is that it allows us to compare multiple different treatments while considering direct and indirect evidence. We recognise that a comprehensive illustration of results is difficult to present, and that there is no standard approach for assessing the certainty of effect estimates generated by NMA. We followed methods suggested by the GRADE Working Group and discussed our approach with the Cochrane methods support unit.

For a comprehensive presentation and assessment of results, we rated the certainty of network effect estimates for every treatment within networks against one exemplary reference treatment. Because there is not a single standard antiemetic treatment, we had to randomly choose an exemplary reference treatment for both HEC and MEC groups. We chose aprepitant + granisetron as an exemplary reference treatment for all outcomes in the HEC group, and granisetron as an exemplary reference treatment for all outcomes in the MEC group. However, theoretically, we could have used every treatment combination as a reference. We rated the certainty of evidence for prioritised outcomes and all comparisons within networks against the chosen exemplary reference treatment.

For both HEC and MEC, we rated the certainty of evidence for the outcomes complete control of nausea in the overall phase (Days 1 to 5), complete control of vomiting in delayed (Days 2 to 5) and overall phases (Days 1 to 5), no impairment in quality of life, on‐study mortality, and SAEs. We had also planned to rate the certainty of evidence for the outcome local reaction at infusion side but could not do so because in the HEC group, no study reported the outcome for our reference treatment (aprepitant + granisetron), and in the MEC group, no study reported the outcome for any comparison. Overall, our confidence in effect estimates for the most important health outcomes ranged from very low to high certainty. 

Highly emetogenic chemotherapy (HEC)

When we compared aprepitant + granisetron with all treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, most of the prioritised outcomes included a range in certainty of evidence across different comparisons. Our reasons for downgrading the evidence varied across comparisons and outcomes.

For the outcome complete control of nausea in the overall phase (Days 1 to 5), our confidence in the evidence was of low to high certainty. Our reasons for downgrading were serious study limitations due to high risk of bias and serious imprecision because the 95% confidence interval (CI) crosses unity and wide confidence intervals.

For the outcome complete control of vomiting in the delayed phase (Days 2 to 5), our confidence in the evidence was of very low to moderate certainty. Our reasons for downgrading were serious study limitations due to high risk of bias, moderate inconsistency within the network, and serious imprecision because the 95% CI crosses unity and wide confidence intervals.

For the outcome complete control of vomiting in the overall phase (Days 1 to 5), our confidence in the evidence was of low to high certainty. Our reasons for downgrading were serious study limitations due to high risk of bias, serious imprecision due to wide confidence intervals, and serious imprecision because the 95% CI crosses unity.

For the outcome no impairment in quality of life, our confidence in the evidence was of very low certainty. Our reasons for downgrading were high inconsistency within the network, very serious imprecision because the 95% CI crosses unity and wide confidence intervals suggesting high benefit for the comparator, serious imprecision because the 95% CI crosses unity, and serious study limitations due to high risk of bias. 

For the outcome on‐study mortality, our confidence in the evidence was of low certainty. Our reason for downgrading was very serious imprecision because the 95% CI crosses unity and wide confidence intervals suggesting high benefit for the comparator. 

For the outcome serious adverse events, our confidence in the evidence was of very low to low certainty. Our reasons for downgrading were serious study limitations due to high risk of bias, moderate inconsistency within the network, very serious imprecision because the 95% CI crosses unity and wide confidence intervals suggesting high possibility of harm, and serious imprecision because the 95% CI crosses unity and wide confidence intervals. 

Moderately emetogenic chemotherapy (MEC)

When we compared granisetron with all treatments, most of the prioritised outcomes included a range of certainty of evidence across the different comparisons. Our reasons for downgrading the evidence also varied across comparisons and outcomes.

For the outcome complete control of nausea in the overall phase (Days 1 to 5), our confidence in the evidence was of low certainty. Our reason for downgrading was very serious imprecision because 95% CIs cross unity, small information size, and wide confidence intervals suggesting high benefit for the comparator, or all.

For the outcome complete control of vomiting in the delayed phase (Days 2 to 5), our confidence in the evidence was of low to high certainty. Our reasons for downgrading were serious study limitations due to high risk of bias, serious imprecision due to wide confidence intervals, and serious imprecision because 95% CIs cross unity and confidence intervals suggesting benefit for the comparator.

For the outcome complete control of vomiting in the overall phase (Days 1 to 5), our confidence in the evidence was of low to high certainty. Our reasons for downgrading were serious study limitations due to high risk of bias, serious imprecision because 95% CIs cross unity, and wide confidence intervals.

For the outcome no impairment in quality of life, our confidence in the evidence was of moderate certainty. Our reason for downgrading was serious imprecision for the small sample size.

For the outcome on‐study mortality, our confidence in the evidence was of low certainty. Our reasons for downgrading were very serious imprecision because 95% CIs cross unity and small information size.

For the outcome serious adverse events. our confidence in the evidence was of low certainty. Our reasons for downgrading were very serious imprecision because 95% CIs cross unity, wide confidence intervals, and small information size.

Potential biases in the review process

Review author IM is an information specialist experienced in medical terminology, who developed the sensitive search strategy with the support of the Cochrane Pain, Palliative and Supportive Care (PaPaS) Review Group's information specialist. We searched all relevant databases, trial registries, conference proceedings, and reference lists and therefore are confident that we identified all relevant trials.

Although we were able to include 107 studies in this systematic review with network meta‐analysis, we identified insufficient studies to produce funnel plots for pair‐wise comparisons to further investigate potential publication bias. We could have created comparison‐adjusted funnel plots, which requires an assumption regarding differences between small studies and large studies (e.g. newer treatments favoured in small trials, active treatment versus placebo, sponsored versus non‐sponsored) (Chaimani 2013). However, the challenge of NMA is that we would need to take into account several comparisons, which means that we do not have one single line of reference. We therefore decided not to create comparison‐adjusted funnel plots. 

To minimise potential biases in the review process, we conducted selection of studies, data extraction, risk of bias assessment, and GRADE assessment in duplicate by two independent review authors and consulted a third review author for cases in which no consensus could be reached. We collated multiple reports of the same study, so that each study rather than each report was the unit of interest in the review. However, grouping of identified records was sometimes difficult, as not all records reported trial registration numbers. In cases for which we were uncertain whether two reports belonged to the same trial, we considered them as representing individual trials. 

For a more comprehensive presentation of results, we estimated absolute treatment effects by using actual reported event rates for our randomly chosen main comparators (aprepitant + granisetron for HEC, granisetron for MEC). However, if we would choose another comparator to estimate absolute event rates, all of these effects could change. Thus, when interpreting the results of our NMA, it must be considered that reported absolute event rates are provided for illustrative purposes (using the following comparators: aprepitant + granisetron for HEC, granisetron for MEC) and do not reflect anticipated real‐life event rates. 

We complied with Cochrane guidelines for every step of our review and consulted the PaPaS Review Group in cases of methodological uncertainty. With respect to available guidance for NMA, we are not aware of any methodological deficiencies in our review. However, in our opinion, 'Summary of findings' tables are not ideal for summing up such extensive analysis. Also, we surmise that the overall judgement of the quality of included trials and the certainty of evidence could diverge between different review author teams. Both the risk of bias tool and the GRADE approach are sensitive to subjective assessments and can be done more or less stringently.

Agreements and disagreements with other studies or reviews

To our knowledge, this is the first comprehensive review with NMA comparing all possible treatment combinations of NK₁ and 5‐HT₃ inhibitors with corticosteroids, or 5‐HT₃ inhibitors with corticosteroids, for prevention and control of CINV caused by HEC and MEC in adults with cancer.

Highly emetogenic chemotherapy (HEC)

We identified one further NMA comparing treatment combinations for prevention and control of CINV caused by HEC (Yokoe 2019). Additionally to our inclusion criteria, Yokoe 2019 included treatment combinations with olanzapine and treatment combinations without corticosteroids. Instead of comparing treatments per used substances versus each other, review authors grouped first‐generation 5‐HT₃ inhibitors into one group (granisetron, ondansetron, azasetron, ramosetron). Palonosetron was considered separately and was further divided into the dosages used. For therapies including an NK₁ inhibitor with a 5‐HT₃ inhibitor and dexamethasone, review authors summarised the NK₁ inhibitors aprepitant, fosaprepitant, and rolapitant into one group, and considered the combination including netupitant and palonosetron separately. In contrast to our inclusion criteria, review authors included only trials investigating antiemetic regimens in adults with solid cancer and excluded haematological malignancies. 

Yokoe 2019 included 27 studies, 18 of which have been included in our review as well. We did not include the remaining nine studies in our review for the following reasons. Five studies included olanzapine in the investigational arm. Two studies used a 5‐HT₃ inhibitor without a corticosteroid. One study presented a combined analysis of two trials over multiple cycles and considered two publications of the same study as different studies; we considered this study only once. However, we identified 55 additional studies (Appendix 2), which we have included in our review. Comparability of our NMA and the NMA of Yokoe 2019 is further limited, as Yokoe and colleagues reported only one of our outcomes of interest; i.e. complete response (in acute, delayed, and overall phases). 

Yokoe 2019 identified treatment combinations that included olanzapine as most efficient for achieving a complete response across all phases. Among treatment combinations that have also been compared in our analysis, Yokoe 2019 identified netupitant + palonosetron and dexamethasone as most efficient in the overall phase, followed by combinations including any NK₁ inhibitor + palonosetron and dexamethasone, and combinations including any NK₁ inhibitor and any 5‐HT₃ inhibitor with dexamethasone. Treatment combinations including only a 5‐HT₃ inhibitor with or without a corticosteroid performed least effectively. 

In contrast to Yokoe 2019, we used only treatments including a 5‐HT₃ inhibitor with a corticosteroid to stabilise the network and focused on differences between treatments combining NK₁ and 5‐HT₃ inhibitors with corticosteroids. However, because immunotherapy agents such as immune checkpoint inhibitors (ICIs) are added to HEC, it is investigated whether the immunosuppressive effects of corticosteroids undermine the action and thus the efficacy of immunotherapy agents (Janowitz 2021). Concerns have been raised that corticosteroid‐including antiemetic prophylaxis reduces the effectiveness of ICI‐HEC. Until the interaction of corticosteroid immunosuppressive effects on the efficacy of immunotherapy agents is better understood, effects of corticosteroid‐sparing or corticosteroid‐free antiemetic treatments might be of particular interest for people receiving ICI‐HEC (Janowitz 2021). Neither our review nor the Yokoe 2019 review has yet been able to adequately answer this open question. 

Moderately emetogenic chemotherapy (MEC)

We did not identify any other NMA comparing antiemetic regimens for prevention of CINV caused by MEC. We identified one meta‐analysis investigating the additional benefit of adding an NK₁ inhibitor to a 5‐HT₃ inhibitor for prevention of CINV caused by MEC (Jordan 2018). All 12 included trials of Jordan 2018 have been included in our systematic review as well. We could not include in this NMA the results of five trials, as only the substance class but not the active substance of the NK₁ inhibitor or the 5‐HT₃ inhibitor, or both, was defined in these trials (Aridome 2016; Ito 2014; Maehara 2015; Nishimura 2015; Yahata 2016). We included 25 additional trials in our analysis. Ten trials have not been included by Jordan 2018, as both treatment arms included a combination of 5‐HT₃ inhibitors and corticosteroids solely (Brohee 1995; Eisenberg 2003; Endo 2012; Ghosh 2010; Herrington 2000; Ho 2010; Jantunen 1992; Kaushal 2010; Raftopoulos 2015; Seol 2016); we have not included two further trials, as both treatment arms included a combination including both an NK₁ inhibitor and a 5‐HT₃ inhibitor (Fujiwara 2015; Jordan 2016a), and we could not include four trials as their publication date falls past the search date of Jordan 2018 (Kim 2017; Song 2017; Sugimori 2017; Xiong 2019). We identified ten additional trials in this systematic review (Arpornwirat 2009; Badar 2015; Kitayama 2015; Matsuda 2014; Miyabayashi 2015; Ozaki 2013; Schnadig 2014; Tsubata 2019; Webb 2010; Yeo 2009), three of which reported sufficient results to be included in NMA (Arpornwirat 2009; Badar 2015; Yeo 2009). Badar 2015 included participants with haematological malignancies, which have not been included by Jordan 2018. We analysed potential differences between types of cancer in subgroup analysis and did not identify any substantial disparities in treatment efficacy. Chemotherapy regimens used by Arpornwirat 2009 and Yeo 2009 have been classified as HEC and/or MEC by Jordan 2018 and therefore were excluded from that analysis. Arpornwirat 2009 described that investigators used cyclophosphamide from 500 mg/m² to 1500 mg/m² in combination with another MEC (not further specified) or from 750 mg/m² to 1500 mg/m² alone or in combination with agents that had been claimed by study authors to have low emetogenic potential: oxaliplatin ≥ 85 mg/m², doxorubicin ≥ 60 mg/m², epirubicin ≥ 90 mg/m², FOLFIRI, or carboplatin at an area under the curve (AUC) ≥ 5. According to the latest definition (Basch 2012), chemotherapy is classified as HEC if cyclophosphamide is used at ≥ 1500 mg/m². This was not the case for Arpornwirat 2009. However, chemotherapy is also classified as HEC if cyclophosphamide is used in combination with an anthracycline (Basch 2012). Arpornwirat 2009 described use of the low emetogenic anthracycline doxorubicin in combination with cyclophosphamide from 750 mg/m² to 1500 mg/m². The proportion of participants receiving this HEC combination has not been described in the trial, and results have not been reported separately. Therefore, this study has been mismatched to the MEC group in our review and will be excluded from analysis in an update of this review. Yeo 2009 also used doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m² for chemotherapy. According to the latest definition of HEC, this study has been mismatched to the MEC group in our review. In an update of this review, we will correct this misclassification and will include Yeo 2009 in the HEC group. 

The meta‐analysis of Jordan 2018 focused on efficacy outcomes (complete response, no emesis, no nausea) and separately analysed the results for carboplatin regimens, oxaliplatin regimens, and other MEC regimens including neither carboplatin nor oxaliplatin. We analysed all types of MEC together. Jordan 2018 identified benefit for antiemetic regimens including an additional NK₁ inhibitor for the outcome complete response during the overall phase for pure MEC regimens; and for the outcomes complete response during acute, delayed, and overall phases, no emesis during delayed and overall phases, and no nausea during delayed and overall phases for carboplatin‐based chemotherapy. Results of the meta‐analysis suggest no differences in efficacy between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, and treatments including a 5‐HT₃ inhibitor solely, for oxaliplatin‐based chemotherapy. In comparison, results of our NMA do not show a clear trend towards combinations including both an NK₁ inhibitor and a 5‐HT₃ inhibitor, neither for the outcome complete response nor for the outcome no nausea*. On the contrary, results of our NMA suggest that the choice of 5‐HT₃ inhibitor may have an impact on response rates. We analysed potential differences between carboplatin‐based chemotherapy and all MEC regimens in subgroup analysis and did not identify any substantial disparities in treatment efficacy.

Disagreements between the meta‐analysis of Jordan 2018 and our NMA could reflect several reasons. First of all, only 7 of 37 studies have been considered in both analyses. Disagreements between analyses may indicate that the information size of study populations was insufficient to reveal the true effect. However, in the case that there is true benefit for regimens including an NK₁ inhibitor for other MEC and carboplatin‐based chemotherapy, this effect could be covered in our NMA through analyses of all types of MEC together. Unfortunately, we have not been able to conduct a test for subgroup differences as described above (Overall completeness and applicability of evidence). Also, pooling of all NK₁ inhibitors and all 5‐HT₃ inhibitors could reveal differences between individual substances, suggesting overall benefit for treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor. 

*We did not investigate the outcome of no emesis in our network meta‐analysis. 

Authors' conclusions

Implications for practice.

General

The findings of our systematic review and network‐meta analysis will support clinicians and patients in decision‐making regarding use of NK₁ and 5‐HT₃ inhibitors for prevention of chemotherapy‐induced nausea and vomiting caused by highly or moderately emetogenic chemotherapy. Our results provide a comprehensive overview of all possible treatment options, including a ranking of treatments for each outcome. However, these rankings should be interpreted with caution and the results of all outcomes should be taken into consideration before a decision is made. Because of missing data in the included trials, not all treatment combinations could be compared to each other for every outcome. 

When interpreting the results of this systematic review, it is important to understand that network meta‐analyses are no substitute for direct head‐to‐head comparisons. It is also important to consider that the results of our network meta‐analysis do not necessarily rule out differences that could be clinically relevant for some individuals.

For adults receiving highly emetogenic chemotherapy

For people receiving highly emetogenic chemotherapy, synthesised evidence does not suggest one superior treatment for prevention and control of chemotherapy‐induced nausea and vomiting. Results of our network meta‐analysis do not necessarily rule out differences that could be clinically relevant for some individuals.

For adults receiving moderately emetogenic chemotherapy

For people receiving moderately emetogenic chemotherapy, synthesised evidence does not suggest superiority of treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor when compared to treatments including a 5‐HT₃ inhibitor alone. Results of our network meta‐analysis rather suggest that the choice of 5‐HT₃ inhibitor may have an impact on the efficacy of treatment in preventing chemotherapy‐induced nausea and vomiting. Results of our network meta‐analysis do not necessarily rule out differences that could be clinically relevant for some individuals.

For clinicians

For people receiving highly or moderately emetogenic chemotherapy, synthesised evidence does not suggest one superior treatment for prevention and control of chemotherapy‐induced nausea and vomiting. For people receiving moderately emetogenic chemotherapy, the results of our network meta‐analysis rather suggest that the choice of 5‐HT₃ inhibitor may have an impact on the efficacy of treatment in preventing chemotherapy‐induced nausea and vomiting. Results of our network meta‐analysis do not necessarily rule out differences that could be clinically relevant for some individuals.

For policy makers

Highly emetogenic chemotherapy

For prevention of chemotherapy‐induced nausea, evidence suggests with moderate certainty that fosaprepitant + palonosetron is likely the most effective treatment in the overall phase (Days 1 to 5). For prevention of chemotherapy‐induced vomiting, evidence suggests with very low to low certainty that there are small differences between treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor in the delayed phase; and with moderate certainty that aprepitant + palonosetron is likely the most effective treatment in the overall phase. Evidence is very uncertain about differences in effects of NK₁ and 5‐HT₃ inhibitors on quality of life. Primary studies have reported few serious adverse events and deaths during the study period, and very uncertain evidence suggests there may be differences between treatments. 

Moderately emetogenic chemotherapy

For people receiving moderately emetogenic chemotherapy, synthesised evidence does not suggest superiority for treatments including both an NK₁ inhibitor and a 5‐HT₃ inhibitor when compared to treatments including a 5‐HT₃ inhibitor alone. For prevention of chemotherapy‐induced nausea, because of limited direct evidence, not all treatments could be compared and ranked in delayed and overall phases; therefore we cannot say whether there are differences between treatments, or to what extent treatments may differ. For prevention of chemotherapy‐induced vomiting, evidence suggests with moderate certainty that aprepitant + palonosetron is likely the most effective treatment in the delayed phase; and with low certainty that aprepitant + palonosetron may be the most effective treatment in the overall phase. We could not compare all treatments versus another for the outcome quality of life. A general interpretation of findings is therefore not possible. Primary studies have reported few serious adverse events and deaths during the study period. However, because of disconnected networks and low certainty of the evidence, we could not compare and rank all treatments for the outcomes serious adverse events and on‐study mortality. 

For funders of the intervention

This field of supportive cancer care is very well researched. However, new drugs and new drug combinations are continuously emerging and must be systematically researched and assessed.

Implications for research.

General implications

This is the first network meta‐analysis comparing combination therapies of 5‐HT₃ inhibitors with corticosteroids, or additionally with NK₁ inhibitors, for prevention of chemotherapy‐induced nausea and vomiting caused by highly or moderately emetogenic chemotherapy. This field of supportive cancer care is very well researched, and we could consider the experience of more than 25,000 people receiving highly emetogenic chemotherapy, and more than 12,000 people receiving moderately emetogenic chemotherapy, in our systematic review. Overall, our confidence in the evidence for the most important health outcomes ranged from very low to high certainty. Our confidence in the evidence was mainly affected by missing data.

New antiemetic agents, as well as new antineoplastic treatment concepts, are constantly introduced and this will require an update of our network meta‐analysis. In particular, the addition of immune checkpoint inhibitors to chemotherapy poses the question of negative interaction between corticosteroids and immunotherapy and prompts the need for additional research on the effects of corticosteroid‐sparing or corticosteroid‐free antiemetic treatments. 

Design

Most of the included studies were of high methodological quality, and results show low risk of bias. We would appreciate if studies would report allocation and masking more transparently. The main limitation of some of the included studies was an open‐label study design leading to high risk of performance bias and detection bias. 

Measurement (endpoints)

Safety outcomes were not consistently reported across studies. To be able to meta‐analyse results, we could consider only those reporting the number of participants with at least one adverse event. We could not consider cumulated events or breakdown in degree of severity, nor further subgroups.

Because of these differences in reporting, not all treatments in the network were connected through direct comparisons, but some were split into sub‐networks. Therefore, we could not compare all identified treatment combinations versus one other for each outcome. This led to limited comparability of treatments, reducing the informative value of our results. 

Other

Consistent reporting of core outcomes and outcome data in trials registries would be most helpful for future trials, but also for already completed trials, to ensure comparability of all possible treatment combinations. 

What's new

Date	Event	Description
4 January 2022	Amended	Search date amended in PLS.

History

Protocol first published: Issue 9, 2017
Review first published: Issue 11, 2021

Date	Event	Description
1 December 2021	Amended	Minor typographical error corrected in Abstract.

Appendices

Appendix 1. Search strategies

Cochrane Central Register of Controlled Trials (CENTRAL)

ID Search

#1 MeSH descriptor: [Antiemetics] explode all trees

#2 (antiemetic* or anti emetic*)

#3 #1 or #2

#4 MeSH descriptor: [Serotonin Antagonists] explode all trees

#5 (5 ht antagonist* or 5ht antagonist*)

#6 (serotonin* near/3 (antagonist* or blockader* or blocker*))

#7 (antiserotonergic* near/2 agent*)

#8 #4 or #5 or #6 or #7

#9 MeSH descriptor: [Serotonin 5‐HT3 Receptor Antagonists] explode all trees

#10 ((5 ht3 or 5ht3) near/2 antagonist*)

#11 #9 or #10

#12 MeSH descriptor: [Granisetron] explode all trees

#13 Granisetron*

#14 (brl‐43694a or brl43694a or brl‐43694 or brl43694)

#15 Kytril*

#16 Sancuso*

#17 #12 or #13 or #14 or #15 or #16

#18 MeSH descriptor: [Ondansetron] explode all trees

#19 Ondansetron*

#20 (gr38032f or gr 38032f)

#21 (sn 307 or sn307)

#22 Zofran*

#23 #18 or #19 or #20 or #21 or #22

#24 Tropisetron*

#25 Navoban*

#26 (ICS 205‐930 or ICS 205930)

#27 #24 or #25 or #26

#28 Dolasetron*

#29 Anzemet*

#30 #28 or #29

#31 Palonosetron*

#32 Aloxi*

#33 #31 or #32

#34 Zatosetron*

#35 (LY277359 or ly 277359)

#36 #34 or #35

#37 Ricasetron*

#38 (BRL‐46470 or BRL46470)

#39 #37 or #38

#40 Bemesetron*

#41 (MDL‐72222 or MDL72222)

#42 #40 or #41

#43 Ramosetron*

#44 Nasea*

#45 (Irribow* or Iribo*)

#46 (Nozia* or IBSet*)

#47 (Ai Ke An* or Lei Mai Xin* or Shan Chen*)

#48 ("Ramea" or Setoral*)

#49 #43 or #44 or #45 or #46 or #47 or #48

#50 "metastron"

#51 (strontium chloride‐89 or Sr‐89)

#52 #50 or #51

#53 itastron*

#54 setron*

#55 #53 or #54

#56 Aprepitant*

#57 Emend*

#58 #56 or #57

#59 Fosaprepitant*

#60 (L‐758,298 or L‐758298)

#61 Fosa

#62 #59 or #60 or #61

#63 Netupitant*

#64 Akynzeo*

#65 "nepa"

#66 #63 or #64 or #65

#67 MeSH descriptor: [Dexamethasone] explode all trees

#68 decameth*

#69 Dexamethason*

#70 Dexamethasone

#71 desamethason*

#72 (dexason* or dexadrol* or dexair* or dexacidin* or dxm*)

#73 (oradexon* or maxidex* or maxitrol* or tobradex* or ak‐dex*)

#74 (hexadecadrol* or oradexon* or decadron* or neodecadron*)

#75 dexametason*

#76 desametason*

#77 (millicorten* or maxidex* or decaspray* or dexpak*)

#78 (hexadrol* or decameth* or methylfluorprednisolon*)

#79 decaject*

#80 #67 or #68 or #69 or #70 or #71 or #72 or #73 or #74 or #75 or #76 or #77 or #78 or #79

#81 MeSH descriptor: [Nausea] explode all trees

#82 MeSH descriptor: [Vomiting] explode all trees

#83 nause*

#84 vomit*

#85 emesis

#86 emet*

#87 emetogenic*

#88 (antiemetic* or anti‐eme*)

#89 sickness*

#90 #81 or #82 or #83 or #84 or #85 or #86 or #87 or #88 or #89

#91 MeSH descriptor: [Neoplasms by Histologic Type] explode all trees

#92 MeSH descriptor: [Neoplasms by Site] explode all trees

#93 neoplas*

#94 (tumor* or tumour*)

#95 (Krebs* or cancer*)

#96 malignan*

#97 (carcino* or karzino*)

#98 karzinom*

#99 sarcom*

#100 (leukem* or leukaem* or leucem*)

#101 lymphom*

#102 melano*

#103 metastas*

#104 (mesothelio* or mesotelio*)

#105 carcinomatos*

#106 (gliom* or glioblastom*)

#107 osteo*sarcom*

#108 (blastom* or neuroblastom*)

#109 #91 or #92 or #93 or #94 or #95 or #96 or #97 or #98 or #99 or #100 or #101 or #102 or #103 or #104 or #105 or #106 or #107 or #108

#110 #3 or #8 or #11 or #17 or #23 or #27 or #30 or #33 or #36 or #39 or #42 or #49 or #52 or #58 or #62 or #66

#111 #110 or #80

#112 #111 and #90 and #109 in Trials

Embase

(via Ovid)

1. exp antiemetic agent/ 

2. (antiemetic* or anti emetic*).tw. 

3. 1 or 2 

4. exp serotonin antagonist/ 

5. (5 ht antagonist* or 5ht antagonist*).tw. 

6. (serotonin* adj3 (antagonist* or blockader* or blocker*)).tw. 

7. (antiserotonergic* adj2 agent*).tw. 

8. or/4‐7 

9. exp serotonin 3 antagonist/ 

10. ((5 ht3 or 5ht3) adj2 antagonist*).tw. 

11. 9 or 10 

12. granisetron/ 

13. (Granisetron* or (brl‐43694a or brl43694a or brl‐43694 or brl43694) or Kytril* or Sancuso*).tw. 

14. 12 or 13 

15. ondansetron/ 

16. (Ondansetron* or (gr38032f or gr 38032f) or (sn 307 or sn307) or Zofran*).tw. 

17. 15 or 16 

18. Tropisetron/ or (Tropisetron* or Navoban* or (ICS 205‐930 or ICS 205930)).tw. 

19. Dolasetron/ or (Dolasetron* or Anzemet*).tw. 

20. Palonosetron/ or (Palonosetron* or Aloxi*).tw. 

21. (Zatosetron* or (LY277359 or ly 277359)).tw. 

22. (Ricasetron* or (BRL‐46470 or BRL46470)).tw. 

23. (Bemesetron* or (MDL‐72222 or MDL72222)).tw. 

24. Ramosetron/ or (Ramosetron* or Nasea* or (Irribow* or Iribo*) or (Nozia* or IBSet*) or (Ai Ke An* or Lei Mai Xin* or Shan Chen*) or "Ramea" or Setoral*).tw. 

25. ("metastron" or (strontium chloride‐89 or Sr‐89)).tw. 

26. (itastron* or setron*).tw. 

27. Aprepitant/ or (Aprepitant* or Emend*).tw. 

28. Fosaprepitant/ or (Fosaprepitant* or (L‐758,298 or L‐758298) or Fosa).tw. 

29. Netupitant/ or (Netupitant* or Akynzeo* or "nepa").tw. 

30. exp dexamethasone/ 

31. decameth*.tw. 

32. (Dexamethason* or Dexamethasone or desamethason*).tw. 

33. (dexason* or dexadrol* or dexair* or dexacidin* or dxm*).tw. 

34. (oradexon* or maxidex* or maxitrol* or tobradex* or ak‐dex*).tw. 

35. (hexadecadrol* or oradexon* or decadron* or neodecadron*).tw. 

36. (dexametason* or desametason* or decaject*).tw. 

37. (millicorten* or maxidex* or decaspray* or dexpak*).tw. 

38. (hexadrol* or decameth* or methylfluorprednisolon*).tw. 

39. 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 

40. exp nausea/ 

41. exp vomiting/ 

42. (nause* or vomit* or emesis or emet* or emetogenic* or (antiemetic* or anti‐eme*) or sickness*).tw. 

43. 40 or 41 or 42 

44. exp neoplasm/ 

45. (neoplas* or tumor* or tumour or Krebs* or cancer* or malignan*).tw. 

46. (carcino* or karzino* or karzinom* or sarcom* or leukem* or leukaem* or leucem*).tw. 

47. (lymphom* or melano* or metastas* or mesothelio* or mesotelio* or carcinomatos*).tw. 

48. (gliom* or glioblastom* or osteo?sarcom* or blastom* or neuroblastom*).tw. 

49. 44 or 45 or 46 or 47 or 48 

50. 3 or 8 or 11 or 14 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 

51. 39 or 50 

52. 43 and 49 and 51 

53. random$.tw. 

54. factorial$.tw. 

55. crossover$.tw. 

56. cross over$.tw. 

57. cross‐over$.tw. 

58. placebo$.tw. 

59. (doubl$ adj blind$).tw. 

60. (singl$ adj blind$).tw. 

61. assign$.tw. 

62. allocat$.tw. 

63. volunteer$.tw. 

64. Crossover Procedure/ 

65. double‐blind procedure.tw. 

66. Randomized Controlled Trial/ 

67. Single Blind Procedure/ 

68. or/53‐67 

69. (animal/ or nonhuman/) not human/ 

70. 68 not 69 
 

MEDLINE

(via OvidSP) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions

#	Searches
1	exp ANTIEMETICS/
2	(antiemetic$ or anti emetic$).tw,kf,ot,nm.
3	or/1‐2
4	SEROTONIN ANTAGONISTS/
5	(5 ht antagonist$ or 5ht antagonist$).tw,kf,ot,nm.
6	((serotonin$ adj3 antagonist$) or (serotonin$ adj3 blocker$) or (serotonin$ adj3 blockader$)).tw,kf,ot,nm.
7	(antiserotonergic$ adj2 agent$).tw,kf,ot,nm.
8	or/4‐7
9	SEROTONIN 5‐HT3 RECEPTOR ANTAGONISTS/
10	((5 ht3 or 5ht3) adj2 antagonist$).tw,kf,ot,nm.
11	or/9‐10
12	GRANISETRON/
13	granisetron$.tw,kf,ot,nm.
14	(brl‐43694a or brl43694a or brl‐43694 or brl43694).tw,kf,ot,nm.
15	kytril$.tw,kf,ot.
16	sancuso$.tw,kf,ot.
17	or/12‐16
18	ONDANSETRON/
19	ondansetron$.tw,kf,ot,nm.
20	(gr38032f or gr 38032f).tw,kf,ot,nm.
21	(sn 307 or sn307).tw,kf,ot,nm.
22	zofran$.tw,kf,ot,nm.
23	or/18‐22
24	TROPISETRON/
25	(tropisetron$ or navoban$).tw,kf,ot,nm.
26	(ICS 205‐930 or ICS 205930).tw,kf,ot,nm.
27	or/24‐26
28	DOLASETRON/
29	(anzemet$ or dolasetron$).tw,kf,ot.
30	or/28‐29
31	APREPITANT/
32	(emend$ or aprepitant$).tw,kf,ot,nm.
33	or/31‐32
34	PALONOSETRON/
35	(palonosetron$ or aloxi$).tw,kf,ot,nm.
36	or/34‐35
37	FOSAPREPITANT/
38	(L‐758,298 or L‐758298).tw,kf,ot,nm.
39	(fosaprepitant$ or fosa$).tw,kf,ot,nm.
40	or/37‐39
41	NETUPITANT/
42	(netupitant$ or akynzeo$).tw,kf,ot,nm.
43	"nepa".tw,kf,ot,nm.
44	or/41‐43
45	zatosetron$.tw,kf,ot,nm.
46	(LY277359 or ly 277359).tw,kf,ot,nm.
47	or/45‐46
48	ricasetron$.tw,kf,ot,nm.
49	(BRL‐46470 or BRL46470).tw,kf,ot,nm.
50	or/48‐49
51	bemesetron$.tw,kf,ot,nm.
52	(MDL‐72222 or MDL72222).tw,kf,ot,nm.
53	or/51‐52
54	RAMOSETRON/
55	(ramosetron$ or nasea$).tw,kf,ot,nm.
56	(irribow$ or iribo$ or nozia$ or IBSet$).tw,kf,ot,nm.
57	("YM 060" or YM060).tw,kf,ot,nm.
58	(Ai Ke An$ or Lei Mai Xin$ or Shan Chen$).tw,kf,ot,nm.
59	("ramea" or setoral$).tw,kf,ot,nm.
60	or/54‐59
61	mirtazapin$.tw,kf,ot,nm.
62	(6‐Azamianserin or 6Azamianserin).tw,kf,ot,nm.
63	mepirzapin$.tw,kf,ot,nm.
64	or/61‐63
65	"metastron".tw,kf,ot,nm.
66	(strontium chloride‐89 or Sr‐89).tw,kf,ot,nm.
67	or/65‐66
68	itastron$.tw,kf,ot,nm.
69	setron$.tw,kf,ot,nm.
70	or/68‐69
71	3 or 8 or 11 or 17 or 23 or 27 or 30 or 33 or 36 or 40 or 44 or 47 or 50 or 53 or 60 or 64 or 67 or 70
72	exp DEXAMETHASONE/
73	decameth$.tw,kf,ot.
74	dexamethason$.tw,kf,ot.
75	dexamethasone.nm.
76	desamethason$.tw,kf,ot,nm.
77	(dexason$ or dexadrol$ or dexair$ or dexacidin$ or dxm$).tw,kf,ot,nm.
78	(oradexon$ or maxidex$ or maxitrol$ or tobradex$ or ak‐dex$).tw,kf,ot,nm.
79	(hexadecadrol$ or oradexon$ or decadron$ or neodecadron$).tw,kf,ot,nm.
80	dexametason$.tw,kf,ot,nm.
81	desametason$.tw,kf,ot,nm.
82	(millicorten$ or maxidex$ or decaspray$ or dexpak$).tw,kf,ot,nm.
83	(hexadrol$ or decameth$ or methylfluorprednisolon$).tw,kf,ot.
84	decaject$.tw,kf,ot,nm.
85	or/72‐84
86	NAUSEA/
87	VOMITING/
88	nause$.tw,kf,ot,nm.
89	vomit$.tw,kf,ot,nm.
90	emesis.tw,kf,ot,nm.
91	emet$.tw,kf,ot,nm.
92	emetogenic$.tw,kf,ot,nm.
93	(antiemetic* or anti‐eme*).tw,kf,ot,nm.
94	sickness*.tw,kf,ot.
95	or/86‐94
96	exp NEOPLASMS BY HISTOLOGIC TYPE/
97	exp NEOPLASMS BY SITE/
98	neoplas$.tw,kf,ot.
99	tumo?r$.tw,kf,ot.
100	(krebs$ or cancer$).tw,kf,ot.
101	malignan$.tw,kf,ot.
102	(carcino$ or karzino$).tw,kf,ot.
103	karzinom$.tw,kf,ot.
104	sarcom$.tw,kf,ot.
105	leuk#?m$.tw,kf,ot.
106	lymphom$.tw,kf,ot.
107	melano$.tw,kf,ot.
108	metastas$.tw,kf,ot.
109	(mesothelio$ or mesotelio$).tw,kf,ot.
110	carcinomatos$.tw,kf,ot.
111	(gliom$ or glioblastom$).tw,kf,ot.
112	osteo?sarcom$.tw,kf,ot.
113	(blastom$ or neuroblastom$).tw,kf,ot.
114	adenocarcinoma$.tw,kf,ot.
115	myeloma$.tw,kf,ot.
116	or/96‐115
117	randomized controlled trial.pt.
118	controlled clinical trial.pt.
119	randomi?ed.ab.
120	placebo.ab.
121	drug therapy.fs.
122	randomly.ab.
123	trial.ab.
124	groups.ab.
125	or/117‐124
126	exp ANIMALS/ not HUMANS/
127	125 not 126
128	(71 or 85) and 95 and 116 and 127
129	limit 128 to ed=19950101‐20000101
130	limit 128 to ed=20000101‐20100101
131	limit 128 to ed=20100101‐20170216
132	limit 128 to ed=20170216‐20171004
133	limit 128 to ed=20171004‐20180409
134	limit 128 to ed=20180409‐20190403

key: exp # /: explode # MeSH subject heading, tw: text word, kf: keyword heading word, ot: original title, ti: title, nm: substance name, pt: publication type, ab: abstract, fs: floating subheading, $: truncation, ?: wildcard, adj#: adjacent within # number of words

Appendix 2. Studies included in HEC group

1. Aapro 2006

2. Abdel‐Malek 2017 (not included in NMA)

3. Aksu 2013

4. Albany 2012 (not included in NMA)

5. Ando 2016 (not included in NMA)

6. Arce‐Salinas 2019(not included in NMA)

7. Bubalo 2005

8. Bubalo 2018 (not included in NMA)

9. Campos 2001

10. Chawla 2003

11. Cheirsilpa 2005

12. Cho 1998 (not included in NMA)

13. Chua 2000 (not included in NMA)

14. Egerer 2010 (not included in NMA)

15. Flenghi 2015 (not included in NMA)

16. Forni 2000 (not included in NMA)

17. Fox‐Geiman 2001 (not included in NMA)

18. Gao 2013 (not included in NMA)

19. Ghosh 2010 (also included in MEC group; not included in NMA)

20. Grunberg 2009

21. Grunberg 2011

22. Hashimoto 2013

23. Herrington 2008

24. Herrstedt 2009

25. Hesketh 1999

26. Hesketh 2003

27. Hesketh 2014

28. Ho 2010 (also included in MEC group)

29. Hu 2014

30. Innocent 2018

31. Ishido 2016

32. Kalaycio 1998 (not included in NMA)

33. Kang 2020

34. Kim 2015

35. Kimura 2015 (not included in NMA)

36. Koizumi 2003 (not included in NMA)

37. Lee 1997 (not included in NMA)

38. Li 2019

39. Mahrous 2020(not included in NMA)

40. Matsumoto 2020

41. Mattiuzzi 2007

42. Mohammed 2019(not included in NMA)

43. Nakamura 2012

44. NCT01640340

45. Ohzawa 2015

46. Poli‐Bigelli 2003

47. Raftopoulos 2015 (also included in MEC group)

48. Rapoport 2015 (a)

49. Rapoport 2015 (b)

50. Rapoport 2015 (c)

51. Roila 1995

52. Rugo 2017

53. Ruhlmann 2017

54. Saito 2009

55. Saito 2013

56. Saito 2017

57. Schmitt 2014

58. Schmoll 2006

59. Schnadig 2016

60. Stewart 1996 (not included in NMA)

61. Stewart 2000 (not included in NMA)

62. Stiff 2013

63. Sugawara 2019

64. Svanberg 2015 (not included in NMA)

65. Takahashi 2010

66. Tsubata 2019(also included in MEC group)

67. Warr 2005

68. Wenzell 2013

69. Wit 2001 (not included in NMA)

70. Yang 2017

71. Zhang 2018 (a)

72. Zhang 2018 (b)

73. Zhang 2020

Appendix 3. Studies included in MEC group

1. Aridome 2016

2. Arpornwirat 2009

3. Badar 2015

4. Brohee 1995 (not included in NMA)

5. Eisenberg 2003

6. Endo 2012

7. Fujiwara 2015 (not included in NMA)

8. Ghosh 2010 (also included in HEC group; not included in NMA)

9. Herrington 2000

10. Hesketh 2012

11. Ho 2010 (also included in HEC group)

12. Ito 2014 (not included in NMA)

13. Jantunen 1992 (not included in NMA)

14. Jordan 2016a

15. Kaushal 2010

16. Kaushal 2015

17. Kim 2017

18. Kitayama 2015

19. Kusagaya 2015

20. Maehara 2015 (not included in NMA)

21. Matsuda 2014

22. Miyabayashi 2015 (not included in NMA)

23. Nishimura 2015 (not included in NMA)

24. Ozaki 2013

25. Raftopoulos 2015 (also included in HEC group)

26. Rapoport 2010

27. Schnadig 2014 (not included in NMA)

28. Schwartzberg 2015

29. Seol 2016 (not included in NMA)

30. Song 2017

31. Sugimori 2017

32. Tanioka 2013

33. Tsubata 2019 (also included in HEC group)

34. Webb 2010 (not included in NMA)

35. Weinstein 2016

36. Xiong 2019

37. Yahata 2016 (not included in NMA)

38. Yeo 2009

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Aapro 2006.

Study characteristics
Methods	Randomised, stratified, parallel‐group, active‐comparator, phase 3 trial with 3 arms comparison of palonosetron 0.25 mg + dexamethasone vs palonosetron 0.75 mg + dexamethasone vs ondansetron 32 mg + dexamethasone Enrolment period: July 2000 to December 2001 673 patients randomised 447 participants received concomitant dexamethasone on Day 1 and were stratified for balance between treatment groups Masking: double‐blind Baseline patient characteristics: reported Follow‐up: subjects were followed 5 days for efficacy endpoints and 15 days for safety endpoints
Participants	Inclusion criteria males and females ≥ 18 years of age with histologically or cytologically confirmed malignant disease naïve or non‐naïve to chemotherapy Karnofsky index ≥ 50% scheduled to receive a single dose of highly emetogenic chemotherapy (i.e. cisplatin ≥ 60 mg/m², cyclophosphamide > 1500 mg/m², carmustine (BCNU) > 250 mg/m², dacarbazine (DTIC), or mechlorethamine) on Day 1 known hepatic, renal, or cardiovascular dysfunction, or had experienced (at maximum) mild nausea following any previous chemotherapy, allowed per investigator discretion Exclusion criteria had received, or were scheduled to receive, any drug with potential antiemetic efficacy within 24 h of study initiation and throughout Day 5 any vomiting, retching, or National Cancer Institute Common Toxicity Criteria grade 2 or 3 nausea in the 24 h preceding chemotherapy ongoing vomiting from any organic aetiology, or with history of moderate to severe nausea or vomiting following any previous chemotherapy active seizure disorder requiring anticonvulsant medication, scheduled to receive any other chemotherapeutic agent with an emetogenicity level ≥ 4 or radiotherapy of the upper abdomen or cranium on Day 2 through Day 6, or with known contraindication to 5‐HT₃ receptor antagonists Mean age ± SD (range), years: 53.4 ± 13.7 (palonosetron 0.25 mg), 50.6 ± 14.1 (palonosetron 0.75 mg), 50.9 ± 14.2 (ondansetron 32 mg) Gender: male + female Tumour/cancer type: malignant tumour (ovarian cancer, lung cancer, Hodgkin lymphoma, gastric cancer, breast cancer) Chemotherapy regimen: cisplatin, cyclophosphamide, dacarbazine Country/continent: North America, Europe (76 centres)
Interventions	Experimental: arm A: palonosetron 0.25 mg palonosetron 0.25 mg i.v. + dexamethasone 20 mg i.v. Experimental: arm B: palonosetron 0.75 mg palonosetron 0.75 mg i.v. + dexamethasone 20 mg i.v. Experimental: arm C: ondansetron 32 mg ondansetron 32 mg i.v. + dexamethasone 20 mg i.v.
Outcomes	Primary endpoint proportion of participants with complete response (CR; defined as no emetic episodes and no use of rescue medication) during the acute phase (0 to 24 h post chemotherapy) Secondary endpoint(s) CR rates for delayed (24 to 120 h post chemotherapy) and overall (0 to 120 h post chemotherapy) phases complete control rates (CCs; defined as no emetic episodes, no use of rescue medication, and no more than mild nausea) number of emetic episodes time to first emetic episode (hours) time to first administration of rescue medication (hours) time to treatment failure (i.e. time to first emetic episode or time to administration of rescue therapy, whichever occurred first) severity of nausea, using a categorical scale of none, mild, moderate, or severe
Notes	supported by Helsinn Healthcare SA, Lugano, Switzerland study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind, double‐dummy ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind, double‐dummy ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both participants and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both participants and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "the intent‐to‐treat (ITT) cohort included all randomized patients who received chemotherapy and study drug (n = 667)"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "the safety cohort (safety analysis) included all patients who received study drug and had at least one safety assessment after treatment (n = 673)"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Abdel‐Malek 2017.

Study characteristics
Methods	Randomised, cross‐over, placebo‐controlled trial with 2 arms comparison of aprepitant 125/80 + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Study period: January 2015 to June 2015 15 patients randomised 12 participants evaluated Masking: single‐blind Baseline patient characteristics: n.r. Follow‐up: yes, time period not mentioned
Participants	Inclusion criteria ≥ 18 years old with diagnosis of relapsed/refractory NHL and receiving ESHAP chemotherapy regimen Exclusion criteria: n.r. Median age (range), years: 45 (38 to 56) Gender: 8 males + 7 females Tumour/cancer type: non‐Hodgkin lymphoma (NHL) Chemotherapy regimen: ESHAP chemotherapy regimen (etoposide 40 mg/m²/d as a 1‐h i.v. infusion from Day 1 to Day 4; cisplatin 25 mg/m²/d as a continuous infusion from Day 1 to Day 4; solumedrol 500 mg/d as a 15‐min i.v. infusion from Day 1 to Day 5; cytarabine 2 g/m² given as a 2‐h i.v. infusion on Day 5) Country: Egypt (single centre)
Interventions	Cross‐over trial Experimental: arm A: aprepitant 125/80 mg, then placebo Day 1: aprepitant 125 mg + ondansetron 8 mg + dexamethasone 8 mg Days 2 to 3: aprepitant 80 mg + ondansetron 8 mg + dexamethasone 8 mg Days 4 to 5: ondansetron 8 mg + dexamethasone 8 mg with cross‐over to the opposite treatment in the third and fourth cycles Experimental: arm B: placebo. then aprepitant 125/80 mg Days 1 to 3: placebo + ondansetron 8 mg + dexamethasone 8 mg Days 4 to 5: ondansetron 8 mg + dexamethasone 8 mg with cross‐over to the opposite treatment in the third and fourth cycles
Outcomes	Primary endpoint complete response for both acute (Days 1 to 5) and delayed (Days 6 to 8) CINV Secondary endpoint participant‐stated preference after the fourth cycle
Notes	no information regarding funding has been reported rescue therapy was determined based on investigator’s choice "conflicts of interest: none"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "treatment group assignments were made by block randomization"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... single‐blinded ..." and "... prospective placebo‐controlled cross‐over study ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Comment: personnel were not blinded
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: personnel were not blinded towards the intervention, which might influence subjective outcome assessments
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "twelve of the 15 patients who entered the study were fully evaluable and completed 4 cycles of ESHAP chemotherapy regimen"
Selective reporting (reporting bias)	Low risk	Comment: outcome measures were described in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Aksu 2013.

Study characteristics
Methods	Randomised, cross‐sectional trial with 2 arms comparison of aprepitant + ondansetron + dexamethasone vs ondansetron + dexamethasone (control) Recruitment period: n.r. 60 participants evaluated Masking: n.r. Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria: n.r. Exclusion criteria: n.r. Median age (range), years: 58 (38 to 72) Gender: male (n = 56, 93%) + female (n = 4, 7%) Tumour/cancer type: non‐small cell lung cancer Chemotherapy regimen: cisplatin (75 mg/m², Day 1) and docetaxel (75 mg/m², Day 1) Country: Turkey
Interventions	Experimental: arm A: aprepitant 125/80 aprepitant (125 mg on Day 1, 80 mg on Days 2 and 3) + p.o. ondansetron 4 mg (4 days, beginning on Day 1 of chemotherapy) + dexamethasone (8 mg on Day 1, 4 mg on Days 2 and 3) Control: arm B p.o. ondansetron 4 mg (4 days, beginning on Day 1 of chemotherapy) + dexamethasone (8 mg on Day 1, 4 mg on Days 2 and 3)
Outcomes	complete response
Notes	no information regarding registration of clinical trial has been reported in the article "no financial disclosure was declared by the authors" conflict of Interest: "no conflict of interest was declared by the authors" the efficacy of both regimens was evaluated by a modified Turkish version of the FLIE scale consisting of 18 questions
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "... patients were prospectively randomized ..." Comment: method of randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not described
Blinding of participants and personnel (performance bias) Blinding of participants	Unclear risk	Comment: blinding not reported
Blinding of participants and personnel (performance bias) Blinding of personnel	Unclear risk	Comment: blinding not reported
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: blinding not reported
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: not reported
Selective reporting (reporting bias)	Low risk	Comment: outcome measure was reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Albany 2012.

Study characteristics
Methods	Randomised, placebo‐ controlled, cross‐over, phase 3 trial with 2 arms comparison of aprepitant 125/80 + 5‐HT₃ RA (except for palonosetron) + dexamethasone vs placebo + dexamethasone (20 mg once per day on Days 1 and 2) + 5‐HT₃ RA (except for palonosetron) Study period: December 2007 to February 2011 71 patients screened 2 patients ineligible 69 patients randomised to aprepitant‐first (35, 51%) and placebo‐first (34, 49%) groups Masking: double‐blind (participants, care provider) Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria ≥ 15 years old with germ cell tumour receiving standard 2 identical courses of 5‐day cisplatin‐based chemotherapy prior chemotherapy allowed no nausea/vomiting for 24 h before study entry no use of antiemetic 72 h before study entry absolute neutrophil count ≥ 1500 cells/µL, WBC count ≥ 3000 cells/µL, platelet count ≥ 100,000 cells/µL, AST and ALT ≤ 3 × ULN, bilirubin ≤ 1.5 × ULN, and creatinine < 2 mg/dL Exclusion criteria no known history of anticipatory nausea or vomiting no use of another antiemetic agent within 72 h before beginning chemotherapy no known central nervous system (CNS) metastasis no known hypersensitivity to any component of study regimen no concurrent participation in a clinical trial that involves another investigational agent no use of warfarin while on study no use of agents expected to induce metabolism of aprepitant, including rifampin, rifabutin, phenytoin, carbamazepine, and barbiturates no use of agents that may impair metabolism of aprepitant, including cisapride, macrolide antibiotics (erythromycin, clarithromycin, azithromycin), azole antifungal agents (ketoconazole, itraconazole, voriconazole, fluconazole), amifostine, nelfinavir, and ritonavir Mean age (range), years: 33 years (16 to 62 years) Gender: male Tumour/cancer type: germ cell tumour Chemotherapy regimen: 2 identical courses of standard 5‐day cisplatin‐based chemotherapy regimen Country: United States (multi‐centre, 6)
Interventions	Cross‐over study Experimental: arm A: aprepitant 125/80, then placebo Days 1 to 2: dexamethasone 20 mg + 5‐HT₃ RA Day 3: aprepitant 125 mg + 5‐HT₃ RA Days 4 to 5: aprepitant 80 mg + 5‐HT₃ RA Days 6 to 7: aprepitant 80 mg + dexamethasone 4 mg twice per day, then received matched placebo PO daily on Days 3 through 7 during study Cycle 2 Experimental: arm B: placebo, then aprepitant 125/80 Days 1 to 2: dexamethasone 20 mg + 5‐HT₃ RA Day 3: placebo + 5‐HT₃ RA Days 4 to 5: placebo + 5‐HT₃ RA Days 6 to 7: placebo + dexamethasone 8 mg twice per day
Outcomes	Primary outcome complete response [Time frame: both acute (Days 1 through 5) and delayed (Days 6 through 8)] Secondary outcome(s) emetic episodes (both acute and delayed) use of rescue medication (acute and delayed) nausea measurement based on visual analogue scale (VAS) patient‐stated preference after second cycle
Notes	study was registered with ClinicalTrials.gov in the United States as NCT00572572 palonosetron was excluded as a 5‐HT₃ RA because of its prolonged half‐life compared with other 5‐HT₃ RAs sponsor and collaborators: Hoosier Cancer Research Network; Merck Sharp & Dohme Corp. "the author(s) indicated no potential conflicts of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not reported
Allocation concealment (selection bias)	Low risk	Quote: "treatment group assignments were made by personnel not otherwise involved with the study to ensure in‐house blinding"
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Comment: NCT00572572 reported that both participants and care providers were blinded
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Comment: NCT00572572 reported that both participants and care providers were blinded
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "sixty of the 69 patients who entered the study were fully evaluable and completed at least 5 days of both cycles"
Selective reporting (reporting bias)	Low risk	Comment: all of the outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Ando 2016.

Study characteristics
Methods	Randomised, controlled study with 2 arms comparison of aprepitant + palonosetron or granisetron or azasetron + dexamethasone vs fosaprepitant meglumine + palonosetron or granisetron or azasetron + dexamethasone Recruitment period: January 2013 to March 2014 101 patients enrolled 93 patients randomised Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria Japanese patients who started to receive chemotherapy including cisplatin (CDDP) (≥ 60 mg/m²) Exclusion criteria nausea or vomiting within 24 h before start of administration of antineoplastic drugs could not receive a drug orally could not answer the questionnaire did not provide consent considered unsuitable for this study Mean age ± SD, years: 61.7 ± 11.7 in aprepitant group, 65.4 ± 10.0 in fosaprepitant group Gender: male (74) + female (19) Tumour/cancer type: malignant tumour (lung cancer, gastric cancer, oesophageal cancer, head and neck cancer) Chemotherapy regimen: CDDP (60 mg/m² or higher) Country: Japan (single centre)
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg + palonosetron 0.75 mg or granisetron 3 mg or azasetron 10 mg + dexamethasone 6.6 to 9.9 mg Days 2 to 4: aprepitant 80 mg + dexamethasone 3.3 to 6.6 mg Day 5: aprepitant 80 mg Experimental: arm B: fosaprepitant Day 1: fosaprepitant meglumine 150 mg + palonosetron 0.75 mg or granisetron 3 mg or azasetron 10 mg + dexamethasone 6.6 to 9.9 mg Days 2 to 4: dexamethasone 3.3 to 6.6 mg
Outcomes	Primary endpoint complete response rate Secondary endpoint(s) complete control rate
Notes	no funding for this work was received study authors declare that they have no conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Comment: no allocation concealment reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... open‐label ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... open‐label ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all randomised patients were included in the analysis
Selective reporting (reporting bias)	Unclear risk	Comment: in the results section, palonosetron, granisetron, and azasetron were not separately reported
Other bias	Low risk	Comment: no information to suggest other sources of bias

Arce‐Salinas 2019.

Study characteristics
Methods	Randomised, open‐label trial efficacy and quality of life analysis of palonosetron vs ondansetron for high and moderate emetogenic chemotherapy for breast cancer arm A received palonosetron, dexamethasone, and fosaprepitant, and arm B, ondansetron, dexamethasone, and fosaprepitant in comparison Study period: n.r. 262 patients were included Masking: open‐label Median follow‐up: n.r. ITT analysis: n.r.
Participants	Inclusion criteria breast cancer patient candidates (AC, TC, TCH regimens) Exclusion criteria had previously received any chemotherapy or radiotherapy Mean age (range), years: n.r.  Gender:  female Tumour/cancer type: breast cancer Chemotherapy regimen: AC, TC, TCH regimens Country: United States (Texas)
Interventions	Experimental: arm A: palonosetron, dexamethasone, and fosaprepitant Experimental: arm B: ondansetron, dexamethasone, fosaprepitant
Outcomes	Primary outcome measures Presence of CINV Emergency room visits due to CINV Secondary outcome measures Quality of life (EORTC QLQ 30 and EORTC B‐23)
Notes	Publication type: conference abstract Approved by local ethics committee
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Comment: open‐label
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Comment: open‐label
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: outcome assessors (participants) not blinded to intervention
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: outcome robust to blinding
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: conference abstract, not fully evaluable
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Unclear risk	Comment: conference abstract, not fully evaluable
Selective reporting (reporting bias)	Unclear risk	Comment: conference abstract, not fully evaluable
Other bias	Unclear risk	Comment: conference abstract, not fully evaluable

Aridome 2016.

Study characteristics
Methods	Randomised, parallel, comparative, phase 2 study with 2 arms comparison of aprepitant + 5‐HT₃ RA + reduced‐dose dexamethasone vs 5‐HT₃ RA + dexamethasone Study period: September 2011 to August 2013 117 patients randomised Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria advanced or recurrent colorectal cancer (CRC) Exclusion criteria: n.r. Mean years ± SD: 66.46 ± 9.81 in aprepitant group, 63.48 ± 10.23 in control group Gender: male (64) + female (49) Tumour/cancer type: colorectal cancer Chemotherapy regimen: oxaliplatin‐based or irinotecan‐based MEC (FOLFOX, XELOX, or FOLFIRI) Country: Japan (18 institutions, multi‐centre)
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg p.o. + 5‐HT₃ RAs + dexamethasone 6.6 mg i.v. Days 2 to 3: aprepitant 80 mg p.o. + dexamethasone 4 mg p.o. Control: arm B Day 1: 5‐HT₃ RAs + dexamethasone 9.9 mg i.v. Days 2 to 3: dexamethasone 8 mg p.o.
Outcomes	Primary endpoint proportions of patients who achieved complete response during the overall phase (0 to 120 h post chemotherapy), the acute phase (0 to 24 h post chemotherapy), and the delayed phase (24 to 120 h post chemotherapy) of the first planned chemotherapy cycle Secondary endpoint(s) complete protection proportions of patients without emetic episodes or nausea patients with no more than moderate nausea during overall, acute, and delayed phases time to treatment failure
Notes	no information regarding financing of the study and registration of the trial reported no information on conflicts of interest reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... randomly assigned to the aprepitant (5‑HT3 RA + reduced‑dose dexamethasone + aprepitant) or standard (5‑HT3 + dexamethasone) regimen group according to a computer‑generated, blinded allocation schedule"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... open‐label ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... open‐label ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis.
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: although this was an open‐label study, we assume that knowledge of both patient and personnel had no influence on objective outcomes (e.g. neutropenia)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "... in total, 113 patients were included in the full analysis set"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: all of the included patients were evaluated for objective outcomes
Selective reporting (reporting bias)	Low risk	Comment: all outcomes have been reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Arpornwirat 2009.

Study characteristics
Methods	Randomised, placebo‐controlled, dose‐ranging, phase 2 trial with 6 arms comparison of placebo + ondansetron + dexamethasone vs casopitant 50 mg + ondansetron + dexamethasone vs casopitant 100 mg + ondansetron + dexamethasone vs casopitant 150 mg + ondansetron + dexamethasone vs casopitant 150 mg + ondansetron + dexamethasone vs casopitant 150 mg + ondansetron 16 mg + dexamethasone Enrolment period: n.r. 723 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria chemotherapy‐naïve patients aged > 18 years with a malignant solid tumour who were scheduled to receive their first course of MEC eligible regimens included at least 1 of the following agents: cyclophosphamide from 500 mg/m² to 1500 mg/m² if given with other MEC, or from 750 mg/m² to 1500 mg/m² if given alone or with agents that had minimal or low emetogenic potential; oxaliplatin ≥ 85 mg/m², doxorubicin ≥ 60 mg/m², epirubicin ≥ 90 mg/m², irinotecan (dosed as part of an irinotecan, leucovorin, 5‐fluorouracil (FOLFIRI) regimen), or carboplatin at an area under the curve (AUC) ≥ 5 Karnofsky performance status score ≥ 70 adequate haematological and metabolic status, which we defined as white blood cells > 3000/mm³, absolute neutrophils > 1500/mm³, platelets > 100,000/mm³, and serum creatinine < 1.5 mg/dL adequate liver function, as demonstrated by laboratory values for aspartate aminotransferase and/or alanine aminotransferase ≤ 2.5 × ULN in patients without known liver metastases or ≤ 5 × ULN in patients with liver metastases all patients of child‐bearing potential were required to use birth control Exclusion criteria previously received cytotoxic chemotherapy or an NK₁ receptor antagonist scheduled to receive (1) highly emetogenic chemotherapy, (2) adjuvant cyclophosphamide‐based chemotherapy, (3) bone marrow transplantation and/or stem cell rescue with current chemotherapy course, or (4) any medication of moderate or high emetogenic risk within 48 h of receiving study medication abdominal or pelvic radiation not allowed from 7 days before to 6 days after initiation of study medication known central nervous system metastases ‐ ineligible unless treated successfully with excision or radiation and for at least 1 week before first dose of study medication receiving other antiemetics or experienced emesis or clinically significant nausea (SN) within 24 h before initiation of study medication, or with another aetiology for emesis and nausea (e.g. gastrointestinal obstruction, increased intracranial pressure, hypercalcaemia, active peptic ulcer) systemic corticosteroid therapy other than for taxane pre‐medication not to be initiated within 72 h before first dose of study medication had taken strong or moderate inhibitors of cytochrome P450 3A4 (CYP3A4) and CYP3A5 within 2 to 14 days of first dose of study medication or inducers of CYP3A4 within 14 days of first dose of study medication use of other investigational drugs within 30 days before study drug initiation or during the study not allowed Mean age (range), years: 57 (22 to 83) in arm A, 58.5 (33 to 88) in arm B, 57.4 (20 to 85) in arm C, 59.2 (26 to 82) in arm D, 57.9 (22 to 84) in arm E, 57.9 (28 to 88) in arm F Gender: male (287) + female (436) Tumour/cancer type: solid malignancy (breast, NSCLC, colon or rectum, ovary, other) Chemotherapy regimen: cyclophosphamide from 500 mg/m² to 1500 mg/m² if given with other MEC, or from 750 mg/m² to 1500 mg/m² if given alone or with agents that had minimal or low emetogenic potential; oxaliplatin ≥ 85 mg/m², doxorubicin ≥ 60 mg/m², epirubicin ≥ 90 mg/m², irinotecan (dosed as part of an irinotecan, leucovorin, 5‐fluorouracil (FOLFIRI) regimen), or carboplatin at an area under the curve (AUC) ≥ 5 Country: 99 centres in 24 countries
Interventions	Control: arm A Day 1: 30 min before MEC (casopitant placebo + ondansetron 8 mg p.o. + dexamethasone 8 mg i.v.), 8 h later (ondansetron 8 mg p.o.) Days 2 to 3: casopitant placebo + ondansetron 8 mg p.o. b.i.d. Primary treatment: arm B Day 1: 30 min before MEC (casopitant 50 mg + ondansetron 8 mg p.o. + dexamethasone 8 mg i.v.), 8 h later (ondansetron 8 mg p.o.) Days 2 to 3: casopitant 50 mg + ondansetron 8 mg p.o. b.i.d. Primary treatment: arm C Day 1: 30 min before MEC (casopitant 100 mg + ondansetron 8 mg p.o. + dexamethasone 8 mg i.v.), 8 h later (ondansetron 8 mg p.o.) Days 2 to 3: casopitant 100 mg + ondansetron 8 mg p.o. b.i.d. Primary treatment: arm D Day 1: 30 min before MEC (casopitant 150 mg + ondansetron 8 mg p.o. + dexamethasone 8 mg i.v.), 8 h later (ondansetron 8 mg p.o.) Days 2 to 3: casopitant 150 mg + ondansetron 8 mg p.o. b.i.d. Exploratory: arm E Day 1: 30 min before MEC (casopitant 150 mg + ondansetron 8 mg p.o. + dexamethasone 8 mg i.v.), 8 h later (ondansetron 8 mg p.o.) Days 2 to 3: casopitant placebo + ondansetron 8 mg p.o. b.i.d. Exploratory: arm F Day 1: 30 min before MEC (casopitant 150 mg + ondansetron 16 mg p.o. + dexamethasone 8 mg i.v.), 8 h later (ondansetron placebo) Days 2 to 3: casopitant 150 mg + ondansetron 16 mg q.a.m., ondansetron placebo q.p.m.
Outcomes	Primary endpoint(s) proportion of patients achieving complete response (CR) during 120‐h evaluation period after first cycle of MEC proportion with significant nausea (SN), which was defined as maximum nausea score ≥ 25 mm on VAS, during the same period Secondary endpoint(s) CR rates during acute phase (0 to 24 h) and delayed phase (24 to 120 h) SN rates during acute phase (0 to 24 h) and delayed phase (24 to 120 h) complete protection (CP) rates total control vomiting rescue medication use
Notes	financial support was provided by GlaxoSmithKline Dr. Grunberg has acted as a consultant and has provided expert testimony for GlaxoSmithKline Dr. Levin is a full‐time employee of GlaxoSmithKline Clinicaltrials.gov: NCT00104403
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were randomized to 1 of 6 treatment groups (Table 5) by a centralized, automated randomization system and were stratified by sex and chemotherapy treatment (taxane‐based or non taxane‐based)"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. neutropenia)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: 723 patients have been included in the efficacy analysis and primary outcomes have been assessed in the intent‐to‐treat (ITT) population
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "the safety population consisted of the 711 patients who received at least 1 dose of study medication in any treatment cycle"
Selective reporting (reporting bias)	Low risk	Comment: all outcomes have been reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Badar 2015.

Study characteristics
Methods	Randomised, comparative, phase 2 study with 2 arms comparison of aprepitant + ondansetron + dexamethasone vs ondansetron + dexamethasone Enrolment period: n.r. 98 patients enrolled Masking: open‐label Baseline patient characteristics: reported Follow‐up: patients were followed for a total of 6 days, starting from first day of chemotherapy
Participants	Inclusion criteria adult patients (≥ 18 years old) with AML; high risk of MDS or chronic myeloid leukemia (CML); receiving cytarabine‐based chemotherapy at a dose ≥ 1 g/m²/d for at least 3 days Exclusion criteria emesis or grade 2 or 3 nausea within 24 h before the start of chemotherapy ongoing emesis due to any organic aetiology known hypersensitivity to study drug or to 5‐HT₃ receptor antagonists receiving pimozide, terfenadine, astemizole, or cisapride due to possible drug‐drug interactions Median age (range), years: 49 (21 to 70) in ondansetron + aprepitant arm, 53 (30 to 68) in ondansetron arm Gender: male (55) + female (43) Tumour/cancer type: AML, MDS, CML Chemotherapy regimen: cytarabine‐based chemotherapy at a dose ≥1g/m²/d for at least 3 days  Country: n.r.
Interventions	Experimental: arm A: aprepitant + ondansetron aprepitant (APREP) 125 mg p.o. plus ondansetron 8 mg i.v. 30 min before cytarabine followed by ondansetron 24 mg i.v. continuous infusion daily until 6 to 12 hours and aprepitant 80 mg p.o. daily until 1 day after the end of last chemotherapy Experimental: arm B: ondansetron Ondansetron (OND) 8 mg i.v. 30 min before cytarabine followed by ondansetron 24 mg i.v. continuous infusion daily until 6 to 12 h after the end of last chemotherapy infusion
Outcomes	Primary endpoint prevention of emesis and avoidance of rescue medication during administration of chemotherapy
Notes	study authors declare there is no conflict of interest regarding publication of this paper Dr. Jorge Cortes received research support from Merck, and Dr. Guillermo Garcia‐Manero received honorarium from Merck
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... open‐label ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... open‐label ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: although patients and personnel were not blinded, we assume no risk of bias for objective outcomes
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "ninety‐eight patients were registered in the study, 49 to each arm. Among them 83 were evaluable for efficacy, 42 in the OND arm and 41 in the OND + APREP arm"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: all patients who had received a single dose of study drug were included for safety analysis (N = 87)
Selective reporting (reporting bias)	Low risk	Comment: all outcomes were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Brohee 1995.

Study characteristics
Methods	Randomised trial with 2 arms comparison of ondansetron + dexamethasone vs granisetron + dexamethasone Enrolment period: n.r. 12 patients randomised Masking: single‐blind (patients) Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria: n.r. Exclusion criteria: n.r. Mean/median age, years: n.r. Gender: male (3) + female (9) Tumour/cancer type: n.r. Chemotherapy regimen: combination therapy with Cy > 600 mg or IFO > 1 g/m² Country: Belgium
Interventions	Experimental: arm A: ondansetron 8 mg ondansetron + 10 mg dexamethasone Experimental: arm B: granisetron 3 mg granisetron + 10 mg dexamethasone
Outcomes	complete response partial response (light nausea) failure (vomiting)
Notes	conference abstract
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "treatment allocation was randomized in blocks of four" Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "the patients were kept blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Unclear risk	Comment: blinding of personnel not reported
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: even though patients were blinded, it is unclear whether personnel were blinded, which could have an impact on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: 12 patients (9 F) enrolled for 53 treatments were included in this study
Selective reporting (reporting bias)	Unclear risk	Comment: conference abstract, not evaluable
Other bias	Unclear risk	Comment: conference abstract, not evaluable

Bubalo 2005.

Study characteristics
Methods	Randomised, parallel‐group, controlled trial with 2 arms comparison of aprepitant 125/80 mg + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Study period: May 2004 to January 2009 40 patients enrolled and randomised Masking: quadruple‐blind (participant, care provider, investigator, outcomes assessor) Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria 18 years of age or older scheduled for an autologous or allogeneic bone marrow or peripheral stem cell transplant Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 must have signed informed consent must be able to swallow tablets and capsules must be receiving a cyclophosphamide‐containing regimen Exclusion criteria known sensitivity to aprepitant, ondansetron, or dexamethasone has received another investigational drug in the past 30 days has had emesis or requires antiemetic agents in the 48 h before beginning conditioning therapy has taken neurokinin₁ antagonists for 14 days before enrolment pregnant, positive serum human chorionic gonadotropin (hCg), or lactating serum creatinine level ≥ 2 × ULN severe hepatic insufficiency (Child‐Pugh score > 9) has been drinking > 5 drinks/d over the last year concurrent illness requiring systemic corticosteroid use other than planned dexamethasone during conditioning therapy Mean age (range), years: 46 ± 12.9 in aprepitant group, 46 ± 13 in placebo group Gender: male (28) + female (12) Tumour/cancer type: n.r. Chemotherapy regimen: cyclophosphamide‐containing regimen before transplant Country: United States (single centre)
Interventions	Experimental: arm A: aprepitant aprepitant: loading dose of 125‐mg capsule once a day for 1 day, then maintenance dose of 80‐mg capsule daily through Day +4 of bone marrow transplant dexamethasone: for cyclophosphamide total body irradiation (CyTBI) patients: dexamethasone study drug 1 capsule p.o. daily, 1 h before chemotherapy, with aprepitant on total body irradiation (TBI) and cyclophosphamide chemotherapy days; for busulfan cyclophosphamide (BuCy) patients: dexamethasone 1 capsule orally once daily, discontinued after last dose of chemotherapy ondansetron: for CyTBI patients: ondansetron 8 mg orally every 12 h, beginning 1 h before first TBI dose and discontinued after last dose; then ondansetron 8 mg i.v. every 12 h × 4 doses, beginning 30 min before first cyclophosphamide chemotherapy; for BuCy patients: ondansetron 8 mg p.o. every 6 h, beginning 1 h before first busulfan dose and discontinued after last busulfan dose is given; then ondansetron 8 mg i.v. every 12 h × 4 doses, beginning 30 min before first cyclophosphamide chemotherapy Experimental: arm B: placebo placebo comparator: sugar pill: loading dose of 125‐mg capsule once a day for 1 day, then maintenance dose of 80‐mg capsule daily through Day +4 of bone marrow transplant dexamethasone and ondansetron: same doses and routine as arm A
Outcomes	Primary outcome measures number of emesis‐free participants during the study period [Time frame: up to 3 weeks] Secondary outcome measures safety in transplant population [Time frame: up to 3 weeks] effects on nausea, appetite, and taste changes [Time frame: up to 3 weeks] pharmacokinetic interaction [Time frame: up to 3 weeks]
Notes	sponsors and collaborators: OHSU Knight Cancer Institute clinicalTrials.gov Identifier: NCT00248547 results from study registry
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Comment: NCT00248547 reported that masking was quadruple (participant, care provider, investigator, outcomes assessor)
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Comment: NCT00248547 reported that masking was quadruple (participant, care provider, investigator, outcomes assessor)
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all randomised patients were assessed for the primary outcome
Selective reporting (reporting bias)	High risk	Comment: primary outcome reported; "effects on nausea, appetite and taste changes" and "pharmacokinetic interaction" are missing
Other bias	Low risk	Comment: no information to suggest other sources of bias

Bubalo 2018.

Study characteristics
Methods	Randomised, prospective, placebo‐controlled, parallel, pilot study with 2 arms comparison of aprepitant 125/80 mg + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Recruitment period: n.r. 40 patients enrolled and randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria 18 years of age or older scheduled for an autologous or allogeneic bone marrow or peripheral blood stem cell transplant Eastern Cooperative Oncology Group performance status ≤ 2 able to swallow tablets and capsules received myeloablative CY/TBI or targeted busulfan (TBu)/CY as the conditioning regimen Exclusion criteria sensitivity to aprepitant, ondansetron, or dexamethasone received another investigational drug within the past 30 days had emesis or required antiemetic agents in the 48 h before beginning conditioning therapy had taken an NK₁ antagonist in the 14 days before enrolment pregnant, positive serum hCG, or lactating serum creatinine level ≥ 2 × ULN severe hepatic insufficiency (Child‐Pugh score > 9) drank > 5 alcoholic drinks/d over the last year concurrent illness requiring systemic corticosteroid use other than planned dexamethasone during conditioning therapy Mean age (range), years: 46 (19 to 60) in aprepitant group, 46 (19 to 63) in placebo group Gender: male (28) + female (12) Tumour/cancer type: acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, non‐Hodgkin lymphoma, myelodysplastic syndrome, myelofibrosis, Waldenstrom’s macroglobulinemia Chemotherapy regimen: very high doses of cyclophosphamide Country: United States (single centre)
Interventions	Experimental: arm A: aprepitant aprepitant 125 mg on Day 1 and 80 mg through Day +4 + ondansetron given per institutional guidelines on each day of chemotherapy or radiation as described in appendix A + dexamethasone 12 mg p.o. for 1 dose given on Day 1, and 8 mg p.o. once daily given on subsequent days Experimental: arm B: placebo placebo + ondansetron + dexamethasone
Outcomes	Primay objective to determine if there was a difference in the number of emesis‐free days among patients who received aprepitant as compared to those who received placebo from the first day of conditioning to Day +4 Secondary objectives to assess the safety of aprepitant in the HSCT population, as well as to evaluate if there was a difference in the incidence of nausea, mucositis, appetite, and dysgeusia between the 2 study groups
Notes	"Joseph Bubalo is on the Merck and Co., Speakers Bureau and also received clinical trial support as a grant from Merck and Co." "this work is partly funded by Merck & Co., Inc."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "a randomization list was generated using a permuted block randomization with a random block size of either 2 or 4"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "the medications were administered on the same schedule to effectively blind the patients and healthcare staff"
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "the medications were administered on the same schedule to effectively blind the patients and healthcare staff"
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included in the efficacy analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: all patients were included in the safety analysis
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Campos 2001.

Study characteristics
Methods	Randomised, parallel‐group trial with 4 treatment arms comparison of granisetron pre‐cisplatin + placebo on Days 2 to 5 vs granisetron and aprepitant (MK‐869) pre‐cisplatin + aprepitant on Days 2 to 5 vs aprepitant the evening before and pre‐cisplatin + aprepitant on Days 2 to 5 vs aprepitant pre‐cisplatin + aprepitant on Days 2 to 5 Recruitment period: n.r. 354 patients received allocation number 351 received study medication; 3 did not receive study medication (1 withdrew consent, 1 vomited within 24 h before first dose of drug, 1 forgot to take the Day ‐1 medication and received no further medication) of the 351 patients who received study medication, 4 were excluded from both acute and delayed analyses because no data were collected Masking: double‐blind Baseline patient characteristics: reported Follow‐up: Days 6 to 8 for adverse events
Participants	Inclusion criteria ≥ 16 years old scheduled to receive first course of cisplatin‐based chemotherapy at a dose ≥ 70 mg/m² Exclusion criteria Karnofsky performance score < 60 allergy or intolerance to metoclopramide, dexamethasone, or granisetron use of another antiemetic agent within 72 h of study Day 1 (serotonin antagonists, phenothiazines, butyrophenones, cannabinoids, metoclopramide, corticosteroids, or lorazepam) episode of vomiting or retching within 24 h before the start of cisplatin infusion on study Day 1 treatment for or history of a seizure within the past 2 years severe concurrent illness other than neoplasia; gastrointestinal obstruction or active peptic ulcer radiation therapy to abdomen or pelvis within 1 week before or after study Day 1 one of the following laboratory measurements: haemoglobin < 8.5 g/dL, WBC < 3500/mL, platelets < 100,000/µL, AST ˃ 2 × ULN, ALT ˃ 2 × ULN, bilirubin ˃ 2 × ULN, alkaline phosphatase ˃ 2 × ULN, albumin < 3 g/dL, serum creatinine ˃ 2.0 mg/dL Mean age ± SD, years: 55 ± 16 (group I), 53 ± 14 (group II), 54 ± 14 (group III), 54 ± 13 (group IV) Gender (male:female): 58:42 (group I), 50:50 (group II), 61:39 (group III), 60:40 (group IV) Tumour/cancer type: solid malignancy (lung cancer, gastrointestinal cancer, head and neck cancer, genitourinary cancer, other) Chemotherapy regimen: cisplatin‐based chemotherapy at a dose ≥ 70 mg/m² Country: n.r. (multi‐centre)
Interventions	Experimental: treatment group I Day 1: placebo (evening pre‐cisplatin), granisetron (10 µg/kg) + dexamethasone (20 mg placebo) + placebo (treatment pre‐cisplatin) Days 2 to 5: placebo Experimental: treatment group II Day 1: placebo (evening pre‐cisplatin), granisetron (10 µg/kg) + dexamethasone (20 mg placebo) + MK‐869 (400 mg placebo) (treatment pre‐cisplatin) Days 2 to 5: MK‐869 (300 mg placebo) Experimental: treatment group III Day 1: MK‐869 (400 mg placebo) (evening pre‐cisplatin), placebo + dexamethasone (20 mg placebo) + MK‐869 (400 mg placebo) (treatment pre‐cisplatin) Days 2 to 5: MK‐869 (300 mg placebo) Experimental: treatment group IV Day 1: placebo (evening pre‐cisplatin), placebo + dexamethasone (20 mg placebo) + MK‐869 (400 mg placebo) (treatment pre‐cisplatin) Days 2 to 5: MK‐869 (300 mg placebo)
Outcomes	proportion of patients without emesis in the delayed phase (Days 2 to 5) patient self‐assessment of nausea
Notes	clinical trial registration number not reported "supported in part by funding from Merck & Co., Inc." study authors did not provide information on potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... computer‐generated, randomized allocation schedule ..."
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. hiccups, laboratory parameters)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "the statistical analysis approach for efficacy was intent‐to‐treat (all patients that had data after cisplatin administration were included). The incidence of emesis in the acute and delayed periods as well as the use of rescue medication in both periods was evaluated"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "all 350 patients who received study medication were included in the analysis of safety"
Selective reporting (reporting bias)	Low risk	Comment: all outcomes measures were described in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Chawla 2003.

Study characteristics
Methods	Randomised, placebo‐controlled trial with 3 arms comparison of aprepitant 375/250 + ondansetron + dexamethasone vs aprepitant 125/80 mg + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Recruitment period: n.r. 663 patients screened 583 enrolled in the study 381 patients enrolled and randomised after dose group adjustment 377 evaluated for primary efficacy Masking: double‐blind Baseline patient characteristics: reported Follow‐up: Days 19 to 29 post cisplatin for follow‐up examination and laboratory tests
Participants	Inclusion criteria ≥ 18 years of age with histologically confirmed solid tumour and Karnofsky score ≥ 60, and scheduled to receive a chemotherapy regimen that included cisplatin ≥ 70 mg/m² female patients of child‐bearing potential required to have a negative β‐human chorionic gonadotropin test result Exclusion criteria concomitant treatment with a non‐approved drug within 4 weeks of study entry significantly abnormal laboratory values (including white blood cell count < 3000/mm³, absolute neutrophil count < 1500/mm³, platelet count < 100,000/mm³, aspartate aminotransferase ˃ 2.5 × ULN; ALT ˃ 2.5 × ULN, bilirubin ˃ 1.5 × ULN, or creatinine ˃ 1.5 × ULN) known central nervous system malignancy active infection or uncontrolled disease that, in the opinion of the investigator, should exclude the patient for safety reasons planned regimen of multiple‐day, cisplatin‐based chemotherapy in a single cycle moderately or highly emetogenic chemotherapy on the days before and/or after cisplatin radiation therapy to abdomen or pelvis within 1 week before Day 1 of the study Mean age ± SD, years: 56.0 ± 13.0 (aprepitant 125/80), 58.4 ± 13.4 (aprepitant 40/25 mg), 53.7 ± 13.2 (placebo) Gender: male + female Tumour/cancer type: solid tumour of respiratory, urogenital, and other origin Chemotherapy regimen: cisplatin at a dose ≥ 70 mg/m² Country: 21 sites in the United States and 29 sites outside the United States (multi‐centre)
Interventions	Experimental: arm A: aprepitant 125/80 mg + standard therapy Day 1: aprepitant 125 mg + ondansetron 32 mg i.v. +  dexamethasone 20 mg p.o. Days 2 to 5: aprepitant 80 mg + dexamethasone 8 mg p.o. Experimental: arm B:aprepitant 40/25 mg + standard therapy Day 1: aprepitant 40 mg + ondansetron 32 mg i.v.+ dexamethasone 20 mg p.o. Days 2 to 5: aprepitant 25 mg + dexamethasone 8 mg p.o. Standard: arm C: placebo + standard therapy Day 1: placebo + ondansetron 32 mg i.v. + dexamethasone 20 mg p.o. Days 2 to 5: placebo + dexamethasone 8 mg p.o. ***Aprepitant 375/250 mg + standard therapy (this arm was replaced by arm B) Day 1: aprepitant 375 mg + ondansetron 32 mg i.v. + dexamethasone 20 mg p.o. Days 2 to 5: aprepitant 250 mg + dexamethasone 8 mg p.o.
Outcomes	Primary endpoint complete response (no emetic episodes and no rescue therapy on Days 1 to 5 (overall study period)) Secondary endpoint(s) proportions of patients who achieved a response to treatment in the following categories: no emesis no rescue therapy no nausea (maximum VAS 5 mm) no significant nausea (maximum VAS 25 mm) total control (no emetic episodes, no use of rescue therapy, maximum nausea VAS 5 mm) Exploratory endpoints time to first emesis total number of emetic episodes complete protection (no emetic episodes, no rescue, maximum nausea VAS 25 mm)
Notes	Dr. Chawla, Dr. Grunberg, Dr. Gralla, and Dr. Hesketh are consultants for Merck and Company, Inc. Ms. Elmer, Ms. Schmidt, Ms. Taylor, Dr. Carides, Dr. Evans, and Dr. Horgan are employees of and potentially hold stock in Merck and Company, Inc. "Merck Research Laboratories" no information regarding registration of the clinical trial is reported in the article ***Aprepitant 375/250‐mg dose regimen in the current study was discontinued and was replaced with an aprepitant 40/25‐mg dose regimen, and a new randomisation schedule was generated after the dose group adjustment
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... were assigned to 1 of 3 treatment groups according to a computer‐generated randomization schedule"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. hiccup, study mortality)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "... all analyses were performed using an intent‐to treat approach ..."
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "the safety analyses are based on data from all patients both before and after the dose‐group adjustment"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Cheirsilpa 2005.

Study characteristics
Methods	Randomised controlled trial with 2 arms comparison of ramosetron + dexamethasone vs granisetron + dexamethasone Enrolment period: February 2003 to August 2003 73 patients enrolled and randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria 20 to 80 years of age first course of CDDP chemotherapy ≥ 70 mg/m² with single‐ or multiple‐dose regimen (Days 1, 2, 3, 4, and 5) treatment with steroids in these patients allowed if such drugs were part of the chemotherapy regimen Exclusion criteria any disorders causing nausea brain tumour, brain metastasis, and epilepsy concomitant disease that may cause vomiting (e.g. active peptic ulcer, gastric outlet obstruction, intestinal obstruction) complications with severe disorder of the heart, kidney, and liver pregnant or possibly pregnant took drugs that may affect the gastrointestinal tract or central nervous system within 24 h before the start of the study (e.g. other antiemetics, psychotropic drugs) or had experienced vomiting in the previous 24 h Mean age ± SD, years: ramosetron group 54.53 ± 10.16, granisetron group 53.97 ± 10.50 Gender: male + female Tumour/cancer type: solid malignancy (head and neck, cervix, lung, ovary, stomach‐oesophagus, urinary bladder, testis, other) Chemotherapy regimen: cisplatin at dose ≥ 70 mg/m² Country: Thailand (single centre)
Interventions	Experimental: arm A: ramosetron i.v. ramosetron (0.3‐mg bolus) on Day 1, 30 min before receiving cisplatin oral preparation of ramosetron (0.1‐mg tablet) on Days 2 to 5, in the morning or 1 h before receiving cisplatin 20 mg dexamethasone before cisplatin administration Active control: arm B: granisetron i.v. granisetron (3‐mg infusion) on Day 1 30 min before receiving cisplatin oral preparation of granisetron (1‐mg tablet) on Days 2 to 5, in the morning or 1 h before receiving cisplatin 20 mg dexamethasone before cisplatin administration
Outcomes	Primary endpoint inhibition of acute and delayed nausea (measured on a 4‐grade scale every 6 h after administration of study drug) Secondary endpoints inhibition of acute and delayed vomiting (time points for vomiting were observed and recorded for 24 h after administration of study drug; frequency of vomiting was recorded every 6 h after administration) response rate of study drug (evaluated on a 4‐grade scale based on the condition of nausea and vomiting according to criteria for evaluation of response rate in the period 0 to 24 h after administration adverse events (nature, duration, severity, clinical course, and measures taken were recorded)
Notes	this study was supported by Yamanouchi (Thailand) no protocol registration identifier is provided study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not reported
Allocation concealment (selection bias)	Low risk	Quote: "... one nurse prepared for the study drug using identical syringes. The study drug was then sent to another nurse confirming that the study drug was stable and identical in appearance. Then a syringe containing the study drug was handed directly to the investigator. The study drug code was sealed and not opened until all evaluations had been finalized after the completion of treatment"
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included in the efficacy analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: adverse events were recorded for all participants
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Cho 1998.

Study characteristics
Methods	Randomised, cross‐over trial with 2 arms comparison of tropisetron + dexamethasone vs ondansetron + dexamethasone Recruitment period: March 1997 to December 1997 21 patients randomised Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria: n.r. Exclusion criteria symptoms of brain metastasis receiving concurrent chemotherapy and radiotherapy pregnant women, lactating women receiving central nervous system drugs or analgesic drugs heart, kidney, renal function abnormality nausea and vomiting due to reasons other than chemotherapy Median age (range), years: 52 (42 to 67) Gender: male + female Tumour/cancer type: solid tumours (stomach, lung, head and neck, ovary, metastasis of unknown origin) Chemotherapy regimen: cisplatin (≥ 50 mg/m²) Country: Korea
Interventions	Cross‐over study Experimental: arm A tropisetron + dexamethasone Experimental: arm B ondansetron + dexamethasone
Outcomes	Primary endpoint control of acute emesis
Notes	study is published in Korean language; therefore, only the abstract was considered
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: cannot be determined due to language barrier
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Comment: open‐label trial
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Comment: open‐label trial
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: cannot be determined due to language barrier
Selective reporting (reporting bias)	Unclear risk	Comment: cannot be judged due to language barrier
Other bias	Unclear risk	Comment: cannot be judged due to language barrier

Chua 2000.

Study characteristics
Methods	Randomised, cross‐over trial with 3 arms comparison of granisetron + dexamethasone vs tropisetron + dexamethasone vs ondansetron + dexamethasone Recruitment period: March 1996 to May 1998 94 patients recruited 89 patients included in analysis Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria age ≥ 18 years chemotherapy‐naïve patients who were to receive at least 3 cycles of high‐dose cisplatin (100 mg/m²) ECOG performance status 0 to 2 no significant cardiac, hepatic, or renal disease Exclusion criteria gastrointestinal obstruction, brain tumour, increase in intracranial pressure, or pre‐existing nausea or vomiting Median age (range), years: 48 (22 to 74) Gender: male (86.5%) + female (13.5 %) Tumour/cancer type: solid malignancy (nasopharynx, oral cavity, hypopharynx, larynx, ear) Chemotherapy regimen: cisplatin at a dose of 100 mg/m² on Day 1 and 5‐fluorouracil (5‐FU) 1000 mg/m² on Days 1 to 3, repeated every 21 days Country: Hong Kong, China
Interventions	Cross‐over study: patients were randomised to receive 1 of the 3 5‐HT₃ antagonists in the first cycle; treatment was crossed over to the other 2 5‐HT₃ antagonists in the second and third cycles Experimental: arm A: granisetron granisetron 3 mg i.v. + dexamethasone 20 mg i.v. Experimental: arm B: tropisetron tropisetron 5 mg i.v. + dexamethasone 20 mg i.v. Experimental: arm C: ondansetron ondansetron 8 mg i.v. + dexamethasone 20 mg i.v. before cisplatin, followed by 2 p.o. doses of 8 mg at 4 and 8 hours after the start of chemotherapy on Day 1
Outcomes	Primary endpoint proportion of patients with complete (no nausea or vomiting, or mild nausea only in the 24 h after the start of chemotherapy) or major (single vomiting episode in the 24 h after the start of chemotherapy, or no vomiting but moderate to severe nausea) response
Notes	"supported by grants from the University of Hong Kong (CRCG grant no. 337/037/0001, 335/037/0001, and 335/037/0002)" study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomization was performed using a computer‐generated code"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... open‐label ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... open‐label ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included in the antiemetic efficacy analysis
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Egerer 2010.

Study characteristics
Methods	Randomised, controlled, parallel‐group, placebo‐controlled trial with 2 arms comparison of aprepitant + granisetron + dexamethasone vs placebo + granisetron + dexamethasone Recruitment period: n.r. 89 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria men and women ≥ 18 years of age patients with multiple myeloma receiving high‐dose chemotherapy (melphalan) and autologous peripheral stem cell transplantation signed informed consent Exclusion criteria nausea and vomiting during the last 12 hours before planned high‐dose chemotherapy receiving antiemetics 24 hours before planned high‐dose chemotherapy intake of steroids history of hypersensitivity to the investigational product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational product simultaneous intake of pimozide, terfenadine, astemizole pregnant or nursing woman mental condition rendering the patient incapable to understand the nature, scope, and possible consequences of the study non‐compliance in completing the patient diary and FLIE score Mean age (range), years: 62.1 (39 to 71) in placebo group, 57.4 (40 to 69) in aprepitant group Gender: male (19) + female (11) Tumour/cancer type: multiple myeloma Chemotherapy regimen: melphalan Country: Germany (single centre)
Interventions	Experimental: arm a: aprepitant aprepitant (125 mg) (1 h infusion of 100 mg m‐2) + granisetron (Kevatril) 2 mg once daily on Days 1 to 4 + dexamethasone 8 mg once daily on Day 1 and 4 mg once daily on Days 2 and 3 Experimental: arm B: placebo matched placebo + granisetron (Kevatril) 2 mg once daily on Days 1 to 4 + dexamethasone 8 mg once daily on Day 1 and 4 mg once daily on Days 2 and 3
Outcomes	Primary endpoint overall complete response (no emesis and no rescue therapy) during and post chemotherapy (0 to 120 h) Secondary objectives effects on emesis in acute and delayed phases during and post chemotherapy effects on vomiting regardless of use of rescue therapy episodes of nausea (no or no significant nausea) use of rescue therapy impact on daily life and safety and tolerability of study medication
Notes	clinical trial register No. EudraCT 2004‐004956‐38 "this investigator initiated study was partly sponsored by a grant from MSD Sharp & Dohme" "competing interests: GE and GM received speakers fee from MSD Sharp & Dohme and GE received consultancy fees from MSD Sharp & Dohme"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... patients were randomized 1:1 to placebo and aprepitant"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Comment: double‐blind
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included in the efficacy analysis
Selective reporting (reporting bias)	High risk	Comment: safety is mentioned in the introduction but no results are provided
Other bias	Low risk	Comment: no information to suggest other sources of bias

Eisenberg 2003.

Study characteristics
Methods	Randomised, parallel, stratified, comparative phase 3 trial with 3 arms comparison of palonosetron 0.25 mg + dexamethasone vs palonosetron 0.75 mg + dexamethasone vs dolasetron + dexamethasone Study period: May 2000 to December 2001 592 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: subjects were followed for 15 days
Participants	Inclusion criteria age ≥ 18 years, with histologically or cytologically confirmed malignant disease naïve or non‐naïve to chemotherapy, with Karnofsky index ≥ 50% scheduled to receive a single dose of moderately emetogenic chemotherapy (i.e. any dose of carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, or mitoxantrone; or methotrexate > 250 mg/m², cyclophosphamide < 1500 mg/m², cyclophosphamide < 1500 mg/m², doxorubicin > 25 mg/m², or cisplatin ≤ 50 mg/m²) on study Day 1 administered over 1 to 4 h) use of reliable contraceptive measures (for females of child‐bearing potential) negative pregnancy test at baseline visit hepatic, renal, or cardiovascular impairment eligible at investigator’s discretion experiencing, at maximum, mild nausea after previous chemotherapy eligible at investigator’s discretion provision of written informed consent Exclusion criteria inability to understand or cooperate with study procedures receipt of investigational drugs ≤ 30 days before study entry scheduled to receive any drug with antiemetic efficacy from 24 h before to 5 days after treatment seizure disorder requiring anticonvulsants unless clinically stable and free of seizure activity emesis, retching, or grade 2 or 3 nausea ≤ 24 h before chemotherapy ongoing emesis due to any organic aetiology moderate or severe nausea and vomiting after any previous chemotherapy scheduled receipt of highly emetogenic chemotherapy (i.e. any dose of nitrogen mustard, dacarbazine, or streptozotocin; or lomustine > 60 mg/m², carmustine ≥ 250 mg/m², or any other chemotherapy with an emetogenicity level of 5) scheduled receipt of any chemotherapeutic agent with an emetogenicity level ≥ 3 during study Days 2 to 6 contraindications to 5‐HT₃ receptor antagonists enrolment in a previous study with palonosetron (RS‐25259; Syntex, Palo Alto, CA) receipt of radiotherapy of the upper abdomen or cranium on study Days 2 to 6 baseline QTc > 500 ms Mean age ± SD, years: 53.3 ± 13.1 in palonosetron 0.25 mg group, 55.2 ± 13.1 in palonosetron 0.75 mg group, 53.6 ± 12.7 in dolasetron group Gender: male (102) + female (467) Tumour/cancer type: malignant disease Chemotherapy regimen: any dose of carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, or mitoxantrone; or methotrexate > 250 mg/m², cyclophosphamide < 1500 mg/m², cyclophosphamide < 1500 mg/m², doxorubicin > 25 mg/m², or cisplatin ≤ 50 mg/m² Country: 61 centres in North America (United States and Mexico)
Interventions	Experimental: arm A: palonosetron 0.25 mg palonosetron 0.25 mg + dexamethasone 20 mg (or, if unavailable, a single dose of p.o. dexamethasone 20 mg or i.v. methylprednisolone 125 mg) Experimental: arm B: palonosetron 0.75 mg palonosetron 0.75 mg + dexamethasone 20 mg (or, if unavailable, a single dose of p.o. dexamethasone 20 mg or i.v. methylprednisolone 125 mg) Experimental: arm C: dolasetron dolasetron 100 mg + dexamethasone 20 mg (or, if unavailable, a single dose of p.o. dexamethasone 20 mg or i.v. methylprednisolone 125 mg)
Outcomes	Primary endpoint proportion of patients considered to have achieved complete response during the first 24 h after chemotherapy administration (acute period) Secondary endpoint(s) proportion of patients with complete response during the delayed (24 to 120 h) time period (Days 2 to 5) and the overall (0 to 120 hours) time period (Days 1 to 5), as well as during successive 24‐h time periods (i.e. 24 to 48, 48 to 72, 72 to 96, and 96 to 120 h) proportion of patients with complete control during acute, delayed, and overall time periods, as well as during successive 24‐h time periods number of emetic episodes time to first emetic episode time to first administration of rescue medication time to treatment failure (time to first emetic episode or administration of rescue medication, whichever occurred first) severity of nausea patient global satisfaction with antiemetic therapy, and QOL (FLIE)
Notes	by a late protocol amendment, and at the discretion of the investigator, a single dose of i.v. dexamethasone 20 mg (or, if unavailable, a single dose of p.o. dexamethasone 20 mg or i.v. methylprednisolone 125 mg), administered 15 min before chemotherapy, was permitted funded by Helsinn Healthcare SA study authors did not provide a statement on potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were randomized using an interactive voice response system across all study sites according to specific procedures"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. on study mortality)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "... 569 patients were included in the ITT cohort analysis"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "the safety cohort included all treated patients who had at least one safety assessment after treatment with study drugs" and "the safety cohort comprised 582 patients"
Selective reporting (reporting bias)	Low risk	Comment: all outcomes have been reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Endo 2012.

Study characteristics
Methods	Randomised study with 2 arms comparison of azasetron + dexamethasone vs granisetron + dexamethasone Enrolment period: November 2010 to March 2012 105 patients enrolled and randomised Masking: n.r. Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria chemo‐naïve patients undergoing carboplatin‐based moderately emetogenic chemotherapy for lung cancer, who were hospitalised at Gifu University Hospital Exclusion criteria age ≥ 18 years use of emetogenic drugs such as opioid analgesics experience of previous chemotherapy organic disorder accompanied by nausea and vomiting Mean age (range), years: 67.8 (41 to 85) in azasetron group, 68.0 (44 to 83) in granisetron group Gender: male (80) + female (25) Tumour/cancer type: lung cancer Chemotherapy regimen: carboplatin (area under the concentration vs time curve of 5 to 6) in combination with paclitaxel (200 mg/m²), etoposide (100 mg/m²), gemcitabine (1000 mg/m²), or pemetrexed (500 mg/m²) Country: Japan (single centre)
Interventions	Experimental: arm A: azasetron Day 1: p.o. azasetron 10 mg + i.v. dexamethasone 12 mg Days 2 to 3: p.o. dexamethasone 8 mg/d Experimental: arm B: granisetron Day 1: i.v. granisetron 3 mg + i.v. dexamethasone 12 mg Days 2 to 3: p.o. dexamethasone 8 mg/d
Outcomes	Primary endpoint complete response during the acute period (0 to 24 h after chemotherapy) Secondary endpoint(s) complete response during delayed (24 to 120 h) and overall (0 to 120 h) periods complete protection from nausea and vomiting each day up to 5 days after chemotherapy constipation and haematological toxicities, including leucopenia, thrombocytopenia, and anaemia
Notes	no information regarding financing and clinical trial registration reported study authors have not provided disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomization was carried out by using the random number table"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Unclear risk	Comment: not reported
Blinding of participants and personnel (performance bias) Blinding of personnel	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: patients were possibly not blinded; therefore we do not know if there is potential for risk of bias
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: although blinding was not reported, we assume that for objective outcomes, there would be no potential for risk of bias
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all participants have been included in the efficacy analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: safety outcomes were reported for all participants
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Flenghi 2015.

Study characteristics
Methods	Randomised, placebo‐controlled, phase 3 trial with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs placebo + palonosetron + dexamethasone Recruitment period: n.r. 122 patients enrolled and randomised Masking: double‐blind Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria received a highly emetogenic cyclophosphamide i.v. chemotherapy (3 g/m²) for autologous PBSC harvesting Exclusion criteria: n.r. Mean/median age (range), years: n.r. Gender: n.r. Tumor/cancer type: n.r. Chemotherapy regimen: cyclophosphamide i.v. chemotherapy (3 g/m²) Country: Italy (single centre)
Interventions	Experimental: arm A aprepitant + palonosetron + dexamethasone Experimental: arm B placebo + palonosetron + dexamethasone
Outcomes	Primary endpoint no emetic episodes and no rescue medication in the first 120 h post chemotherapy Secondary endpoint(s) acute and delayed complete response complete control rate number of emetic events impact of nausea and vomiting on daily life
Notes	abstract
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blinded ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blinded ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "the analysis was performed according to the intention‐to‐treat principle"
Selective reporting (reporting bias)	Unclear risk	Comment: conference abstract, not evaluable
Other bias	Unclear risk	Comment: not evaluable

Forni 2000.

Study characteristics
Methods	Randomised, controlled trial with 3 arms comparison of granisetron + dexamethasone vs tropisetron + dexamethasone vs ondansetron + dexamethasone Recruitment period: n.r. 90 patients randomised Masking: n.r. Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria: n.r. Exclusion criteria: n.r. Mean/median age (range), years: n.r. Gender: n.r. Tumour/cancer type: osteosarcoma Chemotherapy regimen: cisplatin (120 mg/m², 48‐h CI) followed by doxorubicin (75 mg/m², 24‐h CI); then, in the second cycle, delivered 3 weeks later, ifosfamide 15 g/m² (120‐h CI) Country: n.r.
Interventions	Experimental: arm A: granisetron granisetron 2 mg/m² + dexamethasone 8 mg/m² Experimental: arm B: tropisetron tropisetron 5.3 mg/m² + dexamethasone 8 mg/m² Experimental: arm C: ondansetron ondansetron 3.3 mg/m² + dexamethasone 8 mg/m²
Outcomes	complete protection
Notes	conference abstract
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Unclear risk	Comment: blinding not reported
Blinding of participants and personnel (performance bias) Blinding of personnel	Unclear risk	Comment: blinding not reported
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: not reported
Selective reporting (reporting bias)	Unclear risk	Comment: conference abstract, not evaluable
Other bias	Unclear risk	Comment: conference abstract, not evaluable

Fox‐Geiman 2001.

Study characteristics
Methods	Randomised, comparative trial with 3 arms comparison of oral ondansetron + dexamethasone vs oral granisetron + dexamethasone vs intravenous ondansetron + dexamethasone Recruitment period: September 1997 to September 1998 102 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria > 17 years old with malignant disease consumed < 5 alcoholic drinks per day in the past year scheduled to receive chemotherapy or chemotherapy preparative regimens estimated creatinine clearance ≥ 50 mL/min normal liver function, defined as total bilirubin < 1.5 × ULN and AST < 2 × ULN  Exclusion criteria: n.r. Mean age, years: 45 (oral ondansetron), 46 (oral granisetron), 49 (intravenous ondansetron) Gender: male + female Tumour/cancer type: n.r. Chemotherapy regimen: STAMP V, TBI/VP/CY, TANC, Bu/Cy, BEAM, BCNU/VP/CY, ICE, Carboplatin/VP, Carboplatin/MTZ/CY, MMT, Thiotepa/CY, TBI/CY Country: United States (single centre)
Interventions	Experimental: arm A: oral ondansetron ondansetron 8 mg p.o. (every 8 hours) + dexamethasone 10 mg i.v. (once daily) Experimental: arm B: oral granisetron granisetron 1 mg p.o. (every 12 hours each day) + dexamethasone 10 mg i.v. (once daily) Experimental: arm C: intravenous ondansetron ondansetron 32 mg i.v. (single daily dose) + dexamethasone 10 mg i.v. (once daily)
Outcomes	complete response (no or mild nausea and no rescue antiemetics used) over 8 days major response (1 episode of vomiting or, if no vomiting occurs, moderate nausea with rescue antiemetics allowed) minor response (2 to 4 episodes of vomiting, regardless of nausea or rescue antiemetic use) failure (> 4 episodes of vomiting, regardless of nausea or rescue antiemetic use)
Notes	no information regarding clinical trial registration "supported in part by an educational grant from Glaxo‐Wellcome, Inc., Research Triangle Park, NC" study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "the randomization scheme was determined by the study’s biostatistician based on a permuted block design (K = 6)"
Allocation concealment (selection bias)	Low risk	Quote: "the treatment allocation scheme was maintained by the study pharmacist, who assumed responsibility for blinded drug distribution"
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "... the trial was analysed according to intention to‐treat"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Fujiwara 2015.

Study characteristics
Methods	Randomised, prospective, cross‐over, comparative study with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs aprepitant + granisetron + dexamethasone Enrolment period: January 2011 to January 2012 38 patients enrolled Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria female patients older than 20 years of age with histologically confirmed gynaecological cancer scheduled to receive a TC regimen ECOG performance status 0 to 2 meeting the following laboratory criteria: aspartate aminotransferase and alanine aminotransferase levels ≤ 2.5 × the ULN range at the facility; total bilirubin level ≤ 1.5 × the ULN range at the facility; and creatinine level ≤ 1.5 × the ULN range at the facility Exclusion criteria history of hypersensitivity to 5‐HT₃ receptor antagonists or dexamethasone risk of vomiting for other reasons (e.g. symptomatic brain metastasis, active peptic ulcer, gastrointestinal obstruction) Median age (range), years: 57.5 (36 to 76) Gender: female (38) Tumour/cancer type: gynaecological cancer (endometrial cancer, cervical cancer, ovarian or tubal cancer, double endometrial and ovarian cancer) Chemotherapy regimen: TC regimen (paclitaxel and carboplatin) Country: Japan (single centre)
Interventions	Cross‐over study Experimental: arm A: palonosetron Day 1: aprepitant 125 mg p.o. + palonosetron 0.75 mg i.v. + dexamethasone 20 mg i.v. Days 2 to 3: aprepitant 80 mg p.o. + dexamethasone 4 mg p.o. Experimental: arm B: granisetron Day 1: aprepitant 125 mg p.o. + granisetron 3 mg i.v. + dexamethasone 20 mg i.v. Days 2 to 3: aprepitant 80 mg p.o. + dexamethasone 4 mg p.o.
Outcomes	Primary endpoint complete response rate during acute (Day 1, 0 to 24 hours) and delayed periods (Days 2 to 7) Secondary endpoint(s) change in dietary intake in both acute and delayed periods
Notes	this work was supported by a JSPS KAKENHI Grant, Number 25462621 (to Y. Terai) "no potential conflict of interest relevant to this article was reported"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "the group assignment was performed by simple randomization using a table of random numbers and patients were informed of which group (arm A or B) they were assigned"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... non‐blinded ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... non‐blinded ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "the intent‐to‐treat population included 19 patients who received palonosetron on Day 1 (Arm A) and 19 patients who received granisetron on Day 1 (Arm B)"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Gao 2013.

Study characteristics
Methods	Randomised, cross‐over, self‐control study with 2 arms comparison of palonosetron + dexamethasone vs granisetron + dexamethasone Recruitment period: n.r. 84 patients randomised Masking: n.r. Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria: n.r. Exclusion criteria: n.r. Mean/median age (range), years: n.r. Gender: n.r. Tumour/cancer type: n.r. Chemotherapy regimen: cisplatin‐based chemotherapy Country: n.r.
Interventions	Cross‐over study Experimental: arm A: palonosetron Day 1: palonosetron 0. 25 mg i.v. + dexamethasone 10 mg i.v. Day 2: dexamethasone 10 mg i.v. Day 3: palonosetron 0. 25 mg i.v. + dexamethasone 10 mg i.v. Experimental: arm B: granisetron Days 1 to 3: granisetron 3 mg i.v. + dexamethasone 10 mg i.v.
Outcomes	not reported
Notes	conference abstract
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Unclear risk	Comment: blinding not reported
Blinding of participants and personnel (performance bias) Blinding of personnel	Unclear risk	Comment: blinding not reported
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: blinding not reported
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: no outcomes reported
Selective reporting (reporting bias)	Unclear risk	Comment: conference abstract, not evaluable
Other bias	Unclear risk	Comment: conference abstract, not evaluable

Ghosh 2010.

Study characteristics
Methods	Randomised, controlled trial with 3 arms comparison of ondansetron + dexamethasone vs granisetron + dexamethasone vs palonosetron + dexamethasone Recruitment period: 5 November 2007 to 30 September 2009 1213 patients were found to be eligible for the study, among them 487 were on highly emetogenic and 726 were on moderately emetogenic chemotherapy Masking: double‐blind Baseline patient characteristics: n.r. Follow‐up: patients were followed for 5 days for efficacy endpoints and for 8 days for safety endpoints
Participants	Inclusion criteria aged 15 years or older confirmed malignant disease moderately or highly emetogenic chemotherapy on Day 1 and lower emetogenic drugs on subsequent days Exclusion criteria severe, uncontrolled, concurrent illness other than neoplasia asymptomatic metastasis to the brain seizure disorder needing anticonvulsants unless clinically stable intestinal obstruction concurrent intake of any other emetogenic drug or radiotherapy or known hypersensitivity to 5‐HT₃ receptor antagonists or dexamethasone Median age (range), years: 48 (ondansetron); 49 (granisetron); 47 (palonosetron) Gender: male + female Tumour/cancer type: malignant disease Chemotherapy regimen highly emetogenic regimens: cisplatin (96.3%) moderately emetogenic regimens: lower‐dose (< 1500 mg/m²) cyclophosphamide (85.8%) and doxorubicin (12.8%) Country: India (multi‐centre)
Interventions	Experimental: arm A: ondansetron Day 1: ondansetron 8 mg i.v. + dexamethasone 16 mg i.v. Day 2: ondansetron 8 mg i.v. + dexamethasone 4 mg i.v. Day 3: dexamethasone 4 mg i.v. Experimental: arm B: granisetron Day 1: granisetron 3 mg i.v. + dexamethasone 16 mg i.v. Day 2: granisetron 3 mg i.v. + dexamethasone 4 mg i.v. Day 3: dexamethasone 4 mg i.v. Experimental: arm C: palonosetron Day 1: palonosetron 0.75 mg i.v. + dexamethasone 16 mg i.v. Days 2 to 3: dexamethasone 4 mg i.v. Day 3: dexamethasone 4 mg i.v.
Outcomes	Primary endpoint proportion of patients with complete response during the acute phase (0 to 24 h post chemotherapy) Secondary endpoints complete response during successive 24‐h time periods (i.e. 24 to 48 h, 48 to 72 h, 72 to 96 h, 96 to 120 h) complete response for overall chronic phase (24 to 120 h post chemotherapy) adverse events
Notes	study limitation: the study has fewer patients taking palonosetron due to financial limitations of patients, which are present in any developing country AEs were reported for combined HEC and MEC cohorts no information provided on funding or potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "all study personnel and patients were blinded to the treatment assignment for the duration of the study and the nursing staffs injecting the drugs were prohibited from divulging any information on drug assignment even to the doctors giving the chemotherapeutic drugs"
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "all study personnel and patients were blinded to the treatment assignment for the duration of the study and the nursing staffs injecting the drugs were prohibited from divulging any information on drug assignment even to the doctors giving the chemotherapeutic drugs"
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all participants were included for the efficacy analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: all participants were included in reporting on adverse events and deaths
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Grunberg 2009.

Study characteristics
Methods	Randomised, placebo‐controlled, phase 3 trial with 3 arms comparison of single oral dose of casopitant + ondansetron + dexamethasone vs 3‐day intravenous/oral casopitant + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Recruitment period: 6 November 2006 to 9 October 2007 810 patients enrolled and randomised 800 included in modified intention‐to‐treat population Masking: double‐blind Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria subject understands nature and purpose of this study and study procedures and has signed an informed consent form for this study to indicate this understanding males or females at least 18 years of age diagnosed with malignant solid tumour and scheduled to receive first course of cytotoxic chemotherapy with cisplatin administered as a single i.v. dose ≥ 70 mg/m² over 1 to 4 h on study Day 1, alone or in combination with other chemotherapeutic agents. For combination regimens, non‐cisplatin agents of moderate to high emetogenic potential will be allowed but must be administered following cisplatin infusion and must be completed no more than 6 hours after initiation of the cisplatin infusion. Chemotherapy agents of minimal to low emetogenic potential may be given on Day 1 following cisplatin or on any subsequent study day. Taxanes (e.g. paclitaxel, docetaxel) may be administered on study Day 1 only following cisplatin ECOG performance status 0, 1, or 2 haematological and metabolic status must be adequate for receiving a highly emetogenic cisplatin‐based regimen and must meet the following criteria: total neutrophils ≥ 1500/mm³ (standard units ≥ 1.5 × 10⁹/L), platelets ≥ 100,000/mm (standard units ≥ 100.0 × 10⁹/L), bilirubin ≤ 1.5 × ULN, serum creatinine ≤ 1.5 mg/dL (standard units ≤ 132.6 µmol/L), creatinine clearance ≥ 60 mL/min liver enzymes must be below the following limits: without known liver metastases: aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 × ULN with known liver metastases: AST and/or ALT ≤ 5.0 × ULN willing and able to complete daily components of the subject diary for each study cycle women of child‐bearing potential: must commit to consistent and correct use of an acceptable method of birth control; GSK acceptable contraceptive methods, when used consistently and in accordance with both product label and instructions of a physician, are as follows: non‐child‐bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is postmenopausal. For purposes of this study, postmenopausal is defined as 1 year without menses) child‐bearing potential: must have a negative serum pregnancy test result or negative urine dipstick pregnancy test within 24 h before first dose of investigational product of Cycle 1 Day 1, and agrees with 1 of the following: male partner who is sterile before female subject's entry into the study and is the sole sexual partner for that female subject oral contraceptives (e.g. oral, injectable, or implantable) with double‐barrier method of contraception consisting of spermicide with condom or diaphragm for a period after the trial to account for a potential drug interaction (minimum 6 weeks) double‐barrier method of contraception consisting of spermicide with condom or diaphragm intrauterine device (IUD) with documented failure rate < 1% per year complete abstinence from intercourse for 2 weeks before exposure to investigational product throughout the clinical trial, and for a period after the trial to account for elimination of the drug (minimum 3 days) if subjects indicate they will remain abstinent during the period described above, they must agree to follow GSK guidelines for consistent and correct use of an acceptable method of birth control should they become sexually active Exclusion criteria has previously received cytotoxic chemotherapy. Previous biological or hormonal therapy will be permitted is scheduled to receive cisplatin treatment on more than 1 day during a single cycle of therapy if female, is pregnant or lactating has received radiation therapy to the thorax, head and neck, abdomen, or pelvis in the 10 days before receiving the first dose of study medication and/or will receive radiation therapy to the thorax, head and neck, abdomen, or pelvis in the 6 days following the first dose of study medication emesis (i.e. vomiting and/or retching) experienced in the 24 h before first dose of study medication clinically significant nausea (e.g. ≥ 25 mm on VAS) in the 24 h before receiving first dose of study medication known central nervous system primary or malignancy metastatic to the CNS, unless successfully treated with excision or radiation and subsequently has been stable for at least 1 week before receiving first dose of study medication history of documented peptic ulcer disease (via endoscopy or X‐ray), active peptic ulcer disease, gastrointestinal obstruction, increased intracranial pressure, hypercalcaemia, or any uncontrolled medical condition (other than malignancy) that in the opinion of the investigator may confound results of the study, represent another potential aetiology for emesis and nausea (other than CINV), or pose an unwarranted risk to the subject known hypersensitivity or contraindication to ZOFRAN, another 5‐HT₃ receptor antagonist, dexamethasone, or any component of casopitant has previously received an NK₁ receptor antagonist active systemic infection or any uncontrolled disease (other than malignancy) that, in the opinion of the investigator, may confound results of the study or pose an unwarranted risk to the subject. Subjects with previous, but not current, history of alcoholism may be permitted, provided that, in the investigator's opinion, the subject's disease state will not confound results of the study receiving or planning to receive a systemic corticosteroid therapy at any dose within 72 h before the first dose of study medication, except when indicated as pre‐medication for a taxane; however, topical steroids and inhaled corticosteroids with a steroid dose ≤ 10 mg prednisone daily or its equivalent are permitted is scheduled to receive bone marrow transplantation and/or stem cell rescue with this course of cisplatin therapy has received an investigational drug within the 30 days or 5 half‐lives (whichever is longer) before receiving the first dose of study medication and/or is scheduled to receive any investigational drug during the study has received moderately and/or highly emetogenic medication within 48 h before the first dose of study medication (opioid narcotics for cancer pain will be permitted if the subject has been on such medication for at least 7 days and has not experienced nausea or emesis from the narcotics) has taken/received any medication with known or potential antiemetic activity within the 24‐h period before receiving study drug. This includes, but is not limited to: 5‐HT₃ receptor antagonists (e.g. ondansetron, granisetron, dolasetron, tropisetron, ramosetron); palonosetron is not permitted within 7 days before administration of investigational product benzamide/benzamide derivatives (e.g. metoclopramide, alizapride) benzodiazepines (except if the subject is receiving such medication for sleep or anxiety and has been on a stable dose for at least 7 days before the first dose of GW679769 investigational product; however, lorazepam is prohibited 24 h before study drug is received regardless of reason for use) phenothiazines (e.g. prochlorperazine, promethazine, fluphenazine, perphenazine, thiethylperazine, chlorpromazine) butyrophenone (e.g. haloperidol, droperidol) corticosteroids (e.g. dexamethasone, methylprednisolone; with the exception of topical steroids for skin disorders, inhaled steroids for respiratory disorders, and prophylactic treatment for taxane or pemetrexed therapy) anticholinergics (e.g. scopolamine) with the exception of inhaled anticholinergics for respiratory disorders (e.g. ipratropium bromide) antihistamines (e.g. cyclizine, hydroxyzine, diphenhydramine), except for prophylactic use for taxane therapy domperidone mirtazapine olanzapine cannabinoids has taken/received strong or moderate inhibitors of CYP3A4 and CYP3A5 before administration of casopitant (GW679769) investigational product has taken/received inducers of CYP3A4 and CYP3A5 within 14 days before administration of casopitant investigational product is taking the antidiabetic agent repaglinide or the diuretic torsemide. Investigators are advised to exercise caution if including patients taking the antidiabetic agent rosiglitazone or pioglitazone, or antimalarial agents such as chloroquine and amodiaquine, as the metabolite of casopitant is a potential inhibitor of CYP2C8 is currently taking or plans to take any of the following CYP3A4 substrates: astemizole, cisapride, pimozide, terfenadine Age (range), years: 57 (20 to 84) in 3‐day i.v. + p.o. casopitant group, 59 (18 to 80) in single‐dose p.o. casopitant group, 59 (20 to 82) in control group Gender: male + female Tumour/cancer type: malignant solid tumour (non‐small cell lung, head and neck, small cell lung, ovary, cervix, bladder, other) Chemotherapy regimen: cisplatin, gemcitabine, vinorelbine, fluorouracil, etoposide, paclitaxel, cyclophosphamide, doxorubicin, docetaxel Country: 22 countries (77 centres)
Interventions	Experimental: arm A: 3‐day i.v. + p.o. casopitant Day 1: casopitant 90 mg i.v. + casopitant placebo p.o. + ondansetron 32 mg i.v. + dexamethasone 12 mg p.o. + dexamethasone placebo p.o. Days 2 to 3: AM (dexamethasone 8 mg p.o. + casopitant 50 mg p.o.), PM (dexamethasone placebo p.o.) Day 4: AM (dexamethasone 8 mg p.o.), PM (dexamethasone placebo p.o.) Experimental: arm B: single‐dose oral casopitant Day 1: casopitant 150 mg p.o. + casopitant placebo i.v. + ondansetron 32 mg i.v. + dexamethasone 12 mg p.o. + dexamethasone placebo p.o. Days 2 to 3: AM (dexamethasone 8 mg p.o. + casopitant placebo p.o.), PM (dexamethasone 8 mg p.o.) Day 4: AM (dexamethasone 8 mg p.o.), PM (dexamethasone 8 mg p.o.) Control: arm C Day 1: casopitant placebo p.o. + casopitant placebo i.v. + ondansetron 32 mg i.v. + dexamethasone 20 mg p.o. Days 2 to 3: AM (dexamethasone 8 mg p.o. + casopitant placebo p.o.), PM (dexamethasone 8 mg p.o.) Day 4: AM (dexamethasone 8 mg p.o.), PM (dexamethasone 8 mg p.o.)
Outcomes	Primary endpoint number of participants who achieved complete response [Time frame: up to 120 h of Cycle 1 of HEC] Secondary endpoint(s) number of participants who achieved complete response during acute (0 to 24 h) and delayed (24 to 120 h) phases following first cycle of HEC [Time frame: up to 120 h of Cycle 1 of HEC] number of participants who achieved complete response during overall (0 to 120 h) phase following subsequent cycles of HEC [Time frame: up to 120 h of Cycles 2 to 6 of HEC] maximum nausea score (to assess severity of nausea) as assessed by a visual analogue scale (VAS) [Time frame: up to 120 h of each HEC cycle (up to 24 months)] number of participants who use antiemetic rescue medication [Time frame: up to 120 h of each HEC cycle (up to 24 months)] number of participants with first emetic event [Time frame: up to 120 h of each HEC cycle (up to 24 months)] number of participants who received antiemetic rescue medication [Time frame: up to 120 h of Cycle 1 of HEC] number of participants who vomited/retched [Time frame: up to 120 h of Cycle 1 of HEC] number of participants who reported significant nausea (≥ 25 mm on VAS) [Time frame: up to 120 h of Cycle 1 of HEC] number of participants who reported nausea (≥ 5 mm on VAS) [Time frame: up to 120 h of Cycle 1 of HEC] number of participants who achieved complete protection, defined as no vomiting/retching, no significant nausea, and no rescue medication [Time frame: up to 120 h of Cycle 1 of HEC] number of participants who achieved total control, defined as no vomiting/retching, no nausea, and no rescue medication [Time frame: up to 120 h of each HEC cycle (up to 24 months)] impact on participant's daily life activities for first 120 h following first cycle of chemotherapy as assessed by the Functional Living Index‐Emesis (FLIE) questionnaire score [Time frame: up to 120 h of each HEC cycle (up to 24 months)] percentage of participants with impact on daily life activities for first 120 h following first cycle of chemotherapy as assessed by the FLIE questionnaire interpretation [Time frame: up to 120 h of each HEC cycle (up to 24 months)] participant satisfaction with prophylactic antiemetic regimens, as assessed by participant satisfaction questionnaire [Time frame: up to 120 h of each HEC cycle (up to 24 months)] willingness of participant to use the same treatment during future chemotherapy, as assessed by participant willingness questionnaire [Time frame: up to 120 h of each HEC cycle (up to 24 months)] number of participants with nausea as assessed by a categorical scale over the first 120 h following HEC [Time frame: up to 120 h of each HEC cycle (up to 24 months)] number of participants with adverse events (AEs) and serious adverse events (SAEs) [Time frame: up to 24 months after last dose of investigational product] number of participants with abnormalities of grade 3 and 4 in laboratory parameters (clinical chemistry and haematology) [Time frame: up to end of cycle (approximately 28 days per cycle); maximum up to 24 months] summary of abnormal electrocardiogram findings [Time frame: up to end of cycle (approximately 28 days per cycle); maximum up to 24 months] summary of mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) [Time frame: up to end of cycle (approximately 28 days per cycle); maximum up to 24 months] summary of mean respiratory rate [Time frame: up to end of cycle (approximately 28 days per cycle); maximum up to 24 months] summary of mean heart rate [Time frame: up to end of cycle (approximately 28 days per cycle); maximum up to 24 months]
Notes	"GlaxoSmithKline sponsored the study" "this trial was designed through a collaboration of academic researchers (including SMG and JH), and the study sponsor, GlaxoSmithKline Research and Development" "statistical analyses were done by GlaxoSmithKline Research and Development, according to a predefined plan approved by JH and SMG with periodic reports provided to the independent data safety monitoring board" "this study is registered with ClinicalTrials.gov, NCT00431236" "conflicts of interest: SMG is a consultant for GlaxoSmithKline, Merck, Helsinn, and Schering, and owns stock in Schering. He has received honoraria and research funds from Merck. SL, MWR, PW, MG, and OW are employed by and own stock in GlaxoSmithKline. JH is a consultant for GlaxoSmithKline, Helsinn, and Schering, and has received research funds from Merck. The remaining authors declared no conflicts of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were then randomly assigned, through a second telephone call ..." and "randomisation was performed centrally at the study level ..."
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "these supplies were blinded to the pharmacist, the investigator, and the patient"
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "these supplies were blinded to the pharmacist, the investigator, and the patient"
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. neutropenia, on‐study mortality)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "efficacy analysis were done in the modified intention‐to‐treat population"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "safety analyses were done with all patients who received placebo or study drug"
Selective reporting (reporting bias)	Low risk	Comment: all outcomes were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Grunberg 2011.

Study characteristics
Methods	Randomised, parallel‐group, phase 3 trial with 2 arms comparison of fosaprepitant + ondansetron + dexamethasone vs aprepitant + ondansetron + dexamethasone Recruitment period: n.r. 2322 patients enrolled, pre‐stratified by gender and randomised to treatment 2247 patients evaluated for efficacy Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria must have been scheduled to receive first course of cisplatin (≥ 70 mg/m²) for documented solid malignancy Karnofsky performance score ≥ 60 predicted life expectancy ≥ 3 months pre‐menopausal female patients of reproductive potential must have demonstrated a negative urine pregnancy test and agreed to use a double‐barrier form of contraception at least 14 days before and throughout the study, and for at least 1 month following the last dose of study medication must have been able to read, understand, and complete a study diary and questionnaire; understand study procedures; and give written informed consent Exclusion criteria symptomatic primary or metastatic central nervous system (CNS) malignancy radiation therapy to abdomen/pelvis in the week before treatment stem cell rescue therapy with cisplatin vomiting less than 25 h before treatment Day 1 treatment with multiple‐day chemotherapy with cisplatin in single cycle or moderately/highly emetogenic chemotherapy (< 6 days before and/or during the 6 days following cisplatin infusion) active infection or uncontrolled disease history of any illness that might confound results of the study or pose unwarranted risk in administering the study drug to the patient history of illicit drug use or alcohol abuse mental incapacitation or emotional or psychiatric disorder history of hypersensitivity to aprepitant, ondansetron, or dexamethasone breast‐feeding participated in an aprepitant/investigational drug study within 4 weeks of treatment Day 1 concurrent medication condition that would preclude administration of dexamethasone for 4 days had received systemic corticosteroid therapy had abnormal laboratory values Median age (range), years: 56 (19 to 86) in i.v. fosaprepitant group, 57 (19 to 82) in oral aprepitant group Gender: male + female Tumour/cancer type: solid tumour (lung cancer, gastrointestinal cancer, reproductive or genitourinary cancer, miscellaneous or site unspecified, renal and urinary tract cancer, breast cancer, lymphoma, hepatic and biliary cancer, endocrine cancer) Chemotherapy regimen: cisplatin at a dose ≥ 70 mg/m² Country/continent: North America, South America, Europe, Asia‑Pacific, Africa
Interventions	Experimental: arm A: i.v. fosaprepitant Day 1: 150 mg fosaprepitant dimeglumine + 32 mg i.v. ondansetron + 12 mg p.o. dexamethasone Day 2: 8 mg p.o. dexamethasone Days 3 to 4: 8 mg p.o. dexamethasone twice a day Experimental: arm B: p.o. aprepitant 125/80 Day 1: 125 mg p.o. aprepitant + 32 mg i.v. ondansetron + 12 mg p.o. dexamethasone Days 2 to 3: 80 mg p.o. aprepitant + 8 mg p.o. dexamethasone Day 4: 8 mg p.o. dexamethasone
Outcomes	Primary endpoint evaluating the non‐inferiority of fosaprepitant compared with aprepitant for complete response, defined as no vomiting and no use of rescue therapy, during the overall phase (120 h following initiation of cisplatin therapy) Secondary endpoint(s) assessment of the proportion of patients with complete response in the delayed phase (25 to 120 h following initiation of cisplatin therapy) assessment of the proportion of patients with no vomiting overall
Notes	study is registered with ClinicalTrials.gov, NCT00619359 "supported by Merck by provision of aprepitant and of financial support for the conduct of the study" conflicts of interest: "employment or leadership position: Suzanne DeVandry, Merck (C); Judith A. Boice, Merck (C); James S. Hardwick, Merck (C); Elizabeth Beckford, Merck (C); Arlene Taylor, Merck (C); Alexandra Carides, Merck (C); consultant or advisory role: Steven Grunberg, GlaxoSmithKline (C), Helsinn (C), Merck (C), Shin Nippon Biomedical Laboratories (C); Jose´ Dinis, Merck, Sharp, and Dohme (C); Fausto Roila, Merck (C), Helsinn (C); Jørn Herrstedt, GlaxoSmithKline (C); stock ownership: Steven Grunberg, Merck; Judith A. Boice, Merck; James S. Hardwick, Merck; Alexandra Carides, Merck Honoraria: Steven Grunberg, Merck; Fausto Roila, Merck, Helsinn, GlaxoSmithKline; Jørn Herrstedt, Merck; research funding: Fausto Roila, GlaxoSmithKline, Merck; Jørn Herrstedt, Merck, Helsinn; expert testimony: none; other remuneration: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: patients were stratified by sex and were randomly assigned to treatment groups according to a computer‐generated, blinded allocation schedule
Allocation concealment (selection bias)	Low risk	Comment: to ensure in‐house blinding, treatment group assignments were made by personnel not otherwise involved with the study
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‑blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‑blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. infusion site reaction)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included from the efficacy analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: all included patients were checked for adverse events
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Hashimoto 2013.

Study characteristics
Methods	Randomised, phase 3 trial with 2 arms comparison of aprepitant 125/80 mg + palonosetron + dexamethasone vs aprepitant 125/80 mg + granisetron + dexamethasone Enrolment period: July 2011 to June 2012 842 patients enrolled 827 patients evaluated Masking: double‐blind Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria malignant solid tumour and receiving HEC containing ≥ 50 mg/m² cisplatin (CDDP) as first line performance status (ECOG) 0 to 2 20 years old or over at the time of giving informed consent regimens involve standard treatment for vomiting with dexamethasone, aprepitant, and 5‐HT₃ receptor antagonist adequate organ function as defined by (each of the following values is examined within 8 days before entry): AST ≤ 100 IU/L, ALT ≤ 100 IU/L; T‐Bill ≤ 2.0 mg/dL; Ccr ≥ 60 mL/min; all subjects must be able to provide informed written consent before entry Exclusion criteria known prior severe hypersensitivity to 5‐HT₃ receptor antagonist, corticosteroids, and aprepitant not enough whole body state for antineoplastic agent treatment known symptomatic brain metastasis convulsive disorder that needs anticonvulsant therapy symptom of ascites or pleural effusion that needs puncture obstruction of gastrointestinal tract, for example, gastric outlet or ileus pregnant or breast‐feeding woman enforced radiotherapy at the bottom of the diaphragm in the period between 6 days before and 6 days after of the date of first therapy taking a medicine regularly, for example, 5‐HT₃ receptor antagonists, corticosteroids, anti‐dopamine agonists, phenothiazine tranquilisers, antihistamine drugs, benzodiazepine agents judged by the investigator to be inappropriate for inclusion in this study Mean age (range), years: n.r. Gender: n.r. Tumour/cancer type: malignant solid tumour Chemotherapy regimen: HEC containing ≥ 50 mg/m² cisplatin (CDDP) Country: Japan
Interventions	Experimental: arm A: palonosetron Day 1: aprepitant 125 mg p.o. + palonosetron 0.75 mg i.v. + dexamethasone 9.9 mg i.v. Days 2 to 3: aprepitant 80 mg p.o. + dexamethasone 6.6 mg i.v. Day 4: dexamethasone 6.6 mg i.v. Experimental: arm B: granisetron Day 1: aprepitant 125 mg p.o. + granisetron 1 mg i.v. + dexamethasone 9.9 mg i.v. Days 2 to 3: aprepitant 80 mg p.o. + dexamethasone 6.6 mg i.v. Day 4: dexamethasone 6.6 mg i.v.
Outcomes	Primary endpoint complete response at the overall (0 to 120 h) phase Secondary endpoints complete response at acute (0 to 24 h) and delayed (24 to 120 h) phases total control at overall, acute, and delayed phases
Notes	clinical trial information: UMN000004863 Pharma Valley Center, Shizuoka Organization for Creation Industries (non‐profit foundation) "no conflict of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomization was done centrally using the minimization method with stratification with respect to center, age (< 60 versus ≥ 60 years), gender, and cisplatin dose (< 70 versus ≥ 70 mg/m2)"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "at each center, one pharmacist was pre‐designated who was notified of treatment label ... All other staffs (physicians, study pharmacists, and nurses involved in the study) as well as patients were kept blinded to the assigned treatments"
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "at each center, one pharmacist was pre‐designated who was notified of treatment label ... All other staffs (physicians, study pharmacists, and nurses involved in the study) as well as patients were kept blinded to the assigned treatments"
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Quote: "...our study designated study pharmacists at each center who were blinded (masked) to treatment allocation and who evaluated efficacy end points for each patient every day based on diary data and interview"
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included in the efficacy analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: all patients were included for safety analysis
Selective reporting (reporting bias)	Low risk	Comment: all pre‐specified outcomes were reported
Other bias	Low risk	Comment: no information to suggest other sources of bias

Herrington 2000.

Study characteristics
Methods	Randomised study with 2 arms comparison of ondansetron + dexamethasone vs granisetron + dexamethasone Enrolment period: July 1997 to February 1999 65 patients entered Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria men and non‐pregnant women 18 years of age or older scheduled to receive emetogenic chemotherapy alone or in combination with another moderately or mildly emetogenic agent except taxanes Exclusion criteria had received emetogenic chemotherapy unstable medical disorder, severe hepatic insufficiency, primary or secondary brain neoplasm, intestinal disease or disorder that may inhibit digestion or absorption of oral agents received long‐term or concurrent (within 24 h of first dose of study drug) treatment with agents known to have significant antiemetic activity (antihistamines, phenothiazines, butyrophenones, cannabinoids, corticosteroids, metoclopramide) radiation therapy to any abdominal field (T10 to L5) within 24 h before the dose of study drug was given or during 24‐hour assessment period (study Days 0 to 1) hypersensitivity to any 5‐HT₃ receptor antagonist or corticosteroid experienced nausea within 1 h and/or emesis (vomiting and/or retching) within 24 h before dosing with study drug Median age (range), years: 59 (20 to 91) in ondansetron group, 62.5 (25 to 84) in granisetron group Gender: male (15) + female (46) Tumour/cancer type: breast, lymphoma, multiple myeloma, other Chemotherapy regimen: moderately emetogenic chemotherapy (carboplatin ≥ 300 mg/m², cisplatin ≥ 20 to < 50 mg/m², cyclophosphamide, p.o. ≥ 100 mg/m², cyclophosphamide, i.v. ≥ 500 to < 1000 mg/m², dacarbazine ≥ 350 to < 500 mg/m², daunorubicin ≥ 45 mg/m², doxorubicin ≥ 40 mg/m² as a single agent or ≥ 25 mg/m² combined with other chemotherapeutic agents, idarubicin ≥ 12 mg/m², ifosfamide ≥ 1000 mg/m², methotrexate ≥ 250 mg/m², mitoxantrone ≥ 12 mg/m²) Country: n.r. (multi‐centre)
Interventions	Experimental: arm A: ondansetron p.o. single‐dose ondansetron 16 mg + dexamethasone 12 mg Experimental: arm B: granisetron p.o. granisetron 1 mg + dexamethasone 12 mg
Outcomes	Primary objective percentage of patients experiencing total control of nausea and emesis over 24 h after start of chemotherapy Secondary objective(s) percentage of patients experiencing nausea including its severity frequency of rescue antiemetics number of emetic episodes during 24‐h evaluation time to first significant (moderate, severe) nausea and first emetic episode
Notes	"funded in part by SmithKline Beecham Pharmaceuticals,Philadelphia, Pennsylvania" study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... open‐label ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... open‐label ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "sixty‐five patients (75% women) took part in the study, but only 61 were included in the analysis (Table 6)"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Herrington 2008.

Study characteristics
Methods	Randomised, pilot, placebo‐controlled, comparative trial with 3 arms comparison of 3‐day aprepitant 125/80 mg + palonosetron + dexamethasone vs 1‐day aprepitant 125 mg + palonosetron + dexamethasone vs placebo + palonosetron + dexamethasone Patient evaluation period: June 2005 to May 2007 82 patients randomised 75 patients included Masking: double‐blind Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria 18 years of age or older with histologically or cytologically confirmed malignant disease Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 Exclusion criteria experienced an episode of emesis within 24 h before the start of chemotherapy documented primary or secondary brain neoplasm receiving radiation to abdomen or pelvis, medications with known antiemetic activity, or medications known to induce cytochrome P450 enzymes (e.g. phenytoin, carbamazepine, rifampin) Age ± SD, years: 59.6 ± 10.7 (palonosetron + 3‐day aprepitant), 58.3 ± 10.5 (palonosetron + 1‐day aprepitant), 56.1 ± 12.6 (palonosetron + placebo) Gender: male + female Tumour/cancer type: solid malignancy (breast cancer, lung cancer, head and neck cancer, other) Chemotherapy regimen highly emetogenic regimens included cisplatin ≥ 50 mg/m² breast cancer regimens included anthracycline and cyclophosphamide combinations (e.g. AC, FEC, TAC) Country: United States (single institute)
Interventions	Experimental: arm A: palonosetron + 3‐day aprepitant Day 1: aprepitant 125 mg p.o. + palonosetron 0.25 mg i.v. + dexamethasone 12 mg p.o. Days 2 to 3: aprepitant 80 mg p.o. + dexamethasone 8 mg p.o. Day 4: dexamethasone 8 mg p.o. Experimental: arm B: palonosetron + 1‐day aprepitant Day 1: aprepitant 125 mg p.o. + palonosetron 0.25 mg i.v. + dexamethasone 12 mg p.o. Days 2 to 3: matching placebo + dexamethasone 8 mg p.o. Day 4: dexamethasone 8 mg p.o. Experimental: arm C: palonosetron + placebo Day 1: placebo + palonosetron 0.25 mg i.v. + dexamethasone 18 mg p.o. Days 2 to 4: dexamethasone 8 mg p.o.
Outcomes	Primary endpoint proportion of patients with emesis in acute (Day 1) and delayed (Days 2 to 5) phases after chemotherapy Secondary endpoint(s) number of breakthrough antiemetics administered severity of nausea during the 120‐h study period complete response
Notes	"it was found that all of the patients experiencing emesis were in Arm C (n = 8 of 16 experienced emesis vs none in the other arms). Therefore, the study was temporary halted, and the protocol was amended with the removal of Arm C. The descriptive statistics of patients in Arm C will be presented, but this study group will not be included in the statistical comparison among groups" funding: "MGI Pharma and Scott & White. Grant Number: R3429" study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included for efficacy analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Unclear risk	Quote: "there were no reports of serious adverse events that were related to study medication" Probably for all patients
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Unclear risk	Comment: the study was temporarily halted, and the protocol was amended with removal of arm C. Descriptive statistics for patients in arm C were not included in the report

Herrstedt 2009.

Study characteristics
Methods	Randomised, placebo‐controlled, parallel‐group, phase 3 controlled trial with 4 arms comparison of casopitant single oral dose + dexamethasone + ondansetron vs casopitant 3‐day oral dosage + dexamethasone + ondansetron vs casopitant 3‐day i.v./oral dosage + dexamethasone + ondansetron vs placebo + dexamethasone + ondansetron Recruitment period: n.r. 1933 patients randomised 1917 patients included in mITT analysis (all patients who received study drug and chemotherapy) Masking: double‐blind Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria ≥ 18 years of age chemotherapy naïve ECOG performance status 0, 1, or 2 had to be scheduled to receive 1 of the following AC‐based regimens for treatment of a solid malignant tumour: cyclophosphamide administered intravenously (i.v.; 500 to 1500 mg/m²) and doxorubicin i.v. (≥ 40 mg/m²) or cyclophosphamide i.v. (500 to 1500 mg/m²) and epirubicin i.v. (≥ 60 mg/m²) required to have laboratory values demonstrating adequate haematological status (absolute neutrophil count ≥ 1500/µL, platelets ≥ 100,000/µL) and adequate liver function (bilirubin ≤ 1.5 × ULN, AST/ALT ≤ 2.5 × ULN, or, in the presence of known liver metastases, AST/ALT ≤ 5.0 × ULN) all patients of child‐bearing potential were required to use birth control Exclusion criteria previously received chemotherapy or an NK₁ receptor antagonist or any drug with moderate or high emetogenic potential in the 48 h before receiving the first study drug received an investigational drug in the 30 days before receiving study drugs or medications with known or potential antiemetic activity within the 24 h before receiving study drug scheduled to receive taxane therapy during Cycle 1 as a result of concomitant administration of corticosteroids taking the CYP3A4 substrate astemizole, pimozide, terfenadine, repaglinide, or torsemide known hypersensitivity to dexamethasone or 5‐HT₃ receptor antagonist received CYP3A4 and CYP3A5 inducers within 14 days or strong or moderate CYP3A4/CYP3A5 inhibitors 2 days before the first dose of drug pregnant or lactating Median age, years: 51 in single p.o. dose group, 51 in 3‐day p.o. group, 53 in 3‐day i.v./p.o. group, 52 in control group Gender: male (40) + female (1893) Tumour/cancer type: breast cancer and other Chemotherapy regimen: anthracycline and cyclophosphamide (AC)‐based regimen Country: 196 centres in 32 countries
Interventions	Experimental: arm A: casopitant single oral dosage Day 1: casopitant 150 mg p.o. + casopitant placebo i.v. + ondansetron 8 mg p.o. twice daily + dexamethasone 8 mg i.v. Days 2 to 3: casopitant placebo p.o. + ondansetron 8 mg p.o. twice daily Experimental: arm B: casopitant 3‐day oral dosage Day 1: casopitant 150 mg p.o. + casopitant placebo i.v. + ondansetron 8 mg p.o. twice daily + dexamethasone 8 mg i.v. Days 2 to 3: casopitant 50 mg p.o. + ondansetron 8 mg p.o. twice daily Experimental: arm C: casopitant 3‐day intravenous/oral dosage Day 1: casopitant placebo p.o. + casopitant 90 mg i.v. + ondansetron 8 mg p.o. twice daily + dexamethasone 8 mg i.v. Days 2 to 3: casopitant 50 mg p.o. + ondansetron 8 mg p.o. twice daily Control: arm D Day 1: casopitant placebo p.o. + casopitant placebo i.v. + ondansetron 8 mg p.o. twice daily + dexamethasone 8 mg i.v. Days 2 to 3: casopitant placebo p.o. + ondansetron 8 mg p.o. twice daily
Outcomes	Primary endpoint proportion of patients achieving complete response (no vomiting/retching or rescue medications) in first 120 h Secondary endpoints proportion of patients achieving complete response in acute (0 to 24 h) and delayed (24 to 120 h) phases maximum nausea score (VAS) time to first antiemetic rescue medicine and time to withdrawal time to first emetic event and time to withdrawal proportion of patients receiving rescue medicine no vomiting overall (0 to 120 h) no vomiting in acute (0 to 24 h) and delayed (24 to 120 h) phases no nausea (VAS < 5 mm) no significant nausea (VAS < 25 mm) complete protection (complete response and no significant nausea) total control (complete response and no nausea) impact on daily life activities (0 to 120 h) subject satisfaction with antiemetic regimens safety and tolerability (0 to 120 h)
Notes	sponsors and collaborators: GlaxoSmithKline conflict of interest: "employment or leadership position: Mark W. Russo, GlaxoSmithKline (C); Jeremey Levin, GlaxoSmithKline (C); Salabha Ranganathan, GlaxoSmithKline (C); Mary Guckert, GlaxoSmithKline (C); consultant or advisory role: Jørn Herrstedt, Helsinn (C), Schering‐Plough (C), GlaxoSmithKline (C); Simon Van Belle, GlaxoSmithKline (C); Steven M. Grunberg, GlaxoSmithKlein (C), Merck (C), Schering‐Plough (C), Helsinn (C); stock ownership: Mark W. Russo, GlaxoSmithKline; Jeremey Levin, GlaxoSmithKline; Salabha Ranganathan, GlaxoSmithKline; Mary Guckert, GlaxoSmithKline; Steven M. Grunberg, Schering‐Plough; honoraria: Jørn Herrstedt, Merck; Fausto Roila, GlaxoSmithKline; Steven M. Grunberg; Merck research funding: Jørn Herrstedt, Merck; Fausto Roila, GlaxoSmithKline; Steven M. Grunberg; Merck expert testimony: none; other remuneration: none" clinicalTrials.gov, NCT00366834 results submitted to ClinicalTrials.gov, second submission cycle cancelled
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "after the initial screening visit, investigators used a Randomisation and Medication system to register patients for the trial ..." Comment: method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. study mortality, infusion/injection site reaction)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "of the 1,933 patients randomly assigned to the study, a modified intent to treat (mITT) population (n=1,917) was used for the efficacy analysis"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "the safety population (n=1,920) included all patients randomly assigned to a study arm who received any investigational drug (casopitant or casopitant placebo)"; and "there was a single death in each study arm, none of which were attributed to the investigational drug by the investigator"
Selective reporting (reporting bias)	Unclear risk	Comment: most outcome measures were reported in the results section. Results were submitted to study registry, then were cancelled. Satisfaction and impact on daily life were not reported
Other bias	Low risk	Comment: no information to suggest other sources of bias

Hesketh 1999.

Study characteristics
Methods	Randomised, phase 2 trial with 2 arms comparison of ezlopitant (CJ‐11,974) + granisetron + dexamethasone vs placebo + granisetron + dexamethasone Recruitment period: n.r. 61 patients enrolled Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria pathologically confirmed cancer age ≥ 18 years Karnofsky performance status ≥ 60% chemotherapy to include cisplatin at a dose ≥ 100 mg/m² administered over a period ≤ 3 h normal screening electrocardiogram with stable heart rhythm WBC count ≥ 3500/μL, platelet count ≥ 75,000/μL, bilirubin level < 1.8 mg/dL, AST and ALT levels < 2 × ULN, and creatinine clearance ≥ 55 mL/min Exclusion criteria primary CNS malignancy or untreated brain metastasis prior treatment with cisplatin multiple‐day therapy with highly emetogenic chemotherapy known seizure disorder clinically significant neuromuscular disorder or degenerative disorder of the nervous system clinically significant gastrointestinal disease clinically significant endocrine abnormalities not controlled with current therapy congestive heart failure or active angina significant arrhythmia or myocardial infarction within the past 6 months history of significant hypersensitivity to multiple drugs use of any medication with potential antiemetic action within 24 h of cisplatin radiation therapy to abdominal or pelvic areas within 48 h before the study period pregnancy or lactation Mean age (range), years: 66 (36 to 81) in ezlopitant group, 62 (40 to 76) in placebo group Gender: male + female Tumour/cancer type: solid tumour (lung cancer, ovary cancer, oesophagus/oropharynx cancer, other/unspecified) Chemotherapy regimen: cisplatin at a dose ≥ 100 mg/m² Country: n.r. (10 institutions, multi‐centre)
Interventions	Experimental: arm A: Gran/Dex + CJ‐11,974 granisetron 10 μg/kg i.v. 30 min before cisplatin + dexamethasone 20 mg i.v. 30 min before cisplatin + CJ‐11,974 100 mg orally 30 min before and 12 h after cisplatin, and twice daily on Days 2 through 5 after cisplatin Experimental: arm B: Gran/Dex + placebo granisetron 10 μg/kg i.v. 30 min before cisplatin + dexamethasone 20 mg i.v. 30 min before cisplatin + identical‐appearing placebo capsules orally 30 min before and 12 h after cisplatin, and twice daily on Days 2 through 5 after cisplatin
Outcomes	Primary efficacy endpoint proportion of patients with complete control (no emetic episodes) during Days 2 to 5 after cisplatin administration (delayed emesis period) (24 to 120 h after start of chemotherapy) Secondary efficacy endpoints complete control of emesis during the acute period (24 h) after chemotherapy control of nausea, time to administration of rescue therapy total number of emetic episodes
Notes	"supported by Pfizer Central Research, Pfizer, Inc, Groton, CT" study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "three (two from group 1 and one from group 2) of the 61 total patients who received the study drug were not included in efficacy analyses because assessments were not recorded..."
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "all 61 patients treated on the study were considered assessable for adverse events. Safety results are listed in Table 8"
Selective reporting (reporting bias)	Low risk	Comment: all efficacy measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Hesketh 2003.

Study characteristics
Methods	Randomised, placebo‐controlled trial with 2 arms comparison of aprepitant 125/80 + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Recruitment period: n.r. 562 patients screened 530 patients randomised 521 patients (260 patients in the aprepitant group and 261 patients in the standard therapy group) included in the efficacy analysis Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria cisplatin‐naïve patients ≥ 18 years old Karnofsky score ≥ 60 scheduled to receive first cycle of chemotherapy including cisplatin ≥ 70 mg/m² female patients of childbearing potential required to have a negative beta human chorionic gonadotropin test result Exclusion criteria use of illicit drugs or signs of current alcohol abuse abnormal laboratory values (including WBC < 3000/mm³ and absolute neutrophil count < 1500/mm³, platelet count < 100,000/mm³, AST > 2.5 × ULN, ALT > 2.5 × ULN, bilirubin > 1.5 × ULN, or creatinine > 1.5 × ULN) uncontrolled disease for which, in the opinion of the investigator, the patient should be excluded for safety reasons multiple‐day cisplatin‐based chemotherapy in a single cycle radiation therapy to abdomen or pelvis within 1 week before study Day 1 or between Days 1 and 6 Mean age (range) ± SD, years: 59 (18 to 84) ± 12, aprepitant 125/80 regimen; 58 (19 to 83) ± 12, placebo group Gender: male + female Tumour/cancer type: solid malignancy (respiratory cancer, urogenital cancer, others) Chemotherapy regimen: cisplatin ≥ 70 mg/m² Country: 15 centres in United States, 14 centres in other countries
Interventions	Experimental: arm A: aprepitant 125/80 Day 1: p.o. aprepitant 125 mg + i.v. ondansetron 32 mg + p.o. dexamethasone 12 mg Days 2 to 3: p.o. aprepitant 80 mg + p.o. dexamethasone 8 mg Day 4: p.o. dexamethasone 8 mg Standard therapy: arm B Day 1: i.v. ondansetron 32 mg + p.o. dexamethasone 20 mg Days 2 to 4: p.o. dexamethasone 8 mg twice per day
Outcomes	Primary endpoint proportion of patients with complete response (no emetic episodes and no rescue therapy (i.e. medication taken for established nausea or vomiting) overall (Days 1 to 5)) Secondary endpoints no emesis no use of rescue therapy complete protection (no emesis, no rescue therapy, no significant nausea (VAS score < 25 mm)) total control (no emesis, no rescue therapy, no nausea (VAS score < 5 mm)) impact of CINV on daily life (as measured by FLIE total score > 108) no nausea (VAS score < 5 mm) no significant nausea (VAS score < 25 mm)
Notes	"this study was funded by Merck Research Laboratories, Whitehouse Station, NJ" "the sponsor managed the data and performed the analyses for this study" "no conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock: Alexandra D. Carides, Merck; Scott Reines, Merck; Judith K. Evans, Merck; Klaus Beck, Merck; Kevin J. Horgan, Merck. Acted as a consultant within the last 2 years: Paul J. Hesketh, Merck; Steven M. Grunberg, Merck; Ronald de Wit, Merck; Richard J. Gralla, Merck; Fausto Roila, Merck; David G. Warr, Merck; Sant P. Chawla, Merck. Performed contract work within the last 2 years: Paul J. Hesketh, Merck; Steven M. Grunberg, Merck; Ronald de Wit, Merck; Richard J. Gralla, Merck; Fausto Roila, Merck; David G. Warr, Merck; Sant P. Chawla, Merck. Received more than $2,000 a year from a company for either of the last 2 years: Paul J. Hesketh, Merck; Steven M. Grunberg, Merck; Ronald de Wit, Merck; Richard J. Gralla, Merck; Fausto Roila, Merck; Scott Reines, Merck; Mary E. Elmer, Merck; Judith K. Evans, Merck; Alexandra D. Carides, Merck; Juliana Ianus, Merck; Kevin J. Horgan, Merck" 052 study group
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... computer‐generated random assignment schedule ..."
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: a modified intent‐to‐treat approach, which included all patients who received cisplatin, took study drug, and had at least 1 post‐treatment assessment, was used to analyse the data
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "all patients who received cisplatin and at least one dose of study drug were included in the statistical analyses for safety"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Hesketh 2012.

Study characteristics
Methods	Randomised, active‐controlled, parallel‐group, phase 3 study with 2 arms comparison of casopitant + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Study period: 2008 March 10 to 13 April 2009 710 patients randomised 710 subjects included in the ITT population and 707 in the mITT population Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria males and non‐pregnant females ≥ 18 years of age receiving oxaliplatin doses between 85 and 130 mg/m² in first cycle of therapy Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 haematological and metabolic status adequate for receiving oxaliplatin had to be able to complete a study diary Exclusion criteria had received cytotoxic chemotherapy before the first study cycle (except for previous (neo)adjuvant therapy with 5‐FU/LV or capecitabine) completed at least 6 months before receiving the first dose of study antiemetics, or scheduled to receive radiation therapy or cytotoxic drugs other than study drugs in the 10 days before or the 6 days after the first study dose of antiemetics in the first cycle of chemotherapy if the investigator determined that the patient had experienced vomiting, retching, or clinically significant nausea within 24 h of study drug administration for each cycle, or was receiving or was scheduled to receive contraindicated treatments during the study period Median age (SD), years: 61.3 (11.03) in casopitant group, 61.3 (10.77) in placebo group Gender: male (392) + female (318) Tumour/cancer type: colorectal cancer Chemotherapy regimen: oxaliplatin doses between 85 and 130 mg/m² Country: 89 centres (hospitals or outpatient clinics) in 11 countries (multi‐centre)
Interventions	Experimental: arm A: casopitant casopitant + ondansetron + dexamethasone Control: arm B: placebo placebo + ondansetron + dexamethasone
Outcomes	Primary outcome percentage of participants who achieved complete response in the overall phase (0 to 120 h) Secondary outcome(s) percentage of participants who achieved complete response in the acute phase of Cycle 1 [Time frame: 0 to 24 h in the first cycle of chemotherapy] percentage of participants who achieved complete response in the delayed phase of Cycle 1 [Time frame: 24 to 120 h (delayed phase) in the first cycle of chemotherapy] percentage of participants who achieved complete response in the overall phase of Cycle 2 [Time frame: 0 to 120 h in the second cycle of chemotherapy] maximum nausea score, assessed by VAS [Time frame: 0 to 24 h, 24 to 120 h, and 0 to 120 h in the first cycle of chemotherapy] percentage of participants who received rescue medication [Time frame: 0 to 24 h, 24 to 120 h, and 0 to 120 h in the first cycle of chemotherapy] percentage of participants who vomited and/or retched [Time frame: 0 to 24 h, 24 to 120 h, and 0 to 120 h in the first cycle of chemotherapy] percentage of participants who reported significant nausea, defined as maximum score ≥ 25 mm on VAS [Time frame: 0 to 24 h, 24 to 120 h, and 0 to 120 h in the first cycle of chemotherapy] percentage of participants who reported nausea, defined as maximum score ≥ 5 mm on VAS [Time frame: 0 to 24 h, 24 to 120 h, and 0 to 120 h in the first cycle of chemotherapy] percentage of participants who achieved complete protection, defined as complete responders with no significant nausea [Time frame: 0 to 24 h, 24 to 120 h, and 0 to 120 h in the first cycle of chemotherapy] percentage of participants who achieved total control, defined as complete responders who had no nausea [Time frame: 0 to 24 h, 24 to 120 h, and 0 to 120 h in the first cycle of chemotherapy] percentage of participants whose daily life activities were impacted in the overall phase of Cycle 1 assessed by FLIE questionnaire [Time frame: 0 to 120 h in the first cycle of chemotherapy] severity of nausea in overall, acute, and delayed phases of Cycle 1 assessed by a categorical scale [Time frame: 0 to 24 h, 24 to 120 h, and 0 to 120 h in the first cycle of chemotherapy] single‐dose pharmacokinetic (PK) parameters: AUC 0 to infinity (0 to ∞), AUC 0 to t (0 to t) and AUC 0 to 24 h (0 to 24) for casopitant; AUC (0 to t) and AUC (0 to 24) for metabolites GSK525060, GSK517142, and GSK631832 [Time frame: pre‐dose, end of infusion, and 0.5, 1, 3, 5, 8, 12, 16, 24 h after the end of infusion] single‐dose pharmacokinetic parameters: maximum observed drug concentration (Cmax) for casopitant and metabolites GSK525060, GSK517142, and GSK631832 [Time frame: pre‐dose, end of infusion, and 0.5, 1, 3, 5, 8, 12, 16, 24 h after the end of infusion] single‐dose pharmacokinetic parameters: time to maximum observed drug concentration (Tmax) and observed elimination half‐life (t1/2) for casopitant and metabolites GSK525060, GSK517142, and GSK631832 [Time frame: pre‐dose, end of infusion, and 0.5, 1, 3, 5, 8, 12, 16, 24 h after the end of infusion] single‐dose pharmacokinetic parameters: clearance (CL) for casopitant [Time frame: pre‐dose, end of infusion, and 0.5, 1, 3, 5, 8, 12, 16, 24 h after the end of infusion] single‐dose pharmacokinetic parameters: volume of distribution (Vdss) for casopitant [Time frame: pre‐dose, end of infusion, and 0.5, 1, 3, 5, 8, 12, 16, 24 h after the end of infusion] number of participants with adverse events (AEs) and serious adverse events (SAEs) [Time frame: up to 35 days] number of participants with haematology toxicity grade shifts from baseline to toxicity grades 3 and 4 [Time frame: baseline (Day 1) to Day 24] number of participants with clinical chemistry toxicity grade shifts from baseline to toxicity grades 3 and 4 [Time frame: up to Day 24] evaluation of vital signs: mean diastolic blood pressure (DBP) and systolic blood pressure (SBP) [Time frame: up to end of cycle for 6 cycles, average of 24 days per cycle] evaluation of vital signs: mean heart rate [Time frame: up to end of cycle for 6 cycles, average of 24 days per cycle] time to first antiemetic rescue medication [Time frame: 0 to 120 h in first cycle of chemotherapy] time to first emetic event [Time frame: 0 to 120 h in first cycle of chemotherapy]
Notes	ClinicalTrials.gov Identifier: NCT00601172 "sponsors and collaborators: GlaxoSmithKline" "S.L., M.R., J.L., and O.W. receive remuneration from GSK. S.L. and M.R. may own stock and/or hold stock options in the company. P.D. is a consultant and/or holds an advisory role for Sanofi Aventis, Novartis, Roche, and AstraZeneca. P.H. is a consultant and/or holds an advisory role for Merck, Eisai, Hellsin, and GSK. P.H. receives funding from Merck and Eisai"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. neutropenia)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "the efficacy endpoints were analyzed for the modified intention to treat (MITT) population which comprised the subset of the intention to treat (ITT) population who received any investigational product and had oxaliplatin administered"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "the safety population included all subjects who received any investigational product"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section and in the study registry
Other bias	Low risk	Comment: no information to suggest other sources of bias

Hesketh 2014.

Study characteristics
Methods	Randomised, parallel‐group, phase 2 trial with 5 arms comparison of placebo + palonosetron + dexamethasone vs netupitant (100 mg) + palonosetron + dexamethasone vs netupitant (200 mg) + palonosetron + dexamethasone vs netupitant (300 mg) + palonosetron + dexamethasone vs aprepitant + ondansetron + dexamethasone Recruitment period: 2008 694 patients randomised 677 patients included in the full analysis set Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria ≥ 18 years with diagnosed histologically or cytologically confirmed malignant solid tumour naïve to chemotherapy and scheduled to receive first course of cisplatin‐based chemotherapy at a dose ≥ 50 mg/m² alone or in combination with other chemotherapy agents Karnofsky performance score ≥ 70% able to follow study procedures and complete patient diary Exclusion criteria MEC or HEC from Day 2 to Day 5 following chemotherapy moderately or highly emetogenic radiotherapy within 1 week before Day 1 or from Day 2 to Day 5 bone marrow or stem cell transplant received any drug with potential antiemetic efficacy within 24 h or systemic corticosteroids within 72 h before Day 1 experienced any vomiting or retching, or more than mild nausea, within 24 h before Day 1 no serious cardiovascular disease history or predisposition to cardiac conduction abnormalities, with the exception of incomplete right bundle branch block as NETU is a moderate inhibitor of CYP3A4, long‐term use of any CYP3A4 substrates/inhibitors/inducers or intake within 1 week (substrates/inhibitors) or 4 weeks (inducers) before Day 1 Median age, years: 55 (PALO), 55 (NEPA100), 55 (NEPA200), 53 (NEPA300), 55.5 (APR + OND) Gender: male (386) + female (291) Tumour/cancer type: solid tumour (lung/respiratory, head and neck, ovarian, other urogenital, gastric, other GI, breast, other) Chemotherapy regimen: cisplatin‐based chemotherapy at a dose ≥ 50 mg/m² alone or in combination with other chemotherapy agents Country: 29 sites in Russia, 15 sites in Ukraine
Interventions	Experimental: arm A: PALO Day 1: p.o. palonosetron 0.50 mg + p.o. dexamethasone 20 mg + placebo Days 2 to 4: p.o. dexamethasone 8 mg b.i.d. Experimental: arm B: NEPA100 Day 1: p.o. netupitant 100 mg + p.o. palonosetron 0.50 mg + p.o. dexamethasone 12 mg Days 2 to 4: p.o. dexamethasone 4 mg b.i.d. Experimental: arm C: NEPA200 Day 1: p.o. netupitant 200 mg + p.o. palonosetron 0.50 mg + p.o. dexamethasone 12 mg Days 2 to 4: p.o. dexamethasone 4 mg b.i.d. Experimental: arm D: NEPA300 Day 1: p.o. netupitant 300 mg + p.o. palonosetron 0.50 mg + p.o. dexamethasone 12 mg Days 2 to 4: p.o. dexamethasone 4 mg b.i.d. Experimental: arm E: APR + OND Day 1: p.o. aprepitant 125 mg + i.v. ondansetron 32 mg + p.o. dexamethasone 12 mg Days 2 to 3: p.o. aprepitant 80 mg in morning + p.o. dexamethasone 4 mg b.i.d. Day 4: p.o. dexamethasone 4 mg b.i.d.
Outcomes	Primary efficacy endpoint complete response during the overall (0 to 120 h) phase post chemotherapy Secondary efficacy endpoints CR rates during acute (0 to 24 h) and delayed (25 to 120 h) phases no emesis no significant nausea (VAS score < 25 mm) complete protection (CR + no significant nausea) rates during acute/delayed/overall phases safety
Notes	"this work was supported by Helsinn Healthcare, SA, who provided the study drugs and the funding for this study" conflicts of interest: "PH: non‐compensated consultant for Helsinn Healthcare. MP, G. Rossi, and G. Rizzi: employees of Helsinn Healthcare. RG: advisor for Merck, Helsinn Healthcare, and Eisai. All remaining authors have declared no conflicts of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. hiccups, study mortality)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "15 patients did not receive study treatment and were not included in the safety population and 677 (98%) patients were included in the full analysis set"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "15 patients did not receive study treatment and were not included in the safety population and 677 (98%) patients were included in the full analysis set"; and "one patient (NEPA100) died during the study due to multiple organ failure. His death was not considered related to study medication"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Ho 2010.

Study characteristics
Methods	Randomised, parallel, comparative, active‐control trial with 2 arms comparison of ramosetron + dexamethasone vs granisetron + dexamethasone Recruitment period: January 2006 to December 2007 288 patients enrolled 287 patients randomised 262 patients evaluable Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria 20 to 74 years old (inclusive) of either sex i.v. infusion, alone in 1 single dose or combined with other chemotherapy regimens: cisplatin ≥ 50 mg/m², with infusion time 2 h ± 10 min; doxorubicin ≥ 50 mg/m², with infusion time ≤ 1 h; epirubicin ≥ 60 mg/m², with infusion time ≤ 1 h; and oxaliplatin ≥ 65 mg/m², with infusion time 2 h ± 10 min no symptoms of vomiting for at least 1 week before dosing trial medication Eastern Cooperative Oncology Group (ECOG) performance status scale no greater than 2 (ECOG 2) Exclusion criteria had received radiotherapy to abdomen or pelvis within 4 weeks before entering this study had received chemotherapy including 1 of 4 regimens, namely, cisplatin, doxorubicin, epirubicin, or oxaliplatin, within 6 months before entering the study known heart failure or myocardial infarction or laboratory abnormalities at screening including serum creatinine more than 2 × ULN, AST and ALT more than 3 × ULN  known concurrent disease that may cause vomiting, such as gastrointestinal tract obstruction, epilepsy, brain metastasis, brain tumour, or intracranial hypertension had taken medications that could influence the outcome of the study within 3 days before entering the study, such as antiepilepsy drugs, antiemetics, antipsychotics, or adrenocorticoids history of allergy or intolerance to ramosetron, granisetron, or dexamethasone pregnant or breast‐feeding life expectancy < 3 months participated in other investigational drug trial within 1 month before entering this study Median age (range), years: 51 (29 to 73) in ramosetron + dexamethasone group, 51 (22 to 74) in granisetron + dexamethasone group Gender: male (110) + female (175) Tumour/cancer type: solid malignancy (breast, lung, nasopharynx, mouth, rectum, liver, bladder, stomach, oesophagus, testis, brain, other) Chemotherapy regimen: cisplatin, doxorubicin, epirubicin, or oxaliplatin Country: Taiwan (4 centres)
Interventions	Experimental: arm A: ramosetron + dexamethasone ramosetron 0.3 mg + dexamethasone 20 mg Experimental: arm B: granisetron + dexamethasone granisetron 3 mg + dexamethasone 20 mg
Outcomes	Primary endpoint complete response (CR) rate (24 h after the start of chemotherapy) Secondary endpoint(s) To be evaluated during first, second, third, and fourth 6‐h durations and total 24‐h period after the start of chemotherapy proportion of patients with vomiting nausea degree evaluated by patient’s 10‐cm visual analogue scale (VAS) total control rate with no vomiting plus nausea VAS 0.5 cm proportion of subjects that had received rescue drug(s)
Notes	"this trial was sponsored by Astellas Pharma Taiwan, Inc." conflicts of interest: "none declared"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: Both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included for the efficacy analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: safety data were reported for all randomised patients who received the study drug
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Hu 2014.

Study characteristics
Methods	Randomised, placebo‐controlled, phase 3 trial with 2 arms comparison of an aprepitant + granisetron + dexamethasone vs placebo + granisetron + dexamethasone Study period: August 2009 to April 2010 438 patients screened 421 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: follow‐up on Days 19 to 29
Participants	Inclusion criteria ≥ 18 years old with Karnofsky score ≥ 60 scheduled to receive his/her first course of cisplatin chemotherapy at a dose ≥ 70 mg/m² administered a maximum of 3 h predicted life expectancy ≥ 3 months not pregnant Exclusion criteria current illicit drug use evidence of alcohol abuse symptomatic primary or metastatic CNS malignancy administration of chemotherapy of moderate or high emetogenicity within prior 6 days scheduled administration of abdomen/pelvis radiation therapy within 1 week scheduled administration of multiple‐day chemotherapy with cisplatin in a single cycle or stem cell rescue therapy with cisplatin chemotherapy active infection or other uncontrolled disease concurrent medical condition precluding dexamethasone administration abnormal laboratory findings of white blood count < 3000/mm³, absolute neutrophil count < 1500/mm³, platelet count < 100,000/mm³, aspartate transaminase > 2.5 × ULN, ALT > 2.5 × ULN, bilirubin > 1.5 × ULN, or creatinine > 1.5 × ULN Mean age ± SD, years : 53.1 ± 10.1 (aprepitant regimen), 53.6 ± 10.6 (placebo group) Median age, years: 56 (aprepitant regimen), 54 (placebo group) Gender: male + female Tumour/cancer type: solid tumour (lung cancer, nasopharyngeal cancer, gastrointestinal cancer, reproductive cancer, breast cancer, lymphoma, other) Chemotherapy regimen: cisplatin (≥ 70 mg/m²) Country: China (16 independent centres)
Interventions	Experimental: arm A: aprepitant regimen Day 1: aprepitant 125 mg p.o. + granisetron 3 mg i.v. + dexamethasone 6 mg p.o. Day 2: aprepitant 80 mg p.o. + dexamethasone 3.75 mg p.o. Day 3: aprepitant 80 mg p.o. + dexamethasone 3.75 mg p.o. Day 4: dexamethasone 3.75 mg p.o. Standard: arm A Day 1: placebo + granisetron 3 mg i.v. + dexamethasone 10.5 mg p.o. Day 2: placebo + dexamethasone 7.5 mg p.o. Day 3: placebo + dexamethasone 7.5 mg p.o. Day 4: dexamethasone 7.5 mg p.o.
Outcomes	Primary endpoint proportion of participants with complete response 120 h following initiation of high‐dose cisplatin chemotherapy in the overall phase of Cycle 1 [Time frame: 0 to 120 h] Secondary endpoints · proportion of participants with complete response in the acute phase of Cycle 1 [Time frame: 0 to 24 h] proportion of participants with complete response in the delayed phase of Cycle 1 [Time frame: 25 to 120 h] proportion of participants with no vomiting in the overall phase of Cycle 1 [Time frame: 0 to 120 h] proportion of participants with no vomiting in the acute phase of Cycle 1 [Time frame: 0 to 24 h] proportion of participants with no vomiting in the delayed phase of Cycle 1 [Time frame: 25 to 120 h] proportion of participants with no impact on daily life in Cycle 1 [Time frame: 0 to 120 h] time to first vomiting episode in Cycle 1 [Time frame: 0 to 120 h]
Notes	"the study was registered with ClinicalTrials.gov in the USA as NCT00952341" "this study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA" conflicts of interest: "Li Zhang has received research support from Boehringer Ingelheim, Bayer, Astra Zeneca, Lilly, and Sanofi Aventis. Denesh K. Chitkara and Darcy A. Hille are employees of Merck and may own stock or stock options in the company. All remaining authors have declared no conflicts of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: computer‐generated randomisation
Allocation concealment (selection bias)	Low risk	Quote: "... computer‐generated blinded allocation ..."
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "all patients treated with cisplatin or aprepitant who underwent one or more posttreatment assessments were included in the modified intent‐to‐treat analysis"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: safety data were reported for all randomised patients who received the study drug
Selective reporting (reporting bias)	Low risk	Comment: all outcomes were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Innocent 2018.

Study characteristics
Methods	Randomised, cross‐over study with 2 arms comparison of ondansetron + dexamethasone vs granisetron + dexamethasone Recruitment period: n.r. 34 patients enrolled Masking: double‐blind Baseline patient characteristics: n.r. Follow‐up: yes
Participants	Inclusion criteria 18 years of age or older cancer patients Exclusion criteria: n.r. Mean age, years: 53.5 Gender: male (10) + female (24) Tumour/cancer type: cervical cancer and head and neck cancers were predominant Chemotherapy regimen: cisplatin‐based Country: n.r.
Interventions	Cross‐over study Experimental: arm A: ondansetron Day 1: ondansetron 12 mg i.v. + dexamethasone 8 mg i.v. Days 2 to 5: ondansetron 8 mg p.o. b.d. + dexamethasone 4 mg p.o. b.d. Experimental: arm B: granisetron Day 1: granisetron 12 mg i.v. + dexamethasone 8 mg i.v. Days 2 to 5: granisetron 1 mg p.o. b.d. + dexamethasone 4 mg p.o. b.d.
Outcomes	acute nausea delayed nausea no nausea mild nausea moderate nausea severe nausea acute vomiting delayed vomiting complete response major response minor response failure
Notes	financial support: Rwanda Military Hospital conflicts of interest: "the authors declare that, the research has been conducted without any conflict of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised study but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote. "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote. "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included in the patient‐reported outcome analysis
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Ishido 2016.

Study characteristics
Methods	Randomised, cross‐over, phase 2 trial with 2 arms comparison of aprepitant + granisetron + dexamethasone vs palonosetron + dexamethasone Recruitment period: November 2010 to August 2013 85 patients enrolled 84 patients evaluated for efficacy analysis (1 patient died) Masking: open‐label Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria 20 to 79 years old advanced or recurrent oesophageal or gastric carcinoma chemotherapy‐naïve 2 or more courses of chemotherapy including cisplatin ≥ 60 mg/m² Exclusion criteria no previous chemotherapy serious heart disease, serious renal disease, serious liver disease, poorly controlled diabetes woman during pregnancy or with possibility of pregnancy severe mental disorder allergic past history for serotonin receptor antagonist nausea, vomiting due to brain tumour or ileus planning to receive radiotherapy for chest, abdomen, or pelvis using antiemetic drug within 48 h before chemotherapy judged by the investigator as inappropriate for study entry Median age (range), years: 65 (30 to 75) in aprepitant + granisetron + dexamethasone group, 64 (33 to 77) in palonosetron + dexamethasone group Gender: male + female Tumour/cancer type: advanced or recurrent oesophageal or gastric cancer Chemotherapy regimen S‐1 and cisplatin (SP) S‐1, cisplatin, and docetaxel (DCS) docetaxel, cisplatin, and 5‐fluorouracil (DCF) capecitabine, cisplatin, and trastuzumab (XPT) Country: Japan (single centre)
Interventions	Cross‐over trial Experimental: arm A: aprepitant + granisetron + dexamethasone, then palonosetron + dexamethasone 1 h before start of treatment with cisplatin: 125 mg aprepitant (administered p.o.) + 3 mg granisetron (administered i.v.) + 6.6 mg dexamethasone (administered i.v.) after 24 h and 48 h: 80 mg aprepitant (administered p.o.) + 4 mg dexamethasone (administered p.o.) during second cycle, study treatments were crossed over, that is, aprepitant + granisetron + dexamethasone group received palonosetron + dexamethasone Experimental: arm B: palonosetron + dexamethasone, then aprepitant + granisetron + dexamethasone before treatment with cisplatin: 0.75 mg palonosetron (administered i.v.) + 13.2 mg dexamethasone (administered i.v.) after 24 h and 48 h: 8 mg dexamethasone (administered p.o.) during second cycle, study treatments were crossed over, that is, palonosetron + dexamethasone group received aprepitant + granisetron + dexamethasone
Outcomes	Primary endpoint complete response within 120 h after start of the first course of chemotherapy Secondary endpoints incidences of nausea and vomiting developing within 120 h and proportion of patients who received rescue medication during the first cycle patient preference quality of life assessed on the basis of the FLIE questionnaire adverse events food intake status
Notes	study registered with University Hospital Medical Information Network Clinical Trials Registry (UMIN‐CTR) of Japan (ID UMIN 000005623) self‐funded by Kitasato University School of Medicine, Department of Gastroenterology conflicts of interest: "there are no conflicts of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients scheduled to receive chemotherapy who provided informed consent were assigned randomly to receive AGD or PD in a 1: 1 ratio"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... open ‐no one is blinded ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... open ‐no one is blinded ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: although this was an open‐label study, both patients and personnel had no influence on objective outcomes (e.g. hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "effectiveness and safety were evaluated in the remaining 84 patients ..."
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "effectiveness and safety were evaluated in the remaining 84 patients ..."
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were described in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Ito 2014.

Study characteristics
Methods	Randomised, parallel‐group, phase 2 study with 2 arms comparison of aprepitant + 5‐HT₃ receptor antagonist + dexamethasone vs 5‐HT₃ receptor antagonist + dexamethasone Enrolment period: n.r. 134 patients enrolled and randomised Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria aged ≥ 20 years chemotherapy‐naïve with pathologically confirmed inoperable stage IIIB or IV NSCLC who received carboplatin‐based chemotherapy adequate haematopoietic, renal, and hepatic function Exclusion criteria nausea and vomiting within 24 h or use of antiemetic agents within 48 h before administration of chemotherapy use of pimozide uncontrolled diabetes mellitus symptomatic brain metastasis gastrointestinal obstruction active gastrointestinal ulcer Median age (range), years: 67 (34 to 84) in aprepitant group, 66 (44 to 81) in control group Gender: male (110) + female (24) Tumour/cancer type: adenocarcinoma, squamous cell carcinoma, other Chemotherapy regimen: carboplatin + paclitaxel, carboplatin + paclitaxel + bevacizumab, carboplatin + pemetrexed, carboplatin + pemetrexed + bevacizumab Country: Japan (multi‐centre)
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg + first‐generation 5‐HT₃ antagonist + dexamethasone 8 mg Days 2 to 3: aprepitant 80 mg + dexamethasone 8 mg Control: arm B Day 1: first‐generation 5‐HT₃ antagonist + dexamethasone 8 mg Days 2 to 3: dexamethasone 8 mg
Outcomes	Primary endpoint complete response rate in the overall phase (during 120 h after administration of chemotherapy agents) Secondary endpoint(s) complete response rate in the acute phase (during first 24 h after administration of chemotherapy agents) complete response rate in the delayed phase (from 24 to 120 h after chemotherapy) nausea in overall, acute, and delayed phases safety
Notes	"no financial support was provided for this study" conflicts of interest: "all authors declare no actual or potential conflicts of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomization was done centrally using a computer program and stratified by sex and non‐platinum agent"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... open‐label ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... open‐label ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: although this was an open‐label study, both patients and personnel had no influence on objective outcomes (e.g. hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: 1 patient discontinued due to anaphylactic shock, and remaining 133 patients were included in the efficacy analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "all 134 patients (including one patient who could not complete chemotherapy because of anaphylactic shock due to paclitaxel) were included in the safety analysis"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Unclear risk	Quote: "additional antiemetic agents and other supportive treatments were administered at the discretion of the treating physicians"

Jantunen 1992.

Study characteristics
Methods	Randomised, prospective, cross‐over study with 2 arms comparison of ondansetron + dexamethasone vs tropisetron + dexamethasone Enrolment period: n.r. 47 patients entered Masking: open‐label Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria outpatients and inpatients designated to receive 2 similar courses of non‐cisplatin‐containing chemotherapy separated by at least 14 days Exclusion criteria brain metastases signs of bowel obstruction experienced vomiting within 12 h before start of the study Median age, years: 58.3 in males, 49.5 in females Gender: male (14) + female (33) Tumour/cancer type: solid tumour (breast, lung, melanoma, other) Chemotherapy regimen: non‐cisplatin‐containing chemotherapy (CNF, CMF, CEF, VAC, carboplatin‐containing, DTIC‐containing, epirubicin‐containing, MTX‐5‐FU, MMM) Country: n.r.
Interventions	Cross‐over study Experimental: arm A: ondansetron 8 mg ondansetron + 10 mg dexamethasone (loading dose of ondansetron was followed by 8 mg ondansetron given orally twice at 8‐h intervals) Experimental: arm B: tropisetron 5 mg tropisetron + 10 mg dexamethasone
Outcomes	control of vomiting during first 24 h was scored as total: no vomiting partial: 1 to 4 vomits failure: more than 4 vomits
Notes	no information regarding sponsor and clinical trial registration reported study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Comment: open‐label
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Comment: open‐label
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "thirty‐nine patients were evaluable for cross‐over analysis"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Jordan 2016a.

Study characteristics
Methods	Randomised, parallel, phase 3 study with 2 arms comparison of netupitant + palonosetron + dexamethasone vs aprepitant + palonosetron + dexamethasone Enrolment period: July 2011 to September 2012 196 patients evaluated from NCT01376297 receiving carboplatin Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria signed written informed consent naïve to cytotoxic chemotherapy; previous biological or hormonal therapy permitted diagnosed malignant tumour if scheduled to receive repeated consecutive courses of chemotherapy, a single dose of 1 or more of the following agents administered on Day 1 is allowed highly emetogenic chemotherapy: any i.v. dose of cisplatin, mechlorethamine, streptozocin, cyclophosphamide ≥ 1500 mg/m², carmustine, dacarbazine moderately emetogenic chemotherapy: any i.v. dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin, cyclophosphamide i.v. (< 1500 mg/m²), cytarabine i.v. (> 1 g/m²), azacitidine, alemtuzumab, bendamustine, or clofarabine if scheduled to receive combination regimens, the most emetogenic agent to be given as first on Day 1 and infusion must be completed within 6 h if scheduled to receive chemotherapy agents of minimal to low emetogenic potential, to be given on Day 1 following the most emetogenic agent or on any subsequent study day ECOG performance status 0, 1, or 2 female patients of non‐child‐bearing potential or child‐bearing potential with commitment to use contraceptive methods throughout the clinical trial haematological and metabolic status adequate for receiving a moderately emetogenic regimen based on laboratory criteria (total neutrophils, platelets, bilirubin, liver enzymes, serum creatinine, or creatinine clearance) Exclusion criteria if female, lactating or pregnant current use of illicit drugs or current evidence of alcohol abuse scheduled to receive cyclophosphamide i.v. (500 to 1500 mg/m²) and i.v. doxorubicin (≥ 40 mg/m²), or cyclophosphamide i.v. (500 to 1500 mg/m²) and i.v. epirubicin (≥ 60 mg/m²) scheduled to receive moderately or highly emetogenic chemotherapy from Day 2 to Day 5 following Day 1 chemotherapy administration active infection or uncontrolled disease except for malignancy that may pose unwarranted risks in administering study drugs to the patient known hypersensitivity or contraindication to 5‐HT₃ receptor antagonists or dexamethasone previously received an NK₁ receptor antagonist participation in a clinical trial involving oral netupitant administered in combination with palonosetron any investigational drugs taken within 4 weeks before Day 1 of Cycle 1, and/or scheduled to receive any investigational drug during the study systemic corticosteroid therapy at any dose within 72 h before Day 1 of Cycle 1; topical and inhaled corticosteroids with steroid dose ≤ 10 mg of prednisone daily or its equivalent are permitted; non‐study drug dexamethasone as pre‐medication in patients scheduled to receive taxanes is allowed scheduled to receive bone marrow transplantation and/or stem cell rescue therapy scheduled to receive any strong or moderate inhibitor of CYP3A4 or its intake within 1 week before Day 1 scheduled to receive any of the following CYP3A4 substrates: terfenadine, cisapride, astemizole, pimozide scheduled to receive any CYP3A4 inducer or its intake within 4 weeks before Day 1 history or predisposition to cardiac conduction abnormalities, except for incomplete right bundle branch block history of risk factors for torsades de pointes (heart failure, hypokalaemia, family history of long QT syndrome) severe cardiovascular disease within 3 months before Day 1, including myocardial infarction, unstable angina pectoris, significant valvular or pericardial disease, history of ventricular tachycardia, symptomatic congestive heart failure, and severe uncontrolled arterial hypertension any illness or condition that, in the opinion of the investigator, may confound results of the study or pose unwarranted risk in administering the investigational product to the patient concurrent medical condition that would preclude administration of dexamethasone for 4 days such as systemic fungal infection or uncontrolled diabetes Mean age ± SD, years: 57 ± 10 in NEPA group, 58 ± 11 in APR + PALO group Gender: male (106) + female (90) Tumour/cancer type: solid malignancy (lung/respiratory, gynaecological, head and neck, breast, other) Chemotherapy regimen: carboplatin Country: multi‐national, multi‐centre
Interventions	Experimental: arm A: netupitant + palonosetron + dexamethasone oral netupitant/palonosetron (300 mg/0.50 mg) hard capsule (on Day 1) with oral dexamethasone before each scheduled chemotherapy cycle Active comparator: arm B: aprepitant + palonosetron + dexamethasone oral aprepitant hard capsule 125 mg (on Day 1) + 80 mg daily (for the following 2 days) and oral palonosetron soft capsule 0.50 mg (on Day 1) given with oral dexamethasone at each scheduled chemotherapy cycle
Outcomes	overall complete response rate (0 to 120 h) proportion of patients with no significant nausea (0 to 120 h)
Notes	ClinicalTrials.gov: NCT01376297 oral DEX was open‐label and identical in both groups study authors acknowledged Jennifer Vanden Burgt for editorial support during writing of this manuscript, funded by Eisai, Inc. "the NEPA study was supported by Helsinn Healthcare, SA, who provided the study drugs and the funding for this study" conflicts of interest: "Karin Jordan: consultant and advisor for Helsinn Healthcare, Merck, MSD, and Tesaro. Richard Gralla: advisor for Eisai, Helsinn Healthcare, Merck, and Tesaro. Kimia Kashef: employee of Eisai, Inc. Giada Rizzi: employee of Helsinn Healthcare"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were randomly allocated in a 3:1 ratio to receive one of the following treatments ..."
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all included patients have been analysed in the efficacy analysis
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Kalaycio 1998.

Study characteristics
Methods	Randomised trial with 2 arms comparison of granisetron + dexamethasone vs ondansetron + dexamethasone Enrolment period: September 1994 to April 1996 48 patients enrolled 45 patients evaluated Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria histologically proven breast cancer and treated in an adjuvant fashion for high‐risk localised disease or for metastatic disease; none had a history of intolerance to either ondansetron or granisetron Exclusion criteria central nervous system disease receiving antiemetics at the time of study entry active peptic ulcer disease, uncontrolled diabetes mellitus, other contraindications for corticosteroids Median age, years: 43.5 in granisetron group, 43 in ondansetron group Gender: n.r. Tumour/cancer type: breast cancer Chemotherapy regimen: 1500 mg cyclophosphamide/m²/d, 125 mg thiotepa/m²/d, 200 mg carboplatin/m²/d Country: n.r.
Interventions	Experimental: arm A: granisetron granisetron as a 0.5‐mg i.v. bolus 30 min before chemotherapy followed by continuous infusion of 0.04 mg/h (1 mg/d) for 7 days + 10 mg dexamethasone/d i.v. for 7 days Experimental: arm B: ondansetron ondansetron as 8‐mg i.v. bolus 30 min before chemotherapy followed by continuous infusion of 1 mg/h (24 mg/d) for 7 days + 10 mg dexamethasone/d i.v. for 7 days
Outcomes	Primary endpoint subjective feelings of nausea and headache episodes of emesis adverse events
Notes	"the costs of granisetron and ondansetron were obtained from the Cleveland Clinic Foundation Department of Pharmacy" study authors did not provide disclosure of conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... computer generated a list whereby each patient was assigned to either arm 1 or arm 2 as they were enrolled on the trial"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "both patient and treatment team remained blinded to the identity of the study drug throughout the patient's hospitalization"
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "both patient and treatment team remained blinded to the identity of the study drug throughout the patient's hospitalization"
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote. "of the 48 patients enrolled, 45 were evaluable"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: all patients were included for assessed adverse events Comment: not reported
Selective reporting (reporting bias)	Low risk	Comment: outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Kang 2020.

Study characteristics
Methods	Randomised trial with 2 arms comparison of aprepitant + ramosetron + dexamethasone vs aprepitant + palonosetron + dexamethasone Enrolment period: August 2015 to September 2017 309 patients evaluated 292 patients randomised Masking: single‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria age 19 to 75 years pathologically confirmed malignant disease Eastern Cooperative Oncology Group performance status 0 to 2 scheduled to receive HEC on first day of treatment required to have adequate bone marrow, hepatic, and renal function Exclusion criteria medications, medical illness, or medical conditions and procedures that could affect nausea or vomiting Mean age (SD), years: 59.4 (12.0) in ramosetron group, 60.3 (11.8) in palonosetron group Gender: 37.2% (62.8% male) female in ramosetron group, 38.7% female (61.3% male) in palonosetron group Tumour/cancer type: solid tumours (lung and thymus, breast, head and neck, gynaecological and genitourinary, gastrointestinal, others) Chemotherapy regimen: individual highly emetogenic chemotherapies: 71.5% in ramosetron group, 72.5% in palonosetron group received cisplatin Country: Korea, multi‐centre
Interventions	Experimental: arm A: ramosetron aprepitant (Day 1, 125 mg p.o. 1 h before chemotherapy; Days 2 to 3, 80 mg p.o.), ramosetron (Day 1, 0.3 mg i.v. 30 min before chemotherapy), and dexamethasone (Day 1, 12 mg p.o. or i.v. 30 min before chemotherapy; Days 2 to 4, 8 mg p.o.) Experimental: arm B: palonosetron aprepitant (Day 1, 125 mg p.o. 1 h before chemotherapy; Days 2 to 3, 80 mg p.o.), palonosetron (Day 1, 0.25 mg i.v. 30 min before chemotherapy), and dexamethasone (Day 1, 12 mg p.o. or i.v. 30 min before chemotherapy; Days 2 to 4, 8 mg p.o.)
Outcomes	Primary endpoint overall complete response (CR), defined as no vomiting, including retching, and no requirement for rescue antiemetics within 5 days of HEC Secondary endpoints CR, complete protection (CP; CR + nausea score < 25 mm; 0 to 100 mm), and total control (TC; CR + nausea score < 5 mm; 0 to 100 mm) in acute (0 to 24 h), delayed (Day 2 to Day 5), and overall (Day 0 to Day 5) periods severity of nausea (determined using a 0 to 100 mm visual analogue scale); time to first occurrence of vomiting; QoL assessed by validated patient self‐assessment Functional Living Index‐Emesis (FLIE) questionnaire safety, clinical, and laboratory adverse events (AEs) between start day and day before the next chemotherapy, assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI‐CTCAE)
Notes	"funding from Astellas Pharma Korea, Inc." "JH Kang has acted as an advisor for Amgen, Roche, Merck, MSD, Ono/BMS, AstraZeneca, YooHan, SL Bigen, has received research funding from AstraZeneca, Boehringer Ingelheim, Ono, Yoohan, and ChongKunDang, and has acted as a speaker for AstraZeneca,Roche, Merck, and Boehringer Ingelheim. JH Sohn has received research funding from MSD, Roche, Novartis, AstraZeneca, Lilly,Pfizer, Bayer, GSK, CONTESSA, and Daiichi Sankyo. JS Ahn reports personal fees from Amgen, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Menarini, personal fees from Roche, personal fees from Eisai, personal fees from BoehringerIngelheim, personal fees from BMS‐Ono, personal fees from MSD, personal fees from Janssen, personal fees from Samsung Bioepis,outside the submitted work. All remaining authors declare no conflicts of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "stratified block randomization was conducted with a 1:1 ratio between groups, randomly mixing block sizes of 2 and 4, considering (1) chemotherapeutic regimen (cisplatin vs.non‐cisplatin), (2) treatment schedule (single‐day vs. multiple‐ day), and (3) sex (male vs. female), as stratification factors"; "patients were assigned according to a pre‐defined randomization sequence created by an independent investigator with no clinical involvement in the trial"
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Single‐blinded; participants were not aware of treatment
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Physicians were aware of treatment
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Outcome assessors (participants) were blinded to intervention
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Outcome was robust to blinding
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	High risk	Modified ITT was analysed (participants who received at least 1 treatment)
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	High risk	Safety population (ITT) analysed, but not all participants received intervention
Selective reporting (reporting bias)	Low risk	No reasons for any concerns detected
Other bias	Low risk	No other sources of bias detected

Kaushal 2010.

Study characteristics
Methods	Randomised, cross‐over study with 2 arms comparison of palonosetron + dexamethasone vs ondansetron + dexamethasone Enrolment period: n.r. 30 patients randomised Masking: open‐label Baseline patient characteristics: not reported Follow‐up: n.r.
Participants	Inclusion criteria histologically confirmed head and neck cancers receiving moderately emetogenic cancer chemotherapeutic drugs at the Department of Radiotherapy, Post Graduate Institute of Medical Sciences, Rohtak, India Exclusion criteria receiving antiemetic therapy and developed nausea and vomiting 24 h before cancer chemotherapeutic drug administration, or had nausea and vomiting due to any other cause (e.g. intestinal obstruction, uraemia, raised intracranial pressure) several concurrent illnesses other than neoplasms (e.g. acute) peptic ulcer, severe diabetes mellitus receiving concurrent therapy with corticosteroids grossly abnormal liver function tests except when attributed to liver metastasis pregnant Mean/median age, years: n.r. Gender: n.r. Tumour/cancer type: head and neck cancer Chemotherapy regimen: moderately emetogenic cancer chemotherapeutic drugs (i.v. docetaxel 60 mg/m², i.v. carboplatin 300 mg/m², and i.v. 5‐fluorouracil 600 mg/m²) Country: India (single centre)
Interventions	Cross‐over study Experimental: arm A: palonosetron palonosetron 0.25 mg i.v. + dexamethasone 16 mg i.v. (half hour before chemotherapy) Experimental: arm B: ondansetron ondansetron 16 mg i.v. + dexamethasone 16 mg i.v. (half hour before chemotherapy)
Outcomes	number of patients with complete response in acute (Day 1), delayed (Days 2 to 5) and overall (Days 1 to 5) phases number of patients with major response in acute (Day 1), delayed (Days 2 to 5), and overall (Days 1 to 5) phases number of patients with minor response in acute (Day 1), delayed (Days 2 to 5), and overall (Days 1 to 5) phases number of patients with failure in acute (Day 1), delayed (Days 2 to 5), and overall (Days 1 to 5) phases number of patients with no nausea in acute (Day 1), delayed (Days 2 to 5), and overall (Days 1 to 5) phases number of patients with mild nausea in acute (Day 1), delayed (Days 2 to 5), and overall (Days 1 to 5) phases number of patients with moderate nausea in acute (Day 1), delayed (Days 2 to 5), and overall (Days 1 to 5) phases number of patients with severe nausea in acute (Day 1), delayed (Days 2 to 5), and overall (Days 1 to 5) phases
Notes	no information regarding sponsor and clinical trial registration reported study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Comment: open‐label
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Comment: open‐label
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all 30 patients have been included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Kaushal 2015.

Study characteristics
Methods	Randomised, prospective study with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs ondansetron + dexamethasone Enrolment period: n.r. 60 patients randomised Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria Karnofsky performance status ≥ 70 normal complete haemogram blood biochemistry within normal limits Exclusion criteria distant metastases pregnant or lactating female history of allergy to ondansetron palonosetron or aprepitant; receipt of chemotherapy during 7 days before study drug administration any associated medical condition causing nausea/vomiting (e.g. renal, liver, heart disease) Median age (range): 52 (36 to 70) in PDA group, 51 (34 to 69) in OD group Gender: male (52) + female (8) Tumour/cancer type: head and neck cancer (squamous cell carcinoma of head and neck) Chemotherapy regimen: docetaxel 60 mg/m² intravenously (i.v.), carboplatin 300 mg/m² i.v., and 5‐FU (5‐fluorouracil) 600 mg/m² i.v. Country: India (single centre)
Interventions	Experimental: arm A: aprepitant + palonosetron + dexamethasone (PDA) Day 1: p.o. aprepitant 125 mg + palonosetron 0.25 mg i.v. + dexamethasone 12 mg i.v. Days 2 to 3: capsule aprepitant 80 mg o.d. + tablet dexamethasone 8 mg b.d. Control: arm B: ondansetron + dexamethasone (OD) Day 1: ondansetron 16 mg i.v. + dexamethasone 12 mg i.v. + ondansetron 8 mg b.d. (after chemotherapy) Days 2 to 3: ondansetron 8 mg b.d. + dexamethasone 8 mg b.d.
Outcomes	Primary endpoint complete response during acute (0 to 24 h) and delayed (24 to 120 h) phases after chemotherapy Secondary endpoint(s) complete response over entire (0 to 120 h) period safety
Notes	study was limited by small sample size no information regarding financing and clinical trial registration reported study authors have no conflicts of interest to declare
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... open label ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... open label ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included in the efficacy analysis
Selective reporting (reporting bias)	High risk	Comment: the result of safety analysis was not reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Kim 2015.

Study characteristics
Methods	Randomised, prospective, phase 3 trial with 2 arms comparison of aprepitant 125/80 mg + ramosetron + dexamethasone vs aprepitant 125/80 mg + ondansetron + dexamethasone Enrolment period: June 2011 to September 2012 340 patients screened 338 patients enrolled 299 patients included in mITT Masking: single‐blind (participant) Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria age > 19 years and diagnosis of a malignancy that can be treated with highly emetogenic chemotherapeutic agents (NCCN Guideline v1.0 2011 antiemesis) ECOG performance status 0 to 2 ability to receive orally administered study drugs submission of informed consent for indicating awareness of the investigational nature of the study in keeping with hospital policy Exclusion criteria severe hypertension, severe heart disease, kidney disease (serum creatinine > 3 mg/dL), liver disease (AST, ALT > 3 × upper normal range, ALP > 2 × upper normal range) GI obstruction, active gastric ulcer, or other disease that could provoke nausea and vomiting nausea and vomiting within 1 week before chemotherapy taking steroid, antiemetics, pimozide, terfenadine, astemizole, cisapride, rifampin, carbamazepine, phenytoin, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, or nelfinavir for treatment of other disease brain tumour, brain metastasis, or seizure receiving chemotherapy within 12 months before enrolment need radiation therapy during study period or receiving radiation therapy within 2 weeks before chemotherapy develop known allergies or severe side effects in response to drugs used in this study pregnant or lactating women, women who wish to become pregnant patients whom the investigator judges inappropriate as subjects for this study Mean age ± SD, years: 58.9 ± 10.4 in ramosetron group, 59.0 ± 11.6 in ondansetron group Gender: male + female Tumour/cancer type: solid tumour (lung cancer, lymphoma, stomach cancer, head and neck cancer, breast cancer, oesophagus cancer, hepatobiliary and pancreas cancer, other) Chemotherapy regimen: highly emetogenic chemotherapeutic agents (NCCN Guideline v1.0 2011 antiemesis) Country: Korea (17 institutions, multi‐centre)
Interventions	Experimental: arm A: ramosetron Day 1: ramosetron 0.3 mg i.v. + aprepitant 125 mg p.o. + dexamethasone 12 mg p.o. Days 2 to 3: aprepitant 80 mg p.o. + dexamethasone 8 mg p.o. Day 4: dexamethasone 8 mg p.o. Experimental: arm B: ondansetron Day 1: ondansetron 16 mg i.v. + aprepitant 125 mg p.o. + dexamethasone 12 mg p.o. Days 2 to 3: aprepitant 80 mg p.o. + dexamethasone 8 mg p.o. Day 4: dexamethasone 8 mg p.o.
Outcomes	Primary endpoint complete response (CR) [Time frame: acute phase (within 24 h after onset of chemotherapy)] Secondary endpoints complete response rates in delayed (Days 2 to 5) and overall (Days 1 to 5) periods adverse events
Notes	ClinicalTrials.gov (NCT01536691) this study was supported by the Korean Cancer Study Group conflicts of interest: "Jin‐Hyoung Kang: Pfizer, Ono Pharmaceutical Co., Boehringer Ingelheim, Eli Lilly (C/A), Eli Lilly, AstraZeneca (RF), Boehringer Ingelheim, AstraZeneca (H); Jin Seok Ahn: AstraZeneca, Lilly, Roche, Boehringer Ingelheim (H). The other authors indicated no financial relationships; (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were assigned to the RAD or OAD groups (1:1 ratio) according to a stratified block randomization table"
Allocation concealment (selection bias)	Unclear risk	Comment: not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... single‐blind ..." Comment: patients were blinded
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... single‐blind ..." Comment: only patients were blinded
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: although patients were blinded, unblinded personnel might have an influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: although this was a single‐blind study, both patients and personnel had no influence on objective outcomes (e.g. study mortality)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "... an m‐ITTpopulation of 299 was subjected to the efficacy analysis ..."
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "three deaths of OAD patients during the study were considered unrelated to the medication"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Kim 2017.

Study characteristics
Methods	Randomised, active‐comparator, phase 4 trial (MK‐0869‐225) with 2 arms comparison of aprepitant + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Study period: 2012 December 28 to 4 August 2014 510 patients screened 494 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria 21 years of age or older histologically or cytologically confirmed malignant disease scheduled to receive a single dose of 1 or more moderately emetogenic chemotherapeutic agents during Cycle 1 ECOG performance status 0 to 2 or Karnofsky score ≥ 60 predicted life span ≥ 4 months laboratory values demonstrating adequate haematological status pre‐menopausal female must not be pregnant or lactating and must agree to use effective birth control Exclusion criteria received chemotherapy within 6 months before start of study drugs scheduled to receive subsequent treatment due to refractory response to first‐ or second‐line chemotherapy received an investigational drug within 30 days before start of study drugs radiation therapy to abdomen or pelvis in the week before start of study drugs vomiting in the 24 h before start of study drugs active infection (e.g. pneumonia) or any uncontrolled disease (e.g. diabetic ketoacidosis, gastrointestinal obstruction) except for malignancy known hypersensitivity to aprepitant (EMEND), dexamethasone, or 5‐HT₃ receptor antagonist presentation with gastrointestinal obstruction symptoms symptomatic primary or metastatic central nervous system malignancy Mean age ± SD (range), years: 59.7 ±11.4 (23 to 84) in aprepitant group, 60.9 ± 11.5 (28 to 85) in control group Gender: male (263) + female (217) Tumour/cancer type: solid malignancy (gastrointestinal, lung, gynaecological, other) Chemotherapy regimen: carboplatin, oxaliplatin, irinotecan‐based Country: South Korea (multi‐centre, 20 sites)
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg capsule p.o. + ondansetron 16 mg i.v.  + dexamethasone 12 mg p.o. Days 2 to 3: aprepitant 80 mg capsule p.o. + placebo for ondansetron 8 mg p.o. twice daily (b.i.d.) Control: arm B Day 1: aprepitant placebo capsule  p.o. + ondansetron 16 mg i.v. + dexamethasone 20 mg p.o. Days 2 to 3: aprepitant placebo capsule p.o. + ondansetron 8 mg p.o. b.i.d.
Outcomes	Primary endpoint percentage of participants with no vomiting ‐ overall (approximately 120 h) Secondary endpoint(s) percentage of participants with complete response ‐ overall, acute, and delayed stages (approximately 120 h) number of emetic events ‐ overall stage (approximately 120 h) percentage of participants with no vomiting and no significant nausea ‐ overall stage [Time frame: Day 1 to Day 5] percentage of participants with no impact on daily life ‐ overall stage [Time frame: Day 6] number of participants with no use of rescue therapy ‐ overall, acute, and delayed stages [Time frame: Day 1 to Day 5] percentage of participants with 1 or more clinical adverse event [Time frame: Day 1 through Day 29 (up to 28 days after first dose of study drug)] percentage of participants with no vomiting ‐ acute and delayed stages [Time frame: Day 1, Day 2 to Day 5] Exploratory endpoint subgroup analysis of no vomiting according to chemotherapy regimen
Notes	trial registration ClinicalTrials.gov NCT01636947 sponsors and collaborators: Merck Sharp & Dohme Corp. conflicts of interest: "Hun Jung, Cho Eun Kim, and Kyung Wan Min are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., who may potentially own stock and/or hold stock options in the company. The remainder of the authors have nothing to disclose"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "eligible patients were randomised (1:1) to receive either a 3‐day aprepitant or control regimen"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. neutropenia, hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "of the 494 randomized subjects, 480 were included in the modified intent‐to‐treat population"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "the all‐patients‐as treated (APaT) population was used for safety analyses"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Kimura 2015.

Study characteristics
Methods	Randomised, cross‐over trial with 2 arms comparison of aprepitant 125/80 mg + palonosetron + dexamethasone vs aprepitant 125/80 mg + granisetron + dexamethasone Enrolment period: 1 April 2011 to 31 March 2013 24 patients enrolled and randomly assigned Masking: single‐blind Baseline patient characteristics: reported Follow‐up: patients were followed up for 10 days during each course for efficacy and safety endpoints
Participants	Inclusion criteria 15 years of age or older confirmed high‐grade malignant bone and soft tissue tumour scheduled to receive chemotherapy with multiple emetogenic anticancer drugs ECOG performance status 0 to 2 adequate bone marrow function (white blood cell count ≥ 2 × 10³ cells/L), hepatic function (aspartate aminotransferase and alanine aminotransferase < 100 U/L), and renal function (creatinine clearance ≥ 60 mL/min) Exclusion criteria vomiting, retching, or grade ≥ 2 nausea according to Common Terminology Criteria for Adverse Events (CTCAE), version 4, before administration of study drug known hypersensitivity to palonosetron, granisetron, other 5‐HT₃ RAs, or dexamethasone participation in another drug study or receipt of any investigational agent within a month of study entry treatment with an antiemetic drug within 24 h before administration of study drug Age (range), years: 36.1 (15 to 65) in palonosetron arm, 50.6 (18 to 70) in granisetron arm Gender: male + female Tumour/cancer type: osteosarcoma, malignant fibrous histiocytoma, synovial sarcoma, leiomyosarcoma, rhabdomyosarcoma, dedifferentiated liposarcoma, myxoid liposarcoma, clear cell sarcoma Chemotherapy regimen: cisplatin + doxorubicin, ifosfamide + doxorubicin/ifosfamide + etoposide Country: Japan
Interventions	Cross‐over study Experimental: arm A: palonosetron Day 1: p.o. 125 mg aprepitant  + i.v. 0.75 mg palonosetron  + i.v. 6.6 mg dexamethasone  Days 2 to 5: 80 mg aprepitant + 6.6 mg dexamethasone Experimental: arm B: granisetron Day 1: p.o. 125 mg aprepitant + i.v. 3 mg × 2 granisetron + i.v. 6.6 mg dexamethasone Days 2 to 5: 80 mg aprepitant + 3 mg × 2 granisetron + 6.6 mg dexamethasone
Outcomes	Primary endpoints proportions of patients with complete response and total control during overall phase (0 to 240 h post chemotherapy), acute phase (0 to 72 h post chemotherapy), and delayed phase (72 to 240 h post chemotherapy) Secondary endpoints complete response and total control rates for overall phase, acute phase, and delayed phase after first course of chemotherapy and during courses 1 to 4 of chemotherapy complete response and total control rates for each chemotherapeutic regimen antiemetic regimen preferred by patients time to administration of rescue therapy severity of nausea
Notes	no funding source reported conflicts of interest: "none declared"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "a single randomization method was used to assign eligible patients to the palonosetron or granisetron arm"
Allocation concealment (selection bias)	Unclear risk	Commen: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "all participants were blinded to the antiemetic treatment assignments for the duration of the study"
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Comment: only patients were blinded to the study intervention
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: although patients were blinded, unblinded personnel might have an influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: although this was a single‐blind study, we assume that both patients and personnel had no influence on objective outcomes (e.g. hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "all patients were eligible for efficacy analysis ..."
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "safety was assessed for all patients who received treatment"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Kitayama 2015.

Study characteristics
Methods	Randomised, cross‐over study with 2 arms comparison of fosaprepitant + granisetron + dexamethasone vs palonosetron + dexamethasone Study period: April 2013 to November 2014 39 patients randomised, 35 available for analysis Masking: single‐blind Baseline patient characteristics: yes Follow‐up: n.r.
Participants	Inclusion criteria chemotherapy‐naïve adult histologically or cytologically confirmed solid malignant tumour receiving MEC required to have acceptable haematological, hepatic, and renal function for administration of chemotherapy adequate ECOG performance status 0, 1, or 2 Exclusion criteria  known hypersensitivity to 5‐HT₃ RA, fosaprepitant, or dexamethasone central nervous system malignancy; any other organic cause of nausea and vomiting unrelated to chemotherapy administration radiotherapy within 30 days before chemotherapy initiation or during the study period, and unrelated nausea or vomiting within 24 h before initiation of chemotherapy  inability to understand or cooperate with study procedures pregnant or nursing woman All patients provided written informed consent before entering the study Mean/median age, years: 80% ≥ 50 years Gender: 37% male Tumour/cancer type: colorectal, breast, other Chemotherapy regimen: MEC (oxaliplatin base, irinotecan base, other) Country: n.r.
Interventions	Experimental: arm A: fosaprepitant Day 1: fosaprepitant 150 mg + granisetron 3 mg + dexamethasone 4.95 mg Experimental: arm B: palonosetron Day 1: i.v. palonosetron 0.75 mg + dexamethasone 9.9 mg
Outcomes	Primary endpoint  complete response (CR), defined as no vomiting and no rescue therapy at acute, delayed, and overall intervals Secondary endpoints complete control rate of nausea and vomiting, defined as CR with no more than mild nausea (NRS ≤ 3) at acute, delayed, and overall intervals total control rate of nausea, defined as no nausea at acute, delayed, and overall intervals therapy chosen by patients for third and subsequent cycles of antiemetic therapy
Notes	no trial registration number nor funding source reported conflict of interest: "all of the authors, except Yasushi Tusji, declare that they have no conflict of interest. Yasushi Tusji has received lecture fees from Ono Pharmaceutical Co., Ltd."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: "... minimization method ..."
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Comment: single‐blind
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Comment: single‐blind only
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: single‐blind study; knowledge of treatment may have affected outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: single‐blind study; we assume that knowledge of treatment would not influence objective outcomes
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "the total of 35 patients and 70 therapies was available for analysis" and "we analyzed the per‐protocol cohort including all patients who received the study medication and completed the follow‐up period" Comment: 2 participants did not start study treatment; 2 withdrew because they could not complete chemotherapy
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: adverse events reported for all patients who completed chemotherapy and study treatment
Selective reporting (reporting bias)	Low risk	Comment: outcomes only for the overall phase have been reported, as no significant difference was found in any other evaluation points
Other bias	Unclear risk	Comment: participants did not record the incidence and severity of CINV daily, but only on Days 2 and 5

Koizumi 2003.

Study characteristics
Methods	Randomised, cross‐over trial with 2 arms comparison of granisetron + methylprednisolone sodium vs ramosetron + methylprednisolone sodium Patient hospitalisation period: March 1998 to June 1999 36 patients registered 6 patients excluded Masking: double‐blind Baseline patient characteristics: reported Follow‐up: recorded daily for 7 days after the start of chemotherapy
Participants	Inclusion criteria gastric or oesophageal cancer scheduled to receive at least 2 courses of combined chemotherapy, including intravenous infusion of cisplatin (≥ 60 mg/m²) Exclusion criteria concurrent illness such as severe cardiovascular, renal, or hepatic disease pregnant or possibly pregnant treatment with psychotropic or antiepileptic drugs history of allergy to serotonin receptor antagonists symptoms of nausea or vomiting due to cerebral metastasis or intestinal obstruction therapy with any of the study drugs (including anticancer agents) within previous 4 weeks, and radiotherapy scheduled to be given during the study Median age (range), years: 61.2 (26 to 81) in granisetron‐ramosetron group, 58.7 (33 to 77) in ramosetron‐granisetron group Gender: male + female Tumour/cancer type: solid tumour (gastric cancer, oesophageal cancer) Chemotherapy regimen: 2 courses of combined chemotherapy (including ≥ 60 mg/m² cisplatin) Country: Japan
Interventions	Cross‐over study Experimental: arm A: granisetron‐ramosetron granisetron 3 mg i.v. during treatment phase 1, followed by ramosetron 0.3 mg i.v. during treatment phase 2 + methylprednisolone sodium (Solumedrol) 250 mg i.v. immediately before and 6 h after chemotherapy Experimental: arm B: ramosetron‐granisetron ramosetron 0.3 mg i.v. during treatment phase 1, followed by granisetron 3 mg i.v. during treatment phase 2 + methylprednisolone sodium (Solumedrol) 250 mg i.v. immediately before and 6 h after chemotherapy
Outcomes	Primary endpoint patient preference Secondary endpoints frequency of vomiting degree of nausea grade of appetite symptom score number of adverse events experienced by patients
Notes	no information regarding clinical trial registration and financing reported study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Low risk	Quote: "the study drug code was sealed, preserved at the registration center and not opened until all evaluations had been finalized, after the completion of treatment phase 2"
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: "clinical response was evaluated in the remaining 30 patients"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: all included patients recorded adverse events
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Kusagaya 2015.

Study characteristics
Methods	Randomised, controlled, prospective, parallel‐group trial with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs palonosetron + dexamethasone Enrolment period: April 2013 to February 2015 81 patients enrolled and randomised Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria aged ≥ 20 years chemotherapy‐naïve with pathologically confirmed inoperable stage IIIB or IV NSCLC ECOG performance status 0 or 1 receiving carboplatin‐based chemotherapy adequate hematopoietic, renal, and hepatic function Exclusion criteria nausea and vomiting within 24 h use of antiemetic agents and corticosteroids within 24 h before administration of chemotherapy use of pimozide uncontrolled diabetes mellitus conditions likely to induce emesis regardless of chemotherapy, including symptomatic brain metastasis, gastrointestinal obstruction, and active gastrointestinal ulcer pregnant female, nursing mom Median age, years: 70 (57 to 90) in aprepitant group, 73 (43 to 84) in control group Gender: male (57) + female (23) Tumour/cancer type: non‐small cell lung cancer Chemotherapy regimen: carboplatin + paclitaxel, carboplatin + paclitaxel + bevacizumab, carboplatin + pemetrexed, carboplatin + pemetrexed + bevacizumab, carboplatin + S‐1 Country: Japan (multi‐centre)
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg + palonosetron 0.75 mg + dexamethasone 8 mg Days 2 to 3: aprepitant 80 mg + dexamethasone 8 mg Control: arm B Day 1: palonosetron 0.75 mg + dexamethasone 8 mg Days 2 to 3: dexamethasone 8 mg
Outcomes	Primary endpoint complete response rate in the overall phase (during 120 h after chemotherapy administration) Secondary endpoint(s) complete response rate in acute (first 24 h after chemotherapy administration) and delayed phases (24 to 120 h after chemotherapy) nausea in overall, acute, and delayed phases safety
Notes	trial was registered with University Hospital Medical Information Network (UMIN) Clinical Trial Registry: UMIN000010056 funding source: Hamamatsu University School of Medicine conflicts of interest: "all authors declare no actual or potential conflicts of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomization was performed centrally by computer software and stratified by sex, age, and non‐platinum chemotherapy agent"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment was not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... open‐label ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... open‐label ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: although this was an open‐label study, both patients and personnel had no influence on objective outcomes (e.g. neutropenia, hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "one patient withdrew consent before chemotherapy, and 80 patients (41 in the aprepitant group and 39 in the control group) were assessed for efficacy and safety"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "one patient withdrew consent before chemotherapy, and 80 patients (41 in the aprepitant group and 39 in the control group) were assessed for efficacy and safety"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Lee 1997.

Study characteristics
Methods	Randomised, cross‐over trial with 2 arms comparison of ondansetron + dexamethasone vs tropisetron + dexamethasone Recruitment period: n.r. 39 patients randomised Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria 18‐ to 75‐year‐old receiving cisplatin‐based chemotherapy haematological and biochemical tests normal and not accompanied by significant medical complications able to cooperate with the clinician Exclusion criteria pregnant or lactating severe liver dysfunction causes of nausea and vomiting other than anticancer drugs such as intestinal obstruction, brain metastasis CNS medication and narcotic analgesics (lorazepam, bezodiazepine, demerol, morphine, solumedrol) receiving chemotherapy and radiotherapy simultaneously Median age (range), years: 61 (32 to 77) in arm A, 58.5 (30 to 71) in arm B Gender: male (29) + female (10) Tumour/cancer type: solid tumour (lung cancer, head and neck tumour, unknown tumour, oesophageal cancer, gastric cancer, malignant lymphoma) Chemotherapy regimen: cisplatin (≥ 50 mg/m²), ifosfamide (≥ 3000 mg/m²), mitomycin (6 mg/m²), fluorouracil (1000 mg/m²), etoposide (80 mg/m²) Country: Korea (multi‐centre)
Interventions	Cross‐over study Experimental: arm A first ondansetron + dexamethasone, then tropisetron + dexamethasone Experimental: arm B first tropisetron + dexamethasone, then ondansetron + dexamethasone
Outcomes	not readable
Notes	not assessable due to language barrier
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: not evaluable due to language barrier
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Comment: open‐label
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Comment: open‐label
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: for objective outcomes, we assume that not blinding participants and personnel would not influence risk of bias
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: not evaluable because of language barrier
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Unclear risk	Comment: not evaluable because of language barrier
Selective reporting (reporting bias)	Unclear risk	Comment: not evaluable because of language barrier
Other bias	Unclear risk	Comment: not evaluable because of language barrier

Li 2019.

Study characteristics
Methods	Randomised, prospective study with 2 arms comparison of aprepitant + tropisetron + dexamethasone vs tropisetron + dexamethasone Recruitment period: June 2015 to February 2018 100 patients randomised Masking: n.r. Baseline patient characteristics: reported Follow‐up: patients were followed on Days 6 to 8 and on Days 19 to 21
Participants	Inclusion criteria patients beyond 18 years old Karnofsky performance ≥ 70 without previous treatment of aprepitant scheduled to receive 2‐day anthracycline‐based chemotherapy (30 mg/m²/d for pirarubicin or 45 mg/m²/d for epirubicin) Exclusion criteria alcohol abuse central nervous system metastasis advanced or metastatic breast cancer administration of sensitised chemotherapy over last 10 days schemed radiation therapy before enrolment had vomited in 24 h before treatment Day 1 controllable disease abnormal laboratory values including white blood cell count < 3000/mm³ and absolute neutrophil count < 1500/mm³, platelet count < 100,000/mm³, alanine transaminase > 2.5 × ULN, aspartate aminotransferase > 2.5 × ULN, creatinine > 1.5 × ULN, or bilirubin > 1.5 × ULN Mean age ± SD, years: 51.74 ± 7.082 in aprepitant group, 47.46 ± 8.180 in standard group Gender: female Tumour/cancer type: breast cancer Chemotherapy regimen: anthracycline (30 mg/m²/d for pirarubicin or 45 mg/m²/d for epirubicin) and cyclophosphamide Country: Mongolia, China (single centre)
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg p.o. + tropisetron 5 mg i.v. + dexamethasone 6 mg p.o. Day 2: aprepitant 80 mg p.o. + tropisetron 5 mg i.v. + dexamethasone 3.75 mg p.o. Day 3: aprepitant 80 mg p.o. + dexamethasone 3.75 mg p.o. Day 4: dexamethasone 3.75 mg p.o. Standard: arm B Day 1: tropisetron 5 mg i.v. + dexamethasone 10.5 mg p.o. Day 2: tropisetron 5 mg i.v. + dexamethasone 7.5 mg p.o. Days 3 to 4: dexamethasone 7.5 mg p.o.
Outcomes	Primary endpoints complete response (CR) during the overall phase (0 to 120 h following chemotherapy) no vomiting and nausea in overall phase use of rescue therapy Secondary endpoints CR in the acute phase (0 to 24 h following chemotherapy), delay phase (24 to 120 h following chemotherapy) time to first vomiting FLIE questionnaire scoring
Notes	"the statistical analysis of this study was carried out by the sponsor" "the study received no funding" "potential conflicts of interest: none"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised study but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Unclear risk	Comment: blinding not reported
Blinding of participants and personnel (performance bias) Blinding of personnel	Unclear risk	Comment: blinding not reported
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: blinding was not reported; therefore it is possible that knowledge of allocated treatment could have posed a risk of bias
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: not reported
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Maehara 2015.

Study characteristics
Methods	Randomised, parallel‐design study with 2 arms comparison of aprepitant + 5‐HT₃ receptor antagonist + dexamethasone vs 5‐HT₃ receptor antagonist + dexamethasone Enrolment period: November 2010 to October 2012 26 patients enrolled 23 patients randomised Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria patient undertaking first TC therapy as postoperative adjuvant chemotherapy at Fukuoka University Hospital Exclusion criteria carried risk of vomiting for other reasons (symptomatic primary or metastatic malignancy in central nervous system, active peptic ulcer, or gastrointestinal obstruction) had vomited in the 24 h before treatment had abnormal laboratory values (white blood cell count < 3000/mm³, absolute neutrophil count < 1500/mm³, platelet count < 100,000/mm³, aspartate aminotransferase > 2.5 × ULN, alanine aminotransferase > 2.5 × ULN, total bilirubin > 1.5 × ULN, or creatinine > 1.5 × ULN) patients under systemic corticosteroid therapy (at any dose) or taking pimozide patients who had condition (such as ileus, taking opioid, apparent infection, and more) that the doctor judged to be unsuitable Mean age ± SD, years: 54.5 ± 11.9 in control group, 62.6 ± 12.7 in aprepitant group Gender: n.r. Tumour/cancer type: ovarian cancer, endometrial cancer Chemotherapy regimen: paclitaxel and carboplatin (TC) Country: Japan (single centre)
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg p.o. + first‐generation 5‐HT₃ antagonist 3 mg + dexamethasone 8 or 16 mg i.v. Days 2 to 3: aprepitant 80 mg p.o. + dexamethasone 8 or 4 mg p.o. Control: arm B Day 1: first‐generation 5‐HT₃ antagonist 3 mg + dexamethasone 8 or 4 mg i.v. Days 2 to 3: dexamethasone 8 or 16 mg p.o.
Outcomes	Primary outcome percentage of patients with complete response (CR) Secondary outcome(s) percentage of patients with CR in the overall phase since second cycle, or CR or no episode of nausea in acute phase and delayed phase in all cycles safety
Notes	no information regarding financing of the study and registration of the trial reported study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Low risk	Quote: "twenty‐three eligible patients were divided randomly into two groups (A and B) using sealed opaque envelopes"
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... open‐label ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... open‐label ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all 23 patients were included in patient‐reported efficacy analysis
Selective reporting (reporting bias)	High risk	Quote: "safety was evaluated using general laboratory tests" Comment: no results regarding the safety analysis were reported
Other bias	Low risk	Comment: no information to suggest other sources of bias

Mahrous 2020.

Study characteristics
Methods	Randomised, open‐label study comparative study between clinical effects of palonosetron and granisetron as antiemetic therapy for patients receiving highly emetogenic chemotherapy regimens patients receiving at least 4 courses of palonosetron and granisetron as antiemetic therapy all patients received dexamethasone in combination with the 5‐HT₃ receptor antagonist Study period: n.r.  115 patients were included Masking: open‐label Baseline patient characteristics: n.r. Median follow‐up: n.r. ITT analysis: n.r.
Participants	Inclusion criteria n.r. Exclusion criteria n.r. Mean age (range), years: n.r. Gender:  n.r. Tumour/cancer type:  n.r.  Chemotherapy regimen: cisplatin‐based, or combination of cyclophosphamide and anthracyclines  Country: Egypt
Interventions	Experimental: arm A: granisetron with dexamethasone Experimental: arm B: palonosetron with dexamethasone
Outcomes	Primary outcome measures Chemotherapy‐induced nausea in acute phase (0 to 24 h) and in delayed phase (24 to 120 h)  Chemotherapy‐induced vomiting in acute phase (0 to 24 h) and in delayed phase (24 to 120 h)  Secondary outcome measures: adverse events
Notes	Publication type: conference abstract No funding received COIs reported: no special COIs for authors
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Comment: open‐label
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Comment: open‐label
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: outcome assessors (participants) not blinded to intervention
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: outcome robust to blinding
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: conference abstract, not fully evaluable
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Unclear risk	Comment: conference abstract, not fully evaluable
Selective reporting (reporting bias)	Unclear risk	Comment: conference abstract, not fully evaluable
Other bias	Unclear risk	Comment: conference abstract, not fully evaluable

Matsuda 2014.

Study characteristics
Methods	Randomised study with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs palonosetron + dexamethasone Enrolment period: n.r. 75 patients randomised Masking: n.r. Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria: n.r. Exclusion criteria: n.r. Mean/median age, years: n.r. Gender: n.r. Tumour/cancer type: n.r. Chemotherapy regimen: n.r. Country: Japan
Interventions	Experimental: arm A: aprepitant aprepitant + palonosetron + dexamethasone Control: arm B palonosetron + dexamethasone
Outcomes	Primary endpoint complete response rate of restraining emesis (CR) over 5 days after chemotherapy Secondary endpoint(s) time to treatment failure (TTF) complete controlled rate (CC) other side effects
Notes	conference abstract
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Unclear risk	Comment: blinding not reported
Blinding of participants and personnel (performance bias) Blinding of personnel	Unclear risk	Comment: blinding not reported
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: blinding not reported
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: blinding not reported; however, this should not affect objective outcomes
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included in the efficacy analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	All patients were included in the analysis
Selective reporting (reporting bias)	Low risk	Comment: not reported
Other bias	Low risk	Comment: no information to suggest other sources of bias

Matsumoto 2020.

Study characteristics
Methods	Randomised trial with 2 arms comparison of fosaprepitant + palonosetron 0.75 mg + dexamethasone vs fosaprepitant + granisetron 1 mg + dexamethasone Enrolment period: December 2012 to October 2014 326 patients enrolled Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria invasive breast cancer confirmed by histological diagnosis eligible for AC/EC/FAC/FEC chemotherapy and planning for it over 20 years old ECOG performance status 0, 1, or 2 adequate organ function defined as WBC ≥ 3000 mm³, ANC ≥ 1500 mm³, Hb ≥ 8 g/dL, Plt ≥ 10 × 10⁴/mm³, AST/ALT ≤ 100 IU/ L, T‐Bil ≤ 1.5 mg/dL, sCr ≤ 1.2 mg/dL, PaO₂ ≥ 60 Torr, or SpO₂ ≥ 93% (room air) estimated survival > 90 days written informed consent obtained Exclusion criteria prior cancer chemotherapy prior radiation therapy during last 14 days receiving antiemetic medication during last 72 hours vomiting at entry nausea grade 2 or higher (CTCAE ver 4) at entry local or systemic infection requiring treatment severe comorbid condition such as GI bleeding, ileus, heart disease, glaucoma, diabetes history of severe hypersensitivity severe psychological problem pregnant or lactating woman, or woman not going to use contraception HBsAg positive judged as ineligible by treating physician Median age, years: 54 (27 to 82) in granisetron group, 54 (30 to 74) in palonosetron group Gender: female Tumour/cancer type: breast cancer Chemotherapy regimen: anthracycline plus cyclophosphamide (AC) regimen Country: Japan
Interventions	Experimental: arm A: palonosetron fosaprepitant + palonosetron 0.75 mg + dexamethasone Experimental: arm B: granisetron fosaprepitant + granisetron 1 mg + dexamethasone
Outcomes	Primary endpoint complete response for emesis in delayed phase (> 24 to 120 h) Secondary endpoints complete response rate for emesis in acute (0 to 24 h) and overall (0 to 120 h) phases complete response rate for nausea or vomiting for acute, delayed, and overall phases safety
Notes	sponsor: West Japan Oncology Group, self‐funding conflicts of interest disclosure: comprehensive list of potential conflicts of interest provided in journal article clinical trial information: UMIN000008897
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised study but method of randomisation not described
Allocation concealment (selection bias)	Low risk	Quote: "concealment: central registration"
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: 326 patients were evaluable
Selective reporting (reporting bias)	High risk	Comment: safety was planned but not reported; complete response for nausea in acute and overall phases not reported
Other bias	Low risk	Comment: no information to suggest other sources of bias

Mattiuzzi 2007.

Study characteristics
Methods	Randomised, phase 2 trial with 3 arms comparison of ondansetron Days 1 to 5 + dexamethasone vs palonosetron Days 1 to 5 + dexamethasone vs palonosetron Days 1, 3, and 5 + dexamethasone Recruitment period: n.r. n = 95 Masking: n.r. Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria: n.r. Exclusion criteria: n.r. Mean/median age (range), years: n.r. Gender: n.r. Tumour/cancer type: acute myeloid leukemia, myelodysplastic syndrome Chemotherapy regimen: MD‐HD‐CHEMO with HDAC‐containing regimens Country: n.r.
Interventions	Experimental: arm A: ONDA 1 to 5 ONDA 8 mg i.v. bolus, then 24 mg i.v., continuous infusion on Day 1 through Day 5 and for 12 h after Ara C infusion ends Experimental: arm B: PALO 1 to 5 PALO 0.25 mg i.v. bolus over 30 seconds on Day 1 through Day 5 of Ara C infusion Experimental: arm C: PALO 1, 3, 5 PALO 0.25 mg i.v. bolus over 30 seconds on Days 1, 3, and 5 of Ara C infusion All patients received Solumedrol 40 mg i.v. before Ara C
Outcomes	Primary endpoint(s) complete response complete control
Notes	abstract only "disclosure: consultancy: MGI, Pfizer, Merck. Research funding: Astellas, MGI, Novartis"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "open randomized comparative trial"
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "open randomized comparative trial"
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: 95 patients were evaluable
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Unclear risk	Comment: conference abstract, not evaluable

Miyabayashi 2015.

Study characteristics
Methods	Randomised, prospective, phase 2 study with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs granisetron + dexamethasone Study period: January 2011 to April 2014 180 patients enrolled Masking: n.r. Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria chemotherapy‐naïve lung cancer patients scheduled to receive MEC Exclusion criteria: n.r. Mean/median age, years: n.r. Gender: n.r. Tumour/cancer type: lung cancer Chemotherapy regimen: MEC Country: n.r.
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg p.o. + palonosetron 0.75 mg i.v. + dexamethasone 4.95 mg i.v. Days 2 to 3: aprepitant 80 mg p.o. + dexamethasone 4 mg p.o. Experimental: arm B Day 1: granisetron 3 mg i.v. + dexamethasone 9.9 mg i.v. Days 2 to 3: dexamethasone 8 mg p.o.
Outcomes	Primary endpoint complete response (CR) rate during overall first‐cycle phase (0 to 120 h)
Notes	conference abstract
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Unclear risk	Comment: not reported
Blinding of participants and personnel (performance bias) Blinding of personnel	Unclear risk	Comment: not reported
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: not reported
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included in the efficacy analysis
Selective reporting (reporting bias)	Unclear risk	Comment: conference abstract only
Other bias	Unclear risk	Comment: conference abstract, not evaluable

Mohammed 2019.

Study characteristics
Methods	Randomised, parallel‐design study with 2 arms comparison of aprepitant + ondansetron + dexamethasone vs ondansetron + dexamethasone Enrolment period: January to December 2015 70 patients enrolled 63 patients randomised Masking: single‐blind Baseline patient characteristics: sex and age reported Follow‐up: n.r.
Participants	Inclusion criteria Hodgkin lymphoma receiving ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine) chemotherapy age between 18 and 70 years receiving first day of chemotherapy Exclusion criteria another type of tumour or treated with another chemotherapy regimen pregnancy severe hepatic impairment, congestive heart failure, renal failure radiation therapy to abdomen or pelvis any time from 1 week before Day 1 to Day 6 active infection symptomatic primary or metastatic CNS malignancy vomiting and dry heaves/retching 24 h before chemotherapy Mean age (SD), years: 47.8 (14.4) Gender: 63.5% female, 36.5% male Tumour/cancer type: Hodgkin lymphoma Chemotherapy regimen: Adriamycin, Bleomycin, Vinblastine, Dacarbazine Country: Iraq (single centre)
Interventions	Experimental: arm A oral aprepitant on Days 1 to 3 (Day 1, 125 mg 1 h before chemotherapy; Days 2 to 3, 80 mg), ondansetron on Day 1 (Day 1, 32 mg i.v. infusion over 15 min at 30 to 60 min before chemotherapy), oral dexamethasone on Days 1 to 4 (Day 1, 12 mg 30 min before chemotherapy; Days 2 to 4, 8 mg in the morning) Control: arm B ondansetron on Days 1 to 4 (Day 1, 32 mg i.v. infusion over 15 min at 30 to 60 min before chemotherapy; Days 2 to 4, 8 mg p.o. twice daily), p.o. dexamethasone on Days 1 to 4 (Day 1, 20 mg 20 min before chemotherapy; Days 2 to 4, 8 mg twice daily)
Outcomes	Primary endpoint no impact on daily living, assessed with FLIE score Secondary endpoints nausea and vomiting scores, assessed with FLIE score
Notes	funding source not reported study authors disclose no potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "computer‐generated, random allocation schedule"
Allocation concealment (selection bias)	Low risk	Quote: "computer‐generated, random allocation schedule"
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Comment: single‐blinded; participants not aware of assigned treatment
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "the selection of both groups was known by the researcher after taking the agreement of physician responsible for patients' treatment"
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Outcome assessors (participants) blinded to intervention
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: mean scores reported, but unclear whether data on all participants were included in analysis
Selective reporting (reporting bias)	Low risk	Comment: no reasons for any concerns detected
Other bias	Low risk	Comment: no reasons for any concerns detected

Nakamura 2012.

Study characteristics
Methods	Randomised, cross‐over trial with 2 arms comparison of azasetron + dexamethasone, then granisetron + dexamethasone vs granisetron + dexamethasone, then azasetron + dexamethasone Recruitment period: March 2009 to April 2010 27 patients randomised 27 patients evaluated Masking: single‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria: patients ≥ 20 years of age with breast cancer who were preparing to initiate FEC100 (high emetic risk) treatment performance status score 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale Exclusion criteria ECOG performance status 3 or 4, with severe hepatic, renal, or cardiac disease as a complication pregnancy or breast‐feeding other cause of nausea or vomiting and receiving radiotherapy during this study Median age (range), years: 51 (36 to 73) in azasetron first group, 50 (42 to 68) in granisetron NK first group Gender: female Tumour/cancer type: breast cancer Chemotherapy regimen: FEC100 (5‐FU (500 mg/m²), epirubicin hydrochloride (100 mg/m²), and cyclophosphamide hydrate (500 mg/m²) on Day 1, every 3 weeks) Country: Japan (single centre)
Interventions	Cross‐over study Experimental: arm A: azasetron first azasetron 10 mg mixed with dexamethasone and intravenously infused over 30 min before administration of FEC100 regimen granisetron hydrochloride 2 mg and dexamethasone 8 mg p.o. administered for 3 days after FEC100 regimen Experimental: arm B: granisetron NK first granisetron NK 3 mg mixed with dexamethasone and intravenously infused over 30 min before administration of FEC100 regimen granisetron hydrochloride 2 mg and dexamethasone 8 mg p.o. administered for 3 days after FEC100 regimen
Outcomes	Primary endpoint grade and number of CINV treated with granisetron NK compared with azasetron Secondary endpoints adverse events quality of life
Notes	this work was supported by a non‐profit organisation “Epidemiological and Clinical Research Information Network” (ECRIN) study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... single‐blind ..." Comment: patients were blinded
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... single‐blind ..." Comment: personnel were not blinded
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: although patients were blinded, unblinded personnel might have had an influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: although personnel were not blinded, we assume that this had no effect on objective outcomes
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included in the efficacy analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: all patients were included in analysis of adverse events
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

NCT01640340.

Study characteristics
Methods	Randomised study with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs aprepitant + ondansetron + dexamethasone Study period: January 2011 to August 2011 40 patients enrolled and randomised Masking: open‐label Baseline patient characteristics: yes Follow‐up: yes
Participants	Inclusion criteria confirmed malignancy chemotherapy naïve or treated with only low or minimally emetogenic chemotherapy in the past (as defined by National Comprehensive Cancer Network version [v].2.201 Antiemetic Guidelines) scheduled to receive first dose of first cycle of HEC receiving multi‐day chemotherapy; HEC portion must be on Day 1 and remaining days of chemotherapy must be minimally emetogenic (i.e. fluorouracil) ECOG performance status grade 0 to 2 ability to provide informed consent ability to read and write in English or having someone who can that can translate and record diary entries ability to take oral medications allowed to participate in a concurrent clinical trial, if the other trial does not mandate an antiemetic regimen that interferes with this study, allows antiemetic administration at the physician's discretion, and does not prohibit the patient from participating in this study willing to participate with daily diary entries for 5 days following chemotherapy and to have a 5‐min follow‐up call on Day 2 or 3 and on Day 5, 6, or 7 Exclusion criteria stage IV (metastatic) disease known hypersensitivity to ondansetron, palonosetron, aprepitant, or dexamethasone received or will receive agents that are strong cytochrome P450 3A4 (CYP450 3A4) inducers and/or inhibitors and known to cause clinically relevant drug interactions within 1 week before study treatment and continuing through Day 5; any vomiting or retching within 24 h before administration of chemotherapy grade 2 nausea or greater, according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v 4.0), within 24 h before administration of chemotherapy received an antiemetic within 24 hours before study drug administration, excluding use of benzodiazepines alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2.5 × ULN total bilirubin > 1.5 × ULN Mean/median age, years: n.r. Gender: female Tumour/cancer type: malignant neoplasm Chemotherapy regimen: HEC Country: United States (single centre)
Interventions	Experimental: arm A: palonosetron palonosetron 0.25 mg Day 1; aprepitant 125 mg Day 1, 80 mg Days 2 to 3; dexamethasone 12 mg Day 1, 8 mg Days 2 to 4 Experimental: arm B: ondansetron ondansetron 24 mg Day 1; aprepitant 125 mg Day 1, 80 mg Days 2 to 3; dexamethasone 12 mg Day 1, 8 mg Days 2 to 4
Outcomes	Primary endpoint overall complete response after first course of HEC [Time frame: up to 120 h after completion of chemotherapy] Secondary endpoints acute complete response [Time frame: 0 to 24 hours after chemotherapy] delayed complete response [Time frame: 24 to 120 h after chemotherapy] percentage of patients who experienced grade 1, 2, or 3 nausea from time 0 to 120 h [Time frame: time 0 to 120 h] visual analogue scale (VAS) scores [Time frame: up to 7 days after completion of study treatment] use of rescue medication for each treatment arm [Time frame: from time 0 to 120 h] percentage of patients who experienced grade 1, 2, or 3 vomiting from time 0 to 120 h [Time frame: from time 0 to 120 h]
Notes	sponsor: Ohio State University Comprehensive Cancer Center ClinicalTrials.gov Identifier: NCT01640340
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Comment: open‐label
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Comment: open‐label
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the study results tab
Other bias	Low risk	Comment: no information to suggest other sources of bias

Nishimura 2015.

Study characteristics
Methods	Randomised, parallel‐group study with 2 arms comparison of aprepitant or fosaprepitant + 5‐HT₃ receptor antagonist + dexamethasone vs 5‐HT₃ receptor antagonist + dexamethasone Study period: April 2011 to March 2014 413 patients randomised Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria ≥ 20 years old colon/rectal cancer and first underwent FOLFOX, XELOX, or SOX regimen including oxaliplatin at ≥ 85 mg/m² (naïve patient), or had already started chemotherapy and had nausea of grade 2 or higher in the last course or in an earlier course (non‐naïve patient) stage: not specified (neoadjuvant/adjuvant chemotherapy, advanced or recurrent type allowed) combination of molecular targeted therapy: allowable written informed consent for participation in the study Exclusion criteria severe liver or kidney disease nausea/vomiting within 24 h before chemotherapy treatment with antiemetics within 24 h before chemotherapy presence of factors causing nausea/vomiting other than chemotherapy (e.g. brain tumour, gastrointestinal obstruction, active peptic ulcer disease, brain metastasis) presence of disease precluding 3‐day administration of dexamethasone (e.g. uncontrollable diabetes) pregnant or lactating women, women who plan to become pregnant current treatment with pimozide any patient judged by the investigator to be inappropriate for the study Mean age, years: 64.1 in aprepitant group, 64.2 in control group Gender: male (252) + female (161) Tumour/cancer type: colorectal cancer Chemotherapy regimen: oxaliplatin‐based chemotherapy (FOLFOX, XELOX, or SOX regimen including oxaliplatin at ≥ 85 mg/m²) Country: 25 hospitals in Japan (multi‐centre)
Interventions	Experimental: arm A: aprepitant or fosaprepitant Day 1: p.o. aprepitant 125 mg + i.v. 5‐HT₃ receptor antagonist + dexamethasone 6.6 mg Days 2 to 3: aprepitant 80 mg + p.o. dexamethasone 2 mg twice daily Day 1: i.v. fosaprepitant 150 mg + 5‐HT₃ receptor antagonist + dexamethasone 6.6 mg Day 2: p.o. dexamethasone 2 mg twice daily Day 3: p.o. dexamethasone 4 mg twice daily Control: arm B Day 1: i.v. 5‐HT₃ receptor antagonist + dexamethasone 9.9 mg Days 2 to 3: p.o. dexamethasone (4 mg) twice daily
Outcomes	Primary outcome patient diary recording nausea, emesis, food ingestion, and rescue therapy [Time frame: from initiating administration of anticancer agents to Day 6 (120 h)]
Notes	trial was registered with ClinicalTrials.gov, number NCT01344304 "this study is supported by a grant from The Supporting Center for Clinical Research and Education (Osaka, Japan), a non‐profit foundation" sponsors and collaborators: Multicenter Clinical Study Group of Osaka, Colorectal Cancer Treatment Group conflicts of interest: "TS has received consulting fees from Eli Lilly, Daiici Sankyo, Ono Pharmaceutical, Merck Serono Co. Ltd, Bayer Pharmaceutical Co. Ltd and Chugai Pharmaceutical Co. Ltd and honoraria from Chugai Pharmaceutical Co. Ltd, Merck Serono Co. Ltd, Bristol‐Myers K.K., Taiho pharmaceutical Co. Ltd, Bayer Pharmaceutical Co. Ltd and Takeda Pharmaceutical Co. Ltd and departmental research grants from Chugai Pharmaceutical Co. Ltd and Yakult Honsha Co. Ltd. TK, and DS has departmental research grants from Chugai Pharmaceutical Co. Ltd and Yakult Honsha Co. Ltd. JN, MF, HT, KN, YI, TF, TM, MY, SM, MU, TH, IT, TM, YO, HY, MS, RN, YD, and MM declare no competing interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "the allocation of patients was performed using the minimisation method with age, sex, chemotherapy‐naive/non‐naive status, regimen (FOLFOX, XELOX or SOX) and study centre as the adjustment factors"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... open‐label ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... open‐label ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: although this was an open‐label study, both patients and personnel had no influence on objective outcomes (e.g. hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all 413 patients have been included in the full analysis set (Fig. 1)
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "tolerability analyses included 398 patients who received oxaliplatin‐based chemotherapy in the first cycle"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Ohzawa 2015.

Study characteristics
Methods	Prospective, stratified, randomised, cross‐over, comparative trial with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs aprepitant + granisetron + dexamethasone Recruitment period: n.r. 40 patients were assigned to palonosetron‐first (19) and granisetron‐first (21) groups Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria females (≥ 20 years old; age range, 35 to 75 years) with histologically confirmed breast cancer scheduled to receive chemotherapy including anthracycline drugs and cyclophosphamide at the Department of Breast Surgery Exclusion criteria: n.r. Median age (range), years: 53 (35 to 75) in palonosetron‐first group, 53 (40 to 71) in granisetron‐first group Gender: female Tumour/cancer type: breast cancer Chemotherapy regimen AC treatment, adriamycin (60 mg/m²) and cyclophosphamide (600 mg/m²) EC treatment, epirubicin (90 mg/m²) and cyclophosphamide (600 mg/m²) FEC treatment, 5‐fluorouracil (500 mg/m²), epirubicin (90 mg/m²), and cyclophosphamide (500 mg/m²) Country: Japan (single centre)
Interventions	Cross‐over study Experimental: arm A: palonosetron‐first Day 1: aprepitant p.o. 125 mg + palonosetron i.v. 0.75 mg + dexamethasone i.v. 13.2 mg Days 2 to 3: aprepitant p.o. 80 mg + dexamethasone p.o. 8 mg Day 4: dexamethasone p.o. 8 mg Experimental: arm A: granisetron‐first Day 1: aprepitant p.o. 125 mg + granisetron i.v. 3 mg + dexamethasone i.v. 13.2 mg Days 2 to 3: aprepitant p.o. 80 mg + dexamethasone p.o. 8 mg Day 4: dexamethasone p.o. 8 mg
Outcomes	complete response (complete control of acute and delayed vomiting) complete control (complete control of emetic events)
Notes	when additional antiemetic treatment was required, metoclopramide was administered orally, or additional APR was administered orally on the fourth and fifth days following chemotherapy study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... stratified randomization ...", "... using a table of random numbers ..."
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... non‑blinded ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... non‑blinded ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were described in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Ozaki 2013.

Study characteristics
Methods	Randomised, phase 2 study with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs palonosetron + dexamethasone Enrolment period: August 2011 to March 2013 60 patients enrolled and randomised Masking: n.r. Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria: n.r. Exclusion criteria: n.r. Mean/median age, years: n.r. Gender: n.r. Tumour/cancer type: colorectal cancer Chemotherapy regimen: standard MEC regimen Country: Japan (multi‐centre)
Interventions	Experimental: arm A: aprepitant aprepitant + palonosetron + dexamethasone Control: arm B palonosetron + dexamethasone
Outcomes	Primary endpoint proportion of complete response Secondary endpoint(s) proportions of complete protection no vomiting no rescue medication no nausea no nausea at least moderate time to treatment failure dietary intake situation
Notes	conference abstract "no conflict of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Unclear risk	Comment: blinding not reported
Blinding of participants and personnel (performance bias) Blinding of personnel	Unclear risk	Comment: blinding not reported
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: blinding not reported
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	High risk	Quote: "fifteen patients were excluded because of insufficient diary and protocol violation. Finally, we analyzed 45 patients (26 male, 19 female) for this study" Comment: the percentage of excluded patients was 25% of the initial included population
Selective reporting (reporting bias)	Unclear risk	Comment: only complete response was reported in detail; other secondary outcomes were not reported with statistical figures, as no significant differences were observed between the 2 groups. Conference abstract only, not evaluable
Other bias	Unclear risk	Comment: conference abstract, not evaluable

Poli‐Bigelli 2003.

Study characteristics
Methods	Randomised, parallel‐group, phase 3, placebo‐controlled trial with 2 arms comparison of aprepitant 125/80 mg + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Recruitment period: n.r. 624 patients screened 569 patients randomised 523 patients were evaluated for efficacy, and 568 patients were evaluated for safety Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria > 18 years old cisplatin‐naïve patients who had histologically confirmed solid tumours and were scheduled to receive a chemotherapy regimen that included cisplatin 70mg/m² Karnofsky score 60 female patients of child‐bearing potential were required to have a negative human chorionic gonadotropin test result Exclusion criteria abnormal laboratory values active infection or uncontrolled disease that, in the opinion of the investigator, excluded the patient for safety reasons planned regimen of multiple‐day, cisplatin‐based chemotherapy in a single cycle radiation therapy to abdomen or pelvis within 1 week before Day 1 of the study or between Day 1 and Day 6; moderately or highly emetogenic chemotherapy on the 6 days before and/or after the day of cisplatin infusion additional chemotherapeutic agents of high emetogenicity (Hesketh level 3) were permitted only on Day 1; additional antiemetics were prohibited within 2 days before Day 1 or between Day 1 and Day 6 of the study, unless such medications were given as rescue therapy for established nausea or vomiting Mean age ± SD (range), years: 54 ± 13 (18 to 82) in aprepitant regimen group, 53 ± 14 (18 to 81) in standard therapy regimen group Gender: male + female Tumour/cancer type: solid tumours (respiratory, urogenital, eyes/ears/nose/throat, other) Chemotherapy regimen: chemotherapy regimen that included cisplatin 70 mg/m² Country: Argentina, Brazil, Chile, Colombia, Guatemala, Mexico, Peru, Venezuela (18 centres)
Interventions	Experimental: arm A: aprepitant 125/80 mg Day 1: p.o. aprepitant 125 mg + i.v. ondansetron 32 mg + p.o. dexamethasone 12 mg Days 2 to 3: p.o. aprepitant 80 mg + p.o. dexamethasone 8 mg Day 4: p.o. dexamethasone 8 mg Standard: arm B Day 1: i.v. ondansetron 32 mg + p.o. dexamethasone 20 mg Days 2 to 4: p.o. dexamethasone 8 mg twice daily
Outcomes	Primary endpoint complete response (no emesis and no rescue therapy) during the 5‐day period post cisplatin Secondary endpoints no emesis no use of rescue therapy complete protection (no emesis, no rescue therapy, no significant nausea (VAS score < 25 mm)) total control (no emesis, no rescue therapy, no nausea (VAS score < 5 mm)) impact of CINV on daily life (as measured by FLIE total score > 108) no significant nausea (VAS score < 25 mm) no nausea (VAS score < 5 mm)
Notes	supported by Merck Research Laboratories conflicts of interest: "all authors with the exception of Drs. Sergio Poli‐Bigelli and Jose Rodrigues‐Pereira are employees of Merck and Company, Inc., and potentially own stock and/or stock options in the company" 054 study group
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... computer‐generated randomization ..."
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: a modified intent‐to‐treat approach was used to analyse efficacy data
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Raftopoulos 2015.

Study characteristics
Methods	Randomised, prospective, parallel‐group, phase 3 trial with 3 arms comparison of palonosetron hydrochloride i.v. + placebo subcutaneously (SC) + dexamethasone i.v. vs granisetron SC + placebo i.v. + dexamethasone i.v. vs granisetron SC at a higher dose + placebo i.v. + dexamethasone i.v. Study period: June 2006 to February 2009 609 MEC patients and 690 HEC patients enrolled Masking: double‐blind (participant, investigator) Baseline patient characteristics: n.r. Follow‐up: after completion of study treatment, patients are followed at approximately 30 days
Participants	Inclusion criteria 18 to 120 years of age scheduled to receive a single day of moderately or highly emetogenic chemotherapy regimen (≤ 4 courses) not pregnant or nursing no known allergy or hypersensitivity to other selective 5‐HT₃ receptor antagonist or local anaesthetic no cardiac abnormality predisposing the patient to arrhythmia no psychological problem that, in the opinion of the investigator, is severe enough to preclude study participation no recent history (i.e. ≤ 1 year) of alcohol or drug abuse no concurrent condition that, in the opinion of the investigator, could affect assessment of study medication or interfere with the nausea/vomiting response (e.g. severe renal or hepatic impairment) Exclusion criteria: n.r. Mean/median age (range), years: MEC: APF530 250 mg: 60.3 (SD 12.5); APF530 500 mg: 59.1 (SD 13.3); palonosetron 0.25 mg: 60.4 (12.8); HEC: APF530 250 mg: 53.0 (SD 12.7); APF530 500 mg: 52.8 (SD 11.9); palonosetron 0.25 mg: 54.5 (SD 12.8) Gender: male + female Tumour/cancer type: solid tumour (lung cancer, breast cancer, ovarian cancer, lymphoma) Chemotherapy regimen: cyclophosphamide + doxorubicin or epirubicin (78% of MEC participants and 75% of HEC participants) Country: United States (52 study locations, multi‐centre)
Interventions	Active comparator: arm A Day 1 of chemotherapy course 1: palonosetron hydrochloride i.v. + placebo subcutaneously (SC) + dexamethasone i.v. patients in high‐risk (level 5) stratum also receive oral dexamethasone on Days 2 to 4 of all treatment courses Experimental: arm B Day 1 of chemotherapy course 1: APF530 SC + placebo i.v. + dexamethasone i.v. Day 1 of chemotherapy courses 2 to 4: APF530 SC + dexamethasone i.v. patients in high‐risk (level 5) stratum also receive oral dexamethasone as in arm A Experimental: arm C Day 1 of chemotherapy course 1: APF530 SC at higher dose + placebo i.v. + dexamethasone i.v. Day 1 of chemotherapy courses 2 to 4: APF530 SC (at same higher dose) + dexamethasone i.v. patients in high‐risk (level 5) stratum also receive oral dexamethasone as in arm A
Outcomes	Primary outcome measures proportion of patients with complete response (CR) during acute phase (0 to 24 h) after administration of chemotherapy course 1 [Time frame: 0 to 24 hours) proportion of patients with CR during delayed‐onset phase (24 to 120 h) after administration of chemotherapy course 1 [Time frame: 24 to 120 h] Secondary outcome measures proportion of patients with complete control during acute phase (0 to 24 hours), delayed‐onset phase (24 to 120 hours), and chemotherapy course 1 [Time frame: 0 to 120 h] proportion of patients with total response during acute phase, delayed‐onset phase, and chemotherapy course 1 [Time frame: 0 to 120 h] number of emetic episodes [Time frame: Days 1 to 5] time to first treatment failure [Time frame: 0 to 120 h]; proportions of subjects event free at 24, 48, 72, 96, and 120 h after chemotherapy administration first and overall use of rescue medication [Time frame: 0 to 120 h] severity of nausea daily and during chemotherapy course 1 (0 to 120 h) [Time frame: 0 to 120 h]; maximum severity of nausea, Days 1 to 5 sustainability of antiemetic effect of APF530 over multiple chemotherapy courses [Time frame: 0 to 120 h]; sustainability of overall complete response (CR 0 to 120 h) over 2, 3, and 4 cycles quality of life and impact of nausea and vomiting on Day 5 [Time frame: 5 days]; functional living index patient's global satisfaction with antiemetic therapy during acute phase and chemotherapy course 1 [Time frame: 0 to 24 h]; subjects very satisfied on Day 1
Notes	clinical trial information: NCT00343460 sponsors and collaborators: Heron Therapeutics conflicts of interest: "H Raftopoulos has served in a consultant /advisory role for Merck & Co. R Boccia has received clinic funding for the trial only. W Cooper has served in a consultant /advisory role for TFS International. E O’Boyle has served in a consultant/advisory role and has stock ownership as a previous employee of A.P. Pharma. RJ Gralla is a consult‐ant and advisor to Merck & Co, to Helsinn, and to Eisai Inc. The authors declare that they have full control of the primary data and agree to allow the journal to review these data. This study was sponsored by Heron Therapeutics (formerly A.P. Pharma, Inc.)"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were randomized 1:1:1 to ..."
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. injection site reaction)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "efficacy analyses were performed separately for ASCO‐derived MEC and HEC strata and were based on a modified intent‐to‐treat (mITT) population"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "the safety population in this reanalysis comprised all 1395 patients who were randomized and received study drug ..."
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Rapoport 2010.

Study characteristics
Methods	Randomised, prospective, parallel‐group, controlled trial with 2 arms comparison of aprepitant + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Study period: January 2007 to December 2008 949 patients screened for inclusion in the study 848 patients randomised Masking: double‐blind (participant, investigator) Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria 18 years of age and older naïve to emetogenic chemotherapy with histologically or cytologically confirmed malignant disease scheduled to receive a single dose of moderately emetogenic chemotherapy on study Day 1 Karnofsky score ≥ 60 predicted life expectancy ≥ 4 months scheduled to be treated with a single dose of 1 or more of the following agents: any i.v. dose oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin, cyclophosphamide i.v. (< 1500 mg/m²), or cytarabine i.v. (> 1 g/m²) Exclusion criteria scheduled to receive any dose of cisplatin will receive abdominal or pelvic radiation a week before and up to 6 days after initiation of chemotherapy any allergy to study drugs or antiemetics taking CYP3A4 substrates/prohibited medication significant medical or mental condition abnormal laboratory values (platelets, absolute neutrophils, AST, ALT, bilirubin, or creatinine) Mean age ± SD, years: 57.1 ± 11.8 in aprepitant group, 55.9 ± 12.6 in control group Gender: male (196) + female (652) Tumour/cancer type: solid malignancy (breast cancer, colorectal cancer, lung cancer, ovarian cancer) Chemotherapy regimen: non‐AC (anthracycline (doxorubicin and epirubicin) and cyclophosphamide), AC (anthracycline (doxorubicin and epirubicin) and cyclophosphamide) Countries: USA, Mexico, Canada, Chile, Brazil, Peru, Colombia, Panama, Hong Kong, Australia, South Africa, France, Germany, Israel, Russia
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg p.o. 1 h before chemotherapy + ondansetron 8 mg p.o. 30 to 60 min before chemotherapy; 8 mg p.o. 8 h after first dose + dexamethasone 12 mg p.o. 30 min before chemotherapy Days 2 to 3: aprepitant 80 mg p.o. + ondansetron placebo p.o. b.i.d. Control: arm B: placebo Day 1: aprepitant placebo p.o. 1 h before chemotherapy + ondansetron 8 mg p.o. 30 to 60 min before chemotherapy; 8 mg p.o. 8 h after first dose + dexamethasone 20 mg p.o. 30 min before chemotherapy Days 2 to 3: aprepitant placebo p.o. + ondansetron 8 mg p.o. b.i.d.
Outcomes	Primary outcome measure number of patients who reported no vomiting [Time frame: overall phase (0 to 120 h post initiation of MEC) in Cycle 1) Secondary outcome measure number of patients who reported complete response [Time frame: overall phase (0 to 120 h post initiation of MEC) in Cycle 1)
Notes	NCT registry number: NCT00337727 "this study was funded by Merck & Co., Inc., manufacturer of aprepitant" conflicts of interest: "J.A.B., A.T., C.B., J.S.H., and A.C. are employees of Merck & Co., Inc. who may own stock and/or hold stock options in the Company. B.L.R., K. J., and H.J.S. have served as scientific advisors to Merck & Co., Inc."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... computer‐generated, random, blinded allocation schedule ..."
Allocation concealment (selection bias)	Low risk	Comment: allocation was blinded
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Comment: double‐blind (participant, investigator)
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Comment: double‐blind (participant, investigator)
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. neutropenia)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "the analysis of efficacy was based on the full analysis set population, which included those patients who received MEC, took a dose of study drug, and completed at least one posttreatment efficacy assessment"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "all patients who received at least one dose of study drug were included in the safety analyses"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Rapoport 2015 (a).

Study characteristics
Methods	Randomised, parallel‐group, placebo‐controlled, dose‐ranging,phase 2 trial with 5 arms comparison of rolapitant 9 mg + ondansetron 32 mg i.v. + dexamethasone 8 mg (2× daily on Days 2, 3, and 4) vs rolapitant 22.5 mg + ondansetron 32 mg i.v. + dexamethasone 8 mg (2× daily on Days 2, 3, and 4) vs rolapitant 90 mg + ondansetron 32 mg i.v. + dexamethasone 8 mg (2× daily on Days 2, 3, and 4) vs rolapitant 180 mg + ondansetron 32 mg i.v. + dexamethasone 8 mg (2× daily on Days 2, 3, and 4) vs placebo + ondansetron 32 mg i.v. + dexamethasone 8 mg (2× daily on Days 2, 3, and 4) Study period: September 2006 to March 2008 454 patients randomised Masking: double‐blind (participant, investigator) Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria 18 years of age or older never been treated with cisplatin and is to receive first course of cisplatin‐based chemotherapy (≥ 70 mg/m²) Karnofsky performance score ≥ 60 predicted life expectancy ≥ 3 months adequate bone marrow, kidney, and liver function as evidenced by absolute neutrophil count ≥ 1500/mm³ and white blood cell count ≥ 3000/mm³, platelet count ≥ 100,000/mm³, AST ≤ 2.5 × ULN range, ALT ≤ 2.5 × ULN, bilirubin ≤ 1.5 × ULN, except for subjects with Gilbert's syndrome, creatinine ≤ 1.5 × ULN ability to read, understand, and complete questionnaires Exclusion criteria any current treatment or medical history (e.g. subject is mentally incapacitated, subject has a psychiatric disorder) that, in the opinion of the investigator, would confound results of the study or would pose any unwarranted risk in administering study drug to the subject contraindication to administration of cisplatin, ondansetron, or dexamethasone including, but not limited to, history of hypersensitivity to drugs or their components, severe renal impairment, severe bone marrow suppression, hearing impairment, or systemic fungal infection scheduled to receive any other chemotherapeutic agent with emetogenicity level ≥ 3 (Hesketh Scale) from Day ‐2 through Day 6 scheduled to receive any radiation therapy to abdomen or pelvis within 5 days before and/or during Days 1 through 5 following cisplatin infusion symptomatic primary or metastatic central nervous system (CNS) disease ongoing vomiting caused by any aetiology or history of anticipatory nausea and vomiting Median age (range), years: 55 (22 to 86) in rolapitant 9‐mg group, 53 (26 to 76) in rolapitant 22.5‐mg group, 57 (19 to 79) in rolapitant 90‐mg group, 56 (20 to 75) in rolapitant 180‐mg group, 54 (18 to 77) in control group Gender: male (244) + female (210) Tumor/cancer type: n.r. Chemotherapy regimen: HEC (≥ 70 mg/m² cisplatin‐based chemotherapy) Country: 75 sites in 21 countries
Interventions	Experimental: arm A: rolapitant 9 mg Day 1: rolapitant 9 mg administered approximately 2 h before first dose of chemotherapeutic agent on Day 1 of Cycle 1 + i.v. ondansetron 32 mg 0.5 h before initiation of chemotherapy + oral dexamethasone 20 mg 0.5 h before initiation of chemotherapy Days 2 to 4: dexamethasone 8 mg twice daily Experimental: arm B: rolapitant 22.5 mg Day 1: rolapitant 22.5 mg administered approximately 2 h before first dose of chemotherapeutic agent on Day 1 of Cycle 1 + i.v. ondansetron 32 mg 0.5 h before initiation of chemotherapy + oral dexamethasone 20 mg 0.5 h before initiation of chemotherapy Days 2 to 4: dexamethasone 8 mg twice daily Experimental: arm C: rolapitant 90 mg Day 1: rolapitant 90 mg administered approximately 2 h before first dose of chemotherapeutic agent on Day 1 of Cycle 1 + i.v. ondansetron 32 mg 0.5 h before initiation of chemotherapy + oral dexamethasone 20 mg 0.5 h before initiation of chemotherapy Days 2 to 4: dexamethasone 8 mg twice daily Experimental: arm D: rolapitant 180 mg Day 1: rolapitant 180 mg administered approximately 2 h before first dose of chemotherapeutic agent on Day 1 of Cycle 1 + i.v. ondansetron 32 mg 0.5 h before initiation of chemotherapy + oral dexamethasone 20 mg 0.5 h before initiation of chemotherapy Days 2 to 4: dexamethasone 8 mg twice daily Control: arm E Day 1: placebo + i.v. ondansetron 32 mg 0.5 h before initiation of chemotherapy + oral dexamethasone 20 mg 0.5 h before initiation of chemotherapy Days 2 to 4: dexamethasone 8 mg twice daily
Outcomes	Primary outcome measure primary efficacy endpoint is overall complete response rate (no emesis and no use of rescue medication from 0 through 120 hours following initiation of cisplatin‐based chemotherapy) [Time frame: Days 1 through 6] Secondary outcome measures complete response rates for acute (0 through 24 hours) and delayed (> 24 through 120 hours) phases of CINV [Time frame: Days 1 through 6] adverse events, physical examination, vital signs, electrocardiogram, safety laboratory values [Time frame: throughout the study and up to 30 days after subject completes or discontinues from the study]
Notes	this study was registered at clinicaltrials.gov: NCT00394966 "the phase III studies were designed through a collaboration of academic researchers and the study sponsor, TESARO, Inc. Study data were collected by clinical investigators, and trials conducts were monitored by TESARO, Inc. Statistical analyses were managed by TESARO, Inc., according to a predefined statistical plan; data presented here include post hoc analyses" conflicts of interest: "BR has received honoraria for speaking engagements from MSD and Roche Malaysia; he has been a consultant and has had travel/accommodations paid for by MSD and TESARO, Inc. LS has served as a consultant for TESARO, Inc. Helsinn, and Eisai. DP is an employee of TESARO, Inc. SA has received contracting fees from TESARO, Inc., to direct statistical analyses during this study and outside the submitted work. IS has served on an advisory board for TESARO, Inc. MC and RN have declared no conflicts of interest" no results for this study posted on ClinicalTrials.gov
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Comment: double‐blind (participant, investigator)
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Comment: double‐blind (participant, investigator)
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. febrile neutropenia, neutropenia)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included for the efficacy analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: all patients were included for the safety analysis
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Rapoport 2015 (b).

Study characteristics
Methods	Randomised, active‐controlled, parallel‐group, phase 3 trial with 2 arms comparison of rolapitant + granisetron + dexamethasone vs placebo + granisetron + dexamethasone Study period: February 2012 to May 2014 532 patients randomised overall number of baseline participants = 526 Masking: double‐blind Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria 18 years of age or older, of either gender, of any race never been treated with cisplatin and is to receive first course of cisplatin‐based chemotherapy (≥ 60 mg/m²) Karnofsky performance score ≥ 60 predicted life expectancy ≥ 4 months adequate bone marrow, kidney, and liver function Exclusion criteria contraindication to cisplatin, granisetron, or dexamethasone pregnant or breast‐feeding has previously received cisplatin or is planning to receive multiple days of cisplatin in a single cycle has taken the following agents within the last 48 h: 5‐HT₃ antagonists, phenothiazines, benzamides, domperidone, cannabinoids, NK₁ antagonists, benzodiazepines scheduled to receive any other chemotherapeutic agent with emetogenicity level ≥ 4 (Hesketh Scale) from Day 2 through Day 6, except on Day 1 scheduled to receive any radiation therapy to abdomen or pelvis from Day ‐5 through Day 6 has received systemic corticosteroids or sedative antihistamines within 72 h of Day 1 of the study, except as pre‐medication for chemotherapy (e.g. taxanes, pemetrexed) symptomatic primary or metastatic CNS disease ongoing vomiting, retching, clinically significant nausea caused by any aetiology, or history of anticipatory nausea and vomiting has vomited and/or has had dry heaves/retching within 24 hours before the start of cisplatin‐based chemotherapy on Day 1 in Cycle 1 Mean age ± SD, years: 57.0 ± 10.08 in rolapitant group, 57.7 ± 11.15 in placebo group Gender: male (304) + female (222) Tumour/cancer type: solid tumour (breast, colon or rectum, head and neck, lung, ovary, stomach, and other tumours) Chemotherapy regimen: cisplatin‐based chemotherapy (≥ 60 mg/m²) Country: United States (multi‐centre)
Interventions	Experimental: arm A: rolapitant Day 1: oral dose of rolapitant 180 mg (equivalent to 200 mg rolapitant hydrochloride monohydrate) 1 to 2 h before administration of chemotherapy + granisetron (10 µg/kg i.v.) + dexamethasone (20 mg p.o.) Days 2 to 4: dexamethasone (8 mg p.o.) to be administered orally b.i.d. Control: arm B Day 1: placebo + granisetron (10 µg/kg i.v.) + dexamethasone (20 mg p.o.) Days 2 to 4: dexamethasone (8 mg p.o.) to be administered orally b.i.d.
Outcomes	Primary endpoint no emetic episodes and no rescue medication [Time frame: > 24 to 120 h post chemotherapy] Secondary endpoint(s) acute phase response [Time frame: 0 to 24 h] overall response rate [Time frame: 0 to 120 h]
Notes	clinicalTrials.gov Identifier: NCT01499849 sponsors and collaborators: Tesaro, Inc. "the study sponsor was also unaware of treatment allocation" conflicts of interest: "BLR and IDS are advisory board consultants for the sponsor TESARO, outside the submitted work. AP and VK are employees of the sponsor TESARO. SA has received contracting fees from TESARO during this study and outside the submitted work. LSS is a consultant for TESARO, Helsinn, and Eisai, outside the submitted work. All other authors declare no competing interests"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "for randomisation of patients, we used an interactive web‐based randomisation system (IWRS) at cycle 1"
Allocation concealment (selection bias)	Low risk	Quote: "an independent group not involved with study implementation created a randomisation schedule for study drug labelling"
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Comment: double‐blind (participant, investigator)
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Comment: double‐blind (participant, investigator)
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. febrile neutropenia, neutropenia)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: analysis included modified ITT population
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "the safety population included all patients who were randomly allocated to a treatment group and who received at least one dose of study drug"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Rapoport 2015 (c).

Study characteristics
Methods	Randomised, parallel‐group, active‐controlled, phase 3 trial with 2 arms comparison of rolapitant + granisetron + dexamethasone vs placebo + granisetron + dexamethasone Study period: February 2012 to March 2014 555 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria 18 years of age or older, of either gender, of any race never treated with cisplatin and is to receive first course of cisplatin‐based chemotherapy (≥ 60 mg/m²) Karnofsky performance score ≥ 60 predicted life expectancy ≥ 4 months adequate bone marrow, kidney, and liver function Exclusion criteria contraindication to cisplatin, granisetron, or dexamethasone pregnant or breast‐feeding has previously received cisplatin or is planning to receive multiple days of cisplatin in a single cycle has taken the following agents within the last 48 h: 5‐HT₃ antagonists, phenothiazines, benzamides, domperidone, cannabinoids, NK₁ antagonists, benzodiazepines scheduled to receive any other chemotherapeutic agent with emetogenicity level ≥ 4 (Hesketh Scale) from Day 2 through Day 6, except on Day 1 scheduled to receive any radiation therapy to abdomen or pelvis from Day ‐5 through Day 6 has received systemic corticosteroids or sedative antihistamines within 72 h of Day 1 of the study except as pre‐medication for chemotherapy (e.g. taxanes, pemetrexed) symptomatic primary or metastatic CNS disease ongoing vomiting, retching, clinically significant nausea caused by any aetiology, or history of anticipatory nausea and vomiting has vomited and/or has had dry heaves/retching within 24 h before the start of cisplatin‐based chemotherapy on Day 1 in Cycle 1 Mean age ± SD, years: 58.5 ± 10.05 in rolapitant group, 58.5 ± 9.25 in placebo group Gender: male (369) + female (175) Tumour/cancer type: solid tumour (breast, colon or rectum, head and neck, lung, ovary, stomach, and other tumours) Chemotherapy regimen: cisplatin‐based chemotherapy (≥ 60 mg/m²) Country: United States (multi‐centre)
Interventions	Experimental: arm A: rolapitant Day 1: oral dose of rolapitant 180 mg (equivalent to 200 mg rolapitant hydrochloride monohydrate) 1 to 2 h before administration of chemotherapy + granisetron (10 µg/kg i.v.) + dexamethasone (20 mg p.o.) Days 2 to 4: dexamethasone (8 mg p.o.) to be administered orally b.i.d. Control: arm B Day 1: placebo + granisetron (10 µg/kg i.v.) + dexamethasone (20 mg p.o.) Days 2 to 4: dexamethasone (8 mg p.o.) to be administered orally b.i.d.
Outcomes	Primary endpoints no emetic episodes and no rescue medication [Time frame: > 24 to 120 h post chemotherapy] Secondary endpoints acute phase response [Time frame: 0 to 24 h] overall response rate [Time frame: 0 to 120 h]
Notes	clinicalTrials.gov Identifier: NCT01500213 sponsors and collaborators: Tesaro, Inc. "the study sponsor was also unaware of treatment allocation" conflicts of interest: "BLR and IDS are advisory board consultants for the sponsor TESARO, outside the submitted work. AP and VK are employees of the sponsor TESARO. SA has received contracting fees from TESARO during this study and outside the submitted work. LSS is a consultant for TESARO, Helsinn, and Eisai, outside the submitted work. All other authors declare no competing interests"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "for randomisation of patients, we used an interactive web‐based randomisation system (IWRS) at cycle 1"
Allocation concealment (selection bias)	Low risk	Quote: "an independent group not involved with study implementation created a randomisation schedule for study drug labelling"
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "double‐blind (participant, investigator)"
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "double‐blind (participant, investigator)"
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention; therefore they probably had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. febrile neutropenia, neutropenia)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: analysis included modified ITT population
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "the safety population included all patients who were randomly allocated to a treatment group and who received at least one dose of study drug"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Roila 1995.

Study characteristics
Methods	Double‐blind, multi‐centre, randomised trial with 2 arms comparison of ondansetron + dexamethasone vs granisetron + dexamethasone Recruitment period: December 1992 to July 1994 973 patients enrolled 966 evaluated for efficacy according to ITT Masking: double‐blind Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria scheduled to receive for the first time cisplatin at doses ≥ 50 mg/m², used alone or in combination with other antineoplastic agents Exclusion criteria  presence of nausea or vomiting or use of antiemetics in the 24 h before chemotherapy severe concurrent illness other than neoplasia; other cause for vomiting (e.g. gastrointestinal obstruction, central nervous system metastasis, hypercalcaemia) contraindications to dexamethasone administration (active peptic ulceration or previous gastrointestinal bleeding due to peptic ulcer) concurrent therapy with corticosteroids (unless given as physiological supplements) or benzodiazepines (unless given for night sedation) abdominal radiotherapy pregnancy Mean/median age (range), years: 61 Gender: male + female Tumour/cancer type: solid tumours Chemotherapy regimen: cisplatin at doses ≥ 50 mg/m², used alone or in combination with other antineoplastic agents Country: Italy (multi‐centre)
Interventions	Experimental: arm A: ondansetron ondansetron 8 mg i.v. diluted in 50 mL normal saline and administered 15 min, 30 min before chemotherapy + dexamethasone 20 mg i.v. added to 5‐HT₃ antagonist and administered 15 min, 45 min before chemotherapy Experimental: arm B: granisetron granisetron 3 mg i.v. diluted in 50 mL normal saline and administered 15 min, 30 min before chemotherapy + dexamethasone 20 mg i.v. added to 5‐HT₃ antagonist and administered 15 min, 45 min before chemotherapy
Outcomes	Primary endpoint complete protection from vomiting (acute and delayed phases, Day 1 vs Day 2 to 6) complete protection from nausea (acute and delayed phases, Day 1 vs Days 2 to 6) intensity of nausea number of emetic episodes adverse events
Notes	"supported in part by a grant from the Umbrian Cancer Association (A.U.C.C.)" study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "using a centralized list of computer‐generated random permuted blocks of 10 patients for each centre ..."
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Comment: double‐blind study
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Comment: double‐blind study
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "a total of 973 patients took part in the study and 966 of them were evaluated for efficacy according to the intention‐to‐treat principle" Comment: some patients missing without reasons provided; however, we judged this number to be small
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: 967 participants were included for adverse events assessment; this number represents nearly the entire enrolled cohort
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Rugo 2017.

Study characteristics
Methods	Randomised, active‐controlled, parallel‐group, phase 3 trial with 2 arms comparison of netupitant + palonosetron + dexamethasone vs placebo + palonosetron + dexamethasone Study period: April 2011 to November 2012 1455 patients enrolled and randomised 1286 entered multiple‐cycle extension Masking: quadruple‐blind (participant, care provider, investigator, outcomes assessor) Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria 18 years of age and older naïve to cytotoxic chemotherapy; previous biological or hormonal therapy permitted scheduled to receive first course of an anthracycline and cyclophosphamide‐containing chemotherapy for treatment of a solid malignant tumour: cyclophosphamide i.v. (500 to 1500 mg/m²) and i.v. doxorubicin (≥ 40 mg/m²) or cyclophosphamide i.v. (500 to 1500 mg/m²) and i.v. epirubicin (≥ 60 mg/m²) scheduled to receive chemotherapy agents of minimal to low emetogenic potential that could be given on any day ECOG performance status 0, 1, or 2 females of non‐child‐bearing potential or child‐bearing potential with a commitment to use contraceptive methods throughout the clinical trial haematological and metabolic status adequate for receiving a moderately emetogenic regimen based on laboratory criteria (total neutrophils, platelets, bilirubin, liver enzymes, serum creatinine, or creatinine clearance) The following inclusion criteria must be checked before inclusion at each cycle of the multiple‐cycle extension participation in the study during the next cycle of chemotherapy is considered by the investigator to be satisfactory study compliance in the preceding cycle of chemotherapy and related study procedures scheduled to receive the same chemotherapy regimen as Cycle 1 adequate haematological and metabolic status as defined for Cycle 1 Exclusion criteria if female, pregnant or lactating current use of illicit drugs or current evidence of alcohol abuse scheduled to receive any highly emetogenic chemotherapy (HEC) from Day 1 to Day 5, or moderately emetogenic chemotherapy (MEC) from Day 2 to Day 5, following the allowed MEC regimen received or scheduled to receive radiation therapy to abdomen or pelvis within 1 week before Day 1 or between Days 1 and 5 in Cycle 1 any vomiting, retching, or mild nausea within 24 h before Day 1 symptomatic primary or metastatic central nervous system (CNS) malignancy active peptic ulcer disease, gastrointestinal obstruction, increased intracranial pressure, hypercalcaemia, active infection or any uncontrolled medical condition (other than malignancy) that, in the opinion of the investigator, may confound results of the study, represent another potential aetiology for emesis and nausea (other than chemotherapy‐induced nausea and vomiting, CINV), or pose unwarranted risk in administering study drugs to the patient known hypersensitivity or contraindication to 5‐HT₃ receptor antagonist or dexamethasone previously received a neurokinin‐1 (NK₁) receptor antagonist participation in a clinical trial involving oral netupitant administered in combination with palonosetron any investigational drugs taken within 4 weeks before Day 1 of Cycle 1 and/or scheduled to receive any investigational drug during the study systemic corticosteroid therapy at any dose within 72 hours prior to day 1 of cycle 1 scheduled to receive bone marrow transplantation and/or stem cell rescue therapy any medication with known or potential antiemetic activity within 24 h before Day 1 of Cycle 1 scheduled to receive any strong or moderate inhibitor of cytochrome P450 3A4 (CYP3A4) or its intake within 1 week before Day 1 scheduled to receive any of the following CYP3A4 substrates: terfenadine, cisapride, astemizole, pimozide scheduled to receive any CYP3A4 inducer or its intake within 4 weeks before Day 1 history or predisposition to cardiac conduction abnormalities, except for incomplete right bundle branch block history of risk factors for torsades de pointes (heart failure, hypokalaemia, family history of long QT syndrome) severe cardiovascular disease, including myocardial infarction within 3 months before Day 1, unstable angina pectoris, significant valvular or pericardial disease, history of ventricular tachycardia, symptomatic congestive heart failure (CHF), New York Heart Association (NYHA) class III to IV, severe uncontrolled arterial hypertension any illness or condition that, in the opinion of the investigator, may confound results of the study or pose unwarranted risk in administering the investigational product to the patient concurrent medical condition that would preclude administration of dexamethasone such as systemic fungal infection or uncontrolled diabetes The following exclusion criteria must be checked before inclusion at each cycle of the multiple‐cycle extension if female, pregnant or lactating active infection or uncontrolled disease except for malignancy started any of the restricted medications any vomiting, retching, or mild nausea within 24 h before Day 1 Mean age (SD), years: 53.7 (10.66) in netupitant + palonosetron group, 54.1 (10.65) in palonosetron group Gender: male + female Tumour/cancer type: breast cancer Chemotherapy regimen: anthracycline and cyclophosphamide‐containing chemotherapy Country: United States (28), Argentina (9), Belarus (6), Brazil (12), Bulgaria (12), Croatia (9), Germany (11), Hungary (8), India (13), Italy (5), Mexico (5), Poland (10), Romania (10), Russian Federation (22), Ukraine (12) (172 centres)
Interventions	Experimental: arm A: NEPA + dexamethasone Day 1: oral netupitant/palonosetron (300 mg/0.50 mg) hard capsule with oral dexamethasone before each scheduled chemotherapy cycle Experimental: arm B: palonosetron + dexamethasone Day 1: oral palonosetron 0.50 mg (Aloxi) with oral dexamethasone before each scheduled chemotherapy cycle
Outcomes	Primary outcome measure percentage of patients with complete response (CR) [Time frame: 25 to 120 h] Secondary outcome measures percentage of patients with complete response (CR) [Time frame: 0 to 24 h] percentage of patients with complete response (CR) [Time frame: 0 to 120 h]
Notes	clinicalTrials.gov Identifier: NCT01339260 "the trials described within this paper were sponsored by Helsinn Healthcare SA, Lugano, Switzerland. Helsinn Healthcare SA also participated in the writing, review, and approval of the manuscript" conflicts of interest: "Hope S. Rugo: receives funding from Pfizer, Novartis, Lilly, Genentech, Macrogenics, OBI Pharma, Merck for contracted or investigator initiated research. This money is paid to the University of California. Giorgia Rossi: employee at Helsinn Healthcare SA. Giada Rizzi: employee at Helsinn Healthcare SA. Matti Aapro: consultant or advisory role for Eisai, Helsinn, Merck, Mundipharma, Roche, and Tesaro"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "quadruple (participant, care provider, investigator, outcomes assessor)"
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "quadruple (participant, care provider, investigator, outcomes assessor)"
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: patients, personnel, investigator, and outcome assessor were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all randomised patients were included in the ITT population
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Ruhlmann 2017.

Study characteristics
Methods	Randomised, placebo‐controlled, phase 3 study with 2 arms comparison of fosaprepitant + palonosetron + dexamethasone vs placebo + palonosetron + dexamethasone Recruitment period: June 2010 to March 2015 234 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria woman with cervical cancer receiving fractionated radiotherapy and weekly cisplatin 40 mg/m² understands the nature and purpose of this study and study procedures and has signed informed consent aged > 18 years both chemotherapy and radiotherapy (RT) naïve. NB: previous low‐voltage RT or electron RT for non‐melanoma skin cancer is allowed scheduled to receive fractionated radiotherapy and concomitant weekly cisplatin at a dose ≥ 40 mg/m² for at least 5 weeks brachytherapy scheduled to be initiated after third cycle of weekly cisplatin, and preferentially after fifth week of treatment chemotherapy with emetic risk potential of minimal or mild (up to 30%) allowed on Days 1 to 4 WHO performance status ≤ 2 Exclusion criteria current malignant diagnosis other than cervical cancer, with exception of non‐melanoma skin cancer aged < 18 years scheduled to receive less than 5 weeks of fractionated radiotherapy and concomitant weekly cisplatin brachytherapy is planned to be initiated before third cycle of weekly cisplatin previous treatment with radiotherapy and/or chemotherapy, with exception of treatment with low‐voltage RT or electron RT for non‐melanoma skin cancer WHO performance status > 2 Mean/median age, years (median, range): fosaprepitant group: 48 (25 to 74); placebo group: 47 (26 to 77) Gender: female Tumour/cancer type: cervical cancer Chemotherapy regimen: cisplatin 40 mg/m² Country: 8 centres in 4 countries (Germany, Australia, Norway, Denmark)
Interventions	Experimental: arm A: fosaprepitant fosaprepitant + palonosetron + dexamethasone Experimental: arm B: placebo placebo + palonosetron + dexamethasone
Outcomes	Primary endpoint proportion of subjects with no vomiting during 5 weeks of radiotherapy and concomitant weekly cisplatin [Time Frame: 35 days] Secondary endpoints proportion of subjects with complete response in the 7 days following initiation of radiotherapy and concomitant weekly cisplatin [Time frame: 7 days] proportion of subjects with no significant nausea during 5 weeks of fractionated radiotherapy and concomitant weekly cisplatin at a dose ≥ 40 mg/m² [Time frame: 35 days] complete response in the 35 days following initiation of fractionated radiotherapy and concomitant weekly cisplatin at a dose ≥ 40 mg/m² [Time frame: 35 days] proportion of subjects with no nausea during 5 weeks (35 days) of fractionated radiotherapy and concomitant weekly cisplatin at a dose ≥ 40 mg/m² [Time frame: 35 days] number of days to first emetic episode [Time frame: 0 to 35 days] quality of life using the FLIE questionnaire [Time frame: 0 to 35 days] tolerability of both regimens [Time frame: 0 to 35 days]
Notes	EudraCT number: 2009‐014691‐21. ClinicalTrials.gov: NCT 01074697 funding: "private and hospital or university funding, unrestricted grants from Biovitrum and Helsinn Healthcare SA" conflicts of interest: "FH reports grants from Riemser Pharma during the conduct of the study. PF reports grants from Riemser Pharma during the conduct of the study and advisory consultant for MSD outside the submitted work. DK reports grants from Helsinn Healthcare and clinical trial support from Merck outside the submitted work. JH reports unrestricted grants from Helsinn Healthcare and SOBI during the conduct of the study, and personal fees from Tesaro outside the submitted work. All other authors declare no competing interests"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "the randomisation numbers were generated by an independent research staff member using a web randomisation sequence generator"
Allocation concealment (selection bias)	Unclear risk	Quote: "the blocks, in sealed envelopes, were provided to the pharmacists who were not masked to treatment at the study centres, and sealed blinding envelopes unique to each randomisation number were provided to the centres."; "To avoid treatments being visually distinguishable, study drug and placebo were provided in identically wrapped and labelled infusion bags of the same volume"
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. neutrophil count decreased)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "... the 234 patients receiving study medication represented the modified intention‐to‐treat population (figure 1) and were all included in the analysis of the primary and secondary outcomes and in the safety analysis"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "... the 234 patients receiving study medication represented the modified intention‐to‐treat population (figure 1) and were all included in the analysis of the primary and secondary outcomes and in the safety analysis"
Selective reporting (reporting bias)	Low risk	Comment: study authors mentioned explicitly that FLIE results are not reported in this article
Other bias	Low risk	Comment: no information to suggest other sources of bias

Saito 2009.

Study characteristics
Methods	Randomised, parallel‐group, comparative, phase 3, active‐comparator trial with 2 arms comparison of palonosetron + dexamethasone vs granisetron + dexamethasone Study period: July 2006 to May 2007 1143 patients enrolled 1119 patients treated 1114 patients included in mITT analysis Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria ≥ 20 years of age at the time when they give consent malignant disease diagnosed naïve to chemotherapy or treated with single administration of antitumour drugs classified as low emetogenicity in the first edition of the 2006 NCCN Clinical Practice Guidelines cisplatin ≥ 50 mg/m², doxorubicin + cyclophosphamide: AC, epirubicin + cyclophosphamide; EC WBC ≥ 3000/mm³, AST < 100 IU/L, ALT < 100 IU/L, creatinine clearance ≥ 60 mL/min ECOG performance status 0 to 2 Exclusion criteria severe (requiring hospitalisation) and uncontrollable complications metastasis to the brain that is symptomatic seizure disorder requiring anticonvulsant medication unless clinically stable and free of seizure activity symptomatic and invasive procedure indicating ascites or pleural effusion. gastric outlet stenosis or intestinal obstruction. ongoing emesis or CTCAE ≥ grade 2 nausea QTc > 470 msec in 12‐lead ECG within 8 days before registration known anaphylactic to ingredients of study drug, namely, palonosetron or granisetron hydrochloride injection, or other 5‐HT₃ receptor antagonist known anaphylactic to ingredients of dexamethasone pregnant woman, breast‐feeding woman, any male or female not willing to practice adequate contraception during the study period Mean age ± SD, years: 58.4 ± 10.4 in palonosetron arm, 58 ± 10.5 in granisetron arm Gender: male + female Tumour/cancer type: solid tumour (non‐small cell lung cancer, small cell lung cancer, breast cancer, others) Chemotherapy regimen: cisplatin, doxorubicin + cyclophosphamide/epirubicin + cyclophosphamide Country: Japan (75 centres)
Interventions	Experimental: arm A: palonosetron i.v. injection of 0.75 mg palonosetron (5 mL), then granisetron placebo before administration of highly emetogenic chemotherapy, concomitantly administered with corticosteroids Experimental: arm B granisetron i.v. injection of palonosetron placebo, then 40 μg/kg granisetron hydrochloride before administration of highly emetogenic chemotherapy, concomitantly administered with corticosteroids
Outcomes	Primary outcome measure complete response (CR: no emetic episode and no rescue medication) rate in acute and delayed nausea and vomiting Secondary outcome measures complete response for the overall phase (0 to 120 h) proportion of patients with complete control number of emetic episodes time to first emetic episode time to administration of rescue therapy time to treatment failure severity of nausea overall patient satisfaction safety profile
Notes	"this trial was funded by Taiho Pharmaceutical (Tokyo, Japan)" conflicts of interest: "the authors declared no conflicts of interest" clinicalTrials.gov number: NCT00359567
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomisation was done centrally by computer ..."; "a non‐deterministic minimisation method with a stochastic‐biased coin was applied to the randomisation of patients"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Comment: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Comment: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. study mortality)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "the modified ITT cohort was used for the primary efficacy analysis"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "... including one death caused by bleeding from pulmonary carcinoma in the granisetron group..."
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Saito 2013.

Study characteristics
Methods	Randomised, placebo‐controlled, parallel, phase 3 trial with 2 arms comparison of fosaprepitant + granisetron + dexamethasone vs placebo + granisetron + dexamethasone Recruitment period: August 2009 to December 2009 347 patients enrolled and randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria aged ≥ 20 years received cancer chemotherapy containing cisplatin (≥ 70 mg/m²) ECOG performance status 0 to 2 and estimated life expectancy ≥ 3 months white blood cell count ≥ 3000/mm³, neutrophil count ≥ 1500/mm³, platelet count ≥ 100,000/mm³, aspartate transaminase and ALT ≤ 2.5 × ULN, total bilirubin ≤ 1.5 × ULN, and creatinine ≤ 1.5 × ULN Exclusion criteria would receive at least moderately emetogenic antitumour agent(s) in combination with cisplatin at any point from 6 days before cisplatin dosing (Day –6) to Day 6 except for the day of cisplatin dosing would receive paclitaxel in combination with cisplatin previously treated with cisplatin without vomiting risk of vomiting for other reasons concomitant use of the following drugs was prohibited: all antiemetics other than fosaprepitant from 48 h before cisplatin dosing to Day 6; CYP3A4 substrates and inhibitors from Day –7 to Day 15; and CYP3A4 inducers from Week –4 to Day 6 history of hypersensitivity to granisetron or dexamethasone phosphate previously treated with fosaprepitant or aprepitant pregnant (or potentially pregnant) and nursing women Median age (range), years: 62 (26 to 86) in fosaprepitant group, 63 (25 to 85) in placebo group Gender: male (257) + female (90) Tumour/cancer type: solid tumour (respiratory, genitourinary, digestive, head and neck, other) Chemotherapy regimen: chemotherapy including cisplatin (≥ 70 mg/m²) Country: Japan (68 institutions)
Interventions	Experimental: arm A: fosaprepitant Day 1: i.v. fosaprepitant (150 mg) + granisetron (40 μg/kg) + dexamethasone phosphate (10 mg) Day 2: dexamethasone phosphate (4 mg) Day 3: dexamethasone phosphate (8 mg) Experimental: arm B: placebo Day 1: placebo + granisetron (40 μg/kg body weight) + dexamethasone phosphate (20 mg) Days 2 to 3: dexamethasone phosphate (8 mg)
Outcomes	Primary endpoint percentage of patients with complete response in the overall phase Secondary endpoints percentages of patients with complete response in acute and delayed phases time to first episode of vomiting percentages of patients with complete protection total control no emesis no rescue therapy no nausea no significant nausea
Notes	registered at www.clinicaltrials.jp as JapicCTI090829 "this study was funded by Ono Pharmaceuticals (Osaka, Japan)" conflicts of interest: "HS received honoraria and research funding from Ono Pharmaceuticals; HY received honoraria and research funding from Ono Pharmaceuticals; NK received payment from Ono Pharmaceuticals in relation to consultant or advisory roles, and received honoraria from Ono Pharmaceuticals; MK received payment from Ono Pharmaceuticals in relation to consultant or advisory roles, and received honoraria from Ono Pharmaceuticals; KE received honoraria and research funding from Ono Pharmaceuticals; all other authors have declared that they have no conflicts of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Comment: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Comment: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. study mortality, neutropenia)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "the efficacy analysis was carried out on the modified intention‐to‐treat (ITT) population"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "therefore, 340 patients (167 in the standard arm and 173 in the fosaprepitant arm) were assessable in the modified ITT analysis, and 344 patients were included in the safety analysis"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Saito 2017.

Study characteristics
Methods	Randomised, comparative, interventional, parallel, phase 3 trial with 2 arms comparison of aprepitant 125/80 mg + palonosetron + dexamethasone vs aprepitant 125/80 mg + granisetron + dexamethasone Recruitment period: 2012 to 2015 491 patients enrolled Masking: double‐blind Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria ≥ 20 years old and ≤ 75 years old (at the time informed consent was obtained) female primary breast cancer stages I to III and scheduled to receive AC therapy ECOG performance status 0 to 1 Can correctly fill in a symptom diary meet the following standard values in general clinical tests: white blood cells ≥ 3000/mm³, neutrophils ≥ 1500/mm³, blood platelet count ≥ 100,000/mm³, AST (GOT) and ALT (GPT) ≤ 2.5 times high end of normal range at the facility, total bilirubin ≤ 1.5 times high end of normal range at the facility, creatinine ≤ 1.5 times high end of normal range at the facility normal cardiac function: ECG within normal range; no symptoms; no abnormality requiring treatment; cardiac function determined to be normal by Interview, echocardiography, chest X‐ray, BNP, etc. Exclusion criteria history of administration of moderately to highly emetogenic chemotherapy receiving an antiemetic drug (5‐HT₃ receptor antagonist, phenothiazine, butyrophenone, benzamide, dopamine receptor antagonist) received a benzodiazepine or a narcotic formulation within 48 h before commencement of AC therapy received systemic corticosteroid therapy within 72 h before commencement of AC therapy history of gastrointestinal tract surgery (excluding appendectomy) received or scheduled to receive radiation therapy for abdominal region (diaphragm or lower) or pelvis for a period from 6 days before commencement of AC therapy until Day 6 of AC therapy had vomiting or dry vomiting within 24 h before commencement of AC therapy active multiple cancer (synchronous multiple cancer or metachronous multiple cancer with disease‐free interval ≤ 5 years) symptomatic cerebral tumour (including a benign tumour) received the following drugs within 7 days before commencement of AC therapy: clarithromycin, erythromycin, ketoconazole, itraconazole, and digoxin received the following drugs within 4 weeks before commencement of AC therapy: barbiturate drug, rifampicin, phenytoin, and carbamazepine pregnant or lactating patients, patients who may be pregnant, patients hoping to become pregnant during the study period, and patients taking an oral contraceptive with coexisting disease, such as systemic infection, hepatitis, and uncontrollable diabetes, for whom dexamethasone sodium phosphate cannot be administered history of hypersensitivity to granisetron, palonosetron, aprepitant, or dexamethasone judged by investigator to be inappropriate for inclusion in the study Mean/median age (range), years: n.r. Gender: female Tumour/cancer type: breast cancer Chemotherapy regimen: anthracycline and cyclophosphamide‐containing regimens (AC) Country: Japan (11 institutions)
Interventions	Experimental: arm A: palonosetron Day 1: aprepitant (125 mg) + palonosetron (0.75 mg) + dexamethasone (9.9 mg) Days 2 to 3: aprepitant (80 mg) Experimental: arm B: granisetron Day 1: aprepitant (125 mg) + granisetron (40 μg/kg) + dexamethasone (9.9 mg) Days 2 to 3: aprepitant (80 mg)
Outcomes	Primary outcome proportion of patients who showed complete response (no vomiting and no salvage treatment) during a period from 24 to 120 hours after AC therapy Secondary outcomes proportion of patients who showed complete response (no vomiting and no salvage treatment) from 0 to 24 hours of AC therapy proportion of patients who showed complete response (no vomiting and no salvage treatment) from 0 to 120 hours of AC therapy proportion of patients who showed no nausea/degree of nausea quality of life dietary intake adverse events
Notes	registration ID: UMIN000007882 funding source: non‐profit organisation: Japan Clinical Research Support Unit conference abstract, results are still unpublished
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included for patient‐reported outcomes analysis
Selective reporting (reporting bias)	High risk	Comment: only complete response and quality of life were reported in the results section
Other bias	Unclear risk	Comment: conference abstract, not evaluable

Schmitt 2014.

Study characteristics
Methods	Randomised, placebo‐controlled, phase 3 trial with 2 arms comparison of aprepitant + granisetron + dexamethasone vs matching placebo + granisetron + dexamethasone Recruitment period: July 2005 to January 2012 609 patients screened 246 patients excluded (131 declined participation, 30 with high‐dose therapy other than melphalan, 59 with contraindications, 4 with previous participation in same trial, 12 with participation in other trial, 10 with other reasons) 363 patients randomly assigned 362 patients were available for efficacy analysis per‐protocol set thus comprised 145 and 135 patients in aprepitant and placebo arms, respectively Masking: double‐blind Baseline patient characteristics: n.r. Follow‐up: Days 5 to 7
Participants	Inclusion criteria ≥ 18 years of age with multiple myeloma undergoing autologous transplantation after high‐dose melphalan conditioning Exclusion criteria nausea or vomiting within 12 h before planned high‐dose chemotherapy any antiemetic treatment within 24 h before planned high‐dose chemotherapy intake of corticosteroids known hypersensitivity to investigational product Median age (range), years: 58.3 (27 to 72) in aprepitant arm, 57.9 (35 to 72) in placebo arm Gender: male + female Tumour/cancer type: multiple myeloma Chemotherapy regimen: high‐dose melphalan therapy Country: Heidelberg University Hospital, Heidelberg, Germany (single centre)
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg + granisetron 2 mg + dexamethasone 4 mg Days 2 to 3: aprepitant 80 mg + granisetron 2 mg + dexamethasone 2 mg Day 4: aprepitant 80 mg + granisetron 2 mg Experimental: arm B: placebo Day 1: placebo 125 mg + granisetron 2 mg + dexamethasone 8 mg Days 2 to 3: placebo 80 mg + granisetron 2 mg + dexamethasone 4 mg Day 4: placebo 80 mg + granisetron 2 mg
Outcomes	Primary endpoint overall complete response (no emesis and no rescue therapy within 120 h of melphalan administration) Secondary endpoint complete response (no emesis and no rescue therapy in acute (0 to 24 hours) or delayed (25 to 120 hours) phase) rates of emesis no nausea and no significant nausea total control number of adverse events impact on quality of daily life, as assessed by modified Functional Living Index‐Emesis score
Notes	NCT00571168 conflicts of interest: "employment or leadership position: none; consultant or advisory role: Hartmut Goldschmidt, Janssen Pharmaceuticals (C), Celgene (C), Novartis (C), Onyx Pharmaceuticals (C), Millennium Pharmaceuticals (C); Markus Thalheimer, Merck Sharp & Dohme (C); Gerlinde Egerer, Merck Sharp & Dohme (C); stock ownership: none; honoraria: Hartmut Goldschmidt, Janssen Pharmaceuticals, Celgene, Novartis, Chugai Pharmaceutical, Onyx Pharmaceuticals, Millennium Pharmaceuticals; Markus Thalheimer, Merck Sharp & Dohme; Gerd Mikus, Merck Sharp & Dohme; Jürgen Burhenne, Merck Sharp & Dohme; Gerlinde Egerer, Merck Sharp & Dohme; research funding: Hartmut Goldschmidt, Janssen Pharmaceuticals, Celgene, Novartis, Chugai Pharmaceutical; Jürgen Burhenne, Merck Sharp & Dohme; Gerlinde Egerer, Merck Sharp & Dohme; expert testimony: none; patents, royalties, and licenses: none; other remuneration: Thomas Schmitt, Merck Sharp & Dohme" sponsor: Heidelberg University; collaborator: Merck Sharp & Dohme Corp.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... computer‐generated randomization list ..."
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "362 patients underwent ITT analysis out of 363 randomly assigned patients"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: ITT data set used for safety analysis
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Schmoll 2006.

Study characteristics
Methods	Randomised, parallel‐group trial with 2 arms comparison of aprepitant 125/80 mg + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Enrolment period: patients were enrolled from 2 January 2004 and were followed up until 30 September 2004 516 patients screened 489 patients randomised 484 patients included in mITT analysis Masking: double‐blind, with sponsor blinding Baseline patient characteristics: reported Follow‐up: follow‐up visit on Days 19 to 29
Participants	Inclusion criteria cisplatin‐naïve patients ≥ 18 years old with confirmed solid malignancies scheduled for chemotherapy that included cisplatin ≥ 70 mg/m² in Cycle 1 Karnofsky score ≥ 60 and life expectancy ≥ 3 months women of childbearing potential had to have negative β‐hCG pregnancy test Exclusion criteria planned receipt of concomitant stem cell rescue therapy or planned receipt of multiple‐day cisplatin in Cycle 1 moderately or highly emetogenic chemotherapy permitted only on the same day as cisplatin infusion, but not within 6 days before or 6 days after cisplatin infusion for agents of low emetogenic potential, timing of administration was not restricted, except a taxol could be given only on the same day as cisplatin receipt of 5‐HT₃ RAs within 48 h of Day 1 radiation therapy to abdomen or pelvis any time from 1 week before Day 1 to Day 6 active infection symptomatic primary or metastatic CNS malignancy uncontrolled disease other than malignancy that the investigator determined might pose an unwarranted risk vomiting and/or dry heaves/retching 24 h before cisplatin abnormal laboratory values (absolute neutrophil count < 1500/mm³, WBC < 3000/mm³, platelet count <100,000/mm³, AST > 2.5 × ULN, ALT > 2.5 × ULN, bilirubin > 1.5 × ULN, or creatinine > 1.5 × ULN) Mean age ± SD (range), years: 59 ± 11 (20 to 79) in aprepitant regimen, 58 ±11 (23 to 82) in control regimen Gender: male + female Tumour/cancer type: solid tumour (respiratory, urogenital, gastrointestinal, eyes/ears/nose/throat, other) Chemotherapy regimen: chemotherapy including cisplatin ≥ 70 mg/m²in Cycle 1 Country: 56 investigator sites in Europe, North America, South America, and Korea
Interventions	Experimental: arm A: aprepitant 125/80 mg Day 1: p.o. aprepitant 125 mg + i.v. ondansetron 32 mg + p.o. dexamethasone 12 mg Days 2 to 3: p.o. aprepitant 80 mg + p.o. ondansetron placebo twice daily + p.o. dexamethasone 8 mg in the morning and placebo in the evening Day 4: p.o. ondansetron placebo twice daily + p.o. dexamethasone 8 mg in the morning and placebo in the evening Control: arm B Day 1: aprepitant placebo + i.v. ondansetron 32 mg + p.o. dexamethasone 20 mg Days 2 to 3: aprepitant placebo + p.o. ondansetron 8 mg twice daily + p.o. dexamethasone 8 mg twice daily Day 4: p.o. ondansetron 8 mg twice daily + p.o. dexamethasone 8 mg twice daily
Outcomes	Primary efficacy endpoint percentage of patients reporting complete response in the overall phase Secondary endpoints percentage of patients with complete response in the delayed phase percentage of patients with no vomiting in the delayed phase percentage of patients with no vomiting in the overall phase Exploratory endpoints percentage of patients with complete response in the acute phase (Day 1, i.e. 0 to 24 h post cisplatin) percentage of patients with no vomiting in the acute phase percentage of patients with no significant nausea (defined as < 25 mm on a visual analogue scale) in the overall phase percentage of patients with time to first vomiting episode in the overall phase
Notes	clinicalTrials.gov: NCT00090207 aprepitant protocol 801 was funded by Merck & Co., Inc. study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients received either the aprepitant or the control regimen in a 1:1 ratio according to a sponsor‐supplied, computer‐generated, random allocation schedule"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind, parallel‐group trial with sponsor blinding ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind, parallel‐group trial with sponsor blinding ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. febrile neutropenia, hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "the efficacy analyses used a modified intention‐to‐treat (mITT) population ..."
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: all patients were included for the tolerability analysis
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were described in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Schnadig 2014.

Study characteristics
Methods	Randomised, phase 3 study with 2 arms comparison of rolapitant + granisetron + dexamethasone vs placebo + granisetron + dexamethasone Enrolment period: n.r. 1369 patients randomised Masking: double‐blind Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria chemo‐naïve subjects treated with MEC (cyclophosphamide, doxorubicin, epirubicin, carboplatin, irinotecan, daunorubicin, or cytarabine) Exclusion criteria: n.r. Mean/median age, years: n.r. Gender: n.r. Tumour/cancer type: n.r. Chemotherapy regimen: MEC (cyclophosphamide, doxorubicin, epirubicin, carboplatin, irinotecan, daunorubicin, or cytarabine) Country: n.r.
Interventions	Experimental: arm A: rolapitant rolapitant + granisetron + dexamethasone Experimental: arm B: placebo placebo + granisetron + dexamethasone
Outcomes	Primary endpoint complete response in delayed phase (> 24 to 120 h) Secondary endpoints complete response in acute (0 to 24 h) and overall (0 to 120 h) phases
Notes	conference abstract funding source and disclosure of potential conflicts of interest not provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "...were randomized 1:1 to either ..." Comment: sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: one thousand three hundred forty‐four evaluable patients were included for efficacy analysis
Selective reporting (reporting bias)	Unclear risk	Comment: conference abstract only, not evaluable
Other bias	Unclear risk	Comment: conference abstract only, not evaluable

Schnadig 2016.

Study characteristics
Methods	Randomised, prospective, double‐dummy, parallel‐group, phase 3 trial with 2 arms comparison of fosaprepitant + granisetron + dexamethasone vs fosaprepitant + ondansetron + dexamethasone Study period: March 2014 to May 2015 942 patients randomised Masking: quadruple‐blind (participant, care provider, investigator, outcomes assessor) Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria males or non‐pregnant females 18 to 87 years of age at the time of enrolment histologically or cytologically confirmed malignant disease undergoing treatment with HEC regimen according to 2011 ASCO CINV guidelines life expectancy > 6 months able to receive standardised doses of dexamethasone as required in the protocol for prevention of emesis characterised as having ECOG performance status 0 or 1 adequate bone marrow, kidney, and liver function ability to swallow oral medications (pills) without difficulty entering first cycle of current chemotherapy regimen willing and able to comply with all testing and requirements defined in the protocol able to provide voluntary, written, informed consent to participate in this study and able to fully understand study requirements females cannot be pregnant and must be adequately protected from conception for duration of the study, using at least 1 form of contraception. It is recommended that females and female partners of male subjects remain adequately protected from conception during the study and for up to 1 year following study participation Exclusion criteria known hypersensitivity to granisetron or any 5‐HT₃ receptor antagonist history or presence of clinically significant abnormal 12‐lead ECG or ECG with QTc by Bazett's correction > 450 msec in men and > 470 msec in women on the screening ECG PR > 240 msec, QRS > 110 msec, or history of prolongation of QT interval family history of long QT syndrome history of cardiac disease, including congenital long QT syndrome, angina, myocardial ischaemia or infarction, congestive heart failure, myocarditis, or chest pain or dyspnoea on exertion electrolyte disturbance, such as uncorrected hypokalaemia/hyperkalaemia, hypomagnesaemia, or hypocalcaemia idiopathic cardiomyopathy, syncope, epilepsy, hypertrophic cardiomyopathy, or other clinically significant cardiac disease pregnant or breast‐feeding planning to receive multiple‐day chemotherapy has taken any of the following agents within 7 days before initiation of chemotherapy (the study): 5‐HT₃ receptor antagonist, phenothiazines, benzamides, domperidone, cannabinoids, or NK₁ receptor antagonist has taken any benzodiazepine within 1 day (24 h) before initiation of chemotherapy (the study) scheduled to receive any other chemotherapeutic agent from Day 2 through Day 6 scheduled to receive any radiation therapy to the abdomen or pelvis from Day ‐5 through Day 6 has received systemic corticosteroids or sedative antihistamines within 72 h of Day 1 of the study, except as pre‐medication for chemotherapy (e.g. taxanes, pemetrexed) symptomatic primary or metastatic central nervous system (CNS) disease ongoing vomiting, retching, or nausea caused by any aetiology, or history of anticipatory nausea and vomiting has vomited and/or has had dry heaves or retching within 24 h before the start of HEC on Day 1 NOT able to swallow oral medications (pills) without difficulty Mean age ± SD, years: 55.7 ± 11.75 in granisetron group, 55.6 ± 11.94 in ondansetron group Gender: male + female Tumour/cancer type: malignant disease Chemotherapy regimen: anthracycline + cyclophosphamide Country: United States (77 centres)
Interventions	Experimental: arm A: fosaprepitant + granisetron + dexamethasone Day 1: single SC dose of APF530 500 mg (10 mg granisetron) + placebo for ondansetron i.v. + fosaprepitant 150 mg i.v. + dexamethasone 12 mg i.v. Day 2: dexamethasone 8 mg p.o. QD Days 3 to 4: dexamethasone 8 mg p.o. b.i.d. Experimental: arm B: fosaprepitant + ondansetron + dexamethasone Day 1: single i.v. dose of ondansetron 0.15 mg/kg (to maximum of 16 mg) + placebo for APF530 SC + fosaprepitant 150 mg i.v. + dexamethasone 12 mg i.v. Day 2: dexamethasone 8 mg p.o. QD Days 3 to 4: dexamethasone 8 mg p.o. b.i.d.
Outcomes	Primary outcome measure delayed phase complete response (CR) rate [Time frame: 24 to 120 h] Secondary outcome measures delayed phase complete response (CR) rate [Time frame: 24 to 120 h] delayed complete control (CC) rate [Time frame: 24 to 120 h] overall complete control rate [Time frame: 0 to 120 h] rate of no emetic episodes [Time frame: 0 to 120 h]
Notes	clinicalTrials.gov NCT02106494 sponsors and collaborators: Heron Therapeutics conflicts of interest: IDS: Compass Oncology, Heron Therapeutics, Tesaro; NG: ION Pharma, Amgen, Boehringer Ingelheim, Celgene, Janssen, Johnson & Johnson, Karyopharm Therapeutics, Sanofi, Taiho Pharmaceutical, Heron, Acerta, Biothera; RES Jr.: Cardinal Health, Flatiron Health; CT: Heron Therapeutics; LSS: Eisai, Helsinn, Tesaro; WC: TFS, Amgen, BMS, Merck, Pfizer, Heron Therapeutics; MCM: Heron Therapeutics; JYP: Heron Therapeutics, Johnson & Johnson; MJK: Drug Safety Navigator; Heron Therapeutics; JLV: Caris Life Sciences; Flatiron Health, Heron Therapeutics, Spectrum Pharmaceuticals
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "masking: quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)"
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "masking: quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)"
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. injection‐site reactions, neutropenia)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "efficacy analyses were performed on the modified intent‐to‐treat (mITT) population, comprising all randomized patients who received study drug and an HEC regimen and had post baseline efficacy data"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "safety analyses were based on the safety population, comprising all randomized patients who received study drug"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Schwartzberg 2015.

Study characteristics
Methods	Randomised, parallel‐group, active‐controlled, phase 3 study with 2 arms comparison of rolapitant + granisetron + dexamethasone vs placebo + granisetron + dexamethasone Study period: 5 March to 6 September 2013 1369 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria ≥ 18 years of age, of either gender, of any race naïve to moderately or highly emetogenic chemotherapy, and will receive a first course of MEC including ≥ 1 of the following agents: cyclophosphamide i.v. (< 1500 mg/m²), doxorubicin, epirubicin, carboplatin, idarubicin, ifosfamide, irinotecan, daunorubicin, cytarabine i.v. (> 1 g/m²) Karnofsky performance score ≥ 60 predicted life expectancy ≥ 4 months adequate bone marrow, kidney, and liver function Exclusion criteria contraindication to administration of prescribed MEC agent, granisetron, or dexamethasone pregnant or breast‐feeding has taken the following agents within the last 48 h: 5‐HT₃ antagonists, phenothiazines, benzamides, domperidone, cannabinoids, NK₁ antagonist, benzodiazepines scheduled to receive any other chemotherapeutic agent with emetogenicity level ≥ 3 (Hesketh Scale) from Day ‐2 through Day 6, except on Day 1 scheduled to receive any radiation therapy to the abdomen or pelvis from Day ‐5 through Day 6 has received systemic corticosteroids or sedative antihistamines within 72 h of Day 1 of the study, except as pre‐medication for chemotherapy (e.g. taxanes) symptomatic primary or metastatic CNS disease ongoing vomiting, retching, clinically significant nausea caused by any aetiology, or history of anticipatory nausea and vomiting has vomited and/or has had dry heaves/retching within 24 h before the start of MEC on Day 1 in Cycle 1 Median age (range), years: 58 (22 to 86) in rolapitant group, 56 (22 to 88) in active control group Gender: male (265) + female (1067) Tumour/cancer type: malignant solid tumour (breast, colon or rectum, head and neck, lung, ovary, stomach, other tumours) Chemotherapy regimen: MEC including ≥ 1 of the following agents: cyclophosphamide i.v. (< 1500 mg/m²), doxorubicin, epirubicin, carboplatin, idarubicin, ifosfamide, irinotecan, daunorubicin, cytarabine i.v. (> 1 g/m²) Country: 170 cancer centres in 23 countries (multi‐centre)
Interventions	Experimental: arm A: rolapitant Day 1: rolapitant (200 mg p.o.) + granisetron (2 mg p.o.) + dexamethasone (20 mg p.o.) Days 2 to 3: granisetron (2 mg p.o.) administered orally Control: arm B Day 1: placebo + granisetron (2 mg p.o.) + dexamethasone (20 mg p.o.) Days 2 to 3: granisetron (2 mg p.o.) administered orally
Outcomes	Primary outcome no emetic episodes and no rescue medication [Time frame: > 24 to 120 h post chemotherapy] Secondary outcome(s) acute phase response [Time frame: 0 to 24 h] overall response rate [Time frame: 0 to 120 h]
Notes	ClinicalTrials.gov Identifier: NCT01500226 sponsors and collaborators: Tesaro, Inc. sponsor remained unaware of treatment allocation conflicts of interest: "LSS is a consultant for TESARO, Helsinn, and Eisai, outside the submitted work. BLR and IDS are advisory board consultants for TESARO, outside the submitted work. AP is an employee of the funder TESARO. SA has received contracting fees from TESARO to direct statistical analyses during this study and outside the submitted work. All other authors declare no competing interests"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "for randomisation of patients, we used an interactive web‐based randomisation system (IWRS) at cycle 1"
Allocation concealment (selection bias)	Low risk	Quote: "for masking, a double‐blind technique was used. Placebo capsules were identical in appearance to rolapitant capsules. Through out the study, neither the patient nor the investigators and assessors knew which treatment the patient was receiving."; "... an independent group with no further role in study implementation ..."
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. neutropenia, febrile neutropenia)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "therefore, in cycle 1, the modified intention‐to‐treat population comprised 666 patients in each treatment group"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "the safety population consisted of all patients who received at least one dose of study drug"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Seol 2016.

Study characteristics
Methods	Randomised, cross‐over, active‐controlled, phase 4 study with 2 arms comparison of granisetron and palonosetron + dexamethasone vs palonosetron and granisetron + dexamethasone Enrolment period: 17 August 2012 to 14 February 2014 196 patients randomised Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria men and women aged ≥ 20 scheduled to receive MEC, combining 5‐fluorouracil/leucovorin with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) in 2 consecutive chemotherapy cycles ECOG performance status 0 to 2 expected over 3 months of survival Exclusion criteria severe, uncontrolled, concurrent illness other than neoplasia asymptomatic metastasis to the brain seizure disorder needing anticonvulsants unless clinically stable gastric outlet or intestinal obstruction any vomiting, retching, or grade 2 or higher nausea according to CTCAE known hypersensitivity to palonosetron, granisetron, or other 5‐HT₃ RAs or dexamethasone ingredients received an antiemetic drug within 72 h before administration of study drug vomiting, retching, or grade 2 or higher nausea according to CTCAE within 72 h before administration of study drug Mean age± SD, years: 58.88 ± 10.53 in granisetron and palonosetron group, 60.41 ± 10.06 in palonosetron and granisetron group Gender: male (117) + female (71) Tumour/cancer type: n.r. Chemotherapy regimen: MEC, FOLFIRI, or FOLFOX Country: 6 tertiary referral hospitals in Korea (multi‐centre)
Interventions	Cross‐over study Experimental: arm A: granisetron and palonosetron transdermal granisetron (1 GTDS patch, 7 days) in the first cycle, palonosetron (i.v. 0.25 mg/d, 1 day) in the second cycle before receiving MEC in 2 consecutive cycles prophylactic dexamethasone (i.v. 10 mg) within 30 min before chemotherapy on Day 1 Experimental: arm B: palonosetron and granisetron palonosetron in the first cycle and GTDS in the second cycle prophylactic dexamethasone (i.v. 10 mg) within 30 min before chemotherapy on Day 1
Outcomes	Primary endpoint proportion of patients achieving complete response during first 24 h following MEC Secondary endpoint(s) proportion of patients achieving complete response during delayed 24– to 72‐h time period and cumulative overall 0‐ to 72‐h time period, as well as during successive 24‐h time periods (i.e. 24 to 48 h, 48 to 72 h) proportion of patients achieving complete control for 0 to 24, 24 to 72, and 0 to 72 h intervals proportion of patients achieving total control for 0 to 24, 24 to 72, and 0 to 72 h intervals number of emetic episodes daily and cumulatively for 24 to 72 and 0 to 72 h intervals severity of nausea measured daily for 0 to 72 h interval patient global satisfaction with antiemetic therapy and quality of life (QoL), measured via a modified functional living index ‐ emesis (FLIE) questionnaire, which specifically addresses the impact of nausea and emesis on daily functioning, for 0 to 72 h interval higher score represented higher level of symptoms
Notes	conflicts of interest: "the authors declare that they have no competing interests" no information on source of funding provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... open‐label ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... open‐label ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: blinding should not affect risk of bias of objective outcomes
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	High risk	Quote: "three hundred thirty‐three cycles were included in the per protocol analysis ‐ 165 cycles for the GTDS and 168 cycles for the palonosetron were analyzed (Fig. 2)" Comment: per‐protocol analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: safety assessed for all completed cycles
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Song 2017.

Study characteristics
Methods	Randomised, prospective, comparative clinical trial with 2 arms comparison of aprepitant + ondansetron + prednisone vs ondansetron + prednisone Enrolment period: October 2013 to March 2015 108 patients enrolled Masking: open‐label Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria adult patients (≥ 18 years old) with B‐ or T‐cell non‐Hodgkin lymphoma receiving i.v. cyclophosphamide (750 mg/m²), epirubicin (60 mg/m²), vincristine (1.4 mg/m²) (maximum 2 mg) for 1 day, and p.o. prednisone 100 mg/d for 5 days ECOG score of 0 to 2 received no more than 4 cycles of chemotherapy Exclusion criteria serious complications, active infection, ongoing emesis and/or systemic steroids due to any organic aetiology received abdomen/pelvis radiation therapy within 1 week current illicit drug use, such as pimozide, terfenadine, astemizole, or cisapride due to possible drug–drug interaction vomiting within 24 h before start of chemotherapy abnormal laboratory values (including white blood count < 3000/mm³, absolute neutrophil count < 1500/mm³, platelet count < 100,000/mm³, aspartate transaminase > 2.5 × ULN, alanine aminotransferase > 2.5 × ULN, bilirubin > 1.5 × ULN, or creatinine > 1.5 × ULN) Mean age ± SD, years: 41.2 ± 4.57 in aprepitant group, 39.6 ± 6.85 in control group Gender: male (74) + female (34) Tumour/cancer type: B‐ or T‐cell non‐Hodgkin lymphoma Chemotherapy regimen: cyclophosphamide (750 mg/m²), epirubicin (60 mg/m²), vincristine (1.4 mg/m²) Country: China (single centre)
Interventions	Experimental: arm A: aprepitant Day 1: p.o. aprepitant 125 mg + i.v. ondansetron 24 mg + p.o. prednisone 100 mg Days 2 to 3: p.o. aprepitant 80 mg + prednisone 100 mg once daily Days 4 to 5: p.o. prednisone 100 mg once daily Control: arm B Day 1: i.v. ondansetron 24 mg + p.o. prednisone 100 mg Days 2 to 5: p.o. prednisone 100 mg once daily
Outcomes	Primary endpoint complete response (CR) in acute phase (0 to 24 h), delayed phase (25 to 120 h), and overall study period Secondary endpoint(s) proportions of patients with no emesis in any phase complete protection (CP) in any phase no nausea in any phase
Notes	Merck Sharp & Dohme supplied all drugs for this clinical trial no information regarding clinical trial registration reported conflicts of interest: study authors have declared no potential conflict of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were assigned to one of the two treatment groups, according to a computer‐generated random assignment schedule"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... open‐label ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... open‐label ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards intervention and therefore might influence subjective outcomes analysis
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: although it was an open‐label study, both patients and personnel had no influence on objective outcomes (e.g. hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: 101 patients have been included in the efficacy analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: safety data reported for all 101 patients
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Stewart 1996.

Study characteristics
Methods	Randomised trial with 2 arms comparison of granisetron + dexamethasone vs ondansetron + dexamethasone Recruitment period: n.r. Enrolled/randomised patient number: n.r. Masking: double‐blind Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria: n.r. Exclusion criteria: n.r. Mean/median age (range), years: n.r. Gender: n.r. Tumour/cancer type: n.r. Chemotherapy regimen: cisplatin Country: n.r.
Interventions	Experimental: arm A: granisetron granisetron + dexamethasone (8 mg i.v., then treatment 4 mg t.d.s. for 3 days afterwards) Experimental: arm B: ondansetron ondansetron + dexamethasone (8 mg i.v., then treatment 4 mg t.d.s. for 3 days afterwards)
Outcomes	not reported
Notes	poster presentation
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised study but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Comment: double‐blind
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: not reported
Selective reporting (reporting bias)	Unclear risk	Comment: not evaluable, conference abstract only
Other bias	Unclear risk	Conference abstract, not evaluable

Stewart 2000.

Study characteristics
Methods	Randomised, cross‐over, controlled trial with 2 arms comparison of ondansetron + dexamethasone vs granisetron + dexamethasone Recruitment period: n.r. 21 patients entered Masking: double‐blind Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria patients attending Airedale General Hospital over 18‐month period for treatment with highly emetogenic chemotherapy, including cisplatin Exclusion criteria hypersensitivity to ondansetron, granisetron, or related substance Mean age (range), years: 56 (37 to 74) for all patients Gender: male (9) + female (12) Tumour/cancer type: n.r. Chemotherapy regimen: highly emetogenic chemotherapy, including cisplatin, mean dose 74 mg/m² Country: UK
Interventions	Cross‐over study Experimental: arm A: ondansetron ondansetron 8 mg + i.v. bolus dexamethasone 8 mg immediately before chemotherapy and p.o. dexamethasone 4 mg 3 times a day on Days 2 to 4 Experimental: arm B: granisetron granisetron 3 mg by infusion + i.v. bolus dexamethasone 8 mg immediately before chemotherapy and p.o. dexamethasone 4 mg 3 times a day on Days 2 to 4
Outcomes	nausea and vomiting scores on Days 1 to 7 post chemotherapy
Notes	no information regarding clinical trial registration and funding reported study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... random allocation using a Latin square design in sets of four"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Comment: double‐blind
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Comment: double‐blind
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all patients were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	Comment: outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Stiff 2013.

Study characteristics
Methods	Randomized, comparative, phase 3 trial with 2 arms comparison of aprepitant 125/80 mg + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Registration period: September 2004 to July 2008 264 patients seen during registration 181 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria diagnosis of cancer, admitted for myelosuppressive stem cell transplantation. Preparative regimens include TBI/VP16/CY, TBI/CY, BU/CY (p.o. & i.v.), and BCV age 18 years or older alcohol intake < 100 g/d for the last year (< approximately 5 drinks per day) renal function: estimated or measured CrCl 50 mL/min liver function: T bili < 1.5, AST < 2 × ULN, unless due to disease ability to swallow tablets and capsules Exclusion criteria age < 18 years high alcohol intake (> 100 g/d in the last year) allergy or intolerance to ondansetron or dexamethasone renal dysfunction (measured or estimated CrCl < 50 mL/min) liver dysfunction: T bili > 1.5, AST > 2 × ULN, unless due to disease inability to swallow tablets or capsules concurrent condition requiring systemic steroid use non‐myeloablative SCT, patients receiving conditioning regimens not included (see inclusion criteria) history of anticipatory nausea and vomiting Median age (range), years: 50 (20 to 75) in aprepitant 125/80 mg group, 51 (19 to 79) in placebo group Gender: male + female Tumour/cancer type: malignant disease (non‐Hodgkin lymphoma, AML, multiple myeloma, ALL, Hodgkin lymphoma, CML, myelodysplastic syndrome, myeloproliferative disorder, chronic lymphocytic leukaemia, myelofibrosis) Chemotherapy regimen: high‐dose cyclophosphamide preparative regimens Country: United States (single centre)
Interventions	Experimental: arm A: aprepitant 125/80 mg aprepitant 125 mg p.o. Day 1, then 80 mg daily during preparative regimen + 3 days dexamethasone 7.5 mg i.v. daily during preparative regimen + 1 day ondansetron 8 mg p.o. q8h daily during preparative regimen + 1 day Experimental: arm B: placebo placebo p.o. daily during preparative regimen + 3 days dexamethasone 10 mg i.v. daily during preparative regimen + 1 day ondansetron 8 mg p.o. q8h daily during preparative regimen + 1 day
Outcomes	Primary endpoints complete response [Time frame: 14 days] progression‐free survival overall survival Secondary endpoints acute complete response, % no emesis all days, % average nausea score (VAS) MR% composite MR% composite F% composite ME = CR + MR time to first emesis, days (mean) number of PRN doses used Additional analyses patients with no emesis, % < grade 3 nausea all days ‐ PRN allowed < grade 3 nausea all days ‐ no PRN
Notes	clinicalTrials.gov Identifier NCT00781768 "this study was supported in part by a research grant from Merck and Co., West Point, Pennsylvania" conflicts of interest: "the authors have nothing further to disclose"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: patients who received the study drug were included in the intent‐to‐treat analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "five patients died in the aprepitant arm due to sepsis (3 patients), toxic epidermal necrolysis and sepsis (1 patient), and veno‐occlusive disease of the liver (1 patient), whereas 2 patients died in the control arm due to viral pneumonia/encephalitis (1 patient) and fungal pneumonia (1 patient) within 30 days"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Sugawara 2019.

Study characteristics
Methods	Multi‐centre, randomised, double‐blind, placebo‐controlled, parallel‐group, phase 2 study with 3 arms comparison of fosnetupitant + palonosetron + dexamethasone vs placebo + palonosetron + dexamethasone Registration period: September 2016 to November 2017 594 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria aged ≥ 20 years with confirmed malignant solid tumour scheduled to receive cisplatin at a dose ≥ 70 mg/m² had received no chemotherapy or prior low or minimally emetogenic chemotherapy regimen required to have an Eastern Cooperative Oncology Group performance status 0 or 1 and adequate haematological, hepatic, and renal function Exclusion criteria gastrointestinal stenosis any vomiting, retching, or nausea within 24 hours before enrolment severe complications, infection, or diabetes mellitus that could be associated with difficulties with administration of dexamethasone; hypersensitivity to NK₁ RAs, 5‐HT₃ RAs, or dexamethasone had received a cytochrome P450 3A4 inhibitor or inducer, had received an opioid analgesic, had undergone surgery, had undergone radiotherapy within 7 days before registration pregnant and nursing women Median age (range), years: 67 (36 to 79) in placebo group, 66 (41 to 76) in fosnetupitant 81‐mg group, 67 (37 to 78) in fosnetupitant 235‐mg group Gender: 24.2% female (75.8% male) in placebo group, 25.1% female (74.9% male) in fosnetupitant 81‐mg group, 24.1% female (75.9% male) in fosnetupitant 235‐mg group Tumour/cancer type: confirmed malignant solid tumour Chemotherapy regimen: cisplatin‐based, cisplatin at a dose ≥ 70 mg/m² Country: Japan (multi‐centre)
Interventions	Experimental: arm A: fosnetupitant 81 mg Fosnetupitant (81 mg intravenously, approximately 60 min before administration of cisplatin and infused for 30 min on Day 1), palonosetron (0.75 mg intravenously, approximately 60 min before administration of cisplatin and infused for 30 min on Day 1), dexamethasone (Day 1, 60 min before administration of cisplatin, 9.9 mg; Days 2 to 4, 6.6 mg administered intravenously in the morning) Experimental: arm B: fosnetupitant 235 mg Fosnetupitant (235 mg intravenously, approximately 60 min before administration of cisplatin and infused for 30 min on Day 1), palonosetron (0.75 mg intravenously, approximately 60 min before administration of cisplatin and infused for 30 min on Day 1), dexamethasone (Day 1, 60 min before administration of cisplatin, 9.9 mg; Days 2 to 4, 6.6 mg administered intravenously in the morning) Control: arm C: placebo Placebo, palonosetron (0.75 mg intravenously, approximately 60 min before administration of cisplatin and infused for 30 min on Day 1), dexamethasone (Day 1, 60 min before administration of cisplatin,13.2 mg; Days 2 to 4, 6.6 mg administered intravenously in the morning)
Outcomes	Primary endpoint complete response (CR; no emesis and no rescue medication) during the overall phase (0 to 120 h after cisplatin administration) Secondary endpoints CR during acute (0 to 24 hours) and delayed (24 to 120 hours) phases, and during 24 to 168 h after cisplatin administration complete protection (CR plus no more than mild nausea) during acute, delayed, and overall phases, as well as during 24 to 168 h after initiation of cisplatin total control (CR plus no nausea) during acute, delayed, and overall phases, as well as during 24 to 168 h after initiation of cisplatin no vomiting, no nausea, and no significant nausea during acute, delayed, and overall phases, as well as during 24 to 168 h after initiation of cisplatin rates of adverse events (AEs) frequency of infusion site reactions (ISRs)
Notes	sponsor: Taiho Pharmaceutical Co., Ltd. conflict of interest disclosures: comprehensive list of potentially relevant conflicts of interest disclosed in journal article
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Minimisation method used for random allocation, stratified by sex and age class (age < 55 years vs age ≥ 55 years)
Allocation concealment (selection bias)	Low risk	Quote: "treatment assignment was masked from all patients, investigators, and study personnel except for the pharmacists who were preparing the study drugs at the institutions, who were prohibited from divulging any information regarding drug assignment"
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "treatment assignment was masked from all patients, investigators, and study personnel except for the pharmacists who were preparing the study drugs at the institutions, who were prohibited from divulging any information regarding drug assignment"
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "treatment assignment was masked from all patients, investigators, and study personnel except for the pharmacists who were preparing the study drugs at the institutions, who were prohibited from divulging any information regarding drug assignment"
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "treatment assignment was masked from all patients, investigators, and study personnel except for the pharmacists who were preparing the study drugs at the institutions, who were prohibited from divulging any information regarding drug assignment"
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Quote: "treatment assignment was masked from all patients, investigators, and study personnel except for the pharmacists who were preparing the study drugs at the institutions, who were prohibited from divulging any information regarding drug assignment"
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Data available for nearly all participants (194/197 in placebo group, 195/199 in fosnetu 81‐mg group, 195/198 in fosnetu 235‐mg group)
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	All participants who received ≥ 1 dose included in safety analysis
Selective reporting (reporting bias)	Low risk	No reason for any concern detected
Other bias	Low risk	No other bias detected

Sugimori 2017.

Study characteristics
Methods	Randomised, prospective, phase 2 study with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs palonosetron + dexamethasone Enrolment period: November 2010 to March 2014 78 patients randomised Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria women over 20 years of age with primary gynaecological cancer (cervical, endometrial, or ovarian) without previous history of chemotherapy ECOG performance status 0 to 2 adequate renal function (calculated creatinine clearance ≥ 60 mL/min) adequate hepatic function (aspartate aminotransferase level < 100 IU/L, alanine aminotransferase level < 100 IU/L, and Child–Pugh Score ≤ 9 points) adequate marrow function (absolute white blood cell count ≥ 3000/μL and platelet count ≥ 100,000/μL) Exclusion criteria receipt of any agent that could affect study results (such as an antiemetic, a steroid, or pimozide) before the start of chemotherapy symptomatic brain metastasis gastrointestinal obstruction or any other condition that could provoke nausea and vomiting known allergy or severe reaction to any study drug Median age, years: 58.5 in aprepitant group, 57.7 in control group Gender: female Tumour/cancer type: gynaecological cancer Chemotherapy regimen: carboplatin target area under the curve of 5 and 175 mg/m² paclitaxel (TC) therapy Country: Japan (single centre)
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg + palonosetron 0.75 mg + dexamethasone 6.6 mg Days 2 to 3: aprepitant 80 mg + dexamethasone 8 mg Control: arm B Day 1: palonosetron 0.75 mg + dexamethasone 13.2 mg Days 2 to 3: dexamethasone 8 mg
Outcomes	Primary endpoint complete response in the delayed phase Secondary endpoint(s) complete response in the acute phase complete control (CC) in acute and delayed phases time to treatment failure (TTF) adverse events
Notes	Clinical Trials Registry (No. UMIN000019122) "the study is registered in the University Hospital Medical Information Network" self‐funded by Juntendo Nerima Hospital conflicts of interest: "no authors declare any conflict of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "... open‐label ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Quote: "... open‐label ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: although participants were not blinded, we assume that this does not affect objective outcomes
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: all 78 patients were included in the efficacy analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: side effects reported as percentage of all patients
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Svanberg 2015.

Study characteristics
Methods	Randomised, placebo‐controlled trial with 2 arms comparison of aprepitant (Emend) + T Navobane (tropisetron) + betamethasone vs placebo + T Navobane (tropisetron) + betamethasone Recruitment period: June 2010 to June 2012 119 patients invited 14 patients with myeloma and 9 patients with lymphoma declined to participate 96 patients randomised to control (47) and experimental (49) groups 6 patients non‐completers (3 from each group) Masking: double‐blind (attending nurse and patient) Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria ≥ 18 years of age able to communicate in Swedish able to swallow oral medication scheduled for myeloablative therapy and autologous SCT at Akademiska University Hospital in Uppsala, Sweden Exclusion criteria nausea at baseline gastrointestinal obstruction or active peptic ulcer or current illness requiring long‐term systemic steroids or long‐term use of antiemetic agent(s) Mean age ± SD, years : 58.11 ± 8.84 (experimental group), 56.52 ± 8.25 (control group) Gender: 64 male + 32 female Tumour/cancer type: lymphoma (38) and myeloma (58) Chemotherapy regimen: BEAM, BEAC for lymphoma patients and high‐dose melphalan, BBM for myeloma patients Country: Sweden (single centre)
Interventions	Experimental: arm A 6 mg of betamethasone (T Betapred 0.5 mg, 12 tablets daily) + T Navobane (tropisetron) (5 mg) + aprepitant (Emend), started 1 h before first HDCT dose for SCT and administered daily until 7 days after the end of chemotherapy Control: arm B 6 mg of betamethasone (T Betapred 0.5 mg, 12 tablets daily) + T Navobane (tropisetron) (5 mg) + placebo, started 1 h before first HDCT dose for SCT and administered daily until 7 days after the end of chemotherapy
Outcomes	Primary efficacy endpoint complete response (no nausea/vomiting and no use of rescue therapy) during chemotherapy and in the delayed phase (up to 10 days after the end of cytostatic therapy) between patients in experimental and control groups
Notes	clinical trial number not reported source of funding not reported study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation was not reported
Allocation concealment (selection bias)	Low risk	Quote: "a random assignment to the experimental (EXP) or control (CTR) group was performed by research nurses not participating in any other way in the study"
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "study drug or placebo was unknown to the attending nurse and the patient in the study"
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "study drug or placebo was unknown to the attending nurse and the patient in the study"
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "the analysis is made on an intention‐to‐treat basis"
Selective reporting (reporting bias)	Unclear risk	Comment: adverse events mentioned as not differing, no proportions provided. All other outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Takahashi 2010.

Study characteristics
Methods	Randomised, placebo‐controlled, parallel, comparative, phase 2 trial with 3 arms comparison of aprepitant 40 ⁄ 25 mg + granisetron + dexamethasone vs aprepitant 125 ⁄ 80 mg + granisetron + dexamethasone vs granisetron + dexamethasone Study start date: August 2005 453 patients enrolled 449 patients included in the safety analysis set, 439 patients included in the FAS Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria ≥ 20 years of age with malignant tumour who are to be intravenously administered cisplatin as a single dose ≥ 70 mg/m² in under 3 h ECOG performance status 0 to 2 estimated life expectancy ≥ 3 months had to meet the following laboratory criteria: white blood cell count ≥ 3000/mm³; neutrophil count ≥ 1500/mm³; platelet count ≥ 100,000/mm³; AST (glutamic oxaloacetic transaminase (GOT) and alanine aminotransferase (ALT) (glutamic pyruvate transaminase (GPT)) ≤ 2.5 × ULN at the facility; total bilirubin ≤ 1.5 × ULN at the facility; and creatinine ≤ 1.5 × ULN at the facility Exclusion criteria risk of vomiting for other reasons (symptomatic brain metastasis, meningeal infiltration, epilepsy, active peptic ulcer, gastrointestinal obstruction, concomitant abdominal, pelvic radiotherapy, etc.) pregnant, nursing, or possibly pregnant women Mean age ± SD, years : 63.3 ± 9.4 (aprepitant 40 ⁄ 25 + standard therapy), 60.5 ± 9.7 (aprepitant 125 ⁄ 80 mg + standard therapy), 62.2 ± 9.8 (standard therapy) Gender: male + female Tumour/cancer type: solid malignant tumour Chemotherapy regimen: cisplatin at a dose ≥ 70 mg/m² Country: Japan (9 facilities)
Interventions	Experimental: arm A: aprepitant 40 ⁄ 25 + standard therapy Day 1: aprepitant 40 mg + dexamethasone 8 mg + granisetron 40 µg/kg Days 2 to 3: aprepitant 25 mg + dexamethasone 6 mg Days 4 to 5: aprepitant 25 mg Experimental: arm B: aprepitant 125 ⁄ 80 mg + standard therapy Day 1: aprepitant 125 mg + dexamethasone 6 mg + granisetron 40 µg/kg Days 2 to 3: aprepitant 80 mg + dexamethasone 4 mg Days 4 to 5: aprepitant 80 mg Standard: arm C Day 1: placebo + dexamethasone 12 mg + granisetron 40 µg/kg Days 2 to 3: placebo + dexamethasone 8 mg Days 4 to 5: placebo
Outcomes	Primary endpoint percentage of patients with complete response (no emesis and no rescue therapy) Secondary endpoints no emesis no rescue therapy complete protection (no emesis, no rescue therapy, and no significant nausea (nausea score: 0 and 1)) total control (no emesis, no rescue therapy, and no nausea (nausea score: 0)) no significant nausea (nausea score: 0 and 1) and no nausea (nausea score: 0) Both primary and secondary endpoints were assessed in the overall phase (Days 1 to 5), the acute phase (Day 1), and the delayed phase (Days 2 to 5)
Notes	clinicalTrials.gov number, NCT00212602 "this study was designed and funded by Ono Pharmaceutical Co., Ltd, and Merck & Co., Inc., the manufacturer of aprepitant" conflicts of interest: "the authors have no conflict of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "treatment assignment (dynamic allocation) was performed using a minimization method for balancing four factors (sex, presence or absence of at least one emetogenic antitumour agent used in combination with cisplatin, presence or absence of previous treatment with cisplatin, and institution) between the treatment and control groups"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. study mortality)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "of these, 449 patients were included in the safety analysis set, 439 subjects were included in the FAS"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "all 453 enrolled subjects were included in the safety analysis" Quote: "serious adverse events led to the death of one patient in the standard therapy group and one in the 125 ⁄80 mg group. The former died of febrile neutropenia, acute respiratory distress syndrome (ARDS) and septic shock, and the latter died of cardiac failure"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Tanioka 2013.

Study characteristics
Methods	Randomised, placebo‐controlled, phase 2 study with 2 arms comparison of aprepitant + granisetron + dexamethasone vs placebo + granisetron + dexamethasone Study period: January 2011 to September 2012 94 patients enrolled and randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria women aged 20 to 69 years with histologically confirmed malignancy who were naïve to aprepitant and scheduled to receive carboplatin‐ or irinotecan‐based regimens Eastern Cooperative Oncology Group PS of 0 to 2 estimated life expectancy ≥ 3 months had to meet the following laboratory criteria: neutrophil count ≥ 1500 mm‐3; platelet count ≥ 100,000 mm‐3; aspartate aminotransferase and alanine aminotransferase ≤ 2.5 times ULN at the facility; total bilirubin ≤ 1.5 times ULN at the facility; creatinine ≤ 1.5 times ULN at the facility Exclusion criteria history of alcohol consumption, defined as ≥ 1 alcoholic drinks per week at risk of vomiting for other reasons (symptomatic brain metastasis, meningeal infiltration, epilepsy, active peptic ulcer, gastrointestinal obstruction, concomitant abdominal or pelvic radiotherapy) pregnant, nursing, or possibly pregnant women Median age, years: 53 (36 to 67) in aprepitant group, 59 (33 to 69) in placebo group Gender: female Tumour/cancer type: ovarian cancer (early/advanced), endometrial cancer, other, ascites or peritoneal dissemination Chemotherapy regimen: carboplatin + intravenous cytotoxic anti‐tumour drugs such as paclitaxel and pemetrexed; carboplatin + paclitaxel; carboplatin + liposomal doxorubicin; irinotecan + fluorouracil, bevacizumab, or cetuximab Country: Japan (multi‐centre)
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg p.o. + granisetron 1 mg i.v. + dexamethasone 12 mg i.v. Days 2 to 3: aprepitant 80 mg p.o. + dexamethasone 4 mg i.v. Experimental: arm B: placebo Day 1: placebo 0 mg p.o. + granisetron 1 mg i.v. + dexamethasone 20 mg i.v. Days 2 to 3: placebo 0 mg p.o. + dexamethasone 8 mg i.v.
Outcomes	Primary endpoint rate of complete response for 120 h from start of first cycle of MEC, in acute (0 to 24 h), delayed (24 to 120 h), and overall (0 to 120 h) phases Secondary endpoint(s) no emesis no rescue therapy no significant nausea no nausea total control (no emesis, no rescue therapy, and no nausea)
Notes	this study has been registered in the University Medical Information Network Clinical Trials Registry as No. 000004998 "the study protocol was funded by the Hanshin Oncology Study Group" conflicts of interest: "HM reported having accepted an unrestricted research grant and received honoraria from Ono Pharmaceutical Co., Ltd. The other authors declare no conflict of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... randomly assigned to the aprepitant group or placebo group according to a computer‐generated, blinded allocation schedule"
Allocation concealment (selection bias)	Unclear risk	Comment: precise allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "of these, 91 patients were included in the full analysis set"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "safety was evaluated in all the 92 subjects who were assigned to treatment, including the patient who discontinued chemotherapy due to a hypersensitivity reaction"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Tsubata 2019.

Study characteristics
Methods	Randomised, prospective, single‐centre, comparative, phase 3 trial translational and randomised study of 5‐HT3 receptor antagonists for evaluation of chemotherapy‐induced nausea and vomiting‐related biomarkers Study period: October 2010 to January 2013  35 patients included Masking: open‐label Baseline patient characteristics: reported Median follow‐up: n.r. ITT analysis: n.r.
Participants	Inclusion criteria ≥ 20 years of age  histologically or cytologically confirmed malignant disease chemotherapy naïve  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2 Exclusion criteria dementia planned whole brain irradiation active infection symptomatic brain metastasis symptomatic hypercalcaemia or hyponatraemia Median age, years: 68 Gender:  22 men and 13 women Tumour/cancer type: NSCLC, SCLC, BC Chemotherapy regimen: HEC or MEC; not further specified Country: Japan (single centre)
Interventions	Experimental: arm A  HEC: i.v. PAL (0.75 mg) and dexamethasone (9.9 mg) on Day 1, followed by p.o. dexamethasone (8 mg daily) on Days 2 to 4. p.o. aprepitant (125 mg) was administered on Day 1 followed by 80 mg daily on Days 2 and 3 MEC: i.v. PAL (0.75 mg) and dexamethasone (9.9 mg) on Day 1, followed by p.o. dexamethasone (8 mg daily) on Days 2 and 3, and without oral or intravenous aprepitant Experimental: arm B  HEC: i.v. GRA (3 mg) and dexamethasone (9.9 mg) on Day 1, followed by p.o. dexamethasone (8 mg daily) on Days 2 to 4. Oral aprepitant (125 mg) was administered on Day 1 followed by 80 mg daily on Days 2 and 3 MEC: i.v. GRA (3 mg) and dexamethasone (9.9 mg) on Day 1, followed by p.o. dexamethasone (8 mg daily) on Days 2 and 3, without oral or intravenous aprepitant
Outcomes	Primary outcome measure score of late‐phase CINV on MAT questionnaire Secondary outcome measures score of nausea or vomiting on FLIE questionnaire proportion of patients who achieved CR (defined as no emetic episode and no use of rescue medication) plasma concentrations of biomarkers
Notes	all study authors have no conflicts of interest to disclose
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stratified and 1:1 randomised; method not further described
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Open‐label
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Open‐label
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Outcome assessors (participants) not blinded to intervention
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Data available for all randomised participants
Selective reporting (reporting bias)	Unclear risk	Wrong UMIN ID provided in paper; UMIN ID 000005268 is a clinical trial to evaluate effect of spectacle lens that reduces myopia progression
Other bias	Low risk	No other sources of bias detected

Warr 2005.

Study characteristics
Methods	Randomised, parallel‐group, placebo‐controlled, phase 3 trial with 2 arms comparison of aprepitant + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Recruitment period: October 2002 to December 2003 866 patients included Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria ≥ 18 years old naïve to emetogenic chemotherapy (Hesketh Level 3 or higher) diagnosed breast carcinoma predicted life expectancy ≥ 4 months Karnofsky score ≥ 60 Exclusion criteria symptomatic CNS malignancy received radiation therapy to abdomen or pelvis in the week before treatment had vomited in the 24 h before treatment Day 1 active infection, active systemic fungal infection, or any severe concurrent illness except for malignancy abnormal laboratory values taking systemic corticosteroid therapy at any dose Mean age (range), years: 53.1 (aprepitant regimen), 52.1 (control regimen) Gender: male (2) + female (864) Tumour/cancer type: breast cancer Chemotherapy regimen: anthracycline plus cyclophosphamide‐based chemotherapy regimen (the following agents were administered alone or in combination: i.v. cyclophosphamide 750 to 1500 mg/m² (± 5%); i.v. cyclophosphamide 500 to 1500 mg/m² (± 5%) and i.v. doxorubicin ≤ 60 mg/m² (± 5%); i.v. cyclophosphamide 500 to 1500 mg/m² (± 5%) and i.v. epirubicin ≤ 100 mg/m² (± 5%). Other chemotherapeutic agents, Hesketh level 2 or lower, could be added to the above chemotherapeutic regimens) Country: 95 centres in the United States, Germany, Austria, Canada, Hong Kong, Hungary, Spain, United Kingdom, Italy, Australia, and Greece
Interventions	Experimental: arm A: aprepitant 125/80 mg Day 1: p.o. aprepitant 125 mg + p.o. ondansetron 8 mg (30 to 60 min before chemotherapy and again 8 h after chemotherapy) + p.o. dexamethasone 12 mg Days 2 to 3: p.o. aprepitant 80 mg Control: arm B: placebo Day 1: placebo + p.o. ondansetron 8 mg (30 to 60 min before chemotherapy and again 8 h after chemotherapy) + p.o. dexamethasone 20 mg Days 2 to 3: placebo + p.o. ondansetron 8 mg
Outcomes	Primary endpoint complete response (no emetic episodes and no rescue therapy) in the overall 5‐day study period
Notes	matching placebos given to maintain blinding "the studies described in this paper were funded by Merck Research Laboratories, manufacturers of aprepitant" conflicts of interest: "Drs. Carides, Evans, and Horgan are employees of Merck Research Laboratories. Drs. Warr, Grunberg, Gralla, Hesketh, Roila, and de Wit have received funding from Merck Research Laboratories for the conduct of clinical studies of aprepitant"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... using a computer‐generated allocation schedule with a block size of four"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "... modified intent‐to‐treat analysis was conducted, including all patients who received chemotherapy, took the study drug, and had at least one post‐treatment assessment"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: all patients were included in the safety analysis
Selective reporting (reporting bias)	Low risk	Comment: outcome measure was reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Webb 2010.

Study characteristics
Methods	Randomised study with 2 arms comparison of aprepitant + ondansetron + dexamethasone vs ondansetron + dexamethasone Enrolment period: n.r. 439 patients randomised (439 patients among 832 patients had breast cancer) Masking: double‐blind Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria confirmed malignancy, naïve to HEC or MEC agent received ≥ 1 MEC agent Exclusion criteria: n.r. Mean/median age, years: n.r. Gender: female Tumour/cancer type: breast cancer Chemotherapy regimen: MEC Country: n.r.
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg p.o. + ondansetron 8 mg p.o. b.i.d. + dexamethasone 12 mg p.o. Days 2 to 3: aprepitant 80 mg p.o. Control: arm B: ondansetron Day 1: ondansetron 8 mg p.o. b.i.d. + dexamethasone 20 mg p.o. Days 2 to 3: ondansetron 8 mg p.o. b.i.d.
Outcomes	proportions of patients with no vomiting during the overall phase (120 h post chemotherapy) proportions of patients with complete response during the overall phase (120 h post chemotherapy)
Notes	post hoc subgroup analysis conference abstract
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: breast cancer patients were also included in the modified intent‐to‐treat population
Selective reporting (reporting bias)	Unclear risk	Comment: conference abstract only, not evaluable
Other bias	Unclear risk	Comment: conference abstract, not evaluable

Weinstein 2016.

Study characteristics
Methods	Randomised, active‐comparator, parallel‐group, phase 3 superiority trial (PN031) with 2 arms comparison of fosaprepitant + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Enrolment period: 30 October 2012 to 03 November 2014 1150 patients screened 1015 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria aged ≥18 years with confirmed malignant disease scheduled to receive ≥ 1 i.v. dose of MEC on Day 1 (combinations of MEC ± low emetogenic chemotherapy (LEC) were permitted from Days 1 to 3 when part of an overall MEC regimen and were in accordance with current emetogenicity classification guidelines) Exclusion criteria vomiting in the 24‐h period before Day 1 antiemetic use within 48 h of Day 1 symptomatic primary or metastatic central nervous system malignancy causing nausea and/or vomiting use of any dose of cisplatin or other HEC Mean age ± SD, years: 60.0 ± 11.8 in fosaprepitant group, 59.1 ± 12.3 in control group Gender: male (409) + female (591) Tumour/cancer type: malignant disease (lung, breast, colorectal, gynaecological, gastrointestinal, head and neck, other) Chemotherapy regimen: MEC agents except for the combination of anthracycline and cyclophosphamide Country: 125 sites across 30 countries
Interventions	Experimental: arm A: fosaprepitant Day 1: fosaprepitant 150 mg intravenous (i.v.) infusion, ~ 30 minutes before chemotherapy + dexamethasone 12 mg orally (p.o.) ~ 30 minutes before chemotherapy + ondansetron 16 mg total dose: 8 mg p.o. ~ 30 to 60 minutes before chemotherapy, followed by 8 mg p.o. 8 hours after first dose + dexamethasone placebo, p.o. ~ 30 minutes before chemotherapy Days 2 to 3: ondansetron placebo, p.o. every 12 hours Control: arm B: fosaprepitant Day 1: fosaprepitant placebo, 150 mL i.v. infusion, ~ 30 minutes before chemotherapy + dexamethasone 20 mg, p.o. ~ 30 minutes before chemotherapy + ondansetron 16 mg total dose: 8 mg p.o. ~ 30 to 60 minutes before chemotherapy; followed by 8 mg p.o. 8 hours after first dose Days 2 to 3: ondansetron 8 mg p.o. every 12 hours
Outcomes	Primary endpoint(s) percentage of participants with complete response from 25 to 120 hours after initiation of moderately emetogenic chemotherapy [Time frame: 25 to 120 h after initiation of MEC] percentage of participants with infusion site thrombophlebitis [Time frame: Day 1 through Day 17, inclusive] percentage of participants with severe infusion site reaction [Time frame: Day 1 through Day 17, inclusive] Secondary endpoint(s) percentage of participants with complete response from 0 to 120 hours after initiation of MEC [Time frame: 0 to 120 h after initiation of MEC] percentage of participants with complete response from 0 to 24 hours after initiation of MEC [Time frame: 0 to 24 h after initiation of MEC] percentage of participants with no vomiting from 0 to 120 hours after initiation of MEC [Time frame: 0 to 120 h after initiation of MEC]
Notes	ClinicalTrials.gov identifier (NCT number): NCT01594749 this study was not supported by a grant; this work was supported by Merck & Co., Inc., Kenilworth, NJ, USA conflicts of interest: "CW is an employee and stockholder of Merck & Co., Inc. KJ has received honoraria for consultancy from Merck Sharp & Dohme (MSD), Merck & Co., Inc., Helsinn, and Pro‐Strakan. SG, EBB, and WV are employees and stockholders of Merck & Co., Inc., and LWL is an employee of Merck & Co., Inc. SN has received honoraria from Millenium and served as a consultant or in an advisory role for Amgen and Millenium (now Takeda Oncology). BLR has served as a consultant or in an advisory role for and has received payment for travel, accommodations, or expenses from MSD and Tesaro. BLR has also received payments for participation on speakers bureaus for MSD and Roche"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "subjects were randomized (1:1) to the single‐dose fosaprepitant or control regimen via an interactive voice response system/interactive web response system, and stratified based on sex"
Allocation concealment (selection bias)	Low risk	Quote: "study medications were supplied in a blinded manner as fosaprepitant/placebo i.v. bags, ..."
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. neutropenia)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "the ITT and ASaT populations comprised 1000 and 1001 subjects, respectively (Figure 1)"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "the ITT and ASaT populations comprised 1000 and 1001 subjects, respectively (Figure 1)"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Wenzell 2013.

Study characteristics
Methods	Randomised, prospective, pilot study with 2 arms comparison of aprepitant 125/80 mg + palonosetron + dexamethasone vs aprepitant 125/80 mg + ondansetron + dexamethasone Study period: January 2011 to July 2011 40 patients enrolled Masking: open‐label Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria confirmed malignancy between the ages of 18 and 89 years scheduled to receive first dose of first cycle of HEC (in patients receiving multi‐day chemotherapy, HEC portion had to be given on Day 1, and remaining days of chemotherapy could be minimally emetogenic) required to be chemotherapy‐naïve or treated with only low or minimally emetogenic chemotherapy in the past, as defined by NCCN v.2.2010 Antiemetic Guidelines ECOG performance status 0 to 2 capable of taking oral medication Exclusion criteria vomiting or retching within 24 h before administration of study medications or administration of an antiemetic within 24 h before study medication administration, excluding use of benzodiazepines grade 2 nausea or greater, according to CTCAE v4.0, within 24 h before administration of chemotherapy administration of strong CYP450 3A4 inducers and/or inhibitors known to cause clinically relevant drug interactions within 1 week before study treatment and continuing through Day 5 alanine aminotransferase and/or aspartate aminotransferase > 2.5 times ULN or total bilirubin > 1.5 times ULN known hypersensitivity to ondansetron, palonosetron, aprepitant, or dexamethasone Mean age ± SD, years: 52.9 ± 12.7 in ondansetron group, 50.9 ± 9.2 in palonosetron group Gender: female Tumour/cancer type: breast cancer (N = 39), lymphoma (N = 1) Chemotherapy regimen: AC (doxorubicin/cyclophosphamide), AC plus bevacizumab, ABVD Country: USA (single centre)
Interventions	Experimental: arm A: palonosetron Day 1: aprepitant 125 mg p.o. + palonosetron 0.25 mg i.v. + dexamethasone 12 mg p.o. Days 2 to 3: aprepitant 80 mg p.o. + dexamethasone 8 mg p.o. Day 4: dexamethasone 8 mg p.o. Experimental: arm B: ondansetron Day 1: aprepitant 125 mg p.o. + ondansetron 24 mg p.o.  Days 2 to 3: aprepitant 80 mg p.o. + dexamethasone 8 mg p.o. Day 4: dexamethasone 8 mg p.o.
Outcomes	Primary endpoint overall complete response (0 to 120 h) Secondary endpoints achievement of complete response in acute setting (0 to 24 h) complete response in delayed setting (24 to 120 h) grade of nausea and vomiting use of rescue medication for each treatment group as well as for subgroups of the population
Notes	no study identifier provided "there has been no funding provided to this research study" conflicts of interest: "the authors have no conflicts of interest to disclose"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... randomized to one of two treatments according to a permuted block‐design with block sizes of 2, 4, or 6"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Comment: open‐label
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	Comment: open‐label
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: patients and personnel were not blinded towards the intervention and therefore might influence subjective outcomes analysis
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "an intention to‐treat approach was used to evaluate patients"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Wit 2001.

Study characteristics
Methods	Randomised, cross‐over trial with 2 arms comparison of granisetron + dexamethasone vs ondansetron + dexamethasone Recruitment period: n.r. 45 patients randomised 5 patients excluded after randomisation Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria protection failure (defined as ≥ 2 vomits severe nausea (no significant intake possible) or nausea > 4 hours) within 24 hours after single‐day cisplatin ≥ 50 mg m–2 or cyclophosphamide ≥ 500 mg m–2 based chemotherapy on antiemetic prophylaxis with ondansetron 8 mg i.v. and dexamethasone 10 mg i.v. no planned dose attenuations no use of other antiemetic agents, benzodiazepines, or opiates no emesis in the 24 hours preceding the study cycle Exclusion criteria: n.r. Median age (range), years: 46 (29 to 71) in granisetron, 46 (30 to 73) in ondansetron Gender: male (4) + female (36) Tumour/cancer type: solid tumour (breast, ovarian, lung, other) Chemotherapy regimen: cisplatin ≥ 50 mg m–2 or cyclophosphamide ≥ 500 mg m–2 Country: n.r.
Interventions	Cross‐over study Experimental: arm A: granisetron granisetron 3 mg i.v. + dexamethasone 10 mg i.v. Experimental: arm B: ondansetron patients with previous treatment failure continued treatment with ondansetron 8 mg i.v. + dexamethasone 10 mg i.v.
Outcomes	Primary endpoints complete protection (CP) partial protection (PP) failure (F)
Notes	no information regarding funding and clinical trial registration is reported study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but the method of randomisation was not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment was not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: 40 patients were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Xiong 2019.

Study characteristics
Methods	Randomised trial with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs palonosetron + dexamethasone Recruitment period: March 2014 to March 2017 108 patients randomised Masking: open‐label Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria older than 18 years of age histologically confirmed diagnosis of bone or soft tissue sarcoma Karnofsky score ≥ 60 predicted life expectancy ≥ 3 months Exclusion criteria central nervous system malignancy vomited in the 24 h before treatment Day 1 abnormal laboratory values (including absolute neutrophil count < 1500/mm³, WBC < 3000/mm³, platelet count < 100,000/ mm³, aspartate transaminase > 2.5 × ULN, ALT > 2.5 × ULN, bilirubin > 1.5 × ULN, or creatinine > 1.5 × ULN) taking systemic corticosteroid therapy at any dose antiemetic agents administered within 48 h before treatment Mean ± SD, years: 39.8 ± 8.6 in aprepitant group, 41.5 ± 9.4 in control group Gender: male (54) + female (51) Tumour/cancer type: bone or soft tissue sarcoma Chemotherapy regimen: 30 mg/m² on Days 1 and 2 for doxorubicin and 3 g/m² on Days 1 to 3 for ifosfamide Country: China
Interventions	Experimental: arm A: aprepitant Day 1: 125 mg p.o. aprepitant + 0.25 mg i.v. palonosetron + 5 mg i.v. dexamethasone Days 2 to 3: 80 mg p.o. aprepitant + 5 mg i.v. dexamethasone Control: arm B Day 1: 0.25 mg i.v. palonosetron + 10 mg i.v. dexamethasone Days 2 to 3: 10 mg i.v. dexamethasone
Outcomes	Primary endpoints complete response rate (acute, delayed, and overall phases) no nausea (acute, delayed, and overall phases) no vomiting (acute, delayed, and overall phases) rescue therapy (acute, delayed, and overall phases) Secondary endpoint tolerability (adverse events and laboratory assessments)
Notes	"sponsorship for this study and article processing charges were funded by the Clinical Research Physician Program of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei province, China" conflicts of interest: "Xiong Jie, Zhao Guifang, Yang Shengli, and Chen Jing declare that they have no conflict of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... using a computer‐generated allocation schedule with a block size of four"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	Quote: "we have no placebo, and the administration of dexamethasone is different in the two groups, so it is difficult for us to make this trial double blinded"
Blinding of participants and personnel (performance bias) Blinding of personnel	Unclear risk	Quote: "we have no placebo, and the administration of dexamethasone is different in the two groups, so it is difficult for us to make this trial double blinded"
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	High risk	Comment: study was not blinded; knowledge of treatment may affect outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: although the study was not blinded, we assume that knowledge of treatment had no effect on outcome assessment for objective outcomes
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "105 patients (51 patients in the aprepitant group and 54 patients in the control group) were included in the efficacy analyses"; "three patients were excluded from both the efficacy and safety analyses because they did not receive at least 1 day’s dose of study drug"; modified ITT analysis
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: "three patients were excluded from both the efficacy and safety analyses because they did not receive at least 1 day’s dose of study drug"; modified ITT analysis
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Yahata 2016.

Study characteristics
Methods	Randomised, placebo‐controlled, parallel‐group trial with 2 arms comparison of aprepitant + granisetron or ondansetron + dexamethasone vs placebo + granisetron or ondansetron + dexamethasone Study period: April 2011 to December 2013 324 patients screened 307 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria Japanese patients with gynaecological cancer (age range 20 to 80 years) who were treated with TC combination chemotherapy regimen of paclitaxel at a dose of 175 to 180 mg/m² and carboplatin at a dose of 5 to 6 AUC (concentration vs time curve) every 3 weeks Eastern Cooperative Oncology Group performance status 0 to 2 Exclusion criteria severe liver or renal dysfunction (serum aspartate transaminase > 2.5 × ULN), ALT > 2.5 × ULN, bilirubin > 1.5 × ULN, creatinine > 1.5 × ULN) risk of vomiting for other reasons (active peptic ulcer, gastrointestinal obstruction, etc.) history of chemotherapy or radiation vomiting 24 h before administration of TC combination chemotherapy continuing steroid treatment insulin treatment for diabetes mellitus pregnancy Mean age (range), years: 59 (26 to 77) in aprepitant group, 59 (24 to 79) in placebo group Gender: female Tumour/cancer type: gynaecological cancer (ovarian cancer, endometrial cancer, cervical cancer, peritoneal cancer, tubal cancer) Chemotherapy regimen: TC combination chemotherapy (paclitaxel and carboplatin) Country: Japan (9 institutes, multi‐centre)
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg p.o. + granisetron/ondansetron ¼ mg + dexamethasone 20 mg i.v. Days 2 to 3: aprepitant 80 mg p.o. Experimental: arm B: placebo Day 1: placebo 0 mg p.o. + granisetron/ondansetron ¼ mg + dexamethasone 20 mg i.v.
Outcomes	Primary endpoint proportion of patients with hypersensitivity reaction (HSR) Secondary endpoint(s) proportions of patients with no vomiting and no significant nausea complete response proportion of patients with no nausea
Notes	"this study is registered in the University Medical Information Network Clinical Trials Registry (No. 000005215)" "this study was supported in part by a grant‐in‐aid for scientific research from the Japan Society for the Promotion of Science (Numbers 24592520 and 24592519)" conflicts of interest: "the authors declare that they have no conflicts of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: randomised trial but method of randomisation not described
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "efficacy analyses were conducted with the full analysis set, which was defined as all randomized patients who received at least one dose of the study drugs"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	High risk	Quote: "safety was evaluated in all patients taking the study drugs", but "adverse events obviously caused by paclitaxel and/or carboplatin (e.g. alopecia, neutropenia) were excluded, and only toxicities not related to the study drugs were recorded"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Yang 2017.

Study characteristics
Methods	Randomised, active‐control, parallel‐group, phase 3 trial with 2 arms comparison of fosaprepitant + granisetron + dexamethasone vs aprepitant + granisetron + dexamethasone Recruitment period: November 2014 to July 2015 645 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: yes
Participants	Inclusion criteria were administered HEC (according to NCCN Clinical Practice Guidelines in Oncology: Antiemesis version 1.2014) and thus were eligible for enrolment in the study age 18 to 75 years ECOG score 0 to 2 estimated survival ≥ 3 months no major organ dysfunction women of childbearing age should agree to use contraceptives during study period and up to 3 months after, no pregnancy, no lactating women Exclusion criteria uncontrolled nausea (≥ grade 2) and vomiting within 72 h before chemotherapy initiation and/or HEC given within 2 weeks received any antiemetic drugs (including glucocorticoids) within 24 h before chemotherapy (except according to study protocol) needed upper abdominal or cranial radiotherapy within 2 to 7 days after receiving or taking the drug who cannot eat for any reason underlying disease that must be treated with glucocorticoids severe heart and lung dysfunction poor compliance, or cannot be combined with treatment, and narrative response allergic to study drugs Median age (range), years: 55 (20 to 79) in fosaprepitant group, 53 (18 to 74) in aprepitant group Gender: male (326) + female (319) Tumour/cancer type: n.r. Chemotherapy regimen: HEC (according to NCCN Clinical Practice Guidelines in Oncology: Antiemesis version 1.2014) Country: China (21 centres)
Interventions	Experimental: arm A: fosaprepitant Day 1: fosaprepitant 150 mg i.v. + granisetron 3 mg i.v. + dexamethasone 6 mg p.o. or i.v. Day 2: dexamethasone 3.75 mg p.o. Day 3: dexamethasone 3.75 mg p.o. every 12 h Day 4: dexamethasone 3.75 mg p.o. every 12 h Experimental: arm B: aprepitant Day 1: aprepitant 125 mg p.o. + granisetron 3 mg i.v. + dexamethasone 6 mg p.o. or i.v. Day 2: aprepitant 80 mg p.o. + dexamethasone 3.75 mg p.o. Day 3: aprepitant 80 mg p.o. + dexamethasone 3.75 mg p.o. Day 4: dexamethasone 3.75 mg p.o.
Outcomes	Primary efficacy endpoint complete response (CR) during the 120 h after initiation of chemotherapy (overall phase ‐ OP) Secondary efficacy endpoints proportions of patients who achieved CR during acute and delayed phases (0 to 24 and 25 to 120 h after chemotherapy initiation, respectively) time to first vomiting episode and frequency of vomiting per day time to first rescue therapy from chemotherapy initiation (hours) and proportion of patients receiving rescue therapy proportion of patients without significant nausea and proportion of patients without nausea change in ECOG
Notes	registered with www.chinadrugtrials.org.cn (CTR20140900) "this work was sponsored by Chia Tai Tianqing Pharmaceutical Group Co., Ltd" study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were randomized in a 1:1 ratio using a central randomization system ..."
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. hiccups)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "assessments of efficacy, tolerability and safety variables were performed for 5 days after the start of chemotherapy (0–120 hr), including the acute and delayed phases"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "a total of 645 patients were included in the safety study"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Yeo 2009.

Study characteristics
Methods	Randomised, placebo‐controlled study with 2 arms comparison of aprepitant + ondansetron + dexamethasone vs placebo + ondansetron + dexamethasone Enrolment period: n.r. 127 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria ethnic Chinese female over 18 years of age with diagnosed breast cancer scheduled to receive first course of adjuvant chemotherapy that consisted of i.v. doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² predicted life expectancy ≥ 4 months Karnofsky score ≥ 60 negative for pregnancy test and agreed to use a double‐barrier method of contraception prior to, throughout, and for at least 14 days following the last dose of study medication (for pre‐menopausal patients) able to read, understand, and complete study questionnaires and diary, including questions requiring a visual analogue scale response able to understand procedures and agreed to participate in the study by giving written informed consent Exclusion criteria abnormal laboratory results including absolute neutrophil count < 1500/mm³, WBC < 3000/mm³, platelet count < 100,000/mm³, aspartate transaminase or alanine transaminase > 2.5 × ULN, bilirubin > 1.5 × ULN, or serum creatinine > 1.5 × ULN received or would receive radiation therapy to abdomen or pelvis in the week before study treatment had vomited in the 24 h before study treatment history of treatment with emetogenic chemotherapy (Hesketh Level 3 or above) active infection or any uncontrolled disease alcohol abuse or use of any illicit drugs mentally incapacitated or with significant emotional or psychiatric disorder and history of hypersensitivity to ondansetron or dexamethasone Median age (range), years: 46.5 (32 to 66) in aprepitant group, 48.5 (26 to 68) in standard group Gender: female (124) Tumour/cancer type: invasive ductal carcinoma, invasive lobular carcinoma, other Chemotherapy regimen: doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m² Country: Hong Kong, China (single centre)
Interventions	Experimental: arm A: aprepitant Day 1: aprepitant 125 mg, ondansetron 8 mg, dexamethasone 12 mg, before chemotherapy and ondansetron 8 mg 8 h later Days 2 to 3: aprepitant 80 QD Standard: arm B: ondansetron Day 1: ondansetron 8 mg and dexamethasone 20 mg before chemotherapy and ondansetron 8 mg 8 h later Days 2 to 3: ondansetron 8 mg b.i.d.
Outcomes	Primary objective comparison of the efficacy of aprepitant‐based antiemetic regimen and standard antiemetic regimen for prevention of CINV in Chinese breast cancer patients receiving first cycle of moderately emetogenic chemotherapy AC (doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m²) Secondary objective(s) comparison of patient‐reported quality of life in these 2 groups of patients
Notes	no information reported regarding clinical trial registration "this study has been supported by an educational grant from Merck Sharpe & Dohme (Asia) Ltd" study authors did not provide disclosure of potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were assigned to 1 of 2 anti‐emetic regimens according to an in‐house blinding and allocation schedule of random numbers"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. neutropenia, febrile neutropenia)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "thus, data from 124 evaluable patients (62 in each arm) was available for analysis. The modified intention‐to‐treat (mITT) approach was used for all efficacy analyses"
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Comment: all patients were included for safety analysis
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Zhang 2018 (a).

Study characteristics
Methods	Randomised, single initial cycle, parallel‐group, international, phase 3 trial with 2 arms comparison of netupitant + palonosetron + dexamethasone vs aprepitant + granisetron i.v. + dexamethasone Recruitment period: n.r. 834 patients randomised 2 patients did not receive study treatment and therefore were excluded Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria ≥ 18 years with diagnosed histologically or cytologically confirmed malignant solid tumour naïve to chemotherapy and scheduled to receive first course of cisplatin‐based chemotherapy at a dose ≥ 50 mg/m² alone or in combination with other chemotherapy agents Karnofsky performance score ≥ 70% able to follow study procedures and complete the patient diary ECOG performance status 0 to 2 Exclusion criteria MEC or HEC from Days 2 to 5 following cisplatin moderately or highly emetogenic radiotherapy within 1 week before Day 1 or between Days 1 and 5 bone marrow or stem cell transplant receipt of medication with antiemetic effect < 24 h of Day 1 vomiting, retching, or mild nausea < 24 h before Day 1 serious cardiovascular disease history or predisposition to cardiac conduction abnormalities except for incomplete right bundle branch block long‐term use of select CYP3A4 inducers < 4 weeks or substrate or inhibitor < 1 week before Day 1 Mean age ± SD, years: 54.6 ± 9.63 in NEPA group, 54.5 ± 10.24 in APR/GRAN group Gender: male (589) + female (240) Tumour/cancer type: solid tumour (lung, head and neck, and other) Chemotherapy regimen: cisplatin‐based chemotherapy at a dose ≥ 50 mg/m² alone or in combination with other chemotherapy agents Country: 30 sites in China, 5 sites in Taiwan, 3 sites in Thailand, 8 sites in Korea (46 centres)
Interventions	Experimental: arm A: NEPA Day 1: NEPA (300 mg netupitant and 0.5 mg palonosetron) + dexamethasone 12 mg Days 2 to 4: dexamethasone 8 mg daily Experimental: arm B: APR/GRAN Day 1: aprepitant 125 mg + 3 mg i.v. granisetron + dexamethasone 12 mg Days 2 to 3: aprepitant 80 mg daily + dexamethasone 8 mg daily Day 4: dexamethasone 8 mg daily
Outcomes	Primary efficacy endpoint complete response during the overall phase Secondary efficacy endpoints CR during acute and delayed phases and each individual day no emesis during acute and delayed phases and each individual day no significant nausea (NSN: VAS score < 25 mm) no nausea (VAS score < 5 mm) no rescue medication during acute, delayed, and overall phases FLIE scores reflecting NIDL during acute/delayed phases were also evaluated as a secondary ‘quality of life’ endpoint safety
Notes	"Helsinn Healthcare, SA, Lugano, Switzerland, who provided the study drugs and the funding for this study (no grant number applies)" conflicts of interest: "LZ: consultant for MSD; research funding from Helsinn, Lilly, and MSD; SL: consultant for Boehringer and Roche; speaker’s bureau for Lilly; travel reimbursed by Hutchison and Medipharm Limited; JC: medical advisor for QuintilesIMS; SC: employee of Helsinn Healthcare; CL: employee of Helsinn Healthcare; KJ: consultant for Helsinn Healthcare, Merck, MSD and Tesaro; travel reimbursed by MSD; MA: consultant/investigator for Helsinn Healthcare, Merck and Tesaro. All remaining authors have declared no conflicts of interest"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were stratified by gender and randomly assigned (1:1) to receive either NEPA or APR/GRAN treatment ..."
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "... double‐blind ..."
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "... double‐blind ..."
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Comment: both patients and personnel were blinded towards the intervention and thus had no influence on outcome assessment (e.g. study mortality)
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "the full analysis set (FAS) population (efficacy analyses) was defined as all patients who were randomized and received protocol‐required cisplatin and study treatment ...": of 334 randomised, 328 were included in FAS
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	Quote: "the safety analysis population consisted of all patients who received study treatment"
Selective reporting (reporting bias)	Low risk	Comment: all outcome measures were reported in the results section
Other bias	Low risk	Comment: no information to suggest other sources of bias

Zhang 2018 (b).

Study characteristics
Methods	Randomised study with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs placebo + palonosetron + dexamethasone Recruitment period: n.r. 244 patients randomised Masking: n.r. Baseline patient characteristics: n.r. Follow‐up: n.r.
Participants	Inclusion criteria diagnosed locally advanced or metastatic lung cancer received full‐dose single‐day cisplatin‐based chemotherapy Exclusion criteria: n.r. Mean/median age, years: n.r. Gender: n.r. Tumour/cancer type: locally advanced or metastatic lung cancer Chemotherapy regimen: cisplatin‐based combination chemotherapy Country: China
Interventions	Experimental: arm A: aprepitant aprepitant + palonosetron + dexamethasone Experimental: arm B: placebo placebo + palonosetron + dexamethasone
Outcomes	Primary endpoint complete response of nausea and vomiting in the overall period (0 to 120 h) in first cycle Secondary endpoints proportion of nausea and vomiting response of cross‐over patients safety
Notes	abstract
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "random sequence generation not reported"
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment not reported
Blinding of participants and personnel (performance bias) Blinding of participants	Unclear risk	Comment: blinding not reported
Blinding of participants and personnel (performance bias) Blinding of personnel	Unclear risk	Comment: blinding not reported
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: blinding not reported; therefore we do not know if this was a risk of bias
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Unclear risk	Comment: unclear whether all randomised patients were included for efficacy analysis
Selective reporting (reporting bias)	Unclear risk	Comment: conference abstract, not evaluable
Other bias	Unclear risk	Comment: conference abstract, not evaluable

Zhang 2020.

Study characteristics
Methods	Randomised study with 2 arms comparison of fosaprepitant + palonosetron + dexamethasone vs aprepitant + palonosetron + dexamethasone Recruitment period: October 2014 to November 2015 648 patients evaluated 644 patients randomised Masking: double‐blind Baseline patient characteristics: reported Follow‐up: n.r.
Participants	Inclusion criteria aged ≥ 18 and ≤ 75 years histologically confirmed solid malignant tumour Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 predicted life expectancy ≥ 3 months scheduled for a single day of cisplatin (dosage ≥ 50 mg/m² and infusion time ≤ 3 hours) Exclusion criteria mentally disabled or suffering from emotional disorder current illicit drug use, including alcohol abuse scheduled for administration of stem cell rescue therapy during cisplatin chemotherapy participated in other clinical trials in the past 4 weeks treated with chemotherapy including ordinary paclitaxel (using cator oil as a solvent) active infection or uncontrolled disease other than malignancy scheduled for multi‐day cisplatin chemotherapy treated with moderately or highly emetogenic chemotherapy within 6 days before initial cisplatin infusion and/or 6 days after cisplatin infusion scheduled to receive radiation therapy to abdomen or pelvis within a week of treatment absolute neutrophil count < 1500 cells/L, WBC count < 3000 cells/L, platelet count < 100,000 cells/L, AST and ALT > 2.5 upper limit of normal (ULN), bilirubin > 1.5 ULN, and creatinine > 1.5 ULN pregnant or breast‐feeding taking systemic corticosteroids not including topical and inhaled corticosteroids vomiting or nausea in the 24 hours before treatment Mean age (SD), years: 55.88 (10.37) in fosaprepitant group, 55.88 (10.19) in aprepitant group Gender: 40.50% female (59.50% male) in fosaprepitant group, 40.87% female (59.13% male) in aprepitant group Tumour/cancer type: solid malignant tumour Chemotherapy regimen: single day of cisplatin (dosage ≥ 50 mg/m² and infusion time ≤ 3 hours) Country: China
Interventions	Experimental: arm A: fosaprepitant fosaprepitant (Day 1, 150 mg i.v.) + palonosetron (0.25 mg i.v.) + dexamethasone (6 mg on Day 1 followed by 3.75 mg on Day 2 and 3.75 mg p.o. every 12 hours on Days 3 to 4) + aprepitant simulating agents (placebo, scheduled as received in aprepitant group) Experimental: arm B: aprepitant aprepitant (Day 1, 125 mg, p.o.; Days 2 to 3, 80 mg p.o.) + palonosetron + dexamethasone (6 mg on Day 1 followed 3.75 mg on Days 2 to 4, with dexamethasone simulation agent 3.75 mg p.o. on Days 3 to 4), fosaprepitant simulating agent (placebo, scheduled as received in fosaprepitant group)
Outcomes	Primary endpoint complete response (CR), defined as no vomiting and no use of rescue therapy in the overall phase (OP) Secondary endpoints complete response in the acute phase (AP, 0 to 24 h after HEC initiation) and in the delayed phase (DP, 24 to 120 h after HEC initiation) no vomiting and significant nausea during OP, AP, and DP
Notes	Funding: "Li Zhang has received research support from the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDA12020101 to J.D.). Yan Huang has received research support from Science and Technology Program of Guangzhou (201704020072). Yunpeng Yang was supported by Outstanding Young Talents Program of Sun Yat‐sen University Cancer Center (16zxyc03) and Central Basic Scientific Research Fund for Colleges‐Young Teacher Training Program of Sun Yat‐sen University (17ykpy85)" "the authors have no conflicts of interest to declare"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "computer‐generated, blinded allocation schedule. Patients firstly stratified by gender and then based on whether the first administration of chemotherapy or not and the emetogenic potential of anticancer agents (excluding cisplatin) were randomized to different treatment groups"
Allocation concealment (selection bias)	Low risk	Computer‐generated, blinded allocation schedule
Blinding of participants and personnel (performance bias) Blinding of participants	Low risk	Quote: "both patients and researchers were blinded to the therapeutic grouping"
Blinding of participants and personnel (performance bias) Blinding of personnel	Low risk	Quote: "both patients and researchers were blinded to the therapeutic grouping"
Blinding of outcome assessment (detection bias) Subjective outcomes (Patient reported outcomes)	Low risk	Quote: "both patients and researchers were blinded to the therapeutic grouping"
Blinding of outcome assessment (detection bias) Objective outcomes (including mortality and safety)	Low risk	Quote: "both patients and researchers were blinded to the therapeutic grouping"
Incomplete outcome data (attrition bias) Subjective outcomes (Patient reported outcomes)	Low risk	Data available for nearly all participants (1/322 participants in fosa group and 3/326 participants from apre group excluded because no study drug received)
Incomplete outcome data (attrition bias) Objective outcomes (including mortality and safety data)	Low risk	All participants who received at least 1 dose included in safety analysis
Selective reporting (reporting bias)	Low risk	No reasons for any concern detected
Other bias	Low risk	No other sources of bias detected

5‐HT₃: serotonin.

5‐HT₃ RA: 5‐HT₃ receptor antagonist.

ABVD: doxorubicin (Adriamycin), bleomycin, vinblastine (Velbe), dacarbazine (DTIC).

AC: doxorubicin, cyclophosphamide.

ALT: alanine aminotransferase.

AML: acute myeloid leukemia.

APF: granisetron.

AST: aspartate aminotransferase.

AUC: area under the curve.

BBM: berbamine.

BCNU: carmustine.

BEAM: carmustine, etoposide, cytarabine, and melphalan.

BEAC: carmustine, etoposide, cytarabine, cyclophosphamide.

β‐hCG: β‐subunit of human chorionic gonadotropin.

b.i.d.: twice daily.

Bu: busulfan.

CDDP: cisplatin.

CEF: cyclophosphamide, epirubicin, 5‐fluorouracil.

CINV: chemotherapy‐induced nausea and vomiting.

CNF: cyclophosphamide, novantrone, and 5‐fluorouracil.

CNS: central nervous system.

CMF: cyclophosphamide, mitoxantrone, and 5‐fluorouracil.

CML: chronic myeloid leukemia.

CR: complete response.

CrCl: creatinine clearance.      

CTCAE: Common Terminology Criteria for Adverse Events.

Cy: cyclophosphamide.

CyTBI: cyclophosphamide total body irradiation.

EC: epirubicin, cyclophosphamide.

ECG: electrocardiogram.

ECOG: Eastern Cooperative Oncology Group.

ESHAP: multi‐day cisplatin along with etoposide, methylprednisolone, high‐dose cytarabine.

FAC: 5‐fluorouracil (5‐FU) + AC.

FEC: fluorouracil, epirubicin, cyclophosphamide.

FLIE: Functional Living Index‐Emesis.

FOLFOX: 5‐fluorouracil + leucovorin + oxaliplatin.

g/m²: gram per square meter.

GTDS: granisetron transdermal delivery system.

h: hour.

hCG: human chorionic gonadotropin.

HDCT: high‐dose chemotherapy.

HEC: highly emetogenic chemotherapy.

HSCT: haematopoietic stem cell transplantation.

IFO: ifosfamide.

ITT: intention‐to‐treat.

IU/L: international units per litre.

i.v.: intravenous.                       

L: litre.   

MEC: moderately emetogenic chemotherapy.

μg: microgram.

mg: milligram.

mg/dL: milligrams per decilitre.

mg/m²: milligram per square meter.

min: minutes.

mITT: modified intention‐to‐treat.

MMT: paclitaxel.

msec: millisecond.

MTZ: mitoxantrone.

NCCN: National Comprehensive Cancer Network.

NSCLC: non‐small cell lung carcinoma.

NK₁: neurokinin‐1.

n.r.: not reported.

PBSC: peripheral blood stem cell.

p.o.: per os (orally).

PRN: medicine as required.

q8h: every 8 hours.

QAM: in the morning.

QD: once a day.

QoL: quality of life.

QPM: in the evening.

SC: subcutaneously.

SCT: stem cell transplantation.

SOX: S‐1, oxaliplatin.

SPAMP V: cyclophosphamide, thiotepa, carboplatin.

TAC: docetaxel, doxorubicin, cyclophosphamide.

TANC: paclitaxel, mitoxantrone, carboplatin.

TBI: total body irradiation.

TC: paclitaxel, carboplatin.

ULN: upper limit of normal.

VAS: visual analogue scale.

VP: etoposide.

vs: versus.

WBC: white blood cell count.

XELOX: capecitabine, oxaliplatin.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Abali 2007	non‐randomised study
Adamo 1994	antiblastic therapy used as treatment regimen
Albany 2014	non‐randomised study
Audhuy 1996	application of dexamethasone has not been reported
Ballatori 1995	dexamethasone has been used in only 1 arm
Barrajon 2000	cost‐benefit analysis
Belle 2002	no use of 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonists in first 2 arms, along with neurokinin‐1 (NK₁) receptor antagonist
Bianchi 1996	application of dexamethasone has not been reported
Bonneterre 1994	a letter
Bonneterre 1995	application of dexamethasone has not been reported
Bubalo 2001	application of dexamethasone has not been reported
Bubalo 2012	objectives of this article are (1) to assess the pharmacokinetics of aprepitant in cancer patients undergoing HSCT, and (2) to examine the potential drug–drug interaction between aprepitant and cyclophosphamide
Campora 1994	application of dexamethasone has not been reported
Chiou 2000	chemotherapy regimen is not clearly reported
Choi 2014	non‐randomised study
Cocquyt 2001	use of 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonist has been reported in only 1 arm
Craver 2011	non‐randomised study
Creed 1999	no information given regarding randomisation, no comparator against ondansetron
Dandamudi 2011	docetaxel belongs to low emetogenic chemotherapy regimen
Dong 2011	dexamethasone was permitted as rescue medication
Fauser 1995	application of dexamethasone has not been reported
Fauser 1996	application of dexamethasone has not been reported
Fauser 1999	dexamethasone has been used in only 1 arm
Fedele 1995	correspondence
Feng 2000	application of dexamethasone has not been reported
Feng 2002	application of dexamethasone has not been reported
Fengyi 2002	application of dexamethasone has not been reported
Gebbia 1994	application of dexamethasone has not been reported
Goldschmidt 1997	no use of dexamethasone reported
Gralla 1998	application of dexamethasone has not been reported
Gralla 2003	application of dexamethasone has not been reported
Hesketh 1996	application of dexamethasone has not been reported
Huang 1998	comparison of identical dose of Zudan and Zofran; both are ondansetron
Huang 2001	no information available regarding randomisation
Huang 2013	application of dexamethasone has not been reported
Huc 1998	application of dexamethasone has not been reported
Hudis 2003	retrospective subset analysis
Humphreys 2013	cost‐effectiveness study
Iihara 2012	application of dexamethasone has not been reported
Italian Group for Antiemetic Research 1993	use of metoclopramide in 1 arm
Italian Group for Antiemetic Research 1995 (a)	on Days 2 to 4 after chemotherapy, all patients received oral metoclopramide + intramuscular dexamethasone as antiemetic prophylaxis for delayed emesis
Italian Group for Antiemetic Research 1995 (b)	use of metoclopramide
Jantunen 1993	application of dexamethasone has not been reported
Kang 2002	application of dexamethasone has not been reported
Kawaguchi 2015	concurrent chemoradiotherapy
Kilickap 2013	chemotherapy regimen is not clearly reported
Kim 1998	application of dexamethasone has not been reported
Kim 2004	application of dexamethasone has not been reported
Kim 2012	detailed chemotherapy regimens within the HEC group have not been reported
Lacerda 2000	addition of lorazepam in all treatment arms
Lavoie 2012	use of 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonist has not been reported
Lee 2014	chemotherapy regimen is not clearly mentioned
Leonardi 1996	application of dexamethasone has not been reported
Lindley 2005	comparison of ondansetron, prochlorperazine, and dexamethasone in 3 individual arms
Lofters 1995	dolasetron (dol) vs ondansetron (ond) with and without dexamethasone (dex) to evaluate additive effects of i.v. DEX with each drug
Long 2002	no information available regarding randomisation
Loos 2007	pharmacokinetic study
Mandanas 2005	addition of lorazepam in all treatment arms
Martoni 1996	application of dexamethasone has not been reported
Marty 1995	application of dexamethasone has not been reported
Matsui 1996	patients were randomly assigned to receive granisetron alone (arm 1) or granisetron, dexamethasone, and prochlorperazine (arm 2)
Matsuoka 2003	treatment arms include granisetron + dexamethasone vs granisetron alone
Meiri 2007	efficacy determination of dronabinol alone and in combination with ondansetron vs ondansetron alone
Micha 2016	application of dexamethasone has not been reported in Cycle 1
Molassiotis 2013	study type: pooled analysis of different trials
Monda 1994	no information given regarding randomisation
Moore 2007	cost‐effectiveness study
Nasu 2013	application of dexamethasone has not been reported
Navari 2016	review
NCT04636632	comparison of different preparations of the same drug
Nishimura 2015 (a)	5‐HT₃ not defined and use of both fosaprepitant and aprepitant in 1 group reported
Nishimura 2015 (b)	5‐HT₃ not defined and use of both fosaprepitant and aprepitant in 1 group reported
Noble 1994	application of dexamethasone has not been reported
Noda 2002	application of dexamethasone has not been reported
Öge 2000	application of dexamethasone has not been reported
Ogihara 1999	dexamethasone has been reported in only 1 group
Ohta 1992	ondansetron or saline injection has been given to patients
Ottoboni 2014	pharmacokinetic and dose‐finding study
Park 1997	application of dexamethasone has not been reported
Pater 1997	non‐randomised study
Pectasides 2007	application of dexamethasone has not been reported
Perez 1996	no information given regarding randomisation
Perez 1998 (a)	application of dexamethasone has not been reported
Perez 1998 (b)	dexamethasone or methylprednisolone was permitted as a prophylactic component of pre‐therapy
Peterson 1996	dexamethasone has been reported in only 1 group
Plasencia‐Mota 1993	no information given regarding randomisation
Poon 1998	application of dexamethasone has not been reported
Qiu 2011	application of dexamethasone has not been reported
Roila 2009	dose‐finding study
Roscoe 2012	no individual data have been provided for HEC and MEC regimens
Ruff 1994	application of dexamethasone has not been reported
Ruhlmann 2016	5 weeks of fractionated radiotherapy and concomitant weekly cisplatin have been used
Rzepecki 2009	non‐randomised study; historical control group
Saito 2015	chemotherapy regimen is not clearly reported
Sheng 2010	application of dexamethasone and chemotherapy regimen have not been reported
Shi 2007	application of dexamethasone has not been reported
Silvestris 2013	a letter
Slabý 2000	application of dexamethasone has not been reported
Spector 1998	application of dexamethasone has not been reported
Stewart 1995	application of dexamethasone has not been reported
Sun 2014	application of dexamethasone has not been reported
Suzuki 2015	pharmacogenomics study
Takenaka 2007	no information given regarding randomisation
Takeshima 2014	non‐randomised study and no comparator has been used
Tan 2004	no individual data have been provided for HEC and MEC regimens
Tang 2013	application of dexamethasone has not been reported
Tanimura 1998	dose‐finding study
Tian 2011	application of dexamethasone has not been reported
Tominaga 1996	application of dexamethasone has not been reported
Tong 2012	concurrent radiochemotherapy
Tong 2014	application of dexamethasone and chemotherapy regimen have not been reported
Tremont‐Lukats 2017	application of dexamethasone has not been reported
Tsavaris 1996	application of dexamethasone has not been reported
Tsubata 2015	no use of dexamethasone has been reported
Tsuji 2016	pharmacogenomics study
Tsukuda 1995	application of dexamethasone has not been reported
Uchino 2012	retrospective study
Vadhan‐Raj 2011	pharmacological study
Vadhan‐Raj 2012	pharmacological study
Vadhan‐Raj 2014	pharmacological study
Vadhan‐Raj 2015	pharmacological study
Van Belle 2002	no use of 5‐hydroxytryptamine‐3 (5‐HT₃) receptor antagonist has been reported in 2 of 3 arms
Van der Vorst 2021	metoclopramide used as part of the antiemetic regimen
Walko 2012	pharmacological study
Weant 2017	application of dexamethasone has not been reported
Xie 2003	use of dexamethasone has not been reported
Yahata 2016 (a)	no clear distinction in presenting results for granisetron and ondansetron
Yalçin 1999	application of dexamethasone has not been reported
Yang 2005	application of dexamethasone has not been reported
Yano 2005	application of dexamethasone has not been reported
Yu 2009	application of dexamethasone has not been reported
Zeidman 1998	non‐randomised study
Zeng 2001	application of dexamethasone and chemotherapy regimen have not been reported
Zhang 1996	application of dexamethasone has not been reported
Zhang 1999	application of dexamethasone has not been reported
Zhang 2002	phase 1, pharmacokinetic study
Zhang 2003	use of dexamethasone has not been reported
Zhang 2003 (a)	application of dexamethasone has not been reported
Zhang 2007	application of dexamethasone has not been reported
Zhang 2012	phase 1, pharmacokinetic study

Characteristics of studies awaiting classification [ordered by study ID]

ChiCTR‐INR‐17010779.

Methods	Randomised, cross‐over study with 2 arms comparison of palonosetron + dexamethasone vs tropisetron + dexamethasone Study period: April 2017 to March 2020 target sample size: 150 Masking: open‐label Baseline patient characteristics: n.r.
Participants	Inclusion criteria aged 18 to 70 years, male or female ECOG  = 2 histologically or cytologically confirmed malignant tumour willing to accept chemotherapy and tolerated 2 cycles of chemotherapy at least regimens of chemotherapy must be standard regimens recommended in domestic and international clinical practice guidelines for relevant malignant tumour at least 1 chemotherapeutic with high emetic risk contained in the chemotherapy regimen, such as cisplatin, doxorubicin 60 mg/m², epirubicin > 90 mg/m², ifosfamide 2 g/m², used for 3 to 5 days normal function of major organs should meet the following criteria: routine blood examination must be in accordance with standard as follows: Hb 90 g/L, WBC 3.0 × 10⁹/L, ANC 1.5 × 10⁹/L, PLT 80 × 10⁹/L; TBIL 1.5 × ULN (higher than normal limit), ALT and AST 2.5 × ULN (if liver metastasis ALT and AST 5 × ULN); serum Cr 1 × ULN, endogenous creatinine clearance > 50 mL/min (Cockcroft‐Gault formula) women of child‐bearing age willing to using appropriate methods of contraception during the test and 8 weeks after having the last experimental drug; should have a pregnancy check before testing if necessary and result should be negative willing to join in this study, sign informed consent, practise good adherence, and cooperate with follow‐up Exclusion criteria pregnant or nursing female; needing radiotherapy during the study gastrointestinal tract obstruction serious heart disease, liver and kidney disease, or metabolic dysfunction epilepsy or use of psychiatric drug or sedative used antiemetic within 24 h of starting study treatment, or vomited before chemotherapy metastatic brain tumour, vomiting because of intracranial hypertension irritability of 5‐HT₃ receptor antagonist contraindications on chemotherapy currently or 4 weeks before the start of the study involved in other drug clinical trial Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: histologically or cytologically confirmed malignant tumour Chemotherapy regimen: cisplatin, doxorubicin ≥ 60 mg/m², epirubicin > 90 mg/m², ifosfamide ≥ 2 g/m² Country: China
Interventions	Cross‐over study Experimental: arm A Cycle 1: palonosetron 0.25 mg on Day 1, Day 3 + dexamethasone 10 mg on Day 1, 5 mg on Days 2 to 5 Cycle 2: tropisetron 5 mg on Days 1 to 3/5 + dexamethasone 10 mg on Day 1, 5 mg on Days 2 to 5 Experimental: arm B Cycle 1: tropisetron 5 mg on Days 1 to 3/5 + dexamethasone 10 mg on Day 1, 5 mg on Days 2 to 5 Cycle 2: palonosetron 0.25 mg on Day 1, Day 3 + dexamethasone 10 mg on Day 1, 5 mg on Days 2 to 5
Outcomes	Primary outcome complete response of delayed chemotherapy‐induced nausea and vomiting Secondary outcomes complete response of acute chemotherapy‐induced nausea and vomiting complete response of overall chemotherapy‐induced nausea and vomiting
Notes	main ID: ChiCTR‐INR‐17010779 sponsor: Affiliated Tumor Hospital of Guangxi Medical University

CTRI/2017/10/010163.

Methods	Randomised, interventional, parallel study with 2 arms comparison of granisetron + dexamethasone vs ondansetron + dexamethasone Recruitment period: November 2017 to April 2018 sample size: 94 Masking: open‐label Baseline patient characteristics: n.r.
Participants	Inclusion criteria aged between 20 and 65 years when giving consent males and females diagnosed with cancer by the Medical Oncologist naïve to chemotherapy or have been treated with single cycle of chemotherapy with moderate emetogenicity and low emetogenicity chemotherapeutic agents scheduled to receive chemotherapy with any dose of moderate or low emetogenic potential chemotherapeutic agents except for carboplatin Exclusion criteria known allergic to ondansetron or granisetron or dexamethasone too sick to give informed consent baseline prolonged QTc interval with arrhythmias and conduction defects severe and uncontrollable complications abnormal serum levels of potassium, calcium, and magnesium metastasis to the brain that is symptomatic seizure disorder requiring anticonvulsant medication unless clinically stable and free of seizure activity symptomatic or invasive procedure indicating ascites or pleural effusion gastric outlet stenosis or intestinal obstruction ongoing emesis or greater nausea liver failure and kidney failure pregnant women and lactating mothers any male or female who is not willing to practice adequate contraceptive measures during the study period currently enrolled in another investigational drug study Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: malignancy Chemotherapy regimen: moderate or low emetogenic potential chemotherapeutic agents except for carboplatin Country: India
Interventions	Experimental: arm A: granisetron Day 1: i.v. injections of granisetron 1 mg + i.v. dexamethasone 8 mg given 30 min before administration of moderate emetogenic and mild emetogenic chemotherapy agents Days 2 to 5: p.o. granisetron 1 mg once daily before food Control: arm B: ondansetron Day 1: i.v. injections of ondansetron 8 mg + i.v. dexamethasone 8 mg given 30 min before administration of moderate emetogenic chemotherapy agents and low chemotherapeutic agents Days 2 to 5: p.o. ondansetron 8 mg once daily before food
Outcomes	Primary outcomes complete prevention of emesis complete prevention of nausea adverse events during the study electrocardiographic changes before and after treatment Secondary outcomes number of emetic episodes number of patients with treatment failure (taken rescue medication) total cost of treatment per patient in each group functional living index of every patient body weight changes at the end of Day 5
Notes	main ID: CTRI/2017/10/010163 source of monetary support: Sri Ramachandra Medical College and Research Institute, Sri Ramachandra University, Ramachandra Nagar, Porur, Chennai, Tamil Nadu ‐ 600116

EUCTR2004‐000371‐34.

Methods	Randomised, phase 2, placebo‐ and active‐controlled study with 3 arms comparison of casopitant 50 mg + ondansetron + dexamethasone vs casopitant 100 mg + ondansetron + dexamethasone vs casopitant 150 mg + ondansetron + dexamethasone Masking: double‐blind Baseline patient characteristics: reported
Participants	Inclusion criteria  male or female at least 18 years of age diagnosed malignant solid tumour and scheduled to receive first course of chemotherapy with cisplatin as a single i.v. dose > 70 mg/m² on study Day 1, given over 1 to 4 h (as per local institutional standards), alone or in combination with other chemotherapeutic agents. Additional chemotherapeutic agents of low to high emetogenic potential (e.g. cyclophosphamide, doxorubicin, ifosfamide) must be administered after initiation of cisplatin and must be completed within 6 h from the time that cisplatin was initiated. Chemotherapeutic agents of low emetogenic potential (e.g. gemcitabine), may be administered at the time of or after initiation of cisplatin administration, as per usual institutional practices. Taxanes (e.g. paclitaxel, docetaxel) may be administered on study Day 1 only Karnofsky performance scale score ≥ 70 adequate haematological and metabolic status for receiving cisplatin chemotherapy (WBC > 3000/mm³, platelets > 100,000/mm³, serum creatinine < 1.5 mg/dL ability and willingness to complete VAS, questionnaires, and daily components of the subject diary from Day 1 until the end of the 120‐h follow‐up assessment period, plus availability to respond to follow‐up by study personnel at the 120‐h study period post infusion of HEC not of child‐bearing potential (i.e. physically incapable of becoming pregnant, including postmenopausal females and those who have attained such status via surgical means) or pre‐menopausal and demonstrating negative serum or negative urine pregnancy test within 24 h before first administration of any study medication or GW679769 investigational product understands the nature and purpose of the study and its procedures and signs an informed consent form to indicate this understanding before any study procedures or dosing Exclusion criteria  has previously received cytotoxic chemotherapy scheduled to receive more than 1 day of cisplatin treatment during a single cycle of therapy or adjuvant chemotherapy with cyclophosphamide‐containing regimens pregnant or lactating unwillingness of the male to use a condom with spermicide in addition to having female partner use another form of contraception has received radiation therapy to abdomen or pelvis in the 7 days before receiving first dose of study medication, or will receive radiation therapy to abdomen or pelvis in the 6 days following first dose of study medication emesis (i.e. vomiting and/or retching) experienced in the 24 h before receiving first dose of study medication clinically significant nausea in the 24 h before receiving first dose of study medication known central nervous system primary or metastatic malignancy, unless successfully treated with excision or radiation, and stable for at least 1 week before receiving first dose of study medication aetiology for emesis and nausea including, but not limited to, gastrointestinal obstruction, increased intracranial pressure, hypercalcaemia, active peptic ulcer known history of peptic ulcer disease or irritable bowel disease active systemic infection or any uncontrolled disease (other than malignancy) that, in the opinion of the Investigator, may confound results of the study previous, but not current, history of alcoholism ‐ may be permitted provided that, in the investigator's opinion, the disease state will not confound results of the study initiated systemic corticosteroid therapy at any dose within 72 h before receiving first dose of study medication except when indicated as prophylactic medication for taxane therapy (e.g. paclitaxel, docetaxel) scheduled to receive bone marrow transplantation and/or stem cell rescue with this course of cisplatin therapy known hypersensitivity or contraindication to ondansetron hydrochloride or ondansetron, another 5‐HT₃ receptor antagonist, dexamethasone, or any component of GW679769 has previously received an NK₁ receptor antagonist has received any investigational drug within 30 days or 5 half‐lives (whichever is longer) before receiving first dose of study medication and/or scheduled to receive any investigational drug during the study has received moderately and/or highly emetogenic medication within 48 h before first dose of study medication. Opioid narcotics for cancer pain will be permitted if patient has been receiving a stable dose of such medication for at least 7 days and has experienced neither emesis nor nausea from the narcotics has taken/received palonosetron within 7 days before initial dose of study medication/investigational product has taken/received any medication with known or potential antiemetic activity within the 24‐h period before receiving study drug. This includes, but is not limited to has taken/received strong or moderate inhibitors of CYP3A4 and CYP3A5 within the following duration before first administration of GW679769 investigational product or aprepitant two (2) days: clarithromycin, diltiazem, erythromycin, grapefruit juice, ketoconazole, verapamil fourteen (14) days: fluconazole, itraconazole has taken/received inducers of CYP3A4 within 14 days before first dose of study medication including carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, barbiturates, efavirenz, nevirapine, St. John’s wort, and troglitazone abnormal laboratory values in AST and/or ALT > 2.5 × ULN without known liver metastases, > 5.0 × ULN with liver metastases Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: solid tumours Chemotherapy regimen: cisplatin‐based chemotherapy Country: 47 centres in 18 countries (multi‐centre)
Interventions	Experimental: arm A casopitant 50 mg + ondansetron + dexamethasone Experimental: arm B casopitant 100 mg + ondansetron + dexamethasone Experimental: arm C casopitant 150 mg + ondansetron + dexamethasone
Outcomes	Primary outcome proportion of patients who achieved complete response (defined as no vomiting, no retching, no rescue therapy, no premature discontinuation from the study) during the 120‐h evaluation period following initiation of highly emetogenic cisplatin‐based chemotherapy Secondary outcomes proportion of patients with complete response during acute (0 to 24 h) and delayed (24 to 120 h) phases proportion of patients with complete protection (no vomiting, no retching, no rescue therapy, no premature withdrawal, maximum nausea < 25 on VAS) vomiting during overall (0 to 120 h), acute (0 to 24 h), and delayed (24 to 120 h) phases proportion of patients with significant nausea (maximum nausea VAS ≥ 25) during acute, delayed, and overall phases nausea (maximum nausea VAS ≥ 5) during acute, delayed, and overall phases time to emesis time to rescue safety assessments patient satisfaction questionnaire population pharmacokinetic/pharmacodynamic parameters for GW679769 and its metabolite GSK525060
Notes	sponsor: GlaxoSmithKline Group of Companies EUCTR2004‐000371‐34

EUCTR2004‐001020‐20.

Methods	Randomised, placebo‐controlled, dose‐ranging study Recruitment period: February 2005 to n.r. target sample size: 708 Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria male or female not of child‐bearing potential (i.e. physically incapable of becoming pregnant, including postmenopausal females and those who have attained such status via surgical means) or pre‐menopausal women who demonstrate negative serum or negative urine pregnancy test within 24 h before first administration of any study medication or GW679769 investigational product, agreeing to: abstain from sexual intercourse for two (2) weeks before administration of first dose of study medication or GW679769 investigational product until 30 days after final dose of study medication or GW679769 investigational product use hormonal methods of birth control (e.g. oral, injectable, implantable) or other highly effective method of contraception (e.g. intrauterine device (IUD)) in conjunction with a barrier method of contraception (condom, spermicidal foam, sponge, gel, diaphragm) if engaging in sexual intercourse for at least seven (7) days before first dose of study medication or GW679769 investigational product and continuing until 30 days after final dose of study medication or GW679769 investigational product at least 18 years of age diagnosed malignant solid tumour, and scheduled to receive first course of chemotherapy Karnofsky performance scale score ≥ 70 haematological and metabolic status must be adequate for receiving moderately emetogenic chemotherapy regimen previously described and must meet the following criteria: WBC > 3000/mm³ platelets > 100,000/mm³ absolute neutrophil count (ANC) > 1500/mm³ serum creatinine < 1.5 mg/dL liver enzymes must be below the following limits: without known liver metastases: AST and/or ALT < 2.5 × ULN with known liver metastases: AST and/or ALT < 5.0 × ULN able and willing to complete daily components of subject diary on study Day 1 and until the end of the 120‐h follow‐up assessment period (beginning at initiation of chemotherapy on study Day 1) available to respond to daily follow‐up contacts by study personnel and to complete a study Day 6 to 10 visit should understand the nature and purpose of this study and study procedures and should signed an informed consent form for this study to indicate this understanding Exclusion criteria previously received cytotoxic chemotherapy scheduled to receive highly emetogenic chemotherapeutic agents as defined by this protocol scheduled to receive adjuvant chemotherapy with cyclophosphamide‐containing regimens pregnant or lactating unwillingness of the male to use a condom with spermicide in addition to having female partner use another form of contraception such as an IUD, a diaphragm with spermicide, oral contraceptives, injectable progesterone, subdermal implants, or a tubal ligation if the woman could become pregnant from the time of the first dose of GW679769 investigational product until 84 days following administration of the final dose of GW679769 investigational product received radiation therapy to abdomen or pelvis in the seven (7) days before receiving first dose of study medication or GW679769 investigational product and/or will receive radiation therapy to abdomen or pelvis in the six (6) days following first dose of study medication or GW679769 investigational product has experienced emesis (i.e. vomiting and/or retching) or clinically significant nausea in the 24 h before receiving first dose of any study medication or GW679769 investigational product known central nervous system primary or metastatic malignancy aetiology for emesis and nausea including, but not limited to, gastrointestinal obstruction, increased intracranial pressure, hypercalcaemia, and/or active peptic ulcer known history of peptic ulcer disease active systemic infection or any uncontrolled disease (other than malignancy) that, in the opinion of the Investigator, may confound results of the study or pose unwarranted risk to the subject. Subjects with previous, but not current, history of alcoholism may be permitted provided that, in the investigator's opinion, the subject's disease state will not confound results of the study initiated systemic corticosteroid therapy at any dose within 72 h before receiving first dose of study medication or GW679769 investigational product except when indicated as prophylactic medication for taxane therapy known hypersensitivity or contraindication to ondansetron hydrochloride or ondansetron, another 5‐HT₃ receptor antagonist, dexamethasone, or any component of GW679769 or GW679769B previously received an NK₁ receptor antagonist, with the exception of GW679769 previously administered in study cycles for subjects continuing study participation beyond Cycle 1 received an investigational drug in previous 30 days or scheduled to receive any investigational drug in addition to GW679769 during the study period, with the exception of GW679769 previously administered in study cycles for subjects continuing study participation beyond Cycle 1 has taken/received any medication of moderate or high emetogenic potential within 48 h before first dose of study medication Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: solid malignancy Chemotherapy regimen: MEC Country: Czech Republic, Germany, Hungary, Ireland, Spain, United Kingdom
Interventions	oral neurokinin₁ receptor antagonist, GW679769, administered as 50 mg, 100 mg, and 150 mg oral tablets in combination with ondansetron hydrochloride and dexamethasone
Outcomes	Primary endpoints proportion of subjects who achieve complete response (defined as no vomiting, no retching, no rescue therapy, and no premature discontinuation from the study) for each treatment arm during the 120‐h evaluation period following initiation of moderately emetogenic chemotherapy proportion of subjects experiencing significant nausea during the 120‐h evaluation period following initiation of first cycle of moderately emetogenic chemotherapy, as assessed by a visual analogue scale (VAS) Secondary objectives to quantify the impact on daily life activities of oral GW679769 when administered in combination with ondansetron hydrochloride and dexamethasone during the first 120 h to subjects receiving their first cycle of moderately emetogenic chemotherapy to evaluate population pharmacokinetics and pharmacodynamics of oral GW679769 and its active metabolites when administered in combination with ondansetron hydrochloride and dexamethasone to subjects receiving their first cycle of moderately emetogenic chemotherapy
Notes	main ID: EUCTR2004‐001020‐20‐ES primary sponsor: GlaxoSmithKline Group of Companies

EUCTR2004‐004956‐38.

Methods	Randomised, placebo‐controlled study with 2 arms comparison of aprepitant + granisetron + dexamethasone vs placebo + granisetron + dexamethasone Recruitment period: June 2005 to n.r. target sample size: 362 Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria men and women ≥ 18 years of age multiple myeloma receiving high‐dose chemotherapy (melphalan) and autologous peripheral stem cell transplantation signed informed consent Exclusion criteria nausea and vomiting during the last 12 h before planned high‐dose chemotherapy receiving antiemetics 24 h before planned high‐dose chemotherapy intake of steroids history of hypersensitivity to the investigational product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational product simultaneous intake of pimozide, terfenadine, astemizole pregnant or nursing woman mental condition rendering the subject incapable to understand the nature, scope, and possible consequences of the study non‐compliance in completing the subject's diary and FLIE score Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: multiple myeloma Chemotherapy regimen: high‐dose melphalan Country: Germany (single centre)
Interventions	Experimental: arm A aprepitant + granisetron + dexamethasone Experimental: arm B placebo + granisetron + dexamethasone
Outcomes	Primary outcome overall complete response (no emesis and no rescue therapy) during and post chemotherapy (0 to 120 h) Secondary outcomes evaluation of effects on emesis in acute and delayed phases during and post chemotherapy evaluation of effects on vomiting regardless of use of rescue therapy for episodes of nausea (no or no significant nausea) use of rescue therapy impact on daily life safety and tolerability of study medication
Notes	main ID: EUCTR2004‐004956‐38‐DE primary sponsor: Gerlinde Egerer (MD); Internal Medicine, Department V

EUCTR 2005‐000137‐37‐cz 2005.

Methods	Randomised, parallel‐group, cross‐over study with 3 arms comparison of palonosetron 0.25 mg + dexamethasone vs palonosetron 0.50 mg + dexamethasone vs palonosetron 0.75 mg + dexamethasone Recruitment period: September 2009 to n.r. target sample size: 640 Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria male or female ≥ 18 years of age histologically or cytologically confirmed malignant disease naïve or non‐naïve to cancer chemotherapy if non‐naïve, must have experienced no more than mild nausea and no vomiting following any previous chemotherapy cycle Karnofsky index ≥ 50% scheduled to receive a single intravenous dose of ≥ 1 of the following agents administered on Day 1: any dose of oxaliplatin, carboplatin, epirubicin, idarubicin, doxorubicin, ifosfamide, irinotecan, or daunorubicin; or cyclophosphamide < 1500 mg/m² or cytarabine > 1 g/m² scheduled to receive the most emetogenic chemotherapeutic agent during maximum of 4 hours written informed consent (with additional legal representative’s or parent’s consent if required) known hepatic, renal, or cardiovascular impairment and scheduled to receive above mentioned chemotherapeutic agents ‐ may be enrolled in this study at the discretion of the investigator known history or predisposition to cardiac conduction interval abnormalities, including QTc ‐ may be enrolled in the study at the discretion of the investigator female of childbearing potential ‐ must be using reliable contraceptive measures with negative pregnancy test at pre‐treatment (screening) visit Exclusion criteria inability to understand or cooperate with study procedures any investigational drugs within 30 days before the start of study treatment any drug with potential antiemetic efficacy (5‐HT₃ receptor antagonists, aprepitant, metoclopramide, phenothiazine antiemetics (such as prochlorperazine, thiethylperazine, and perphenazine), scopolamine, diphenhydramine, chlorpheniramine maleate, trimethobenzamide, all benzodiazepines except for triazolam or zolpidem used once nightly for sleep, haloperidol, droperidol, tetrahydrocannabinol, nabilone, any corticosteroid (such as dexamethasone, hydrocortisone, methylprednisolone, and prednisone) within 24 h of the start of study treatment any antacid medication within 24 h of the start of study treatment any vomiting, retching, or NCI Common Toxicity Criteria grade 2 or 3 nausea in the 24 h preceding chemotherapy treatment with US, EU, or Mexican commercially available i.v. palonosetron 0.25 mg (Aloxi; Onicit) within 2 weeks before the start of study treatment enrolment in a previous study with palonosetron ongoing vomiting from any organic aetiology presence of clinically unstable seizure disorder with seizure activity requiring anticonvulsant medication (prophylactic anticonvulsant medication is allowed for patients free of seizure activity) any moderately or highly emetogenic chemotherapy or radiotherapy received within 1 week before the start of study treatment scheduled to receive: orally or intravenously: any dose of cisplatin, dacarbazine, streptozotocin, carmustine, mechlorethamine, hexamethylmelamine, or procarbazine; or cyclophosphamide ≥ 1500 mg/m² during Days 1 to 5 of the study radiotherapy of upper abdomen or cranium or total body irradiation during Days 1 to 5 of the study docetaxel, paclitaxel, or pemetrexed on Day 1 in association with corticosteroids for prevention of hypersensitivity reactions any low‐level emetogenic chemotherapeutic agent during Days 2 to 5, if this chemotherapy, in the investigator's opinion, requires co‐administration of antiemetics known contraindication to 5‐HT₃ receptor antagonists Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: histologically or cytologically confirmed malignant disease Chemotherapy regimen any dose of oxaliplatin, carboplatin, epirubicin, idarubicin, doxorubicin, ifosfamide, irinotecan, or daunorubicin or cyclophosphamide < 1500 mg/m² or cytarabine > 1 g/m² Country: n.r.
Interventions	Cross‐over study Experimental: arm A palonosetron 0.25 mg + dexamethasone 8 mg Experimental: arm B palonosetron 0.50 mg + dexamethasone 8 mg Experimental: arm C palonosetron 0.75 mg + dexamethasone 8 mg
Outcomes	Primary endpoint proportion of patients considered to have achieved complete response (CR) [Time frame: 0 to 24 hours] Secondary endpoints complete response daily for the 24‐h to 120‐h interval, for cumulative time periods (except 24 to 120 hours) and for the overall 0 to 120‐hour interval (Days 1 to 5) complete control (defined as complete response and no more than mild nausea) daily and cumulative for the 0 to 120‐h interval, for the overall 0 to 120‐h interval (Days 1 to 5), and for the 24 to 120‐h period number of emetic episodes daily for the 0 to 120‐h interval and for the overall 0 to 120‐h interval (Days 1 to 5) time to first emetic episode time to first administration of rescue therapy time to treatment failure (time to first emetic episode or to administration of rescue therapy, whichever will occur first) Additional secondary outcomes adverse events vital signs physical examination 12‐lead ECG clinical laboratory parameters
Notes	main ID: EUCTR2005‐000137‐37‐CZ sponsor: Helsinn Healthcare SA

EUCTR2006‐000781‐37.

Methods	Randomised, phase 3, active‐controlled study Masking: double‐blind Baseline patient characteristics: reported
Participants	Inclusion criteria  understands the nature and purpose of this study and study procedures and has signed an informed consent form for this study to indicate this understanding at least 18 years of age scheduled to receive first course of an anthracycline and cyclophosphamide‐containing moderately emetogenic chemotherapy regimen for treatment of a solid malignant tumour Karnofsky performance status ≥ 70 haematological and metabolic status must be adequate for receiving a moderately emetogenic regimen and must meet the following criteria: total neutrophils ≥ 1500/mm³ (standard units ≥ 1.5 × 10⁹/L) platelets ≥ 100,000/mm³ (standard units ≥ 100.0 × 10⁹/L) bilirubin ≤ 1.5 × ULN liver enzymes must be below the following limits: without known liver metastases: AST and/or ALT ≤ 2.5 × ULN with known liver metastases: AST and/or ALT ≤ 5.0 × ULN willing and able to complete daily components of the subject diary for each study cycle women of child‐bearing potential must commit to consistent and correct use of an acceptable method of birth control Exclusion criteria previously received cytotoxic chemotherapy ‐ history of previous biological or hormonal therapy will be permitted pregnant or lactating received radiation therapy to the brain, abdomen, or pelvis in the 10 days before first dose of study medication or casopitant investigational product and/or will receive radiation therapy to the brain, abdomen, or pelvis in the 6 days following first dose of study medication (ZOFRAN and dexamethasone) or casopitant investigational product scheduled to receive taxane therapy during Cycle 1 ‐ note that subjects will be permitted to receive taxane therapy in conjunction with 1 of the allowed MEC regimens during subsequent cycles has experienced emesis (i.e. vomiting and/or retching) or clinically significant nausea in the 24 h preceding first dose of study medication or casopitant investigational product known central nervous system primary or metastatic malignancy, unless successfully treated with excision or radiation, and medically stable for at least 1 week before receiving first dose of study medication or casopitant investigational product history of documented peptic ulcer disease (via endoscopy or X‐ray), active peptic ulcer disease, gastrointestinal obstruction, gastrointestinal carcinoma, increased intracranial pressure, hypercalcaemia, or any uncontrolled medical condition (other than malignancy) that, in the opinion of the investigator, may confound results of the study, represent another potential aetiology for emesis and nausea (other than CINV), or pose unwarranted risk to the subject known hypersensitivity or contraindication to ZOFRAN, another 5‐HT₃ receptor antagonist, dexamethasone, or any component of casopitant previously received an NK₁ receptor antagonist received an investigational drug in previous 30 days or scheduled to receive any investigational drug other than casopitant during the study period has taken/received any medication of moderate or high emetogenic potential within 48 h before first dose of study medication or casopitant investigational product ‐ opioid narcotics for cancer pain will be permitted if the subject has been on a stable dose and has not experienced emesis or nausea from the narcotics has taken/received any medication with known or potential antiemetic activity within the 24‐h period before receiving study drug  has taken/received strong or moderate inhibitors of CYP3A4 and CYP3A5 for a specified period before administration of casopitant investigational product has taken/received inducers of CYP3A4 and CYP3A5 within 14 days before administration of casopitant investigational product is taking the antidiabetic agent repaglinide or the diuretic torsemide ‐ investigators are advised to exercise caution if including patients taking the antidiabetic agent rosiglitazone or pioglitazone, or antimalarial agents such as chloroquine and amodiaquine, as the metabolite of casopitant is a potential inhibitor of CYP2C8 Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: n.r. Chemotherapy regimen: MEC Country: 196 centres in 32 countries (multi‐centre)
Interventions	casopitant + ondansetron + dexamethasone
Outcomes	Primary endpoints complete response, defined as no vomiting/retching and no rescue therapy over the first 120 h following initiation of the first cycle of MEC Secondary endpoints for Cycle 1  complete response in acute (0 to 24 h) and delayed (24 to 120 h) phases vomiting nausea (by visual analogue scale or categorical scale) complete protection (complete responders who had no significant nausea) total control (complete responders who had no nausea) in overall (0 to 120 h), acute (0 to 24 h), and delayed (24 to 120 h) phases rescue medication use time to first emetic event/rescue medication use health outcomes measures
Notes	sponsor: GlaxoSmithKline Research and Development Ltd. EUCTR2006‐000781‐37‐sk

EUCTR2006‐003512‐22.

Methods	Randomised, parallel‐group study Recruitment period: November 2006 to n.r. target sample size: 700 Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria at least 18 years of age histologically or cytologically confirmed malignant disease naïve to emetogenic cancer chemotherapy of moderate or high level per Hesketh scheduled to be treated with a single dose of 1 of the following moderately emetogenic chemotherapy agents (given intravenously) on treatment Day 1: oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, or mitoxantrone methotrexate (> 250 mg/m²) cyclophosphamide (< 1500 mg/m²) doxorubicin (> 25 mg/m²) Karnofsky score ≥ 60 Exclusion criteria scheduled to receive any dose of cisplatin has received or will receive radiation therapy to abdomen or pelvis in the week before Day 1 through Day 6 has vomited in the 24 h before Day 1 Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: solid malignancy Chemotherapy regimen oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, or mitoxantrone methotrexate (> 250 mg/m²) cyclophosphamide (< 1500 mg/m²) doxorubicin (> 25 mg/m²) Country: France, Germamy
Interventions	aprepitant, fosaprepitant, ondansetron, dexamethasone
Outcomes	Primary endpoints no vomiting in the 120 h following initiation of MEC complete response (no vomiting and no use of rescue therapy) in the 120 h following initiation of MEC Secondary objectives to demonstrate that the aprepitant regimen is superior to the control regimen in terms of time to first vomiting episode in the overall period to demonstrate that the aprepitant regimen is superior to the control regimen in terms of proportions of patients with: no vomiting (acute and delayed) complete response (acute and delayed) no use of rescue therapy (overall, acute, and delayed) no impact on daily life (FLIE score > 108) (overall) no vomiting and no significant nausea (VAS < 25 mm) (overall)
Notes	main ID: EUCTR2006‐003512‐22‐FR primary sponsor: Laboratoires Merck Sharp & Dohme‐Chibret

EUCTR2007‐004043‐30.

Methods	Randomised, active‐controlled, parallel‐group study Recruitment period: March 2008 to n.r. target sample size: 2292 Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria female or male 18 years of age or older scheduled to receive first course of cisplatin chemotherapy for a documented solid malignancy at a dose ≥ 70 mg/m² Karnofsky score ≥ 60 able to understand study procedures and agrees to participate in the study by giving written informed consent Exclusion criteria symptomatic primary or metastatic CNS malignancy has received or is scheduled to receive radiation therapy to abdomen or pelvis in the week before treatment Day 1 through Day 6 has vomited in the 24 h before treatment Day 1 is to receive multiple‐day chemotherapy with cisplatin in a single cycle is to receive chemotherapy of moderate or high emetogenicity (per Hesketh Classification of Emetogenic Chemotherapy Agents) during the 6 days before cisplatin infusion and/or during the 6 days following cisplatin infusion Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: solid malignancy Chemotherapy regimen: cisplatin Country: Denmark, Germany, Hungary, Italy, Lithuania, Netherlands, Poland, Portugal, Spain, Sweden
Interventions	single dose of intravenous MK‐0517
Outcomes	Primary endpoints fosaprepitant dimeglumine is non‐inferior to the aprepitant regimen with respect to the proportion of patients with complete response (no vomiting and no use of rescue therapy) overall (in the 120 h following initiation of cisplatin) single‐dose fosaprepitant dimeglumine regimen is well tolerated in the first cycle of cisplatin‐based HEC Secondary objectives to compare the single‐dose fosaprepitant dimeglumine regimen and the aprepitant regimen in terms of proportions of patients with complete response (no vomiting and no use of rescue therapy) in the delayed phase (25 to 120 h following initiation of cisplatin)
Notes	main ID: EUCTR2007‐004043‐30‐ES primary sponsor: Merck Sharp & Dohme de España, S.A.

EUCTR2007‐005169‐36.

Methods	Randomised, parallel‐group study Recruitment period: February 2008 to n.r. target sample size: 720 Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria understands the nature and purpose of this study and study procedures and has signed an informed consent form for this study to indicate this understanding at least 18 years of age scheduled to receive oxaliplatin at a dose between 85 mg/m² and 130 mg/m² in the first cycle of therapy for treatment of colorectal cancer, administered as a single i.v. dose over 2 to 6 h on Day 1 only, in combination with 5‐FU/LV, or in combination with capecitabine ECOG performance status 0, 1, or 2 haematological and metabolic status adequate for receiving an oxaliplatin‐based moderately emetogenic regimen and meeting the following criteria: total neutrophils 1500/mm³ platelets 100,000/mm³ bilirubin 1.5 × ULN serum creatinine 1.5 mg/dL creatinine clearance 60 mL/min without known liver metastases: AST and/or ALT 2.5 × ULN with known liver metastases: AST and/or ALT 5.0 × ULN willing and able to complete daily components of the subject diary for Cycle 1 and Cycle 2 without assistance from others female eligible to enter and participate in this study if: of non‐child‐bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is postmenopausal) of child‐bearing potential: must have negative serum pregnancy test result or negative urine dipstick pregnancy test within 24 h before first dose of investigational product on Cycle 1 Day 1 of child‐bearing potential with commitment to consistent and correct use of an acceptable method of birth control using GSK acceptable contraceptive methods, consistently and in accordance with both product label and instructions of the physician, as follows: male partner who is sterile before entry of female into the study and is the sole sexual partner for that female oral contraceptives (e.g. oral, injectable, implantable) with double‐barrier method of contraception consisting of spermicide with condom or diaphragm for a period after the trial to account for a potential drug interaction (minimum 6 weeks) double‐barrier method of contraception consisting of spermicide with condom or diaphragm intrauterine device with documented failure rate < 1% per year complete abstinence from intercourse for 2 weeks before exposure to investigational product throughout the clinical trial, and for a period after the trial to account for elimination of the drug (minimum 3 days) will remain abstinent during the period described above ‐ must agree to follow GSK guidelines Exclusion criteria has received cytotoxic chemotherapy before first study cycle of chemotherapy, with the exception that previous adjuvant therapy with 5‐FU/LV or capecitabine is permitted, provided that the last dose of adjuvant therapy was completed at least 6 months before first dose of study medication or investigational product scheduled to receive chemotherapy with any cytotoxic agents or biological agents other than the protocol‐allowed chemotherapy described in inclusion criteria (above) pregnant or lactating has received radiation therapy in the 10 days before first dose of study medication or investigational product and/or scheduled to receive such radiation therapy in the 6 days following first dose of study medication or investigational product in the first cycle of chemotherapy has experienced emesis or clinically significant nausea in the 24 h preceding first dose of study medication or investigational product for each cycle of chemotherapy has known central nervous system metastasis, unless previously successfully treated with excision or radiation, and has been stable for at least 1 week immediately before receiving first dose of study medication or investigational product has increased intracranial pressure, hypercalcaemia, active systemic infection, or any uncontrolled medical condition (other than malignancy) that, in the opinion of the investigator, may confound results of the study, represent another potential aetiology for emesis and nausea (other than CINV), or pose unwarranted risk to the subject known hypersensitivity or contraindication to ondansetron, another 5‐HT₃ receptor antagonist, dexamethasone, or any component of casopitant has received an NK₁ receptor antagonist before first study cycle of chemotherapy has received an investigational drug within previous 30 days or 5 half‐lives (whichever is longer) before receiving first dose of study medication or investigational product, or scheduled to receive any investigational drug other than casopitant/placebo during the study period has taken/received any medication of moderate or high emetogenic potential within the 48 h before first dose of study medication or investigational product in each cycle has taken/received any medication with known or potential antiemetic activity within the 24‐h period (unless otherwise stated) before receiving first dose of study medication or investigational product or expected to require use of such medication during the 120‐h assessment period for Cycle 1 of therapy only. This includes, but is not limited to: 5‐HT₃ receptor antagonists ‐ palonosetron is not permitted within 7 days before administration of study medication or investigational product benzamide/benzamide derivatives benzodiazepines (except if receiving such medication for sleep or anxiety and has on a stable dose for at least 7 days before first dose of investigational product; however, lorazepam is prohibited for 24 h) Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: colorectal cancer Chemotherapy regimen: oxaliplatin at a dose between 85 mg/m² and 130 mg/m² Country: Bulgaria, Czech Republic, Germany, Hungary. Italy, Slovakia
Interventions	casopitant + ondansetron + dexamethasone
Outcomes	Primary endpoint proportion of subjects who achieve complete response in the overall phase (0 to 120 h) Secondary objectives prevention of emesis over acute (0 to 24 h) and delayed (24 to 120 h) phases following initiation of first cycle prevention of emesis over the overall (0 to 120 h) phase following second cycle control of nausea over overall, acute, and delayed phases following initiation of first cycle
Notes	main ID: EUCTR2007‐005169‐36‐SK primary sponsor: GlaxoSmithKline Research and Development Limited

EUCTR2008‐001339‐37.

Methods	Randomised, parallel‐group study Recruitment period: April 2008 to n.r. target sample size: 560 Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria submitted for the first time to cisplatin chemotherapy administered in a single dose over 18 years old signed informed consent Exclusion criteria submitted on Days 2 to 4 after cisplatin to other antineoplastic agents except for 5‐fluorouracil, VP16, VM26, vincristine, vinblastine, vindesine, vinorelbine, gemcitabine already submitted to cisplatin serious disease or predisposition to emesis such as gastrointestinal obstruction, active peptic ulcer, hypercalcaemia, and brain metastasis contraindication to dexamethasone administration (i.e. active peptic ulcer, previous blooding from peptic ulcer) receiving concomitant radiotherapy Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: malignancy Chemotherapy regimen: cisplatin Country: Italy
Interventions	aprepitant
Outcomes	Primary endpoint percentage of complete responses (no vomiting and no rescue treatment) on Days 2 to 5 after cisplatin administration Secondary objectives evaluation of impact on quality of life of the 2 antiemetic regimens evaluation of prognostic factors for delayed emesis in patients receiving a combination of aprepitant, palonosetron, and dexamethasone for prevention of acute emesis
Notes	main ID: EUCTR2008‐001339‐37‐IT primary sponsor: azienda ospedaliera s. maria di terni

EUCTR2009‐016775‐30.

Methods	Randomised, phase 3, active‐controlled, parallel‐group study with 2 arms comparison of netupitant + palonosetron + dexamethasone vs palonosetron + dexamethasone Recruitment period: April 2011 to November 2012 Sample size: 726 Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria signed written informed consent male or female 18 years of age or older naïve to cytotoxic chemotherapy ‐ previous biological or hormonal therapy is permitted scheduled to receive first course of an anthracycline and cyclophosphamide‐containing MEC regimen for treatment of a solid malignant tumour: i.v. cyclophosphamide (500 to 1500 mg/m²) and i.v. doxorubicin (≥ 40 mg/m²) or i.v. cyclophosphamide (500 to 1500 mg/m²) and i.v. epirubicin (≥ 60 mg/m²) ‐ If scheduled to receive chemotherapy agents of minimal to low emetogenic potential, they could be given on any day ECOG performance status 0, 1, or 2 female of non‐child‐bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is postmenopausal), or of child‐bearing potential with negative urine dipstick pregnancy test within 24 h before first dose of investigational product of Day 1 and with commitment to consistent and correct use throughout the clinical trial of one of  the recommended contraceptive methods haematological and metabolic status adequate for receiving a moderately emetogenic regimen and meeting the following criteria: total neutrophils ≥ 1500/mm³ (standard units: ≥ 1.5 × 10⁹/L) platelets ≥ 100,000/mm³ (standard units: ≥ 100.0 × 10⁹/L) bilirubin ≤ 1.5 × ULN liver enzymes without known liver metastases, AST and/or ALT ≤ 2.5 × ULN with known liver metastases, AST and/or ALT ≤ 5.0 × ULN serum creatinine ≤ 1.5 mg/dL (standard units: ≤ 132.6 micromol/L) or creatinine clearance ≥ 60 mL/min able to read, understand, and follow study procedures and complete patient diary Exclusion criteria pregnant or lactating current use of illicit drugs or current evidence of alcohol abuse scheduled to receive any highly emetogenic chemotherapy (HEC) from Day 1 to Day 5, or moderately emetogenic chemotherapy (MEC) from Day 2 to Day 5, following the allowed MEC regimen received or scheduled to receive radiation therapy to abdomen or the pelvis within 1 week before Day 1 or between Days 1 and 5 in Cycle 1 any vomiting, retching, or mild nausea (grade ≥ 1 as defined by National Cancer Institute) within 24 h before Day 1 symptomatic primary or metastatic CNS malignancy active peptic ulcer disease, gastrointestinal obstruction, increased intracranial pressure, hypercalcaemia, active infection, or any uncontrolled medical condition (other than malignancy) that, in the opinion of the investigator, may confound results of the study, represent another potential aetiology for emesis and nausea (other than chemotherapy‐induced nausea and vomiting, CINV), or pose unwarranted risk in administering study drugs to the patient known hypersensitivity or contraindication to 5‐HT₃ receptor antagonists (e.g. palonosetron, ondansetron, granisetron, dolasetron, tropisetron, ramosetron) or dexamethasone previously received an NK₁ receptor antagonist (e.g. aprepitant, casopitant) participated in a clinical trial involving oral netupitant administered in combination with palonosetron any investigational drug taken within 4 weeks before Day 1 Cycle 1 and/or scheduled to receive any investigational drug during the study systemic corticosteroid therapy at any dose within 72 h before Day 1 Cycle 1. However topical and inhaled corticosteroids with steroid dose ≤ 10 mg prednisone daily or its equivalent are permitted scheduled to receive bone marrow transplantation and/or stem cell rescue therapy any medication with known or potential antiemetic activity within 24 hours before Day 1 Cycle 1 scheduled to receive any strong or moderate inhibitor of CYP3A4 or its intake within 1 week before Day 1 scheduled to receive any of the following CYP3A4 substrates: terfenadine, cisapride, astemizole, pimozide scheduled to receive any CYP3A4 inducer or its intake within 4 weeks before Day 1 history or predisposition to cardiac conduction abnormalities, except for incomplete right bundle branch block history of risk factors for torsades de pointes (heart failure, hypokalaemia, family history of long QT syndrome) severe cardiovascular disease, including myocardial infarction within 3 months before Day 1, unstable angina pectoris, significant valvular or pericardial disease, history of ventricular tachycardia, symptomatic congestive heart failure (CHF) NYHA Class III to IV, severe uncontrolled arterial hypertension any illness or condition that, in the opinion of the investigator, may confound results of the study or pose unwarranted risk in administering the investigational product to the patient concurrent medical condition that would preclude administration of dexamethasone, such as systemic fungal infection or uncontrolled diabetes Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: solid tumours Chemotherapy regimen: MEC Countries: Argentina, Brazil, Bulgaria, Croatia, Germany, Hungary, India, Italy, Mexico, Poland, Romania, Russian Federation, Ukraine, United States
Interventions	Experimental: arm A netupitant + palonosetron + dexamethasone Experimental: arm B palonosetron + dexamethasone
Outcomes	Primary endpoint proportion of patients with CR (defined as no emesis, no rescue medication) in the delayed phase (time interval 25 to 120 h after start of MEC administration) at Cycle 1 Secondary endpoints  CR during acute phase (0 to 24 h) CR during overall phase (0 to 120 h) proportion of patients with no emesis during delayed, acute, and overall phases proportion of patients with no rescue medication during delayed, acute, and overall phases proportion of patients with no significant nausea (visual analogue scale (VAS) < 25 mm) during delayed, acute, and overall phases proportion of patients with no nausea (VAS < 5 mm) during delayed, acute, and overall phases proportion of patients with complete protection (no emesis, no rescue medication, and no significant nausea (maximum nausea VAS < 25 mm)) during delayed, acute, and overall phases proportion of patients with total control (no emesis, no rescue medication, and no nausea (maximum VAS < 5 mm)) during delayed, acute, and overall phases severity of nausea, defined as maximum nausea on the VAS in acute, delayed, and overall phases time to first emetic episode, time to first rescue medication intake, and time to treatment failure (based on time to first emetic episode or time to first rescue medication intake, whichever occurs first) impact on daily life activities for the first 120 h following administration of MEC as assessed by the Functional Living Index‐Emesis (FLIE) questionnaire
Notes	EUCTR2009‐016775‐30 (NETU‐08‐18) Helsinn Healthcare SA

EUCTR2009‐017603‐28.

Methods	Randomised, phase 3, placebo‐controlled study Recruitment period: February 2010 to n.r. target sample size: n.r. Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria male or female ≥ 18 years of age able to understand study procedures and agrees to participate in the study by giving written informed consent scheduled to receive a highly emetogenic cyclophosphamide i.v. chemotherapy (3 g/m²) for autologous PBSC harvesting Karnofsky score ≥ 60 normal hepatic function (bilirubin < 1.5 mg/dL) and renal function (creatinine < 2 mg/dL) normal ECG HBV‐, HCV‐, and HIV‐negative negative urine pregnancy test for women of childbearing age Exclusion criteria serious accompanying disorder or impaired organ function (in particular, impaired left ventricular function or severe cardiac arrhythmia) platelets < 100,000/mm³, leukocytes < 2500/mm³ known hypersensitivity to medications to be used known HIV positivity active hepatitis infection pregnancy and lactation periods Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: multiple myeloma, Hodgkin lymphoma, non‐Hodgkin lymphoma Chemotherapy regimen: cyclophosphamide i.v. chemotherapy (3 g/m²) Country: Italy
Interventions	aprepitant
Outcomes	Primary endpoint complete response (CR) rate in first 120 h post chemotherapy Secondary objective to monitor peripheral blood stem cell harvest
Notes	main ID: EUCTR2009‐017603‐28‐IT primary sponsor: AZIENDA OSPEDALIERA DI PERUGIA

EUCTR2010‐023297‐39.

Methods	Randomised, phase 3, double‐blind, active‐control study Recruitment period: July 2011 to September 2012 Sample size: 309 Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria signed written informed consent male or female 18 years of age or older naïve to cytotoxic chemotherapy ‐ previous biological or hormonal therapy is permitted diagnosed malignant tumour scheduled to receive repeated consecutive courses of chemotherapy ‐ a single dose of 1 or more of the following agents administered on Day 1 is allowed (see protocol) scheduled to receive combination regimens; the most emetogenic agent according to MASCC/ESMO Antiemetic Guidelines 2010 is to be given first on Day 1 and infusion must be completed within 6 h; If scheduled to receive chemotherapy agents of minimal to low emetogenic potential (Appendix 4), they are to be given on Day 1 following the most emetogenic agent, or on any subsequent study day ECOG performance status 0, 1, or 2 (Appendix 5) female patients of non‐child‐bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is postmenopausal) haematological and metabolic status adequate for receiving a chemotherapy regimen and fulfilment of the following criteria: total neutrophils ≥ 1500/mm³ (standard units: ≥ 1.5 × 10⁹/L) platelets ≥ 100,000/mm³ (standard units: ≥ 100.0 × 10⁹/L) bilirubin ≤ 1.5 × ULN liver enzymes: without known liver metastases, AST and/or ALT ≤ 2.5 × ULN with known liver metastases, AST and/or ALT < 5.0 × ULN serum creatinine ≤ 1.5 mg/dL (standard units: ≤ 132.6 micromol/L) or creatinine clearance ≥ 60 mL/min able to read, understand, and follow study procedures and complete patient diary Exclusion criteria lactating or pregnant (i.e. positive urine dipstick pregnancy test within 24 h before Day 1 of each cycle) current use of illicit drugs or current evidence of alcohol abuse scheduled to receive i.v. cyclophosphamide (500 to 1500 mg/m²) and i.v. doxorubicin (≥ 40 mg/m²) or i.v. cyclophosphamide (500 to 1500 mg/m²) and i.v. epirubicin (≥ 60 mg/m²) scheduled to receive moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) from Day 2 to Day 5 following Day 1 chemotherapy administration active infection or uncontrolled disease except for malignancy that may pose unwarranted risk in administering study drugs to the patient known hypersensitivity or contraindication to 5‐HT₃ receptor antagonists (e.g. palonosetron, ondansetron, granisetron, dolasetron, tropisetron, ramosetron) or dexamethasone previously received an NK₁ receptor antagonist (e.g. aprepitant, casopitant) participated in a clinical trial involving oral netupitant administered in combination with palonosetron any investigational drugs taken within 4 weeks before Day 1 Cycle 1 and/or scheduled to receive any investigational drug during the study systemic corticosteroid therapy at any dose within 72 h before Day 1 Cycle 1. However, topical and inhaled corticosteroids with a steroid dose ≤ 10 mg prednisone daily or its equivalent are permitted. Non‐study drug dexamethasone as pre‐medication in patients scheduled to receive taxanes is allowed scheduled to receive bone marrow transplantation and/or stem cell rescue therapy or any strong or moderate inhibitor of CYP3A4 or its intake within 1 week before Day 1 scheduled to receive any of the following CYP3A4 substrates: terfenadine, cisapride, astemizole, pimozide; scheduled to receive any CYP3A4 inducer or its intake within 4 weeks before Day 1 history of or predisposition to cardiac conduction abnormalities, except for incomplete right bundle branch block history of risk factors for torsades de pointes (heart failure, hypokalaemia, family history of long QT syndrome) severe cardiovascular disease within 3 months before Day 1, including myocardial infarction, unstable angina pectoris, significant valvular or pericardial disease, history of ventricular tachycardia, symptomatic congestive heart failure (CHF) NYHA Class III to IV, and severe uncontrolled arterial hypertension any illness or condition that, in the opinion of the investigator, may confound results of the study or pose unwarranted risk in administering investigational product to the patient concurrent medical condition that would preclude administration of dexamethasone for 4 days, such as systemic fungal infection or uncontrolled diabetes Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: malignant tumours Chemotherapy regimen  HEC: cisplatin, mechlorethamine, streptozocin, cyclophosphamide ≥ 1500 mg/m², carmustine, dacarbazine MEC: any i.v. dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, or doxorubicin; i.v. cyclophosphamide (< 1500 mg/m²), i.v. cytarabine (> 1 g/m²); azacitidine, alemtuzumab, bendamustine, or clofarabine Countries: Bulgaria, Czech Republic, Germany, Hungary, India, Poland, Russian Federation, Serbia, Ukraine, United States
Interventions	Experimental: arm A netupitant + palonosetron + dexamethasone Experimental: arm B aprepitant + palonosetron + dexamethasone
Outcomes	Primary objective to assess the safety and tolerability of a single oral dose of a fixed‐dose combination of netupitant and palonosetron (300 mg/0.50 mg) in initial and repeated cycles of chemotherapy Secondary objectives to describe the efficacy of a single oral dose of a fixed‐dose combination of netupitant and palonosetron (300 mg/0.50 mg) with oral dexamethasone during acute (0 to 24 h), delayed (25 to 120 h), and overall (0 to 120 h) phases of initial and repeated cycles of chemotherapy complete response (no emetic episode, no rescue medication) during delayed, acute, and overall phases no significant nausea (maximum visual analogue scale (VAS) < 25 mm) during delayed, acute, and overall phases
Notes	sponsor: Helsinn Healthcare SA EUCTR2010‐023297‐39

EUCTR2015‐001800‐74.

Methods	Randomised, phase 3, active‐controlled study Recruitment period: December 2015 to n.r. target sample size: 400  Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria signed written informed consent male or female 18 years of age or older histologically or cytologically confirmed solid tumour malignancy naïve to cytotoxic chemotherapy scheduled to receive at least 4 repeated consecutive cycles of the following highly emetogenic reference chemotherapies (HEC), alone or in combination with other chemotherapeutic agents, on Day 1: cisplatin administered as a single i.v. dose of 70 mg/m² cyclophosphamide 1500 mg/m² carmustine (BCNU) > 250 mg/m² dacarbazine (DTIC) mechlorethamine (nitrogen mustard) if a patient is female, she shall be: of non‐child‐bearing potential; or of child‐bearing potential and using reliable contraceptive measures and having a negative urine pregnancy test haematological and metabolic status adequate for receiving HEC regimen and meeting the following criteria: total neutrophils 1500/mm³ platelets 100,000/mm³ bilirubin 1.5 × ULN adequate liver enzymes adequate serum creatinine able to read, understand, and follow study procedures and complete patient diary Exclusion criteria lactating woman active infection or uncontrolled disease except for malignancy that may pose unwarranted risk in administering study drugs to the patient current use of illicit drugs or current evidence of alcohol abuse scheduled to receive moderately or highly emetogenic chemotherapies from Day 2 to Day 5 received or scheduled to receive radiation therapy to abdomen or pelvis within 1 week before start of reference chemotherapy administration on Day 1 or between Days 1 and 5 any vomiting, retching, or nausea (grade 1 as defined by National Cancer Institute) within 24 h before start of reference chemotherapy administration on Day 1 symptomatic primary or metastatic CNS malignancy known hypersensitivity or contraindication to 5‐HT₃ receptor antagonists, to dexamethasone, or to NK₁ receptor antagonists known contraindication to i.v. administration of 50 mL 5% glucose solution previously received an NK₁ receptor antagonist participated in a previous clinical trial involving i.v. pro‐netupitant or oral netupitant administered alone or in combination with palonosetron any investigational drugs (other than those given in this study) taken within 4 weeks before Day 1 and/or scheduled to receive any investigational drug during the present study systemic corticosteroid therapy at any dose within 72 h before start of reference chemotherapy administration on Day 1 scheduled to receive bone marrow transplantation and/or stem cell rescue therapy scheduled to receive any strong or moderate inhibitor of CYP3A4 or its intake within 1 week before Day 1 scheduled to receive any of the following CYP3A4 substrates within 1 week before Day 1: terfenadine, cisapride, astemizole, pimozide received within 4 weeks before Day 1 or scheduled to receive any CYP3A4 inducer any medication with known or potential antiemetic activity within 24 h before start of reference chemotherapy administration on Day 1 Cycle 1, including: 5‐HT₃ receptor antagonists NK₁ receptor antagonists benzamide phenothiazines benzodiazepines (except if the patient is receiving such medication for sleep or anxiety and has been on a stable dose for at least 7 days before Day 1) butyrophenones anticholinergics antihistamines domperidone mirtazapine olanzapine prescribed cannabinoids over‐the‐counter (OTC) antiemetics, OTC cold and allergy medications history of or predisposition to cardiac conduction abnormalities, except for incomplete right bundle branch block history of torsades de pointes or known history of risk factors for torsades de pointes severe cardiovascular disease diagnosed within 3 months before Day 1 Cycle 1, including myocardial infarction, unstable angina pectoris, significant valvular or pericardial disease, history of ventricular tachycardia, symptomatic congestive heart failure (CHF) NYHA Class III to IV, and severe uncontrolled arterial hypertension any illness or condition that, in the opinion of the investigator, may confound results of the study or pose unwarranted risk in administering investigational product to the patient concurrent medical condition that would preclude administration Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: solid tumour malignancy Chemotherapy regimen cisplatin administered as a single i.v. dose of 70 mg/m² cyclophosphamide 1500 mg/m² carmustine (BCNU) > 250 mg/m² dacarbazine (DTIC) mechlorethamine (nitrogen mustard) Country: Austria, Croatia, Czech Republic, Germany, Israel, Italy, Poland, Serbia, South Africa, Spain, Ukraine, United States
Interventions	pro‐netupitant (260 mg) + palonosetron (0.25 mg) + dexamethasone
Outcomes	Primary endpoints physical examination  vital signs 12‐lead electrocardiogram  laboratory test (haematology, blood chemistry, urinalysis) adverse events (AEs) assessment Secondary endpoints proportion of patients with complete response (no emetic episodes and no rescue medication) during acute, delayed, and overall phases proportion of patients with no emetic episodes during acute, delayed, and overall phases proportion of patients with no significant nausea (visual analogue scale (VAS) < 25 mm) during acute, delayed, and overall phases (because VAS is assessed daily, for delayed and overall phases, the maximum VAS value in the relevant phase will be considered)
Notes	main ID: EUCTR2015‐001800‐74‐DE primary sponsor: Helsinn Healthcare SA

JapicCTI‐194691.

Methods	Randomised, interventional, phase 3 study with 2 arms comparison of fosnetupitant vs fosaprepitant Target sample size: 100 Masking: n.r. Baseline patient characteristics: not available
Participants	Inclusion criteria provided written informed consent scheduled to receive cancer chemotherapy including HEC agents (AC/EC) ECOG performance status 0 to 1 Exclusion criteria infection, diabetes mellitus, or other disease with difficulty to administer dexamethasone, as defined in the protocol  unable or unwilling to cooperate in the implementation of study procedures (e.g. writing a study report) Mean/median age, years: minimum 20 years Gender: male and female Tumour/cancer type: not specified Chemotherapy regimen: AC/EC Country: Japan
Interventions	Experimental: arm A Fosnetupitant 235 mg i.v. before start of chemotherapy Active control: arm B Fosaprepitant 150 mg i.v. before start of chemotherapy
Outcomes	Primary outcome Incidence of side effects Secondary outcomes Safety (not further defined) Efficacy (not further defined)
Notes	CRIS Registration Number: JapicCTI‐194691 primary sponsor: Taiho Pharmaceutical Co., Ltd.

Mylonakis 1996.

Methods	Randomised, comparative study with 2 arms comparison of ondansetron vs tropisetron Recruitment period: n.r. number of randomised subjects: n.r. Masking: n.r. Baseline patient characteristics: n.r.
Participants	Inclusion criteria: n.r. Exclusion criteria: n.r. Mean/median age, years: n.r. Gender: n.r. Tumour/cancer type: n.r. Chemotherapy regimen: moderately emetogenic chemotherapy regimen Country: n.r.
Interventions	Experimental: arm A ondansetron Experimental: arm B tropisetron
Outcomes	n.r.
Notes	only title is available

NCT00169572.

Methods	Randomised, phase 2, parallel‐assignment study Study start date: February 2005 Study completion date: not provided number of enrolled subjects: 492 Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria willing to provide written informed consent before receiving any study‐specific procedures or assessments diagnosed solid malignant tumour has not previously received chemotherapy scheduled to receive chemotherapy conducive to regimens outlined in the study protocol Exclusion criteria has not received any investigational product within 30 days of enrolment into the study must not be pregnant must not be of child‐bearing potential or willing to use specific barrier methods outlined in the protocol must not be scheduled to receive radiation therapy to abdomen or pelvis within seven (7) days before the start of study medication must not be currently under treatment for a condition that may cause nausea or vomiting (e.g. active peptic ulcer disease, gastric obstruction) must not have a history of peptic ulcer disease Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: solid malignancy Chemotherapy regimen: n.r. Country: Argentina, Austria, Belgium, Chile, Croatia, Czech Republic, Hong Kong, Hungary, Italy, Mexico, Netherlands, Pakistan, Peru, Philippines, Poland, Romania, Singapore, Slovakia, Taiwan
Interventions	Drug: aprepitant, ondansetron, GW679769, dexamethasone Study arms: not provided
Outcomes	Primary outcome number of subjects who do not experience vomiting, retching, or nausea over a 5‐day period following initiation of chemotherapy Secondary outcomes routine physical exam findings, vital signs, routine clinical laboratory tests, clinical monitoring and/or observation, adverse events reporting
Notes	ClinicalTrials.gov identifier (NCT number): NCT00169572 sponsors and collaborators: GlaxoSmithKline

NCT01101529.

Methods	Randomised, phase 2 study with 2 arms comparison of aprepitant + tropisetron + dexamethasone vs placebo + tropisetron + dexamethasone Study period: May 2010 to December 2012 estimated number of enrolled subjects: 90 Masking: triple (participant, care provider, investigator) Baseline patient characteristics: n.r.
Participants	Inclusion criteria age ≥ 18 years able to communicate in Swedish diagnosis of lymphoproliferative disease scheduled for myeloablative therapy and autologous stem cell transplantation written informed consent able to swallow oral medications Exclusion criteria nausea at baseline (immediately before start of chemotherapy) gastrointestinal obstruction or active peptic ulcer current illness requiring long‐term systemic steroids or long‐term use of antiemetic agent(s) hypersensitivity to any component of the study regimen pregnancy or nursing unrelenting hiccups radiation therapy to pelvis or abdomen within 1 week before or after study Day 1 psychiatric illness or multi‐system organ failure hepatic insufficiency, with AST and ALT 3 times over reference value renal insufficiency, with creatinine value 3 times over reference value Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: lymphoproliferative disease Chemotherapy regimen: myeloablative chemotherapy + autologous stem cell transplantation Country: Sweden
Interventions	Experimental: arm A aprepitant given orally 125 mg the first day, then 80 mg daily during the chemotherapy course + 1/dexamethasone 6 mg daily during chemotherapy days + 2/tropisetron (Navoban) 5 mg daily during chemotherapy and 2 days after Control: arm B placebo + 1/dexamethasone 6 mg daily during chemotherapy days + 2/tropisetron (Navoban) 5 mg daily during chemotherapy and 2 days after
Outcomes	Primary outcome vomiting and nausea [Time frame: 7 days] Secondary outcome Safety and tolerability of aprepitant regimen for CINV [Time frame: 3 weeks]
Notes	ClinicalTrials.gov identifier (NCT number): NCT01101529 sponsors and collaborators: Uppsala University Hospital

NCT02407600.

Methods	Randomised, placebo‐controlled, cross‐over study with 2 arms Recruitment period: April 2015 to February 2018 target sample size: 150 Masking: quadruple (participant, care provider, investigator, outcomes assessor) Baseline patient characteristics: n.r.
Participants	Inclusion criteria age > 18 years able to sign informed consent ECOG performance status 0 to 2 stage IV or recurrent NSCLC treated with carboplatin‐based regimen with palliative intent acceptable chemotherapy regimens including carboplatin (AUC 5 or 6) every 21 days with: paclitaxel every 21 days docetaxel every 21 days pemetrexed every 21 days (non‐squamous histology with vitamin B12 and folate supplementation) gemcitabine administered on Days 1 and 8 every 21 days vinorelbine administered on Days 1 and 8 every 21 days addition of bevacizumab to chemotherapy permitted when indicated and clinically appropriate received prior adjuvant chemotherapy for lung cancer (> 1 year prior) that recurred ‐ eligible if it has been > 1 year since completion of adjuvant chemotherapy treated for locally advanced lung cancer with concurrent chemoradiation but completed such therapy > 1 year ago ‐ eligible provided all other inclusion criteria are met received prior adjuvant chemotherapy for lung cancer (> 1 year prior) that recurred ‐ eligible if it has been > 1 year since completion of adjuvant chemotherapy treated for locally advanced lung cancer with concurrent chemoradiation but completed such therapy > 1 year ago ‐ eligible provided all other inclusion criteria are met laboratory parameters: serum creatinine < 2.0 AST, ALT < 3 × ULN platelet count ≥ 100,00/mm³ ANC ≥ 1500/mm³ on day of therapy (Day 1 of the cycle) haemoglobin > 8.0 g/dL Exclusion criteria history of allergic reaction to aprepitant or fosaprepitant use of other investigational agents concurrently with chemotherapy uncontrolled systemic hypertension, with SBP > 180 and/or DBP > 110 concurrent use of pimozide, terfenadine, astemizole, or cisapride (fosaprepitant is a dose‐dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4)) pregnant or lactating women of child‐bearing age must have negative pregnancy test within 3 days of treatment and must agree to use contraception during the study period use of any of the CYP450 inducers such as phenytoin, carbamazepine, barbiturates, rifampicin, rifabutin, or St. John's wort within 30 days Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: non‐small cell lung cancer Chemotherapy regimen: carboplatin‐based combination chemotherapy Country: United States
Interventions	Cross‐over study Experimental: arm A fosaprepitant (Emend) for injection; 150 mg was administered, 1 time, i.v. on Day 1 only, as an infusion with a duration of 30 minutes Experimental: arm B saline placebo intravenously on Day 1 of first chemotherapy cycle
Outcomes	Primary outcome impact of addition of fosaprepitant upon complete response (CR) rate [Time frame: Days 1 to 5 following first 2 cycles of carboplatin‐based combination chemotherapy] Secondary outcomes no emesis [Time frame: collection of data at completion of 2 cycles, Day 42] nausea assessment based on visual analogue scale (VAS) [Time frame: collection of data at completion of 2 cycles, Day 42] patient's preferred cycle [Time frame: collection of data at completion of 2 cycles, Day 42]
Notes	ClinicalTrials.gov identifier (NCT number): NCT02407600 sponsors and collaborators: Ajeet Gajra, Merck Sharp & Dohme Corp.

NCT02550119.

Methods	Randomised study with 2 arms comparison of aprepitant + dolasetron mesylate + dexamethasone vs dolasetron mesylate + dexamethasone Recruitment period: 19 April 2006 to 1 April 2010 target sample size: 19 Masking: open‐label Baseline patient characteristics: n.r.
Participants	Inclusion criteria diagnosis of gastrointestinal malignancy and scheduled to receive initial treatment with an oxaliplatin‐containing regimen in combination with 5‐fluorouracil; these include combinations such as fluorouracil, oxaliplatin, and leucovorin calcium (FOLFOX), FOLFOX + bevacizumab, FOLFOX + cetuximab standard antiemetic therapy with initial treatment that must include dolasetron and dexamethasone; minimum adequate doses include: dolasetron (Anzemet) 100 mg p.o./i.v. or 1.8 mg/kg i.v. dexamethasone (Decadron) 10 mg p.o./i.v. patient must agree, as part of informed consent, to keep a journal of episodes of nausea, vomiting, retching, and quantities of rescue medication used on Days 1 to 5 (Day 1 = day of treatment) signed informed consent Exclusion criteria allergy or intolerance to dolasetron and dexamethasone use of another antiemetic agent (5‐HT₃ antagonists, phenothiazines, butyrophenones, cannabinoids, metoclopramide, or corticosteroids) within 72 h of Day 1 of the study episode of vomiting or retching within 24 h before the start of initial treatment with oxaliplatin‐containing regimen severe concurrent illness other than neoplasia gastrointestinal obstruction or active peptic ulcer radiation therapy to abdomen or pelvis within 1 week before or after Day 1 of the study absolute neutrophil count < 1.5 × 10⁹/L (unless physician approves to proceed with chemotherapy) or platelets < 100 × 10⁹/L (unless physician approves to proceed with chemotherapy) total bilirubin > 2 × ULN pregnant or breast‐feeding non‐English‐speaking cancer‐induced nausea and vomiting grade 1 or greater using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: gastrointestinal malignancy Chemotherapy regimen: oxaliplatin‐containing regimen in combination with 5‐fluorouracil (combinations such as fluorouracil, oxaliplatin, and leucovorin calcium (FOLFOX), FOLFOX + bevacizumab, FOLFOX + cetuximab) Country: United States
Interventions	Experimental: arm A dolasetron mesylate p.o. or i.v., dexamethasone p.o. or i.v., and aprepitant p.o. 1 day before chemotherapy; dexamethasone p.o. and aprepitant p.o. on Days 2 and 3 after chemotherapy begins during Course 2 to 3 Experimental: arm B dolasetron mesylate and dexamethasone as in arm A and placebo p.o. 1 day before chemotherapy; dexamethasone p.o. and placebo p.o. on Days 2 and 3 after chemotherapy begins during Courses 2 to 3
Outcomes	Primary outcome proportion of patients with complete response, defined as no emesis and no use of rescue medication [Time frame: within first 24 h of treatment (Day 1)] Secondary outcome proportion of patients who agreed to be randomised out of all patients who qualify for randomisation [Time frame: 28 days]
Notes	ClinicalTrials.gov Identifier: NCT02550119 sponsor and collaborators: University of Southern California, National Cancer Institute (NCI)

NCT02732015.

Methods	Randomised, interventional, phase 2, parallel study with 2 arms comparison of rolapitant + ondansetron + dexamethasone vs fosaprepitant + ondansetron + dexamethasone Estimated enrolled patients: 91, terminated per principal investigator's request after enrolment of 37 participants Masking: open‐label Baseline patient characteristics: not available
Participants	Inclusion criteria sarcoma that is locally advanced and at high risk for relapse or metastatic, for which treatment with doxorubicin plus ifosfamide (AI) or AI and vincristine (VAI) is indicated estimated life expectancy ≥ 4 months in the opinion of investigators males and females of child‐bearing potential must use acceptable methods of birth control, which include oral contraceptives; spermicide with a condom, a diaphragm, or a cervical cap; an intrauterine device (IUD); or abstinence female patients must have negative pregnancy test at screening female patients of child‐bearing potential must agree to use an acceptable method of birth control (excluding hormonal birth control methods) for 72 h before admission and to continue its use during the study and for at least 30 days after the final dose male patients must agree to use an acceptable form of birth control from study Day 1 through at least 30 days after the final dose absolute neutrophil count > 1500/mm³ platelet count > 100,000/mm³ serum creatinine < 1.5 mg/dL serum bilirubin count < 1.5 × ULN serum glutamic‐oxaloacetic transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) < 2.5 × ULN; for subjects with known liver metastases, < 5 × ULN Karnofsky performance status > 60% signed informed consent form required to read and understand English to comply with protocol requirements Exclusion criteria any current treatment, medical history, or uncontrolled condition, other than malignancy (e.g. alcoholism or signs of alcohol abuse, seizure disorder, medical or psychiatric condition) that, in the opinion of the investigator, would confound results of the study or pose any unwarranted risk in administering study drug to the subject known hypersensitivity to administration of any prescribed oral or intravenous study medication or metabolite, including but not limited to a history of hypersensitivity to drugs or their components, severe renal impairment, severe bone marrow suppression, or systemic infection woman who has a positive urine or serum pregnancy test within 3 days before study drug administration, is breast‐feeding, or is planning to conceive children within the projected duration of study treatment has taken antiemetic agents within the last 48 h before the start of treatment with study drug: 5‐hydroxytryptamine (HT)₃ antagonists (ondansetron, granisetron, dolasetron, tropisetron, etc.); palonosetron is not permitted within 7 days before administration of investigational product phenothiazines (prochlorperazine, fluphenazine, perphenazine, thiethylperazine, chlorpromazine, etc.) benzamides (metoclopramide, alizapride, etc.) domperidone cannabinoids neurokinin (NK₁ antagonist (aprepitant)) benzodiazepines (lorazepam, alprazolam, etc.) herbal medications or preparations in doses designed to ameliorate nausea or emesis received systemic corticosteroids or sedative antihistamines (dimenhydrinate, diphenhydramine, etc.) within 72 h of Day 1 of the study except as pre‐medication for chemotherapy (e.g. taxanes); those receiving inhaled steroids for respiratory conditions or topical steroids for skin disorders can be enrolled symptomatic primary or metastatic central nervous system (CNS) disease ongoing vomiting, retching, dry heaves, or clinically significant nausea caused by any aetiology, or such symptoms within 24 h before the start of Day 1 of the study intervention, or history of anticipatory nausea and vomiting must not have been dosed with test drug or blinded study drug in another investigational study within 30 days or 5 half‐lives of the biological activity of the test drug, whichever is longer, before the time of first study dose participating in study of any investigational agent that is not Food and Drug Administration (FDA)‐approved uncontrolled angina, congestive heart failure (New York Heart Association > Class II or known ejection fraction < 40%), uncontrolled cardiac arrhythmia or hypertension, or acute myocardial infarction within 3 months prior surgery or radiotherapy (RT) within 2 weeks of study entry psychological, social, familial, or geographical reasons that would prevent scheduled visits and follow‐up Mean/median age, years: not available Gender: male + female Tumour/cancer type: sarcoma Chemotherapy regimen: doxorubicin + ifosfamide (AI) or ifosfamide (AI) and vincristine (VAI) is indicated Country: United States
Interventions	Experimental: arm A: rolapitant i.v. dexamethasone daily and ondansetron i.v. on Days 1 to 5, and p.o. rolapitant hydrochloride on Day 1 treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity Experimental: arm B: fosaprepitant i.v. dexamethasone and i.v. ondansetron on Days 1 to 5, and i.v. fosaprepitant dimeglumine over 30 min on Day 1 Cycle 2. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity
Outcomes	Primary outcomes rate of complete response (CR) of rolapitant hydrochloride administered as a single dose [Time frame: up to Course 1] rate of complete response (CR) of rolapitant hydrochloride vs fosaprepitant dimeglumine [Time frame: up to Course 1] Secondary outcomes incidence of toxicity [Time frame: Course 1] response rates in 0 to 24 h [Time frame: up to 24 h] response rates in 24 to 120 h [Time frame: up to 120 h] response rates in 120 to 240 h [Time frame: up to 240 h]
Notes	ClinicalTrials.gov Identifier: NCT02732015 sponsors and collaborators: M.D. Anderson Cancer Center

NCT03403712.

Methods	Randomised, phase 3b study with 2 arms comparison of fosnetupitant + palonosetron + dexamethasone vs netupitant + palonosetron + dexamethasone Study period: 16 March 2018 to 19 September 2018 number of enrolled subjects: 404 Masking: quadruple (participant, care provider, investigator, outcomes assessor) Baseline patient characteristics: n.r.
Participants	Inclusion criteria read, understood, and signed written informed consent before any study‐related activity, agreeing to participate in the study and to comply with study requirements female patient at least 8 years of age histologically or cytologically confirmed breast cancer, including recurrent or metastatic naïve to moderately or highly emetogenic antineoplastic agents scheduled to receive at least 4 consecutive cycles of an AC combination regimen ECOG performance status 0 or 1 patient of non‐child‐bearing potential, or patient of child‐bearing potential using reliable contraceptive measures and having a negative urine pregnancy test within 24 h before dose of investigational product haematological and metabolic status adequate for receiving a cycle of AC chemotherapy based on investigator's assessment if the patient has known hepatic or renal impairment, may be enrolled in the study at the discretion of the Investigator able to read, understand, and follow study procedures and complete patient diary Exclusion criteria lactating patient current use of illicit drugs or current evidence of alcohol abuse scheduled to receive moderately or highly emetogenic antineoplastic agent in addition to the AC regimen, from 6 h after the start of AC chemotherapy on Day 1 and up to Day 1 of Cycle 2 received or scheduled to receive radiation therapy to abdomen or pelvis within 1 week before the start of AC chemotherapy administration on Day 1 or between Days 1 and 5, inclusive any vomiting, retching, or nausea (grade 1 as defined by National Cancer Institute) within 24 h before the start of AC chemotherapy administration on Day 1 symptomatic primary or metastatic central nervous system (CNS) malignancy active peptic ulcer disease, gastrointestinal obstruction, increased intracranial pressure, hypercalcaemia, active infection or any illness or medical condition (other than malignancy) that, in the opinion of the investigator, may confound results of the study, represent another potential aetiology for emesis and nausea (other than chemotherapy‐induced nausea and vomiting (CINV)), or pose unwarranted risk in administering study drugs to the patient known hypersensitivity or contraindication to 5 hydroxytryptamine type 3 (5‐HT₃) receptor antagonists (e.g. palonosetron, ondansetron, granisetron, dolasetron, tropisetron, ramosetron), to dexamethasone, or to neurokinin‐1 (NK₁) receptor antagonists (e.g. aprepitant, rolapitant) known contraindication to i.v. administration of 50 mL 5% glucose solution participation in a previous clinical trial involving i.v. fosnetupitant or oral netupitant administered alone or in combination with palonosetron any investigational drugs taken within 4 weeks before Day 1 and/or scheduled to receive any investigational drug (other than those planned by the study protocol) during the present study systemic corticosteroid therapy within 72 h before the start of AC chemotherapy administration on Day 1, except for dexamethasone provided as additional study drug. However, topical and inhaled corticosteroids are permitted scheduled to receive bone marrow transplantation and/or stem cell rescue therapy during study participation other than treatment administered as part of study protocol, any medication with known or potential antiemetic activity within 24 h before the start of AC chemotherapy administration on Day 1, including: 5‐HT₃ receptor antagonists (e.g. ondansetron, granisetron, dolasetron, tropisetron, ramosetron, palonosetron) NK₁ receptor antagonists (e.g. aprepitant, fosaprepitant, rolapitant, or any other new drug of this class) benzamides (e.g. metoclopramide, alizapride) phenothiazines (e.g. prochlorperazine, promethazine, fluphenazine, perphenazine, thiethylperazine, chlorpromazine) benzodiazepines (except if the subject is receiving such medication for sleep or anxiety and has been on a stable dose for at least 7 days before Day 1) butyrophenones (e.g. haloperidol, droperidol) anticholinergics (e.g. scopolamine, with the exception of inhaled anticholinergics for respiratory disorders, e.g. ipratropium bromide) antihistamines (e.g. cyclizine, hydroxyzine, diphenhydramine, chlorpheniramine) domperidone mirtazapine olanzapine prescribed cannabinoids (e.g. tetrahydrocannabinol, nabilone) over‐the‐counter (OTC) antiemetics, OTC cold or allergy medications scheduled to receive any strong or moderate inhibitor of CYP3A4 during efficacy assessment period (Day 1 to Day 5, inclusive) or its intake within 1 week before Day 1 scheduled to receive any CYP3A4 inducer during efficacy assessment period (Day 1 to Day 5, inclusive) or its intake within 4 weeks before Day 1, with the exception of corticosteroids (for which exclusion criteria above apply) history of or predisposition to cardiac conduction abnormalities, except for incomplete right bundle branch block history of risk factors for torsades de pointes (heart failure, hypokalaemia, family history of long QT syndrome) severe or uncontrolled cardiovascular disease, including myocardial infarction within 3 months before Day 1, unstable angina pectoris, significant valvular or pericardial disease, history of ventricular tachycardia, symptomatic congestive heart failure (CHF) New York Heart Association (NYHA) Class III to IV, and severe uncontrolled arterial hypertension Mean/median age, years: n.r. Gender: female Tumour/cancer type: breast cancer Chemotherapy regimen: anthracycline + cyclophosphamide Country: United States, Georgia (multi‐centre)
Interventions	Experimental: arm A i.v. fosnetupitant/ palonosetron (260 mg/0.25 mg) fixed‐dose combination, administered as a 30‐min infusion of a 50‐mL solution on Day 1 of each cycle p.o. dexamethasone will be administered on Day 1 of each cycle (12 mg) Control: arm B p.o. netupitant/palonosetron (300 mg/0.50 mg) fixed‐dose combination on Day 1 of each cycle p.o. dexamethasone will be administered on Day 1 of each cycle (12 mg)
Outcomes	Primary outcomes treatment‐emergent AEs at Cycle 1 [Time frame: at the end of Cycle 1 (each cycle is 21 days)] treatment‐emergent AEs at Cycle 2 [Time frame: at the end of Cycle 2 (each cycle is 21 days)] treatment‐emergent AEs at Cycle 3 [Time frame: at the end of Cycle 3 (each cycle is 21 days)] treatment‐emergent AEs at Cycle 4 [Time frame: at the end of Cycle 4 (each cycle is 21 days)] Secondary outcomes emetic episodes [Time frame: 120 h after the start of AC chemotherapy administration] rescue therapy [Time frame: 0 to 120‐h interval (Day 1 to Day 5) after the start of AC chemotherapy administration] severity of nausea [Time frame: each day of the 0 to 120‐h interval (Days 1 to 5, inclusive)] functional living index ‐ emesis (FLIE) questionnaire [Time frame: Cycles 1 and 2]
Notes	ClinicalTrials.gov identifier (NCT number): NCT03403712 sponsors and collaborators: Helsinn Healthcare SA, George Clinical Pty. Ltd., The Physicians' Services Incorporated Foundation

PER‐055‐12.

Methods	Randomised, multi‐centre, parallel‐group, active‐controlled, phase 3 study Recruitment period  target sample size: 40 Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria 18 years of age or older, of either gender, of any race never been treated with cisplatin and is to receive first course of cisplatin‐based chemotherapy (≥ 60 mg/m²) Karnofsky performance score ≥ 60 predicted life expectancy ≥ 4 months adequate bone marrow, kidney, and liver function as evidenced by absolute neutrophil count ≥ 1500/mm³, platelet count ≥ 100,000/mm³, AST ≤ 2.5 × ULN, for subjects with known liver metastases ≤ 5 × ULN, ALT ≤ 2.5 × ULN; for subjects with known liver metastases ≤ 5 × ULN; bilirubin ≤ 5 × 1.5 × ULN, except for subjects with Gilbert's syndrome, creatinine ≤ 1.5 × ULN; if a single or multiple laboratory test value exceeds, but is close to, the limit(s) of the reference range(s) as defined in the protocol inclusion criteria, subjects will be allowed to repeat these out‐of‐range tests once. If the repeated test results meet study requirements, these subjects can be enrolled Exclusion criteria  any current treatment, medical history, or uncontrolled condition, other than malignancy (e.g. alcoholism or signs of alcohol abuse, seizure disorder, medical or psychiatric condition) that, in the opinion of the investigator, would confound results of the study or pose any unwarranted risk in administering study drug to the subject contraindication to administration of cisplatin, granisetron, or dexamethasone including, but not limited to, a history of hypersensitivity to the drugs or their components, severe renal impairment, severe bone marrow suppression, or systemic infection woman of child‐bearing potential with positive urine or serum pregnancy test within 3 days before study drug administration, or breast‐feeding previously received cisplatin or is planning to receive multiple days of cisplatin in a single cycle has taken the following agents within the last 48 h before the start of treatment with study drug: 5‐HT₃ antagonists (ondansetron, granisetron, dolasetron, tropisetron, etc.); palonosetron not permitted within 7 days before administration of investigational product; phenothiazines (prochlorperazine, fluphenazine, perphenazine, thiethylperazine, chlorpromazine, etc.); benzamides (metoclopramide, alizapride, etc.) Mean/median age, years: 18 to 99 Gender: male + female Tumour/cancer type: n.r. Chemotherapy regimen: HEC Country: n.r. (multi‐centre)
Interventions	rolapitant will be administered 1 to 2 hours before initiation of chemotherapy on Day 1. Granisetron and dexamethasone will be administered approximately 30 min before initiation of chemotherapy on Day 1, except in subjects receiving taxanes as part of cisplatin‐based chemotherapy (Section 7.4.1.3)
Outcomes	all events of emesis and use of rescue medication for established nausea and/or vomiting severity of nausea experienced in each of the previous 24 h as reported in the subject diary before HEC administration through Day 6 Cycle 1 health‐related quality of life measured by the FLIE questionnaire on Day 6 Cycle 1 safety and tolerability assessed by clinical review of AEs, physical examination including complete neurological assessment, vital signs, electrocardiograms, and safety laboratory values including BUN and creatinine
Notes	PER‐055‐12 primary sponsor: TESARO, Inc.

Spina 1995.

Methods	Randomised study with 2 arms comparison of granisetron vs ondansetron Recruitment period: n.r. number of randomised participants: n.r. Masking: n.r. Baseline patient characteristics: n.r.
Participants	Inclusion criteria: n.r. Exclusion criteria: n.r. Mean/median age, years: n.r. Gender: n.r. Tumour/cancer type: HIV‐related non‐Hodgkin lymphoma (HIV‐NHL) Chemotherapy regimen: moderately emetogenic chemotherapy regimen Country: n.r.
Interventions	Experimental: arm A granisetron Experimental: arm B ondansetron
Outcomes	n.r.
Notes	only title is available

UMIN000004826.

Methods	Randomised, interventional, phase 2 study with 2 arms comparison of aprepitant + granisetron + dexamethasone vs aprepitant + palonosetron + dexamethasone Recruitment period: October 2010 to n.r. number of target subjects: 60 Masking: open‐label Baseline patient characteristics: n.r.
Participants	Inclusion criteria histologically or cytologically confirmed head and neck cancer stage III to IV head and neck cancer without prior treatment age ≥ 20 and < 75 scheduled to receive high emetogenic chemotherapy (cisplatin ≥ 60 mg/m²) sufficient function of important organs WBC ≥ 3000/mm³ AST < 100 IU/L ALT < 100 IU/L CCr ≥ 60 mL/min/body ECOG performance status 0 to 1 written informed consent Exclusion criteria seizure disorder needing anticonvulsants unless clinically stable vomiting, retching, or grade 2 or higher nausea according to CTCAE QTc prolongation by electrocardiography (QTc > 470 msec) severe allergy to palonosetron, granisetron, aprepitant, and dexamethasone pregnant or nursing women women who would like to be pregnant and men with partner willing to get pregnant receiving an antiemetic drug receiving pimozide  history of mental disorder or treating it at the moment doctor's decision not to be registered in this study Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: head and neck cancer Chemotherapy regimen: cisplatin ≥ 60 mg/m² Country: Japan
Interventions	Cross‐over study Experimental: arm A: granisetron aprepitant was administered p.o. at 125 mg/body 1 h or 1 h and a half before cisplatin administration. On Days 2 and 3, aprepitant was administrated p.o. at 80 mg/body granisetron 40 μg/body and dexamethasone 12.3 mg/body were administered i.v. 30 min before cisplatin administration. On Days 2 and 3, granisetron 40 μg/body and dexamethasone 6.6 mg/body were administered Experimental: arm B: palonosetron aprepitant was administered p.o. at 125 mg/body 1 h or 1 h and a half before cisplatin administration. On Days 2 and 3, aprepitant was administrated p.o. at 80 mg/body palonosetron 0.75 mg/body and dexamethasone 12.3 mg/body were administered i.v. 30 min before cisplatin administration. On Days 2 and 3, dexamethasone 6.6 mg/body was administered
Outcomes	Primary outcomes proportion of patients with complete protection during the overall phase (0 to 120 h post chemotherapy) proportion of patients with complete response during the overall phase Secondary outcomes proportion of patients with complete protection during the acute phase (0 to 24 h post chemotherapy) and the delayed phase (24 to 120 h post chemotherapy) proportion of patients with complete response during the overall phase and during acute and delayed phases proportion of patients with complete control during the overall phase and during acute and delayed phases proportion of patients without nausea proportion of patients without emesis time to treatment failure safety
Notes	main ID: JPRN‐UMIN000004826 sponsor and funding: Yokohama City University Graduate School of Medicine

UMIN000004863.

Methods	Randomised, phase 3, active‐controlled study with 2 arms comparison of aprepitant + granisetron + dexamethasone vs aprepitant + palonosetron + dexamethasone Study period: May 2011 to June 2012 number of target subjects: 840 Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria malignant tumour except for haematopoietic malignancy ECOG performance status 0 to 2 20 years old or over at the time of giving informed consent receiving chemotherapy involving cisplatin as first line dose of cisplatin 50 mg/m² over regimens involving standard treatment for vomiting with dexamethasone, aprepitant, and 5‐HT₃ receptor antagonist adequate organ function as defined by (each of the following values are examined within 8 days before entry): AST ≤ 100 IU/L, ALT ≤ 100 IU/L T‐Bill ≤ 2.0 mg/dL CCr ≥ 60 mL/min all subjects must be able to provide written informed consent before entry Exclusion criteria known prior severe hypersensitivity to 5‐HT₃ receptor antagonist, corticosteroids, and aprepitant individuals who do not have enough whole body state for antineoplastic agent treatment known symptomatic brain metastasis convulsive disorder that needs anticonvulsant therapy symptom of ascites or pleural effusion that needs puncture obstruction of gastrointestinal tract, for example, gastric outlet or ileus, etc. pregnant, breast‐feeding woman enforced radiotherapy at bottom of diaphragm in the period between 6 days before and 6 days after date of first therapy taking a medicine regularly, for example, 5‐HT₃ receptor antagonists, corticosteroids, antidopamine agonists, phenothiazine tranquilisers,antihistamine drugs, benzodiazepine agents, etc. judged by investigator to be inappropriate for this study Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: solid malignancy (lung cancer, gastric cancer, oesophagus cancer, cervical cancer, endometrial cancer, head and neck cancer, etc.) Chemotherapy regimen: cisplatin ≥ 50 mg/m² Country: Japan
Interventions	Experimental: arm A: granisetron granisetron 1 mg + dexamethasone (Days 1 to 4) + aprepitant (Days 1 to 3) Experimental: arm B: palonosetron palonosetron 0.75 mg + dexamethasone (Days 1 to 4) + aprepitant (Days 1 to 3)
Outcomes	Primary outcome complete response rate of vomiting within 120 h from cisplatin administration Secondary outcomes complete control rate of events associated with vomiting within 120 h from cisplatin administration total control rate of nausea and vomiting within 120 h from cisplatin administration time to treatment failure (TTF) adverse events
Notes	main ID: JPRN‐UMIN000004863 sponsor: Pharma Valley Center, Shizuoka Organization for Creation Industries

UMIN000004998.

Methods	Randomised, phase 2 study with 2 arms comparison of aprepitant + granisetron + dexamethasone vs granisetron + dexamethasone Recruitment period: January 2011 to January 2013 number of target subjects: 94 Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria woman younger than 70 years old without alcohol drinking habit lung, colorectal, gynaecological, or primary unknown cancer treated with carboplatin‐ or irinotecan‐ (> 150 mg/m²) based regimens Exclusion criteria anthracycline and cyclophosphamide (AC) regimens Mean/median age, years: n.r. Gender: female Tumour/cancer type: haematology and clinical oncology Chemotherapy regimen: carboplatin‐ or irinotecan‐ (> 150 mg/m²) based regimens Country: Japan
Interventions	Experimental: arm A Day 1, aprepitant 125 mg, granisetron 1 mg, and dexamethasone 12 mg before chemotherapy; Days 2 through 3, aprepitant 80 mg QD and dexamethasone 4 mg QD Control: arm B Day 1, granisetron 1 mg and dexamethasone 20 mg before chemotherapy; Days 2 through 3, dexamethasone 8 mg QD
Outcomes	Primary outcome proportion of patients with complete response (CR), defined as no vomiting and no use of rescue therapy, during 120 h after initiation of chemotherapy in Cycle 1 Secondary outcomes proportions of women with no vomiting with rescue use during 120 h post chemotherapy proportions of women with total control (no nausea, no vomiting, and no rescue use) during 120 h post chemotherapy
Notes	main ID: JPRN‐UMIN000004998 sponsor and funding source: Hanshin Cancer Study Group

UMIN000008041.

Methods	Randomised, cross‐over, active‐controlled study with 2 arms Recruitment period: February 2012 to n.r. target sample size: 100 Masking: open‐label Baseline patient characteristics: n.r.
Participants	Inclusion criteria gastric cancer or colorectal cancer receiving FOLFILI, CPT‐11 monotherapy, FOLFOX, or XELOX regimen ECOG performance status 0 to 2 Exclusion criteria severe liver failure or renal failure vomited or provoked nausea in the 24 h before the start of chemotherapy factor that induces nausea or vomiting except for chemotherapy (brain tumour, obstruction of gastrointestinal tract, active peptic ulcer, brain metastasis, etc.) considered inappropriate as a target patient by physician‐in‐charge Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: advanced/recurrent gastric cancer or colorectal cancer Chemotherapy regimen: FOLFILI, CPT‐11 monotherapy, FOLFOX, or XELOX regimen Country: Japan
Interventions	Cross‐over study Experimental: arm A first course: palonosetron 0.75 mg i.v. on first day + dexamethasone 9.9 mg i.v. on first day, 8 mg p.o. on second day and on third day second course: palonosetron 0.75 mg i.v. on first day + dexamethasone 4.95 mg i.v. on first day, 4 mg p.o. on second day and on third day + aprepitant (125 mg p.o. on first day, 80 mg p.o. on second day and on third day) Experimental: arm B first course: palonosetron 0.75 mg i.v. on first day + dexamethasone 4.95 mg i.v. on first day, 4 mg p.o. on second day and on third day + aprepitant (125 mg p.o. on first day, 80 mg p.o. on second day and on third day) second course: palonosetron 0.75 mg i.v. on first day + dexamethasone 9.9 mg i.v. on first day, 8 mg p.o. on second day and on third day
Outcomes	Primary outcomes frequency of vomiting severity of nausea Secondary outcomes grading of appetite amount of per‐request medication used
Notes	main ID: JPRN‐UMIN000008041 sponsor: Osaka Medical College Hospital

UMIN000008552.

Methods	Randomised, active‐controlled, cross‐over study with 2 arms comparison of NK₁ receptor antagonist (fosaprepitant) + 5‐HT₃ receptor antagonist + dexamethasone vs palonosetron + dexamethasone Recruitment period: August 2012 to n.r. target sample size: 300 Masking: single‐blind (participants were blinded) Baseline patient characteristics: n.r.
Participants	Inclusion criteria gynaecological cancer and chemotherapy including carboplatin (> AUC 5) for the first time regimen used in the first chemotherapy course is also planned for second and later courses written consent to participate in the study Exclusion criteria serious hepatic disorders or renal disorders nausea and vomiting within 24 h before initiation of cancer chemotherapy antiemetic agent within 48 h before initiation of cancer treatment nausea and vomiting due to causes other than cancer chemotherapy (brain tumour, digestive passage disorder, active peptic ulcer, brain metastasis, use of opioids, etc.) associated disease, including uncontrolled diabetes, that prevents administration of dexamethasone for 3 days under medication with pimozide abdominal radiotherapy planned history of vomiting in past chemotherapy judged to be inappropriate for the study by the physician in charge Mean/median age, years: n.r. Gender: female Tumour/cancer type: gynaecological cancer Chemotherapy regimen: carboplatin (> AUC 5) Country: Japan
Interventions	Cross‐over study Experimental: arm A NK₁ receptor antagonist (fosaprepitant) + 5‐HT₃ receptor antagonist + dexamethasone Experimental: arm B palonosetron + dexamethasone
Outcomes	Primary outcome percentage of patients with complete response (no vomiting and no salvage treatment) throughout first course of chemotherapy
Notes	main ID: JPRN‐UMIN000008552 sponsor: St. Mariannna University, School of Medicine

UMIN000008897.

Methods	Randomised, interventional, phase 3 study with 2 arms comparison of granisetron + dexamethasone vs palonosetron + dexamethasone Recruitment period: November 2012 to n.r. target sample size: 330 Masking: double‐blind Baseline patient characteristics: n.r.
Participants	Inclusion criteria invasive breast cancer confirmed by histological diagnosis eligible for perioperative AC/EC/FAC/FEC chemotherapy and planning for it over 20 years old ECOG performance status 0, 1, or 2 adequate organ function defined as: WBC ≥ 3000/mm³ ANC ≥ 1500/mm³ Hb ≥ 8 g/dL Plt ≥ 10 × 10⁴/mm³ AST, ALT ≤ 100 IU/L T‐Bil ≤ 1.5 mg/dL sCr ≤ 1.2 mg/dL PaO₂ ≥ 60 Torr or SpO₂ ≥ 93% (room air) estimated survival > 90 days written informed consent Exclusion criteria prior cancer chemotherapy prior radiation therapy during past 14 days receiving antiemetic medication during last 72 h vomiting at entry nausea grade 2 or more (CTCAE ver. 4) at entry local or systemic infection requiring treatment severe comorbid condition such as GI bleeding, ileus, heart disease, glaucoma, diabetes history of severe hypersensitivity severe psychological problem pregnant or lactating woman, or woman not going to use contraception HBsAg‐positive judged as ineligible by treating physician Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: breast cancer Chemotherapy regimen: AC/EC/FAC/FEC chemotherapy Country: Japan
Interventions	Experimental: arm A: granisetron granisetron + dexamethasone Experimental: arm B: palonosetron palonosetron + dexamethasone
Outcomes	Primary outcome complete response rate for delayed emesis (24 to 120 h after chemotherapy) Secondary outcomes complete response rate for emesis in acute phase (0 to 24 h after chemotherapy) complete response rate for emesis in overall phase (0 to 120 h after chemotherapy) complete response rate for nausea or vomiting for acute/delayed/overall phase safety
Notes	main ID: JPRN‐UMIN000008897 sponsor: West Japan Oncology Group

UMIN000010056.

Methods	Randomised, active‐controlled, phase 2 study with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs palonosetron + dexamethasone Recruitment period: April 2014 to n.r. target sample size: 80 Masking: open‐label Baseline patient characteristics: n.r.
Participants	Inclusion criteria advanced, metastatic or recurrent NSCLC adequate function of bone marrow, liver, and kidney ECOG performance status 0 to 2 Exclusion criteria severe complications brain metastasis convulsive disorder requiring treatment pleural effusion or ascites requiring treatment gastrointestinal obstruction drug sensitivities received antiemetic therapy as below in the 24 h before chemotherapy: 5‐HT₃ receptor antagonist NK₁ receptor antagonist adrenocortical steroid antidopaminergic agent phenothiazine derivative antihistamine benzodiazepine compound pregnant female, nursing mom Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: lung cancer Chemotherapy regimen: carboplatin Country: Japan
Interventions	Experimental: arm A aprepitant + palonosetron + dexamethasone Experimental: arm B palonosetron + dexamethasone
Outcomes	n.r.
Notes	main ID: JPRN‐UMIN000010056 sponsor: Hamamatsu University School of Medicine

UMIN000010186.

Methods	Randomised study with 2 arms comparison of aprepitant + granisetron + dexamethasone vs palonosetron + dexamethasone Recruitment period: May 2013 to October 2015 target sample size: 200 Masking: open‐label Baseline patient characteristics: n.r.
Participants	Inclusion criteria age ≥ 20 years gender not specified cancer patients receiving chemotherapy containing carboplatin (AUC ≥ 4) for the first time stage not specified (not specified with respect to postoperative adjuvant chemotherapy and advanced/recurrent cancer) combined use of molecular‐targeting drugs not specified consent to participation in this study obtained in writing Exclusion criteria serious hepatopathy or nephropathy nausea or vomiting within 24 h before the start of chemotherapy antiemetic drugs within 24 h before the start of chemotherapy emetogenic factors other than chemotherapy (such as brain tumour, gastrointestinal obstruction, active peptic ulcer, and brain metastasis) received radiation therapy or scheduled to receive it to abdominal region or pelvis within 1 week before or after start of the study concomitant disease that makes 3‐day dexamethasone therapy impossible, such as uncontrolled diabetes mellitus pregnant women, women who wish to become pregnant, breast‐feeding women treatment with pimozide patients whom investigator considers to be unfit for enrolment in the study Mean/median age, years: n.r. Gender: male + female Tumour/cancer type: n.r. Chemotherapy regimen: carboplatin (CBDCA)‐based moderately emetogenic chemotherapy (MEC) Country: Japan
Interventions	Experimental: arm A aprepitant (Day 1: 125 mg, Days 2 to 3: 80 mg) + granisetron 3 mg + dexamethasone (Day 1: 6.6 mg i.v., Days 2 to 3: 2 mg POX2) Experimental: arm B palonosetron 0.75 mg + dexamethasone (Day 1: 9.9 mg i.v., Days 2 to 3: 4 mg POX2)
Outcomes	Primary outcome percentage of patients with complete protection (no vomiting, therapeutic intervention, or significant nausea) during first course of treatment Secondary outcomes percentage of patients with complete protection (CP: no vomiting, therapeutic intervention, or moderate to severe nausea) from second course of chemotherapy percentage of patients with complete response (CR: no vomiting or therapeutic intervention) percentage of patients with complete control (CC: no vomiting, therapeutic intervention, or nausea) percentage of patients without vomiting percentage of patients without therapeutic intervention percentage of patients without nausea percentage of patients without significant nausea (CTCAE (ver.4) grade ≥ 2) evaluation of quality of life (QoL) related to nausea using the Functional Living Index‐Emesis (FLIE) questionnaire food intake total cost of medications (prevention + therapeutic intervention) for nausea/vomiting percentage of patients continuing treatment changes in nausea and vomiting (CP, CR, CC, etc.) over time (courses of chemotherapy) time to treatment failure (TTF: time to first episode of vomiting)
Notes	main ID: JPRN‐UMIN000010186 sponsor: Kyushu Medical Center Clinical Research Institute

UMIN000019122.

Methods	Randomised, phase 2 study with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs palonosetron + dexamethasone Recruitment period: November 2011 to n.r. target sample size: 76 Masking: open‐label Baseline patient characteristics: n.r.
Participants	Inclusion criteria 20 years of age with gynaecological cancer and scheduled to receive single‐day chemotherapy with carboplatin target area under the concentration curve of 5, and paclitaxel at 175 mg/m² ECOG performance status 0 to 2 adequate renal function, adequate hepatic function, adequate marrow function all patients provided written informed consent for participation in the study Exclusion criteria receipt of any agent that could affect study results (such as an antiemetic, steroid, or pimozide) before the start of chemotherapy symptomatic brain metastasis, gastrointestinal obstruction, or any other condition that could provoke nausea and vomiting known allergy or severe reaction to any of the study drugs Mean/median age, years: n.r. Gender: female Tumour/cancer type: gynaecological cancer Chemotherapy regimen: carboplatin (area under the concentration curve of 5) and paclitaxel at 175 mg/m² Country: Japan
Interventions	Experimental: arm A p.o. administration of 125 mg aprepitant 90 min before administration of chemotherapy drug on Day 1 and of 80 mg on Days 2 and 3, and 0.75 mg + palonosetron administered i.v. on Day 1 + 6 mg dexamethasone administered i.v. on Day 1 and 4 mg dexamethasone administered p.o. on Days 2 and 3 Experimental: arm B 0.75 mg palonosetron administered i.v. on Day 1 + 6 mg dexamethasone administered i.v. on Day 1 and 4 mg dexamethasone administered p.o. on Days 2 and 3
Outcomes	Primary outcome complete response (CR, defined as complete absence of emetic events) in the delayed phase
Notes	main ID: JPRN‐UMIN000019122 sponsor: Juntendo Nerima Hospital

5‐FU: 5‐fluorouracil.

5‐HT₃: serotonin (5‐hydroxytryptamine).

AC: doxorubicin, cyclophosphamide.

ALT: alanine aminotransferase.

AST: aspartate aminotransferase.

CNS: central nervous system.

Cr: creatinine.

CPT‐11: camptothecin‐11.

CTCAE: Common Terminology Criteria for Adverse Events.

d: day (e.g., d1, d3).              

EC: epirubicin.

ECG: electrocardiogram. 

ECOG: Eastern Cooperative Oncology Group.

ESMO: European Society for Medical Oncology.

FAC: 5‐fluorouracil (5FU) + AC.

FEC: fluorouracil, epirubicin, cyclophosphamide.

FLIE: Functional Living Index‐Emesis.

FOLFILI: folinic acid, fluorouracil, and irinotecan.

FOLFOX: folinic acid, fluorouracil, and oxaliplatin.

g/L: gram per litre.

g/m²: gram per square meter.  

h: hour.

Hb: haemoglobin.

HBV: hepatitis B virus.

HCV: hepatitis C virus.

HEC: highly emetogenic chemotherapy.

HIV: human immunodeficiency virus.

IU: international unit.

i.v.: intravenous.

L: litre.

MASCC: Annual Meeting on Supportive Cancer Care.

MEC: moderately emetogenic chemotherapy.

mg: milligram.

mL/min: millilitre per minute.

msec: millisecond.

NCI: National Cancer Institute.

NK₁: neurokinin‐1.

n.r.: not reported.

NSCLC: non‐small cell lung carcinoma.

PLT: platelets.

p.o.: oral.

QD: once a day.

QTc: QT interval corrected for heart rate.

SOX: S‐1 plus oxaliplatin.

TBIL: total bilirubin.

ULN: upper limit of normal.

VAS: visual analogue scale.

VP‐16: etoposide.

VM‐26: teniposide.

vs: versus.

WBC: white blood cell count.

XELOX: capecitabine, oxaliplatin.

Characteristics of ongoing studies [ordered by study ID]

ChiCTR1900025227.

Study name	A randomized, open, parallel controlled phase II clinical study comparing the efficacy and safety of dexamethasone, palonosetron, or aprepitant in the control of acute and delayed vomiting in non‐small cell lung cancer patients receiving multiple moderately emetogenic chemotherapy regimens
Methods	Randomised, interventional, active‐controlled study with 2 arms comparison of aprepitant + palonosetron + dexamethasone vs palonosetron + dexamethasone Target sample size: 100 Masking: open‐label Baseline patient characteristics: not available
Participants	Inclusion criteria treatment‐naïve non‐small cell lung cancer patients who can complete 4 to 6 cycles of moderate emetic regimen chemotherapy aged > 18 years delayed vomiting after chemotherapy and subsequent chemotherapy Karnofsky score > 60 life expectancy > 3 months main organ functions normal, that is to say, the following criteria should be met: blood routine examination criteria: HB > 90 g/L (no blood transfusion within 14 days) ANC > 1.5 × 10⁹/L PLT > 75 × 10⁹/L biochemical examination criteria: TBIL < 1.5 ULN (upper limit of normal value) ALT and AST < 3.0 ULN if liver metastasis, ALT and AST < 3.0 ULN AST < 5 ULN, serum Cr < 1 ULN, endogenous creatinine clearance rate > 60 mL/min (Cockcroft‐Gault formula) can read, understand, and complete research questionnaires and logs, including the Nausea and Vomiting Questionnaire (FLIE) and dietary diary questions  Exclusion criteria received research drugs outside the scope of the study in the past 4 weeks or during the study period, and toxicity of recent treatment has not been eliminated pregnant women, breast‐feeding women, women of child‐bearing age who want to be pregnant or who use only oral contraceptives important organ disorder or disease, such as history of myocardial infarction, severe epilepsy requiring medication, etc. mental disability or severe emotional or mental disorder history of other malignant tumour within 5 years (excluding cured cervical or skin basal cell carcinoma) uncontrolled diseases, such as active infection (such as pneumonia) or diabetic ketoacidosis or gastrointestinal obstruction may be biased by results of the study or exposed to unnecessary risk in patients receiving the drug receiving any dose of systemic glucocorticoid therapy; however, local and inhaled glucocorticoids are allowed  Mean/median age, years: not available Gender: both Tumour/cancer type: non‐small cell lung cancer Chemotherapy regimen: not reported, moderately emetogenic chemotherapy Country: China
Interventions	Experimental: arm A: aprepitant/palonosetron/dexamethasone Intervention details not reported Experimental: arm B: palonosetron/dexamethasone Intervention details not reported
Outcomes	Primary outcomes complete response rate of acute CINV complete response rate of delayed CINV Secondary outcomes none reported
Starting date	15 August 2019
Contact information	Research and public contact: Zhang Lemeng (Hunan Cancer Hospital, 283 Tongzipo Road, Yuelu District, Changsha, Hu'nan, China, email: zhanglemeng@hnca.org.cn)
Notes	funding: Hunan Cancer Hospital  unique ID issued by ChiCTR: ChiCTR1900025227

IRCT20191103045317N1.

Study name	Comparison between the effect of Triplet Aprepitant/Dexamethasone/Ondansetron vs doublet Dexamethasone/Ondansetron for prevention of moderately emetogenic chemotherapy: placebo‐controlled double blind, randomised clinical trial of efficacy
Methods	Randomised, interventional, active‐controlled study with 2 arms comparison of aprepitant + ondansetron + dexamethasone vs ondansetron + dexamethasone Target sample size: 90 (actual sample size reached: 160) Masking: double‐blind Baseline patient characteristics: not available
Participants	Inclusion criteria 18 to 70 years of age Karnofsky index ≥ 50% woman at reproductive age should have received an appropriate contraceptive Exclusion criteria causes of nausea or vomiting unrelated to chemotherapy uraemia or electrolyte disturbance active infection uncontrolled seizure candidate for radiation therapy of brain or upper abdomen in less than a week received an antiemetic 24 h before lab studies: WBC < 3000/mm³ ANC < 1500/mm³ plt < 100,000/mm³ ALT and AST > 2.5 × ULN Bill and Cr > 1.5 × ULN opium addicted poor compliance received corticosteroids longer than 3 months and more than 50 mg prednisone daily Carlson’s comorbidity scale score ≥ 3 Mean/median age, years: not available Gender: not available Tumour/cancer type: not available Chemotherapy regimen: not available, moderately emetogenic chemotherapy Country: Iran
Interventions	Experimental: arm A: aprepitant/dexamethasone/ondansetron p.o. administration of 125 mg aprepitant, i.v. injection of 12 mg dexamethasone and 8 mg ondansetron on Day 1, followed by 80 mg Abitant on Days 2 and 3  Experimental: arm B: dexamethasone/ondansetron i.v. injection of 12 mg dexamethasone and 8 mg ondansetron on Day 1
Outcomes	Primary outcome Proportion of patients experiencing nausea and vomiting on Memorial Sloan Kettering Cancer Center (MSKCC) questionnaire Secondary outcomes complete response on Day 1 and Day 5 of chemotherapy complete control on Day 1 and Day 5 of chemotherapy overall response on Day 1 and Day 5 of chemotherapy resistance to treatment on Day 1 and Day 5 of chemotherapy
Starting date	21 December 2018
Contact information	Research and public contact: Mania Rajabzadeh Kheradmardi (Shahid Beheshti University of Medical Sciences, Jorjani Center of Radiation Oncology, Imam Husein Hospital, Shahid Madani Ave, Nezam Abad Town, Tehran, Iran, email: mania_008@yahoo.com)
Notes	funding: Abidi Pharmaceutical Iran unique ID issued by IRCT: IRCT20191103045317N1 trial completion date: 3 March 2019

KTC0001495.

Study name	A randomized, double‐blind, double‐dummy, parallel group, international multi center study assessing the efficacy and safety of a netupitant‐palonosetron Fixed Dose Combination (FDC) compared to an extemporary combination of granisetron and aprepitant on the prevention of highly emetogenic chemotherapy‐induced nausea and vomiting in patients with cancer
Methods	Randomised, interventional, phase 3 study with 2 arms comparison of netupitant + palonosetron + dexamethasone vs aprepitant + granisetron + dexamethasone Target sample size: 832 Masking: double‐blind Baseline patient characteristics: not available
Participants	Inclusion criteria male or female aged 18 years or over cytotoxic chemotherapy naïve histologically or cytologically confirmed solid tumour malignancy scheduled to receive first course of cisplatin‐based chemotherapy regimen (50 mg/m²) that is to be administered over 1 to 4 hours on Day 1 (alone or in combination with other chemotherapy agents) Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 non‐fertile patient or fertile patient (male or female) using reliable contraceptive measures female patient of child‐bearing potential ‐ must have negative urine pregnancy test must be able to read, understand, and follow study procedures and to complete patient diary independently must provide written informed consent Exclusion criteria current use of illicit drugs or current evidence of alcohol abuse scheduled to receive MEC or HEC from Day 2 to Day 5 following cisplatin‐based chemotherapy administration scheduled to receive bone marrow or stem cell transplant moderately or highly emetogenic radiotherapy within 1 week before Day 1 or scheduled for study Days 1 to 5 any drug with potential antiemetic efficacy taken within 24 h before Day 1 systemic corticosteroid therapy (including but not limited to dexamethasone, hydrocortisone, methylprednisolone, or prednisolone) other than that required by the protocol given within 72 h before Day 1 (Note: topical or inhaled steroids are permitted) NK₁ receptor antagonists or any investigational drugs taken within 4 weeks before Day 1 haematological and metabolic status inadequate for receiving a cisplatin‐based HEC regimen, including any of the following criteria: ANC < 1500/mm³, WBC count < 3000/mm³, platelet count < 100,000/mm³, bilirubin > 1.5 × ULN, serum creatinine 1.5 mg/dL (standard units: 132.6 µmol/L), creatinine clearance 50 mL/min; liver enzymes: in patients without known liver metastases: aspartate aminotransferase (AST) 2.5 × ULN, alanine aminotransferase (ALT) 2.5 × ULN; in patients with known liver metastases: AST 5.0 × ULN, ALT 5.0 × ULN active infection (e.g. pneumonia) or any uncontrolled disease (e.g. diabetic ketoacidosis, gastrointestinal obstruction) that, in the opinion of the Investigator, may confound results of the study or pose unwarranted risk in administering study drug treatments history of or predisposition to cardiac conduction abnormalities except for incomplete right bundle branch block serious cardiovascular disease, including acute myocardial infarction, unstable angina pectoris, significant valvular or pericardial disease, history of ventricular tachycardia, symptomatic chronic heart failure, and severe uncontrolled arterial hypertension history of any illness that, in the opinion of the Investigator, may confound results of the study or pose unwarranted risk in administering study treatments any vomiting, retching, or more than mild nausea within 24 h before Day 1 ongoing or recent history of somatic disease causing nausea or vomiting symptomatic primary or metastatic central nervous system malignancy long‐term use of any CYP3A4 substrates or inhibitors (e.g. terfenadine, cisapride, astemizole, clarithromycin, ketoconazole, itraconazole) or their intake within 1 week before Day 1 long‐term use of any CYP3A4 inducers (e.g. barbiturates, rifampicin, rifabutin, phenytoin, carbamazepine) or their intake within 4 weeks before Day 1 concurrent medical condition that would delay dexamethasone administration by 4 days (e.g. systemic fungal infection, uncontrolled diabetes) known contraindication to NK₁ receptor antagonists, 5‐HT₃ receptor antagonists, or dexamethasone enrolment in a previous study with netupitant (alone or in combination with palonosetron) Mean/median age, years: not available Gender: male + female Tumour/cancer type: solid tumour malignancy Chemotherapy regimen: cisplatin‐based chemotherapy regimen Country: multi‐national (7 centres)
Interventions	Experimental: arm A p.o. administration of NETU‐PALO FDC (containing 300 mg netupitant and 0.5 mg palonosetron) on Day 1 (with adjusted dexamethasone regimen: 12 mg on Day 1 + 8 mg daily from Day 2 to Day 4) Active control: arm B p.o. aprepitant 125 mg (on Day 1) + 80 mg daily (on Days 2 and day 3) and 3 mg i.v. granisetron on Day 1 (with adjusted dexamethasone regimen: 12 mg on Day 1 + 8 mg daily from Day 2 to Day 4)
Outcomes	Primary outcome complete response within 120 h after the start of administration of cisplatin‐based HEC Secondary outcomes complete response for 0 to 24 hours, for 25 to 120 hours, and for each 24‐h interval after the start of cisplatin‐based HEC absence of significant nausea absence of nausea absence of emesis absence of rescue medication use severity of nausea (measured by VAS) for each 24‐h interval time to first emetic episode, time to first rescue medication intake, time to treatment failure impact on daily life activities in acute and delayed phases following administration of cisplatin‐based chemotherapy
Starting date	15 January 2015
Contact information	Younyoung Cho, Konkuk University Medical Center
Notes	CRIS Registration Number: KCT0001495 (FDA‐CTR20130417, NETU‐12‐07) primary sponsor: Helsinn Healthcare

NCT03606369.

Study name	Effectiveness and quality of life analysis of palonosetron against ondansetron combined with dexamethasone and fosaprepitant in prevention of acute and delayed emesis associated to chemotherapy moderately and highly emetogenic in breast cancer
Methods	Randomised, interventional, parallel study with 2 arms comparison of fosaprepitant + palonosetron + dexamethasone vs fosaprepitant + ondansetron + dexamethasone Estimated enrolled patients: 560 Masking: open‐label Baseline patient characteristics: not available
Participants	Inclusion criteria 18 years of age or older not metastatic breast cancer confirmed with biopsy candidates to receive chemotherapy with anthracyclines combined with cyclophosphamide or carboplatin combined with docetaxel or docetaxel combined with cyclophosphamide no previous treatment with radiotherapy or chemotherapy adequate haematological function (Hb > 10 g/dL, neutrophils > 1500, platelets > 100,000) and renal (creatinine < 1.2 or creatinine depuration > 60 mL/min), hepatic (liver enzymes < 2.5 normal value), and cardiologic (electrocardiogram) function adequate physical state (ECOG 0 to 1) accept to enter into protocol and sign informed consent Exclusion criteria prolonged QT (> 480 msec) comorbidities of the airway intolerance to swallow medications Mean/median age, years: not available Gender: female Tumour/cancer type: breast cancer Chemotherapy regimen: anthracyclines combined with cyclophosphamide or carboplatin combined with docetaxel or docetaxel combined with cyclophosphamide Country: Mexico
Interventions	Experimental: arm A: palonosetron early emesis: palonosetron 0.25 mg i.v. + dexamethasone 12 mg i.v. + fosaprepitant 150 mg i.v. delayed emesis: dexamethasone 8 mg p.o. on Days 2, 3, and 4 Experimental: arm B: ondansetron early emesis: ondansetron 16 mg i.v. + dexamethasone 12 mg i.v. + fosaprepitant 150 mg i.v. delayed emesis: metoclopramide 10 mg p.o. every 6 hours + dexamethasone 8 mg p.o. every 24 hours
Outcomes	Primary outcome acute nausea control [Time frame: within first 24 h after first dose of chemotherapy] Secondary outcome delayed nausea control [Time frame: between 24 and 120 h after first dose of chemotherapy]
Starting date	5 November 2015
Contact information	Contact: Claudia H. Arce Salinas, MD; phone: 56280400 ext 12065; email: c.arce.salinas@gmail.com Contact: Juan P González Serrano, BD; phone: 5519480352; email: jpablogs_9@hotmail.com
Notes	ClinicalTrials.gov Identifier: NCT03606369 sponsor: Instituto Nacional de Cancerologia de Mexico

UMIN000004021.

Study name	Study of oral neurokinin‐1 antagonist, aprepitant for the prevention of nausea and vomiting in patients receiving chemotherapy with irinotecan alone or combination of irinotecan plus cisplatin for unresectable gastric cancer
Methods	Randomised, cross‐over, interventional, placebo‐controlled study with 2 arms comparison of aprepitant + granisetron + dexamethasone vs placebo + granisetron + dexamethasone Target sample size: 80 Masking: double‐blind Baseline patient characteristics: not available
Participants	Inclusion criteria ≥ 20 years old pathological diagnosis of gastric cancer possible state of oral intake unresectable gastric cancer ECOG performance status 0 to 2 WBC > 3000/mm³, platelets > 10,000/mm³ understand study contents and give informed consent by themselves Exclusion criteria known hypersensitivity to any component of study regimen receiving pimozide or atazanavir sulphate active infectious disease active interstitial pneumonia or pulmonary fibrosis large quantity of pleural effusion or ascites frequent diarrhoea (watery) jaundice ileus pregnant or lactating regarded as ineligible by the doctor who participates in this study Mean/median age, years: not available Gender: male + female Tumour/cancer type: gastric cancer Chemotherapy regimen: irinotecan alone or combination of irinotecan plus cisplatin Country: Japan
Interventions	Cross‐over study Experimental: arm A: aprepitant aprepitant: 125 mg p.o./d on Day 1 followed by 80 mg p.o./d on Days 2 and 3 dexamethasone: 3.3 mg i.v./body on Days 1 to 3 granisetron: 40 μg i.v./kg on Day 1 Experimental: arm B: placebo placebo: placebo capsules p.o. on Days 1 to 3 dexamethasone: 6.6 mg i.v./body on Days 1 to 3 granisetron: 40 μg i.v./kg on Day 1
Outcomes	Primary outcomes overall complete response (no vomiting and no rescue treatment) [Time frame: during and post chemotherapy (0 to 120h)] complete response acute/delayed phase [Time frame: during and post chemotherapy (0 to 120 h)] overall complete protection (no vomiting, no rescue treatment, and no significant nausea (VAS < 25 mm)) [Time frame: during and post chemotherapy (0 to 120 h)] complete protection in acute/delayed phase [Time frame:during and post chemotherapy (0 to 120 h)] Secondary outcomes proportion of patients without vomiting and nausea, frequency of vomiting, no rescue treatment, and time to first vomiting or first rescue treatment [Time frame: during and post chemotherapy (0 to 120 h)] evaluation of nausea, vomiting, and appetite loss using CTCAE, VAS scale, and Functional Living Index‐Emesis (FLIE) scale [Time frame: during and post chemotherapy (0 to 120 h)] investigation of potential factors predisposing patients to nausea and vomiting (e.g. patient's sense of anxiety)
Starting date	1 August 2010
Contact information	Research contact: Hiroto Miwa (Division of Upper Gastroenterology, Department of Internal Medicine; Hyogo College of Medicine; 1‐1 Mukogawa‐cho, Nishinomiya, Hyogo, Japan) Public contact: Junji Tanaka (Division of Upper Gastroenterology, Department of Internal Medicine; Hyogo College of Medicine; 1‐1 Mukogawa‐cho, Nishinomiya, Hyogo, Japan)
Notes	funding: self‐funded by Hyogo College of Medicine unique ID issued by UMIN: UMIN000004021

UMIN000005317.

Study name	Effect of oral neurokinin‐1 antagonist, aprepitant for chemotherapy‐induced nausea and vomiting in patients with gynecologic cancer receiving carboplatin/paclitaxel chemotherapy
Methods	Randomised, interventional, parallel, active‐controlled study with 2 arms comparison of aprepitant + granisetron + dexamethasone vs granisetron + dexamethasone Target sample size: 60 Masking: open‐label Baseline patient characteristics: not available
Participants	Inclusion criteria 20 years old and over gynaecological cancer patients scheduled to receive first course of TC regimen (carboplatin/paclitaxel) chemotherapy Exclusion criteria serious hepatic insufficiency or renal failure nausea or vomiting within 24 h before chemotherapy treated with antiemetic agents within 48 h before chemotherapy any illness (e.g. central nervous system tumour, gastrointestinal obstruction, active peptic ulcer, brain metastasis) causing nausea or vomiting except for chemotherapy‐induced nausea and vomiting unable to receive administered dexamethasone for 3 days due to associated illness such as out‐of‐control diabetes mellitus receiving pimozide judged inappropriate by the investigator as a subject for this study Mean/median age, years: not available Gender: female Tumour/cancer type: gynaecological cancer Chemotherapy regimen: carboplatin/paclitaxel Country: Japan
Interventions	Experimental: arm A: aprepitant aprepitant 125 mg p.o. on Day 1 aprepitant 80 mg p.o. on Days 2 to 3 granisetron 3 mg i.v. on Day 1 dexamethasone 16 mg or 8 mg i.v. on Day 1 dexamethasone 4 mg p.o. on Days 2 to 3 Experimental: arm B granisetron 3 mg i.v. on Day 1 dexamethasone 16 mg or 8 mg i.v. on Day 1 dexamethasone 8 mg p.o. on Days 2 to 3
Outcomes	Primary outcome proportion of patients with complete response (no vomiting and no use of rescue therapy) during overall phase (5 days following initiation of chemotherapy) in first cycle
Starting date	29 November 2010
Contact information	Research contact: Hiroshi Tsujioka (Department of Gynecology; Fukuoka University Hospital; 7‐45‐1 Nanakuma, Jonan‐ku, Fukuoka, Japan)
Notes	funding: self‐funded by Department of Gynecology, Fukuoka University Hospital unique ID issued by UMIN: UMIN000005317

UMIN000005494.

Study name	Aprepitant for nausea, vomiting with the TC therapy of the gynecology cancer patient or the DC therapy, fosaprepitant, granisetron, protective efficacy of the dexamethasone combination therapy
Methods	Randomised, interventional, active‐controlled study with 2 arms comparison of aprepitant/fosaprepitant + granisetron + dexamethasone vs granisetron + dexamethasone Target sample size: 140 Masking: open‐label Baseline patient characteristics: not available
Participants	Inclusion criteria 20 to 70 years old scheduled to receive first course of paclitaxel/carboplatin or docetaxel/carboplatin for gynaecological cancer has not received highly or moderately emetogenic chemotherapy able to sign an approved informed consent able to complete a diary Exclusion criteria serious hepatic insufficiency or renal failure nausea or vomiting within 24 h before chemotherapy treated with antiemetic agents within 48 h before chemotherapy any illness (e.g. central nervous system tumour, gastrointestinal obstruction, active peptic ulcer, brain metastasis) causing nausea or vomiting except for chemotherapy‐induced nausea and vomiting scheduled to receive radiation therapy to the abdomen collateral symptom that the dosage of dexamethasone is impossible for 4 days has received pimozide judged inappropriate by the investigator as a subject for this study Mean/median age, years: not available Gender: female Tumour/cancer type: uterine cancer, ovarian cancer Chemotherapy regimen: paclitaxel/carboplatin or docetaxel/carboplatin Country: Japan
Interventions	Experimental: arm A: aprepitant/fosaprepitant aprepitant on Days 1 to 3 (or fosaprepitant on Day 1) granisetron on Day 1 dexamethasone on Days 1 to 4 Experimental: arm B granisetron on Day 1 dexamethasone on Days 1 to 4
Outcomes	Primary outcome proportion of patients with no emesis in overall phase (0 to 120 h after administration of carboplatin on Day 1)
Starting date	1 May 2011
Contact information	Research contact: Hideaki Masuzaki (Department of Obstetrics and Gynecology; Nagasaki University (graduate school); 1‐7‐1 Sakamoto, Nagasaki, Japan) Public contact: Shuhei Abe (Department of Obstetrics and Gynecology; Nagasaki University (graduate school); 1‐7‐1 Sakamoto, Nagasaki, Japan; email: koutabe@yahoo.co.jp)
Notes	funding: self‐funded by Department of Obstetrics and Gynecology, Nagasaki University (graduate school) unique ID issued by UMIN: UMIN000005494

UMIN000006773.

Study name	Randomized phase II study of aprepitant in patients with colorectal cancer receiving FOLFOX, FOLFIRI, or XELOX chemotherapy regimen
Methods	Randomised, phase 2, parallel, interventional controlled study with 2 arms comparison of aprepitant + 5‐HT₃ receptor antagonist + dexamethasone vs 5‐HT₃ receptor antagonist Target sample size: 100 Masking: n.r. Baseline patient characteristics: not available
Participants	Inclusion criteria 20 years old or over colorectal cancer, scheduled to be treated with first FOLFOX, FOLFILI, or XELOX chemotherapy, including oxaliplatin ≥ 85 mg/m², or irinotecan ≥ 150 mg/m² Exclusion criteria serious hepatic insufficiency or renal failure nausea or vomiting within 24 h before chemotherapy treated with antiemetic agents within 24 h before chemotherapy risk of nausea or vomiting for other reasons (e.g. central nervous system tumour, gastrointestinal obstruction, active peptic ulcer, brain metastasis) unable to be administered dexamethasone for 3 days due to comorbidity, such as out‐of‐control diabetes mellitus pregnant woman or patient with pregnancy desire or lactating woman receiving pimozide judged as inappropriate for inclusion in this study Mean/median age, years: not available Gender: male + female Tumour/cancer type: colon and rectal cancer Chemotherapy regimen: FOLFOX, FOLFIRI, or XELOX chemotherapy regimen Country: Japan
Interventions	Experimental: arm A: aprepitant aprepitant 125 mg p.o. on Day 1 aprepitant 80 mg p.o. on Days 2 and 3 5‐HT₃ receptor antagonist i.v. on Day 1 dexamethasone 6.6 mg i.v. on Day 1 dexamethasone 4 mg p.o. on Days 2 and 3 Experimental: arm B 5‐HT₃ receptor antagonist i.v. on Day 1 dexamethasone 9.9 mg i.v. on Day 1 dexamethasone 8 mg p.o. on Days 2 and 3
Outcomes	Primary outcome percentage of patients with complete response (defined as no emetic episode and no rescue therapy) Secondary outcomes percentage of patients with complete protection (defined as no emesis, no rescue therapy, and no significant nausea) percentage of patients with no emesis percentage of patients with no nausea percentage of patients with no significant nausea time to treatment failure (defined as time to first emetic episode or time to first use of rescue therapy)
Starting date	1 November 2011
Contact information	Contact 1: Shoji Natsugoe (Department of Digestive Surgery, Breast and Thyroid Surgery; Kagoshima University Graduate School of Medical and Dental Sciences; 8‐35‐1 Sakuragaoka, Kagoshima, Japan; telephone: 099‐275‐5358) Contact 2: Sumiya Ishigami (Department of Digestive Surgery, Breast and Thyroid Surgery; Kagoshima University Graduate School of Medical and Dental Sciences; 8‐35‐1 Sakuragaoka, Kagoshima, Japan; telephone: 099‐275‐5360)
Notes	primary sponsor: Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences unique ID issued by UMIN: UMIN000006773

UMIN000007882.

Study name	Multicenter double‐blind randomized comparative parallel study with concomitant therapy of 3 drugs, aprepitant + dexamethasone+palonosetron or aprepitant + dexamethasone+ granisetron, for prevention of nausea/vomiting in breast cancer patients receiving AC therapy
Methods	Randomised, interventional, controlled study with 2 arms comparison of aprepitant + granisetron + dexamethasone vs aprepitant + palonosetron + dexamethasone Target sample size: 660 Masking: double blind Baseline patient characteristics: not available
Participants	Inclusion criteria ≥ 20 years old and ≤ 75 years old (at the time informed consent was obtained) female primary breast cancer of stages I to III and scheduled to receive AC therapy ECOG performance status 0 to 1 can correctly fill in a symptom diary meet the following standard values in general clinical tests: white blood cells ≥ 3000/mm³, neutrophils ≥ 1500/mm³, blood platelet count ≥ 100,000/mm³, AST (GOT) and ALT (GPT) ≤ 2.5 × high end of normal range at the facility, total bilirubin ≤ 1.5 × high end of normal range at the facility, creatinine ≤ 1.5 × high end of normal range at the facility normal cardiac function: ECG within normal range, no symptoms, and no abnormality requiring treatment; cardiac function has been determined to be normal by interview, echocardiography, chest X‐ray, BNP, etc. Exclusion criteria history of administration of moderately to highly emetogenic chemotherapy receiving administration of an antiemetic drug (5‐HT₃ receptor antagonist, phenothiazine, butyrophenone, benzamide, or dopamine receptor antagonist) received administration of a benzodiazepine or narcotic formulation within 48 h before commencement of AC therapy received systemic corticosteroid therapy within 72 h before commencement of AC therapy history of gastrointestinal tract surgery (excluding appendectomy) received or scheduled to receive radiation therapy to abdominal region (diaphragm or lower) or pelvis for a period from 6 days before commencement of AC therapy until Day 6 of AC therapy vomiting or dry vomiting within 24 h before commencement of AC therapy active multiple cancer (synchronous multiple cancer or metachronous multiple cancer with disease‐free interval ≤ 5 years) symptomatic cerebral tumour (including a benign tumour) received administration of the following drugs within 7 days before commencement of AC therapy: clarithromycin, erythromycin, ketoconazole, itraconazole, and digoxin received administration of the following drugs within 4 weeks before commencement of AC therapy: barbiturate drug, rifampicin, phenytoin, and carbamazepine pregnant or lactating, may be pregnant, hoping to become pregnant during the study period, taking an oral contraceptive coexisting disease, such as systemic infection, hepatitis, and uncontrollable diabetes, for which dexamethasone sodium phosphate cannot be administered history of hypersensitivity to granisetron, palonosetron, aprepitant, or dexamethasone other patients judged by the investigator to be inappropriate for inclusion in the study Mean/median age, years: not available Gender: female Tumour/cancer type: breast cancer Chemotherapy regimen: doxorubicin hydrochloride (adriamycin) and cyclophosphamide Country: Japan
Interventions	Experimental: arm A: granisetron aprepitant (Day 1: 125 mg, Days 2 to 3: 80 mg) + dexamethasone (Day 1: 9.9 mg) + granisetron (Day 1: 40 (microgram)/kg) Experimental: arm B: palonosetron aprepitant (Day 1: 125 mg, Days 2 to 3: 80 mg) + dexamethasone (Day 1: 9.9 mg) + palonosetron (Day 1: 0.75 mg)
Outcomes	Primary outcome proportion of patients who showed complete response (no vomiting and no salvage treatment) during a period from 24 to 120 h after AC therapy Secondary outcomes proportion of patients who showed complete response (no vomiting and no salvage treatment) from 0 to 24 h of AC therapy proportion of patients who showed complete response (no vomiting and no salvage treatment) from 0 to 120 h of AC therapy proportion of patients who showed no nausea/degree of nausea QoL dietary intake adverse events
Starting date	1 June 2012
Contact information	Research and public contact: Mitsue Saito (Department of Breast Oncology; Juntendo University Hospital; 3‐1‐3, Hongo, Bunkyo‐ku, Tokyo 113‐8421; email: mitsue@juntendo.ac.jp)
Notes	primary sponsor: Juntendo Clinical Research Support Center co‐sponsor: Juntendo Nerima Hospital, Juntendo Urayasu Hospital,Juntendo Shizuoka Hospital, Shizuoka General Hospital, Mie University Hospital, Sapporo Medical University Hospital, Toho University Omori Medical Center, Ome Municipal General Hospital, Nippon Medical School Musashi Kosugi Hospital, Tottori University Hospital, Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Tokyo Medical University Hospital unique ID issued by UMIN: UMIN000007882

UMIN000012500.

Study name	Effect of aprepitant for nausea and vomiting during paclitaxel + carboplatin (TC) therapy
Methods	Randomised, cross‐over, interventional study with 2 arms comparison of aprepitant + 5‐HT₃ receptor antagonist + dexamethasone vs 5‐HT₃ receptor antagonist + dexamethasone Target sample size: 50 Masking: open‐label Baseline patient characteristics: not available
Participants	Inclusion criteria 20 years of age and older gynaecological malignancy for which TC is taken as first‐line chemotherapy ECOG performance status < 2 Exclusion criteria ECOG performance status ≥ 2 judged as inadequate for inclusion in the study Mean/median age, years: not available Gender: female Tumour/cancer type: gynaecological malignancy Chemotherapy regimen: paclitaxel + carboplatin (TC) regimen Country: Japan
Interventions	Cross‐over study Experimental: arm A first course 5‐HT₃ receptor antagonist + dexamethasone i.v. second course 5‐HT₃ receptor antagonist + dexamethasone i.v. + aprepitant p.o. Experimental: arm B first course 5‐HT₃ receptor antagonist + dexamethasone i.v. + aprepitant p.o. second course 5‐HT₃ receptor antagonist + dexamethasone i.v.
Outcomes	Objective to review utility of aprepitant for antinausea effect during paclitaxel + carboplatin (TC) therapy for the patient with gynaecological malignancy
Starting date	18 January 2011
Contact information	Research contact: Masahide Ohmichi; Department of Obstetrics and Gynecology; Osaka Medical College; 2‐7, Daigaku‐machi, Takatsuki, Osaka; email: m‐ohmichi@poh.osaka‐med.ac.jp Public contact: Masanori Kanemura; Department of Obstetrics and Gynecology; Osaka Medical College; 2‐7, Daigaku‐machi, Takatsuki, Osaka; email: gyn044@poh.osaka‐med.ac.jp
Notes	self‐funded by Department of Obstetrics and Gynecology, Osaka Medical College unique ID issued by UMIN: UMIN000012500

UMIN000032860.

Study name	Palonosetron versus granisetron in combination with fosaprepitant and dexamethasone for TC therapy in patients with gynecologic cancer
Methods	Randomised, factorial, active‐controlled study with 2 arms comparison of fosaprepitant + palonosetron + dexamethasone vs fosaprepitant + granisetron + dexamethasone Target sample size: 240 Masking: open‐label Baseline patient characteristics: not available
Participants	Inclusion criteria female older than 20 years histologically confirmed gynaecological cancer no history of administration with chemotherapy scheduled to receive TC regimen Exclusion criteria severe complications and/or brain metastasis history of convulsive disorder gastrointestinal obstruction Mean/median age, years: not available Gender: female Tumour/cancer type: gynaecological cancer Chemotherapy regimen: paclitaxel + carboplatin (TC) regimen Country: Japan
Interventions	Experimental: arm A: palonosetron fosaprepitant + palonosetron + dexamethasone Experimental: arm B: granisetron fosaprepitant + granisetron + dexamethasone
Outcomes	Primary outcome proportion of patients with no vomiting and no nausea
Starting date	10 June 2018
Contact information	Research and contact person: Soshi Kusunoki; Department of Obstetrics and Gynecology; Faculty of Medicine, Juntendo University; Bunkyoku, Tokyo, Japan; email: skusuno@juntendo.ac.jp
Notes	unique ID issued by UMIN: UMIN000032860 self‐funded by Department of Obstetrics and Gynecology, Faculty of Medicine, Juntendo University

UMIN000041004.

Study name	To establish of optimal antiemetic therapy for trastuzumab deruxtecan therapy‐induced nausea and vomiting in patients with breast cancer: an open‐label, randomized pilot study
Methods	Randomised, interventional, controlled study with 2 arms comparison of aprepitant (fosaprepitant) + granisetron + dexamethasone vs granisetron + dexamethasone Target sample size: 40 Masking: open‐label Baseline patient characteristics: not available
Participants	Inclusion criteria female patient with breast cancer no history of administration of trastuzumab deruxtecan ≥ 20 years old do not take medicine regularly, for example, 5‐HT₃ receptor antagonists, NK₁ receptor antagonists, corticosteroids, antidopamine agonists, phenothiazine tranquilisers, antihistamine drugs, benzodiazepine agents, etc. meeting the following standard values in general clinical tests: AST and ALT ≤ 100 U/L total bilirubin ≤ 2.0 mg/dL  Written informed consent Exclusion criteria history of hypersensitivity or allergy to study drugs or similar compounds. needing antiemetics at enrolment. starting to take opioids within 48 h before enrolment unstable angina, ischaemic heart disease, cerebral haemorrhage or apoplexy, active gastric or duodenal ulcer within 6 months before enrolment convulsive disorder requiring anticonvulsant therapy ascites effusion requiring paracentesis gastrointestinal obstruction pregnant, breast‐feeding, not wishing to use contraception psychosis or psychiatric symptoms that interfere with daily life judged by the investigator to be inappropriate for inclusion in the study Mean/median age, years: not available Gender: female Tumour/cancer type: breast cancer Chemotherapy regimen: trastuzumab deruxtecan Country: Japan
Interventions	Experimental: arm A granisetron + dexamethasone + aprepitant (fosaprepitant) Experimental: arm B granisetron + dexamethasone
Outcomes	Primary outcome complete response (no emesis, no rescue medication) rate within 120 h from the start of chemotherapy Secondary outcomes none reported
Starting date	1 July 2020
Contact information	Research and public contact: Hirotoshi Iihara (Gifu University Hospital, Department of Pharmacy, 500‐1194 1‐1 Yanagido, Gifu, email: dai0920@gifu‐u.ac.jp)
Notes	primary sponsor: Gifu University, self‐funding co‐sponsor: none unique ID issued by UMIN: UMIN000041004

AC: doxorubicin, cyclophosphamide.

ALT: alanine transaminase.

AST: aspartate aminotransferase.

CINV: chemotherapy‐induced nausea and vomiting.

ECG: electrocardiogram. 

ECOG: Eastern Cooperative Oncology Group.

dL: decilitre.

FOLFILI: folinic acid, fluorouracil, and irinotecan.

FOLFOX: folinic acid, fluorouracil, and oxaliplatin.

g: gram.

i.v.: intravenous. 

kg: kilogram.

min: minute.

mL: millilitre.

NK₁: neurokinin‐1.

p.o.:  oral.

QoL: quality of life.

ULN: upper limit of normal.

VAS: visual analogue scale.

WBC: white blood cell count.

XELOX: capecitabine, oxaliplatin.

Differences between protocol and review

Criteria for considering studies for this review

Types of interventions

At protocol stage, we defined that the corticosteroid dexamethasone had to be included in the antiemetic treatment regimen. We named dexamethasone because this is the corticosteroid that is most widely used. However, we had missed that methylprednisolone is sometimes used as the corticosteroid in these antiemetic regimens. We discussed this with a clinical expert (KJ) and decided that because the mechanism of action and the antiemetic role are comparable for these corticosteroids, trials using other corticosteroids (e.g. methylprednisolone) were eligible for inclusion. 

Types of outcome measures

We re‐ordered outcome measures and grouped them into efficacy, quality of life, and safety because we think differentiating between primary and secondary outcomes is more appropriate for clinical trials. We added an overview table of all outcomes including their prioritisation according to consumer relevance. 

We retrospectively added the outcome "serious adverse events", as we realised during preparation of our data extraction sheet that we missed listing it during preparation of the protocol.

Search methods for identification of studies

Searching other resources

We had planned to search the metaRegister of controlled trials (mRCT) (www.controlled‐trials.com/mrct) for ongoing or completed, but not yet published, trials. We could not do so because the study register is no longer available. 

Data collection and analysis

Assessment of risk of bias in included studies

At protocol stage, we had planned to consider sample size as one domain in our bias assessment. Because this is no longer recommended by the PaPaS Group, we removed this domain and considered other sources of bias instead. We did not pre‐specify this item, to provide us with some freedom to consider potential causes of bias that are not addressed in the other domains.

Summary of findings and assessment of the certainty of the evidence

At protocol stage, we had planned to include two 'Summary of findings' tables (one for HEC and one for MEC). Because it was not possible to include the information for all prioritised outcomes and all comparisons within a network in one comprehensive table, we discussed with the PaPaS Group and the Method Support Unit to include instead one 'Summary of findings' table per outcome. For a comprehensive illustration of our results, we randomly chose an exemplary reference treatment. 

At protocol stage, we had planned to rate the certainty of evidence for each outcome using the GRADE approach. Because the latest guidance of the GRADE Working Group suggests that the certainty of evidence of no more than seven outcomes should be assessed (Guyatt 2013), we graded only the outcomes that are most critical or important for decision‐making. These are the outcomes that we have included in the 'Summary of findings' tables.

Based on recommendations by the PaPaS Group, we decided to downgrade twice for imprecision in case of very imprecise or very sparse data. 

Contributions of authors

Drafting the protocol	NS
Developing and running the search strategy	IM PaPaS Information Specialist provided support
Providing clinical advice	KJ
Obtaining copies of studies	NS, MH
Selecting which studies to include (2 people)	NS, MH, BS
Extracting data from studies (2 people)	VP, MH, BS, NK
Assessing risk of bias	MH, NK
Entering data into RevMan	VP, MH
Carrying out the analysis	AA, KK
Interpreting the analysis	VP, NS
Performing GRADE assessment	VP, BS
Drafting the final review	VP, MH
Taking responsibility for updates	NS, VP

Sources of support

Internal sources

• University Hospital Cologne, Germany

  Cochrane Cancer, Department I of Internal Medicine

External sources

• German Ministry for Education and Research (BMBF), Germany

  Grant no: 01KG1510

• National Institute for Health Research (NIHR), UK

  Cochrane Infrastructure funding to the Cochrane Pain, Palliative and Supportive Care Review Group (PaPaS)

Declarations of interest

VP: none known.

AA: none known.

MH: none known.

BS: none known.

NK: none known.

IM: none known.

KJ is a specialist oncology physician who manages patients with CINV. She received consultancy fees or honoraria from Hexal (2016‐2020), Riemser (2016‐2021), Pfizer (2016‐2017), and Voluntis (2016‐2021). Moreover, she was an investigator on Jordan 2016a; Rapoport 2010; and Weinstein 2016. She was not involved in study selection, bias assessment, or data extraction or interpretation, but served as a content expert.

KK: none known.

NS: none known.

Edited (no change to conclusions)