Combination versus sequential single agent chemotherapy for metastatic breast cancer

Rachel F Dear; Kevin McGeechan; Marisa C Jenkins; Alexandra Barratt; Martin HN Tattersall; Nicholas Wilcken

doi:10.1002/14651858.CD008792.pub2

. 2013 Dec 18;2013(12):CD008792. doi: 10.1002/14651858.CD008792.pub2

Combination versus sequential single agent chemotherapy for metastatic breast cancer

Rachel F Dear ^1,^✉, Kevin McGeechan ², Marisa C Jenkins ³, Alexandra Barratt ², Martin HN Tattersall ¹, Nicholas Wilcken ^1,⁴

Editor: Cochrane Breast Cancer Group

PMCID: PMC8094913 PMID: 24347031

Abstract

Background

Combination chemotherapy can cause greater tumour cell kill if the drug dose is not compromised, while sequential single agent chemotherapy may allow for greater dose intensity and treatment time, potentially meaning greater benefit from each single agent. In addition, sequentially using single agents might cause less toxicity and impairment of quality of life, but it is not known whether this might compromise survival time.

Objectives

To assess the effect of combination chemotherapy compared to the same drugs given sequentially in women with metastatic breast cancer.

Search methods

We searched the Cochrane Breast Cancer Group Specialised Register, using the search terms "advanced breast cancer" and "chemotherapy", MEDLINE and EMBASE on 31 October 2013. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov were also searched (22 March 2012).

Selection criteria

Randomised controlled trials of combination chemotherapy compared to the same drugs used sequentially in women with metastatic breast cancer in the first‐, second‐ or third‐line setting.

Data collection and analysis

Two authors independently extracted data from published trials. Hazard ratios (HR) were derived from time‐to‐event outcomes where possible, and a fixed‐effect model was used for meta‐analysis. Response rates were analysed as dichotomous variables (risk ratios (RR)), and toxicity and quality of life data were extracted where available.

Main results

Twelve trials reporting on nine treatment comparisons (2317 patients randomised) were identified. The majority of trials (10 trials) had an unclear or high risk of bias. Time‐to‐event data were collected for nine trials for overall survival and eight trials for progression‐free survival. All 12 trials reported results for tumour response. In the 12 trials there were 1023 deaths in 2317 women randomised. There was no difference in overall survival, with an overall HR of 1.04 (95% confidence interval (CI) 0.93 to 1.16; P = 0.45), and no significant heterogeneity. This result was consistent in the four subgroups analysed (risk of bias, line of chemotherapy, type of schema of chemotherapy, and relative dose intensity). In particular, there was no difference in survival according to the type of schema of chemotherapy, that is whether chemotherapy was given on disease progression or after a set number of cycles. In the seven trials that reported progression‐free survival (time to first progression in the sequential arm), 637 women progressed out of the 846 women randomised. There was weak evidence of a higher risk of progression in the combination arm (HR 1.11; 95% CI 0.99 to 1.25; P = 0.08) with no significant heterogeneity. This result was consistent in all subgroups. Overall tumour response rates were higher in the combination arm (RR 1.16; 95% CI 1.06 to 1.28; P = 0.001) but there was significant heterogeneity for this outcome across the trials. In the seven trials that reported treatment‐related deaths, there was no significant difference between the two arms, although the CIs were very wide due to the small number of events (RR 1.53; 95% CI 0.71 to 3.29; P = 0.28). The risk of febrile neutropenia was higher in the combination arm (RR 1.32; 95% CI 1.06 to 1.65; P = 0.01). There was no statistically significant difference in the risk of neutropenia, nausea and vomiting, or treatment‐related deaths. Overall quality of life showed no difference between the two groups, but only three trials reported this outcome.

Authors' conclusions

There is weak evidence that sequential single agent chemotherapy has a positive effect on progression‐free survival, whereas combination chemotherapy has a higher response rate and a higher risk of febrile neutropenia in metastatic breast cancer. There is no difference in overall survival time between these treatment strategies, both overall and in the subgroups analysed. In particular, there was no difference in survival according to the schema of chemotherapy (giving chemotherapy on disease progression or after a set number of cycles) or according to the line of chemotherapy (first‐line versus second‐ or third‐line). Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid disease progression.

Plain language summary

Combination (several drugs at the same time) versus sequential chemotherapy (same drugs given one after the other) for metastatic breast cancer

Metastatic breast cancer is not currently a curable disease but one that can be very effectively treated with chemotherapy, endocrine therapy and targeted therapies. Average survival is about two years but some women live for many years longer. It is important to investigate the best way to give chemotherapy to treat metastatic breast cancer in order to optimise survival and quality of life and to minimise the side effects from treatment.

This review investigated whether giving a combination of drugs at the same time was more effective than giving the same drugs one at a time (sequential treatment).

A literature search conducted in October 2013 resulted in 12 randomised controlled studies with 2317 patients that could be included in the analysis. The patients had metastatic breast cancer and either they had not been treated or had received one or two treatments after their diagnosis of metastatic breast cancer. The primary outcomes were overall survival and progression‐free survival (time from randomisation to the time of disease progression). Secondarily, we compared the degree the tumour shrunk in response to chemotherapy (overall response rate), toxicity and quality of life.

There was no difference in overall survival between the two groups but we found that when drugs were given one at a time there maybe more time before the tumours grew back again (longer progression‐free survival). However, combination chemotherapy caused tumours to shrink more, although this did not result in longer survival than when using sequential chemotherapy. Rates of febrile neutropenia (infection) were higher in the combination arm but there was no difference in the rates of neutropenia (low white blood cells). There was no difference in quality of life between the two groups but there were only three trials that reported this information. Quality of life should be included as an outcome in future trials addressing this question. Overall, the studies did not consistently report the way patients were randomised and this may be a source of bias in the results.

Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid disease progression.

Background

Description of the condition

Breast cancer is the most common type of cancer and the second leading cause of cancer deaths in women. In 2002, there were over 1.1 million new cases and approximately 410,000 deaths from breast cancer, worldwide (Ferlay 2004).

If breast cancer becomes metastatic, it is treatable but not curable. The aims of treatment include improving survival and quality of life. There has never been a randomised trial comparing systemic therapy to best supportive care to demonstrate that systemic therapy can improve survival in women with metastatic breast cancer. Despite this, data from single institution series and population‐based registries show that the survival of patients with metastatic breast cancer has improved over time, from approximately 16 months in the early 1990s to beyond 24 months in 2001 (Chia 2007; Giordano 2004), although some women may live for many years (Hayes 1995). This improvement coincides with the availability of new systemic agents (taxanes, aromatase inhibitors, trastuzumab and capecitabine) and a higher proportion of women with metastatic breast cancer receiving systemic therapy (Chia 2007). While longer survival cannot be attributed conclusively to the use of improved systemic therapies it is believed they have contributed. The optimal combination, sequence and timing of systemic agents for metastatic breast cancer remains unresolved. Selection of treatment is based on consideration of the site of recurrence, symptoms, anticipated response to treatment, expected toxicities, quality of life and patient preference. Ultimately most women with metastatic breast cancer will receive chemotherapy because they have hormone receptor negative disease, their disease has become refractory to endocrine therapy, they are symptomatic, or they have rapidly progressive visceral disease (Hortobagyi 1996).

Description of the intervention

Combination chemotherapy can achieve several important objectives that are less probable with single agent chemotherapy. Combination therapy firstly provides increased cell kill within the range of acceptable toxicity for each drug, as long as dosing is not compromised and the tumour is sensitive to each drug; secondly used with an heterogeneous tumour cell population it increases the probability of some cells being responsive compared with a single agent; and thirdly the combination may delay the development of drug resistance if there is rapid cell kill and a reduced cell mass.

The scheduling of multiple drug regimens may influence both the effectiveness and toxicity of the regimen. The Goldie and Coldman model predicts that drug resistant cells may be present even in small tumours (Goldie 1982). They propose alternating non cross‐resistant drug combinations as early as possible as a means of eliminating resistant clones. Norton and Day predicted that the sequential use of drug combinations would outperform alternating cycles because no two combinations were likely to be strictly non‐cross resistant or have equal cell killing capacity (Day 1986; Norton 1991). In the adjuvant setting, a randomised trial observed that four three‐week cycles of doxorubicin followed by eight three‐week cycles of cyclophosphamide methotrexate fluorouracil (CMF) in women with high‐risk primary breast cancer (four or more positive lymph nodes) was more effective than an alternating schedule of doxorubicin and CMF in terms of disease‐free and overall survival (Bonadonna 1995).

A potential limitation of the effectiveness of combination chemotherapy is that dose levels of the component drugs may need to be reduced to limit toxicity. Another limitation of combination treatment is that it may use non‐cross resistant agents rapidly. In contrast, these agents given as sequential monotherapy may allow for more cycles of effective treatment. The use of sequential monotherapy may allow for greater dose intensity and allow for a treatment approach that gets maximum time and benefit from each agent.

Optimal dosing of chemotherapy is challenging because of the different effects on normal and tumour tissues. Most cancer chemotherapeutic agents show a steep dose‐response curve in the linear phase of tumour growth. A reduction in drug dose when the tumour is in this linear phase of the dose‐response curve almost always results in a reduction in the probability of cure before a reduction in antitumour activity is observed. This observation has led cancer clinicians and researchers to conclude that when cure is a reasonable treatment expectation, increasing the dose intensity of treatment will increase the rate and duration of tumour response and improve the survival rate (Hryniuk 1987). However, there are limitations to the effectiveness of dose intensity, as demonstrated by the use of high‐dose chemotherapy. A Cochrane Review (Farquhar 2008) of six randomised trials comparing high‐dose chemotherapy and autograft with conventional chemotherapy for women with metastatic breast cancer demonstrated no statistically significant evidence of benefit in overall survival. Increased dose intensity also comes at a cost of increased toxicity to normal tissues. If palliation is the primary goal of treatment, and anticipated survival is limited, then toxicity and quality of life become important factors when deciding on a treatment regimen.

Combination therapy can also refer to the combination of chemotherapy with a biological agent. This regimen is most commonly used in women with human epidermal growth factor receptor 2‐positive (HER2‐positive) metastatic breast cancer, for example a taxane and trastuzumab or capecitabine and lapatinib. This review focuses only on the combination of chemotherapeutic agents compared to the same agents given as sequential monotherapy.

How the intervention might work

The question of interest is whether patients receiving combination chemotherapy regimens have better health outcomes, including longer survival and less toxicity, than for sequential single agent chemotherapy. Sequential single agent use has evolved to maintain dose intensity while limiting toxicity, and without sacrificing survival. Sequential therapy may refer to the consecutive administration of single agents with each agent introduced after disease progression or it may refer to a planned sequence of single agents given without interruption between the regimens.

Why it is important to do this review

The comparison of combination chemotherapy with the same agents given sequentially as monotherapy is a clinically important question that addresses a common clinical scenario facing medical oncologists treating women with metastatic breast cancer. This is because the role of combination chemotherapy in metastatic breast cancer is still unresolved. Combination chemotherapy is often given to obtain a response in immediately life‐threatening circumstances whereas sequential monotherapy is given for less urgent treatment needs. A Cochrane review showed that combination chemotherapy gave a statistically significant improvement in response rate, time to progression and overall survival but was more toxic compared to single agent chemotherapy (Carrick 2009). Few studies included in this review formally compared women's quality of life between combination and single agent therapy. While the review by Carrick et al tested the benefit of two agents given in combination compared to a single agent it did not address the benefit of two agents given in combination versus the same drugs given as sequential monotherapy. It is not known if it is more beneficial to give a combination of drugs at the same time or to give the same drugs as single agents administered sequentially. Furthermore, regarding sequential single agents, there is still debate about whether single agents should be given until disease progression (when the drugs are changed) or whether a planned sequence of single agents should be given that involves changing the drug before resistance develops and disease progression occurs (see Objectives).

Objectives

To assess the effect of combination chemotherapy compared to the same drugs given sequentially in women with metastatic breast cancer.

We compared the use of single chemotherapy agents given sequentially with regimens using a combination of the same agents for the management of women with metastatic breast cancer to determine their effect on survival. This involved examining two different chemotherapy schemata:

schema 1: the combination given until disease progression versus sequential single agents given on disease progression, e.g. cycles of combination AB until disease progression versus cycles of drug A until disease progression followed by cycles of drug B until disease progression;
schema 2: the combination given for a set number of cycles versus sequential single agents given as a set number of cycles, e.g. eight cycles of AB versus four cycles of A followed by four cycles of B.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled clinical trials that compared a combination of drugs with the same single chemotherapy agents given sequentially for women with metastatic breast cancer.

Types of participants

Women diagnosed with all types of advanced (metastatic) breast cancer. Metastatic breast cancer was defined as stage IV by the TNM classification of malignant tumours. Adults aged 18 years and above were included.

Types of interventions

The intervention was any chemotherapy regimen containing a combination of chemotherapeutic agents given as first‐line or second‐line and third‐line treatment.

The comparison was sequential single agent use of the drugs in the combination chemotherapy regimen given as first‐line or second‐line and third‐line treatment. The sequential single agents may have been administered according to either schema 1 or schema 2 as described under Objectives.

Trials were excluded that included a single agent chemotherapeutic agent alone (drug A alone).

Types of outcome measures

Primary outcomes

Overall survival
Progression‐free survival (or time to progression)

Secondary outcomes

Tumour response rate
Quality of life measures
Toxicity

Outcome definitions

Overall survival (OS): time from date randomised to date of death (any cause).
Progression‐free survival (PFS): time from date randomised to date of progression or death from any cause. We used time to progression (TTP) (time from randomisation to date of progression) when PFS was not reported.
Overall response rate (RR): the percentage of patients with a complete or partial response. Complete and partial responses were defined according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria (Therasse 2000). That is, a complete response was the disappearance of all target lesions and a partial response was at least a 30% decrease in the sum of the longest diameter of target lesions. The composite response rate was used for sequential single agent chemotherapy. This was calculated as the percentage of patients responding at some point during any of the single agent regimens.
Quality of life was defined as an expression of well‐being and measured using a validated scale (e.g. Short Form‐36 (SF‐36), European Organisation for Research and Treatment of Cancer (EORTC), Functional Assessment of Cancer Therapy (FACT)).
Toxicities: restricted in our analyses to serious side effects as classified by the World Health Organization (WHO) or National Cancer Institution Criteria (NCIC) grading 3 or more.

Search methods for identification of studies

See: Breast Cancer Group methods used in reviews.

Only trials published in English were included.

Electronic searches

We searched the following databases.

The Cochrane Breast Cancer Group (CBCG) Specialised Register (searched on 31 October 2013). Details of search strategies used by the CBCG for the identification of studies and the procedures used to code references are outlined in the CBCG's module at www.mrw.interscience.wiley.com/cochrane/clabout/articles/BREASTCA/frame.html). Trials with the key words 'advanced breast cancer', 'metastatic breast cancer', 'combination chemotherapy', 'sequential single agent chemotherapy' and 'single agent chemotherapy' were extracted and considered for inclusion in the review.
MEDLINE (via OvidSP) (searched on 31 October 2013), see Appendix 1.
EMBASE (via Embase.com) (searched on 31 October 2013), see Appendix 2.
The WHO International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/Default.aspx) for prospectively registered and ongoing trials (searched on 22 March 2012), see Appendix 3.
ClinicalTrials.gov (http://clinicaltrials.gov/ct2/search/advanced) (searched on 22 March 2012), see Appendix 4.

Searching other resources

(a) Bibliography searching

We tried to identify further studies from reference lists of identified relevant trials or reviews. A copy of the full article for each reference reporting a potentially eligible trial was obtained, where possible. Where this was not possible, we attempted to make contact with the authors to provide additional information.

(b) Handsearching of journals

We handsearched the database of abstracts on the treatment of metastatic breast cancer from the annual meetings of the American Society of Clinical Oncology (1987 to 2000; 2003) and San Antonio Breast Cancer Conference (1981 to 2002). A list of journals currently being handsearched by The Cochrane Collaboration is available at the US Cochrane Center Handsearch master list page (http://us.cochrane.org/master-list).

Data collection and analysis

We performed the analysis in accordance with the guidelines published in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (Higgins 2011).

Selection of studies

Two authors (RD, MT) independently screened the results of the search. We applied the selection criteria described above to each trial and recorded any reasons for exclusion. A full copy of trials likely to be included in the review were retrieved and read. For unpublished trials, we assessed the available information from conference proceedings. Any discrepancies were resolved by a third author. Only manuscripts published in English were included.

Data extraction and management

Data were extracted from trial publications by two authors (RD, MT). A standardised data extraction form was used to record details of study design, participants, setting, interventions, follow‐up, quality components, efficacy outcomes, toxicity and quality of life. The form is available from the authors upon request. A third author (NW) was available to resolve any discrepancies regarding the extraction of quantitative data and a fourth author (AB) was available to resolve any discrepancies regarding the assessment of the quality of the randomised controlled trials. When a trial was presented in abstract form, we sought further information, as necessary, from the internet, contacting the authors, or checking for the next best available resource or publication.

In the case of published papers, we also contacted the authors for additional information if it was not reported in the paper. For studies with more than one publication, we extracted data from all the publications, however we considered the final or updated version of the trial as the primary reference.

Assessment of risk of bias in included studies

Quality assessment was based on the assessment of a list of procedures related to the design and reporting of trials that are known to minimise the risk of bias. Therefore, trials were assessed by the degree they addressed each of the following items.

Random sequence generation

Low risk: if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing of a coin, shuffling of cards or throwing dice were considered as adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure.
Unclear risk: if the trial was described as randomised but the method used for the allocation sequence generation was not described.
High risk: if the trial used a system involving dates, names, admittance numbers or alternating allocation.

Allocation concealment

Low risk: if the allocation of patients involved a central independent unit; sequentially numbered identical drug containers; or serially numbered, sealed, opaque envelopes.
Unclear risk: if the trial was described as randomised but the method used to conceal the allocation was not described.
High risk: if the allocation sequence was known to the investigators who assigned participants; the envelopes did not have all three safeguards; or if a non‐random sequence was used.

Blinding of participants, personnel and outcome assessors

Low risk: if the trial was described as double‐blind or single‐blind i.e. double‐blind (method described and technique used meant that neither the participant nor the care provider or assessor knew which treatment was given) and single‐blind (participant or care provider or assessor was aware of the treatment given).
Unclear risk: if the trial was described as double‐blind or single‐blind but the method of blinding was not described.
High risk: if the trial was open label (all parties were aware of the treatment).

Incomplete outcome data addressed

The completeness of outcome data were described for each main outcome. The description included whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomised participants), reasons for attrition and exclusions and any re‐inclusions in the analysis.

Low risk: no missing data; or reasons for missing data were not related to outcome, were balanced across groups with similar reasons or numbers of participants missing, or plausible effect size was not enough to change observed effect.
Unclear risk: attrition and exclusions reported but reasons were not included.
High risk: incomplete outcome data were not addressed.

Free of selective outcome reporting

We stated how the possibility of selective outcome reporting was examined by the review authors and what was found.

Low risk: all pre‐specified outcomes were reported in a pre‐specified way.
Unclear risk: expected outcomes were reported but not pre‐specified.
High risk: outcomes were not reported as planned or expected; or the outcomes were reported in a way they could not be used in the review, e.g. only direction of effect and significance.

Other sources of bias

Comments were made regarding the following.

If the treatment groups were similar at baseline regarding the most important prognostic factors.
If the trial was stopped early using a data‐dependent process (including formal stopping rule).
If analysis was by intention to treat (or enough data were provided to replicate such an analysis i.e. number of withdrawals, dropouts and losses to follow‐up in each group).

We contacted authors of the primary trial reports, when necessary, to clarify data and provide missing information. We entered the characteristics and outcomes of the included trials and details of the excluded trials into our database.

Each selected study was assessed as low, unclear or high risk of bias based on assessments of the domains described above (random sequence generation, allocation concealment, blinding, incomplete data addressed, free of selective outcome reporting and other sources of bias). Since the selected studies had different levels of risk of bias (with most being of high or unclear risk of bias), we conducted a primary analysis including all trials and then performed a sensitivity analysis to show how the conclusions were affected if studies of unclear or high risk of bias were excluded.

Measures of treatment effect

We extracted the hazard ratio (HR) and associated variances for overall survival and progression‐free survival (or time to progression) directly from the trial publications.

We obtained a pooled HR through the generic inverse variance approach, from the log HR and the standard error of the log HR, using fixed‐effect and random‐effects models along with assessments of heterogeneity (Deeks 2006). The pooled HR represented the overall risk of an event on combination chemotherapy regimens compared to single agent sequential chemotherapy.

We reported ratios of treatment effects for time‐to‐event outcomes so that HRs less than 1.0 favoured combination chemotherapy regimens and values greater than 1.0 favoured single agent sequential chemotherapy regimens. The forest plots for overall survival and progression‐free survival presented the hazard ratio (HR) and 95% confidence interval (CI).

We analysed an indicator of response as a dichotomous variable (complete or partial response versus stable disease or no response) and derived a pooled relative risk (RR). We reported responses on an intention‐to‐treat basis. If the majority of trials only reported results based on assessable (not randomised) patients, we used assessable responses. We reported ratios of treatment effects for response so that risk ratios (RRs) more than 1.0 favoured combination chemotherapy regimens and values less than 1.0 favoured single agent sequential chemotherapy regimens.

Unit of analysis issues

Four trials were three‐arm studies (Cresta 2004; Koroleva 2001; Sledge 2003 Soto 2006). Two out of three of the arms in each of these trials were combined. For Cresta 2004, there was one combination arm of doxorubicin and docetaxel, a single agent arm where these two drugs were given on an alternating schedule, and another single agent arm where the drugs were given sequentially. The two single agent arms were combined in this trial. In Koroleva 2001 there were two combination arms using doxorubicin and docetaxel but at different doses, and one sequential single agent arm. The two combination arms were combined in this trial. In Sledge 2003 there was one combination arm that included doxorubicin and paclitaxel, one single agent arm that started with doxorubicin, and another single agent arm that began treatment with paclitaxel. The two single agent arms were combined in this arm. In Soto 2006 there was one sequential single agent arm that included capecitabine followed by a taxane (either docetaxel or paclitaxel), a combination arm that included capecitabine and docetaxel, and another combination arm that included capecitabine and paclitaxel. The two combination arms were combined in this trial.

Dealing with missing data

If data were missing, we made multiple attempts to contact the original investigators. This was successful in the case of four studies (Alba 2004 Fountzilas 2001 Park 2010; Sledge 2003). When we were unable to obtain data, two authors extracted data from published Kaplan‐Meier curves (Tierney 2007). If there was a discrepancy between authors, we took an average of the two values at each time point and used the averaged values to generate a new HR. To allow for premature follow‐up, we adjusted the numbers at risk based upon estimated minimum and maximum follow‐up times. If these were not reported we estimated minimum follow‐up using the estimated time taken to complete treatment. We estimated maximum follow‐up using the last event reported in the relevant time‐to‐event curve. We have presented these follow‐up estimates in the Characteristics of included studies table under 'Notes'.

Assessment of heterogeneity

We included all outcomes available from the individual studies in the meta‐analysis with heterogeneity reported by the Q (Chi²) and the I² statistics. Statistical significance of the Q statistic was judged as P < 0.10 because of the low statistical power of the test. The I² statistic indicates the per cent variability due to between‐study (or inter‐study) variability, as opposed to within‐study (or intra‐study) variability. An I² statistic greater than 50% was considered large (Higgins 2002), however this was considered alongside the magnitude and direction of effects and the P value from the Chi² test for heterogeneity.

Assessment of reporting biases

Reporting bias was assessed using the Cochrane Collaboration's assessment tool (Table 8.6a) in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Data synthesis

We used a fixed‐effect model for meta‐analysis. HRs and RRs were calculated with a generic inverse variance fixed‐effect model analysis. Response rates were analysed as dichotomous variables and we derived a pooled relative risk. We used the Mantel‐Haenszel method with zero‐cell corrections for the analysis of treatment‐related deaths because this was a rare event, however we used the inverse variance method to pool the RRs for the other toxicity outcomes (neutropenia, febrile neutropenia and nausea and vomiting) because these outcomes are not rare events. We also analysed all toxicity outcomes using conditional logistic regression.

Subgroup analysis and investigation of heterogeneity

As outlined in the protocol, we pre‐specified three subgroups. We extracted data on these subgroups from all trial publications, where available.

Schedule of single agent: schema 1 versus schema 2 (see Objectives).
Dose of chemotherapy: trials where the dose used in the combination regimen was the same as the doses of the single agents compared to trials where the doses were not equivalent in the two arms of the study.
Line of chemotherapy for metastatic breast cancer (first‐line versus second‐line or third‐line chemotherapy).

Sensitivity analysis

A sensitivity analysis comparing the outcomes using studies at low risk of bias with outcomes of studies of unclear or high risk of bias was performed. Trials were assessed for quality by the degree to which they addressed the following seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and if the analysis was by intention to treat. Each selected study was assessed as low, unclear or high risk of bias based on assessing each of these domains. If the majority of the seven categories (that is four or more out of seven) were considered at unclear or high risk of bias the trial was considered to be at risk of bias.

Results

Description of studies

See: Characteristics of included studies and Characteristics of excluded studies.

Results of the search

We searched the Cochrane Breast Cancer Group Specialised Register, EMBASE, MEDLINE, the WHO ICTRP and ClinicalTrials.gov. From these databases 2299 were coded as references to studies of advanced breast cancer and chemotherapy (Figure 1). Of these 160 were duplicate studies, leaving 2139 remaining studies. Of these 18 were trials that compared combination chemotherapy with drugs given as sequential single agents. Two were excluded because the drugs given in the sequential arm were different from those in the combination arm. Two studies (Campone 2013; Zhang 2013) were categorised as 'study awaiting classification' because the trials were completed but with insufficient data for inclusion at present. The results from these two small trials will be included in an updated version of this review. The remaining 14 references reported the results of 14 randomised trials. One report (Chlebowski 1989) combined the results from two separate but similar trials, both of which were reported earlier (Chlebowski 1979; Smalley 1976). Both of these publications were therefore excluded from the review. The 12 eligible trials reported on nine treatment comparisons, summarised in Table 1. The details of the chemotherapy protocols used are detailed in Table 2. The trials included in the forest plots are labelled by primary author and date of publication. Nine of the trials were published in full while three were only available in abstract form.

Results of search strategy applied 31 October 2013 for combination versus sequential single agent chemotherapy for metastatic breast cancer.

1. Summary of treatment comparisons.

Combination	Sequential	Number of trials
doxorubicin + docetaxel	doxorubicin → docetaxel	Alba 2004 Cresta 2004(included alternating regimen) Koroleva 2001 (included 2 combination arms with different doses)
5‐fluorouracil + cyclophosphamide + vincristine	5‐fluorouracil → cyclophosphamide → vincristine	Baker 1974
capecitabine + docetaxel or paclitaxel	capecitabine → docetaxel or paclitaxel	Beslija 2006 Soto 2006
5‐fluorouracil + cyclophosphamide + prednisone + thyroxine or vincristine	5‐fluorouracil → cyclophosphamide → thyroxine or vincristine → prednisone	Chlebowski 1989
epirubicin + paclitaxel	epirubicin → paclitaxel	Conte 2004
epirubicin + paclitaxel	dose dense epirubicin→ paclitaxel	Fountzilas 2001
gemcitabine + vinorelbine	gemcitabine → vinorelbine	Park 2010
doxorubicin + paclitaxel	doxorubicin → paclitaxel or paclitaxel → doxorubicin	Sledge 2003
docetaxel + gemcitabine	docetaxel → gemcitabine	Tomova 2010

Trial name	Arm I	Arm II
Alba 2004	Arm I: AT= Doxorubicin 50 mg/m² and docetaxel 75 mg/m² both on day 1. Cycles repeated every 21 days for 6 cycles. If prior anthracyclines: given 3 cycles of AT at above doses followed by 3 cycles of docetaxel 100 mg/m²	Arm II: A→T= Doxorubicin 75 mg/m² intravenously day 1 for 3 cycles followed by docetaxel 100 mg/m2 intravenously day 1 for 3 cycles. If prior anthracyclines given 2 cycles of doxorubicin 75 mg/m² followed by 4 cycles of docetaxel 100 mg/m². Cycles repeated every 21 days
Baker 1974	Arm I: FCV= 5‐fluorouracil 7.5 mg/kg intravenously days 1‐5 plus cyclophosphamide 4 mg/kg intravenously days 1 to 5 plus vincristine 0.015 mg/kg intravenously days 1 and 8. Cycles repeated every 28 days until disease progression	Arm II: F→C→V= 5‐fluorouracil 15 mg/kg intravenously days 1 to 5 every 28 days until disease progression then cyclophosphamide 8 mg/kg intravenously days 1 to 5 every 28 days until disease progression then vincristine 0.02 mg/kg intravenously weekly until disease progression
Beslija 2006	Arm I: XT= Capecitabine (Xeloda, X) 1250 mg/m² twice daily orally from days 1 to 14 and docetaxel (Taxotere, T) 75 mg/m² intravenously day 1. Cycle repeated every 21 days until disease progression	Arm II: T→X= Docetaxel 100 mg/m² intravenously day 1 until disease progression then capecitabine 1250 mg/m² twice daily orally from days 1 to 14 until disease progression. Cycles repeated every 21 days
Chlebowski 1989	WCSG Arm I: CMFTP= Cyclophosphamide 2 mg/kg/day orally, plus 5‐fluorouracil 15 mg/kg every 2 weeks intravenously from day 1, plus methotrexate 30 mg/m² every 2 weeks intravenously beginning on day 8, plus prednisone 0.5 mg/kg/day orally, plus triiodothyronine 0.005 mg daily. Cycle repeated until disease progression. SECSG Arm I: Cyclophosphamide 400 mg/m² intravenously day 1 every 28 days, plus 5‐fluorouracil 400 mg/m² intravenously day 1 and day 8 every 28 days, plus methotrexate 30 mg/m² intravenously day 1 and day 8 every 28 days, plus vincristine 1 mg/m² intravenously day 1 and day 8 every 28 days, plus prednisone 80mg orally daily from days 1 to 7 every 28 days. Cycle repeated until disease progression. or Cyclophosphamide 100 mg orally daily, plus 5‐fluorouracil 400 mg/m² intravenously weekly, plus methotrexate 20 mg/m² orally weekly, plus vincristine 1 mg/m² intravenously weekly, plus prednisone 45 mg orally daily for 14 days, then 30 mg daily for 14 days then 15 mg daily for 28 days. Cycle repeated until disease progression	WCSG Arm II: F→C→TP→M= 5‐fluorouracil 15 mg/kg weekly intravenously from day 1 for a minimum of 4 weeks until disease progression then cyclophosphamide 2 mg/kg/day orally for a minimum of 4 weeks until disease progression then triiodothyronine 0.005 mg daily plus prednisone 0.5 mg/kg/day for a minimum of 6 weeks until disease progression then methotrexate 30 mg/m² intravenously weekly for a minimum of 4 weeks SECSG Arm II: F→MC→V→P= 5‐fluorouracil 600 mg/m² intravenously weekly until disease progression then methotrexate 20 mg/m² orally biweekly until disease progression then cyclophosphamide 100 mg/m² orally daily until disease progression then vincristine 1 mg/m² intravenously weekly until disease progression then prednisone 45 mg orally daily for 14 days then 30 mg daily for 14 days then 15 mg daily for 30 days
Conte 2004	Arm I: EP= Epirubicin 90 mg/m² plus paclitaxel 200 mg/m² intravenously day 1. Cycles repeated every 21 days for 8 cycles	Arm II: E→P= Epirubicin 120 mg/m² intravenously day 1 for 4 cycles then paclitaxel 250 mg/m² intravenously day 1 for 4 cycles. Cycles repeated every 21 days
Cresta 2003	Arm I: AT= Doxorubicin 60 mg/m² plus docetaxel 60 mg/m² intravenously day. Cycles repeated every 21 days for 8 cycles	Arm II: A→T (sequential regimen)= Doxorubicin 75 mg/m² intravenously on day 1 for 4 cycles followed by docetaxel 75 mg/m² intravenously on day 1 for 4 cycles. Cycles repeated every 21 days. Maximum 8 cycles. Arm III: T then A (alternating regimen)= Docetaxel 100 mg/m² intravenously on day 1 for 4 cycles alternating with doxorubicin 75 mg/m² intravenously on day 1 for 4 cycles. Cycles repeated every 21 days. Maximum 8 cycles
Fountzilas 2001	Arm I: P= Epirubicin 80 mg/m² plus paclitaxel 175 mg/m² intravenously day 1. Cycles repeated every 21 days for 6 cycles	Arm II: E→P Epirubicin 110 mg/m² intravenously day 1 for 4 cycles followed by paclitaxel 225 mg/m² intravenously day 1 for 4 cycles. Cycles repeated every 14 days with G‐CSF support (dose dense regimen)
Koroleva 2001	Arm I: AT= Doxorubicin 50 mg/m² plus docetaxel 75 mg/m² intravenously day 1. Cycles repeated every 21 days for 8 cycles	Arm II: T→A= Docetaxel 100 mg/m² intravenously day 1 for 4 cycles followed by doxorubicin 75 mg/m² intravenously day 1 for 4 cycles. Cycles repeated every 21 days. Arm III: AT= Doxorubicin 60 mg/m² plus docetaxel 60 mg/m² intravenously day 1. Cycles repeated every 21 days for 8 cycles
Park 2010	Arm I: GV= Gemcitabine 1,000 mg/m² plus vinorelbine 25 mg/m² intravenously days 1 and 8. Cycles repeated every 21 days until disease progression	Arm II: G→V= Gemcitabine 1,200 mg/m² intravenously on days 1 and 8 until disease progression then vinorelbine 30 mg/m² intravenously days 1 and 8 until disease progression. Cycles repeated every 21 days
Sledge 2003	Arm I: AT= Doxorubicin 50 mg/m² plus paclitaxel 150 mg/m² over 24 hours intravenously day 1. Cycles repeated every 21 days until disease progression	Arm II: A (→P)= Doxorubicin 60 mg/m² intravenously day 1 for a maximum of 8 cycles. If disease progressed crossed over to paclitaxel 175 mg/m² intravenously over 24 hours on day 1. Cycles repeated every 21 days. Arm III: P (→A)= Paclitaxel 175 mg/m² intravenously over 24 hours on day 1. If disease progressed crossed over to doxorubicin 60 mg/m² intravenously day 1. Cycles repeated every 21 days
Soto 2006	Arm I: XT= Capecitabine 825 mg/m² twice daily orally from days 1 to 14 plus docetaxel 75 mg/m² intravenously on day 1 until disease progression. Cycles repeated every 21 days	Arm II: X→T (docetaxel or paclitaxel)= Capecitabine 1250 mg/m² twice daily orally days 1 to 14 until disease progression then docetaxel 100 mg/m² or paclitaxel 175 mg/m² intravenously on day 1 until disease progression. Cycles repeated every 21 days. Arm III: XP= Capecitabine 825 mg/m² twice daily orally from days 1 to 14 plus paclitaxel 175 mg/m² intravenously on day 1 until disease progression. Cycles repeated every 21 days
Tomova 2010	Arm I: TG= Docetaxel 75 mg/m² intravenously on day 1 plus gemcitabine 1,000 mg/m² intravenously on days 1 and 8. Cycles repeated every 21 days for 8 cycles	Arm II: T→G= Docetaxel 100 mg/m² intravenously on day 1 for 4 cycles followed by gemcitabine 1,250 mg/m² intravenously on days 1 and 1 for 4 cycles. Cycles repeated every 21 days

Date	Event	Description
21 November 2014	Amended	Added new data for progression‐free survival analysis for Schema 1 (where drugs changed on disease progression). The analysis now includes a comparison of time to first progression in the combination arm versus time to first progression (not after second progression) in the sequential arm (refer to analyses 2.1, 9.1, 16.1, 23.1 and 30.1). This review version also includes new data obtained for Sledge 2003.
21 January 2014	Amended	Corrected labels for Analysis 10.1, 17.1, 24.1 (Figure 6) and 31.1, and also the number of participants in the Beslija trial for the outcome overall response

1	randomised controlled trial.pt.
2	randomized controlled trial.pt.
3	controlled clinical trial.pt.
4	randomized.ab.
5	randomised.ab.
6	placebo.ab.
7	randomly.ab.
8	trial.ab.
9	groups.ab.
10	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9
11	exp Breast Neoplasms/
12	metastatic breast cancer$.ti,ab,tw.
13	metastatic breast neoplas$.ti,ab,tw.
14	metastatic breast tumour$.ti,ab,tw.
15	metastatic breast tumor$.ti,ab,tw.
16	metastatic breast carcinoma$.ti,ab,tw.
17	advance$ breast cancer$.ti,ab,tw.
18	advance$ breast neoplas$.ti,ab,tw.
19	advance$ breast tumour$.ti,ab,tw.
20	advance$ breast tumor$.ti,ab,tw.
21	advance$ breast carcinoma$.ti,ab,tw.
22	12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21
23	11 and 22
24	exp Drug Therapy, Combination/
25	combination chemotherapy.mp.
26	sequential single agent chemotherapy.mp.
27	(sequential adj6 single adj6 agent adj6 chemotherap$).mp.
28	24 or 25 or 26 or 27
29	10 and 23 and 28
30	Animals/
31	Humans/
32	30 not 31
33	29 not 32

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Progression‐free survival (amended analysis)	7	1483	Hazard Ratio (IV, Fixed, 95% CI)	1.11 [0.99, 1.25]
2.2 Progression‐free survival (all trials)	8		Hazard Ratio (IV, Fixed, 95% CI)	1.16 [1.03, 1.31]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
8.1 Overall survival ‐ risk of bias	9	Hazard Ratio (IV, Fixed, 95% CI)	1.04 [0.93, 1.16]
8.1.1 Low risk of bias	2	Hazard Ratio (IV, Fixed, 95% CI)	1.21 [0.93, 1.58]
8.1.2 High/unclear risk of bias	7	Hazard Ratio (IV, Fixed, 95% CI)	1.01 [0.90, 1.14]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
9.1 Progression‐free survival ‐ risk of bias (amended analysis)	7	Hazard Ratio (IV, Fixed, 95% CI)	1.11 [0.99, 1.25]
9.1.1 Low risk of bias	2	Hazard Ratio (IV, Fixed, 95% CI)	1.15 [0.94, 1.41]
9.1.2 High/unclear risk of bias	5	Hazard Ratio (IV, Fixed, 95% CI)	1.09 [0.94, 1.26]
9.2 Progression‐free survival ‐ risk of bias	8	Hazard Ratio (IV, Fixed, 95% CI)	1.16 [1.03, 1.31]
9.2.1 Low risk of bias	2	Hazard Ratio (IV, Fixed, 95% CI)	1.15 [0.94, 1.41]
9.2.2 High/unclear risk of bias	6	Hazard Ratio (IV, Fixed, 95% CI)	1.17 [1.01, 1.35]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Overall response ‐ risk of bias	12	2140	Risk Ratio (IV, Fixed, 95% CI)	1.16 [1.06, 1.28]
10.1.1 Low risk of bias	2	381	Risk Ratio (IV, Fixed, 95% CI)	0.91 [0.76, 1.10]
10.1.2 High/unclear risk of bias	10	1759	Risk Ratio (IV, Fixed, 95% CI)	1.26 [1.13, 1.39]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Treatment‐related deaths ‐ risk of bias	7	902	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.71, 3.29]
11.1.1 Low risk of bias	1	198	Risk Ratio (M‐H, Fixed, 95% CI)	2.60 [0.28, 24.60]
11.1.2 High/unclear risk of bias	6	704	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [0.62, 3.20]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
12.1 Neutropaenia ‐ risk of bias	12	Risk Ratio (IV, Fixed, 95% CI)	0.94 [0.87, 1.02]
12.1.1 Low risk of bias	2	Risk Ratio (IV, Fixed, 95% CI)	0.62 [0.50, 0.76]
12.1.2 High/unclear risk of bias	10	Risk Ratio (IV, Fixed, 95% CI)	1.00 [0.92, 1.09]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
13.1 Febrile neutropenia ‐ risk of bias	9	Risk Ratio (IV, Fixed, 95% CI)	1.32 [1.06, 1.65]
13.1.1 Low risk of bias	2	Risk Ratio (IV, Fixed, 95% CI)	1.60 [0.72, 3.57]
13.1.2 High/unclear risk of bias	7	Risk Ratio (IV, Fixed, 95% CI)	1.30 [1.03, 1.64]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
14.1 Nausea and vomiting ‐ risk of bias	8	Risk Ratio (IV, Fixed, 95% CI)	0.88 [0.57, 1.34]
14.1.1 Low risk of bias	1	Risk Ratio (IV, Fixed, 95% CI)	1.03 [0.21, 4.99]
14.1.2 High/unclear risk of bias	7	Risk Ratio (IV, Fixed, 95% CI)	0.87 [0.56, 1.35]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
15.1 Overall survival ‐ line of chemotherapy	9	Hazard Ratio (IV, Fixed, 95% CI)	1.04 [0.93, 1.16]
15.1.1 First line chemotherapy	7	Hazard Ratio (IV, Fixed, 95% CI)	1.04 [0.93, 1.18]
15.1.2 Second/third line chemotherapy	2	Hazard Ratio (IV, Fixed, 95% CI)	1.03 [0.76, 1.40]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
16.1 Progression free survival ‐ line of chemotherapy (amended analysis)	7	Hazard Ratio (IV, Fixed, 95% CI)	1.11 [0.99, 1.25]
16.1.1 First line chemotherapy	6	Hazard Ratio (IV, Fixed, 95% CI)	1.11 [0.99, 1.26]
16.1.2 Second/third line chemotherapy	1	Hazard Ratio (IV, Fixed, 95% CI)	0.85 [0.24, 2.99]
16.2 Progression free survival ‐ line of chemotherapy	8	Hazard Ratio (IV, Fixed, 95% CI)	1.16 [1.03, 1.31]
16.2.1 First line chemotherapy	6	Hazard Ratio (IV, Fixed, 95% CI)	1.16 [1.02, 1.31]
16.2.2 Second/third line chemotherapy	2	Hazard Ratio (IV, Fixed, 95% CI)	1.25 [0.80, 1.95]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
17.1 Overall response ‐ subgroup analysis, line of chemotherapy	12	2140	Risk Ratio (IV, Fixed, 95% CI)	1.16 [1.06, 1.28]
17.1.1 First line chemotherapy	9	1778	Risk Ratio (IV, Fixed, 95% CI)	1.10 [1.00, 1.22]
17.1.2 Second/third line chemotherapy	3	362	Risk Ratio (IV, Fixed, 95% CI)	1.54 [1.22, 1.93]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
18.1 Treatment‐related deaths ‐ line of chemotherapy	7	902	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.71, 3.29]
18.1.1 First line chemotherapy	5	722	Risk Ratio (M‐H, Fixed, 95% CI)	1.72 [0.70, 4.18]
18.1.2 Second/third line chemotherapy	2	180	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.23, 4.94]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
19.1 Neutropaenia ‐ line of chemotherapy	12	Risk Ratio (IV, Fixed, 95% CI)	0.92 [0.84, 1.01]
19.1.1 First‐line chemotherapy	9	Risk Ratio (IV, Fixed, 95% CI)	0.96 [0.87, 1.05]
19.1.2 Second/third‐line chemotherapy	3	Risk Ratio (IV, Fixed, 95% CI)	0.64 [0.48, 0.85]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
20.1 Febrile neutropenia ‐ line of chemotherapy	9	Risk Ratio (IV, Fixed, 95% CI)	1.32 [1.06, 1.65]
20.1.1 First‐line chemotherapy	7	Risk Ratio (IV, Fixed, 95% CI)	1.34 [1.07, 1.68]
20.1.2 Second/third‐line chemotherapy	2	Risk Ratio (IV, Fixed, 95% CI)	0.86 [0.24, 3.15]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
21.1 Nausea and vomiting ‐ line of chemotherapy	8	Risk Ratio (IV, Fixed, 95% CI)	0.88 [0.57, 1.34]
21.1.1 First‐line chemotherapy	5	Risk Ratio (IV, Fixed, 95% CI)	0.85 [0.55, 1.33]
21.1.2 Second/third‐line chemotherapy	3	Risk Ratio (IV, Fixed, 95% CI)	1.25 [0.27, 5.74]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
22.1 Overall survival ‐ Schema 1 versus Schema 2	9	Hazard Ratio (IV, Fixed, 95% CI)	1.04 [0.93, 1.16]
22.1.1 Schema 1	5	Hazard Ratio (IV, Fixed, 95% CI)	0.98 [0.86, 1.12]
22.1.2 Schema 2	4	Hazard Ratio (IV, Fixed, 95% CI)	1.22 [0.99, 1.49]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
23.1 Progression‐free survival ‐ Schema 1 versus Schema 2 (amended analysis)	7	Hazard Ratio (IV, Fixed, 95% CI)	1.11 [0.99, 1.25]
23.1.1 Schema 1	3	Hazard Ratio (IV, Fixed, 95% CI)	1.11 [0.94, 1.31]
23.1.2 Schema 2	4	Hazard Ratio (IV, Fixed, 95% CI)	1.12 [0.94, 1.33]
23.2 Progression‐free survival ‐ Schema 1 versus Schema 2	8	Hazard Ratio (IV, Fixed, 95% CI)	1.16 [1.03, 1.31]
23.2.1 Schema 1	4	Hazard Ratio (IV, Fixed, 95% CI)	1.20 [1.03, 1.40]
23.2.2 Schema 2	4	Hazard Ratio (IV, Fixed, 95% CI)	1.12 [0.94, 1.33]

PERMALINK

Combination versus sequential single agent chemotherapy for metastatic breast cancer

Rachel F Dear

Kevin McGeechan

Marisa C Jenkins

Alexandra Barratt

Martin HN Tattersall

Nicholas Wilcken

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Outcome definitions

Search methods for identification of studies

Electronic searches

Searching other resources

(a) Bibliography searching

(b) Handsearching of journals

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Random sequence generation

Allocation concealment

Blinding of participants, personnel and outcome assessors

Incomplete outcome data addressed

Free of selective outcome reporting

Other sources of bias

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

1. Summary of treatment comparisons.

2. Chemotherapy details.

Included studies

Excluded studies

Risk of bias in included studies

2.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

2.2. Analysis.

9.2. Analysis.

16.2. Analysis.

23.2. Analysis.

30.2. Analysis.

2.1. Analysis.

9.1. Analysis.

16.1. Analysis.

23.1. Analysis.

30.1. Analysis.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
24.1 Overall response ‐ Schema 1 versus Schema 2	12	2140	Risk Ratio (IV, Fixed, 95% CI)	1.16 [1.06, 1.28]
24.1.1 Schema 1	6	1344	Risk Ratio (IV, Fixed, 95% CI)	1.46 [1.28, 1.65]
24.1.2 Schema 2	6	796	Risk Ratio (IV, Fixed, 95% CI)	0.92 [0.80, 1.04]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
25.1 Treatment‐related deaths ‐ Schema 1 versus Schema 2	7	902	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.71, 3.29]
25.1.1 Schema 1	3	379	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.36, 2.44]
25.1.2 Schema 2	4	523	Risk Ratio (M‐H, Fixed, 95% CI)	4.00 [0.87, 18.35]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
26.1 Neutropaenia ‐ subgroup analysis, Schema 1 versus Schema 2	12	Risk Ratio (IV, Fixed, 95% CI)	0.94 [0.87, 1.02]
26.1.1 Schema 1	6	Risk Ratio (IV, Fixed, 95% CI)	0.99 [0.87, 1.14]
26.1.2 Schema 2	6	Risk Ratio (IV, Fixed, 95% CI)	0.92 [0.84, 1.01]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
27.1 Febrile neutropenia ‐ Schema 1 versus Schema 2	9	Risk Ratio (IV, Fixed, 95% CI)	1.32 [1.06, 1.65]
27.1.1 Schema 1	3	Risk Ratio (IV, Fixed, 95% CI)	1.76 [1.14, 2.73]
27.1.2 Schema 2	6	Risk Ratio (IV, Fixed, 95% CI)	1.19 [0.92, 1.55]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
28.1 Nausea and vomiting ‐ Schema 1 versus Schema 2	8	Risk Ratio (IV, Fixed, 95% CI)	0.88 [0.57, 1.34]
28.1.1 Schema 1	3	Risk Ratio (IV, Fixed, 95% CI)	0.75 [0.39, 1.46]
28.1.2 Schema 2	5	Risk Ratio (IV, Fixed, 95% CI)	0.98 [0.56, 1.71]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
29.1 Overall survival ‐ relative dose intensity	4	Hazard Ratio (IV, Fixed, 95% CI)	1.14 [0.92, 1.39]
29.1.1 Similar dose intensity	2	Hazard Ratio (IV, Fixed, 95% CI)	1.23 [0.93, 1.62]
29.1.2 Different dose intensity	2	Hazard Ratio (IV, Fixed, 95% CI)	1.03 [0.76, 1.40]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
30.1 Progression‐free survival ‐ relative dose intensity (amended analysis)	3	Hazard Ratio (IV, Fixed, 95% CI)	1.13 [0.90, 1.43]
30.1.1 Similar dose intensity	2	Hazard Ratio (IV, Fixed, 95% CI)	1.15 [0.91, 1.45]
30.1.2 Different dose intensity	1	Hazard Ratio (IV, Fixed, 95% CI)	0.85 [0.24, 2.99]
30.2 Progression‐free survival ‐ relative dose intensity	4	Hazard Ratio (IV, Fixed, 95% CI)	1.17 [0.95, 1.44]
30.2.1 Similar dose intensity	2	Hazard Ratio (IV, Fixed, 95% CI)	1.15 [0.91, 1.45]
30.2.2 Different dose intensity	2	Hazard Ratio (IV, Fixed, 95% CI)	1.25 [0.80, 1.95]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
31.1 Overall response ‐ relative dose intensity	6	679	Risk Ratio (IV, Fixed, 95% CI)	0.90 [0.77, 1.05]
31.1.1 Similar dose intensity	3	355	Risk Ratio (IV, Fixed, 95% CI)	0.88 [0.72, 1.07]
31.1.2 Different dose intensity	3	324	Risk Ratio (IV, Fixed, 95% CI)	0.93 [0.72, 1.20]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
32.1 Treatment‐related deaths ‐ relative dose intensity	4	406	Risk Ratio (M‐H, Fixed, 95% CI)	1.66 [0.45, 6.10]
32.1.1 Similar dose intensity	1	82	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
32.1.2 Different dose intensity	3	324	Risk Ratio (M‐H, Fixed, 95% CI)	1.66 [0.45, 6.10]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
33.1 Neutropaenia ‐ relative dose intensity	6	Risk Ratio (IV, Fixed, 95% CI)	1.01 [0.92, 1.12]
33.1.1 Similar dose intensity	3	Risk Ratio (IV, Fixed, 95% CI)	1.08 [0.97, 1.20]
33.1.2 Different dose intensity	3	Risk Ratio (IV, Fixed, 95% CI)	0.67 [0.51, 0.87]