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. 2024 Nov 26;32(12):822. doi: 10.1007/s00520-024-09035-8

The evolving landscape of antiemetic prophylaxis for chemotherapy-induced nausea and vomiting: inspiration from cisplatin-based antiemetic and non-antiemetic trials

Ya Sun 1,#, Yalan Wang 2,#, Gang Chen 2, Yaxiong Zhang 2, Li Zhang 2,✉, Xi Chen 2,✉
PMCID: PMC11599296  PMID: 39589545

Abstract

Background

Despite the significant advancements in antiemetic regimens for preventing chemotherapy-induced nausea and vomiting (CINV), over 40% of cancer patients undergoing chemotherapy still experience CINV in clinical practice. To figure out underlying reasons and outline the landscape of antiemetic prophylaxis for CINV, our focus centered on cisplatin, one of the most commonly used highly emetogenic chemotherapy drugs. We aimed to elucidate trends in CINV management by analyzing data extracted from cisplatin-based clinical trials.

Methods

We extracted CINV-related data from 156 eligible randomized clinical trials, comprising 39 antiemetic trials and 117 non-antiemetic trials, all with patients undergoing high-dose cisplatin-based chemotherapy. Subsequently, we conducted separate analyses of the extracted CINV data within antiemetic and non-antiemetic trial groups, as well as comparisons between them.

Results

Over the years, both antiemetic and non-antiemetic trials showed significant improvements in no-vomiting rates, although gains in no-nausea rates were more modest. Notably, antiemetic trials frequently underreported outcomes related to nausea control. There was a distinct yet gradually narrowing disparity in vomiting control rates between antiemetic and non-antiemetic trials during the same time frame. While non-antiemetic trials achieved comparable CINV control rates using the same antiemetic regimen as antiemetic trials, they exhibited significantly greater variations in no-vomiting and no-nausea rates.

Conclusions

The landscape of CINV management in cisplatin-based chemotherapy has evolved significantly alongside improvements in antiemetic agents. Substantial progress has been made in emesis control within both antiemetic and non-antiemetic cisplatin-based clinical trials. More attention should be paid on the chemotherapy induced nausea, and multiple approaches are needed to increase guideline adherence in future clinical practice.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00520-024-09035-8.

Keywords: CINV, Cisplatin, Clinical trials, Trend

Introduction

Cisplatin has become a cornerstone of chemotherapeutic regimens since its approval in 1978 [1]. To this day, combination-chemotherapy with cisplatin or other platinum-based compounds remains the first-line treatment for multiple malignancies, including lung cancer, ovarian cancer, cervical cancer, breast cancer, and bladder cancer [2–7]. However, the severe side effects associated with cisplatin often lead to a significant deterioration in patients’ quality of life and may cause dose reduction or chemotherapy discontinuation. One of the most common side effects of cisplatin is chemotherapy-induced nausea and vomiting (CINV), affecting nearly 90% of patients who receive high-dose cisplatin without antiemetic treatment [8].

Over the past four decades, the landscape of CINV prevention has undergone a profound transformation. Beginning with high-dose metoclopramide in the 1980s [9], followed by the first introduction of 5-HT3 receptor antagonists (5-HT3RAs) in the early 1990s [10], and culminating in the approval of NK1-receptor antagonist (NK1RA) in 2003 [11], significant advancements have been made. The recent antiemetic trials have achieved over 80% complete response (CR) rate in acute phase (24 h after cisplatin treatment) and about 70% CR rate in overall phase (0–120 h after cisplatin treatment) with the adoption of NK1RA-based triplet regimens (5-HT3RAs, glucocorticoids, and NK1RAs) [12, 13]. Despite these strides, retrospective studies indicate that more than 40% of cancer patients are still grapple with CINV [14] and adherence to antiemetic guidelines in clinical practice remains inconsistent [15].

Cisplatin has been an honest witness of CINV management over the past four decades, with numerous non-antiemetic cisplatin-based prospective randomized clinical trials (RCTs) providing a wealth of data on CINV management in clinical practice. Therefore, our present study systemically searched and investigated the trends of CINV control in cisplatin-based antiemetic trials (“cisATs” for short) and cisplatin-based non-antiemetic trials (“cisNATs” for short) since the approval of cisplatin. The aim of present study is to uncover the evolving landscape of antiemetic prophylaxis for cisplatin-induced nausea and vomiting in both cisATs and cisNATs, revealing the current status of CINV control and guideline adherence through detailed analysis.

Methods

Search strategy

We conducted a detailed search for all eligible RCTs from 1978 to 2023. Trials were identified through a computer search in PubMed, Embase, and Cochrane Central Register of Controlled Trials databases with restriction in English language. We used a combination of terms of “cisplatin,” “DDP,” “chemotherapy-induced nausea and vomiting,” and “CINV” to find relevant articles, ensuring the inclusion of the latest research progress. Additionally, we examined reference lists, relevant guidelines, and review articles for further guidance. Two authors (CX and SY) independently conducted the literature search.

Inclusion and exclusion criteria

Eligible studies met the following criteria: (a) phase III RCTs or prospective RCTs with more than 100 patients available for CINV analysis; (b) the participants were diagnosed as malignant tumor and received cisplatin-based chemotherapy; (c) the dose of cisplatin administration was not less than 50 mg/m2 given in 1 day; and (d) data on nausea and vomiting related to cisplatin application could be independently extracted from articles. Studies failing to meet these inclusion criteria were excluded.

Outcome measures

Given that complete response rates in antiemetic trials were generally defined as no emesis and no rescue therapy, distinct from no-vomiting rates reported in non-antiemetic trials, we extracted no-vomiting rates and no nausea rates in both cisATs and cisNATs as main results for the analysis of antiemetic effects. To minimize the potential bias, we separately recorded antiemetic outcomes of acute phase and overall phase within cisATs, and then used overall phase results to compare antiemetic outcomes between cisATs and cisNATs.

Study selection and data extraction

The titles, abstracts, and full texts of each study were examined independently by two investigators (CX and SY) to assess their eligibility. Data was extracted independently by each author. For each included study, information regarding the type of clinical trials, study publication time, patient enrollment time, patient number of high-dose cisplatin treatment arm, description of antiemetic interventions, and cisplatin-induced nausea and vomiting outcomes were recorded. It is worth noting that most cisNATs tended to report severe vomiting and nausea rates in safety profiles, which were also specifically documented by us. All extracted data were meticulously checked for internal consistency, with disagreements resolved through discussion among the investigators.

Statistical analysis

No-vomiting rates and no-nausea rates in both cisATs and cisNATs were calculated based on the extracted data. Trends of no-vomiting rates, no-nausea rates in cisNATs and cisATs were presented using bubble scatter chart. Unpaired t test was utilized for comparing no-vomiting rates and no-nausea rates among different groups. All p values corresponded to two-sided tests, and significance was set at p < 0.05. Statistical analysis was conducted using of R version 3.6.0.

Results

Trial flow and characteristics of eligible trials

A total number of 22,560 records were identified through database searching and review of guidelines. After removing duplicates and conducting abstract and full-text screening, data was extracted from 156 eligible trials, comprising 39 cisATs and 117 cisNATs involving patients in chemotherapy treatment arms. A detailed outline of the trial inclusion process is presented in Fig. 1. Baseline characteristics of the included trials are listed in Table S1-3. Notably, specific descriptions of antiemetic regimens were only accessible for 13.68% of cisNATs (Table S3).

Fig. 1.

Fig. 1

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Flow gram of cisplatin-based clinical trial selection. This figure describes the screening procedure of prospective randomized controlled cisplatin-based clinical trials

Overall trends in no-vomiting rates and no-nausea rates

Our results demonstrated continuous improvements in CINV control in both cisATs and cisNATs over the past few decades. Notably, no-vomiting rates exhibited a more pronounced increase over time (Fig. 2a) when compared to no-nausea rates in both settings (Fig. 2b). Furthermore, there was a greater degree of variability in results within cisNATs than in cisATs, both for no-vomiting and no-nausea rates.

Fig. 2.

Fig. 2

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Comparison of no-vomiting rates and no-nausea rates between cisATs and cisNATs. a Comparison of no-vomiting rates between cisATs and cisNATs. b Comparison of no-nausea rates between cisATs and cisNATs. CINV, chemotherapy-induced nausea and vomiting; cisATs, cisplatin-based antiemetic trials; cisNATs, cisplatin-based non-antiemetic trials. Bubble size represents the number of patients in each cisplatin treatment arm

Efficacy comparison among different antiemetic regimens in cisATs

Our analysis showed that the efficacy of cisplatin-induced vomiting control was improved in both acute phase and overall phase with advancements in antiemetic regimens. In terms of no-vomiting rates in acute phase, the use of 5-HT3Ras alone achieved similar control rates when compared with dopamine receptor antagonists plus glucocorticoids (50.46% vs 46.92%, p = 0.44), while a significant enhancement in vomiting control was observed in the combination of 5-HT3RAs with glucocorticoids (50.46% vs 76.98%, p < 0.0001). The addition of NK1RAs further improved no-vomiting rates by 12% in the acute phase (91.30% vs 76.98%, p < 0.0001) (Fig. 3a, b).

Fig. 3.

Fig. 3

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Comparison of antiemetic efficacy in acute phase among different antiemetic regimens in cisATs. a Bubble plot for no-vomiting rates in acute phase. b Box plot for the comparison of no-vomiting rates among different antiemetic regimens. c Bubble plot for no-nausea rates in acute phase. d Box plot for the comparison of no-vomiting rates among different antiemetic regimens. cisATs, cisplatin-based antiemetic trials; DA, dopamine receptor antagonist; G, glucocorticoid; 5-HT3RA, 5-HT3 receptor antagonist; NK1RA, NK1 receptor antagonist; ns, no significance; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Bubble size represents the number of patients in each cisplatin treatment arm

Unfortunately, updates of antiemetic regimens over the past few decades have only brought limited benefits to the control of cisplatin-induced nausea. Significant increases in no-nausea rates in the acute phase were observed only when comparing 5-HT3RAs plus glucocorticoids with 5-HT3RAs (71.41% vs 46.17%, p < 0.0001) (Fig. 3c, d). Similar trends in CINV management were also observed in the overall phase in cisATs (Fig. 4a–d).

Fig. 4.

Fig. 4

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Comparison of antiemetic efficacy in overall phase among different antiemetic regimens in cisATs. a Bubble plot for no-vomiting rates in overall phase. b Box plot for the comparison of no-vomiting rates among different antiemetic regimens. c Bubble plot for no-nausea rates in overall phase. d Box plot for the comparison of no-vomiting rates among different antiemetic regimens. cisATs, cisplatin-based antiemetic trials; DA, dopamine receptor antagonist; G, glucocorticoid; 5-HT3RA, 5-HT3 receptor antagonist; NK1RA, NK1 receptor antagonist; ns, no significance; *p < 0.05, **p < 0.01. ***p < 0.001, ****p < 0.0001. Bubble size represents the number of patients in each cisplatin treatment arm

Comparison of CINV control rates among cisNATs

To more accurately evaluate the impact of CINV guideline recommendations on new antiemetic regimens, cisNATs were divided into three phases based on the introduction of antiemetic guideline recommendations of 5-HT3RA-based doublet regimens (5-HT3RAs and glucocorticoids) [16] and the widespread guideline recommendations of NK1RA-based triplet regimens (5-HT3RAs, glucocorticoids, and NK1RAs) [17], which are generally considered milestones in CINV prevention history. As expected, significant increase in no-vomiting rates was observed after the guideline recommendation of 5-HT3RA-based doublet regimens and NK1RA-based triplet regimens (40.30% vs 54.18%, p = 0.0003; 54.18% vs 66.01%, p = 0.0001, respectively), while no-nausea rates also improved slightly across the three groups (23.32% vs 35.23%, p = 0.0009; 35.23% vs 44.50%, p = 0.0085, respectively) (Table S4).

Notably, after the widespread recommendations of NK1RA-based triplet regimens, no-vomiting rates in cisNATs were also significantly lower than those in the NK1RA-based subgroup of cisATs (66.01% vs 76.92%, p = 0.0005), while no significant difference was found in no-nausea rates (44.50% vs 49.31%, p = 0.24) (Fig. 5a, b). Further analysis revealed that the coefficients of variation in all cisNAT subgroups were significantly higher than those in NK1RA-based subgroup of cisATs (Table S4). To better understand the substantial variations of CINV management among cisNATs, we extracted details of antiemetic regimens and summarized them. Among 117 included cisNATs, 14 (11.97%) of trials only mentioned adherence to local protocols or guidelines, 87 (74.36%) of trials did not mention antiemetic prophylaxis treatment at all, and only 16 (13.68%) of trials reported specific antiemetic regimens or guidelines (Fig. 5c).

Fig. 5.

Fig. 5

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Evolving trend of antiemetic efficacy improvement in cisNATs. a Trend of no-vomiting rates change in cisNATs along with the improvement of antiemetic regimens. b Trend of no-nausea rates change in cisNATs along with the improvement of antiemetic regimens. c Summary of antiemetic regimen details of included cisNATs. cisNATs, cisplatin-based non-antiemetic trials; cisATs, cisplatin-based antiemetic trials; ns, no significance; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001

It is noteworthy that both severe vomiting events and severe nausea events, which are of great concern in cisNATs, significantly decreased after the introduction of antiemetic guideline recommendations of 5-HT3RA-based doublet regimens (severe vomiting comparison: 12.79% vs 6.01%, p < 0.0001; severe nausea comparison: 14.46% vs 5.78%, p < 0.0001). However, no further decrease was observed after the widespread recommendations of NK1RA-based triplet regimens (Fig. 6a, b).

Fig. 6.

Fig. 6

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Evolving trend of severe vomiting and nausea rates in cisNATs. a Trend of severe vomiting rates change in cisNATs along with the improvement of antiemetic regimens. b Trend of severe nausea rates change in cisNATs along with the improvement of antiemetic regimens. cisNATs, cisplatin-based non-antiemetic trials; ns, no significance; *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001

Discussion

Over the past few decades, the landscape of antiemetic prophylaxis for chemotherapy-induced nausea and vomiting undergone dramatic changes. Our study showed that significant progress was made in emesis control in both antiemetic and non-antiemetic cisplatin-based clinical trials, while the improvement in nausea control was minor. To be noticed, although great improvement of CINV control was shown in cisNATs, substantial variations in the effectiveness of antiemetic strategies persist. Furthermore, a disparity in antiemetic effectiveness between cisNATs and cisATs continues to exist.

Firstly, our results reveal consistent progress over time in controlling emesis and nausea in both antiemetic and non-antiemetic cisplatin-based clinical trials. Notably, cisATs have achieved superior emesis and nausea control compared to cisNATs over the same time frame. The emergence of this gap in CINV control can be primarily attributed to the earlier implementation of new antiemetic regimens in cisATs. Encouragingly, this gap has gradually narrowed over time, indicating a growing focus on CINV management in clinical practice. It is essential to recognize that since the approval of the first neurokinin-1 receptor antagonist (NK1RA), aprepitant, there have been no revolutionary breakthroughs in antiemetic agents. This period of relative stability in CINV prevention in recent CINV trials may also contribute to narrowing the gap between the two settings.

Secondly, when we grouped trials based on the key timepoints marking revolutionary progress in antiemetic treatment in cisNATs, we observed that while progress was evident over time, the efficacy of vomiting control in cisNATs, which enrolled patients after the widespread adoption of NK1RA-based triplet regimens, still could not match that of the same regimen in cisATs. Additionally, we found that the variability in CINV control rates in cisNATs with post-NK1RA-based triplet regimen enrollments was significantly higher than that seen in cisATs using the same regimen. A disappointing discovery was that a substantial percentage (74.36%) of the included cisNATs did not even mention antiemetic prophylaxis treatment, implying that guideline-recommended antiemetic treatments are often overlooked, even in the context of clinical trials. Besides, this finding aligns with numerous real-world studies that have indicated inconsistent adherence to antiemetic guidelines, with reported adherence rates ranging from 27 to 71% [18–21]. To be noticed, the lack of information on the antiemetic therapies used in most NATs makes it difficult to assess the emetogenic potential of newly developed antineoplastic agents or regimens. When these promising antineoplastic drugs are approved for clinical application, establishment of standard antiemetic prophylaxis for these new drugs will be challenging since oncologists know little about the vomiting risk from previous trials. Therefore, the standardized and detailed reporting of antiemetic drugs and regimens should be implemented in all clinical trials of antineoplastic drugs. However, several factor may contribute to suboptimal adherence to antiemetic guidelines, including continued education of health care professionals [22, 23], complexity and convenience of antiemetic regimens [24], availability or reimbursement of antiemetic drugs [25, 26], physician preferences, and under-reporting of patients [23, 27]. It is noteworthy that prior observational studies have shown that adhering to CINV guidelines could significantly improve CINV control in real-world settings [28, 29], and various efforts have been made to enhance adherence. For instance, the use of fixed combinations of antiemetic agents, such as NEPA [12, 24, 30], has the potential to improve patient compliance and guideline adherence by packaging guideline-consistent antiemetic prophylaxis in a single, orally administered dosage that taken only once per chemotherapy cycle. Additionally, software-based prophylaxis of CINV, which automatically adds appropriate antiemetics to chemotherapy, has been employed to assist physicians in CINV management [21].

Furthermore, concerning the rates of severe vomiting and nausea, which are frequently reported in cisNATs, we observed a slowing down of the decreasing trend following the initial series of official antiemetic guideline recommendations for 5-HT3RA-based doublet regimens. Even in latest time frame, 5.42% and 6.57% of included patients still undergone severe vomiting and nausea, respectively. Breakthrough CINV can lead to treatment disruption and discontinuation, even when appropriate antiemetic prophylaxis is employed. Severe breakthrough CINV can also trigger anticipatory CINV, significantly impacting a patient’s quality of life and diminishing their willingness to continue treatment [31]. Hence, there remains an urgent requirement for optimized options of severe vomiting and nausea control during the entire chemotherapy-treatment cycles.

Finally, it is important to highlight that although nausea and vomiting are often considered as unified symptoms, our results indicate that the control rate for nausea is much lower than that for vomiting in both cisATs and cisNATs. One key reason for this discrepancy is the relative neglect of nausea control during the development of antiemetic agents. Our study found that outcomes related to nausea control were frequently underreported in cisATs. Specifically, only a small percentage of cisATs reported nausea control outcomes in both the acute and overall phases. Because nausea is a highly subjective symptom, using quantifying nausea symptoms as an endpoint is inappropriate. Indicators like “no severe nausea rate” or “no minimal nausea rate” can be influenced by subjective patient factors, which hinders accurate assessment of no nausea incidence. Therefore, applying “no nausea rate” would be more accurate. Another contributing factor is the limited understanding of the precise physiological mechanisms underlying nausea. The use of olanzapine might offer a solution. A phase III randomized antiemetic clinical trial that incorporated olanzapine into NK1RA-based triplet regimens demonstrated a significant improvement in nausea control [32]. Furthermore, a network meta-analysis provided evidence that olanzapine-based triple regimens achieve significantly higher no-nausea rates in delayed phases than NK1RA-based regimens in patients receiving highly emetogenic chemotherapy [33]. However, it is important to note that most olanzapine studies included a mix of chemotherapy regimens, and data specific to cisplatin subgroups were often not available. As a result, our study included limited olanzapine studies for analysis. More eligible trials are still needed to provide a comprehensive assessment of nausea control in cisATs.

Limitations

Despite relatively detailed analysis for CINV trend, there were still some limitations in our study due to the restriction of extracted data. First of all, most of antiemetic trials conducted before 1990 were excluded for analysis due to small sample size or poorly study design, which could potentially influence the trend analysis of antiemetic treatment in early period. Another limitation was that some early antiemetic studies only report antiemetic outcomes for the acute phase, while data of CINV control in the overall phase were limited. This could introduce bias in the overall trend comparison, especially for the acute phase in the 1990s. Additionally, we were unable to adjust for factors that might affect the incidence of CINV, such as anatomical site of primary tumor, combination of other chemotherapy drugs, and psychological status, because these data were either unreported or unavailable in most trials. But it is worth noting that high-dose cisplatin treatment results in nearly 90% incidence of CINV in patients without antiemetic prophylaxis. Therefore, this study focused specifically on high-dose cisplatin-based clinical trials to minimize the bias introduced by other variables.

Conclusions

The landscape of antiemetic prophylaxis for cisplatin-based chemotherapy has evolved significantly in conjunction with advancements in antiemetic agents. Substantial progress has been achieved in emesis control in both cisATs and cisNATs as major updates were made in antiemetic guidelines. However, there is still a considerable distance to cover to achieve optimal control of chemotherapy-induced nausea. Furthermore, substantial variations in antiemetic effectiveness among different cisNATs emphasize the ongoing need for improved adherence to antiemetic guidelines in clinical practice.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 406 KB) (405.9KB, docx)

Acknowledgements

We would like to acknowledge the hard and dedicated work of all the staff that implemented the intervention and evaluation components of the study.

Author contribution

Conception and design: Xi Chen, Li Zhang Literature retrieval: Ya Sun, Yalan Wang Data extraction and quality assessment: Ya Sun, Yalan Wang Statistical guidance: Gang Chen, Yaxiong Zhang Data analysis and interpretation: Ya Sun Manuscript writing: Ya Sun, Yalan Wang Manuscript reviewing: Xi Chen, Li Zhang Primary revision before submitting: All authors Final approval of manuscript: All authors.

Funding

This work was supported by the National Key R&D Program of China (Grant No. 2016YFC0905500, 2016YFC0905503), Science and Technology Program of Guangdong (Grant No. 2017B020227001, 2016A020215084), Science and Technology Program of Guangzhou (Grant No. 201607020031, 201400000001–2), and Medical Scientific Research Foundation of Guangdong Province, China (Grant No. A2020153).

Data availability

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was conducted with approval from the Ethics Committee of Sun Yat-sen University Cancer Center. This study was conducted in accordance with the declaration of Helsinki. Written informed consent was obtained from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Ya Sun and Yalan Wang contributed equally to this work.

Contributor Information

Li Zhang, Email: zhangli@sysucc.org.cn.

Xi Chen, Email: chenxi@sysucc.org.cn.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (DOCX 406 KB) (405.9KB, docx)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

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