Defining the Clinical Benefits of Adding a Neurokinin-1 Receptor Antagonist to Control Chemotherapy-Induced Nausea and Vomiting in Moderately Emetogenic Chemotherapy: A Systematic Review and Meta-Analysis of the Clinical Practice Guidelines for Antiemesis 2023 from the Japan Society of Clinical Oncology

doi:10.21203/rs.3.rs-4723119/v1

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Research Article

Defining the Clinical Benefits of Adding a Neurokinin-1 Receptor Antagonist to Control Chemotherapy-Induced Nausea and Vomiting in Moderately Emetogenic Chemotherapy: A Systematic Review and Meta-Analysis of the Clinical Practice Guidelines for Antiemesis 2023 from the Japan Society of Clinical Oncology

https://doi.org/10.21203/rs.3.rs-4723119/v1

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Background

Chemotherapy-induced nausea and vomiting (CINV) commonly affects patient quality of life and the overall effectiveness of chemotherapy. This study aimed to evaluate whether adding neurokinin-1 receptor antagonists (NK1RAs) to 5-hydroxytryptamine-3 receptor antagonists (5-HT₃RAs) and corticosteroids provides clinically meaningful benefits in preventing CINV in patients receiving moderately emetogenic chemotherapy (MEC).

Methods

We conducted a systematic review of PubMed, Cochrane Library, and Ichushi-Web to identify clinical studies evaluating NK1RAs combined with 5-HT₃RAs and dexamethasone for managing CINV in MEC. The endpoints were complete response (CR), complete control (CC), total control (TC), adverse events, and costs. The data were analyzed using a random effects model.

Results

From 142 articles identified, 15 randomized controlled trials (RCTs), involving 4,405 patients, were included in the meta-analysis. Approximately 60% of the patients received carboplatin (CBDCA)-based chemotherapy. The meta-analysis showed that triplet antiemetic prophylaxis with NK1RA was significantly more effective for achieving CR than doublet prophylaxis in each phase. Regarding CC, the triplet antiemetic prophylaxis was significantly more effective than the doublet in the overall (risk difference [RD]: 0.11, 95% confidence interval [CI]: 0.06–0.17) and delayed (RD: 0.08, 95% CI: 0.02–0.13) phases. For TC, no significant differences were observed in any phase. Adding NK1RA did not cause adverse events.

Conclusions

Adding NK1RA to CBDCA-based chemotherapy has shown clinical benefits. However, the clinical benefits of NK1RA-containing regimens for overall MEC have not yet been established and require RCTs that exclusively evaluate MEC regimens other than CBDCA-based chemotherapy.

Antiemetics

Carboplatin

Chemotherapy-induced nausea and vomiting

Moderately emetogenic chemotherapy

Neurokinin-1 receptor antagonist

Systematic review and meta-analysis

Chemotherapy-induced nausea and vomiting (CINV) commonly affects patients undergoing cancer treatment, significantly diminishing their quality of life and the overall efficacy of chemotherapy. The introduction of effective antiemetics, such as 5-hydroxytryptamine-3 receptor antagonists (5-HT₃RAs) and neurokinin-1 receptor antagonists (NK1RAs), has significantly improved the management of CINV. Furthermore, international antiemetic guidelines are now available, including those prepared by the American Society of Clinical Oncology [1], Multinational Association of Supportive Care in Cancer (MASCC), European Society of Medical Oncology (ESMO) [2], National Comprehensive Cancer Network [3], and Japan Society of Clinical Oncology [4]. The most widely used antiemetic classification scheme categorizes emetic risk into four levels based on the anticipated frequency of vomiting without antiemetic prophylaxis: minimal emetic risk (< 10%), low emetic risk (10–30%), moderate emetic risk (30–90%), and high emetic risk (> 90%). Notably, the broad range of expected emetic incidences (30–90%) within the moderate category makes it increasingly challenging to recommend appropriate antiemetic therapies for this patient group. Recommending for or against the additional use of NK1RAs in this situation is complicated because of the absence of large-scale, homogeneous studies comparable to those available in high-emetic-risk chemotherapy settings and factors related to treatment. For instance, carboplatin (CBDCA) poses a particularly high risk of CINV in patients receiving MEC, and several international antiemetic guidelines recommend a triplet antiemetic combination that includes NK1RAs. However, the benefit of adding NK1RA to 5-HT₃RA and corticosteroids remains controversial, particularly for patients receiving MEC other than CBDCA [5]. It is also important to weigh the risk/benefit profiles and treatment costs when making treatment decisions.

We conducted a systematic review and meta-analysis to determine whether the addition of NK1RAs provides a clinically meaningful benefit for preventing CINV in patients receiving MEC, according to the current update of the Clinical Practice Guidelines for Antiemesis 2023 from the Japan Society of Clinical Oncology.

This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [6] and the Minds Handbook for Clinical Practice Guideline Development, 2017 [7].

Eligibility criteria

Inclusion criteria were as follows: (a) patients with cancer receiving 5-HT₃RAs and dexamethasone (DEX) or 5-HT₃RAs with DEX and NK1RAs; (b) study designs encompassing randomized controlled trials (RCTs), non-randomized designs, and observational studies; and (c) primary or secondary outcomes focusing on CINV.

Exclusion criteria included guidelines, reviews, letters, abstracts without full articles, laboratory studies, systematic reviews, meta-analyses, gray literature, and studies published in languages other than Japanese or English. There were no restrictions based on sex, age, race, cancer type, or cancer stage.

Outcome measures

We analyzed the following outcomes: (1) complete response (CR, proportion of patients with no vomiting or use of rescue medications), (2) complete control (CC, proportion of patients with no vomiting, no use of rescue medications, and no significant nausea), (3) total control (TC, proportion of patients with no vomiting, no use of rescue medications, and no nausea), (4) adverse events (AEs), and (5) cost. For CR, CC, and TC, we examined data from the acute phase (first 24 h after chemotherapy), the delayed phase (24–120 h after chemotherapy), and the overall phase (first 120 h after chemotherapy). Only the results from Cycle 1 were considered.

Information sources and search strategy

We conducted a comprehensive search to evaluate the efficacy of adding NK1RAs to doublet antiemetic regimens of 5-HT₃RAs and a corticosteroid in patients with cancer receiving MEC. The search included PubMed, Cochrane Library, and Ichushi-Web databases of the Japan Medical Abstract Society. Additionally, we manually searched for relevant studies and reviewed their references to identify additional relevant literature.

The search covered the period from January 1, 1990, to December 31, 2020, using the following keywords: moderately emetogenic chemotherapy, nausea, vomiting, CINV, NK1RA, aprepitant, fosaprepitant, netupitant, fosnetupitant, rolapitant, casopitant, ezlopitant, side effects, cost, and MEC.

Selection process

Initially, all titles and abstracts of the references were reviewed based on the selection criteria. Subsequently, the full texts of potentially relevant articles were assessed to confirm adherence to the inclusion criteria. Articles that failed to meet these criteria were excluded from further analysis. The literature extraction process was independently conducted by two authors (T. H. and S. Y.) following the established search strategy. In cases of disagreement, a third author (Y. M.) was consulted to facilitate discussion and reach a consensus.

Data extraction

T. H. and S. Y. independently extracted data from all eligible studies using a standardized form. The data were entered into Review Manager version 5.41 software (The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark). Key information extracted from each study included the first author, year of publication, study design, country, sample size for both experimental and control groups, participant demographic characteristics, details of antiemetic prophylaxis, and outcomes, such as nausea, vomiting, AEs, and costs.

Quality assessment

For all studies included in our analysis, we independently assessed the risk of bias across the following domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), selective reporting (reporting bias), and other potential sources of bias. Each domain was categorized as low risk of bias, high risk of bias, or uncertain risk of bias. Furthermore, we evaluated the quality of the selected trials according to the Minds Handbook for Clinical Practice Guideline Development, 2017 [7].

The certainty of the evidence was evaluated based on the risk of bias, inconsistency, imprecision, indirectness, and publication bias. The literature quality and body of evidence were evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach and classified into four levels: “strong,” “medium,” “weak,” and “very weak.”

Statistical analysis

Treatment effects were computed using Review Manager version 5.41, and the results were reported following PRISMA guidelines. Risk differences (RD) with 95% confidence intervals (CI) were pooled using a random-effects meta-analysis model. Relative to the vertical line at 0, the difference on the right indicates favoring the NK1RA-containing regimen arm, and the difference on the left indicates favoring the control group.

Heterogeneity among studies was evaluated using the Higgins I² test and χ² test. Significant heterogeneity was defined as an I² value greater than 50% and a p-value less than 0.1.

Literature search results

The PRISMA study selection diagram is shown in Fig. 1. A total of 142 published articles on NK1RAs as antiemetics for patients with cancer receiving MEC were initially identified. After screening the titles and abstracts, 38 articles were closely examined for eligibility, with 17 excluded for various reasons. Ultimately, 21 studies were included in the final systematic review for qualitative synthesis. Among these, 15 RCTs [8–22], involving 4,405 patients, were included in the meta-analysis based on outcomes (Table 1).

Table 1

Characteristics of included randomized controlled trials.
Reference	Patients/ Type of cancer/ MEC	N	Experimental regimens	N	Control regimens	Primary endpoint/ Result	CR Overall Acute Delayed	CC Overall Acute Delayed	TC Overall Acute Delayed	Adverse events All Constipation Headache Hiccup
Arpornwirat (2009) [8]	241/ NSCLC, CRC, Ovarian, Breast, other/ CBDCA, CPA, CPT-11, L-OHP	120	Day 1: OND 16 mg DEX 8 mg CAS 150 mg Days 2–3: OND 16 mg CAS 150 mg	121	Day 1: OND 16 mg DEX 8 mg Placebo Days 2–3: OND 16 mg Placebo	Overall CR/ 84.2% vs. 69.4%	84.2% vs. 69.4%/ 91.7% vs. 89.3%/ 84.2% vs. 69.4%	NA 81.7% vs. 86.0% 60.8% vs. 60.3%	53.3% vs. 49.6% 72.5% vs. 79.3% 60.8% vs. 60.3%	64.0% vs. 71.0% 15.0% vs. 13.0% NA NA
Rapoport (2010) [9]	429/ Breast, CRC, Lung, Ovarian, other/ Ara-C, CPA, CPT-11, IFM, L-OHP	226	Day 1: OND 16 mg DEX 12 mg APR 125 mg Days 2–3: Placebo APR 80 mg	203	Day 1: OND 16 mg DEX 20 mg Placebo Days 2–3: DEX 8 mg Placebo	Overall no vomiting/ 83.2% vs. 70.9%	73.9% vs. 65.5% 93.4% vs. 88.1% 76.1% vs. 70.0%	NA NA NA	NA NA NA	62.8% vs. 67.2% 8.6% vs. 13.4% 10.0% vs. 12.2% NA
Tanioka 2013 [10]	91/ Ovarian, Endocerial, other/ CBDCA, CPT-11	45	Day 1: GRA 1 mg DEX 12 mg APR 125 mg Days 2–3: DEX 4 mg APR 80 mg	46	Day 1: GRA 1 mg DEX 20 mg Placebo Days 2–3: DEX 8 mg Placebo	Overall CR/ 62.0% vs. 52.0%	62.0% vs. 52.0% 97.8% vs. 95.7% 62.0% vs. 52.0%	NA NA NA	47.0% vs. 37.0% NA NA	NA 10.9% vs. 4.3% NA NA
Kitayama (2015) [11]	70/ CRC, Breast, other/ L-OHP, CPA, CPT-11, other	35	GRA 3 mg DEX 4.95 mg FosAPR 150 mg	35	PALO 0.75 mg DEX 9.9 mg	Overall CR/ 74.0% vs. 69.0%	74.0% vs. 69.0% 100% vs. 94.0% 100% vs. 94.0%	60.0% vs. 46.0% 97.0% vs. 91.0% 69.0% vs. 66.0%	60% vs.46.0% 86.0% vs. 77.0% 60% vs.46.0%	NA NA NA NA
Kusagaya (2015) [12]	80/ NSCLC/ CBDCA	41	Day 1: PALO 0.75 mg DEX 8 mg APR 125 mg Days 2–3: DEX 8 mg APR 80 mg	39	Day 1: PALO 0.75 mg DEX 8 mg Days 2–3: DEX 8 mg	Overall CR/ 80.5% vs. 76.9%	80.5% vs. 76.9% 100% vs. 100% 80.5% vs. 76.9%	NA NA NA	NA NA NA	95.1% vs. 94.9% 41.5% vs. 28.2% NA 9.8% vs. 15.4%
Maehara 2015 [13]	23/ Ovarian, Endocerial/ CBDCA	11	Day 1: 5-HT₃RA DEX 8 mg APR 125 mg Days 2–3: DEX 4 mg APR 80 mg	12	Day 1: 5-HT₃RA DEX 16 mg Days 2–3: DEX 8 mg	Overall CR/ 100% vs. 41.7%	100% vs. 41.7% 100% vs. 50% 100% vs. 66.7%	NA NA NA	NA NA NA	NA NA NA NA
Nishimura (2015) [14]	413/ CRC/ L-OHP	207	Day 1: 5-HT₃RA DEX 6.6 mg APR 125 mg or (FosAPR 150 mg) Days 2–3: DEX 4 mg (In cases using FosAPR, Day 2: DEX 4 mg, Day 3: DEX 8 mg) APR 80 mg (FosAPR 0 mg)	206	Day 1: 5-HT₃RA DEX 9.9 mg Days 2–3: DEX 8 mg	Overall no vomiting/ 95.7% vs. 83.6%	85.0% vs. 74.3% 94.7% vs. 92.4% 85.0% vs. 75.4%	79.7% vs. 68.3% 94.1% vs. 90.2% 79.7% vs. 69.4%	NA NA NA	59.9% vs. 63.3% 5.0% vs. 5.6% NA 3.0% vs. 3.1%
Schwartzberg(2015) [15]	629/ CRC, Head and neck, Lung, Ovarian, Gastric, other/ Ara-C, CBDCA, CPA, CPT-11, L-OHP, MIT	322	Day 1: GRA 2 mg DEX 20 mg ROLA 180 mg Day 2–3: GRA 2 mg	307	Day 1: GRA 2 mg DEX 20 mg Placebo Day 2–3: GRA 2 mg	Delayed CR/ 76.0% vs. 64.0%	75.0% vs. 61.0% 91.0% vs. 84.0% 76.0% vs. 64.0%	NA NA NA	NA NA NA	66.0% vs. 64.0% 3.0% vs. 3.0% 2.0% vs. 2.0% NA
Kaushal (2015) [16]	60/ Head and neck/ CBDCA	30	Day 1: PALO 0.25 mg DEX 12 mg APR 125 mg Days 2–3: DEX 16 mg APR80 mg	30	Day 1: OND 16 mg DEX 120mg Days 2–3: OND 16 mg DEX 16 mg	Acute CR, Delayed CR/ 86.7% vs. 60.0%, 53.3% vs. 83.3%	53.3% vs. 83.3% 86.7% vs. 60.0% 53.3% vs. 83.3%	NA NA NA	NA NA NA	NA NA NA NA
Weinstein (2016) [17]	1000/ Lung, Breast, CRC, Gastric, Gyne, Head and neck, other/ CBDCA, L-OHP, other MEC	502	Day 1: OND 16 mg DEX 12 mg FosAPR 150 mg Days 2–3: Placebo	498	Day 1: OND 16 mg DEX 20 mg Placebo Days 2–3: OND 16 mg	Delayed CR/ 78.9% vs. 68.5%	77.1% vs. 66.9% 93.2% vs. 91.0% 78.9% vs. 68.5%	NA NA NA	NA NA NA	61.9% vs. 60.8% 9.3% vs. 10.5% 6.0% vs. 7.0% NA
Yahata (2016) [18]	297/ Ovarian, Endocerial, Cervical, Peritoneal, Tubal/ CBDCA	151	Day 1: 5-HT₃RA (GRA 1 mg or OND 4 mg) DEX 20 mg APR 125 mg Days 2–3: APR 80 mg	146	Day 1: 5-HT₃RA (GRA 1 mg or OND 4 mg) DEX 20 mg Placebo Days 2–3: Placebo	HSR	61.6% vs. 47.3% 94.6% vs. 90.4% 63.6% vs. 49.3%	NA NA NA	NA NA NA	NA NA NA NA
Aridome (2016) [19]	113/ CRC/ CPT-11, L-OHP	59	Day 1: 5-HT₃RA (GRA 3 mg or OND 4 mg or AZA 10 mg or PALO 0.75 mg) DEX 9.9 mg APR 125 mg Days 2–3: DEX 8 mg APR 80 mg	54	Day 1: 5-HT₃RA (GRA 3 mg or OND 4 mg or AZA 10 mg or PALO 0.75 mg) DEX 9.9 mg Days 2–3: DEX 8 mg	Overall CR/ 79.7% vs. 79.6%	79.7% vs. 79.6% 94.9% vs. 94.4% 79.7% vs. 79.6%	NA 93.2% vs. 94.4% 78.0% vs. 79.6%	NA NA NA	100% vs. 100% 1.7% vs. 7.4% NA NA
Hesketh (2016) [20]	401/ Lung, Ovarian, Breast, Uterus, Head and neck, other/ CBDCA	192	Day 1: GRA 2 mg DEX 20 mg ROLA 180 mg Days 2–3: GRA 2 mg	209	Day 1: GRA 2 mg DEX 20 mg Placebo Days 2–3: GRA 2 mg	Overall CR/ 80.2% vs. 64.6%	80.2% vs. 64.6% 91.7% vs. 88.0% 82.3% vs. 65.6%	74.0% vs. 59.3% 88.5% vs. 85.6% 76.0% vs. 60.8%	NA NA NA	61.9% vs. 63.3% NA NA NA
Kim (2017) [21]	480/ CRC, Gastric, Lung, Gyne, other/ CBDCA, CPT-11, L-OHP	237	Day 1: OND 16 mg DEX 12 mg APR 125 mg Days 2–3: Placebo APR 80 mg	243	Day 1: OND 16 mg DEX 20 mg Placebo Days 2–3: OND 16 mg Placebo	Overall no vomiting/ 77.2% vs. 72.0%	73.4% vs. 70.4% 95.8% vs. 97.9% 74.3% vs. 71.2%	NA NA NA	NA NA NA	56.2% vs. 53.2% 0% vs. 8.9% NA 6.2% vs. 0%
Sugimori (2017) [22]	78/ Ovarian, Uterus, Cervix, Double cancer/ CBDCA	39	Day 1: PALO 0.75 mg DEX 6.6 mg APR 125 mg Days 2–3: DEX 8 mg APR 80 mg	39	Day 1: PALO 0.75 mg DEX 13.2mg Days 2–3: DEX 8 mg	Delayed CR/ 97.0% vs. 82.0%	NA 100% vs. 100% 97.0% vs. 82.0%	NA 92.0% vs. 92.0% 65.0% vs. 58.0%	NA NA NA	NA NA NA NA
APR, aprepitant; Ara-C, cytarabine; AZA, azasetron; CAS, casopitant; CBDCA, carboplatin; CPA, cyclophosphamide; CPT-11, irinotecan; CRC, colorectal cancer; DEX, dexamethasone; GRA, granisetron; HSR, hypersensitivity reaction; IFM, ifosfamide; MIT, mitoxantrone; NA, not available; NSCLC, non-small cell lung cancer; L-OHP, oxaliplatin; OND, ondansetron; PALO, palonosetron; ROLA, rolapitant

Risk of bias

A Cochrane risk-of-bias assessment was conducted to evaluate the quality of the 15 RCTs included in the meta-analysis (Fig. 2). Because all studies were RCTs, there was a low risk of bias related to random sequence generation, incomplete outcome data, and selective reporting.

However, two trials showed a high risk of selection bias (allocation concealment), four exhibited a high risk of detection bias (blinding of participants and personnel), and five had a high risk of performance bias (blinding of outcome assessment).

The evidence for antiemetic efficacy (CR, CC, TC, and AEs) was based on RCTs; hence, the strength of this evidence was rated as “strong.” However, the evidence regarding cost was rated as “weak” owing to the inclusion of only one observational study. The introduction of effective antiemetics such as 5-HT₃RAs and NK1RAs markedly enhanced CINV.

Efficacy of NK1RA

Effect of antiemetic treatment

A meta-analysis of RCTs was conducted, comprising 14 trials for overall CR, 15 for acute CR, and 15 for delayed CR. The results consistently showed that triplet antiemetic prophylaxis with NK1RA significantly prevented CINV across all phases. The effect size was smaller for acute CR (RD: 0.03, 95% CI: 0.01–0.05) than for both overall CR (RD: 0.11, 95% CI: 0.08–0.15) and delayed CR (RD: 0.10, 95% CI: 0.08–0.13) (Fig. 3). No risk of bias or publication bias was observed in this meta-analysis.

Four trials on overall CC, six on acute CC, and six on delayed CC were analyzed. The results consistently showed a significant efficacy of triplet antiemetic prophylaxis with NK1RA in preventing CINV in overall CC (RD: 0.11, 95% CI: 0.06–0.17) and delayed CC (RD: 0.08, 95% CI: 0.02–0.13) (Fig. 4). No risk of bias or publication bias was found in this meta-analysis.

For TC, three trials were included for overall TC, two for acute TC, and two for delayed TC. The meta-analysis indicated no significant difference in the efficacy of antiemetic prophylaxis across these phases (Fig. 5). No risk of bias or publication bias was identified in this meta-analysis.

Adverse events

The meta-analysis included 9 trials on all AEs, 10 for constipation, 3 for headaches, and 3 for hiccups. No significant differences were found among these AEs (Fig. 6). No risk of bias or publication bias was identified in this meta-analysis.

Cost

Only one observational study among the eligible articles reported on costs. It was found that triplet antiemetic prophylaxis was more cost-effective than doublet regimens.

In this study, we evaluated whether adding NK1RAs to 5-HT₃RA plus DEX provided a clinically meaningful benefit in preventing CINV in patients receiving MEC. To better define the role of NK1RA in MEC, we conducted a systematic review and meta-analysis of the available evidence. The results consistently showed that triplet antiemetic prophylaxis (NK1RA, 5-HT₃RA, and DEX) was significantly more effective than doublet prophylaxis in terms of overall, acute, and delayed CR. The meta-analysis revealed that the effect size was smaller for acute CR (RD: 0.03, 95% CI: 0.01–0.05) than for overall CR (RD: 0.11, 95% CI: 0.08–0.15) and delayed CR (RD: 0.10, 95% CI: 0.08–0.13) (Fig. 3). Additionally, CC results confirmed that triplet antiemetic prophylaxis was significantly more effective than doublet regimens in the overall (RD: 0.11, 95% CI: 0.06–0.17) and delayed (RD: 0.08, 95% CI: 0.02–0.13) phases. In the TC results, no significant differences were found in any phase—acute, delayed, or overall phase. Adding NK1RA did not increase the incidence of adverse events. Only one observational study [23] on costs was available, and it favored triplet antiemetic prophylaxis over doublet regimens. However, evaluating cost-effectiveness remains challenging owing to insufficient evidence.

NK1RAs inhibit the binding of substance P to the neurokinin-1 receptor in the central nervous system, reducing the incidence of CINV, particularly in the delayed phase [24, 25]. Given the relatively effective control of acute CINV, even with doublet antiemetic prophylaxis without NK1RA, and the properties of NK1RA, the results of this meta-analysis are reasonable.

This meta-analysis showed that the addition of NK1RA was beneficial in CR and CC; however, additional strategies may be needed to achieve TC. Moreover, it should be noted that these findings cannot be universally applied to all MECs, as the classification of MECs is broad and the emetic risk ranges from 30–90%. Although details of the chemotherapy regimens in one trial were unavailable, approximately 60% of patients in the included trials received CBDCA-based chemotherapy. CBDCA is typically administered in combination with other anticancer agents. For combination regimens, guidelines agree that the classification should be based on the anticancer drug with the highest emetic risk. In this study, the anticancer drugs used in combination with CBDCA were pemetrexed (500 mg/m²), paclitaxel (175–200 mg/m²), nab-paclitaxel (100 mg/m²), docetaxel (60 mg/m²), S-1 (40 mg/m² twice a day), and bevacizumab (15 mg/kg). Additionally, gemcitabine, etoposide, and immune checkpoint inhibitors are often administered in combination with CBDCA. Each of these drugs has a low or minimal emetogenic risk, and it is unlikely that they would affect the emetic risk category of a CBDCA-based regimen. In the last update of the Japanese guidelines, the expert panel discussed and recommended adding NK1RA to CBDCA-based chemotherapy [4]. A nationwide survey of antiemetic treatment in Japan [26, 27] also found that triplet antiemetic prophylaxis, including NK1RA, was favorable for patients undergoing CBDCA-based chemotherapy. The chemotherapy regimen with the second highest number of patients after CBDCA-based chemotherapy was oxaliplatin (L-OHP)-based chemotherapy, which accounted for approximately 20% of the patients in our meta-analysis. A meta-analysis conducted by Jordan et al. [5] reported that adding NK1RA had a clinically remarkable effect on CBDCA-based chemotherapy but was less effective for L-OHP-based chemotherapy. However, owing to the high statistical heterogeneity of the three RCTs of patients receiving L-OHP-based chemotherapy included in the meta-analysis, further studies are needed to provide definitive information. The benefit of adding NK1RA to L-OHP-based therapy remains controversial. The latest MASCC/ESMO antiemetic guidelines [2] recommend triplet antiemetic prophylaxis with NK1RA for female patients with cancer aged < 50 years who are receiving L-OHP-based chemotherapy. This is the first recommendation to consider patient-related risk factors in the antiemetic guidelines. More individualized recommendations will be necessary in future updates to antiemetic guidelines. Most of the evidence for antiemetic therapy in MEC involves platinum-based agents, such as CBDCA or L-OHP, but there is a lack of data on the benefit of adding NK1RAs to individual regimens, such as irinotecan-based chemotherapy and other MECs. The wide range of MEC makes it difficult to provide a single antiemetic prophylaxis recommendation suitable for all anticancer agents within this category. Although ongoing studies may further identify subgroups of patients receiving MEC who could benefit from adding NK1RAs, it may be necessary to reconsider the classification of emetic risk, including the subdivision of MEC.

This study has some limitations. First, in the RCTs included in the meta-analysis, most patients received platinum-based chemotherapy, with 60% receiving CBDCA-based regimens and 20% receiving oxaliplatin-based regimens. Second, there was insufficient information on other MECs to evaluate the benefits of adding NK1RA to the overall MEC. Third, some outcome data, especially for CC, TC, and AE, were unavailable in some of the included studies. Fourth, in most patients receiving the CBDCA-based regimen, the CBDCA dose was calculated using an area under the curve of 5–6. However, some RCTs did not report CBDCA doses; therefore, it is unclear whether low-dose CBDCA was included. Fifth, there may be differences in efficacy between palonosetron, a second-generation 5-HT3RA, and first-generation 5-HT3RA s when used in combination with NK1RA. Nishimura [14] reported no significant difference in antiemetic efficacy between palonosetron and first-generation 5-HT3RA s in triplet antiemetic therapy for L-OHP-based regimens. Evidence regarding the superiority of palonosetron in triplet antiemetic therapy for CBDCA-based regimens is lacking. In this meta-analysis, relatively few patients used palonosetron: 191 (8.9%) in the doublet group and 189 (8.7%) in the triplet group, in combination with NK1RA. Nevertheless, the results of the included RCTs were consistent. Therefore, we believe that the generation of 5-HT3RA had no significant effect on the results. Finally, only one observational study reported on costs.

Based on the information available in the articles, we evaluated all included RCTs to identify potential sources of bias following the PRISMA statement. In the meta-analysis, selection bias within studies was unlikely, as we included only RCTs and found no evidence of biased or invalid allocation procedures.

In conclusion, adding NK1RA to CBDCA-based chemotherapy has demonstrated clinical benefits in this systematic review and meta-analysis. However, since the heterogeneous agents used in the MEC category are largely unconfirmed, establishing the benefit of NK1RA-containing antiemetic prophylaxis for the overall MEC category is challenging based on the current evidence. Further studies are necessary to determine the clinical benefits of adding NK1RA to MEC regimens beyond CBDCA-based chemotherapy.

Acknowledgments

We are grateful to Natsuki Fukuda and Kyoko Hamada for their valuable suggestions and dedicated work, as well as to the literature search team members, Naohiko Yamaguchi and Yuko Mitsuoka, for their support. We also thank Editage (www.editage.jp) for English language editing.

Funding

This study was supported by the Japan Society of Clinical Oncology.

Author contributions

All authors contributed to the conception and design of this study. Material preparation, data collection, and analysis were performed by TH, SY, and YM. The first draft of the manuscript was written by TH, and all authors commented on previous versions of the manuscript. All the authors have read and approved the final manuscript.

Data availability

Data associated with this systematic review can be accessed from the corresponding author upon request.

Conflicts of interest

Shun Yamamoto received honoraria from Ono Pharmaceutical Co., Ltd., MSD K.K., Bristol Myers Squibb, and Taiho Pharmaceutical Co., Ltd., as well as fees for promotional materials. Eriko Satomi received honoraria from Shionogi & Co. Ltd. Masayuki Takeda has received honoraria from Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., and Bayer. Takako Eguchi Nakajima received research funding from KBBM, Inc. and Takeda Pharmaceutical Co., Ltd. Junichi Nishimura received honoraria from Taiho Pharmaceutical Co. Ltd. Narikazu Boku received honoraria from Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb, Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Eli Lilly Japan K.K. Koji Matsumoto received honoraria from MSD K.K., Kyowa Kirin Co., Ltd., and Chugai Pharmaceutical Co., Ltd., as well as research funding from Daiichi Sankyo Co., Ltd., MSD K.K., Gilead Sciences, Inc., and Eli Lilly Japan K.K. Nobuyuki Yamamoto received honoraria from MSD K.K., Accuray Japan K.K., AstraZeneca K.K., Abbvie Inc., Amgen Inc., Ono Pharmaceutical Co., Ltd., Guardant Health Japan Corp., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Chugai Foundation for Innovative Drug Discovery Science, Lao Tsumura Co., Ltd., Terumo Corporation, Eli Lilly Japan K.K., Nippon Kayaku Co., Ltd., Novartis AG, Pfizer Global Supply Japan Inc., Merck Biopharma Co., Ltd, Pfizer Global Supply Japan Inc., Merck Biopharma Co., Ltd., Janssen Pharmaceutical K.K., and USACO Corporation, as well as legal fees in case of lawsuit from Taiho Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Nippon Kayaku Co., Ltd., Prime Research Institute for Medical RWD, Inc., AstraZeneca K.K., and A2 Healthcare Corporation. Other authors declare that they have no conflict of interest.

Ethical approval

Not applicable.

Informed consent

Formal consent was not required for this type of study.

Consent to participate

Not applicable.

Consent for publication

All authors consented to the publication of this study.

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