Efficacy and safety of multi-day antiemetic treatment for patients undergoing multi-day chemotherapy: A systematic review of Clinical Practice Guidelines for Antiemesis 2023 from Japan Society of Clinical Oncology

Efficacy and safety of multi-day antiemetic treatment for patients undergoing multi-day chemotherapy: A systematic review of Clinical Practice Guidelines for Antiemesis 2023 from Japan Society of Clinical Oncology | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and safety of multi-day antiemetic treatment for patients undergoing multi-day chemotherapy: A systematic review of Clinical Practice Guidelines for Antiemesis 2023 from Japan Society of Clinical Oncology Kazuhisa Nakashima, Saki Harashima, Rena Kaneko, Ryuhei Tanaka, and 24 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4806737/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Nov, 2024 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background A standardized multi-day antiemetic regimen for multi-day chemotherapy remains elusive. This systematic review evaluated the efficacy and safety of multi-day antiemetic regimens in patients undergoing undergoing multi-day intravenous chemotherapy Methods We conducted a comprehensive search of PubMed, Cochrane Library, and Ichushi-Web databases for relevant studies published from January 1990 to December 2020. We included studies comparing multi-day and single-day antiemetic regimens for preventing chemotherapy-induced nausea and vomiting. Results No studies directly comparing multi-day versus single-day antiemetic regimens were found. Despite expanding control group criteria beyond “single-day antiemetic therapy” limited high-quality studies and variations in cancer types, chemotherapy regimens, and antiemetic treatments precluded meta-analysis. Among the included studies, some randomized controlled trials (RCTs) focused on complete response and vomiting rates. Two studies comparing two- and three-drug combinations reported higher complete response and no-vomiting rates with the three-drug regimen. Limited RCTs explored “nausea control” and “cost,” and assessing “adverse events” proved challenging due to inconsistent reporting. Conclusion Research on multi-day antiemetic therapy is limited, necessitating further investigation. Nonetheless, our findings suggest that three-drug combination therapy, including aprepitant, may offer superior antiemetic efficacy compared to two-drug regimens. Multi-day antiemetic therapy is strongly recommended during multi-day intravenous administration of cytotoxic anticancer drugs. Systematic review Meta-analysis Multi-day chemotherapy Chemotherapy-induced nausea and vomiting Figures Figure 1 INTRODUCTION Chemotherapy-induced nausea and vomiting (CINV) is a distressing symptom in patients with cancer, significantly impacting their quality of life [1]. Most patients seek to avoid experiencing CINV [2], as it can lead to treatment discontinuation and worsen prognoses [3], highlighting the importance of its effective management. Multi-day administration of cytotoxic anticancer drugs is common in treating cancers such as germ cell tumors, bone and soft tissue sarcomas, lymphomas, and lung cancers. However, antiemetic therapy for these treatments varies significantly in terms of drug type, administration method, and dosage, depending on the chemotherapy regimen, complicating the establishment of a standardized antiemetic protocol. While intravenous administration of anticancer drugs over multiple days causes the acute and delayed phases of nausea and vomiting to overlap, resulting in complex conditions, no standard antiemetic therapy currently exists for such treatment regimens. Moreover, the Japanese Society of Clinical Oncology’s clinical practice guidelines do not provide clear recommendations for prophylactic antiemetic therapy in multi-day chemotherapy regimens [4]. To address this gap in knowledge, this systematic review aimed to investigate the efficacy of multi-day antiemetic treatment in patients undergoing multi-day chemotherapy. Given the wide variation in multi-day anticancer drug regimens, we specifically focused on those including multi-day cisplatin and ifosfamide, which are known for their high emetic risk. MATERIALS AND METHODS This systematic review was conducted in accordance with the “Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) 2020 statement” [5] and the “Minds Clinical Practice Guideline Development Guide 2017” [6]. Search strategy We systematically searched the PubMed, Cochrane Library, and Ichushi-Web databases for relevant studies published between January 1990 and December 2020. The search terms included “multiday chemotherapy,” “multiple-day chemotherapy,” “multiday cisplatin,” “antiemetic,” “CINV,” “nausea,” “vomiting,” and “germ cell tumors.” Additional relevant literature obtained through manual search was also included. Two reviewers (S.H. and K.N.) independently conducted two rounds of screening to select eligible literature for evaluation in this systematic review. In cases of disagreement between the two reviewers, a third reviewer (R.K.) was consulted to make the final decision. Primary screening involved assessing titles and abstracts of the articles, while secondary screening was based on the full texts. Selection criteria We prioritized the inclusion of randomized controlled trials (RCTs) that met the population, intervention, comparator, and outcome (PICO) criteria. In the absence of sufficient RCTs, we included non-RCTs, single-arm trials, case-control studies, and observational studies from which data could be extracted. Case reports and case series were excluded due to their low quality of evidence. PICO framework The PICO framework for this clinical question was defined as follows: (a) Population: This refers to patients with cancer undergoing multi-day chemotherapy. (b) Intervention: This involved the administration of multi-day antiemetic therapy. (c) Comparator: This involved the administration of single-day antiemetic therapy. (d) Outcomes: Four primary endpoints were established, namely “vomiting control,” “nausea control,” “adverse events,” and “cost.” “Vomiting control” was evaluated by complete response (CR) rate (no vomiting and no use of rescue therapy) and no vomiting (NV) rate. “Nausea control'' was assessed by the complete control (CC) rate (no vomiting, no rescue, and no significant nausea), total control (TC) rate (no vomiting, no rescue, and no nausea), no nausea (NN) rate, and no significant nausea (NSN) rate. NSN was defined as < 25 mm on the Visual Analog Scale, ≤ 2 on the Numerical Rating Scale, and none or mild on the Categorical Rating Scale. In this study, the acute phase was defined as the period up to day 5 or 120 h after chemotherapy initiation. The delayed phase was defined as the period after day 6 or 120 h. The overall phase included both acute and delayed phases. Data extraction and quality assessment Following the second screening, the reviewer (S.H.) of the systematic review team conducted a reassessment of the selected articles and extracted data using standardized data abstraction forms. The evidence pertaining to critical outcomes relevant to the clinical questions posed by the guideline-creation team was categorized into groups based on study design and quality. The level of evidence was not assessed for individual references but rather for each outcome within studies grouped by study design. The certainty of the evidence was evaluated by considering factors such as risk of bias, inconsistency, imprecision, indirectness, and publication bias. Based on the synthesized body of evidence, its strength and recommendations were determined using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach [7]. RESULTS Literature search A flowchart outlining the search strategy and study selection process is depicted in Fig. 1 . The literature search for this clinical question yielded 40 articles from PubMed, 132 Cochrane, and 31 from Ichushi-Web databases. Additionally, seven articles were identified through manual searches. Ultimately, 210 articles were subjected to primary screening. However, no studies directly comparing multi-day versus single-day antiemetic therapy addressed this clinical question. Consequently, the control group was expanded beyond “single-day antiemetic therapy.” During secondary screening, 46 articles were assessed, resulting in the selection of 23 articles [8–30]. These selected articles are listed in Table 1 . Despite the selection, few studies fully met the PICO criteria. Additionally, variations in cancer types, chemotherapy regimens, and antiemetic therapies among the studies precluded a meta-analysis. Table 1 Selected studies Author Design Type of cancer Type of chemotherapy Antiemetics N Antiemetic effect Fox 1993 [20] RCT Germ cell tumor, Lung cancer Multi-day (4–5 days) cisplatin combination Chemotherapy Three doses of ondansetron 0.15 mg/kg on days 1–4 or 5 DEX 12mg on days 1–2 Chlorpromazine 200 mg on days 1–4 or 5 22 NV in days 1–5: 55% Three doses of ondansetron 0.15 mg/kg on days 1–4 or 5 22 NV in days 1–5: 32% Fauser 2000 [8] RCT Solid tumor Multi-day (2–5 days) cisplatin combination Chemotherapy Dolasetron 100 mg on days 1–2, 3, 4, or 5 DEX 20 mg on days 1–2, 3, 4, or 5 107 CR in overall phase (days 1–5): 72.9% Dolasetron 100 mg on day 1–2, 3, 4, or 5 103 CR in overall phase (days 1–5): 40.8% Herrstedt 2007 [21] RCT Germ cell tumor 5-day cisplatin chemotherapy Tropisetron 5 mg IV on days 1–6 Metopimazine 30 mg orally three times on day 1 and twice on days 2–6 42 NV in overall phase (days 1–9): 40.5% Tropisetron 5 mg IV on days 1–6 40 NV in overall phase (days 1–9): 17.5% Albany 2012 [9] RCT Germ cell tumor 5-day cisplatin chemotherapy APR 125 mg on day 3 and 80 mg on day 4–7 5HT3RA on day1–5 DEX 20 mg on days 1–2 and 4 mg twice on days 6–8 35 CR in overall phase (days 1–8): 42% NV: 84% 5HT3RA on days 1–5 DEX 20 mg on days 1–2, 8 mg twice on days 6–7, 4 mg twice on day 8 34 CR in overall phase (days 1–8): 13% NV: 53% Abdel-Malek 2017 [10] RCT (Prospective cross-over study) Non-Hodgkin lymphoma 4-day cisplatin chemotherapy APR 125 mg on day 1 and 80 mg on days 2, 3 Ondansetrone 8 mg on days 1–5 DEX 8 mg on days 1–5 15 CR: 83.3% Ondansetrone 8 mg on days 1–5 DEX 8 mg on days 1–5 CR: 0% Einhorn 1990 [23] Single-arm intervention study Solid tumor Multi-day (4–5 days) cisplatin combination Chemotherapy Ondansetron 0.15 mg/kg on days 1–3 36 NV on days 1–5: 29% Hainsworth 1991 [24] Single-arm intervention study Solid tumor Multi-day (4–5 days) cisplatin combination Chemotherapy Ondansetron 0.15 mg/kg on days 1–3 or 4 42 NV on days 1–5: 33% Suminaga 1992 [27] Single-arm intervention study Solid tumor Multi-day (3–5 days) cisplatin combination Chemotherapy Ondansetron 4 mg on days 1–3, 4, or 5 9 NV on day 1: 55.6%, on day 2: 66.7%, on day 3: 55.6%, on day 4: 42.9%, on day 5: 28.6% Akasaka 1992 [28] Single-arm intervention study Solid tumor Multi-day (3–5 days) cisplatin combination Chemotherapy Ondansetron 4 mg on days 1–3, 4, or 5 29 NV on day 1: 67%, on day 2: 56%, on day 3: 33%, on day 4: 35%, on day 5: 50% Akaza 1995 [29] Single-arm intervention study Urinary cancer Multi-day (3–5 days) cisplatin combination Chemotherapy Tropisetron 5 mg on days 1–3, 4, or 5 37 NV on day 1: 80.0%, on day 2: 80.0%, on day 3: 62.9%, on day 4: 44.4%, on day 5: 61.5% Taketani 1996 [30] Single-arm intervention study Gynecological cancer Multi-day (2–5 days) cisplatin combination Chemotherapy Ramosetron 1 mg on days 1–2, 3, 4, or 5 18 NV on day 1: 86.7%, on day 2: 66.7%, on day 3: 60.0%, on day 4: 53.3%, on day 5: 53.3% Ariyoshi 1997 [25] Single-arm intervention study Solid tumor Multi-day (3–5 days) cisplatin combination Chemotherapy Ondansetron 4 mg on days 1–3, 4, or 5 20 NV on day 1: 76.5%, on day 2: 70.6%, on day 3: 73.3%, on day 4: 75.0%, on day 5: 72.7% Einhorn 2007 [11] Single-arm intervention study Testicular germ cell tumor 5-day cisplatin combination Chemotherapy PALO 0.25 mg on days 1, 3, and 5 DEX 20 mg on days 1 and 2, 8 mg bid on days 6 and 7, and 4 mg bid on day 8 41 CR on days 1–5: 34.1% CR on days 6–9: 61.0% Jordan 2009 [12] Single-arm intervention study Solid tumor Multi-day (3–5 days) HEC or MEC Granisetron 1 mg i.v. on days 1–3 ~ 5 APR 125 mg on day 1 and 80 mg on days 2–5, 6, or 7 DEX 8 mg on days 1–5, 6, or 7 HEC: 38 MEC: 40 HEC CR in overall phase (days 1–10): 57.9% MEC CR in overall phase (days 1–10): 72.5% Olver 2013 [13] Single-arm intervention study Germ cell tumor 5-day cisplatin chemotherapy APR 125 mg on day 1 and 80 mg on days 2–7 5HT3RA on days 1–5 DEX 8 mg on days 1–8 50 NV in overall phase (days 1–7): 82% CR in overall phase (days 1–7): 41% Hamada 2014 [14] Single-arm intervention study Testicular germ cell tumor 5-day cisplatin combination Chemotherapy PALO 0.75 mg on day 1 APR 125 mg on day 1 and 80 mg on days 2–5 DEX 9.9 mg on day 1 and 6.6 mg on days 2–8 30 CR in overall phase (0–216 h): 90.0% Adra 2016 [15] Single-arm intervention study Testicular germ cell tumor 5-day cisplatin combination Chemotherapy Fosaprepitant 150 mg on days 3 and 5 5HT3-RA days 1–5 (days 1, 3, and 5, if PALO) DEX 20 mg on days 1 and 2, 4 mg bid on days 6, 7, and 8 65 CR in overall phase (days 1–8): 24.1% Ioroi 2018 [16] Single-arm intervention study Testicular germ cell tumor 5-day cisplatin combination chemotherapy. PALO 0.75 mg on day 1 APR 125 mg on day 1 and 80 mg on days 2–7 DEX 6.6 mg on days 1–7 25 CR in overall phase (0–240 h) (days 1–10)): 62.5% Bun 2018 [17] Single-arm intervention study Germ cell tumor, Synovial sarcoma, Spindle cell sarcoma 5-day cisplatin or ifosfamide combination chemotherapy GRA 1 mg iv on days 1–5 DEX 24 mg on days 1–5 OLZ 2.5–10 mg on days 1–5 9 CR in overall phase (0–240 h): 44.4% Aoyama 2010 [26] Retrospective study Bone and soft tissue sarcoma 5-day ifosfamide 5-HT3RA on days 1–5 DEX 8 mg on days 1, 3, and 5 15 NV on days 1–5: 73.4% 5-HT3RA on days 1–5 12 NV on days 1–5: 66.7% Suzuki 2012 [18] Retrospective study Bone and soft tissue sarcoma 5-day ifosfamide APR 125 mg on day 2 and 80 mg on days 3 and 4 GRA 3 mg on days 1–6 DEX 6.6 mg on days 1, 3, and 5 12 CR in overall phase (days 1–10): 91.6% GRA 3 mg iv on days 1–6 DEX 6.6 mg on days 1, 3, and 5 17 CR in overall phase (days 1–10): 41.1% Kim 2012 [19] Retrospective study Solid and nonsolid cancer Multiday (2–5 days) HEC PALO 0.25 mg on day 1 APR 125 mg on day 1 and 80 mg on days 2, 3 DEX 12 mg on day 1, 8 mg on days 2–4 73 CR in overall phase (0–120 h): 53.4% Other 5HT3-RA on days 2–5 APR 125 mg on day 1 and 80 mg on days 2 and 3 DEX 12 mg on day 1, and 8 mg on days 2–4 42 CR in overall phase (0–120 hours): 50.0% Uchiyama 2017 [22] Retrospective study Oral cancer 5-day cisplatin or nedaplatin chemotherapy APR 125 mg on day 1 and 80 mg on days 2, 3 GRA 3 mg on days 1–5 10 NV: 70% Fosaprepitant 150 mg on day 1 GRA 3 mg on days 1–5 10 NV: 70% RCT, randomized controlled study; CR, complete response; NV, No vomiting; PALO, palonosetron; DEX, dexamethasone; APR, aprepitant, 5HT3RA: 5-HT3 receptor antagonist Vomiting control To assess “vomiting control,” we examined the "CR ratio" and "NV ratio" across acute, delayed, and overall periods. Regarding the CR rate, three RCTs [8–10], seven single-arm trials [11–17], and two cohort studies [18, 19] were identified. Two RCTs compared a triple-drug combination therapy group, including aprepitant, with a dual-drug combination therapy group and found significantly higher CR rates in the triple-drug group during the overall period [9, 10]. One of these studies also reported significantly higher CR rates in both the acute and delayed phases for the triple-drug group [9], and another one showed significantly higher CR rates in the acute phase for dual-drug combination therapy, including dexamethasone, compared to 5-hydroxytryptamine 3 (5-HT3) receptor antagonist monotherapy [8]. Among the cohort studies, one study, although not statistically significant, showed a trend towards higher CR rates in the triple-drug combination therapy, including aprepitant, compared with the dual-drug combination therapy across the acute, delayed, and overall periods [18]. Regarding the NV ratio, four RCTs [8, 9, 20, 21], one non-RCT [22], seven single-arm trials [11, 13, 15, 17, 23–25], and three cohort studies were identified [18, 19, 26]. Among them, one RCT found significantly higher NV rates in both the acute and delayed phases for the triple-drug combination therapy (including aprepitant) compared to the dual-drug combination therapy [9]. Similarly, a cohort study reported significantly higher NV rates during the acute and overall periods for the triple-drug combination therapy [18]. Given the identified RCTs and the observed trends in CR and NV rates, the strength of the evidence for this outcome was classified as moderate (B). Nausea control To evaluate “nausea control,” we examined the "CC ratio," "TC ratio," "NN ratio," and "NSN ratio" across acute, delayed, and overall periods. For the CC ratio, two single-arm trials [16, 17] and one cohort study [19] were identified, and for the TC ratio, only two single-arm trials were included [16, 17]. The cohort study compared triple-drug therapy with palonosetron to first-generation 5-HT3 receptor antagonists and found no significant difference in the CC ratio during the acute phase between the two groups [19]. Regarding the NN and NSN ratios, one RCT [21] and one non-RCT [22] were identified, along with two cohort studies [19, 26] and four single-arm trials [12–14, 17] for the NN ratio and three single-arm trials for the NSN ratio [11, 13, 17]. One cohort study revealed that the NN ratio during the acute and delayed phases was significantly higher in a dual-drug therapy group with alternate-day dexamethasone administration compared to a monotherapy group with a 5-HT3 receptor antagonist [26]. Conversely, the other cohort study found no significant difference in the acute phase NN ratio between palonosetron and first-generation 5-HT3 receptor antagonist groups after triple-drug therapy [19]. The evidence for the CC and TC ratios was based on non-RCTs, while only one RCT and one non-RCT were identified for the NN and NSN ratios. The limited number and quality of studies made it challenging to fully evaluate the effectiveness of multi-day antiemetic therapy for nausea control. Consequently, the strength of the evidence for this outcome was classified as very weak (D). Adverse events Four RCTs [8, 9, 20, 21], one non-RCT [22], fourteen single-arm trials [11–17, 23–25, 27–30], and one cohort study were identified for adverse events evaluation [18]. The reported proportion of patients experiencing adverse events was approximately half. However, due to variability in intervention content across studies, individual adverse events were not enumerated, limiting the evaluation to general adverse events. No studies specified the incidence of adverse events, and no serious adverse events were reported in the multi-day antiemetic therapy group. Given these limitations, we were unable to fully evaluate the effects of multi-day antiemetic therapy for adverse events. Therefore, the strength of evidence for this outcome was classified as very weak (D). Cost No study evaluating the cost of multi-day antiemetic therapy was extracted, and consequently, this outcome could not be evaluated. DISCUSSION In this systematic review, we investigated the efficacy of multi-day antiemetic treatment for patients undergoing multi-day intravenous administration of cytotoxic anticancer drugs. Despite an extensive literature search, no studies directly comparing multi-day antiemetic therapy with single-day therapy were found, which aligns with our clinical question. Although we expanded the control group beyond “single-day therapy" and conducted a thorough systematic review, the scarcity of high-quality studies remained a challenge. Despite limited evidence, two RCTs comparing dual-drug therapy with triple-drug therapy showed higher CR and NV ratios in the triple-drug therapy group [9, 10], suggesting the potential benefit of using three drugs for multi-day antiemetic therapy. Moreover, most studies utilizing 5-HT3 receptor antagonists or aprepitants have employed multi-day antiemetic therapy protocols [8–30]. While no serious adverse events were reported with multi-day antiemetic therapy, patients receiving multi-day intravenous administration of cytotoxic anticancer drugs experience persistent nausea and vomiting, leading to significant distress and anxiety. Consequently, there is a strong preference for patients to minimize these symptoms as much as possible [2]. Based on the literature review, the Clinical Practice Guidelines for Antiemesis 2023 from the Japan Society of Clinical Oncology strongly recommend the implementation of multi-day antiemetic therapy in patients receiving multi-day intravenous cytotoxic anticancer drug. However, it is crucial to note that the strength of evidence supporting this recommendation was graded as extremely weak (D), highlighting the need for further research in this area. Recently, there has been increasing recognition of olanzapine’s efficacy in treating CINV. Olanzapine, an atypical antipsychotic with multi-acting receptor targeting properties, has demonstrated strong antiemetic effects when used for several days [31–36]. Additionally, fosnetupitant, a novel intravenous NK1RA drug, has shown promise in improving the delayed phase (24–168 h) of highly emetogenic chemotherapy in a phase III study [37]. Thus, we posit that the inclusion of antiemetic therapies, such as olanzapine and fosnetupitant, may enhance the antiemetic effects of multi-day chemotherapy. In conclusion, studies on multi-day antiemetic therapy are scarce, necessitating further research. Nevertheless, some studies have suggested that three-drug combination therapy, including aprepitant, may offer superior antiemetic effects compared to two-drug combination therapy. Multi-day antiemetic therapy is strongly recommended in patients undergoing multi-day intravenous administration of cytotoxic anticancer drugs. Declarations CONFLICTS OF INTEREST Kazuhisa Nakashima received honoraria from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., and Eli Lilly Japan K.K. Eriko Satomi received honoraria from Shionogi & Co., Ltd. Masayuki Takeda 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, Pfzer Global Supply Japan Inc., Merck Biopharma Co., Ltd, Pfzer 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. 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. Kazuhisa Nakashima wrote the original draft of the manuscript. All other authors reviewed and edited the manuscript. All authors read and approved the final manuscript. ACKNOWLEDGMENTS We thank Ms. Natsuki Fukuda and Ms. Kyoko Hamada for their valuable comments and suggestions, and invaluable supports. We thank Mr. Naohiko Yamaguchi and Ms. Yuko Mitsuoka for their contributions to the literature search. We thank Editage ( www.editage.jp ) for the English language editing. DATA AVAILABILITY Data associated with this systematic review can be accessed from the corresponding author upon request. 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Gan To Kagaku Ryoho 19:1879–1890 Akasaka Y, Taguchi T, Ota K, et al (1992 Aug) Anti-emetic effect and safety of consecutive use of ondansetron injection in cisplatin-induced nausea and emesis (in Japanese). Gan To Kagaku Ryoho 19:1359–1374 Akaza H, Machida T, Akasaka Y, et al (1995 Jul) The antiemetic effect, safety and usefulness of tropisetron capsule in the treatment of nausea and vomiting induced by lower multiple dose of cisplatin (in Japanese). Gan To Kagaku Ryoho 22:1063–1072 Taketani Y, Yoshikawa H, Kinoshita K, et al (1996) The world of obstetrics and gynecology (in Japanese) 48:749–760 Navari RM, Qin R, Ruddy KJ, et al (2016 Jul 14) Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med 375:134–142 Hashimoto H, Abe M, Tokuyama O, et al. (2020 Feb) Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 21:242–249 Jeon SY, Han HS, Bae WK, et al. (2019 Jan) A randomized, double-blind, placebo-controlled study of the safety and efficacy of olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy: results of the Korean south west oncology group (KSWOG) study. Cancer Res Treat 51:90–97 Tanaka K, Inui N, Karayama M, et al (2019 Jul) Olanzapine-containing antiemetic therapy for the prevention of carboplatin-induced nausea and vomiting. Cancer Chemother Pharmacol 84:147–153 Iihara H, Shimokawa M, Hayasaki Y, et al (2020 Mar) Efficacy and safety of 5 mg olanzapine combined with aprepitant, granisetron and dexamethasone to prevent carboplatin-induced nausea and vomiting in patients with gynecologic cancer: A multi-institution phase II study. Gynecol Oncol 156:629–635 Sakai C, Shimokawa M, Iihara H, et al. (2021 Jun) Low-dose olanzapine plus granisetron and dexamethasone for carboplatin-induced nausea and vomiting in patients with thoracic malignancies: A prospective multicenter Phase II trial. Oncologist 26:e1066–e1072 Hata A, Okamoto I, Inui N, et al. (2022 Jan 10) Randomized, double-blind, Phase III study of fosnetupitant versus fosaprepitant for prevention of highly emetogenic chemotherapy-induced nausea and vomiting: CONSOLE. J Clin Oncol 40:180–188 Cite Share Download PDF Status: Published Journal Publication published 12 Nov, 2024 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 10 Aug, 2024 Reviewers agreed at journal 02 Aug, 2024 Reviewers invited by journal 01 Aug, 2024 Editor assigned by journal 30 Jul, 2024 First submitted to journal 26 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4806737","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":334562888,"identity":"c745ea04-963e-4f1d-b65a-45cf18210160","order_by":0,"name":"Kazuhisa Nakashima","email":"data:image/png;base64,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","orcid":"","institution":"Shimane University Hospital: Shimane Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":true,"prefix":"","firstName":"Kazuhisa","middleName":"","lastName":"Nakashima","suffix":""},{"id":334562889,"identity":"a9d7e283-f3d5-4131-8225-6af33a012887","order_by":1,"name":"Saki Harashima","email":"","orcid":"","institution":"University of Tokyo Hospital: Tokyo Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Saki","middleName":"","lastName":"Harashima","suffix":""},{"id":334562890,"identity":"513d490c-ef98-4135-b80d-097611e103b4","order_by":2,"name":"Rena Kaneko","email":"","orcid":"","institution":"Kanto Rosai Hospital: Kanto Rosai Byoin","correspondingAuthor":false,"prefix":"","firstName":"Rena","middleName":"","lastName":"Kaneko","suffix":""},{"id":334562891,"identity":"1f99039a-07ae-4fc1-82be-060693d05c51","order_by":3,"name":"Ryuhei Tanaka","email":"","orcid":"","institution":"Saitama Medical University International Medical Center: Saitama Ika Daigaku Kokusai Iryo Center","correspondingAuthor":false,"prefix":"","firstName":"Ryuhei","middleName":"","lastName":"Tanaka","suffix":""},{"id":334562892,"identity":"e89c8117-fb9e-4c6d-be0a-ff4fcc4462d0","order_by":4,"name":"Masakazu Abe","email":"","orcid":"","institution":"Hamamatsu University School of Medicine: Hamamatsu Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Masakazu","middleName":"","lastName":"Abe","suffix":""},{"id":334562893,"identity":"4ad94893-d908-4d07-9fa8-eac4d95a9df1","order_by":5,"name":"Makoto Wada","email":"","orcid":"","institution":"Osaka International Cancer Institute: Osaka Kokusai Gan Center","correspondingAuthor":false,"prefix":"","firstName":"Makoto","middleName":"","lastName":"Wada","suffix":""},{"id":334562894,"identity":"0b510ac0-2239-467a-8ad7-266643b0dd40","order_by":6,"name":"Keiko Iino","email":"","orcid":"","institution":"National College of Nursing","correspondingAuthor":false,"prefix":"","firstName":"Keiko","middleName":"","lastName":"Iino","suffix":""},{"id":334562895,"identity":"f4b143c4-ec0c-43e0-b0dc-f33384aef108","order_by":7,"name":"Tatuso Akechi","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences and Medical School: Nagoya Shiritsu Daigaku Daigakuin Igaku Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Tatuso","middleName":"","lastName":"Akechi","suffix":""},{"id":334562896,"identity":"a321978b-3cf1-4e30-9a48-8871a93659f3","order_by":8,"name":"Hirotoshi Iihara","email":"","orcid":"","institution":"Gifu University Hospital: Gifu Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Hirotoshi","middleName":"","lastName":"Iihara","suffix":""},{"id":334562897,"identity":"bd26b432-1cef-4490-afa0-294e0e080487","order_by":9,"name":"Chiyo K. Imamura","email":"","orcid":"","institution":"Showa University: Showa Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Chiyo","middleName":"K.","lastName":"Imamura","suffix":""},{"id":334562898,"identity":"bb8d2463-c3f7-49d2-b33b-cfd070c936b9","order_by":10,"name":"Ayako Okuyama","email":"","orcid":"","institution":"St Luke's International University: Sei Roka Kokusai Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Ayako","middleName":"","lastName":"Okuyama","suffix":""},{"id":334562899,"identity":"56a45c12-73d9-4bf6-8e88-6d8803c26b22","order_by":11,"name":"Keiko Ozawa","email":"","orcid":"","institution":"National Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Keiko","middleName":"","lastName":"Ozawa","suffix":""},{"id":334562900,"identity":"13c3c326-4a6c-423e-8e19-3fa4a5703d2c","order_by":12,"name":"Yong-il Kim","email":"","orcid":"","institution":"Yodogawa Christian 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kenji","middleName":"","lastName":"Okita","suffix":""},{"id":334562913,"identity":"0d7a3847-7d5f-4693-9731-670cbf3853f3","order_by":25,"name":"Nobuyuki Yamamoto","email":"","orcid":"","institution":"Wakayama Medical University: Wakayama Kenritsu Ika Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Nobuyuki","middleName":"","lastName":"Yamamoto","suffix":""},{"id":334562914,"identity":"ba0f7652-075a-4f9c-a36b-5d79447e5677","order_by":26,"name":"Kenjiro Aogi","email":"","orcid":"","institution":"Shikoku Cancer Center: Kokuritsu Byoin Shikoku Gan Center","correspondingAuthor":false,"prefix":"","firstName":"Kenjiro","middleName":"","lastName":"Aogi","suffix":""},{"id":334562915,"identity":"740fddbb-e60d-408e-9e70-d2d30e6660ef","order_by":27,"name":"Hidenori Sasaki","email":"","orcid":"","institution":"Fukuoka University Hospital: Fukuoka Daigaku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Hidenori","middleName":"","lastName":"Sasaki","suffix":""}],"badges":[],"createdAt":"2024-07-26 08:57:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4806737/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4806737/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-024-02652-7","type":"published","date":"2024-11-12T15:58:05+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":64143109,"identity":"b2fd8b30-7f27-46a6-ab87-ddd051f1c4ed","added_by":"auto","created_at":"2024-09-08 19:29:13","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":391492,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow chart of the search strategy and study selection process\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4806737/v1/18ee1a77de256cdc0a2c77a4.jpeg"},{"id":69284927,"identity":"b1dc21c6-adc9-444b-9ab9-de0484054d90","added_by":"auto","created_at":"2024-11-18 19:23:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1092883,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4806737/v1/a1cd8a56-8b30-4765-8873-0b1de0b8b010.pdf"}],"financialInterests":"","formattedTitle":"Efficacy and safety of multi-day antiemetic treatment for patients undergoing multi-day chemotherapy: A systematic review of Clinical Practice Guidelines for Antiemesis 2023 from Japan Society of Clinical Oncology","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eChemotherapy-induced nausea and vomiting (CINV) is a distressing symptom in patients with cancer, significantly impacting their quality of life [1]. Most patients seek to avoid experiencing CINV [2], as it can lead to treatment discontinuation and worsen prognoses [3], highlighting the importance of its effective management.\u003c/p\u003e \u003cp\u003eMulti-day administration of cytotoxic anticancer drugs is common in treating cancers such as germ cell tumors, bone and soft tissue sarcomas, lymphomas, and lung cancers. However, antiemetic therapy for these treatments varies significantly in terms of drug type, administration method, and dosage, depending on the chemotherapy regimen, complicating the establishment of a standardized antiemetic protocol. While intravenous administration of anticancer drugs over multiple days causes the acute and delayed phases of nausea and vomiting to overlap, resulting in complex conditions, no standard antiemetic therapy currently exists for such treatment regimens. Moreover, the Japanese Society of Clinical Oncology\u0026rsquo;s clinical practice guidelines do not provide clear recommendations for prophylactic antiemetic therapy in multi-day chemotherapy regimens [4].\u003c/p\u003e \u003cp\u003eTo address this gap in knowledge, this systematic review aimed to investigate the efficacy of multi-day antiemetic treatment in patients undergoing multi-day chemotherapy. Given the wide variation in multi-day anticancer drug regimens, we specifically focused on those including multi-day cisplatin and ifosfamide, which are known for their high emetic risk.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eThis systematic review was conducted in accordance with the \u0026ldquo;Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) 2020 statement\u0026rdquo; [5] and the \u0026ldquo;Minds Clinical Practice Guideline Development Guide 2017\u0026rdquo; [6].\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy\u003c/h2\u003e \u003cp\u003eWe systematically searched the PubMed, Cochrane Library, and Ichushi-Web databases for relevant studies published between January 1990 and December 2020. The search terms included \u0026ldquo;multiday chemotherapy,\u0026rdquo; \u0026ldquo;multiple-day chemotherapy,\u0026rdquo; \u0026ldquo;multiday cisplatin,\u0026rdquo; \u0026ldquo;antiemetic,\u0026rdquo; \u0026ldquo;CINV,\u0026rdquo; \u0026ldquo;nausea,\u0026rdquo; \u0026ldquo;vomiting,\u0026rdquo; and \u0026ldquo;germ cell tumors.\u0026rdquo; Additional relevant literature obtained through manual search was also included.\u003c/p\u003e \u003cp\u003eTwo reviewers (S.H. and K.N.) independently conducted two rounds of screening to select eligible literature for evaluation in this systematic review. In cases of disagreement between the two reviewers, a third reviewer (R.K.) was consulted to make the final decision. Primary screening involved assessing titles and abstracts of the articles, while secondary screening was based on the full texts.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSelection criteria\u003c/h2\u003e \u003cp\u003eWe prioritized the inclusion of randomized controlled trials (RCTs) that met the population, intervention, comparator, and outcome (PICO) criteria. In the absence of sufficient RCTs, we included non-RCTs, single-arm trials, case-control studies, and observational studies from which data could be extracted. Case reports and case series were excluded due to their low quality of evidence.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePICO framework\u003c/h2\u003e \u003cp\u003eThe PICO framework for this clinical question was defined as follows: (a) Population: This refers to patients with cancer undergoing multi-day chemotherapy. (b) Intervention: This involved the administration of multi-day antiemetic therapy. (c) Comparator: This involved the administration of single-day antiemetic therapy. (d) Outcomes: Four primary endpoints were established, namely \u0026ldquo;vomiting control,\u0026rdquo; \u0026ldquo;nausea control,\u0026rdquo; \u0026ldquo;adverse events,\u0026rdquo; and \u0026ldquo;cost.\u0026rdquo;\u003c/p\u003e \u003cp\u003e\u0026ldquo;Vomiting control\u0026rdquo; was evaluated by complete response (CR) rate (no vomiting and no use of rescue therapy) and no vomiting (NV) rate. \u0026ldquo;Nausea control'' was assessed by the complete control (CC) rate (no vomiting, no rescue, and no significant nausea), total control (TC) rate (no vomiting, no rescue, and no nausea), no nausea (NN) rate, and no significant nausea (NSN) rate. NSN was defined as \u0026lt;\u0026thinsp;25 mm on the Visual Analog Scale, \u0026le; 2 on the Numerical Rating Scale, and none or mild on the Categorical Rating Scale.\u003c/p\u003e \u003cp\u003eIn this study, the acute phase was defined as the period up to day 5 or 120 h after chemotherapy initiation. The delayed phase was defined as the period after day 6 or 120 h. The overall phase included both acute and delayed phases.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData extraction and quality assessment\u003c/h2\u003e \u003cp\u003eFollowing the second screening, the reviewer (S.H.) of the systematic review team conducted a reassessment of the selected articles and extracted data using standardized data abstraction forms. The evidence pertaining to critical outcomes relevant to the clinical questions posed by the guideline-creation team was categorized into groups based on study design and quality. The level of evidence was not assessed for individual references but rather for each outcome within studies grouped by study design. The certainty of the evidence was evaluated by considering factors such as risk of bias, inconsistency, imprecision, indirectness, and publication bias. Based on the synthesized body of evidence, its strength and recommendations were determined using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach [7].\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eLiterature search\u003c/h2\u003e \u003cp\u003eA flowchart outlining the search strategy and study selection process is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The literature search for this clinical question yielded 40 articles from PubMed, 132 Cochrane, and 31 from Ichushi-Web databases. Additionally, seven articles were identified through manual searches. Ultimately, 210 articles were subjected to primary screening. However, no studies directly comparing multi-day versus single-day antiemetic therapy addressed this clinical question. Consequently, the control group was expanded beyond \u0026ldquo;single-day antiemetic therapy.\u0026rdquo; During secondary screening, 46 articles were assessed, resulting in the selection of 23 articles [8\u0026ndash;30]. These selected articles are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Despite the selection, few studies fully met the PICO criteria. Additionally, variations in cancer types, chemotherapy regimens, and antiemetic therapies among the studies precluded a meta-analysis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSelected studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDesign\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eType of cancer\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eType of chemotherapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAntiemetics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAntiemetic effect\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFox 1993 [20]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGerm cell tumor, Lung cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMulti-day (4\u0026ndash;5 days) cisplatin combination\u003c/p\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eThree doses of ondansetron 0.15 mg/kg on days 1\u0026ndash;4 or 5\u003c/p\u003e \u003cp\u003eDEX 12mg on days 1\u0026ndash;2\u003c/p\u003e \u003cp\u003eChlorpromazine 200 mg on days 1\u0026ndash;4 or 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV in days 1\u0026ndash;5: 55%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eThree doses of ondansetron 0.15 mg/kg on days 1\u0026ndash;4 or 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV in days 1\u0026ndash;5: 32%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFauser 2000 [8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSolid tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMulti-day (2\u0026ndash;5 days) cisplatin combination\u003c/p\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDolasetron 100 mg on days 1\u0026ndash;2, 3, 4, or 5\u003c/p\u003e \u003cp\u003eDEX 20 mg on days 1\u0026ndash;2, 3, 4, or 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR in overall phase (days 1\u0026ndash;5): 72.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDolasetron 100 mg on day 1\u0026ndash;2, 3, 4, or 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR in overall phase (days 1\u0026ndash;5): 40.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHerrstedt 2007 [21]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGerm cell tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e5-day cisplatin chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTropisetron 5 mg IV on days 1\u0026ndash;6\u003c/p\u003e \u003cp\u003eMetopimazine 30 mg orally three times on day 1 and twice on days 2\u0026ndash;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV in overall phase (days 1\u0026ndash;9): 40.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTropisetron 5 mg IV on days 1\u0026ndash;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV in overall phase (days 1\u0026ndash;9): 17.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAlbany 2012 [9]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGerm cell tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e5-day cisplatin chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPR 125 mg on day 3 and 80 mg on day 4\u0026ndash;7\u003c/p\u003e \u003cp\u003e5HT3RA on day1\u0026ndash;5\u003c/p\u003e \u003cp\u003eDEX 20 mg on days 1\u0026ndash;2 and 4 mg twice on days 6\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR in overall phase (days 1\u0026ndash;8): 42%\u003c/p\u003e \u003cp\u003eNV: 84%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5HT3RA on days 1\u0026ndash;5\u003c/p\u003e \u003cp\u003eDEX 20 mg on days 1\u0026ndash;2, 8 mg twice on days 6\u0026ndash;7, 4 mg twice on day 8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR in overall phase (days 1\u0026ndash;8): 13%\u003c/p\u003e \u003cp\u003eNV: 53%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAbdel-Malek 2017 [10]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRCT (Prospective cross-over study)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNon-Hodgkin lymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e4-day cisplatin chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPR 125 mg on day 1 and 80 mg on days 2, 3\u003c/p\u003e \u003cp\u003eOndansetrone 8 mg on days 1\u0026ndash;5\u003c/p\u003e \u003cp\u003eDEX 8 mg on days 1\u0026ndash;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR: 83.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOndansetrone 8 mg on days 1\u0026ndash;5\u003c/p\u003e \u003cp\u003eDEX 8 mg on days 1\u0026ndash;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR: 0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEinhorn 1990 [23]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-arm intervention study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSolid tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMulti-day (4\u0026ndash;5 days) cisplatin combination\u003c/p\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOndansetron 0.15 mg/kg on days 1\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV on days 1\u0026ndash;5: 29%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHainsworth 1991 [24]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-arm intervention study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSolid tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMulti-day (4\u0026ndash;5 days) cisplatin combination\u003c/p\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOndansetron 0.15 mg/kg on days 1\u0026ndash;3 or 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV on days 1\u0026ndash;5: 33%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuminaga 1992 [27]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-arm intervention study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSolid tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMulti-day (3\u0026ndash;5 days) cisplatin combination\u003c/p\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOndansetron 4 mg on days 1\u0026ndash;3, 4, or 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV on day 1: 55.6%, on day 2: 66.7%, on day 3: 55.6%, on day 4: 42.9%, on day 5: 28.6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAkasaka 1992 [28]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-arm intervention study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSolid tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMulti-day (3\u0026ndash;5 days) cisplatin combination\u003c/p\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOndansetron 4 mg on days 1\u0026ndash;3, 4, or 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV on day 1: 67%, on day 2: 56%, on day 3: 33%, on day 4: 35%, on day 5: 50%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAkaza 1995 [29]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-arm intervention study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUrinary cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMulti-day (3\u0026ndash;5 days) cisplatin combination\u003c/p\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTropisetron 5 mg on days 1\u0026ndash;3, 4, or 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV on day 1: 80.0%, on day 2: 80.0%, on day 3: 62.9%, on day 4: 44.4%, on day 5: 61.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTaketani 1996 [30]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-arm intervention study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGynecological cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMulti-day (2\u0026ndash;5 days) cisplatin combination\u003c/p\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRamosetron 1 mg on days 1\u0026ndash;2, 3, 4, or 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV on day 1: 86.7%, on day 2: 66.7%, on day 3: 60.0%, on day 4: 53.3%, on day 5: 53.3%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAriyoshi 1997 [25]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-arm intervention study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSolid tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMulti-day (3\u0026ndash;5 days) cisplatin combination\u003c/p\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOndansetron 4 mg on days 1\u0026ndash;3, 4, or 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV on day 1: 76.5%, on day 2: 70.6%, on day 3: 73.3%, on day 4: 75.0%, on day 5: 72.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEinhorn 2007 [11]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-arm intervention study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTesticular germ cell tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5-day cisplatin combination\u003c/p\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePALO 0.25 mg on days 1, 3, and 5\u003c/p\u003e \u003cp\u003eDEX 20 mg on days 1 and 2, 8 mg bid on days 6 and 7, and 4 mg bid on day 8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR on days 1\u0026ndash;5: 34.1%\u003c/p\u003e \u003cp\u003eCR on days 6\u0026ndash;9: 61.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJordan 2009 [12]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-arm intervention study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSolid tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMulti-day (3\u0026ndash;5 days) HEC or MEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGranisetron 1 mg i.v. on days 1\u0026ndash;3\u0026thinsp;~\u0026thinsp;5\u003c/p\u003e \u003cp\u003eAPR 125 mg on day 1 and 80 mg on days 2\u0026ndash;5, 6, or 7\u003c/p\u003e \u003cp\u003eDEX 8 mg on days 1\u0026ndash;5, 6, or 7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHEC: 38\u003c/p\u003e \u003cp\u003eMEC: 40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHEC CR in overall phase (days 1\u0026ndash;10): 57.9%\u003c/p\u003e \u003cp\u003eMEC CR in overall phase (days 1\u0026ndash;10): 72.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOlver 2013 [13]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-arm intervention study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGerm cell tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5-day cisplatin chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPR 125 mg on day 1 and 80 mg on days 2\u0026ndash;7\u003c/p\u003e \u003cp\u003e5HT3RA on days 1\u0026ndash;5\u003c/p\u003e \u003cp\u003eDEX 8 mg on days 1\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV in overall phase (days 1\u0026ndash;7): 82%\u003c/p\u003e \u003cp\u003eCR in overall phase (days 1\u0026ndash;7): 41%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHamada 2014 [14]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-arm intervention study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTesticular germ cell tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5-day cisplatin combination\u003c/p\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePALO 0.75 mg on day 1\u003c/p\u003e \u003cp\u003eAPR 125 mg on day 1 and 80 mg on days 2\u0026ndash;5\u003c/p\u003e \u003cp\u003eDEX 9.9 mg on day 1 and 6.6 mg on days 2\u0026ndash;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR in overall phase (0\u0026ndash;216 h): 90.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdra 2016 [15]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-arm intervention study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTesticular germ cell tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5-day cisplatin combination\u003c/p\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFosaprepitant 150 mg on days 3 and 5\u003c/p\u003e \u003cp\u003e5HT3-RA days 1\u0026ndash;5 (days 1, 3, and 5, if PALO)\u003c/p\u003e \u003cp\u003eDEX 20 mg on days 1 and 2, 4 mg bid on days 6, 7, and 8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR in overall phase (days 1\u0026ndash;8): 24.1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIoroi 2018 [16]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-arm intervention study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTesticular germ cell tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5-day cisplatin combination chemotherapy.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePALO 0.75 mg on day 1\u003c/p\u003e \u003cp\u003eAPR 125 mg on day 1 and 80 mg on days 2\u0026ndash;7\u003c/p\u003e \u003cp\u003eDEX 6.6 mg on days 1\u0026ndash;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR in overall phase (0\u0026ndash;240 h) (days 1\u0026ndash;10)): 62.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBun 2018 [17]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle-arm intervention study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGerm cell tumor, Synovial sarcoma, Spindle cell sarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5-day cisplatin or ifosfamide combination chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGRA 1 mg iv on days 1\u0026ndash;5\u003c/p\u003e \u003cp\u003eDEX 24 mg on days 1\u0026ndash;5\u003c/p\u003e \u003cp\u003eOLZ 2.5\u0026ndash;10 mg on days 1\u0026ndash;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR in overall phase (0\u0026ndash;240 h): 44.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAoyama 2010 [26]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRetrospective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBone and soft tissue sarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e5-day ifosfamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5-HT3RA on days 1\u0026ndash;5\u003c/p\u003e \u003cp\u003eDEX 8 mg on days 1, 3, and 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV on days 1\u0026ndash;5: 73.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5-HT3RA on days 1\u0026ndash;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV on days 1\u0026ndash;5: 66.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSuzuki 2012 [18]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRetrospective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBone and soft tissue sarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e5-day ifosfamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPR 125 mg on day 2 and 80 mg on days 3 and 4\u003c/p\u003e \u003cp\u003eGRA 3 mg on days 1\u0026ndash;6\u003c/p\u003e \u003cp\u003eDEX 6.6 mg on days 1, 3, and 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR in overall phase (days 1\u0026ndash;10): 91.6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGRA 3 mg iv on days 1\u0026ndash;6\u003c/p\u003e \u003cp\u003eDEX 6.6 mg on days 1, 3, and 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR in overall phase (days 1\u0026ndash;10): 41.1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eKim 2012 [19]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRetrospective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSolid and nonsolid cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMultiday (2\u0026ndash;5 days) HEC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePALO 0.25 mg on day 1\u003c/p\u003e \u003cp\u003eAPR 125 mg on day 1 and 80 mg on days 2, 3\u003c/p\u003e \u003cp\u003eDEX 12 mg on day 1, 8 mg on days 2\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR in overall phase (0\u0026ndash;120 h): 53.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOther 5HT3-RA on days 2\u0026ndash;5\u003c/p\u003e \u003cp\u003eAPR 125 mg on day 1 and 80 mg on days 2 and 3\u003c/p\u003e \u003cp\u003eDEX 12 mg on day 1, and 8 mg on days 2\u0026ndash;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCR in overall phase (0\u0026ndash;120 hours): 50.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eUchiyama 2017 [22]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRetrospective study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOral cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e5-day cisplatin or nedaplatin chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAPR 125 mg on day 1 and 80 mg on days 2, 3\u003c/p\u003e \u003cp\u003eGRA 3 mg on days 1\u0026ndash;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV: 70%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFosaprepitant 150 mg on day 1\u003c/p\u003e \u003cp\u003eGRA 3 mg on days 1\u0026ndash;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNV: 70%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eRCT, randomized controlled study; CR, complete response; NV, No vomiting; PALO, palonosetron; DEX, dexamethasone; APR, aprepitant, 5HT3RA: 5-HT3 receptor antagonist\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eVomiting control\u003c/h2\u003e \u003cp\u003eTo assess \u0026ldquo;vomiting control,\u0026rdquo; we examined the \"CR ratio\" and \"NV ratio\" across acute, delayed, and overall periods.\u003c/p\u003e \u003cp\u003eRegarding the CR rate, three RCTs [8\u0026ndash;10], seven single-arm trials [11\u0026ndash;17], and two cohort studies [18, 19] were identified. Two RCTs compared a triple-drug combination therapy group, including aprepitant, with a dual-drug combination therapy group and found significantly higher CR rates in the triple-drug group during the overall period [9, 10]. One of these studies also reported significantly higher CR rates in both the acute and delayed phases for the triple-drug group [9], and another one showed significantly higher CR rates in the acute phase for dual-drug combination therapy, including dexamethasone, compared to 5-hydroxytryptamine 3 (5-HT3) receptor antagonist monotherapy [8]. Among the cohort studies, one study, although not statistically significant, showed a trend towards higher CR rates in the triple-drug combination therapy, including aprepitant, compared with the dual-drug combination therapy across the acute, delayed, and overall periods [18].\u003c/p\u003e \u003cp\u003eRegarding the NV ratio, four RCTs [8, 9, 20, 21], one non-RCT [22], seven single-arm trials [11, 13, 15, 17, 23\u0026ndash;25], and three cohort studies were identified [18, 19, 26]. Among them, one RCT found significantly higher NV rates in both the acute and delayed phases for the triple-drug combination therapy (including aprepitant) compared to the dual-drug combination therapy [9]. Similarly, a cohort study reported significantly higher NV rates during the acute and overall periods for the triple-drug combination therapy [18].\u003c/p\u003e \u003cp\u003eGiven the identified RCTs and the observed trends in CR and NV rates, the strength of the evidence for this outcome was classified as moderate (B).\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eNausea control\u003c/h2\u003e \u003cp\u003eTo evaluate \u0026ldquo;nausea control,\u0026rdquo; we examined the \"CC ratio,\" \"TC ratio,\" \"NN ratio,\" and \"NSN ratio\" across acute, delayed, and overall periods.\u003c/p\u003e \u003cp\u003eFor the CC ratio, two single-arm trials [16, 17] and one cohort study [19] were identified, and for the TC ratio, only two single-arm trials were included [16, 17]. The cohort study compared triple-drug therapy with palonosetron to first-generation 5-HT3 receptor antagonists and found no significant difference in the CC ratio during the acute phase between the two groups [19].\u003c/p\u003e \u003cp\u003eRegarding the NN and NSN ratios, one RCT [21] and one non-RCT [22] were identified, along with two cohort studies [19, 26] and four single-arm trials [12\u0026ndash;14, 17] for the NN ratio and three single-arm trials for the NSN ratio [11, 13, 17]. One cohort study revealed that the NN ratio during the acute and delayed phases was significantly higher in a dual-drug therapy group with alternate-day dexamethasone administration compared to a monotherapy group with a 5-HT3 receptor antagonist [26]. Conversely, the other cohort study found no significant difference in the acute phase NN ratio between palonosetron and first-generation 5-HT3 receptor antagonist groups after triple-drug therapy [19].\u003c/p\u003e \u003cp\u003eThe evidence for the CC and TC ratios was based on non-RCTs, while only one RCT and one non-RCT were identified for the NN and NSN ratios. The limited number and quality of studies made it challenging to fully evaluate the effectiveness of multi-day antiemetic therapy for nausea control. Consequently, the strength of the evidence for this outcome was classified as very weak (D).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAdverse events\u003c/h2\u003e \u003cp\u003eFour RCTs [8, 9, 20, 21], one non-RCT [22], fourteen single-arm trials [11\u0026ndash;17, 23\u0026ndash;25, 27\u0026ndash;30], and one cohort study were identified for adverse events evaluation [18]. The reported proportion of patients experiencing adverse events was approximately half. However, due to variability in intervention content across studies, individual adverse events were not enumerated, limiting the evaluation to general adverse events. No studies specified the incidence of adverse events, and no serious adverse events were reported in the multi-day antiemetic therapy group.\u003c/p\u003e \u003cp\u003eGiven these limitations, we were unable to fully evaluate the effects of multi-day antiemetic therapy for adverse events. Therefore, the strength of evidence for this outcome was classified as very weak (D).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eCost\u003c/h2\u003e \u003cp\u003eNo study evaluating the cost of multi-day antiemetic therapy was extracted, and consequently, this outcome could not be evaluated.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this systematic review, we investigated the efficacy of multi-day antiemetic treatment for patients undergoing multi-day intravenous administration of cytotoxic anticancer drugs. Despite an extensive literature search, no studies directly comparing multi-day antiemetic therapy with single-day therapy were found, which aligns with our clinical question. Although we expanded the control group beyond \u0026ldquo;single-day therapy\" and conducted a thorough systematic review, the scarcity of high-quality studies remained a challenge.\u003c/p\u003e \u003cp\u003eDespite limited evidence, two RCTs comparing dual-drug therapy with triple-drug therapy showed higher CR and NV ratios in the triple-drug therapy group [9, 10], suggesting the potential benefit of using three drugs for multi-day antiemetic therapy. Moreover, most studies utilizing 5-HT3 receptor antagonists or aprepitants have employed multi-day antiemetic therapy protocols [8\u0026ndash;30].\u003c/p\u003e \u003cp\u003eWhile no serious adverse events were reported with multi-day antiemetic therapy, patients receiving multi-day intravenous administration of cytotoxic anticancer drugs experience persistent nausea and vomiting, leading to significant distress and anxiety. Consequently, there is a strong preference for patients to minimize these symptoms as much as possible [2]. Based on the literature review, the Clinical Practice Guidelines for Antiemesis 2023 from the Japan Society of Clinical Oncology strongly recommend the implementation of multi-day antiemetic therapy in patients receiving multi-day intravenous cytotoxic anticancer drug. However, it is crucial to note that the strength of evidence supporting this recommendation was graded as extremely weak (D), highlighting the need for further research in this area. Recently, there has been increasing recognition of olanzapine\u0026rsquo;s efficacy in treating CINV. Olanzapine, an atypical antipsychotic with multi-acting receptor targeting properties, has demonstrated strong antiemetic effects when used for several days [31\u0026ndash;36]. Additionally, fosnetupitant, a novel intravenous NK1RA drug, has shown promise in improving the delayed phase (24\u0026ndash;168 h) of highly emetogenic chemotherapy in a phase III study [37]. Thus, we posit that the inclusion of antiemetic therapies, such as olanzapine and fosnetupitant, may enhance the antiemetic effects of multi-day chemotherapy.\u003c/p\u003e \u003cp\u003eIn conclusion, studies on multi-day antiemetic therapy are scarce, necessitating further research. Nevertheless, some studies have suggested that three-drug combination therapy, including aprepitant, may offer superior antiemetic effects compared to two-drug combination therapy. Multi-day antiemetic therapy is strongly recommended in patients undergoing multi-day intravenous administration of cytotoxic anticancer drugs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCONFLICTS OF INTEREST\u003c/h2\u003e \u003cp\u003eKazuhisa Nakashima received honoraria from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., and Eli Lilly Japan K.K. Eriko Satomi received honoraria from Shionogi \u0026amp; Co., Ltd. Masayuki Takeda 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, Pfzer Global Supply Japan Inc., Merck Biopharma Co., Ltd, Pfzer 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.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eETHICAL APPROVAL\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eINFORMED CONSENT\u003c/strong\u003e \u003cp\u003eFormal consent was not required for this type of study.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCONSENT TO PARTICIPATE\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCONSENT FOR PUBLICATION\u003c/strong\u003e \u003cp\u003eAll authors consented to the publication of this study.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFUNDING\u003c/h2\u003e \u003cp\u003eThis study was supported by the Japan Society of Clinical Oncology.\u003c/p\u003e\u003ch2\u003eAUTHOR CONTRIBUTIONS\u003c/h2\u003e \u003cp\u003eAll authors contributed to the conception and design of this study. Kazuhisa Nakashima wrote the original draft of the manuscript. All other authors reviewed and edited the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eACKNOWLEDGMENTS\u003c/h2\u003e \u003cp\u003eWe thank Ms. Natsuki Fukuda and Ms. Kyoko Hamada for their valuable comments and suggestions, and invaluable supports. We thank Mr. Naohiko Yamaguchi and Ms. Yuko Mitsuoka for their contributions to the literature search. We thank Editage (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.editage.jp\" target=\"_blank\"\u003ewww.editage.jp\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.editage.jp\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) for the English language editing.\u003c/p\u003e\u003ch2\u003eDATA AVAILABILITY\u003c/h2\u003e \u003cp\u003eData associated with this systematic review can be accessed from the corresponding author upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBloechl-Daum B, Deuson RR, Mavros P, et al (2006 Sep 20) Delayed nausea and vomiting continue to reduce patients\u0026rsquo; quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment. J Clin Oncol 24:4472\u0026ndash;4478\u003c/li\u003e\n\u003cli\u003eSun CC, Bodurka DC, Weaver CB, et al (2005 Apr) Rankings and symptom assessments of side effects from chemotherapy: insights from experienced patients with ovarian cancer. Support Care Cancer 13:219\u0026ndash;227\u003c/li\u003e\n\u003cli\u003eEpelbaum R, Faraggi D, Ben-Arie Y, et al (1990 Sep 15) Survival of diffuse large cell lymphoma. A multivariate analysis including dose intensity variables. Cancer 66:1124\u0026ndash;1129\u003c/li\u003e\n\u003cli\u003eAogi K, Takeuchi H, Saeki T, et al (2021 Jan) Optimizing antiemetic treatment for chemotherapy-induced nausea and vomiting in Japan: update summary of the 2015 Japan Society of Clinical Oncology Clinical Practice Guidelines for antiemesis. Int J Clin Oncol 26:1\u0026ndash;17\u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM et al. (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Int J Surg 88:105906\u003c/li\u003e\n\u003cli\u003eKojimahara N, Nakayama T, Morizane T, et al. (2017) Minds manual for Guideline 18 development 2017. Japan Council for Quality Health Care, Tokyo\u003c/li\u003e\n\u003cli\u003eJaeschke R, Guyatt GH, Dellinger P, et al. (2008) Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive. BMJ 337:a744\u003c/li\u003e\n\u003cli\u003eFauser AA, Pizzocaro G, Schueller J, et al (2000) A double-blind, randomised, parallel study comparing intravenous dolasetron plus dexamethasone and intravenous dolasetron alone for the management of fractionated cisplatin-related nausea and vomiting. Support Care Cancer 8:49\u0026ndash;54\u003c/li\u003e\n\u003cli\u003eAlbany C, Brames MJ, Fausel C, et al (2012) Randomized, double-blind, placebo-controlled, phase III cross-over study evaluating the oral neurokinin-1 antagonist aprepitant in combination with a 5HT3 receptor antagonist and dexamethasone in patients with germ cell tumors receiving 5-day cisplatin combination chemotherapy regimens: a Hoosier Oncology Group study. J Clin Oncol 30:3998\u0026ndash;4003\u003c/li\u003e\n\u003cli\u003eAbdel-Malek R, Abbas N, Shohdy KS, et al (2017) Addition of 3-day aprepitant to ondansetron and dexamethasone for prophylaxis of chemotherapy-induced nausea and vomiting among patients with diffuse large B cell lymphoma receiving 5-day cisplatin-based chemotherapy. J Egypt Natl Canc Inst 29:155\u0026ndash;158\u003c/li\u003e\n\u003cli\u003eEinhorn LH, Brames MJ, Dreicer R, et al (2007) Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy for germ cell cancer. Support Care Cancer 15:1293\u0026ndash;1300\u003c/li\u003e\n\u003cli\u003eJordan K, Kinitz I, Voigt W, et al (2009) Safety and efficacy of a triple antiemetic combination with the NK-1 antagonist aprepitant in highly and moderately emetogenic multiple-day chemotherapy. Eur J Cancer 45:1184\u0026ndash;1187\u003c/li\u003e\n\u003cli\u003eOlver IN, Grimison P, Chatfield M, et al. (2013) Results of a 7-day aprepitant schedule for the prevention of nausea and vomiting in 5-day cisplatin-based germ cell tumor chemotherapy. Support Care Cancer 21:1561\u0026ndash;1568\u003c/li\u003e\n\u003cli\u003eHamada S, Hinotsu S, Kawai K, et al (2014) Antiemetic efficacy and safety of a combination of palonosetron, aprepitant, and dexamethasone in patients with testicular germ cell tumor receiving 5-day cisplatin-based combination chemotherapy. Support Care Cancer 22:2161\u0026ndash;2166\u003c/li\u003e\n\u003cli\u003eAdra N, Albany C, Brames MJ, et al. (2016) Phase II study of fosaprepitant + 5HT3 receptor antagonist + dexamethasone in patients with germ cell tumors undergoing 5-day cisplatin-based chemotherapy: a Hoosier Cancer Research Network study. Support Care Cancer 24:2837\u0026ndash;2842\u003c/li\u003e\n\u003cli\u003eIoroi T, Furukawa J, Kume M, et al. (2018) Phase II study of palonosetron, aprepitant and dexamethasone to prevent nausea and vomiting induced by multiple-day emetogenic chemotherapy. Support Care Cancer 26:1419\u0026ndash;1423\u003c/li\u003e\n\u003cli\u003eBun S, Yonemori K, Akagi T, et al (2018) Feasibility of olanzapine, multi acting receptor targeted antipsychotic agent, for the prevention of emesis caused by continuous cisplatin- or ifosfamide-based chemotherapy. Investig New Drugs 36:151\u0026ndash;155\u003c/li\u003e\n\u003cli\u003eSuzuki W, Aoyama T, Sugita K, et al (2012) Evaluation of prevention of the emetic effects with 3-day administration of aprepitant in multiple-day chemotherapy. Jpn J Pharm Health Care Sci (in Japanese) 38:163\u0026ndash;169\u003c/li\u003e\n\u003cli\u003eKim KI, Lee DE, Cho I, et al (2012) Effectiveness of palonosetron versus other serotonin 5-HT3 receptor antagonists in triple antiemetic regimens during multiday highly emetogenic chemotherapy. Ann Pharmacother 46:1637\u0026ndash;1644\u003c/li\u003e\n\u003cli\u003eFox SM, Einhorn LH, Cox E, et al (1993) Ondansetron versus ondansetron, dexamethasone, and chlorpromazine in the prevention of nausea and vomiting associated with multiple-day cisplatin chemotherapy. J Clin Oncol 11:2391\u0026ndash;2395\u003c/li\u003e\n\u003cli\u003eHerrstedt J, Sigsgaard TC, Nielsen HA, et al (2007) Randomized, double-blind trial comparing the antiemetic effect of tropisetron plus Metopimazine with tropisetron plus placebo in patients receiving multiple cycles of multiple-day cisplatin-based chemotherapy. Support Care Cancer 15:417\u0026ndash;426\u003c/li\u003e\n\u003cli\u003eUchiyama K, Yamada M, Shiiba Y, et al (2017 Jul) Determination of the effect of aprepitant and fosaprepitant for nausea in patients with oral cancer receiving combination chemotherapy with TPF (in Japanese). Gan To Kagaku Ryoho 44:585\u0026ndash;589\u003c/li\u003e\n\u003cli\u003eEinhorn LH, Nagy C, Werner K, et al. (1990) Ondansetron: a new antiemetic for patients receiving cisplatin chemotherapy. J Clin Oncol 8:731\u0026ndash;735\u003c/li\u003e\n\u003cli\u003eHainsworth JD, Omura GA, Khojasteh A, et al. (1991) Ondansetron (GR 38032F): a novel antiemetic effective in patients receiving a multiple-day regimen of cisplatin chemotherapy. Am J Clin Oncol 14:336\u0026ndash;340\u003c/li\u003e\n\u003cli\u003eAriyoshi Y, Nukariya N, Akasaka Y, et al (1997 Jun) Clinical efficacy of GG032X tablets, a new dosage form of ondansetron (fast dispersing tablet), on cisplatin-induced nausea and emesis (in Japanese). Gan To Kagaku Ryoho 24:995\u0026ndash;1011\u003c/li\u003e\n\u003cli\u003eAoyama T, Sugiyama H, Hiraoka T, et al (2010) Evaluation of alternate-day administration of dexamethasone for prevention of nausea, vomiting and anorexia induced by daily administration of ifosfamide (in Japanese). Jpn J Pharm Health Care Sci 36:542\u0026ndash;548\u003c/li\u003e\n\u003cli\u003eSuminaga M, Furue H, Taguchi T, et al (1992 Sep) Investigation of anti-emetic effect of ondansetron tablet in multiple doses on nausea and emesis associated with cisplatin (in Japanese). Gan To Kagaku Ryoho 19:1879\u0026ndash;1890\u003c/li\u003e\n\u003cli\u003eAkasaka Y, Taguchi T, Ota K, et al (1992 Aug) Anti-emetic effect and safety of consecutive use of ondansetron injection in cisplatin-induced nausea and emesis (in Japanese). Gan To Kagaku Ryoho 19:1359\u0026ndash;1374\u003c/li\u003e\n\u003cli\u003eAkaza H, Machida T, Akasaka Y, et al (1995 Jul) The antiemetic effect, safety and usefulness of tropisetron capsule in the treatment of nausea and vomiting induced by lower multiple dose of cisplatin (in Japanese). Gan To Kagaku Ryoho 22:1063\u0026ndash;1072\u003c/li\u003e\n\u003cli\u003eTaketani Y, Yoshikawa H, Kinoshita K, et al (1996) The world of obstetrics and gynecology (in Japanese) 48:749\u0026ndash;760\u003c/li\u003e\n\u003cli\u003eNavari RM, Qin R, Ruddy KJ, et al (2016 Jul 14) Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med 375:134\u0026ndash;142\u003c/li\u003e\n\u003cli\u003eHashimoto H, Abe M, Tokuyama O, et al. (2020 Feb) Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 21:242\u0026ndash;249\u003c/li\u003e\n\u003cli\u003eJeon SY, Han HS, Bae WK, et al. (2019 Jan) A randomized, double-blind, placebo-controlled study of the safety and efficacy of olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy: results of the Korean south west oncology group (KSWOG) study. Cancer Res Treat 51:90\u0026ndash;97\u003c/li\u003e\n\u003cli\u003eTanaka K, Inui N, Karayama M, et al (2019 Jul) Olanzapine-containing antiemetic therapy for the prevention of carboplatin-induced nausea and vomiting. Cancer Chemother Pharmacol 84:147\u0026ndash;153\u003c/li\u003e\n\u003cli\u003eIihara H, Shimokawa M, Hayasaki Y, et al (2020 Mar) Efficacy and safety of 5 mg olanzapine combined with aprepitant, granisetron and dexamethasone to prevent carboplatin-induced nausea and vomiting in patients with gynecologic cancer: A multi-institution phase II study. Gynecol Oncol 156:629\u0026ndash;635\u003c/li\u003e\n\u003cli\u003eSakai C, Shimokawa M, Iihara H, et al. (2021 Jun) Low-dose olanzapine plus granisetron and dexamethasone for carboplatin-induced nausea and vomiting in patients with thoracic malignancies: A prospective multicenter Phase II trial. Oncologist 26:e1066\u0026ndash;e1072\u003c/li\u003e\n\u003cli\u003eHata A, Okamoto I, Inui N, et al. (2022 Jan 10) Randomized, double-blind, Phase III study of fosnetupitant versus fosaprepitant for prevention of highly emetogenic chemotherapy-induced nausea and vomiting: CONSOLE. J Clin Oncol 40:180\u0026ndash;188\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Systematic review, Meta-analysis, Multi-day chemotherapy, Chemotherapy-induced nausea and vomiting","lastPublishedDoi":"10.21203/rs.3.rs-4806737/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4806737/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eA standardized multi-day antiemetic regimen for multi-day chemotherapy remains elusive. This systematic review evaluated the efficacy and safety of multi-day antiemetic regimens in patients undergoing undergoing multi-day intravenous chemotherapy\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a comprehensive search of PubMed, Cochrane Library, and Ichushi-Web databases for relevant studies published from January 1990 to December 2020. We included studies comparing multi-day and single-day antiemetic regimens for preventing chemotherapy-induced nausea and vomiting.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eNo studies directly comparing multi-day versus single-day antiemetic regimens were found. Despite expanding control group criteria beyond \u0026ldquo;single-day antiemetic therapy\u0026rdquo; limited high-quality studies and variations in cancer types, chemotherapy regimens, and antiemetic treatments precluded meta-analysis. Among the included studies, some randomized controlled trials (RCTs) focused on complete response and vomiting rates. Two studies comparing two- and three-drug combinations reported higher complete response and no-vomiting rates with the three-drug regimen. Limited RCTs explored \u0026ldquo;nausea control\u0026rdquo; and \u0026ldquo;cost,\u0026rdquo; and assessing \u0026ldquo;adverse events\u0026rdquo; proved challenging due to inconsistent reporting.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eResearch on multi-day antiemetic therapy is limited, necessitating further investigation. Nonetheless, our findings suggest that three-drug combination therapy, including aprepitant, may offer superior antiemetic efficacy compared to two-drug regimens. Multi-day antiemetic therapy is strongly recommended during multi-day intravenous administration of cytotoxic anticancer drugs.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of multi-day antiemetic treatment for patients undergoing multi-day chemotherapy: A systematic review of Clinical Practice Guidelines for Antiemesis 2023 from Japan Society of Clinical Oncology","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-08 19:29:09","doi":"10.21203/rs.3.rs-4806737/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2024-08-10T22:21:28+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-08-02T06:27:08+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-01T06:22:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-30T05:37:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2024-07-26T04:57:07+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b50d16c1-f253-4654-a30c-90cc71791a27","owner":[],"postedDate":"September 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-18T19:17:13+00:00","versionOfRecord":{"articleIdentity":"rs-4806737","link":"https://doi.org/10.1007/s10147-024-02652-7","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2024-11-12 15:58:05","publishedOnDateReadable":"November 12th, 2024"},"versionCreatedAt":"2024-09-08 19:29:09","video":"","vorDoi":"10.1007/s10147-024-02652-7","vorDoiUrl":"https://doi.org/10.1007/s10147-024-02652-7","workflowStages":[]},"version":"v1","identity":"rs-4806737","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4806737","identity":"rs-4806737","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}