Neurokinin-1 receptor antagonists in the current management of chemotherapy-induced nausea and vomiting

Abstract

Chemotherapy-induced nausea and vomiting (CINV) is common in patients receiving moderately or highly emetogenic chemotherapy and is caused by the activation of peripheral and central nervous system pathways, with the neurokinin-1 receptor playing a central role in delayed CINV. Neurokinin-1 receptor antagonists (NK1RAs) in combination with other antiemetic agents are recommended in international and Chinese guidelines for the prevention of acute and delayed CINV. Therefore, a summary of current data for NK1RAs would be of great clinical utility. This article summarizes the available clinical and real-world data on the use of NK1RAs in CINV prophylaxis, with a focus on evidence from China, where three NK1RAs, aprepitant, fosaprepitant and netupitant, are currently approved. NK1RAs have demonstrated efficacy and favorable safety in the prevention of acute and delayed CINV. Further research is required to determine the optimal use of these drugs and to identify strategies for CINV management in specific patient populations.

Keywords

antiemetics / neurokinin-1 receptor antagonists / vomiting / China

1 Introduction

Despite the development of targeted therapies and immunotherapies, chemotherapy remains a keystone of cancer treatment and is commonly used in combination with new treatment modalities [1]. Patients receiving chemotherapy often experience chemotherapy-induced nausea and vomiting (CINV) [2], which has a strong negative impact on their health-related quality of life [3] and may lead to treatment delays or discontinuation [4]. CINV can be divided into different subtypes depending on the time to symptom onset after administration of chemotherapy, including acute CINV, which occurs within the first 24 h of receiving chemotherapy [5], and delayed CINV, which occurs 24 h after chemotherapy and may last up to 5 days [6]. Real-world data suggest that the incidences of acute and delayed CINV are 55.3% and 62.3%, respectively, in Chinese patients with cancer receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) [2]. Chow et al. reported that long-delayed CINV (occurring 120–168 h after chemotherapy) affects a substantial number of patients and that the severity of long-delayed nausea is similar to that in the delayed phase; among patients receiving MEC, long-delayed nausea and vomiting occurred in 24% and 6%, respectively; among those receiving HEC, the proportions were 31% and 6%, respectively [7]. Consistently, another Japanese multicenter prospective observational study showed that incidence rates of long-delayed nausea and vomiting were 22.2%–29.1% and 0%–6.7%, respectively [8]. Therefore, optimal control of CINV is crucial in patients receiving chemotherapy.

Numerous antiemetic agents with different mechanisms of action are available for the treatment of CINV, with the primary options consisting of 5-hydroxytryptamine type 3 receptor antagonists (5-HT3RAs), neurokinin-1 receptor antagonists (NK1RAs), and corticosteroids [9]. Considerable advances have been made in the management of acute CINV, with evidence that various antiemetic regimens can provide symptom control [10]. However, in the control of delayed CINV, there are remaining challenges related to multiple factors including inherent treatment resistance of the delayed phase, inadequate prescribing of antiemetics, and patient non-adherence to medication [6].

Guidelines for the management of CINV in clinical practice are available [11]. One of the main considerations when choosing antiemetic strategies is the emetogenic potential of chemotherapy regimens, where minimal and low emetogenic risk chemotherapies cause CINV in < 10% and 10%–30% of patients, respectively, MEC in 30%–90% of patients, and HEC in > 90% [12]. Generally, for prophylaxis of acute CINV in patients receiving MEC, a 5-HT3RA and dexamethasone with or without a NK1RA or olanzapine is recommended [12]. For acute CINV in patients receiving HEC, the recommendation is typically at least a three-drug regimen including a NK1RA, a 5-HT3RA, and dexamethasone [12]. Consensus on options for delayed CINV in patients receiving MEC or HEC is lacking across different guidelines [12]. Documentation of CINV management guidelines in Asia-Pacific populations is limited, although available consensus recommendations are broadly aligned with Western guidelines [13,14].

The management of CINV could be improved by using an individualized approach that accounts not only for the emetogenic potential of chemotherapy regimens, but also patient-related risk factors for CINV as well as other therapy-related factors [15]. Multiple-day chemotherapy regimens represent a particular challenge in the control of CINV, with difficulties in recommending specific antiemetic regimens due to the overlap between acute and delayed CINV after the first day of chemotherapy [14,16].

NK1RAs are approved for the prevention of acute and delayed CINV in adults receiving MEC or HEC [17]. In this review, we summarize current data on the use of NK1RAs in the treatment of CINV, with a focus on evidence from China.

2 The emetic pathway and neurokinin-1 receptor

Both the peripheral and central nervous systems are involved in the pathophysiology of CINV, with different mechanisms responsible for the acute and delayed subtypes [9,18]. Acute CINV is primarily driven by the activation of peripheral nervous system pathways via 5-hydroxytryptamine (5-HT3) receptors [19]. In contrast, delayed CINV is predominantly associated with a central mechanism involving the neurokinin-1 (NK1) receptor [6,9]. However, the CINV process is complex, with some evidence of signaling cross-talk between the 5-HT3 and NK1 pathways, although mechanistic details have not been fully elucidated [9,18]. Fig.1 shows the schematic of the emetic pathway.

The NK1 receptor is the primary receptor for the tachykinin family of peptides, which includes substance P [20]. The NK1 receptor is distributed widely throughout human body including nervous, cardiovascular, genitourinary, and immune systems, as well as salivary glands, skin, and muscle [20]. Consequently, the NK1 receptor is involved in a variety of processes including neuromodulation contributing to brain homeostasis; sensory neuronal transmission associated with depression, anxiety, stress, and vomiting; inflammatory response; and cellular responses such as pain transmission, endocrine and paracrine secretion, vasodilation, and cell proliferation [20].

Since the NK1 receptor is implicated in multiple biological functions, it has become a target for the development of pharmaceutical interventions. NK1RAs, which represent a family of drugs that target the NK1 receptor to prevent the binding of substance P, have been studied for potential therapeutic applications in a variety of conditions including post-operative nausea and vomiting [21] and CINV [17,22]. There is also evidence that NK1RAs may have antitumor activity in certain cancers [23–27].

3 Approved NK1RAs: formulations and indications

Tab.1 provides an overview of the five NK1RAs approved in the USA: aprepitant, fosaprepitant, netupitant, fosnetupitant, and rolapitant. NK1RAs are available as either oral or intravenous formulations, with the latter sometimes preferred for patients who have difficulty in swallowing capsules [28]. Only aprepitant, fosaprepitant, and netupitant are currently available in China. Tab.1 also highlights differences in the formulations and indications that exist between the two countries.

Aprepitant was the first NK1RA to be approved, as an oral formulation given daily on the first 3 days of chemotherapy, in 2003 in the USA (capsules or suspension) and in 2014 in China (capsules only). Subsequently, the single-dose intravenous formulation was further approved in 2017 in the USA and in 2022 in China [29]. The pharmacokinetics of aprepitant have been shown to be similar in Caucasian and Chinese populations [30]. Fosaprepitant, a single-dose, intravenously administered NK1RA available in China and the USA, is a prodrug that is converted to aprepitant following administration [28,31]. The third NK1RA available in both China and the USA is netupitant, a single-dose, long-acting oral agent provided in fixed combination with the 5-HT3RA palonosetron (oral netupitant/palonosetron [NEPA]) [32]. The fixed combination of fosnetupitant and palonosetron (intravenous NEPA) has also been introduced in the USA [32,33]. Both netupitant and palonosetron are long-acting drugs, synergistically improving the sustained antiemetic effect of NEPA throughout the chemotherapy cycle [34]. Lastly, rolapitant, a single-dose, long-acting oral NK1RA, is available in the USA but not in China [35].

4 Efficacy and safety of NK1RAs in CINV control

As the first NK1RA to be approved, aprepitant has the greatest amount of data supporting its efficacy and safety and is typically used as a comparator in phase III non-inferiority studies of other NK1RAs [36–39]. In phase III trials, aprepitant demonstrated efficacy in preventing both acute and delayed CINV regardless of the emetogenic risk of the chemotherapy [36–38,40–49]. Across milestone clinical trials in HEC, multiple-day dosing with aprepitant-based therapy was associated with complete control (no vomiting, no rescue medication) in 62.7%–89.2% of patients [38]. Adding this NK1RA to the previous standard therapy of 5-HT3RA plus dexamethasone significantly increased the efficacy against CINV over multiple cycles of cisplatin chemotherapy, thus altering the standard of care for CINV [38,45,50]. A pooled analysis of safety data across four pivotal clinical trials, including 1412 patients receiving HEC or MEC, showed that the most common adverse events with a higher incidence for aprepitant in combination with ondansetron and dexamethasone compared with ondansetron plus dexamethasone included fatigue (13% versus 12%), diarrhea (9% versus 8%), asthenia (7% versus 6%), dyspepsia (7% versus 5%), abdominal pain (6% versus 5%), hiccups (5% versus 3%), white blood cell count decreased (4% versus 3%), dehydration (3% versus 2%), and alanine aminotransferase increased (3% versus 2%) [50].

Several phase III clinical trials have shown the superior efficacy of fosaprepitant compared with placebo [51–55] and non-inferior efficacy compared with aprepitant [28,38,56,57]. For example, in a randomized, controlled, phase III study including 2322 patients receiving cisplatin, the overall complete control rate was 71.9% with fosaprepitant plus ondansetron plus dexamethasone compared with 72.3% with aprepitant plus ondansetron plus dexamethasone [57]. Complete control rates were also similar for both treatments in the delayed CINV phase from 25 to 120 h (74.3% versus 74.2%, respectively). Fosaprepitant has a similar safety profile to that of aprepitant [28,38,56,57]. For example, in the phase III study conducted in 2322 patients treated with cisplatin, the adverse event profile was generally consistent between the single-dose fosaprepitant-based and 3-day aprepitant-based triple regimens, although the fosaprepitant-based regimen was associated with a higher incidence of infusion site pain (1.4% versus 0.1%), erythema (0.5% versus 0.1%), and thrombophlebitis (0.8% and 0.7%), which may represent a barrier to its clinical use [57].

Oral and intravenous NEPA also have phase III clinical data demonstrating non-inferior efficacy compared with aprepitant [32,58–60]. Moreover, oral NEPA is associated with higher treatment compliance compared with aprepitant due to its convenient administration as a single tablet [61]. Of note, phase III studies have shown that NEPA is effective in preventing delayed CINV, with the treatment effect maintained over several cycles of chemotherapy [32,58,59,62–66]. Among 1862 patients receiving multiple cycles of HEC or MEC in two phase III trials, oral NEPA demonstrated a superior control rate compared with palonosetron alone in both acute and delayed CINV across multiple chemotherapy cycles [66]. Complete control rates with NEPA ranged from 88.4% to 96.6% and 76.9% to 91.5% in the acute and delayed phases, respectively, across four chemotherapy cycles. Complete control rates with intravenous NEPA in phase III trials were similar to those reported with oral NEPA [67]. In comparative clinical trials, (fos)netupitant showed a similar safety profile to aprepitant [32,35,58,60,68], and safety profiles were consistent between fosnetupitant and netupitant [64,67]. In a phase III study of 834 patients from China and Thailand treated with HEC, the incidence of adverse events was similar for a single dose of NEPA plus dexamethasone versus a standard 3-day regimen of aprepitant plus granisetron plus dexamethasone (58.1% versus 57.5%), with the most common treatment-related adverse events being constipation (8.0% versus 6.3%) and hiccups (2.7% versus 1.4%) [32]. Another phase III study in 795 patients receiving HEC reported that fosnetupitant or fosaprepitant, in combination with palonosetron plus dexamethasone, were associated with a similar incidences of treatment-related adverse events (22.2% versus 25.4%), as well as the most common adverse events of constipation (11.2% and 13.7%) and hiccups (4.8% and 7.1%) [60].

Similarly, phase III trials showed that rolapitant effectively prevented delayed CINV, with benefits maintained over multiple cycles of chemotherapy [35,68–72]. In a phase III study of 401 patients receiving MEC, rolapitant (day 1) was given in combination with granisetron (days 1–3) and dexamethasone (day 1). This rolapitant-based regimen was associated with a greater complete control rate compared with granisetron plus dexamethasone in both the overall (80.2% versus 64.6%) and delayed (82.3% versus 65.6%) phases [69]. In 1087 patients receiving HEC in phase III studies, the complete control rate in the delayed phase was greater with rolapitant-based antiemetic prophylaxis versus granisetron plus dexamethasone alone (71% versus 60%) [71]. Finally, in a pooled analysis of randomized phase II and phase III trials of rolapitant plus 5-HT3RA plus dexamethasone in which patients received multiple cycles of MEC or HEC, superior complete control rates versus 5-HT3RA (granisetron or ondansetron) plus dexamethasone were maintained for repeated antiemetic treatment for up to 6 cycles, with no cumulative toxicity [70]. Compared with other oral NK1RAs, the most common treatment-related adverse events for rolapitant included constipation, fatigue, headache, hiccups and dyspepsia, while the incidence was low and similar to that of the active control group in phase III clinical studies [68,71,72].

5 Administration modes of NK1RAs

In patients receiving HEC or MEC, dual or triple regimens are the standard therapy for preventing CINV [73]. Clinical studies [39,41–44,74–76] and systematic reviews [36,39,77–80] have shown that the addition of aprepitant to dexamethasone and 5-HT3RA is associated with a statistically significant and clinically relevant improvement in complete control rates in the prevention of CINV. For example, in a phase III study of 244 patients treated with cisplatin-based chemotherapy, adding aprepitant to palonosetron and dexamethasone improved complete control rates from 79.9% to 92.6% in the overall phase [76]. It is recommended that the 5-HT3RA should be administered prior to the first (and subsequent) dose of MEC or HEC. The frequency or need for repeated administration of the 5-HT3RA depends on the agent chosen and the mode of administration (parenteral/oral/transdermal) [73]. Although prophylactic dexamethasone has been generally considered safe, its administration may be associated with a wide range of side effects in the week after the initiation of chemotherapy [81]. There is interest in minimizing the dose and frequency of dexamethasone use in antiemetic regimens, particularly in older patients and when combining immunotherapy with chemotherapy [81–88]. Dexamethasone-sparing strategies that limit dosing to only 1 day have been shown to maintain efficacy, although careful patient selection may be needed to ensure appropriate use of this approach [83,86].

Clinical evidence supporting the use of NK1RAs (aprepitant, fosaprepitant, netupitant, or rolapitant) in combination with 5-HT3RA and dexamethasone mainly focuses on the administration of the NK1RAs within the first 3 days of chemotherapy [42,43,73,89]. However, a small number of studies have explored extended administration of aprepitant up to day 7 after multiple-day chemotherapy [43,73,90–92]. For example, data from a randomized phase III study with a small sample size supported the use of aprepitant 125 mg on day 3 followed by 80 mg on days 4–7 as part of a triple regimen with 5-HT3RA on days 1–5 and dexamethasone on days 1 and 2 in 69 patients with germline malignancies treated with 5-day cisplatin-based chemotherapy [43,73]. Another randomized study with a small sample size found that prolonged administration of aprepitant for 6 days was associated with acceptable safety and encouraging efficacy in controlling CINV in patients treated with 3-day cisplatin-based chemotherapy [92]. Further studies of extended aprepitant administration are warranted. However, studies investigating dosing of fosaprepitant, netupitant, and rolapitant beyond 3 days are not available [73].

Several clinical studies have demonstrated the anti-emetic efficacy of NK1RA-based regimens in Chinese patients. For example, the addition of aprepitant to a standard anti-emetic regimen (granisetron and dexamethasone) improved CINV control in a phase III trial in 411 Chinese patients receiving HEC, with a complete control rate of 69.6% versus 57.0% overall, 74.0% versus 59.4% in the delayed phase, and 79.4% versus 79.3% in the acute phase, respectively [44]. In another phase III trial, a single-dose fosaprepitant-based triplet regimen demonstrated non-inferior control of CINV compared with a standard 3-day aprepitant-based triplet regimen in 648 Chinese patients receiving HEC, with an overall complete control rate of 72.0% versus 69.4%, respectively [93]. Similarly, in a prespecified analysis of a large subset of 672 Chinese patients receiving HEC in a phase III trial, a single dose of NEPA plus dexamethasone demonstrated similar efficacy in controlling CINV compared with a standard 3-day aprepitant plus granisetron plus dexamethasone regimen [58]. For patients receiving NEPA plus dexamethasone versus the aprepitant-based regimen, no emesis was reported by 75.2% versus 75.6% of patients during days 1 to 5, 85.3% versus 88.1% in the acute phase, and 80.2% versus 77.4% in the delayed phase [58]. A study in 645 Chinese patients receiving HEC also demonstrated that fosaprepitant plus granisetron plus dexamethasone was non-inferior to aprepitant plus granisetron plus dexamethasone therapy, with a complete control rate of 89.3% versus 92.7%, respectively [28]. A randomized, double-blind, multicenter, phase III trial compared fosaprepitant injection (a Chinese domestically produced formulation) with aprepitant tablets, in combination with granisetron and dexamethasone, for the prevention of nausea and vomiting caused by HEC in 649 Chinese patients [94]. This study showed fosaprepitant injection to be non-inferior to aprepitant in preventing CINV, with complete control of vomiting from 0 to 120 h after HEC in 79.3% versus 82.2% of patients, respectively. The two treatments also showed a similar safety profile [94]. Finally, the addition of olanzapine 5 mg to triple anti-emetic therapy with fosaprepitant, ondansetron hydrochloride, and dexamethasone led to an increased control rate and was well tolerated in a phase III trial of Chinese patients receiving multiple-day cisplatin-based HEC [95].

The use of multiple doses of fosaprepitant has been investigated and appears to provide a benefit in patients receiving multiple-day chemotherapy. For example, a multiple-dose regimen of fosaprepitant (on days 1 and 3) alongside palonosetron plus dexamethasone, compared with triple therapy comprising a single dose of fosaprepitant on day 1, led to a significantly lower rate of chemotherapy-induced nausea in the delayed phase and overall but not in the acute phase in 156 Chinese patients receiving HEC [96]. The multiple-dosing approach was superior for controlling vomiting in the delayed phase but not in the overall or acute phases, and the incidence of adverse events for both approaches was comparable [96]. In contrast, a phase III study of patients receiving 3-day cisplatin-based HEC showed that two doses of fosaprepitant on day 1 and 3 were superior to a single dose of fosaprepitant on day 1, when combined with oral palonosetron and oral dexamethasone, for controlling CINV in both the acute and delayed phases [97]. No difference in adverse events was observed for the single and double fosaprepitant dose regimens.

6 Real-world evidence

Although randomized, controlled clinical trials have shown that NK1RAs are effective for the prevention of CINV, further real-world evidence is required to fully understand their application and effectiveness in routine clinical practice. Available real-world data from the USA and Europe supported the use of NK1RAs in the settings investigated during clinical development [98–102] and confirmed the cost-effectiveness of NK1RA-based therapy [103]. Consistent findings have been reported from real-world studies in China [94,104,105]. A post-marketing surveillance study conducted in 1000 Chinese patients across 21 centers showed that aprepitant was effective and safe, alone or in combination with other anti-emetic drugs, for preventing CINV associated with HEC [104]. The rates of no vomiting and no nausea from 0 to 120 h were 71% and 43% with aprepitant monotherapy, 87% and 65% for aprepitant plus one other anti-emetic agent, and 86% and 70% for aprepitant plus two other anti-emetic agents. Only one patient experienced a drug-related serious adverse event, a gastrointestinal disorder that resolved during treatment. In a real-world study of 291 Chinese patients with lung cancer receiving cisplatin-based chemotherapy, the addition of aprepitant given as 125 mg on the first day of chemotherapy followed by 80 mg orally on the second and third days resulted in better control of nausea and vomiting compared with intravenous granisetron and oral dexamethasone alone (69% versus 57% in the acute phase and 72% versus 60% in the delayed phase) [94]. Furthermore, a retrospective analysis of triple antiemetic agent regimens containing aprepitant for managing cisplatin-induced nausea and vomiting in 296 patients with melanoma reported a complete control rate of 84% and favorable tolerability [105].

However, compliance with antiemetic guidelines tends to be low, as demonstrated by a large prospective registry study in Eastern Europe where only 23% of patients were receiving guideline-consistent CINV prophylaxis [106]. Similarly, a study conducted in Sichuan, China, reported that only 21.5% (239/1110) of patients were managed in-line with local guidelines; 27.1% of patients receiving MEC and 4.6% receiving HEC [2]. Moreover, NK1RAs appeared to be under-used in routine clinical practice [106,107]. Understanding the reasons for low levels of guideline adherence among healthcare providers (HCPs) could help improve outcomes for patients, given that patients consider CINV as one of the most distressing side effects of chemotherapy [98,106,108,109]. Delayed CINV is often underestimated by Chinese HCPs, which may contribute to the under-use of NK1RAs in China [110]. In addition to sub-optimal implementation of guidelines by HCPs, patient factors may play a role in non-adherence to CINV prophylaxis. For example, patients may face challenges to follow antiemetic regimens as prescribed, especially during home administration [98,99]. A survey of European oncologists showed that approximately one third of patients made administration mistakes or missed/delayed at least one dose during home administration of antiemetics [111]. The complexity of the antiemetic regimen can also impact adherence and simplified antiemetic regimens may improve CNIV control [111]. With the exception of oral aprepitant, which is administered on the first 3 days of chemotherapy, NK1RAs require only single administration on day 1, reducing the need for home treatment and improving patient compliance with antiemetic regimens [22]. Moreover, NK1RAs are available in different formulations, which can be matched to patient preference [22].

Further research is needed to determine the optimal use of NK1RAs, identify patient populations who may gain the greatest benefit from NK1RA therapy, and understand patient preferences and unmet needs in this setting. A CINV predictive model has undergone real-word validation and optimization for identifying Chinese patients who are at high risk of CINV, which may aid in physicians’ decisions on CINV prevention [112].

7 Conclusions and clinical perspective

The development and approval of NK1RAs has significantly improved CINV management in patients receiving HEC or MEC. These agents have generally favorable safety profiles and efficacy in the prevention of both acute and delayed CINV. The use of these antiemetic drugs has improved management of CINV and resulted in a significant decrease in the incidence and severity of CINV. However, while these agents generally have favorable safety profiles, they can cause side effects such as fatigue, constipation, and hiccups. When choosing an antiemetic agent, it is critical to consider comorbidities and chemotherapy regimens. Further research is needed to determine the best way to use these agents and to identify strategies to manage CINV in specific patient populations, such as those with gastrointestinal disorders.

References

[1] Tilsed CM, Fisher SA, Nowak AK, Lake RA, Lesterhuis WJ. Cancer chemotherapy: insights into cellular and tumor microenvironmental mechanisms of action. Front Oncol 2022; 12: 960317

[2] Sun Y, Zheng Y, Yang X, Xie K, Du C, He L, Gui Y, Fu J, Li C, Zhang H, Zhu L, Bie J, Sun Y, Fu Y, Zhou Y, Shou F, Wang Y, Zhu J. Incidence of chemotherapy-induced nausea and vomiting among cancer patients receiving moderately to highly emetogenic chemotherapy in cancer centers in Sichuan, China. J Cancer Res Clin Oncol 2021; 147(9): 2701–2708

[3] Sommariva S, Pongiglione B, Tarricone R. Impact of chemotherapy-induced nausea and vomiting on health-related quality of life and resource utilization: a systematic review. Crit Rev Oncol Hematol 2016; 99: 13–36

[4] Van Laar ES, Desai JM, Jatoi A. Professional educational needs for chemotherapy-induced nausea and vomiting (CINV): multinational survey results from 2388 health care providers. Support Care Cancer 2015; 23(1): 151–157

[5] Shankar A, Roy S, Malik A, Julka PK, Rath GK. Prevention of chemotherapy-induced nausea and vomiting in cancer patients. Asian Pac J Cancer Prev 2015; 16(15): 6207–6213

[6] Rapoport BL. Delayed chemotherapy-induced nausea and vomiting: pathogenesis, incidence, and current management. Front Pharmacol 2017; 8: 19

[7] Chow R, Yin LB, Baqri W, Huang R, Boldt G, Younus J, Lock M, Prsic E, Zimmermann C, Herrstedt J. Prevalence and predictors of long-delayed (> 120 h) chemotherapy-induced nausea and vomiting (CINV)—a systematic review and individual patient data meta-analysis. Support Care Cancer 2023; 31(8): 505

[8] Hayashi T, Shimokawa M, Matsuo K, Kawada K, Nakano T, Egawa T. Efficacy of 3-day versus 5-day aprepitant regimens for long-delayed chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based chemotherapy. Expert Opin Pharmacother 2023; 24(18): 2221–2226

[9] Adel N. Overview of chemotherapy-induced nausea and vomiting and evidence-based therapies. Am J Manag Care 2017; 23(14 Suppl): S259–S265

[10] Patel P, Robinson PD, Wahib N, Cheung P, Wong T, Cabral S, Parker A, Cohen M, Devine K, Gibson P, Holdsworth MT, Neumann E, Orsey A, Phillips R, Spinelli D, Thackray J, van de Wetering M, Woods D, Sung L, Dupuis LL. Interventions for the prevention of acute phase chemotherapy-induced nausea and vomiting in adult and pediatric patients: a systematic review and meta-analysis. Support Care Cancer 2022; 30(11): 8855–8869

[11] Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, Danso MA, Dennis K, Dupuis LL, Dusetzina SB, Eng C, Feyer PC, Jordan K, Noonan K, Sparacio D, Somerfield MR, Lyman GH. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2017; 35(28): 3240–3261

[12] Razvi Y, Chan S, McFarlane T, McKenzie E, Zaki P, DeAngelis C, Pidduck W, Bushehri A, Chow E, Jerzak KJ. ASCO, NCCN, MASCC/ESMO: a comparison of antiemetic guidelines for the treatment of chemotherapy-induced nausea and vomiting in adult patients. Support Care Cancer 2019; 27(1): 87–95

[13] Chan A, Abdullah MM, Ishak WZBW, Ong-Cornel AB, Villalon AH, Kanesvaran R. Applicability of the National Comprehensive Cancer Network/Multinational Association of Supportive Care in Cancer Guidelines for Prevention and Management of Chemotherapy-Induced Nausea and Vomiting in Southeast Asia: A Consensus Statement. J Glob Oncol 2017; 3(6): 801–813

[14] Xiang-Lin Y. Chinese expert consensus on prevention and treatment of delayed nausea and vomiting (2022 Edition). Oncol Transl Med 2023; 9(4): 147–162

[15] Clemons M. Guidelines versus individualized care for the management of CINV. Support Care Cancer 2018; 26(Suppl 1): 11–17

[16] NCCNClinical Practice Guidelines in Oncology. Antiemesis. Version 2.2023. May 24, 2023. Available at the website of NCCN

[17] Navari RM, Schwartzberg LS. Evolving role of neurokinin 1-receptor antagonists for chemotherapy-induced nausea and vomiting. OncoTargets Ther 2018; 11: 6459–6478

[18] Janelsins MC, Tejani MA, Kamen C, Peoples AR, Mustian KM, Morrow GR. Current pharmacotherapy for chemotherapy-induced nausea and vomiting in cancer patients. Expert Opin Pharmacother 2013; 14(6): 757–766

[19] Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008; 358(23): 2482–2494

[20] Garcia-Recio S, Gascón P. Biological and pharmacological aspects of the NK1-receptor. BioMed Res Int 2015; 2015: 495704

[21] Meyer TA, Habib AS, Wagner D, Gan TJ. Neurokinin-1 receptor antagonists for the prevention of postoperative nausea and vomiting. Pharmacotherapy 2023; 43(9): 922–934

[22] Karthaus M, Schiel X, Ruhlmann CH, Celio L. Neurokinin-1 receptor antagonists: review of their role for the prevention of chemotherapy-induced nausea and vomiting in adults. Expert Rev Clin Pharmacol 2019; 12(7): 661–680

[23] García-Aranda M, Téllez T, McKenna L, Redondo M. Neurokinin-1 receptor (NK-1R) antagonists as a new strategy to overcome cancer resistance. Cancers (Basel) 2022; 14(9): 2255

[24] Muñoz M, Coveñas R. Neurokinin-1 receptor antagonists as antitumor drugs in gastrointestinal cancer: a new approach. Saudi J Gastroenterol 2016; 22(4): 260–268

[25] Muñoz M, Coveñas R. Glioma and neurokinin-1 receptor antagonists: a new therapeutic approach. Anticancer Agents Med Chem 2019; 19(1): 92–100

[26] Robinson P, Rosso M, Muñoz M. Neurokinin-1 receptor antagonists as a potential novel therapeutic option for osteosarcoma patients. J Clin Med 2023; 12(6): 2135

[27] Chen XY, Ru GQ, Ma YY, Xie J, Chen WY, Wang HJ, Wang SB, Li L, Jin KT, He XL, Mou XZ. High expression of substance P and its receptor neurokinin-1 receptor in colorectal cancer is associated with tumor progression and prognosis. Onco Targets Ther 2016; 9: 3595–3602

[28] Yang LQ, Sun XC, Qin SK, Cheng Y, Shi JH, Chen ZD, Wang QM, Zhang HL, Hu B, Liu B, Zhang QY, Wu Q, Wang D, Shu YQ, Dong J, Han BH, Wang KM, Dang CX, Li JL, Wang HB, Li BL, Lu JG, Zhang ZH, Chen YX. Efficacy and safety of fosaprepitant in the prevention of nausea and vomiting following highly emetogenic chemotherapy in Chinese people: a randomized, double-blind, phase III study. Eur J Cancer Care (Engl) 2017; 26(6): e12668

[29] NationalMedical Products Administration. Domestically Produced Drug—Basic Information of “National Medicine Approval Number H20223623.” Available at the website of National Medical Products Administration

[30] Yang MJ, Xu HR, Li H, Chen WL, Yuan F, Li XN. Comparison of pharmacokinetics of aprepitant in healthy Chinese and Caucasian subjects. Drug Des Devel Ther 2020; 14: 1219–1226

[31] Emend (fosaprepitant) for injection, for intravenous use [prescribing information]. February 2016. Available at the website of FDA

[32] Zhang L, Lu S, Feng J, Dechaphunkul A, Chang J, Wang D, Chessari S, Lanzarotti C, Jordan K, Aapro M. A randomized phase III study evaluating the efficacy of single-dose NEPA, a fixed antiemetic combination of netupitant and palonosetron, versus an aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC). Ann Oncol 2018; 29(2): 452–458

[33] Shirley M. Netupitant/palonosetron: a review in chemotherapy-induced nausea and vomiting. Drugs 2021; 81(11): 1331–1342

[34] Rojas C, Thomas AG, Alt J, Stathis M, Zhang J, Rubenstein EB, Sebastiani S, Cantoreggi S, Slusher BS. Palonosetron triggers 5-HT(3) receptor internalization and causes prolonged inhibition of receptor function. Eur J Pharmacol 2010; 626(2-3): 193–199

[35] Heo YA, Deeks ED. Rolapitant: a review in chemotherapy-induced nausea and vomiting. Drugs 2017; 77(15): 1687–1694

[36] Di Maio M, Baratelli C, Bironzo P, Vignani F, Bria E, Sperti E, Marcato M, Roila F. Efficacy of neurokinin-1 receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting in patients receiving carboplatin-based chemotherapy: a systematic review and meta-analysis. Crit Rev Oncol Hematol 2018; 124: 21–28

[37] Karthaus M, Schiel X, Ruhlmann CH, Celio L. Neurokinin-1 receptor antagonists: review of their role for the prevention of chemotherapy-induced nausea and vomiting in adults. Expert Rev Clin Pharmacol 2019; 12(7): 661–680

[38] Aapro M, Carides A, Rapoport BL, Schmoll HJ, Zhang L, Warr D. Aprepitant and fosaprepitant: a 10-year review of efficacy and safety. Oncologist 2015; 20(4): 450–458

[39] Qiu T, Men P, Xu X, Zhai S, Cui X. Antiemetic regimen with aprepitant in the prevention of chemotherapy-induced nausea and vomiting: an updated systematic review and meta-analysis. Medicine (Baltimore) 2020; 99(33): e21559

[40] Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial. Lancet Oncol 2015; 16(4): 385–394

[41] Gralla RJ, de Wit R, Herrstedt J, Carides AD, Ianus J, Guoguang-Ma J, Evans JK, Horgan KJ. Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition to high-dose cisplatin: analysis of combined data from two Phase III randomized clinical trials. Cancer 2005; 104(4): 864–868

[42] Cheng Y, Wu Z, Shi L, Shen C, Zhang J, Hu H, Li W, Cai Y, Xie X, Ling J, Zheng Q, Deng Y. Aprepitant plus palonosetron versus dexamethasone plus palonosetron in preventing chemotherapy-induced nausea and vomiting in patients with moderate-emetogenic chemotherapy: a randomized, open-label, phase 3 trial. EClinicalMedicine 2022; 49: 101480

[43] Albany C, Brames MJ, Fausel C, Johnson CS, Picus J, Einhorn LH. 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 2012; 30(32): 3998–4003

[44] Hu Z, Cheng Y, Zhang H, Zhou C, Han B, Zhang Y, Huang C, Chang J, Song X, Liang J, Liang H, Bai C, Yu S, Chen J, Wang J, Pan H, Chitkara DK, Hille DA, Zhang L. Aprepitant triple therapy for the prevention of chemotherapy-induced nausea and vomiting following high-dose cisplatin in Chinese patients: a randomized, double-blind, placebo-controlled phase III trial. Support Care Cancer 2014; 22(4): 979–987

[45] de Wit R, Herrstedt J, Rapoport B, Carides AD, Guoguang-Ma J, Elmer M, Schmidt C, Evans JK, Horgan KJ. The oral NK(1) antagonist, aprepitant, given with standard antiemetics provides protection against nausea and vomiting over multiple cycles of cisplatin-based chemotherapy: a combined analysis of two randomised, placebo-controlled phase III clinical trials. Eur J Cancer 2004; 40(3): 403–410

[46] Hesketh PJ, Grunberg SM, Gralla RJ, Warr DG, Roila F, de Wit R, Chawla SP, Carides AD, Ianus J, Elmer ME, Evans JK, Beck K, Reines S, Horgan KJ. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—the Aprepitant Protocol 052 Study Group. J Clin Oncol 2003; 21(22): 4112–4119

[47] Rapoport BL, Jordan K, Boice JA, Taylor A, Brown C, Hardwick JS, Carides A, Webb T, Schmoll HJ. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study. Support Care Cancer 2010; 18(4): 423–431

[48] Nishimura J, Satoh T, Fukunaga M, Takemoto H, Nakata K, Ide Y, Fukuzaki T, Kudo T, Miyake Y, Yasui M, Morita S, Sakai D, Uemura M, Hata T, Takemasa I, Mizushima T, Ohno Y, Yamamoto H, Sekimoto M, Nezu R, Doki Y, Mori M. Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (SENRI trial): a multicentre, randomised, controlled phase 3 trial. Eur J Cancer 2015; 51(10): 1274–1282

[49] Qiu YQ, Cui HJ, Peng YM, Liu DW, Song YZ, Liu F, Duan H, Li Q. Meta-analysis of aprepitant in preventing nausea and vomiting caused by moderately and highly emetogenic chemotherapy regimens. Chin J New Drugs (Zhong Guo Xin Yao Za Zhi) 2017; 26(21): 2559–2567

[50] Emend(aprepitant) capsulesfororal useEmend(aprepitant) for oral suspension [prescribing information]. May 2022. Available at the website of FDA

[51] Saito H, Yoshizawa H, Yoshimori K, Katakami N, Katsumata N, Kawahara M, Eguchi K. Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. Ann Oncol 2013; 24(4): 1067–1073

[52] Radhakrishnan V, Joshi A, Ramamoorthy J, Rajaraman S, Ganesan P, Ganesan TS, Dhanushkodi M, Sagar TG. Intravenous fosaprepitant for the prevention of chemotherapy-induced vomiting in children: a double-blind, placebo-controlled, phase III randomized trial. Pediatr Blood Cancer 2019; 66(3): e27551

[53] Clemmons AB, Orr J, Andrick B, Gandhi A, Sportes C, DeRemer D. Randomized, placebo-controlled, phase III trial of fosaprepitant, ondansetron, dexamethasone (FOND) versus FOND plus olanzapine (FOND-O) for the prevention of chemotherapy-induced nausea and vomiting in patients with hematologic malignancies receiving highly emetogenic chemotherapy and hematopoietic cell transplantation regimens: the FOND-O Trial. Biol Blood Marrow Transplant 2018; 24(10): 2065–2071

[54] Ruhlmann CH, Christensen TB, Dohn LH, Paludan M, Rønnengart E, Halekoh U, Hilpert F, Feyer P, Kristensen G, Hansen O, Keefe D, Herrstedt J. Efficacy and safety of fosaprepitant for the prevention of nausea and emesis during 5 weeks of chemoradiotherapy for cervical cancer (the GAND-emesis study): a multinational, randomised, placebo-controlled, double-blind, phase 3 trial. Lancet Oncol 2016; 17(4): 509–518

[55] Weinstein C, Jordan K, Green SA, Camacho E, Khanani S, Beckford-Brathwaite E, Vallejos W, Liang LW, Noga SJ, Rapoport BL. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: results of a randomized, double-blind phase III trial. Ann Oncol 2016; 27(1): 172–178

[56] Garnock-Jones KP. Fosaprepitant dimeglumine: a review in the prevention of nausea and vomiting associated with chemotherapy. Drugs 2016; 76(14): 1365–1372

[57] Grunberg S, Chua D, Maru A, Dinis J, DeVandry S, Boice JA, Hardwick JS, Beckford E, Taylor A, Carides A, Roila F, Herrstedt J. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol—EASE. J Clin Oncol 2011; 29(11): 1495–1501

[58] Chang J, Chen G, Wang D, Wang G, Lu S, Feng J, Li W, Li P, Lanzarotti C, Chessari S, Zhang L. Efficacy of NEPA, a fixed antiemetic combination of netupitant and palonosetron, vs a 3-day aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting (CINV) in Chinese patients receiving highly emetogenic chemotherapy (HEC) in a randomized Phase 3 study. Cancer Med 2020; 9(14): 5134–5142

[59] Jordan K, Gralla R, Rizzi G, Kashef K. Efficacy benefit of an NK1 receptor antagonist (NK1RA) in patients receiving carboplatin: supportive evidence with NEPA (a fixed combination of the NK1 RA, netupitant, and palonosetron) and aprepitant regimens. Support Care Cancer 2016; 24(11): 4617–4625

[60] Hata A, Okamoto I, Inui N, Okada M, Morise M, Akiyoshi K, Takeda M, Watanabe Y, Sugawara S, Shinagawa N, Kubota K, Saeki T, Tamura T. Randomized, double-blind, phase III study of fosnetupitant versus fosaprepitant for prevention of highly emetogenic chemotherapy-induced nausea and vomiting: CONSOLE. J Clin Oncol 2022; 40(2): 180–188

[61] Zelek L, Debourdeau P, Bourgeois H, Wagner JP, Brocard F, Lefeuvre-Plesse C, Chauffert B, Leheurteur M, Bachet JB, Simon H, Mayeur D, Scotté F. A pragmatic study evaluating NEPA versus aprepitant for prevention of chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy. Oncologist 2021; 26(10): e1870–e1879

[62] Aapro M, Karthaus M, Schwartzberg L, Bondarenko I, Sarosiek T, Oprean C, Cardona-Huerta S, Hansen V, Rossi G, Rizzi G, Borroni ME, Rugo H. NEPA, a fixed oral combination of netupitant and palonosetron, improves control of chemotherapy-induced nausea and vomiting (CINV) over multiple cycles of chemotherapy: results of a randomized, double-blind, phase 3 trial versus oral palonosetron. Support Care Cancer 2017; 25(4): 1127–1135

[63] Aapro M, Rugo H, Rossi G, Rizzi G, Borroni ME, Bondarenko I, Sarosiek T, Oprean C, Cardona-Huerta S, Lorusso V, Karthaus M, Schwartzberg L, Grunberg S. A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol 2014; 25(7): 1328–1333

[64] Schwartzberg L, Roeland E, Andric Z, Kowalski D, Radic J, Voisin D, Rizzi G, Navari R, Gralla RJ, Karthaus M. Phase III safety study of intravenous NEPA: a novel fixed antiemetic combination of fosnetupitant and palonosetron in patients receiving highly emetogenic chemotherapy. Ann Oncol 2018; 29(7): 1535–1540

[65] Gralla RJ, Bosnjak SM, Hontsa A, Balser C, Rizzi G, Rossi G, Borroni ME, Jordan K. A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Ann Oncol 2014; 25(7): 1333–1339

[66] Schwartzberg L, Karthaus M, Rossi G, Rizzi G, Borroni ME, Rugo HS, Jordan K, Hansen V. Fixed combination of oral NEPA (netupitant-palonosetron) for the prevention of acute and delayed chemotherapy-induced nausea and vomiting in patients receiving multiple cycles of chemotherapy: efficacy data from 2 randomized, double-blind phase III studies. Cancer Med 2019; 8(5): 2064–2073

[67] Schwartzberg L, Navari R, Clark-Snow R, Arkania E, Radyukova I, Patel K, Voisin D, Rizzi G, Wickham R, Gralla RJ, Aapro M, Roeland E. Phase IIIb safety and efficacy of intravenous NEPA for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with breast cancer receiving initial and repeat cycles of anthracycline and cyclophosphamide (AC) chemotherapy. Oncologist 2020; 25(3): e589–e597

[68] Navari RM. The safety of rolapitant for the treatment of nausea and vomiting associated with chemotherapy. Expert Opin Drug Saf 2019; 18(12): 1127–1132

[69] Hesketh PJ, Schnadig ID, Schwartzberg LS, Modiano MR, Jordan K, Arora S, Powers D, Aapro M. Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in patients receiving carboplatin-based chemotherapy. Cancer 2016; 122(15): 2418–2425

[70] Rapoport B, Schwartzberg L, Chasen M, Powers D, Arora S, Navari R, Schnadig I. Efficacy and safety of rolapitant for prevention of chemotherapy-induced nausea and vomiting over multiple cycles of moderately or highly emetogenic chemotherapy. Eur J Cancer 2016; 57: 23–30

[71] Rapoport BL, Chasen MR, Gridelli C, Urban L, Modiano MR, Schnadig ID, Poma A, Arora S, Kansra V, Schwartzberg LS, Navari RM. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Lancet Oncol 2015; 16(9): 1079–1089

[72] Schwartzberg LS, Modiano MR, Rapoport BL, Chasen MR, Gridelli C, Urban L, Poma A, Arora S, Navari RM, Schnadig ID. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial. Lancet Oncol 2015; 16(9): 1071–1078

[73] Berger MJ, Ettinger DS, Aston J, Barbour S, Bergsbaken J, Bierman PJ, Brandt D, Dolan DE, Ellis G, Kim EJ, Kirkegaard S, Kloth DD, Lagman R, Lim D, Loprinzi C, Ma CX, Maurer V, Michaud LB, Nabell LM, Noonan K, Roeland E, Rugo HS, Schwartzberg LS, Scullion B, Timoney J, Todaro B, Urba SG, Shead DA, Hughes M. NCCN Guidelines Insights: Antiemesis, Version 2.2017. J Natl Compr Canc Netw 2017; 15(7): 883–893

[74] Wang DS, Hu MT, Wang ZQ, Ren C, Qiu MZ, Luo HY, Jin Y, Fong WP, Wang S, Peng J, Zou Q, Tan Q, Wang FH, Li YH. Effect of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in women: a randomized clinical trial. JAMA Netw Open 2021; 4(4): e215250

[75] Hayashi T, Shimokawa M, Matsuo K, Nishimura J, Iihara H, Nakano T, Egawa T. 5HT(3) RA plus dexamethasone plus aprepitant for controlling delayed chemotherapy-induced nausea and vomiting in colorectal cancer. Cancer Sci 2021; 112(2): 744–750

[76] Wu F, Lin X, Yang Z, Sun Z, Zeng F, Heng J, Qu J, Zeng L, Yang N, Zhang Y. Phase III randomized trial of palonosetron and dexamethasone with or without aprepitant to prevent nausea and vomiting induced by full-dose single-day cisplatin-based chemotherapy in lung cancer. Clin Lung Cancer 2018; 19(6): e913–e918

[77] Jordan K, Blättermann L, Hinke A, Müller-Tidow C, Jahn F. Is the addition of a neurokinin-1 receptor antagonist beneficial in moderately emetogenic chemotherapy? A systematic review and meta-analysis. Support Care Cancer 2018; 26(1): 21–32

[78] Yokoe T, Hayashida T, Nagayama A, Nakashoji A, Maeda H, Seki T, Takahashi M, Takano T, Abe T, Kitagawa Y. Effectiveness of antiemetic regimens for highly emetogenic chemotherapy-induced nausea and vomiting: a systematic review and network meta-analysis. Oncologist 2019; 24(6): e347–e357

[79] Piechotta V, Adams A, Haque M, Scheckel B, Kreuzberger N, Monsef I, Jordan K, Kuhr K, Skoetz N. Antiemetics for adults for prevention of nausea and vomiting caused by moderately or highly emetogenic chemotherapy: a network meta-analysis. Cochrane Database Syst Rev 2021; 11(11): CD012775

[80] Chow R, Tsao M, Chiu L, Popovic M, Milakovic M, Lam H, DeAngelis C. Efficacy of the combination neurokinin-1 receptor antagonist, palonosetron, and dexamethasone compared to others for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials. Ann Palliat Med 2018; 7(2): 221–233

[81] Celio L, Cortinovis D, Cogoni AA, Cavanna L, Martelli O, Carnio S, Collovà E, Bertolini F, Petrelli F, Cassano A, Chiari R, Zanelli F, Pisconti S, Vittimberga I, Letizia A, Misino A, Gernone A, Bonizzoni E, Pilotto S, De Placido S, Bria E. Exploratory analysis of the effect of a dexamethasone-sparing regimen for prophylaxis of cisplatin-induced emesis on food intake (LUNG-NEPA study). Sci Rep 2023; 13(1): 1257

[82] Di Renzo N, Musso M, Scimè R, Cupri A, Perrone T, De Risi C, Pastore D, Guarini A, Mengarelli A, Benedetti F, Mazza P, Capria V, Chiusolo P, Cupelli L, Federico V, Bozzoli V, Messa AR, Codega P, Bonizzoni E, Specchia G. Efficacy and safety of multiple doses of NEPA without dexamethasone in preventing nausea and vomiting induced by multiple-day and high-dose chemotherapy in patients with non-Hodgkin’s lymphoma undergoing autologous hematopoietic stem cell transplantation: a phase IIa, multicenter study. Bone Marrow Transplant 2020; 55(11): 2114–2120

[83] Celio L, Bartsch R, Aapro M. Dexamethasone-sparing regimens with NEPA (netupitant/palonosetron) for the prevention of chemotherapy-induced nausea and vomiting in older patients (> 65 years) fit for cisplatin: a sub-analysis from a phase 3 study. J Geriatr Oncol 2023; 14(6): 101537

[84] Nakamura M, Ishiguro A, Muranaka T, Fukushima H, Yuki S, Ono K, Murai T, Matsuda C, Oba A, Itaya K, Sone T, Yagisawa M, Koike Y, Endo A, Tsukuda Y, Ono Y, Kudo T, Nagasaka A, Nishikawa S, Komatsu Y. A prospective observational study on effect of short-term periodic steroid premedication on bone metabolism in gastrointestinal cancer (ESPRESSO-01). Oncologist 2017; 22(5): 592–600

[85] Vardy J, Chiew KS, Galica J, Pond GR, Tannock IF. Side effects associated with the use of dexamethasone for prophylaxis of delayed emesis after moderately emetogenic chemotherapy. Br J Cancer 2006; 94(7): 1011–1015

[86] Hayashi T, Shimokawa M, Matsuo K, Uchiyama M, Kawada K, Nakano T, Egawa T. Effectiveness of palonosetron, 1-day dexamethasone, and aprepitant in patients undergoing carboplatin-based chemotherapy. Oncology 2023; 101(9): 584–590

[87] Okada Y, Oba K, Furukawa N, Kosaka Y, Okita K, Yuki S, Komatsu Y, Celio L, Aapro M. One-day versus three-day dexamethasone in combination with palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a systematic review and individual patient data-based meta-analysis. Oncologist 2019; 24(12): 1593–1600

[88] Janowitz T, Kleeman S, Vonderheide RH. Reconsidering dexamethasone for antiemesis when combining chemotherapy and immunotherapy. Oncologist 2021; 26(4): 269–273

[89] Hesketh PJ, Grunberg SM, Herrstedt J, de Wit R, Gralla RJ, Carides AD, Taylor A, Evans JK, Horgan KJ. Combined data from two phase III trials of the NK1 antagonist aprepitant plus a 5HT 3 antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: effect of gender on treatment response. Support Care Cancer 2006; 14(4): 354–360

[90] Hamada S, Hinotsu S, Kawai K, Yamada S, Narita S, Kamba T, Nishiyama H, Arai Y, Habuchi T, Ogawa O, Kawakami K. 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 2014; 22(8): 2161–2166

[91] Olver IN, Grimison P, Chatfield M, Stockler MR, Toner GC, Gebski V, Harrup R, Underhill C, Kichenadasse G, Singhal N, Davis ID, Boland A, McDonald A, Thomson D. 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 2013; 21(6): 1561–1568

[92] Li Y, Sun Y, Liu B, Sun Y, Chen P, Xie K, Wang Y, Zhu J. Prolonged administration of aprepitant improves cisplatin-based chemotherapy-induced nausea and vomiting. Future Oncol 2022; 18(20): 2533–2543

[93] Zhang Z, Yang Y, Lu P, Li X, Chang J, Zheng R, Zhou L, Chen S, Chen X, Ren B, Gu W, Jiang X, Peng J, Huang M, Feng G, Shen P, Zhang Q, Zhang B, Huang Y, He J, Chen Y, Cao J, Wang H, Li W, Wan H, Nan K, Liao Z, Zhang C, Lin Z, Zhong D, Xu Q, Liu H, Sun T, Deng Y, Zhang L. Fosaprepitant versus aprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based chemotherapy: a multicenter, randomized, double-blind, double-simulated, positive-controlled phase III trial. Ann Transl Med 2020; 8(5): 234

[94] Zhao N, Li X, Qin S, Cheng Y, Cao B, Zhang Q, Wang Z, Zhang B, Fan Y, Li X, Chen Z, Chang B, Sun G, Hu B, Tong Z, Li W, Jiang D, Feng J, Zhu Z, Wang K, Xu Q, Ma R, Li P, Yuan Y, Yu H, Chen Q. A randomized, double-blind, double-simulation, parallel control and multicenter phase III clinical trial comparing fosaprepitant dimeglumine injection with aprepitant tablets in the prevention of nausea and vomiting caused by highly emetogenic chemotherapy in Chinese patients. Chin Clin Oncol (Lin Chuang Zhong Liu Xue Za Zhi) 2020; 25(8): 702–709

[95] Zhao Y, Yang Y, Gao F, Hu C, Zhong D, Lu M, Yuan Z, Zhao J, Miao J, Li Y, Zhu J, Wang C, Han J, Zhao Y, Huang Y, Zhang L. A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial of olanzapine plus triple antiemetic regimen for the prevention of multiday highly emetogenic chemotherapy-induced nausea and vomiting (OFFER study). EClinicalMedicine 2023; 55: 101771

[96] Gao A, Guan S, Sun Y, Wang L, Meng F, Liu X, Gu L, Li G, Zhong D, Zhang L. Prolonged usage of fosaprepitant for prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy. BMC Cancer 2023; 23(1): 609

[97] Li Y, Wan Y, Yang X, Chen P, Gui Y, He L, Xie Y, Tian J, Duan P, Liu G, Sun Y, Zhu J. Two doses of fosaprepitant included prophylactic treatment for the three-day cisplatin-based chemotherapy induced nausea and vomiting. J Cancer Res Clin Oncol 2024; 150(6): 290

[98] Aapro M, Jordan K, Scotté F, Celio L, Karthaus M, Roeland E. Netupitant-palonosetron (NEPA) for preventing chemotherapy-induced nausea and vomiting: from clinical trials to daily practice. Curr Cancer Drug Targets 2022; 22(10): 806–824

[99] Schilling J, Kurbacher CM, Hanusch C, Busch S, Holländer M, Kreiss-Sender J, Rezek D, Flahaut E, Karthaus M. Quality of life effects of an oral fixed combination of netupitant and palonosetron in chemotherapy-induced nausea and vomiting prevention: real-world evidence in patients with breast cancer receiving anthracycline-cyclophosphamide-based chemotherapy. Breast Care (Basel) 2022; 17(2): 130–136

[100] Karthaus M, Oskay-Özcelik G, Wülfing P, Hielscher C, Guth D, Zahn MO, Flahaut E, Schilling J. Real-world evidence of NEPA, netupitant-palonosetron, in chemotherapy-induced nausea and vomiting prevention: effects on quality of life. Future Oncol 2020; 16(14): 939–953

[101] Navari RM, Nelson WW, Shoaib S, Singh R, Zhang W, Bailey WL. Real-world treatment outcomes, healthcare resource use, and costs associated with antiemetics among cancer patients on cisplatin-based chemotherapy. Adv Ther 2023; 40(7): 3217–3226

[102] Dranitsaris G, Moezi M, Dobson K, Phelan R, Blau S. A real-world study to evaluate the safety and efficacy of three injectable neurokinin-1 receptor antagonist formulations for the prevention of chemotherapy-induced nausea and vomiting in cancer patients. Support Care Cancer 2022; 30(8): 6649–6658

[103] Giuliani J, Bonetti A. Cost-effectiveness of newer regimens for the prophylaxis of chemotherapy-induced nausea and vomiting: review of the literature and real-world data. Curr Opin Oncol 2020; 32(4): 269–273

[104] Yang Y, Yang N, Wu L, Ouyang Q, Fang J, Li J, Liao W, Cai K, Huang J, Li J, Zhang Y, Wang X, Zhang H, Xu N, Zhao Q, Hu X, Li W, Zhong W, Zhong D, Cheng G, Ye S, Zhong M, Wang D, Liu H, Zheng J, Liu X, Xu H, Zhang L. Safety and efficacy of aprepitant as mono and combination therapy for the prevention of emetogenic chemotherapy-induced nausea and vomiting: post-marketing surveillance in China. Chin Clin Oncol 2020; 9(5): 68

[105] Zhang Y, Chen W, Li D, Zhao M. Efficacy of triple antiemetic regimens for cisplantin-induced nausea and vomitting in patients with melanoma. Chin J Clin Oncol Rehabil (Zhongguo Zhong Liu Lin Chuang Yu Kang Fu) 2019; 26(4): 490–493

[106] Aapro M, Caprariu Z, Chilingirov P, Chrápavá M, Curca RO, Gales L, Grigorescu AC, Huszno J, Karlínová B, Kellnerová R, Malejčíková M, Marinca M, Petru E, Płużanski A, Pokorná P, Pribulova Z, Rubach M, Steger GG, Tesařová P, Valekova L, Yordanov N, Walaszkowska-Czyz A. Assessing the impact of antiemetic guideline compliance on prevention of chemotherapy-induced nausea and vomiting: results of the nausea/emesis registry in oncology (NERO). Eur J Cancer 2022; 166: 126–133

[107] O’Sullivan CC, Van Houten HK, Sangaralingham LR, Leal AD, Shinde S, Liu H, Ettinger D, Loprinzi CL, Ruddy KJ. Ten-year trends in antiemetic prescribing in patients receiving highly emetogenic chemotherapy. J Natl Compr Canc Netw 2018; 16(3): 294–299

[108] Yu S, Burke TA, Chan A, Kim HK, Hsieh RK, Hu X, Liang JT, Baños A, Spiteri C, Keefe DMK. Antiemetic therapy in Asia Pacific countries for patients receiving moderately and highly emetogenic chemotherapy—a descriptive analysis of practice patterns, antiemetic quality of care, and use of antiemetic guidelines. Support Care Cancer 2015; 23(1): 273–282

[109] Aapro M, Scotté F, Escobar Y, Celio L, Berman R, Franceschetti A, Bell D, Jordan K. Practice patterns for prevention of chemotherapy-induced nausea and vomiting and antiemetic guideline adherence based on real-world prescribing data. Oncologist 2021; 26(6): e1073–e1082

[110] Yuan XL, Supportive-Care CN. Chinese expert consensus on prevention and treatment of delayed nausea and vomiting (2022 Edition). Oncol Transl Med 2023; 9(4): 147–162

[111] Aapro M, Ruffo P, Panteri R, Costa S, Piovesana V. Oncologist perspectives on chemotherapy-induced nausea and vomiting (CINV) management and outcomes: a quantitative market research-based survey. Cancer Rep (Hoboken) 2018; 1(4): e1127

[112] Zhang L, Zeng L, Sun Y, Wang J, Wang C, Liu C, Ding M, Quan M, Pan Z, Zhong D. Real-world validation of the chemotherapy-induced nausea and vomiting predictive model and its optimization for identifying high-risk Chinese patients. Chin Med J (Engl) 2023; 136(11): 1370–1372

[113] Cinvanti(aprepitant) injectable emulsion forintravenous use. March 3, 2022. Heron Therapeutics. Available at the website of cinvanti. com

[114] Emend(fosaprepitant) for injectionforintravenous use [prescribing information]. May 2022. Available at the website of FDA

[115] Akynzeo(netupitantpalonosetron)capsulesfor oral use(fosnetupitantfor injection [prescribing information]palonosetron) . February 2023. Helsinn Therapeutics. Available at the website of akynzeo. com

[116] Varubi(rolapitant) tabletsfororal use. August 2020. TerSera Therapeutics LLC. Available at the website of FDA

RIGHTS & PERMISSIONS

Higher Education Press