Effect of Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Women

Key Points Question Is prophylactic aprepitant therapy combined with palonosetron and dexamethasone effective in preventing nausea and vomiting in women receiving moderately emetogenic chemotherapy? Findings In this randomized phase 3 clinical trial that included 248 women younger than 50 years with no or little alcohol use, the complete response rate in the overall phase for chemotherapy-induced nausea and vomiting was 87% in the aprepitant group vs 67% in the control group. The overall complete response rate was significantly higher in the aprepitant group vs the control group. Meaning Adding aprepitant to palonosetron and dexamethasone was effective in reducing nausea and vomiting for women who received moderately emetogenic chemotherapy.

INTERVENTIONS Patients were randomly assigned to the aprepitant group (aprepitant, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 6 mg, orally 30 minutes before chemotherapy initiation on day 1) or the placebo group (placebo, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally on each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 12 mg, orally 30 minutes before chemotherapy initiation on day 1).

+ Visual Abstract + Supplemental content Introduction
Chemotherapy-associated nausea and vomiting (CINV) are among the most common and distressing adverse effects in patients receiving antineoplastic therapy, which could seriously affect the quality of patients' life and markedly reduce treatment adherence. 1-3 Therefore, the prevention of CINV has a vital role in the overall management of anticancer treatment.
The incidence and severity of CINV depend mainly on the anticancer agents' emetogenicity, which is divided into high, moderate, low, and mild emetogenic chemotherapy, according to the incidence of emesis in the absence of antiemetic prophylaxis. 4 The FOLFOX (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimens are used widely in treatment of gastrointestinal cancers. Oxaliplatin and irinotecan are classified as moderately emetogenic. Previous studies have shown that the vomiting incidence in patients who received FOLFOX or FOLFIRI as first-line therapy was more than 40% for both chemotherapeutic treatments. 4,5 In addition to chemotherapy regimens, CINV has been associated with patient-related risk factors, such as female sex and young age. The incidence of vomiting in these patients has been shown to be high even though they received a standard 2-drug antiemetic regimen consisting of dexamethasone and palonosetron, a highly effective 5-hydroxytryptamine-3 (5-HT3) receptor antagonist (RA). 6 Aprepitant is a neurokinin-1 (NK-1) RA, which has a different mechanism of action from that of 5-HT3 RA and other antiemetics used to prevent CINV. 7 Aprepitant can selectively block the binding of substance P at the NK-1 receptor in the central nervous system, showing benefit in the control of both acute and delayed CINV. In patients receiving high-dose cisplatin-based or combination chemotherapy of anthracycline and cyclophosphamide, the triple-drug combination (NK-1 RA plus a standard regimen of 5-HT3 RA and dexamethasone) improved protection against CINV compared with the standard regimen. 8,9 Thus, both the National Comprehensive Cancer Network guideline and the Multinational Association of Supportive Cancer Care (MASCC)/European Society for Medical Oncology (ESMO) guideline recommend prophylactic use of aprepitant in combination with a 5-HT3 RA and dexamethasone for patients receiving highly emetogenic chemotherapy. 10,11 It remains controversial whether an NK-1 RA-containing prophylactic regimen should be used in moderately emetogenic chemotherapy of various types of cancers. In a multinational phase 3 study, the aprepitant regimen showed superior efficacy compared with the nonaprepitant regimen in preventing CINV with no vomiting during the overall phase (83.2% vs 71.3%; P < .05). 12 In a Korean phase 4 clinical trial, the proportion of patients with no vomiting while receiving the aprepitant regimen was numerically, but not statistically significantly, higher than with the control regimen (77.2% vs 72.0%; P = . 19). 13 In addition, for prophylaxis of oxaliplatin-induced emesis, combining an NK-1 RA with dexamethasone and a 5-HT3 RA is not recommended by MASCC/EMSO guidelines, but it is recommended for select patients with risk factors by the National Comprehensive Cancer Network guideline. 10, 11 This clinical trial was conducted to evaluate the efficacy and safety of

Study Design
This randomized, double-blind, placebo-controlled phase 3 trial was performed at 4 independent centers in China. All included patients provided written informed consent before registration. The study was approved by the independent ethics committee or institutional review board at each participating center. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. The trial protocol is available in Supplement 1. The efficacy of antiemetic therapy was monitored from the start of chemotherapy agent infusion (0 hours on day 1) to the morning of day 6 (approximately 120 hours). Patients were instructed to complete the patient diary to report episodes of emesis, the use of rescue therapy, and assessment of daily nausea and vomiting by a 100-mm visual analog scale. Any episode of vomiting or retching and use of rescue therapy was to be recorded. On day 6, patients needed to immediately complete the Functional Life Index-Emesis (FLIE) questionnaire concerning days 1 to 5. The FLIE is a measurement tool for evaluating the prevalence of CINV and its association with quality of life. The tool consists of 18 questions, with each scaled from 1 to 7. The first 9 questions are related to the grade and effect of nausea, and the last 9 are related to emesis. 14 The completed diary was returned to the study assistant at the patient's next chemotherapy cycle.
Many risk factors are associated with CINV. In this study, we focused on younger age, female sex, and little or no history of alcohol use. Those factors are routinely documented when data on the patient's history are collected. Women aged 18 to 50 years with no history of long-term or excessive alcohol intake (alcohol intake of <5 times per week and 100 g per day), Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2, and a histologically confirmed gastrointestinal carcinoma that was naive to aprepitant and FOLFOX or FOLFIRI regimens were considered eligible.
The major exclusion criteria were inability to read, comprehend, and finish questionnaires, including visual analog scale questions; no history of morning sickness during pregnancy; presence of gastrointestinal tract obstruction or electrolyte imbalance; history of central nervous system disease; concomitant therapy with psychotropic medications, such as olanzapine; and hypersensitivity history or contraindication to use of aprepitant, 5-HT3 RAs, or dexamethasone.
Patients were first stratified according to the chemotherapy regimen (FOLFOX or FOLFIRI).
Then, they were randomized (1:1) to receive the aprepitant or placebo regimen in accordance with the unique, computer-generated, blinded allocation schedule, which was developed using SAS, version 9.13 (SAS Institute Inc) and maintained with confidentiality. The investigators, study coordinators, and patients remained blinded to the study assignments. In addition, the matched placebo with the same configuration as the aprepitant capsule was used to maintain double-blinding.

Regimens and Assessment
Aprepitant, 125 mg, or placebo, 125 mg, was orally administered 60 minutes before initiation of chemotherapy on day 1, and aprepitant, 80 mg, or placebo, 80 mg, was administered orally each The primary end point was the complete response (CR) rate, defined as the proportion of patients without emesis episodes or rescue medication use during the overall phase (0-120 hours).
The secondary end points were (1)

Statistical Analysis
Statistical analysis was conducted on October 30, 2020. In a phase 2 trial comparing the aprepitant group with the placebo group in women younger than 70 years with no alcohol use receiving moderately emetogenic chemotherapy, the CR rates in the overall phase were 62% with aprepitant and 52% with placebo. 15 Thus, we assumed a CR rate of 50% for the placebo regimen and 70% for the aprepitant regimen. After calculation, 248 participants (124 participants per group) were required under a power of 90% and a 2-sided type I error of 5%.
The modified intent-to-treat population (patients who received chemotherapy and a study treatment and were analyzed according to the allocated group) was used to analyze patient baseline characteristics and efficacy analyses. The safety population (patients who received chemotherapy and a study treatment but were analyzed according to the treatment they received) was used to analyze safety and tolerability.
The differences in baseline characteristics between the 2 groups were analyzed by t test for measurement data and by the Pearson χ 2 test or Fisher exact probability method for classification data. The χ 2 test or Fisher exact test was also used to analyze the differences between all kinds of efficacy end points. Logistic regression analysis was used for subgroup analysis of predictive factors for CR in the overall phase. Clinical factors with P values <.20 on univariable analysis and chemotherapy regimen factors were included in multivariable analysis. A 2-sided P value <.05 was regarded as statistically significant. All statistical analyses were performed with SPSS, version 24.0 (IBM Corp).

Baseline Characteristics
A total of 248 women younger than 50 years from 4 independent centers in China were enrolled between August 4, 2015, and March 31, 2020, and were randomly assigned to an aprepitant or placebo regimen in the 1:1 ratio (Figure 1 patients received an aprepitant regimen and 118 patients received a placebo regimen; this was considered the safety population and used to analyze safety and tolerability.
The baseline characteristics were similar in the 2 treatment groups (
There were significant differences in other efficacy end points (

Safety and Tolerability
The incidence of at least 1 adverse event was generally similar in patients treated with the aprepitant

Risk Factors for CR
The results of univariable and multivariable analyses of the risk factors associated with CR in the overall phase are reported in eTable 3 in Supplement 2. Patients' baseline characteristics, chemotherapy regimen, and aprepitant use were included in the analysis. In the univariable analysis, only the use of aprepitant (odds ratio, 3.34; 95% CI, 1.75-6.39; P < .001) had a P value <.10. Thus, clinical factors (age, history of previous chemotherapy, tumor's primary site, and ECOG performance status score) at P < .20 on univariable analysis and chemotherapy regimen factors were included in multivariable analysis. The multivariable analysis indicated that only aprepitant use was a significant risk factor (odds ratio, 3.42; 95% CI, 1.77-6.61; P < .001).

Discussion
The addition of an NK-1RA in the prophylaxis of CINV in patients receiving moderately emetogenic chemotherapy remains controversial. 16,17 In previous studies, the NK-1 RA showed better antiemetic efficacy in patients treated with specific moderately emetogenic chemotherapy regimens, such as anthracycline with cyclophosphamide, which are now categorized as highly emetogenic chemotherapy. 18 For the regimen not including anthracycline and cyclophosphamide, clinical studies have shown conflicting results on the efficacy of the combined use of aprepitant for improving nausea and emesis in various moderately emetogenic chemotherapy regimens and tumor types. 12,13,15,19 The FOLFOX and FOLFIRI regimens have shown survival benefits in treatment of gastrointestinal cancer; however, their use also increased the incidence of CINV compared with fluorouracil alone. 20,21 Moreover, patients with gastrointestinal cancers seem more susceptible to emesis owing to the abdominal pain and gastrointestinal obstruction caused by the tumor.
Nevertheless, the conclusions of 2 large randomized trials showed conflicting outcomes on the role of NK-1 RA in oxaliplatin-based chemotherapy. 22 Aprepitant also had an important role in improving protection against nausea. In the overall phase, the incidence of CINV per day in the aprepitant group remained lower than in the placebo group.
Increases were seen in the proportion of no nausea (16.7%) and no substantial nausea (5.9%). In addition, the reduction in the incidence of CINV improved the patients' quality of life. The proportions of a detrimental effect on quality of life decreased by 18.8% for nausea and 22.8% for emesis according to the FLIE questionnaire scores.
In this study, other risk factors, including history of motion sickness and morning sickness during pregnancy, were not included for the following reasons. First, the diagnoses of motion sickness need to be differentiated from other diseases, such as Meniere disease and benign paroxysmal positional vertigo. Second, most pregnant women experience morning sickness during pregnancy, and the severity of morning sickness may be more associated with the risk of CINV, but there was recall bias in this history. Third, those 2 risk factors are not usually mentioned during routine history interviews.
To make it easier to conduct the research and generalize the research conclusion to clinical practice, we selected only age, sex, and alcohol use history.
The triple-drug combination of aprepitant plus palonosetron and dexamethasone was well tolerated in general. There was no significant difference in the total incidence of all grade adverse events between the 2 groups. However, compared with the placebo group, the total incidence of grade 3 or 4 adverse events seemed numerically higher in the aprepitant group. Most grade 3 or 4 adverse events were abnormal results of hematologic tests, which were slightly associated with aprepitant. The possibility of hematologic adverse events highlights the importance of reminding patients to accept routine blood tests regardless of the antiemetic regimen and chemotherapy regimen being used.

Limitations
This study has limitations. First, the prevention of aprepitant-induced CINV was evaluated solely during the first course of chemotherapy. The role of aprepitant in anticipatory vomiting and during the complete treatment regimen is unknown. Second, in the subgroup analysis, with respect to the chemotherapy regimen, the antiemetic effects of adding aprepitant were just numerically (ie, not significantly) better for patients receiving the FOLFIRI regimen (76.0% vs 68.0%, P = .53). Only 50 patients received the FOLFIRI regimen in our study; thus, future studies with larger sample sizes are warranted. Third, the inclusion of only women younger than 50 years with little or no alcohol use limits the generalizability of the trial results.

Conclusions
This study demonstrates increased antiemetic efficacy of the combination of aprepitant with palonosetron and dexamethasone during FOLFOX or FOLFIRI chemotherapy. The aprepitant regimen was well tolerated by younger women with gastrointestinal cancer who had a history of little or no alcohol consumption.