Prolonged usage of fosaprepitant for prevention of delayed chemotherapy-induced nausea and vomiting(CINV) in patients receiving highly emetogenic chemotherapy

The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Tianjin Medical University General Hospital. Written informed consent was obtained from individual or guardian participants. They were mentioned in the Result part.

Patients were included if their age were 18 years or older with a diagnosis of solid tumor receiving HEC regimen, which includes platinum or anthracycline-based chemotherapy. Patients received carboplatin AUC 5 mg/ml/min i.v. on days 1, cisplatin 75 mg/m2 i.v. on days 1 or epirubicin 90 mg/m2 every 21 days. Patients' Eastern Oncology Collaboration (ECOG) physical status score 0–2 (including boundary values). The regimens were classified as HEC based on NCCN, ESMO and CSCO guidelines [5]. Patients were excluded from the study for mental disorder or if they were taking any prohibited drug (including medicinal marijuana or currently drinking heavily). Patients were also excluded if they were about to receive abdominal or pelvic radiotherapy concurrently with chemotherapy, if they vomited 24 h before chemotherapy, if they had symptomatic brain metastasis, or were receiving systemic corticosteroids chronically.

Patients were randomly assigned to either fosaprepitant 150 mg on day 1 (regular group) or 150 mg once per day on days 1 and 3 (prolonged group). Palonosetron 0.25 mg was administered once per day on days 1. Dexamethasone 6 mg on day 1 and 4 mg once per day on days 2 and 3 was used as baseline antiemetic prophylaxis. Detailed study designs are summarized in Supplementary Fig. 1.

The primary endpoint were incidence of delayed nausea and delayed vomiting. The second endpoint was related AEs. All the endpoints above were defined according to CTCAE 5.0.

To survey the occurrence of nausea and vomiting, we prepared a nausea/vomiting diary based on the MAT (questionnaire about nausea and vomiting), which was developed by the Multinational Association of Supportive Care in Cancer (MASCC) (Supplementary Fig. 2). The patient diary include the recording of any nausea, vomiting, and adverse effects associated with antiemetic drugs, from day 1 to 14 after chemotherapy. Safety was assessed by collection of adverse events (AEs), including constipation, diarrhea, hiccough, fatigue, palpitation and headache. The use of rescue therapy, defined as any medication taken to treat established nausea or emesis, was also recorded. Patients rated nausea and vomiting daily by using CTCAE 5.0. scale rating their nausea and vomiting for the prior 24 h from no nausea and vomiting to the worst nausea and vomiting with a measurement of score 0 to 4. Nausea symptoms were surveyed and recorded by investigators according to the numeric rating scale (NRS; 4-point scale, in which 1 represents a condition without nausea and 4 represents a condition with the worst conceivable nausea). The results were then categorised into ‘grade 0’ (NRS, 1), ‘grade 1’ (2), ‘grade 2’ (3) and ‘grade 3’ (4). For vomiting symptoms, the number of times vomiting (including dry vomiting) occurred was surveyed every day and evaluated according to the National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE ver. 4.0). CTCAE grading is the same as nausea. The incidence of nausea and vomiting were assessed during the acute (0–24 h), delayed (24–120 h) and overall (0–120 h) phases after chemotherapy initiation.

According to previous reports and the results of our pre-experiments, we calculated that a sample of 118 patients (59 in regular group; 59 in prolonged group) would provide the study with 80% power to detect a difference between the group proportions of 20% at a two-sided alpha of 0.05. Given an anticipated dropout rate of 20%, total sample size required is 148 (74 in regular group 1; 74 in prolonged group).

A total of 156 patients were enrolled in the study. All the patients were randomly divided into prolonged group (77 patients) and regular group (79 patients). All patients were chemotherapy naive and were evaluated in the first treatment cycle. Table 1 lists the demographic and clinical characteristics of included patients. These characteristics were similar between the two treatment groups. In the regular group, the median age was 64 years old, 39.2% of patients were female, and 62.0% of patients had lung/respiratory cancer. In prolonged group, the median age was 65, 36.4% of patients were women. The most prevalent cancer was also lung/respiratory cancer (70.1%). All patients in each group received HEC.

The incidence of nausea and vomiting in the acute phase, delayed phase and overall phase were separately compared between two treatment group.

In the overall phase, the proportions of patients experiencing nausea in prolonged group was 5.97%, while that in the regular group was 12.15% (P = 0.0027) (Fig. 1A). A similar numerical advantage of prolonged group was also shown in the delayed phases (Fig. 1B). During the delayed phase, the incidence of grade 1 nausea was 3.90%, as compared with 10.44% in regular group (P = 0.0016). Prolonged group reduces 6.55% of grade 1 delayed nausea compared to regular group (95%CI: 12.40%-0.68%, P = 0.038). 4.16% of patients in the prolonged group experienced grade 1 nausea from day 1 to 14, compared to 9.62% in the regular group (P = 0.0026). Therefore, in both the delayed and overall phases, the prolonged group outperformed the regular group in terms of nausea prevention. However, there was no statistically significant difference between groups in the proportions of patients with nausea in the acute phase.

Multiple-day fosaprepitant regimen was also superior to the regular antiemetic regimen for controlling vomiting in the delayed phase (Fig. 2B), although there was no statistical difference in the overall phase (Fig. 2A). The incidence of vomiting in regular and prolonged group were 3.8% and 1.56% for the overall phase (P = 0.0534), although difference between the two groups were not of statistical significance, the incidence of vomiting in prolonged group tended to be slightly lower. The incidence of grade 1 emesis was lower in the prolonged group than in the regular group during the delayed phase (1.30% versus 3.80%, P = 0.0483) and overall phase (1.30% versus 3.80%, P = 0.0273). Prolonged group reduces 2.52% of grade 1 delayed emesis compared to regular group (95%CI: 2.44%-2.60%, P < 0.001). However, the incidence of grade 2 or higher vomiting and the incidence of acute and delayed vomiting were not statistically different between the two groups.

In addition, the incidence of nausea and vomiting beyond delayed phase (120–336 h) was recorded. However, no significant difference was found between two groups (Supplemental Fig. 3).

The most commonly reported AEs of fosaprepitant were constipation, diarrhea, hiccough, fatigue, palpitation and headache [11] (Fig. 3). The overall incidence of AEs was comparable in both treatment groups across the study. Most AEs reported were mild or moderate, with fatigue (prolong group 4.42%, regular group 5.82%, P = 0.3730) and constipation (prolong group 3.38%, regular group 4.05%, P = 0.6189) being the most commonly reported AEs in both groups. All other AEs had an incidence rate of less than 2%. In comparison to the regular group, there was no evidence of increased AEs and no grade 2 nor more severe AEs were observed in the prolonged group.

Risk factors for nausea and vomiting symptoms were investigated. The risk factors related with CINV included age, anxiety, nausea with pregnancy, etc. However, these factors showed no statistical significance in the univariate analysis (Table 2).