To the best of our knowledge, this is the first prospective trial to evaluate the efficacy and safety of a NK1 receptor antagonist (aprepitant) combined with ondansetron and dexamethasone to prevent nausea and vomiting for patients with HNSCC receiving triweekly cisplatin chemoradiotherapy. The primary endpoint met the target, with the overall CR rate achieving 86.0%, revealing that the triple antiemetic regimen provided effective protection against chemoradiotherapy-induced nausea and vomiting in patients with LA-HNSCC. Prior research has indicated that the addition of an NK1RA into 5-HT3RA and dexamethasone improves antiemetic efficacy in patients with cervical cancer receiving radiotherapy with weekly cisplatin chemotherapy 17, 23. Similar results have now been extended to patients with HNSCC receiving IMRT and triweekly cisplatin chemotherapy.
The primary endpoint of the present trial was complete response, which has used in most clinical antiemetic trials. The “no emesis” represented the control of emesis, while “no use of rescue therapy” as an alternative marker also reflected control of nausea to a certain degree. In the present trial, only 5 patients experienced grade 1 to 2 emesis, and one patient with severe nausea received rescue treatment. Prior prospective studies on NK1RAs for prophylaxis of C-RINV observed that the CR rate was between 48% and 76% 14–16, 18. As against the data of the above studies, our results exhibit that the triple antiemetic regimen achieved excellent antiemetic efficacy. One possible explanation is that the 5-day antiemetics administration increased the cumulative dose of the aprepitant and dexamethasone under the premise of multiple-day cisplatin chemotherapy, potentially having a stronger antiemetic effect. With regard to the secondary endpoints, CP is also a reliable endpoint to evaluate the overall control of nausea and vomiting, often being employed in clinical trials of CINV. The CP rate of this study achieved 72%, which was higher than the data reported in several trials on aprepitant for prevention of CINV 24, 25. However, the concept of “mild nausea” is not objective enough, whether it is based on grade 1 of CTCAE or NVAS < 25mm 26. Conversely, “no vomiting” and “no nausea” are relatively objective indicators, being adopted as secondary endpoints in our study. In the overall phase, 88.4% of patients developed no emesis, higher than the 66%-73% reported in previous studies on NK1RAs for prevention of C-RINV 15, 17, 18, 27. Although the overall nausea-free response rate was only 60.5%, this is approximately consistent with the 40%-61.5% reported in preceding research on NK1RAs for prevention of C-RINV 16, 18, 27.
The control rates of nausea and vomiting under our triple antiemetic regimen were also superior to the data reported in previous studies on concurrent chemoradiotherapy for head and neck squamous cell carcinoma. In actuality, many studies have reported treatment-related toxicities such as nausea and vomiting while publishing primary endpoints, yet few studies specified the antiemetic regimens. In the RTOG 0129 trial 11, 361 patients were subjected to standard fractionation irradiation with a median dose of 69.8Gy and concomitant triweekly cisplatin chemotherapy, and granisetron or ondansetron was used as the antiemetic regimen. In this condition, 65.9% of patients developed nausea and 46.8% of patients experienced vomiting. Further, the incidences of grade 3 nausea and grade 3-4vomiting were both close to 20%. These results implied that single-agent 5-HT3RAs were insufficient to control nausea and vomiting caused by concurrent chemoradiotherapy in head and neck squamous cell carcinoma. In a randomized phase 3 trial 13, the CCRT arm was subjected to radical radiotherapy (66-70Gy) with concurrent weekly cisplatin (30 mg/m2). Employing ondansetron and dexamethasone as antiemetics, the overall incidences of nausea and vomiting were 47.7% and 30%, and the incidences of grade 3 nausea and grade 3-4 vomiting were only 1% and 1.5%. As well as the addition of dexamethasone, the reduction of nausea and vomiting could also be attributed to the weekly cisplatin chemotherapy regimen. A preceding meta-analysis compared weekly low-dose (≤ 50 mg/m2) and triweekly high-dose cisplatin (100 mg/m2) for CCRT in LA-HNSCC, and demonstrated the weekly regimen did lead to a substantially lower proportion of severe nausea and/or vomiting (3% vs 16%) 28. However, the antiemetic efficacy was still superior to the above study under the premise of administrating the stronger emetic triweekly cisplatin regimen in the present study, illustrating that the addition of aprepitant into ondansetron and dexamethasone could more effectively control nausea and vomiting. In a further randomized phase 3 trial 29, Tang et al also divided 100 mg/m2 of cisplatin into three days, and the antiemetic regimen stipulated adding metoclopramide on the basis of ondansetron/ granisetron and dexamethasone. The proportion of patients with nausea and vomiting were both around 80%, and the incidence of grade 3 nausea was only 9%, but the incidence of grade 3-4 vomiting was up to 18%. Numerically, although the triple regimen containing metoclopramide could be more effective in preventing severe nausea, poor prevention of the overall occurrence of nausea and vomiting was demonstrated, in addition to a failure to effectively prevent severe vomiting. Conversely, the majority of patients with nausea presented mainly mild and moderate levels in the present study. Despite the determination of the degree of nausea being subjective, only one patient required rescue antiemetics, and no patient discontinued treatment due to nausea or vomiting, thereby objectively illustrating that the triple regimen containing aprepitant could effectively control the occurrence of severe nausea and vomiting.
Recently, another prospective study evaluating the antiemetic efficacy of aprepitant in patients with LA-HNSCC receiving radiotherapy and concurrent weekly cisplatin (50 mg/m2) chemotherapy was exhibited at the 2020 Annual Meeting of the American Society of Clinical Oncology (ASCO) 27. The incidences of no nausea and no vomiting were 57.7% and 73.2% in patients receiving aprepitant, 5-HT3RA and steroids. The similar antiemetic regimen demonstrated poorer control of nausea and vomiting during concurrent weekly cisplatin and radiation compared with our study. In general, whether horizontally compared with the studies of NK1 RAs for prophylaxis of C-RINV, or longitudinally compared with prior studies of CCRT for head and neck squamous cell carcinoma, our study administrated a triple antiemetic regimen consisting of aprepitant, ondansetron and dexamethasone and presented high antiemetic efficacy. Yet, the incidence of nausea in our study notably remained close to 40%. A small randomized controlled trial had revealed that the addition of olanzapine increased the control rate of nausea from 40–71% 16. In future research, we will consider adding olanzapine to optimise this antiemetic regimen.
In terms of treatment compliance and toxicities, 86.0% of patients completed both cycles of chemotherapy in the present study. Of the six patients who discontinued chemotherapy, only three did so as a result of treatment related adverse events. Owing to the antiemetics that were given together with cisplatin, it was difficult to classify adverse events into antiemetics-related or cisplatin-related, especially fatigue, appetite loss and hepatic dysfunction. Nevertheless, constipation and hiccups with incidences of 65.1% and 16.3% were primarily regarded as antiemetics-related adverse events. The high incidence of constipation could be attributed to an increase of cumulative dose for 5-day administration of antiemetics, in addition to the non-use of prophylactic laxatives. Dexamethasone-induced hiccups are not an uncommon symptom in patients with cancer, Vardy et al. reported a 25% incidence of hiccups after dexamethasone administration 30. Liaw et al. also discovered that more than 40% of patients treated with cisplatin developed hiccups, and 90% of hiccups eased after discontinuation of dexamethasone 31. As against the data of the above studies, the incidence of hiccups in the present study was not unacceptable. A randomized trial confirmed that replacing dexamethasone with methylprednisolone does not compromise the antiemetic efficacy, but reduces the occurrence of hiccups. Hence, if there is a concern that hiccups would affect the quality of life, using methylprednisolone instead of dexamethasone could also be considered 32. Although grade 3 mucositis and leucopenia also exceeded 10%, both toxicities were recognised as being related to concurrent chemoradiotherapy. Overall, the present study demonstrated that the triple regimen is still well tolerated in HNSCC patients.
Notwithstanding the above, several limitations still exist in the present study. Firstly, 3-day administration of cisplatin was primarily owing to the naïve population tolerance and the recommendation of the local ethics committee, which had already been utilised in another large prospective trial 29. The 5-day antiemetic regimen in the present study was designed based on the 3-day administration of cisplatin. Thus, for the more extensively used single-day cisplatin administration, the question of whether this triple antiemetic regimen can achieve the same efficacy as the present study requires further research to answer. Further, the present study was a single-arm phase 2 trial without an optimal control group. When analysing the efficacy, only comparison with historical data was possible. For this reason, further phase 3 randomized controlled trials must be conducted in the future.