A Multicenter Randomized Controlled Phase 3 Trial of Locoregional Radiotherapy in Combination with Chemotherapy in de novo Metastatic Nasopharyngeal Carcinoma

Background: The role of locoregional radiotherapy in de novo metastatic nasopharyngeal carcinoma (mNPC) patients is unclear. Methods: mNPC patients with biopsy-proven disease, who demonstrated complete or partial response (RECIST v1.1) following 3 cycles of cisplatin and 5-fluorouracil chemotherapy, were enrolled. Eligible patients were randomly assigned (1:1) to receive either chemotherapy plus radiotherapy or chemotherapy alone. The chemotherapy regimens were 5-fluorouracil continuous intravenous infusion at 5 gm/m2 over 120 h and 100 mg/m2 intravenous cisplatin on day 1, administered every 3 weeks for six cycles. Patients assigned to the chemotherapy plus radiotherapy group received intensity-modulated radiotherapy (IMRT) after chemotherapy. Primary endpoint of the study was overall survival (OS). Findings: 126 of 173 patients screened were eligible to the study, and randomized to chemotherapy plus radiotherapy (n = 63) or chemotherapy alone (n = 63). Median follow-up duration was 26.7 months (IQR 17.2-33.5). The study met its primary end-point of improved OS (stratified hazard ratio [HR] = 0.42; 95% confidence interval [CI], 0.23-0.77; P = 0.004) in favor of chemotherapy plus radiotherapy. PFS was also improved in the chemotherapy plus radiotherapy group compared to the chemotherapy alone group (stratified HR = 0.36; 95% CI 0.23-0.57). No significant differences in acute hematological or gastrointestinal toxicities were observed between the treatment arms. The frequency of acute ≥grade 3 dermatitis, mucositis, and xerostomia was 8.1%, 33.9%, and 6.5%, respectively, in the chemotherapy plus radiotherapy group. The frequency of late severe ≥grade 3 hearing loss and trismus was 5.2% and 3.4%, respectively, in the chemotherapy plus radiotherapy group. Interpretation: Radiotherapy added to chemotherapy significantly improved OS in chemotherapy-sensitive mNPC patients. Trial Registration: This trial was registered as NCT02111460. Funding Statement: Funding was provided by the Program of Sun Yat-Sen University for Clinical Research 5010 Program (No.201310), the National Natural Science Foundation of China (No.81572912, 81772895, 81874134), Guangdong Province Science and Technology Development Special Funds (Frontier and Key Technology Innovation Direction – Major Science and Technology Project) (No. 703040078088), Guangzhou Science and Technology Planning Project - Production and Research Collaborative Innovation Major Project (No. 201505012235268). MC is supported by the National Medical Research Council Singapore Clinician-Scientist Award - #NMRC/CSA/0027/2018 and the Duke-NUS Oncology Academic Program Proton Research Program. This research is also supported by the National Research Foundation Clinical Research Programme Grant (NRF-CRP17-2017-05). Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: The study protocol was approved by the ethics committee of the Sun Yat-sen University Cancer Center (SYSUCC). The trial was performed in accordance with the Declaration of Helsinki, and the results are reported according to the CONSORT statement. All participants provided written informed consent.