Background: To investigate the safety and efficacy of hypofractionated plus chemotherapy in patients with initially distant metastatic nasopharyngeal carcinoma (mNPC). Methods: Between May 2014 and June 2020, 35 patients initially diagnosed with mNPC were enrolled on prospective trial. The enrolled patients were assigned randomly to receive either hypofractionated plus chemotherapy (HFRT) or conventionally fractionated radiotherapy plus chemotherapy (CFRT). 60 Gy over 25 fractions was administered to the HFRT group (n = 17) and 69.96 Gy over 33 fractions was administered to the CFRT group (n = 18), both groups five times each week. Progression free survival (PFS) comprised the primary endpoint. Overall survival (OS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and acute and late toxicity comprised the secondary endpoints. Results: Twenty-eight patients (seven were excluded) were enrolled. The 2-year PFS was 33.3% (HFRT group) versus 30.0% (CFRT group) (stratified hazard ratio (HR):1.09; 95% confidence interval (CI): 0.45–2.65, P = .843). The 2-year OS was 66.7% (HFRT group) versus 62.5% (CFRT group) (stratified HR, 0.88; 95% CI; 0.31–2.51, P= .806). All patients experienced acute grade 1 or 2, skin toxicity, oral mucositis, dysphagia, dry mouth, but no acute grade 3 or 4 toxicities. All patients had grade 1 late xerostomia. Two patients experienced hearing loss (one grade 1 and one grade 3). One patient developed mucosal necrosis. Conclusions: The two groups had similar outcomes. Improving the balance between severe late toxicities and local control by appropriately reducing the total dose but increasing the fractionated dose has marked clinical significance for patients with initially diagnosed mNPC. The trial has been registered with clinicaltrials.gov (NCT03598218). Clinical trial information: NCT03598218.

Abbreviations: HFRT, hypofractionated radiation; CFRT, conventionally fractionated radiotherapy; n, number.