Background: The benefit of concurrent chemotherapy to treat intermediate-risk (stage II and T3N0M0) nasopharyngeal carcinoma (NPC) remains controversial. We aimed to assess whether concurrent chemotherapy can be omitted safely for intermediate-risk NPC patients treated with intensity-modulated radiotherapy. 

Methods: This multi-centre, noninferiority, open-label, randomised controlled, phase III trial was done at 4 hospitals in China. Patients aged 18–65 years, with histologically confirmed, stage T1-2N1/T2-3N0M0, a Karnofsky score of at least 70 were randomly assigned (1:1) to receive either concurrent chemoradiotherapy (CCRT) (cisplatin 100 mg/m² on days 1, 22, and 43) or radiotherapy alone (RT). Key exclusion criteria included: maximal axial diameter of neck lymph node ≥30mm, positive neck lymph node at level IV or lower, pretherapy plasma EBV DNA level ≥4000 copy/ml. Randomisation was performed with a random number code stratified by treatment centre and stage. The primary endpoint was failure-free survival（FFS).The calculated sample size was 169 per group, with an 80% power (one-sided α 0.05). 

Results: Between November 11, 2015 and August 4, 2020, 341 NPC patients were randomly assigned to receive either RT (n=172) or CCRT（n=169). After a median follow-up of 41 months, intention-to-treat analysis showed that 3-year FFS was 90.7% (95% CI 86.2–95.2) in the RT group, and 92.1% (95%CI 88.8–96.4) in the CCRT group, with a difference of -1.4% (upper limit of the one-sided 95% CI 4.5; p_{non-inferiority}=0.00017). Similarly excellent FFS was found in the per-protocol analysis: 3year FFS for RT versus CCRT was 90.3% (95% CI 85.6–95.0) and 92.1% (95% CI 87.8–96.4), respectively, with a difference of -1.8% (upper limit of the one-sided 95% CI 4.3; p_{non-inferiority}=0.00014). No differences were observed between groups in terms of overall survival, locoregional relapse and distant metastasis. Patients in the CCRT group developed significantly more grade 3-4 hematologic and nonhematologic adverse events such as vomiting (CCRT group 14.8% vs. RT group 1.2%), anorexia (29.9% vs. 4.8%), mucositis (18.9 % vs. 9.7%) and weight loss(4.7% vs. 0.6%). No patients died from treatment-related causes. 

Conclusions: Radiotherapy alone provides comparable disease control or survival and less toxicity compared to CCRT in the intermediate risk NPC.

 Clinical trial information: NCT02633202

Research Sponsor:Sun Yat-sen University Clinical Research 5010 Program.