Effect of Radiotherapy Alone vs Radiotherapy With Concurrent Chemoradiotherapy on Survival Without Disease Relapse in Patients With Low-risk Nasopharyngeal Carcinoma: A Randomized Clinical Trial

Abstract

Importance: Concurrent chemoradiotherapy has been the standard treatment for stage II nasopharyngeal carcinoma (NPC) based on data using 2-dimensional conventional radiotherapy. There is limited evidence for the role of chemotherapy with use of intensity-modulated radiation therapy (IMRT).

Objective: To assess whether concurrent chemotherapy can be safely omitted for patients with low-risk stage II/T3N0 NPC treated with IMRT.

Design, setting, and participants: This multicenter, open-label, randomized, phase 3, noninferiority clinical trial was conducted at 5 Chinese hospitals, including 341 adult patients with low-risk NPC, defined as stage II/T3N0M0 without adverse features (all nodes <3 cm, no level IV/Vb nodes; no extranodal extension; Epstein-Barr virus DNA <4000 copies/mL), with enrollment between November 2015 and August 2020. The final date of follow-up was March 15, 2022.

Interventions: Patients were randomly assigned to receive IMRT alone (n = 172) or concurrent chemoradiotherapy (IMRT with cisplatin, 100 mg/m2 every 3 weeks for 3 cycles [n = 169]).

Main outcomes and measures: The primary end point was 3-year failure-free survival (time from randomization to any disease relapse or death), with a noninferiority margin of 10%. Secondary end points comprised overall survival, locoregional relapse-free survival, distant metastasis-free survival, adverse events, and health-related quality of life (QOL) measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference ≥10 for physical function, symptom control, or health-related QOL; higher score indicates better functioning and global health status or worse symptoms).

Results: Among 341 randomized patients (mean [SD] age, 48 [10] years; 30% women), 334 (98.0%) completed the trial. Median follow-up was 46 months (IQR, 34-58). Three-year failure-free survival was 90.5% for the IMRT-alone group vs 91.9% for the concurrent chemoradiotherapy group (difference, -1.4%; 1-sided 95% CI, -7.4% to ∞; P value for noninferiority, <.001). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. The IMRT-alone group experienced a significantly lower incidence of grade 3 to 4 adverse events (17% vs 46%; difference, -29% [95% CI, -39% to -20%]), including hematologic toxicities (leukopenia, neutropenia) and nonhematologic toxicities (nausea, vomiting, anorexia, weight loss, mucositis). The IMRT-alone group had significantly better QOL scores during radiotherapy including the domains of global health status, social functioning, fatigue, nausea and vomiting, pain, insomnia, appetite loss, and constipation.

Conclusions and relevance: Among patients with low-risk NPC, treatment with IMRT alone resulted in 3-year failure-free survival that was not inferior to concurrent chemoradiotherapy.

Trial registration: ClinicalTrials.gov Identifier: NCT02633202.

Figure 1.. Screening, Randomization, and Patient Flow in a Trial of Intensity-Modulated Radiation Therapy (IMRT) Alone for Low-risk Nasopharyngeal Carcinoma

^aSubcategorical numeric values exceed 240 because 56 patients had more than 1 adverse feature. ^bRandomization was stratified by trial center and staging subset. EBV indicates Epstein-Barr virus.

Figure 2.. Kaplan-Meier Estimates in 341 Patients With Low-risk Nasopharyngeal Carcinoma Stratified by the Randomization Group

The hazard ratios (HRs) and their associated 95% CIs were determined using an adjusted Cox proportional-hazards model.

Figure 3.. Failure-Free Survival According to Subgroup

^aHazard ratios (HRs) and the associated 95% CIs were calculated using an unadjusted Cox proportional hazards model, which was also used to carry out the interaction test, incorporating the interaction term (eg, age × treatment), a covariate of interest (eg, sex), and the trial group. An HR of less than 1 indicated a decreased risk of failure-free survival after intensity-modulated radiation therapy alone compared with that after concurrent chemoradiotherapy. ^bThe index of Karnofsky performance scales is a primarily subjective score of physical ability used to assess the ability of a patient to carry on normal activities in life from normal health (100) to disabled (50) and death (0). ^cAccording to the 7th edition TNM Staging System. ; T1: Nasopharynx, oropharynx or nasal cavity without parapharyngeal extension; T2: Parapharyngeal extension; T3: Bony structures of skull base and/or paranasal sinuses; N0: No regional lymph node metastasis; N1: Unilateral cervical, unilateral or bilateral retropharyngeal lymph nodes, above the supraclavicular fossa; ≤6 cm. ^dStage II includes T2N0 and the T1-2N1 subset; stage III includes T3N0 subset.