Reduced-volume radiotherapy versus conventional-volume radiotherapy after induction chemotherapy in nasopharyngeal carcinoma: An open-label, noninferiority, multicenter, randomized phase 3 trial

Abstract

Background: Nearly 90% locoregionally advanced nasopharyngeal carcinoma (LANPC) responds to induction chemotherapy (IC) with significant tumor volume shrinkage. Radiotherapy always follows IC, and reduced volume has been proposed. However, the efficacy and safety of reduced-volume radiotherapy is uncertain.

Methods: In this multi-center, noninferiority, randomized, controlled trial, patients with LANPC who completed IC were randomly assigned (1:1) to receive reduced-volume radiotherapy based on post-IC tumor volume (Post-IC group) or conventional volume radiotherapy based on pre-IC tumor volume (Pre-IC group). The primary endpoint was locoregional relapse-free survival, with a noninferiority margin of 8%. Secondary endpoints comprised adverse events, and quality of life (QoL).

Results: Between August 7, 2020, and May 27, 2022, 445 patients were randomly assigned to Post-IC (n = 225) or Pre-IC (n = 220) groups. The average volume receiving radical dose was 66.6 cm³ in Post-IC group versus 80.9 cm³. After a median follow-up of 40.4 months, the 3-year locoregional relapse-free survival was 91.5% in the Post-IC group versus 91.2%, with a difference of 0.3% (95% confidence interval -4.9% to 5.5%). The incidence of grade 3-4 radiation-related toxicity was lower in the Post-IC group including: acute mucositis (19.8% vs 34.1%), late otitis media (9.5% vs 20.9%) and late dry month (3.6% vs 9.5%). The Post-IC group had better QoL for global health status, physical functioning, emotional functioning, dry mouth and sticky saliva.

Conclusions: In this trial, reduced-volume radiotherapy was noninferior to conventional volume radiotherapy in locoregional relapse-free survival, and was associated with lower toxicities and improved QoL. (ClinicalTrials.gov identifier NCT04384627).

Keywords: clinical trial; nasopharyngeal carcinoma; noninferiority; reduced‐volume radiotherapy.

FIGURE 1

Flowchart of screening, randomization, and treatment. The intention‐to‐treat population comprised all randomly assigned patients. The safety population comprised all patients who received at least one fraction of their allocated radiotherapy schedule. *Four patients had disease progression after induction chemotherapy, four underwent previous therapeutic surgery to the neck or nasopharynx, three were without adequate hematologic function, two were without adequate renal function, two were without adequate liver function, two with lactation, two with previous malignancy, one with symptomatic heart failure, and one with symptomatic asthma. IC indicates induction chemotherapy; QLQ‐C30, the European Organization for Research and Treatment of Cancer Quality‐of‐Life Core 30‐item questionnaire; QLQ‐H&N35, the European Organization for Research and Treatment of Cancer Quality‐of‐Life Head and Neck 35‐item questionnaire; QOL, quality of life.

FIGURE 2

Kaplan–Meier curves of (A) locoregional relapse‐free survival, (B) overall survival, (C) distant metastasis‐free survival, (D) and failure–free survival in the intention‐to‐treat population. A stratified Cox proportional‐hazards model was used to calculate the hazard ratios and their associated 95% CIs. The stratified log‐rank test was used to calculate p values. All stratified analyses used the same stratification factors that were used for randomization (center and stage). CI indicates confidence interval; IC, induction chemotherapy.