Abstract
OBJECTIVE: To determine the pre-specified long term efficacy (survival and swallowing function) and safety of medial retropharyngeal lymph node (MRLN) region sparing radiotherapy for non-metastatic nasopharyngeal carcinoma. DESIGN: Pre-specified five year analysis of an open label, non-inferiority, multicentre, randomised phase 3 trial. SETTING: Three Chinese medical centres between 20 November 2017 and 3 December 2018. PARTICIPANTS: Adults (18-65 years) with untreated, non-keratinising, non-metastatic nasopharyngeal carcinoma without MRLN involvement. INTERVENTIONS: Eligible patients were randomised (1:1; block size of four) to MRLN sparing radiotherapy or standard radiotherapy. Randomisation was stratified by institution and treatment modality (radiotherapy alone, concurrent chemoradiotherapy, or induction chemotherapy plus radiotherapy or concurrent chemoradiotherapy). MAIN OUTCOME MEASURES: The primary outcome was local relapse-free survival. The three year local relapse-free survival to assess the non-inferiority, with a margin of 8%, of MRLN sparing radiotherapy compared with standard radiotherapy has been reported previously. This updated report focuses on five year survival, toxicity, and quality of life. Additionally, a videofluoroscopic swallowing study and magnetic resonance imaging (MRI) measurements of pharyngeal contractors were used as objective measures of dysphagia RESULTS: This trial enrolled 285 patients in the MRLN sparing group and 283 patients in the standard group. At a median follow-up of 70 months, the MRLN sparing and standard groups had similar five year local relapse-free survival (89.2% (95% confidence interval (CI) 85% to 92%) versus 90.6% (87% to 94%); stratified hazard ratio 1.03 (95% CI 0.61 to 1.74); P=0.90) and overall survival (89.2% (85% to 93%) versus 90.3% (87% to 94%); stratified hazard ratio 1.06 (0.68 to 1.68); P=0.79). Updated safety profiles of the MRLN sparing group showed a lower rate of grade ≥1 dysphagia (45/206 (22%) v 70/216 (32%); P=0.01) and grade ≥2 dry mouth (33/206 (16%) v 55/216 (25%); P=0.02) and enhanced swallowing related quality of life (mean difference -11.9; P<0.001). Videofluoroscopy showed a lower prevalence of vallecular residue (49/66 (74%) v 62/62 (100%); P<0.001), pyriform sinus residue (32/66 (48%) v 45/62 (73%); P=0.01), coating of pharyngeal wall (7/66 (11%) v 17/62 (27%); P=0.01), pharyngeal transit time >1.0 s (1/66 (2%) v 7/62 (11%); P=0.03), and aspiration (8/66 (12%) v 18/62 (29%); P=0.03) in the MRLN sparing group. Additionally, MRI detectable late atrophy in the superior pharyngeal constrictor (mean thickness: 1.80 v 1.65 mm; P=0.005) and middle pharyngeal constrictor (2.34 v 2.15 mm; P=0.01) was less severe after MRLN sparing radiotherapy. CONCLUSIONS: MRLN sparing radiotherapy maintained uncompromised efficacy and better long term swallowing function by reducing radiation damage to pharyngeal contractors, supporting its use as a standard of care for non-metastatic nasopharyngeal carcinoma. TRIAL REGISTRATION: ClinicalTrials.gov NCT03346109.