Medial retropharyngeal nodal region sparing radiotherapy versus standard radiotherapy in patients with nasopharyngeal carcinoma: open label, non-inferiority, multicentre, randomised, phase 3 trial

Abstract

Objectives To address whether sparing the medial retropharyngeal lymph node (MRLN) region from elective irradiation volume provides non-inferior local relapse-free survival versus standard radiotherapy in patients with nasopharyngeal carcinoma. Design Open-label, non-inferiority, multicentre, randomised, phase 3 trial. Setting Three Chinese hospitals between 20 November 2017 and 3 December 2018. Participants Adults (18-65 years) with newly diagnosed, non-keratinising, non-distant metastatic nasopharyngeal carcinoma without MRLN involvement. Interventions Randomisation was done centrally by the Clinical Trials Centre at Sun Yat-sen University Cancer Center. Eligible patients were randomly assigned (1:1; block size of four) to receive MRLN sparing radiotherapy or standard radiotherapy (both medial and lateral retropharyngeal lymph node groups), and stratified by institution and treatment modality as follows: radiotherapy alone; concurrent chemoradiotherapy; induction chemotherapy plus radiotherapy or concurrent chemoradiotherapy. Main outcome measures Non-inferiority was met if the lower limit of the one sided 97.5% confidence interval of the absolute difference in three year local relapse-free survival (MRLN sparing radiotherapy minus standard radiotherapy) was greater than −8%. Results 568 patients were recruited: 285 in the MRLN sparing radiotherapy group; 283 in the standard radiotherapy group. Median follow-up was 42 months (interquartile range 39-45), intention-to-treat analysis showed that the three year local relapse-free survival of the MRLN sparing radiotherapy group was non-inferior to that of the standard radiotherapy group (95.3% v 95.5%, stratified hazard ratio 1.04 (95% confidence interval 0.51 to 2.12), P=0.95) with a difference of −0.2% ((one sided 97.5% confidence interval –3.6 to ∞), P non-inferiority <0.001). In the safety set (n=564), the sparing group had a lower incidence of grade ≥1 acute dysphagia (25.5% v 35.1%, P=0.01) and late dysphagia (24.0% v 34.3%, P=0.008). Patient reported outcomes at three years after MRLN sparing radiotherapy were better in multiple domains after adjusting for the baseline values: global health status (mean difference −5.6 (95% confidence interval –9.1 to –2.0), P=0.002), role functioning (−5.5 (–7.4 to –3.6), P<0.001), social functioning (−6.2 (–8.9 to –3.6), P<0.001), fatigue (7.9 (4.0 to 11.8), P<0.001), and swallowing (11.0 (8.4 to 13.6), P<0.001). The difference in swallowing scores reached clinical significance (>10 points difference). Conclusion Compared with standard radiotherapy, MRLN sparing radiotherapy showed non-inferiority in terms of risk of local relapse with fewer radiation related toxicity and improved patient reported outcomes in patients with non-metastatic nasopharyngeal carcinoma. Trial registration ClinicalTrials.gov NCT03346109

Knowing nodal Rouviére: the power of human intelligence in toxicity reduction

“…Much less effort has been put into the artistry of oncology, such as refining the delineation of target volumes in radiation planning, albeit a significantly less cost-effective and labor-intensive approach [3][4][5][6]. Recently, Mao et al [7], in a multicenter randomized phase III trial, demonstrated how sparing of the medial retropharyngeal nodal group alone in radiation planninga process that solely relies on human intelligence without any additional human effort or technological resources -results in 39% reduction in ≥ grade one clinician-rated acute dysphagia and 24% reduction in ≥ grade one weight loss. In addition, there was a significant improvement in patient-reported quality-of-life outcomes at 3 years, such as global health status, role-social function and swallowing function.…”

“…In a study of 3,100 newly diagnosed NPC, using contemporary MRI techniques, medial PRLN involvement was only identified in 0.2% of the patients, and they were all located at the level of the second or third cervical vertebra [8]. The group by Mao et al [7], by leveraging and transferring the knowledge of lymphatic development and pattern of tumor spread -human intelligence -into clinical treatment planning and toxicity reduction.…”

“…No recurrence was observed in the medial RPLN sparing group. After adjusting for covariates, the regional relapse‐free survival rates were similar in medial RPLN sparing and the medial RPLN non‐sparing groups [ 7 ].…”

“…In the study by Mao et al. [ 7 ], utilizing the medial RPLN sparing approach, the mean dose to the middle pharyngeal constrictors decreased from 54 Gy to 49 Gy. Why would such a mild decrease in dose result in such modest improvement in clinician‐ and patient‐rated swallowing function?…”

“…The group by Mao et al. [ 7 ], by leveraging and transferring the knowledge of lymphatic development and pattern of tumor spread – human intelligence – into clinical treatment planning and toxicity reduction.…”