Benefit of medial retropharyngeal nodal region sparing in nasopharyngeal carcinoma patients: the final answer?

Comment on Mao YP, Wang SX, Gao TS, et al. Medial retropharyngeal nodal region sparing radiotherapy versus standard radiotherapy in patients with nasopharyngeal carcinoma: open label, non-inferiority, multicentre, randomised, phase 3 trial. BMJ. 2023 Feb 6;380:e072133. The retropharyngeal lymph node region is considered, together with the level II lymph nodes, to be the first echelon nodes of the nasopharyngeal lymphatic drainage, as they are involved in approximately 70% of patients with lymph node metastases.1 Covering the whole retropharyngeal in radiotherapy volumes has been considered to be the standard in the nasopharyngeal carcinoma treatment,2 although there is some evidence to suggest that the rate of lymph node involvement in the medial part of the retropharyngeal region (MRLN), between the pharyngeal constrictor muscles and the prevertebral fascia, is very low, if not negligible, compared to the lateral retropharyngeal region. In a prospective study including 3100 patients, Wang and colleagues observed only 6 patients with involved lymph nodes in the MRLN (0.2%) among the 2679 (86.4%) patients who presented involved lymph nodes.3 Tang and colleagues reported no involved medial retropharyngeal lymph nodes in a retrospective cohort of 924 consecutive patients, while 73.5% (679 of 924 patients) presented a lateral retropharyngeal lymph node metastasis at the initial presentation.4 In another study, Lin and colleagues reported only 5 patients out of 959 patients (0.3%) with lymph node metastases located in the MRLN.5 Despite these rather reassuring data, only one retrospective study evaluating the feasibility of the omission of the MRLN existed until recently.6 In this retrospective case-control study, Pan and colleagues have observed no significant difference between the 2 groups of 183 patients in terms of 5 years-local relapse-free survival LRFS (94.8% vs 94.2%), regional relapse-free survival RRFS (98.3% vs 97.1%),distant metastasis-free survival DMFS (88.5% vs 86.7%), and overall survival OS (85.5% vs 84.7%) for the study group and the control groups respectively, and a significant reduction of the incidence of grade III acute oral mucositis in the study group.6 Mao and colleagues are to be commended for their randomized non-inferiority phase III trial that provided new and strong evidence regarding the pending question of the possible omission of MRLN radiotherapy and the potential benefits in terms of reduced toxicity and improved quality of life in patients with nasopharyngeal cancers.7 This study provides us with a number of valuable information, confirming the pre-existing data. In this well-designed trial, 568 patients were recruited between November 2017, and December 2018, and randomly allocated to the MRLN sparing radiotherapy group (n = 285 patients) and the standard radiotherapy group (n = 283). Radiotherapy delineation, plan, dose and schedule were performed according to the consensus guideline (70 Gy (2.12 Gy/fraction) to the planning target volume (PTV) of the gross tumor at the primary site and the involved regional lymph nodes, 66–70 Gy to the PTV of the involved cervical lymph nodes, 60–62 Gy to the PTV of the high risk clinical target volume (CTV), and 54–56 Gy to the PTV of the low risk CTV. The characteristics of the study population were wide. Stage III and IVa represented respectively 43% and 41% of the patients in the MRLN sparing radiotherapy group,and 46% and 44% in the standard radiotherapy group. Concurrent chemoradiotherapy and Induction chemotherapy followed by concurrent chemoradiotherapy represented respectively 34% and 58% of the patients in the MRLN sparing radiotherapy group, and 32% and 59% in the standard radiotherapy group. A pre-treatment EBV DNA test was available for 88% and 89% patients in the MRLN sparing group and the standard group respectively. The primary endpoint was the three year local relapse-free survival defined as any relapse in the primary site and in the retropharyngeal lymph node region, or death from any cause. Sparing the MRLN allowed to decrease the dose to the superior and middle pharyngeal constrictors. The authors have reached their primary objective and have shown that MRLN sparing radiotherapy is non-inferior to standard radiotherapy, with a three year local relapse-free survival of 95.3% (95% confidence interval 92.8 to 97.8) in the MRLN sparing radiotherapy group, and 95.5% (93.0 to 98.0) in the standard radiotherapy group (estimated absolute difference –0.2% (lower boundary of the one-sided 97.5% confidence interval of –3.6, which is not greater than the predefined non-inferiority margin of –8%). This result was consistent in multivariate and subgroup analyses taking into account the stage of the disease, the type of chemotherapy regimen, and the quantification of EBV DNA at baseline. Only six patients (1.1%) presented a lymph node recurrence in the retropharyngeal region, but none in the MRLN. OS, DMFS, and RRFS were not significantly different between the MRLN sparing radiotherapy group and the standard radiotherapy group (95.2% vs 96.4%, 89.7% vs 92.3%, 96.9% vs 94.0% respectively). The lower DMFS observed in the sparing radiotherapy group while the RRFS seemed better (HR 0.67, P = 0.28) may probably be explained by randomness. Finally, sparing MRLN has shown to decrease the 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), and to significantly improve quality of life on multiple domains such as global health status, role functioning, social functioning, fatigue and swallowing. Overall, this study provides a high level of evidence regarding the feasibility of sparing MRLN and the potential benefit on patient quality of life by reducing treatment toxicity. These results thus make it possible to envisage a new lever of action for radiation oncologists, making it possible to improve the tolerance of the treatment, which is important in this population where the prognosis is rather good, and the survival rather long. They are part of the de-escalation approach along with the studies showing the possibility to spare the level IV and Vb of the uninvolved neck of N0-N1 nasopharyngeal cancer patients8 or the studies showing the benefit of elective irradiation to neck level Ib.9 This study has the added advantage of showing the possibility of omitting MRLN irradiation in virtually all patients with cavum cancer, regardless of their stage. Some few questions are still pending such as the generalizability of these findings to a non-endemic nasopharyngeal carcinoma cohort population, and the compatibility of the MRLN sparing with other de-escalate approaches such as dose de-escalation. However, we do believe that the results provided by Mao and colleagues’ study need to be consider in future guidelines of nasopharyngeal non-keratinising carcinoma. In the future, the implementation of even more conformal radiotherapy techniques, such as proton therapy, will certainly allow to gain more benefit of the sparing of MRLN through further dose reduction to the swallowing structures.