Re-examining post-operative chemoradiotherapy in head and neck cancer: an updated long-term combined analysis of RTOG 9501/EORTC 22931.

Background: Post-operative chemoradiation (CRT) is generally recommended for head and neck cancer patients with extranodal extension (ENE) and/or positive margins, but not for patients without these features, based on a post hoc analysis of Radiation Therapy Oncology Group (RTOG) 9501 and European Organisation for Research and Treatment of Cancer (EORTC) 22931. However, this analysis lacked tests of interaction necessary to identify a predictive biomarker. In addition, updated data are now available.

Patients and methods: This study assessed 744 patients enrolled on RTOG 9501 and EORTC 22931, randomized trials that compared CRT with radiation (RT) following surgery. Overall survival (OS) was analyzed with Cox regression. Cancer-specific mortality (CSM), other-cause mortality (OCM), and recurrence outcomes were analyzed with competing risks methodology. Tests of interaction assessed for differential benefits of CRT in various subgroups.

Results: Median follow-up was 6.9 years. Among all patients, CRT improved OS [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.68-0.97, P = 0.026]. Although CRT improved OS in the subgroup with ENE and/or positive margins (HR 0.71, 95% CI 0.57-0.89, P = 0.003) and not in those without these features (HR 0.94, 95% CI 0.68-1.30, P = 0.7), tests of interaction showed no evidence of a differential effect of CRT in these subgroups (P-interaction = 0.17). There was also no evidence of interaction when analyzing other outcomes, or when assessing ENE and margin status individually. While CRT significantly reduced CSM (HR 0.68, 95% CI 0.55-0.83, P < 0.001), it also significantly increased OCM (HR 1.51, 95% CI 1.07-2.12, P = 0.018). Post-operative CRT improved locoregional recurrence (HR 0.64, 95% CI 0.48-0.85, P = 0.002), but not distant metastasis (HR 0.83, 95% CI 0.64-1.08, P = 0.17).

Conclusions: Concurrent chemotherapy improved OS in head and neck cancer patients undergoing post-operative radiotherapy in the combined populations of EORTC 22931 and RTOG 9501. ENE and/or positive margins are not predictive biomarkers, and patients without these features may still benefit from CRT. CRT improved CSM, but this was partly offset by higher OCM. Refining the population most likely to benefit from post-operative CRT, taking into consideration both oncologic and patient-related factors, needs further exploration.