Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2025 Nov;36(11):1379-1388.
doi: 10.1016/j.annonc.2025.07.004. Epub 2025 Jul 16.

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

Z S Zumsteg  1 , M Luu  2 , C Fortpied  3 , J K Jang  4 , M M Chen  5 , J Mallen-St Clair  6 , E Walgama  6 , Q T Le  7 , M Machtay  8 , S Tribius  9 , A Forastiere  10 , S Wong  11 , E M Ozsahin  12 , V Gregoire  13 , J B Vermorken  14 , A S Ho  7 , S S Yom  15
Affiliations
Randomized Controlled Trial

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

Z S Zumsteg et al. Ann Oncol. 2025 Nov.

Abstract

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.

Keywords: chemoradiation; head and neck cancer; post-operative.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest related to this work. JBV has consults/advisory relationships with Merck-Serono, PCI Biotech, AVEO Pharmaceuticals, Cue Biopharma, Nanobiotix, NEKTAR, and WntResearch. ZSZ’s spouse previously did legal work for Johnson & Johnson, Merck, Boehringer Ingelheim, and Allergan through her law firm. All other authors have no disclosures.

References

    1. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004. May 6;350(19):1945–52. - PubMed
    1. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004. May 6;350(19):1937–44. - PubMed
    1. Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2012. Dec 1;84(5):1198–205. doi: 10.1016/j.ijrobp.2012.05.008. Epub 2012 Jun 30. - DOI - PMC - PubMed
    1. Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005. Oct;27(10):843–50. - PubMed
    1. Polley MY, Freidlin B, Korn EL, Conley BA, Abrams JS, McShane LM. Statistical and practical considerations for clinical evaluation of predictive biomarkers. J Natl Cancer Inst 2013. Nov 20;105(22):1677–83. - PMC - PubMed

Publication types

LinkOut - more resources