Postoperative Radiotherapy ± Cetuximab for Intermediate-Risk Head and Neck Cancer
Authors: Machtay Mitchell , Torres-Saavedra Pedro A. , Thorstad Wade , Nguyen-Tân Phuc Felix , Siu Lillian L. , Holsinger F. Christopher , El-Naggar Adel , Chung Christine , Cmelak Anthony , Burtness Barbara , Bednarz Greg , Quon Harry , Breen Stephen L. , Gwede Clement K. , Dicker Adam P. , Yao Min , Jordan Richard C. , Dorth Jennifer , Lee Nancy , Chan Jason W. , Dunlap Neal , Bar-Ad Voichita , Stokes William A. , Chakravarti Arnab , Sher David , Rao Shyam , Harris Jonathan , Yom Sue S. , Le Quynh-Thu ,   on behalf of NRG Oncology RTOG 0920 Collaborating Team, Bar-Ad Voichita , Bednarz Greg , Bowles Daniel W. , Breen Stephen , Burtness Barbara , Chakravarti Arnab , Chan Jason , Chung Christine , Cmelak Anthony , Dicker Adam P. , Dorth Jennifer , Dunlap Neal , El-Naggar Adel , Gwede Clement K. , Harris Jonathan , Holsinger F. Christopher , Jones Christopher U. , Jordan Richard C. , Krempl Greg A. , Le Quynh-Thu , Lee Nancy , Lominska Christopher , Ma Daniel J. , Machtay Mitchell , Mell Loren K. , Nguyen-Tan Phuc Felix , Quon Harry , Raben Adam , Rao Shyam , Samuels Stuart , Sher David , Siu Lillian L. , Spencer Sharon , Stokes William A. , Takiar Vinita , Thorstad Wade , Torres-Saavedra Pedro , Wilke Christopher T. , Yao Min , Yom Sue S. , Young Melissa R. 
Published: January 2025

PURPOSE
Radiotherapy (RT)/cetuximab (C) demonstrated superiority over RT alone for locally advanced squamous head and neck cancer. We tested this in completely resected, intermediate-risk cancer.

METHODS
Patients had squamous cell carcinoma of the head and neck (SCCHN) of the oral cavity, oropharynx, or larynx, with one or more risk factors warranting postoperative RT. Patients were randomly assigned 1:1 to intensity-modulated RT (60-66 Gy) with once-per-week C or RT alone. The primary hypothesis was that RT + C would improve overall survival (OS) in randomly assigned/eligible patients, with a prespecified secondary plan to test this in the human papillomavirus (HPV)–negative subpopulation. Disease-free survival (DFS) and toxicity were secondary end points. OS and DFS were tested via stratified log-rank test; toxicity was compared via Fisher's exact test.

RESULTS

We enrolled 702 patients from November 2009 to March 2018; 577 were randomly assigned/eligible. Most (63.6%) had oral cavity cancer and most (84.6%) had high epidermal growth factor receptor expression. There were fewer deaths (184) than expected. OS (median follow up, 7.2 years) was not significantly improved (hazard ratio [HR], 0.81; one-sided
P
= .0747; 5-year OS 76.5%
v
68.7%), but DFS was (HR, 0.75; one-sided
P
= .0168; 5-year DFS 71.7%
v
63.6%). Benefit of RT + C was only seen in the HPV-negative subpopulation (80.2% of patients in the trial). Grade 3-4 acute toxicity rates were 70.3% (RT + C) versus 39.7% (RT; two-sided
P
< .0001), mostly skin and/or mucosal effects. Late grade ≥3 toxicity rate was 33.2% (RT + C) versus 29.0% (RT; two-sided
P
= .3101). There were no grade 5 toxicities in either arm.

CONCLUSION
RT + C significantly improved DFS, but not OS, with no increase in long-term toxicity, compared with RT alone for resected, intermediate-risk SCCHN. RT + C is an appropriate option for carefully selected patients with HPV-negative disease.