By Jacob Wynne, MD, Medical College of Wisconsin
Hypofractionated radiotherapy regimens developed over the past two decades have substantially improved access to curative therapy for several common malignancies, most notably those of the prostate and breast. However, historical understanding of the relative effects of single and double hit DNA damage in head and neck squamous cell carcinoma (characterized by a high alpha/beta ratio) have prevented the development of isoeffective isotoxic hypofractionated treatment schedules for this disease.
Lester et al. address this gap with the first report from the Headlight Trials: Postoperative Hypofractionated Proton Therapy for Head and Neck Cancers Unrelated to HPV, substantiating hypotheses articulated in a thought-provoking editorial printed in the International Journal of Radiation Oncology, Biology, Physics in 2024.1
Seventy-five patients with newly diagnosed HPV-unrelated squamous cell carcinoma of the oral cavity, oropharynx, larynx or hypopharynx; salivary gland tumors; or skin cancers with indications for nodal treatment were enrolled and treated to 43.5 Gy in 15 fractions to the operative bed and involved nodal areas with elective nodal irradiation to 40.05 Gy in 15 fractions. A simultaneous integrated boost to 45 Gy was allowed for positive margins. Concurrent weekly chemotherapy was also allowed. Patients with pathologic T3/T4a (79%) and pathologic N1+ (67%) oral cavity (75%) and salivary gland (15%) tumors were best represented among those enrolled, as may be expected in a post-operative cohort. 93% completed radiation within 18 – 21 days and 17% received chemotherapy.
Two-year LRR was 12% (95% CI: 5.6-21.6), demonstrating non-inferiority to historical control. Two-year DFS was 66% (95% CI 55.9-78.7), two-year OS was 84% (95% CI 75.8-93.2). G3+ acute adverse events occurred in 28%. 8% experienced weight loss > 10% of baseline by three weeks post-treatment. Four required PEG tubes post-operatively; 8.5% required them during or after radiation. There was one death during radiation therapy from a myocardial infarction in a patient with known cardiovascular disease. G3+ solicited toxicity occurring more than 30 days from radiation completion occurred in six patients.
Post-operative therapy can cause daunting side effects, including mucositis-related pain and weight loss requiring parenteral nutrition. Patients with HPV-unrelated HNSCC often present with complex medical histories, significant comorbidities and socioeconomic challenges that limit their ability to complete recommended therapies. This work represents meaningful progress in establishing the efficacy and tolerability of hypofractionated proton therapy among the population most likely to benefit. A hypofractionated course promises to improve access, and Dr. Lester is hopeful it may also reduce the duration of toxicity. Proton therapy further offers greater sparing of uninvolved lymphatics, potentially increasing the therapeutic ratio as immunotherapy is established as a fourth treatment modality for this disease.
In this work, hypofractionated proton therapy demonstrated non-inferior locoregional recurrence risk compared to a historical control, was effective, and was well-tolerated for postoperative treatment of head and neck cancers. Sensitive to the limitations of regional access to proton therapy, the investigators have completed enrollment on related studies utilizing VMAT delivery in the definitive and post-operative settings, which are currently maturing. We look forward with optimism to the final results of these and other related trials of hypofractionated radiotherapy in squamous cell carcinomas of the head and neck.
References
Abstract 258, First Report from the Headlight Trials: Postoperative Hypofractionated Proton Therapy for Head and Neck Cancers Unrelated to HPV, was presented during SS 30 – Optimizing Therapy, Toxicity, and Supportive Care in Head & Neck Cancers, at ASTRO's 68th Annual Meeting.
Published on: September 30, 2026
