High Recurrence for HPV-Positive Oropharyngeal Cancer With Neoadjuvant Radiation Therapy to Gross Disease Plus Immunotherapy: Analysis From a Prospective Phase Ib/II Clinical Trial

Human papillomavirus (HPV) is the most common cause of oropharyngeal squamous cell carcinoma (OPSCC) in the United States. 1 Mahal BA Catalano PJ Haddad RI et al. Incidence and demographic burden of HPV-associated oropharyngeal head and neck cancers in the United States. Cancer Epidemiol Biomarkers Prev. 2019; 28: 1660-1667 Crossref PubMed Scopus (96) Google Scholar Conventional radiation therapy, although effective, is associated with high rates of morbidity. 2 Machtay M Moughan J Trotti A et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: An RTOG analysis. J Clin Oncol. 2008; 26: 3582-3589 Crossref PubMed Scopus (1058) Google Scholar Various deintensification strategies include decreasing the radiation dose to the primary lesion 3 Yom SS Torres-Saavedra P Caudell JJ et al. Reduced-dose radiation therapy for HPV-associated oropharyngeal carcinoma (NRG Oncology HN002). J Clin Oncol. 2021; 39: 956-965 Crossref PubMed Scopus (136) Google Scholar and reducing regional lymph node dose to 30 to 40 Gy. 4 Tsai CJ McBride SM Riaz N et al. Evaluation of substantial reduction in elective radiotherapy dose and field in patients with human papillomavirus-associated oropharyngeal carcinoma treated with definitive chemoradiotherapy. JAMA Oncol. 2022; 8: 364-372 Crossref PubMed Scopus (0) Google Scholar ,5 Maguire PD Neal CR Hardy SM Schreiber AM. Single-arm phase 2 trial of elective nodal dose reduction for patients with locoregionally advanced squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2018; 100: 1210-1216 Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar However, regardless of dose, elective nodal radiation is always pursued. Large volume neck irradiation (even to a low dose) could be omitted in many patients treated with definitive surgery, but the risk of high-risk pathologic features mandating large volume adjuvant irradiation would persist in a large subset of patients. 6 Kaczmar JM Tan KS Heitjan DF et al. HPV-related oropharyngeal cancer: Risk factors for treatment failure in patients managed with primary transoral robotic surgery. Head Neck. 2016; 38: 59-65 Crossref PubMed Scopus (54) Google Scholar Given the efficacy of immunotherapy in the metastatic/unresectable recurrent setting and evidence supporting radiation therapy as an immune adjuvant, 7 Formenti SC Demaria S. Combining radiotherapy and cancer immunotherapy: A paradigm shift. J Natl Cancer Inst. 2013; 105: 256-265 Crossref PubMed Scopus (755) Google Scholar neoadjuvant immunotherapy and radiation therapy may eliminate the need for large volume irradiation. We hypothesized that treating gross disease only with neoadjuvant stereotactic body radiation therapy (SBRT) in combination with durvalumab and tremelimumab before surgery followed by maintenance durvalumab would have noninferior tumor control (progression-free survival [PFS] 85% at 2 years) compared with conventional large-field adjuvant radiation therapy ± concurrent chemotherapy in patients with locally advanced HPV + OPSCC.