Precision Radiotherapy: Reduction in Radiation for Oropharyngeal Cancer in the 30 ROC Trial.

Abstract

BACKGROUND\nPatients with human papillomavirus-related oropharyngeal cancers have excellent outcomes but experience clinically significant toxicities when treated with standard chemoradiotherapy (70\u2009Gy). We hypothesized that functional imaging could identify patients who could be safely deescalated to 30\u2009Gy of radiotherapy.\n\n\nMETHODS\nIn 19 patients, pre- and intratreatment dynamic fluorine-18-labeled fluoromisonidazole positron emission tomography (PET) was used to assess tumor hypoxia. Patients without hypoxia at baseline or intratreatment received 30\u2009Gy; patients with persistent hypoxia received 70\u2009Gy. Neck dissection was performed at 4\u2009months in deescalated patients to assess pathologic response. Magnetic resonance imaging (weekly), circulating plasma cell-free DNA, RNA-sequencing, and whole-genome sequencing (WGS) were performed to identify potential molecular determinants of response. Samples from an independent prospective study were obtained to reproduce molecular findings. All statistical tests were 2-sided.\n\n\nRESULTS\nFifteen of 19 patients had no hypoxia on baseline PET or resolution on intratreatment PET and were deescalated to 30\u2009Gy. Of these 15 patients, 11 had a pathologic complete response. Two-year locoregional control and overall survival were 94.4% (95% confidence interval = 84.4% to 100%) and 94.7% (95% confidence interval = 85.2% to 100%), respectively. No acute grade 3 radiation-related toxicities were observed. Microenvironmental features on serial imaging correlated better with pathologic response than tumor burden metrics or circulating plasma cell-free DNA. A WGS-based DNA repair defect was associated with response (P\u2009=\u2009.02) and was reproduced in an independent cohort (P\u2009=\u2009.03).\n\n\nCONCLUSIONS\nDeescalation of radiotherapy to 30\u2009Gy on the basis of intratreatment hypoxia imaging was feasible, safe, and associated with minimal toxicity. A DNA repair defect identified by WGS was predictive of response. Intratherapy personalization of chemoradiotherapy may facilitate marked deescalation of radiotherapy.