Patients with human papillomavirus (HPV) or its surrogate marker p16, positive oropharyngeal squamous cell carcinoma (hereafter p16+OPSCC) exhibit favorable overall survival rates of 70-100% at 3 years. These outcomes are dependent on disease burden and patient characteristics and independent of treatment modality. Significant treatment related side effects exist despite advances in radiotherapy technology, surgical techniques, and supportive care. In addition to common acute toxicities, their favorable overall survival potentially places these patients at increased risk for developing long-term treatment-induced side-effects. Therefore, it is important to establish novel management approaches that maintain excellent current clinical outcomes while effectively reducing acute and long-term side effects.

The de-escalation trials for surgical management have explored various combinations of dose-reduction, while preserving favorable oncologic outcomes for patients. Prospective trials have demonstrated efficacy, safety, and functional benefit following treatment reduction to the primary tumor, regional lymph node metastasis, and the elective nodal volume. Therefore, newer approaches of combining the treatment modifications from each of these treatment fields offer the potential to have substantial harm reduction for future patients.

Cell free HPV tumor DNA (ctDNA) has emerged as a method to monitor the presence of disease and is a promising biomarker. Changes in expression of ctDNA post treatment with TransOral Robotic Surgery (TORS) or radiation therapy (RT) with or without chemotherapy are observed and clearance of ctDNA is associated with a favorable prognosis. These promising findings have led several groups to initiate clinical trials evaluating observation in patients after definitive oropharyngeal cancer removal and subsequent clearance of ctDNA levels. Data suggests that patients who initially undergo observation following TORS have similar rates of distant metastases and favorable rates of salvage. To date, an observation-based approach has not been adopted for intermediate risk patients due to challenges identifying optimal cohorts for observation and concern for increased treatment related toxicity for patients who do require salvage. In this trial, the investigators propose use of ctDNA clearance to identify patients who are optimal for observation. This protocol tests the hypothesis that patients currently recommended for adjuvant RT based on intermediate risk factors can be observed post-TORS when ctDNA is cleared.

Patients with p16+OPSCC who are candidates for surgery (TORS) and have positive ctDNA will be offered registration for the study prior to surgical resection. After TORS, all patients will have ctDNA drawn within 2-14 days post operatively. Combined with pathological criteria, all patients will be stratified into one three risk groups; low risk, intermediate risk, high risk. The low risk group will be observed (no radiation) per standard of care (SOC). The intermediate group (intermediate pathological features and negative ctDNA) will also be observed (no radiation) per the experimental arm. The high risk group will receive adjuvant treatment (RT +/- chemotherapy) per SOC.