De-escalated Radiation for Human Papillomavirus-Positive Squamous Cell Carcinoma of the Oropharynx

Inclusion Criteria: * Pathologically (histologically or cytologically) proven (from primary lesion and/or lymph nodes) diagnosis of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma. HPV-positivity will be defined as tumors that are p16-positive by immunohistochemistry. Numerous studies have demonstrated near 100% agreement between p16 and HPV for patients with oropharyngeal cancer. As such, the use of p16 has been accepted as an appropriate surrogate for HPV status. * Clinical stage I, II, or III disease (AJCC Eighth Edition); Note: Patients with M1 tumors (distant metastases) are not eligible; * History/physical examination within 6 weeks prior to registration, including assessment of weight and recent weight loss; * Age ≥ 18; * PET/CT within 6 weeks prior to registration; * Patients must sign a study-specific informed consent form prior to study entry. * Both men and women and members of all races and ethnic groups are eligible for this trial. Non-English speaking, deaf, hard of hearing and illiterate individuals are eligible for this trial. Exclusion Criteria: * Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; * Patients who have had initial surgical treatment other than the diagnostic biopsy of the primary site or nodal sampling of the neck disease are excluded; * Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable; * Rece…