Biomarker-Driven Radiation Therapy Dose Reduction After Transoral Robotic Surgery for the Treatment of HPV-Positive Oropharyngeal Cancer

Inclusion Criteria: * Age \>= 18 years. * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%). * Life expectancy \> 12 weeks as determined by the Investigator. * Has diagnosis of HPV-associated squamous cell carcinoma of the oropharynx * HPV positive either via p16 status or via in situ hybridization * This includes patients with HPV positive squamous cell carcinoma of an unknown primary of the head and neck presumed to be of oropharyngeal origin who have undergone ipsilateral palatine and lingual tonsillectomies. * pT1-2, pN0-1, cM0 disease. * Positive ctHPVDNA titer prior to surgery. * =\< 10 pack-year smoking history. * Completed transoral robotic surgery (TORS) oropharyngectomy and at least ipsilateral neck dissection by an Emory otolaryngologist. * Pathology must demonstrate at least one of the follow intermediate risk factors: * Close margin (1 - 4 mm) * Perineural invasion * Lymphovascular space invasion * 2 - 4 positive lymph nodes without extranodal extension (ENE) * A single positive lymph node \> 3 cm in size, without ENE * Pathology cannot demonstrate \> 4 positive lymph nodes, ENE, or a positive final margin (defined as \< 1 mm). Margins that have been subsequently cleared are allowed. * Radiation increases the risk of birth defects. For this reason, females of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to starting therapy. * FCBP and men must agree to use adequate co…