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 contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 12 months after completion of radiation. A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months.
* Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions.
* Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation.

Exclusion Criteria:

* Patients with a prior history of malignancy in the last two years (excluding non- melanomatous skin cancer).
* Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier (i.e., have residual toxicities \> grade 1).
* Patients who are receiving any other investigational agents or an investigational device within 21 days before administration of first dose of study drugs.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Significant cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association class 3 or 4 congestive heart failure; or uncontrolled grade \>= 3 hypertension (diastolic blood pressure \>= 100 mmHg or systolic blood pressure \>= 160 mmHg) despite antihypertensive therapy.