Study of De_Intensified Postoperative Radiation Therapy for HPV Associated Oropharyngeal Squamous Cell Carcinoma

Inclusion Criteria:

* Histologically or cytologically confirmed squamous cell carcinoma of the tonsil or base of tongue (oropharynx) or unknown primary with p16-positive cervical lymph node metastases
* HPV-associated tumor as defined by: positive p16 immunohistochemistry (\>70%) OR in situ hybridization OR PCR-based methods
* Eligible for curative-intent surgery with anticipated negative margins
* Surgery performed at Brigham \& Women's Hospital
* Age 18 or older years.
* ECOG performance status 0-1 (Karnofsky ≥70%, see Appendix A)
* Normal organ and marrow function as defined below:

  * leukocytes ≥3,000/mcL
  * absolute neutrophil count ≥1,000/mcL
  * platelets ≥100,000/mcL
  * total bilirubin within normal institutional limits
  * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
  * creatinine ≤ 1.5 times the institutional upper limit of normal OR
  * creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.
* Patients with ≤20 pack-years of cumulative cigarette smoking. Pack-years are calculated by multiplying the number of years smoked with the pack of cigarettes smoked per day. One pack is considered to contain 20 cigarettes.
* Tumor clinical stage (AJCC 8th edition): T0 or T1 or T2
* Nodal clinical stage (AJCC 8th edition): N0 or N1
* No distant metastases. Clinical M-stage must be M0 (AJCC 8th edition).
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Prior history of head and neck cancer within 5 years.
* Prior head and neck radiation
* Clinically fixed or matted nodes
* 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. Note: that HIV positive patients will be eligible.
* Pregnant women are excluded from this study because of the teratogenic risks of radiation exposure to the developing fetus. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with radiation therapy and supportive care medications required for symptomatic management of head and neck cancer side effects as well as general anesthesia required for oncologic head and neck surgery, breastfeeding should be discontinued if the mother is enrolled in the study. Pregnancy status will be determined by a serum pregnancy test.