Post Operative Adjuvant Therapy De-intensification Trial for Human Papillomavirus-related, p16+ Oropharynx Cancer

Inclusion Criteria:

* Patient must have histologically confirmed p16 positive squamous cell carcinoma of the oropharynx (OPSCC).
* Patient must have undergone transoral resection of their T1-4a oropharynx primary to a negative margin, and a neck dissection(s).
* Patient's disease must be pathological N-stage positive.
* Patient's disease must show extracapsular spread (ECS) in their nodal metastasis verified by central pathologist's review.
* Patients with synchronous primaries are included.
* Patients with unknown primaries are included if the diagnosis and resection of a primary site in the oropharynx is made from an endoscopic or robotic surgical procedure(s).
* Patients with recent excisional node biopsies/neck dissections are included if material is evaluable for extracapsular spread.
* Patient must be ≥ 21 years of age.
* ECOG performance status ≤ 2 (Karnofsky ≥60%).
* Patients must have normal organ and marrow function as defined below:

  * leukocytes ≥3,000/mcL
  * absolute neutrophil count ≥1,500/mcL
  * platelets ≥100,000/mcL
  * total bilirubin \<1.5 X upper normal institutional limit
  * AST(SGOT)/ALT(SGPT) ≤2.5 X institutional upper limit of normal
  * creatinine within normal institutional limits OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
* Patient (or legally authorized representative) must be able to understand and willing to sign a written informed consent document.

Exclusion Criteria:

* Patient must not have pathologically N stage negative disease.
* Patient must not have outside nodal tissue from previous neck biopsy/neck dissections in which ECS cannot be confirmed or denied.
* Patient must not have a true unknown primary in which permanent section results are negative for malignancy in completely excised ipsilateral oropharyngeal tissue (palatine and lingual tonsil).
* Patient must not have distant metastatic disease at presentation.
* Patient must not have gross residual and/or microscopic disease present after surgery including re-resection(s), per the operative and pathology report.
* Patient must not have transoral robotic surgery (TORS) for a T3 or T4 primary tumor.
* Patient must not have a history of prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; noninvasive cancers (for example, carcinoma in situ of the oral cavity, larynx, breast or cervix are all permissible) are permitted even if diagnosed and treated \< 3 years ago.
* Patient must not have had previous systemic chemotherapy for the study cancer. (Note: prior chemotherapy for a different cancer is allowable).
* Patient must not be receiving any other investigational agents.
* Patient must not have had any prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
* Patient must not have any life-threatening comorbid illnesses e.g. stroke with major sequelae or myocardial infarction/ unstable angina within the preceding 3 months or psychiatric illness/social situations that would limit compliance with study requirements.
* Patient must not be pregnant or breastfeeding. If a woman of childbearing potential, patient must agree to use medically acceptable forms of contraception.

Both men and women and members of all races and ethnic groups are eligible for this trial.