In general, patients with Human Papilloma Virus Positive Oropharyngeal Squamous Cell Carcinoma (HPVOPC) are curable, young and will live for prolonged periods. They are at high risk for long-term toxicity and mortality from therapy. While the long-term consequences of chemotherapy and surgery for head and neck cancer are relatively constrained, high-dose radiotherapy (RT) and chemoradiotherapy (CRT) substantially impact on local tissues and organ function and result in a significant rate of late mortality and morbidity in patients. Studies are now being designed to reduce the impact of RT and CRT for patients.

Patients with intermediate stage HPV positive oropharyngeal cancer will be screened for poor prognostic features and undergo robotic surgery. Patients in whom pathology demonstrates good prognosis features will then be followed without postoperative radiotherapy. Patients with subsequent recurrence will be treated with either surgery and postoperative radiotherapy or postoperative chemoradiotherapy alone. Patients with poor prognostic features (ECS, LVI, PNI) will receive reduced dose radiotherapy or chemoradiotherapy based on pathology. It is expected that over 50% of patients treated with surgery will have had a curative treatment and will avoid radiation therapy entirely and long-term survival will not be changed by withholding radiation therapy to good prognosis patients after surgery. There are exploratory biomarkers of risk of recurrence that will be collected and studied.

There are currently few trials examining the role of de-escalation using surgery alone in intermediate and early T-stage HPV related disease. New surgical techniques have broadened the range of patients capable of achieving a complete resection and the functional outcomes in such patients are outstanding. Furthermore, the sensitivity of HPVOPC to chemotherapy and radiotherapy raise the possibility that delayed or salvage treatment in early stage patients would be highly effective, would result in similar survival outcomes and radiotherapy could be applied to a much smaller population then current standards call for. Looked at from a different perspective, the need for post-operative radiotherapy in this younger, HPV+ and more functional population has not been validated in clinical trials to date.

Inclusion Criteria:

• Patients may be screened and consented if they display clinical features that are consistent with p16 positivity, they are p16+ but and not yet tested for p16 by IHC and for HPV by PCR and if they meet the other eligibility criteria. They will enter the experimental post-surgical portion of the study if they have surgery performed at MSSM and surgical specimens or biopsies proven to be both p16+ on IHC testing and HPV+ on PCR testing

• Participants must have histologically or cytologically confirmed and identified resectable primary squamous cell carcinoma of the oropharynx that is HPV 16 positive or positive for any high risk HPV subtype (i.e., 18, 33, 35, etc.) as determined by PCR at the central laboratory. Patients must have p16+ status as determined by IHC performed or reviewed at the central laboratory prior to consent. Both p16 and HPV status must be determined prior to post-surgical adjuvant treatment assignment. Tissue from the primary site must be available for biomarker studies after surgery.

• Stage 1, 2, 3 or early and intermediate stage IVa (T1N0-2B, T2N0-2B) (Level 2, non-matted) disease without evidence distant metastases or extracapsular extension. Primary site must be lateralized for a functional dissection.

• Age > 18 years.

• No previous surgery, radiation therapy or chemotherapy for SCCHN (other than biopsy or tonsillectomy) is allowed at time of study entry.

• ECOG performance status of 0 or 1.

• No active alcohol addiction (as assessed by medical caregiver).

• No active tobacco use (>10 years tobacco free interval, <20pk/yr. history)

• Ability to understand and the willingness to sign a written informed consent document.

• Participants must have adequate bone marrow, hepatic and renal functions as defined below:

  1. Hematology:

     • Neutrophil count > 1.5 x 109/l.
     • Platelet count > 100 x 109/l.
     • Hemoglobin > 10 g/dl (may achieve by transfusion).

  2. Renal function: > 60 ml/min (actual or calculated by the Cockcroft-Gault method) as follows:

     • CrCl (mL/min) = (140-age) (weight kg)
     • 72 x serum creatinine (mg/dL)
     • N.B. For females, use 85% of calculated CrCl value.
     • Or a Creatinine < the upper limits of normal

Exclusion Criteria:

• Patients < age 18.

• Pregnant or breast feeding women.

• Previous or current malignancies at other sites, with the exception of adequately treated in situ carcinoma of the cervix, basal or squamous cell carcinoma of the skin, thyroid cancer, or other cancer curatively treated by surgery and with no current evidence of disease for at least 5 years.

• Other serious illnesses or medical conditions including but not limited to:

  1. Unstable cardiac disease despite treatment, myocardial infarction with months prior to study entry.
  2. History of significant neurologic or psychiatric disorders including dementia or seizures
  3. Active clinically significant uncontrolled infection
  4. Active peptic ulcer disease defined as unhealed or clinically active
  5. Active drug addiction including alcohol, cocaine or intravenous drug use defined as occurring within the 6 months preceding diagnosis
  6. Chronic Obstructive Pulmonary Disease, defined as being associated with a hospitalization for pneumonia or respiratory decompensation within 12 months of diagnosis. This does not include obstruction from tumor
  7. Autoimmune disease requiring therapy, prior organ transplant, or known HIV infection
  8. Interstitial lung disease
  9. Hepatitis C by history
  10. Concurrent treatment with any other anticancer therapy.
  11. Participation in an investigational therapeutic drug trial within 30 days of study entry.

• Advanced Stage III,IV (N2C, N3) or surgically unresectable disease or disease that cannot be fully resected, obvious radiologic ECS, supraclavicular or matted metastatic disease, >3 cervical nodes. (These patients will be placed on the Quarterback trial due to advanced state of disease and poor prognostic features)

• HPV negative OPSCC as determined by determined by PCR.