Transoral Surgery Followed By Low-Dose or Standard-Dose Radiation Therapy With or Without Chemotherapy in Treating Patients With HPV Positive Stage III-IVA Oropharyngeal Cancer

Inclusion Criteria:

Registration to Surgery (Arm S)

   - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

   - Patients must have newly diagnosed, histologically or cytologically confirmed squamous
   cell carcinoma or undifferentiated carcinoma of the oropharynx; patients must have
   been determined to have resectable oropharyngeal disease; patients with primary tumor
   or nodal metastasis fixed to the carotid artery, skull base or cervical spine are not
   eligible

   - Patients must have American Joint Committee on Cancer (AJCC) TNM tumor stage III, IV
   a, or IV b (with no evidence of distant metastases) as determined by imaging studies
   (performed < 30 days prior to pre-registration) and complete head and neck exam; the
   following imaging is required: computed tomography (CT) scan with IV contrast or
   magnetic resonance imaging (MRI)

   - Patients must have biopsy-proven p16+ oropharynx cancer; the histologic evidence of
   invasive squamous cell carcinoma may have been obtained from the primary tumor or
   metastatic lymph node. It is required that patients have a positive p16 IHC (as
   surrogate for HPV) status from either the primary tumor or metastatic lymph node.

   - Carcinoma of the oropharynx associated with HPV as determined by p16 protein
   expression using immunohistochemistry (IHC) performed by a Clinical Laboratory
   Improvement Amendments (CLIA) approved laboratory; using p16 antibody obtained from
   Roche mtm laboratories AG (CINtec, clone E6H4) is recommended

   - Patients with a history of a curatively treated malignancy must be disease-free for at
   least two years except for carcinoma in situ of cervix and/or non-melanomatous skin
   cancer

   - Patients with the following within the last 6 months prior to pre-registration must be
   evaluated by a cardiologist and/or neurologist prior to entry into the study

      - Congestive heart failure > NYHA Class II

      - Cerebrovascular accident (CVA)/transient ischaemic attack (TIA)

      - Unstable angina

      - Myocardial infarction

   - Absolute neutrophil count >= 1,500/mm^3

   - Platelets >= 100,000/mm^3

   - Total bilirubin =< the upper limit of normal (ULN)

   - Calculated creatinine clearance must be > 60 ml/min using the Cockcroft-Gault formula

Registration/Randomization to Step2 - Arms A, B, C and D

   - Histopathologic assessment of surgical pathology must include examination for
   perineural invasion (PNI) and lymphovascular invasion (LVI) and reported as absent or
   present; the absence or presence of extracapsular extension (ECE) requires gross and
   microscopic assessment and is defined to be:

      - Absent (negative or nodal metastasis with smooth/rounded leading edge confined to
      thickened capsule/pseudocapsule),

      - Present - minimal (tumor extends =< 1 mm beyond the lymph node capsule), or

      - Present - extensive (gross, tumor extends > 1 mm beyond the lymph node capsule
      (includes soft tissue metastasis)

   - Patient must be stratified/classified into one of the following risk categories (the
   highest risk feature assessed pathologically will determine the patient's
   category/treatment arm assignment):

      - Low Risk: T1-T2, N0-N1 AND clear (≥ 3mm) margins, AND no ECE or PNI/LVI

      - High Risk: Any of the following features: one or more positive margin(s) with any
      T stage, OR "Extensive" (> 1mm) ECE, OR ≥ 5 metastatic lymph nodes (regardless of
      primary tumor margin status)

      - Intermediate Risk: Any of the following features: one or more "close" (< 3mm)
      margin(s), OR "Minimal" (≤ 1mm) ECE, OR N2a (1 or more lymph node > 3cm in
      diameter), OR N2b (2-4 lymph nodes positive, any diameter ≤ 6cm), OR with
      perineural invasion or lymphovascular invasion.

      - Unknown Risk: Patients found to have N2C or N3 disease on final pathologic
      analysis are at unknown risk for recurrence, but are not candidates for
      deintensified adjuvant therapy in this trial. These patients will be treated on
      Arm C.

      - Patients not categorized into the appropriate risk category will be considered
      ineligible for the study

   - Patient must be registered/randomized to Step 2 within a maximum of 7 weeks following
   surgery

   - Women of childbearing potential and sexually active males are strongly advised to use
   an accepted and effective method of contraception

Exclusion Criteria:

Registration to Surgery (Arm S)

   - Prior radiation above the clavicles

   - Evidence of extensive or "matted/fixed" pathologic adenopathy on preoperative imaging

   - Women must not be pregnant or breast-feeding due to the teratogenicity of
   chemotherapy; all females of childbearing potential must have a blood test or urine
   study within 2 weeks prior to registration to rule out pregnancy; a female of
   childbearing potential is any woman, regardless of sexual orientation or whether they
   have undergone tubal ligation, who meets the following criteria: has not undergone a
   hysterectomy or bilateral oophorectomy; or 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)

   - Any intercurrent illness likely to interfere with protocol therapy or prevent surgical
   resection

   - Uncontrolled diabetes, uncontrolled infection despite antibiotics or uncontrolled
   hypertension within 30 days prior to pre-registration