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 register to Step 1 prior to surgery
• 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 registration) and complete neck exam from the skull base to the clavicles; the following imaging is required: computed tomography (CT) scan with IV contrast or magnetic resonance imaging (MRI); the primary tumor should be cT1 or T2 and cervical nodes cN1, N2a, or N2b based on clinical or radiographic criteria
• Patients must have biopsy-proven cyclin-dependent kinase inhibitor 2A (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 immunohistochemistry (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
• No prior radiation above the clavicles
• 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, melanoma in-situ (if fully resected), and/or non-melanomatous skin cancer
• Patients with the following within the last 6 months prior to registration must be evaluated by a cardiologist and/or neurologist prior to entry into the study
• Absolute neutrophil count >= 1,500/mm^3 (within 4 weeks prior to registration)
• Platelets >= 100,000/mm^3 (within 4 weeks prior to registration)
• Total bilirubin =< the upper limit of normal (ULN) (within 4 weeks prior to registration)
• Calculated creatinine clearance must be > 60 ml/min using the Cockcroft-Gault formula (within 4 weeks prior to registration)
• REGISTRATION/RANDOMIZATION TO STEP 2 - 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 (>= 3 mm) 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” (> 1 mm) ECE, OR >= 5 metastatic lymph nodes (regardless of primary tumor margin status) * Intermediate risk: any of the following features: one or more “close” (< 3 mm) margin(s), OR “minimal” (=< 1 mm) ECE, OR N2a (1 or more lymph node > 3 cm in diameter), OR N2b (2-4 lymph nodes positive, any diameter =< 6 cm), 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

• Patients must not have 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)
• Patient must not have an intercurrent illness likely to interfere with protocol therapy or prevent surgical resection
• Patients must not have uncontrolled diabetes, uncontrolled infection despite antibiotics or uncontrolled hypertension within 30 days prior to registration