De-intensification of Radiation & Chemotherapy in Low-Risk Human Papillomavirus-related Oropharyngeal Squamous Cell Ca

Inclusion Criteria:

1. ≥ 18 years of age
2. T0-3, N0 to N2c, M0 squamous cell carcinoma of the oropharynx
3. Biopsy proven squamous cell carcinoma that is HPV and/or p16 positive
4. ≤ 10 pack-years smoking history or \> 5 years of abstinence from smoking
5. History/physical examination within 8 weeks prior to registration
6. Radiologic confirmation of the absence of hematogenous metastasis within 12 weeks prior to registration.
7. The Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
8. Complete Blood Count (CBC)/differential obtained within 4 weeks prior to registration, with adequate bone marrow function defined as follows: Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3; Platelets ≥ 100,000 cells/mm3; Hemoglobin ≥ 8.0 g/dl.
9. Adequate renal and hepatic function within 4 weeks prior to registration, defined as follows: Serum creatinine \< 2.0 mg/dl; Total bilirubin \< 2 x the institutional upper limit of normal (ULN); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \< 3 x the institutional ULN.
10. Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing potential.
11. Women of childbearing potential and male participants who are sexually active must practice adequate contraception during treatment and for 6 weeks following treatment.
12. Patients must be deemed able to comply with the treatment plan and follow-up schedule.
13. Patients must provide study specific informed consent prior to study entry.

Exclusion Criteria:

1. Prior history of radiation therapy to the head and neck
2. Prior history of head and neck cancer.
3. Severe, active co-morbidity, defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; Transmural myocardial infarction within the last 6 months; Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; Note, however, coagulation parameters are not required for entry into this protocol; Pre-existing ≥ grade 2 neuropathy; Prior organ transplant.
4. Known HIV positive
5. Significant pre-existing hearing loss, as defined by the patient or treating physician.