The Quarterback Trial: Reduced Dose Radiotherapy for HPV+ Oropharynx Cancer

Inclusion Criteria: * Participants must have histologically or cytologically confirmed squamous cell carcinoma of the oropharynx, unknown primary, or nasopharynx that is HPV positive as determined by PCR and p16 positive as determined by IHC. Tissue from the primary site must be available for biomarker studies. PCR and IHC must be performed in the central laboratory (Zhang, MSSM) * Stage 3 or 4 disease without evidence of distant metastases. * At least one clinically evaluable or uni- or bi-dimensionally measurable lesion by RECIST 1.1 criteria. * Age \> 18 years. * No previous surgery, radiation therapy or chemotherapy for SSCHN (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 and defined as at least 6 months without activity). * Participants must have adequate bone marrow, hepatic and renal functions as defined in the protocol. * Ability to understand and the willingness to sign a written informed consent document. * Patients with Gilbert's Disease and absent hepatic pathology by history and clinical assessment maybe treated on study with bilirubins \> the ULN for the institution if other liver function studies are within the normal range Exclusion Criteria: * Pregnant or breast feeding women, or women and men of childbearing potential not willing to use adequate contraception while on treatment and for at least 3 months thereafter. * 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. * Symptomatic peripheral neuropathy ≥ grade 2 by NCI Common Terminology Criteria (NCI-CTC) version 4. * Symptomatic altered hearing \> grade 2 by NCI-CTCv4 criteria. * Other serious illnesses or medical conditions including but not limited to: 1. Unstable cardiac disease despite treatment, myocardial infarction within 6 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. Hypercalcemia 6. Active drug addiction including alcohol, cocaine or intravenous drug use defined as occurring within the 6 months preceding diagnosis 7. 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 8. Autoimmune disease requiring therapy, prior organ transplant, or HIV infection 9. Interstitial lung disease 10. Hepatitis C (test required) * Patients that have experienced an involuntary weight loss of more than 25% of their body weight in the 2 months preceding study entry. * Concurrent treatment with any other anticancer therapy. * Participation in an investigational therapeutic drug trial within 30 days of study entry. * Active smoking within the past 20 years with a cumulative Pack Year history of \> 20 Pack Years or active smoking (Defined as \> 1 cigarette per day) within the last 2 years