RBD-HPV: Risk-Based De-Intensification for HPV+ HNSCC

Inclusion Criteria: Patients must meet the following inclusion criteria to be eligible for enrollment in RBD-HPV: 1. Histologically-confirmed squamous cell carcinoma of the head and neck, including subsites of the oropharynx, hypopharynx, larynx, and nasopharynx (with data on EBV) 2. P16+ positivity as measured by IHC in a lab that is verified by the central laboratory or if the slides are available for review by the central laboratory 3. HPV positivity by PCR assessed with either tissue or cytology in the central laboratory 4. Stages I, II, III, or IV according to the AJCC 7th edition without evidence of distant metastases 5. Age \> 18 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 7. Adequate marrow function as defined by the following parameters: * Neutrophil count \> 1.5 x 109/l * Platelet count \> 100 x 109/l * Hemoglobin \> 10 g/dl 8. Adequate renal function as defined by a creatinine clearance \> 60 ml/min (actual or calculated by the Cockcroft-Gault equation) 9. Adequate liver function as defined by the following parameters: * Total bilirubin \< institutional upper limit of normal (ULN) (except patients with Gilbert's Syndrome who have no other liver disease or abnormal liver serologies) * AST or ALT and alkaline phosphatase within the ranges described below 10. A negative pregnancy test within 7 days of starting therapy in women of childbearing potential 11. Capacity to understand the study protocol 12. Willingness to provide written consent. Exclusion Criteria: Patients will not be eligible for enrollment in this study if they exhibit any of the following conditions: 1. Women who are currently pregnant or breast-feeding 2. Men or women of childbearing potential who are not using adequate contraception during treatment and at least 3 months after therapy 3. Current or prior malignancy in the last 5 years (excluding basal or squamous cell carcinoma of the skin not requiring systemic or radiation therapies, or prostate CA that is well-controlled and observed, etc) 4. Radiation therapy for prior malignancy (except radioactive iodine for thyroid cancer) 5. Prior chemotherapy for other malignancy or autoimmune disease 6. Metastatic disease at presentation 7. Nasal cavity subsite 8. Active smoking (defined as \> 1 cigarette per day within the last five years) or former smoking (has to have quit \> 10 years ago) with a cumulative pack year history \> 40 pack years 9. Prior radiation therapy or chemotherapy for HNSCC (prior surgery alone is permitted) 10. Active substance use disorder (ETOH or drugs, excluding marijuana) 11. Prior use of IV drugs 12. Significant peripheral neuropathy (\> grade 2 according to NCI CTC) 13. Prior hematologic or solid organ transplant 14. Major medical comorbidity including: * Significant cardiovascular disease. * Significant neurologic disorder, including dementia and seizures. * Significant psychiatric disorder. * Active infection that is uncontrolled. * PUD (peptic ulcer disease) that is clinically active or unhealed. * Hypercalcemia. * COPD with hospitalization in the last 12 months for pneumonia or respiratory failure. * Interstitial lung disease. * Autoimmune disease requiring therapy. * Uncontrolled HIV infection (not on HAART, CD4 \< 200). * Active Hepatitis C (+ RNA). 15. Enrollment in a therapeutic clinical trial within 30 days of study entry 16. Concurrent treatment with any other antineoplastic therapy 17. Significant weight loss (\> 25% of TBW) in the 2 months prior to study entry 18. Patient has a history of non-adherence to medical care 19. Patient will not be able to engage in comprehensive follow-up at Mount Sinai.