EValuating the Safety Of De-escaLated Head and Neck Irradiation in HPV positivE Oropharynx Cancer in Non-smokers/Minimal Smokers

Inclusion Criteria: * Age \> 18 years * Histologic confirmation of tumor of the oropharynx * Radiation therapy (de-escalated head and neck irradiation) decision has been made * Human Papilloma Virus (HPV) associated cancer as determined by positive p16 immunohistochemistry * HPV positivity is defined by p16 IHC staining of \> 70% of tumor cells (strong and diffuse nuclear and cytoplasmic staining) * For cases that are indeterminate or if p16 testing cannot be accurately performed, HPV positivity can be confirmed by high-risk HPV DNA Testing which covers the following HPV subtypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 * \< 10 pack year smoking history OR \< 10 year nicotine use history * No current tobacco/nicotine use (including electronic cigarettes and chewing tobacco) * T1-T3, N0-N2 (AJCC8) requiring definitive therapy greater than surgery alone * Ability to provide informed written consent * Willingness to return to Sanford Cancer Center for follow-up * Life expectancy \> 12 weeks * ECOG performance status \< 3 (Appendix B) * Adequate organ function for chemotherapy and radiotherapy Exclusion Criteria: * Any of the following because the inclusion criteria require delivery of radiotherapy and chemotherapy which is known to be genotoxic, and is associated with mutagenic and teratogenic effects: pregnant women, nursing women, men or women of childbearing potential who are unwilling to employ adequate contraception. * Prior head and neck radiotherapy * Any factor precluding safe delivery of chemotherapy