HYHOPE: De-intensified Hypofractionated Radiation Therapy for HPV-associated Oropharynx Cancer

Inclusion Criteria: 1. Pathologically-proven diagnosis of T1-3 (up to 6 cm), N0-2 (AJCC 8th edition) p16 positive squamous cell carcinoma of the oropharynx (except T1-2N0 as noted in the exclusion criteria) 2. ≤10 pack-year smoking history and not actively smoking 3. Age ≥18 years 4. ECOG performance status 0-2 or Karnofsky Performance Status 50-100 5. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). 6. Negative serum or urine pregnancy test within 2 weeks before registration for women of childbearing potential. 7. Ability to understand and the willingness to sign a written informed consent. Exclusion Criteria: 1. Distant metastasis 2. T1-2N0 (AJCC 8th edition) p16 positive squamous cell carcinoma of the oropharynx (candidates for definitive RT alone or surgery alone) 3. Inability to receive concurrent weekly cisplatin due to comorbid conditions 4. Synchronous non-skin cancer primaries outside of the oropharynx, oral cavity, larynx, and hypopharynx except for low- and intermediate-risk prostate cancer and well-differentiated thyroid cancer. For prostate cancer, patient should not be receiving active treatment. For thyroid cancer, thyroid surgery may occur before or after radiation treatment, provided all other eligibility criteria are met. 5. Prior invasive malignancy with an expected disease-free interval of less than 3 years 6. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation fields 7. Subjects may not be receiving any other investigational agents for the treatment of the cancer under study. 8. History of allergic reactions attributed to compounds of similar chemical or biologic composition to the chemotherapy agents in this study 9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements 10. Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants. 11. History of severe immunosuppression, including HIV, organ or autologous or allogeneic stem cell transplant, or active immunosuppressive medication at the time of enrollment