Surgery Followed by Risk-Directed Post-Operative Adjuvant Therapy for HPV-Related Oropharynx Squamous Cell Carcinoma: "The Minimalist Trial (MINT)"

Inclusion Criteria: * Histologically or cytologically confirmed HPV-related stages I-III OPSCC (8th edition of AJCC/UICC Staging Manual) or HPV-related neck node with unknown primary. HPV-related may be defined by p16 IHC stain and/or HPV-ISH or PCR using standard definitions of positive and negative test results. * Primary tumor that will be resected via a transoral oral approach (conventional surgery, transoral laser microsurgery, transoral robotic surgery) * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2. * Normal organ and marrow function defined as: * Creatinine clearance \> 50 cc/min. * ANC \> 1,000/mcL. * Platelet count \>100,000/mcL. * At least 18 years of age. * Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. * Patient (or legally authorized representative) must be able to understand and willing to sign a written informed consent document. Exclusion Criteria: * Prior curative therapy for HNSCC. * Patient must not have known distant metastatic disease at presentation. * History of prior invasive malignancy diagnosed within 2 years prior to study enrollment; exceptions are malignancies with a low risk of metastasis or death (e.g., expected 5-year overall survival (OS) \> 90%) that were treated with an expected curative outcome, such as squamous cell carcinoma of the skin, in-situ carcinoma of the cervix uteri, non-melanomatous skin cancer, carcinoma in situ of the breast, or incidental histological finding of prostate cancer (TNM stage of T1a or T1b). * Receiving any other investigational agents. * Uncontrolled serious inter-current illness or serious psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant and/or breastfeeding. A negative serum or urine pregnancy test is required at screening for all female patients of childbearing potential.