Phase II Trial of Surgery Followed by Risk-Directed Post-Operative Adjuvant Therapy for HPV-Related Oropharynx Squamous Cell Carcinoma: "The Minimalist Trial-2 (MINT-2)"

Inclusion Criteria: * Histologically or cytologically confirmed HPV-related, clinical stages I-II OPSCC (8th edition of AJCC/UICC Staging Manual) or HPV-related neck node with unknown primary. Clinical T1N0M0 and T2N0M0 disease are excluded. HPV-related may be defined by p16 IHC stain and/or HPV-High Risk RNA ISH/HPV DNA genotyping by PCR, using standard definitions of positive and negative test results. * Planned resection of the primary tumor site by a transoral approach (TORS, TLM, or conventional surgery). * Planned unilateral or contralateral selective neck dissection. * ECOG PS 0-2. * Adequate organ and marrow function defined as: * Creatinine clearance ≥ 50 mL/min. * ANC ≥ 1.0 K/cumm. * Platelet count ≥100 K/cumm. * 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. * Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants. Exclusion Criteria: * Clinical T1N0M0 or T2N0M0 disease. * Prior radiation therapy for HNSCC. * Planned free-flap reconstruction of the resected primary site. * Cirrhosis with Child-Pugh Score B or C. * 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 OS \> 90%) that were treated with curative-intent therapy. * 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 pregnancy test is required at screening for all female patients of childbearing potential.