Using CircuLating Tumor DNA to Risk Adapt Post-Operative Therapy for HPV-associated Oropharyngeal Cancer

Inclusion Criteria: * AJCC 8th edition T0-3N0-2 p16-positive oropharyngeal (tonsil, base of tongue, glossotonsillar sulcus, soft palate, oropharyngeal wall) squamous cell carcinoma or squamous cell carcinoma of unknown primary involving the cervical lymph nodes. Cytologic diagnosis from a cervical lymph node is sufficient for diagnosis in the presence of clinical evidence of a primary tumor in the oropharynx. * For patients with pT0 tumors (unknown primary), there must be at least one metastatic lymph node present in cervical level II. * p16 is strongly positive by immunohistochemistry or high-risk HPV is detected by in-situ hybridization. * Have undergone or will undergo gross total resection of all known disease in the head and neck via transoral robotic surgery. For patients with clinical unknown primary tumors, a patient must undergo both ipsilateral tonsillectomy and base of tongue resection unless the primary is identified clinically or pathologically at the time of surgery. If the primary is identified, then only resection of the primary site is required. If the primary tumor is resected with negative margins with a non-robotic surgery, such as a diagnostic tonsillectomy, this is considered acceptable and further robotic surgery is not necessary. * Have undergone or will undergo neck dissection. * Have at least one of the following after surgery: * Pathologic stage T3 * 2 or more positive lymph nodes * At least one lymph node \>3cm * Contralateral lymph node involvement * Lymphovascular invasion * Perineural invasion * Extranodal extension * Close/positive margins: Close margins are considered ≤3mm from the peripheral margins and ≤1mm from the deep margin on the en bloc specimen, unless the area of close margin is re-resected and without carcinoma. * Patients consented preoperatively are required to have detectable cTTMV-HPV DNA based on pre-operative NavDx testing. For patients consented post-operatively, NavDx testing should be performed on the tumor tissue to ensure detectable HPV DNA and for HPV subtyping. * Age ≥ 18 years old * ECOG performance status 0 or 2 within 56 days of start of chemoradiation. * Women of childbearing potential require a negative serum or urine pregnancy test within 28 days prior to start of chemoradiation. * Written informed consent obtained from subject and ability for subject to comply with the requirements of the study. * Adequate hematologic and renal function within 56 days of start of chemoradiation, defined as: * Hemoglobin ≥ 9.0 g/dL * Platelets ≥ 100, 000 cells/mm3 * ANC ≥ 1.5 X 109/L * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) * Aspartate aminotransferase/alanine aminotransferase ≤ 3.0 x upper limit of normal (ULN) * Serum creatinine ≤1.5 x upper limit of normal (ULN) OR a calculated creatinine clearance ≥50 mL/min estimated using the following Cockcroft-Gault equation Exclusion Criteria: * AJCC 8th edition pT4 or cN3 disease. * Radiologic or clinical evidence of distant metastasis. * Recurrent disease. * Inability to achieve gross total resection at time of surgery. * Greater than 56 days (8 weeks) after surgical resection of the primary site. * Prior radiation to the head and neck \> 30 Gy. * Prior active invasive (not in situ) malignancy within the prior 2 years, excluding cutaneous basal cell or squamous cell carcinoma, low or intermediate risk prostate cancer, papillary thyroid cancer, stage T1aN0 kidney cancer, low-grade T1-2N0 salivary cancer, AJCC 8th edition stage I-II breast cancer, well-differentiated neuroendocrine tumors (e.g., carcinoid tumors), low grade non-Hodgkin lymphoma, or Stage 0, I, and III cutaneous melanomas. Patients with synchronous or multifocal oropharyngeal cancers are not excluded, as long as at least one of these tumors meet inclusion criteria for the trial. * Severe, active co-morbidity, defined as follows: * Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months * Transmural myocardial infarction within the last 6 months * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of enrollment * Hepatic insufficiency resulting in clinical jaundice and/or known coagulation defects * Moderate to severe hearing loss. * Active connective tissue disease (e.g. systemic lupus erythematous, scleroderma) requiring immunosuppression. * Pregnant or breast-feeding women. * Prior allergic reaction to cisplatin. * Live vaccines within 30 days prior to the first dose of chemoradiation. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral vaccine). Season influenza vaccines for injection are generally killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not allowed.