Risk-adapted Therapy in HPV+ Oropharyngeal Cancer Using Circulating Tumor (ct)HPV DNA Profile - The ReACT Study

Inclusion Criteria: * Participants must meet the following eligibility criteria at the time of screening to be eligible to participate in the study: * Subject must have histologically or cytologically confirmed, stage I, II, or III (N3 disease excluded), HPV associated oropharyngeal (tongue base or tonsil) squamous cell carcinoma, as defined by 2017 American Joint Committee on Cancer (AJCC), 8th edition staging. \-- Patients with HPV-associated disease of unknown primary (cT0) are eligible * HPV status should be confirmed on tissue biopsy or cytologic sample by any of the following: * Immunohistochemical staining for p16 with ≥70% expression * Confirmatory DNA testing (PCR or ISH) for high-risk subtype * Willing to provide blood and tissue from a diagnostic biopsy and blood samples before, during, and after treatment. * Detectable HPV ctDNA blood sample at baseline, prior to treatment, using the NavDx® assay that detects HPV subtype 16 * Age 22 years or older * ECOG performance status ≤ 2 * Participants should have adequate organ and marrow function if they are to receive chemotherapy (cisplatin, or carboplatin and paclitaxel) with radiation concurrently as determined by standard institutional guidelines and investigator preference (parameters suggested below). * absolute neutrophil count (ANC) ≥ 1000 * platelet count ≥ 100,000 * total bilirubin of 1.5 or less * creatinine of 1.6 or less (or a CrCl ≥50 mL/min) per institutional standards. * Planning to receive non-surgical management for HPV+ oropharyngeal cancer * Ability to understand and the willingness to sign a written informed consent document. * Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of (chemo)radiation therapy. "Women of childbearing potential (WOCBP)" is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level above 40 mIU/mL. * Men who are sexually active with WOCBP must agree to use any contraceptive method with a failure rate of less than 1% per year. Men who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 1 month after treatment. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception. Exclusion Criteria: * Patients with AJCC 2017 8th edition stage IVC (metastatic) disease; or patients with fixed cervical nodal disease suggesting extranodal extension or N3 disease as suggested by lymph nodes measuring \>6 cm. * Subject who has had prior radiation and/or chemotherapy for head and neck cancer. * Any history of oncologic surgical resection (transoral robotic surgery, TORS) or oncologic neck dissection prior to undergoing definitive RT or chemoradiation. Note: prior tonsillectomy as part of identification of the primary tumor site or biopsy and excisional nodal biopsy is/are acceptable provided the patient would be standardly treated to definitive treatment doses of therapy off protocol. Patients with HPV-associated unknown primary should not have undergone a neck dissection to be eligible. * Undetectable baseline HPV ctDNA result by NavDx® testing or detectable baseline HPV ctDNA result for subtypes 18, 31, 33, or 35. * Pregnant or lactating women. * Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, and low risk prostate adenocarcinoma being managed with active surveillance. A history of another separate malignancy in remission without evidence of active disease is permitted if chance3 of recurrence is thought to be low.