A Phase II Study for p16+ Oropharyngeal Cancer PerSonalized De-escalation Treatment at University of MIchigan (CuSToMIze)

Inclusion Criteria: Patients must have FDG-avid (maximum SUV ≥ 4.0) (from PET scan of any date, any scanner) and histologically or cytologically proven squamous cell carcinoma of the oropharynx (tonsil, base of tongue, oropharyngeal wall, soft palate) or unknown primary that is p16 positive by immunohistochemistry or HPV positive by in situ hybridization Clinical stage: Stage I-II AJCC 8th edition staging Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup: History/physical examination, including documentation of weight within 4 weeks prior to registration; FDG-PET/CT scan for staging within 4 weeks prior to registration; Zubrod Performance Status 0-1 within 4 weeks prior to registration; Age ≥ 18; Able to tolerate PET/CT imaging required to be performed For Cohort A, tumors must be potentially surgically resectable via a transoral approach, at the discretion of the treating surgeon. CBC/differential obtained within 4 weeks prior to registration on study, with adequate bone marrow function defined as follows: Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; Platelets ≥ 100,000 cells/mm3; Hemoglobin ≥ 8.0 g/dL Serum creatinine within normal institutional limits or a creatinine clearance ≥ 45 ml/min within 4 weeks prior to registration. Women of childbearing potential and male participants must agree to use a medically effective means of birth control throughout their participation in the treatment phase of the study. The patient must provide study-specific informed consent prior to study entry. Exclusion Criteria: cT4, cN3, or cM1 disease (also explained as AJCC 8th edition, Stage 3 or 4 disease) Patients with radiographic ECE or matted lymph nodes, defined as three nodes abutting one another with loss of intervening fat plane that is a replaced with radiologic evidence of extracapsular spread. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible); Any prior therapy for the study cancer; note that prior chemotherapy for a different cancer is allowable if >3 years prior to study; Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields; 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 3 months; Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; Chronic Obstructive Pulmonary Disease (COPD) exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition. Note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol. Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. For Cohort B, poorly controlled diabetes (defined as fasting glucose level > 200 mg/dL) despite 2 attempts to improve glucose control by fasting duration and adjustment of medications. Patients with diabetes will preferably be scheduled in the morning and instructions for fasting and use of medications will be provided in consultation with the patients' primary physicians. Active enrollment on another clinical trial involving active treatment for the study cancer.