This study builds on the results of several prior studies that we have been involved with to test the hypothesis that Risk-Adapted De-Intensification of Radiation Therapy and chemotherapy based on HPV subtype, plasma circulating free HPV DNA (cfHPV DNA) level, and cfHPV DNA clearance rate produces Local-Regional Control rates that are similar to what has been achieved with more aggressive therapy in patients with Favorable Prognosis Oropharyngeal Squamous Cell Carcinoma (OPSCC).

Inclusion Criteria:

1. ≥ 18 years of age (no upper age limit)

2. T0-3, N0 to N2, M0 squamous cell carcinoma of the oropharynx by AJCC 8th Edition staging. If T0 the adenopathy must be predominantly in Level 2.

3. Tissue diagnosis of HPV and/or p16 positivity from the primary site or an associated lymph node.

4. Radiologic confirmation of the absence of lung metastasis within 12 weeks prior to treatment; at a minimum, CT of the chest is required. PET-CT is acceptable.

5. ECOG Performance Status 0-2

6. ≤10 pack-years of smoking or no smoking for ≥ 10 years

7. Eligible for chemotherapy

8. CBC/differential obtained within 12 weeks prior to treatment, with adequate bone marrow function defined as follows:

   • Platelets ≥ 100,000 cells/mm3
   • Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.)

9. Adequate renal and hepatic function within 12 weeks prior to treatment, defined as follows:

   • Serum creatinine < 2.0 mg/dl
   • Total bilirubin < 2 x the institutional ULN (upper limit of normal)
   • AST or ALT < 3 x the institutional ULN
   • Note that physician attestation of patient having no known history of liver disease can take the place of bilirubin and AST/ALT labs.

10. Negative pregnancy test within 3 weeks prior to treatment for women of childbearing potential.

11. People of childbearing potential (POCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 14 months after the last dose of study drug to minimize the risk of pregnancy. Prior to study enrollment, people of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy.

    POCBP includes any person who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined as:

    • Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or
    • For people with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.

12. Subjects with partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 14 months following the last dose of study drug.

13. Patients must provide study specific informed consent prior to study entry.

Exclusion Criteria:

1. Prior radiotherapy for oropharyngeal squamous cell carcinoma (OPSCC) OR to the head and neck that, if combined with the protocol therapy, is deemed likely to compromise critical organs at risk in the opinion of the investigator.

2. Prior cancer within the last 10 years.

   •This exclusion does not apply to the history or presence of any non-oropharynx cancer when the treating physician (or PI) deems that it is resolved or expected to have an indolent growth rate such that evaluation of the efficacy of the study treatment is unlikely to be compromised.

3. Prior surgery with curative intent for this OPSCC.

4. Patients who have undergone tonsillectomy for diagnosis or excisional biopsy of a neck node for diagnosis are eligible provided there is "gross" cancer present at the primary site or in the neck at the start of radiation therapy on this protocol with "gross" defined as visible on an imaging study.

5. Inhalation smoking of tobacco within the last 10 years with > 10 pack-year equivalent history.

6. Currently taking Disease Modifying Rheumatoid Drugs (DMRDs) or immunosuppressive medication, for example as for organ transplant or multiple sclerosis.

7. 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 registration
   • Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
   • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; Note, however, coagulation parameters are not required for entry into this protocol.
   • Evidence of ACTIVE systemic lupus or scleroderma
   • Psoriatic arthritis

8. Known HIV positivity. HIV positive patients are known to have worse clinical outcomes especially for local, regional, and distant cancer control. This poorer prognosis is thought to be secondary to a compromised immune system. Thus, de-intensification of radiation and chemotherapy is not justifiable in this population. HIV testing at the time of enrollment is not required.

9. Subjects of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 14 months after the last dose of study drug.

10. People who are pregnant or breastfeeding.

11. Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.