Risk Adapted De-Intensification of Radio-Chemotherapy for Oropharyngeal Squamous Cell Carcinoma

Inclusion Criteria:

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

2. T0-3 ≤4cm, N0 to N2, M0 squamous cell carcinoma of the oropharynx by AJCC 8thEdition 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 associatedlymph node.

4. Radiologic confirmation of the absence of lung metastasis within 12 weeks prior totreatment; 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 bonemarrow function defined as follows:

• Platelets ≥ 100,000 cells/mm3

• Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention toachieve Hgb ≥ 8.0 g/dl is acceptable.)

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

• 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 liverdisease can take the place of bilirubin and AST/ALT labs.

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

11. People of childbearing potential (POCBP) must be using an adequate method ofcontraception to avoid pregnancy throughout the study and for at least 14 monthsafter the last dose of study drug to minimize the risk of pregnancy. Prior to studyenrollment, people of childbearing potential must be advised of the importance ofavoiding pregnancy during trial participation and the potential risk factors for anunintentional pregnancy. POCBP includes any person who has experienced menarche and who has not undergonesuccessful surgical sterilization (hysterectomy, bilateral tubal ligation, orbilateral 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 replacementtherapy (HRT), a documented serum follicle-stimulating hormone (FSH) level ofgreater than 35 mIU/mL.

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

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

Exclusion Criteria:

1. Prior radiotherapy or chemotherapy for this cancer.

2. Prior surgery with curative intent for this OPSCC.

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

4. Prior history of radiation therapy to the head and neck, with the exception of skincancer treated with a small (≤ 9cm3) field with 6 - 9 MeV electron beam or 50 - 250kVp photon beam.

5. Prior history of chemotherapy or immunotherapy for cancer within the last 10 years

6. Prior history within 5 years of invasive cancer with the exception of:

• Basal cell carcinoma of the skin

• Squamous cell carcinoma of the skin, stage 1-2

• Prostate cancer without distant metastases (stage M0)

• Thyroid cancer without distant metastases (stage M0)

7. Prior history of invasive squamous cell carcinoma of a mucosal site in the head orneck treated with surgery alone within the last 5 years.

8. Prior history of invasive malignant melanoma or Merkel cell carcinoma of the head orneck treated with surgery alone in the past 5 years.

9. Inhalation smoking of tobacco within the last 10 years with > 10 pack-yearequivalent history.

10. Currently taking Disease Modifying Rheumatoid Drugs (DMRDs) or immunosuppressivemedication, for example as for organ transplant or multiple sclerosis.

11. Severe, active co-morbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalizationwithin the last 6 months

• Transmural myocardial infarction within the last 6 months

• Acute bacterial or fungal infection requiring intravenous antibiotics at thetime of registration

• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illnessrequiring hospitalization or precluding study therapy at the time ofregistration

• Hepatic insufficiency resulting in clinical jaundice and/or coagulationdefects; Note, however, coagulation parameters are not required for entry intothis protocol.

• Evidence of ACTIVE systemic lupus or scleroderma

• Psoriatic arthritis

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

13. Subjects of childbearing potential who are unwilling or unable to use an acceptablemethod to avoid pregnancy for the entire study period and for at least 14 monthsafter the last dose of study drug.

14. People who are pregnant or breastfeeding.

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