Radiation De-escalationA Single Arm Phase II Trial in p16-positive Oropharynx Cancer of Selective Dose De-escalation of nodAl VolumEs at Minimal Risk and Primary Site Disease (SAVED)

4.1 Step 1 Registration 4.1.1 Step 1 Inclusion

(Y) 1. Is there pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma) of the oropharynx or squamous cell carcinoma unknown primary? Note: specimen from cervical lymph nodes with a well-defined primary site documented clinically or radiologically is acceptable; in patients with carcinoma of unknown primary this will be sufficient for pathologic confirmation without a clinically or radiographically defined primary site.

(Y) 2. Is the patient ≥ 18 years of age?

(Y) 3. Did the patient provide study specific informed consent prior to study entry, including consent for mandatory submission of tissue for required p16 review?

(Y) 4. Clinical TNM staging criteria by cohort (AJCC 8th edition):

TORS candidate patients must be:

• cT0-4 and N0, N1, N3

Non-TORS candidate patients must be either:

• cT1-4 N0, N1, N3
• cT1-3 N2 with < 10 pack years

4.1.2 Step 1 Exclusion

(N) 1. Patient who are clinical N2 and have ≥10 pack years smoking history

(N) 2. Patients who are clinical T4N2

(N) 3. Patients with distant metastasis (M1)

4.2 Step 2 Registration 4.2.1 Step 2 inclusion

(Y) 1. Does the patient have pathologically (histologically or cytologically) proven P16+ status?

(Y) 2. Does the patient have appropriate imaging (PET/CT preferred, CT neck with IV contrast and CT chest without contrast as recommended alternative to PET/CT) completed within 90 days of enrollment?

(Y) 3. Does the patient have clinical or pathological M0 staging? (Y) 4. Patients who have undergone TORS must have pathological stage pT1-4 N0, N1 or N3. TORS patients found to be clinical N2 post TORS or have contralteral neck dissection and positive nodes will be excluded.

(Y) 5. Is the patient a candidate for bilateral radiation based on evaluation by ENT, Rad Onc, or Med Onc and review at multi-disciplinary tumor board?

(Y) 6. Non-TORS patients who are cT1-3 N0, N1, N2 and have <10 PY must have completed a ctDNA evaluation prior to Step 2 enrollment.

(Y) 7. Non-TORS patients who are cT1-3 N2 must have a positive ctDNA result prior to Step 2 enrollment.

(Y) 8. Was a general history and physical examination performed by a radiation oncologist, medical oncologist, or head and neck surgeon within 60 days prior to registration?

(Y) 9. Was the patient's Zubrod Performance Status 0-1 within 30 days prior to registration?

(Y) 10. If a woman of child-bearing potential or sexually active male, is the patient willing to use effective contraception throughout their participation in the treatment phase of the study and at least 180 days following the last study treatment.

4.2.2 Step 2 Exclusion

(N) 1. Does the patient have cancer considered to be from an oral cavity site (oral tongue, floor mouth, alveolar ridge, buccal or lip), nasopharynx, hypopharynx, or larynx?

(N) 2. Does the patient have distant metastasis?

(N) 3. Does the patient have prior invasive malignancy (except non-melanomatous skin cancer and low/intermediate risk prostate cancer) unless disease free for a minimum of 3 years?

(N) 4. Did the patient have prior systemic chemotherapy for the study cancer (prior chemotherapy for a different cancer is allowable)?

(N) 5. Did the patient have prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields?

(N) 6. Did the patient have prior cancer-related surgeries of curative intent of the head and neck excluding superficial removal of cutaneous skin malignancies?

(N) 7. Does the patient have any co-morbid condition or concern that may interfere with follow up per experimental arm?

(N) 8. Does the patient have an active drug or alcohol dependency that in the opinion of the investigator would limit compliance with study requirements?

(N) 9. Is the patient pregnant or nursing (an exception will be made for nursing patients that are not receiving chemotherapy)?