This study will look at whether monitoring HPV ctDNA levels is an effective way to detect cancer relapse risk in people with HPV-OPC. All participants will have recently had surgery to treat their disease, or they will be scheduled to have this surgery.

In Arm A the researchers will see whether monitoring participants' HPV ctDNA levels can safely identify patients who do not need radiation therapy (RT) after surgery and whose RT can be delayed until their HPV ctDNA levels become detectable.

In Arm B, the researchers will see whether patients who usually need 6-6.5 weeks of CRT can be selected by HPV ctDNA to receive 3 weeks of CRT.

Inclusion Criteria:

• Age ≥ 18

• ECOG 0-2

• HPV-16 squamous cell carcinoma of the oropharynx or HPV-16 head and neck squamous cell carcinoma of unknown primary . HPV status must be confirmed by in-situ hybridization.

• HPV ctDNA detectable by HPV digital PCR (Naveris assay) with a minimum of 50 copies/mL pre-operatively.

• Surgical resection of all gross disease with no gross disease visualized on post-operative imaging.

  o For patients with pT0 (unknown primary) evaluation for the primary should include PET/CT, direct laryngoscopy, ipsilateral tonsillectomy, and targeted biopsy. This should be followed by a neck dissection.

• Two, undetectable (<1 copy/mL) post-operative HPV ctDNA within 2-6 weeks following surgery (blood drawn at least one week apart preferred).

• A minimum of one of the following pathologic criteria: (Arm A)

  • AJCC 7 Stage: pT0N1-N2b, pT1N1, pT2N1, or ≥pT3
  • AJCC 7 ≥pN2
  • Lymphovascular invasion
  • Perineural invasion
  • Close pathologic margin (≤ 3 mm)

• Signed informed consent form by the participant or their legally authorized representative (LAR).

• A minimum of one of the following pathologic criteria (Arm B):

  • Microscopic positive margin
  • Extracapsular extension

• Signed informed consent form by the participant or their legally authorized representative (LAR).

Additional criteria for Arm B only:

• Adequate hematologic function within 30 days prior to registration, defined as follows:

  • White Blood Count (WBC) ≥ 2 K/mcL
  • Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3
  • 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

• Adequate renal function within 30 days prior to registration, defined as follows:

  • Serum creatinine < 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula:
  • CCr male = [(140 - age) x (wt in kg)] divided by [(Serum Cr mg/dl) x (72)]
  • CCr female = 0.85 x (CrCl male)

• Adequate hepatic function within 30 days prior to registration, defined as follows:

  - Bilirubin < 2 mg/dl o AST or ALT < 3 x the upper limit of normal

• Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential

Exclusion Criteria:

• Metastatic disease

• Non-HPV16 genotype (i.e. HPV-18,-31, -33, -35)

• Patients who receive surgery at outside institution. Exceptions can be made for high-volume surgical centers at the discretion of the PI/co-PI

• Prior head and neck radiation

• Patients without pre-operative HPV ctDNA or pre-operative HPV ctDNA ≤ 50 copies/mL

• Subjects with simultaneous primary cancers outside of the oropharynx

  o Note: Exceptions can be made for patients with simultaneous primaries outside of the oropharynx if determined by the PI/Co-PI, then the patient can proceed with protocol activities

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 3 years or if cure rate from treatment at 5 years is 90% or greater

  o Note: Exceptions can be made for patients with prior invasive malignancy if determined by the PI/Co-PI, then the patient can proceed with protocol activities

• Prior systemic chemotherapy for the study cancer

  o Note: prior chemotherapy for a different cancer is allowable

• 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 within 30 days of registration
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

• Lack of ability to understand and willingness to sign a written informed consent and complete questionnaires.

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.