A Study on Using Cell-Free Tumor DNA (ctDNA) Testing to Decide When to StartRoutine Treatment in People With Human Papilloma Virus (HPV)- Associated Oropharynx Cancer (OPC)

Eligibility 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.
• * 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).
• * 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:
• * Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential
• * 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
• * 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
• * Prior systemic chemotherapy for the study cancer
• * 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.