Inclusion Criteria:
* Patients must have histologically or cytologically confirmed and identified resectable primary OPSCC with positive p16 immunohistochemistry, defined as strong and diffuse nuclear and cytoplasmic staining in \> 70% of tumor cells. Immunohistochemistry must be performed or reviewed at the central laboratory. P16 status may be determined prior to consent and must be confirmed by surgical specimen if a biopsy is unavailable. HR-HPV status and postoperative cfHPVDNA testing must be performed and resulted prior to treatment assignment. Tissue from the primary site must be available for biomarker studies after surgery.
* Patients enrolled in the trial must have pre-surgery baseline cfHPVDNA using the NavDX assay (Naveris, Cambridge, MA). Detectable baseline cfHPVDNA copy number is defined as ≥ 10 fragments/mL and is required for inclusion in the trial.
* Undetectable cfHPVDNA after surgery. All patients should have a repeat cfHPVDNA test within 1 to 5 weeks post-operatively and prior to treatment assignment. Undetectable cfHPVDNA is defined as \< 5 fragments/mL.
* AJCC 7th edition early and intermediate stage (T1N0-2B, T2N0-2B) (non-matted) disease without evidence of distant metastases or gross extranodal extension.
* Age ≥ 18 years at screening
* No previous surgery, radiation therapy, or chemotherapy for head and neck cancer (other than excision/incisional biopsy of the primary site, excisional/incisional nodal biopsy, or tonsillectomy) is allowed at time of study entry.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* No active tobacco use (≥1cigarette or cigarette-equivalent per day within the last 5 years) and no cumulative smoking history of \>20 pack years. 1 cigar = 4 cigarette-equivalent exposure
* Ability to understand and the willingness to sign a written informed consent document.
* Participants must have adequate bone marrow, hepatic and renal functions as defined below:
* Platelet count ≥ 90 x 109/l.
* Hemoglobin ≥ 10 g/dl (may achieve by transfusion).
* Renal function: eGFR ≥ 50 ml/min
Exclusion Criteria
* Age \< 18 years at screening
* Pregnant or breast-feeding women.
* Previous or current malignancies at other sites, except for adequately treated in situ carcinoma of the cervix, basal or squamous cell carcinoma of the skin, thyroid cancer, prostate cancer treated with surgery/radiotherapy, ductal carcinoma in situ of the breast treated with surgery/radiotherapy, or other cancer curatively treated and with no current evidence of disease for at least 3 years.
* Other serious illnesses or medical conditions including but not limited to:
* Unstable cardiac disease despite treatment or myocardial infarction within 6 months prior to study entry.
* History of significant neurologic or psychiatric disorders including severe dementia or poorly controlled seizures
* Active clinically significant uncontrolled infection
* Active peptic ulcer disease defined as unhealed or clinically active
* Active drug addiction including alcohol, cocaine or intravenous drug use defined as occurring within the 6 months preceding diagnosis
* Severe chronic obstructive pulmonary disease, defined as being associated with a hospitalization for pneumonia within 12 months of diagnosis.
* Prior organ transplant
* Interstitial lung disease
* Concurrent treatment with any other anti-cancer therapy
* Participation in an investigational therapeutic drug trial within 30 days of study entry. Participation in additional investigational radiation studies will exclude participation in SIRS. Participation in non-therapeutic, non-oncologic investigational studies (i.e. pain control studies, nutritional studies, etc.) will be allowed amongst SIRS participants, provided there is no alteration of treatment planning, oncologic therapy, or surveillance, and additional studies comply with SIRS safety criteria and stopping rules as outlined in the SIRS protocol.
* Active hepatitis C by history
* Advanced nodal stage (AJCC 7th edition N2C, N3) or surgically unresectable disease or disease that cannot be fully resected, unequivocal radiographic extranodal extension, unequivocal radiographic or clinical supraclavicular or matted metastatic disease, \> 3 unequivocally radiographic pathologic cervical nodes.
* Non-HR-HPV subtype on initial biopsy or final pathology.
* 5 or more positive nodes, irrespective of size, on final pathology.
* p16 or HPV negative OPSCC as determined by IHC and PCR or ISH, respectively.
* Undetectable or \< 10 fragments/mL baseline cfHPVDNA prior to surgery.
* Autoimmune disease treated with chemotherapy agents or anti TNF agents within the last 2 years.
* Detectable repeat cfHPVDNA 1-5 weeks postoperatively via the NavDX assay, defined as \> 5 fragments/mL.
