Inclusion Criteria:

• Age ≥ 18 years.
• Histological confirmation of p16+ OPSCC or HPV(+) OPSCC.
• Plan for gross total surgical resection via trans oral surgery with curative intent and at least unilateral neck dissection OR chemoradiotherapy.
• Absence of distant metastases on standard diagnostic work-up ≤ 16 weeks prior to registration. (Chest CT or PET/CT).
• ECOG Performance Status (PS) ≤ 1 (Appendix I).
• Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willing to provide tissue and blood samples for correlative research purposes, including anonymous shipment of samples to for NavDx Testing.

Exclusion Criteria

• Any of the following:
  • Pregnant women;
  • Nursing women;
• Men or women of childbearing potential who are unwilling to employ adequate contraception.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV+.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Other active malignancy ≤ 5 years prior to registration.
• EXCEPTIONS:
  • Nonmelanotic skin cancer or carcinoma-in-situ of the cervix, or prostate or localized endometrioid endometrial cancer.
  • NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer.
• Prior history of radiation therapy to the affected site.
• Prior systemic chemotherapy in the last 5 years.
• Contraindication to radiation therapy as determined by the treating team.
• History of allergic reaction to docetaxel.
• Receiving any medications or substances which in the opinion of the investigators would interfere with treatment. Examples could include strong inhibitors of CYP3A4 at oncologist discretion.
• Severe pre-existing ototoxicity or neuropathy that would, in the opinion of the investigator, preclude the use of cisplatin chemotherapy.
• cT4 primary tumor:
  • NOTE: Patients with no intermediate risk factors after surgery, low risk patients, as defined by T1, T2, tumors with lymph node less than 3cm, no intermediate or high risk factors such as LVSI, ENE, PNI, positive 22 margin, will go off study and be observed per current clinical standard of care. Patients found to have HPV non 16 type, or HPV detectability in blood less than < 20 TTMV will not be candidates for de-escalation in Groups 1 and 2 and will be treated in Group 3. They will receive 60 Gy +/- cisplatin or acceptable alternate regimen when drug shortages of cisplatin exist, see section 7. If treated primarily with chemoRT (Group 4), these patients will not be candidates for de-escalation if TTMV is < 50 TTMV but can remain on study receiving 70 Gy with all corresponding correlative studies applying. Patients with unknown (radiologic/clinically occult) primaries but p16+ or HPV+ neck adenopathy can be registered to go on study. Should after primary resection, no primary tumor be identified, the patient will go off study and be treated per institutional standard of care.
  • All treatment primarily, including surgery and chemotherapy will be performed at the enrolling institution.

Eligibility last updated 7/26/23. Questions regarding updates should be directed to the study team contact.