This is a single-arm, phase II study that is designed to investigate nodal and primary tumor CTV dose de-escalation (30 Gy) in HPV positive oropharyngeal cancer.

The purpose of this research is to determine if a decrease in the dose of radiation to regions which have no visible cancer will be as effective as the standard dose. The dose to all visible cancer remains unchanged to the standard radiation approach. The researchers believe that a lower dose could be just as helpful for treatment, while reducing the side effects of radiation and improving quality of life.

The current standard care treatment for OPSCC can have debilitating side effects. Using a decreased dose of 30 Gy from 46-54 Gy to regions without visible cancer but which have a risk of microscopic cancer might be just as effective for treating cancer with less side effects. The combination of these approaches is not considered the current standard of care. Patients will continue to receive standard systemic therapy of cisplatin during radiation therapy.

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed history of squamous cell carcinoma of the oropharynx (OPSCC) planned for definitive chemoradiation.
2. Squamous cell carcinoma of the oropharynx (OPSCC) must be confirmed to be p16 positive based on immunohistochemical staining.
3. OPSCC must be clinical stage T1-4N1-3M0 or T3-T4N0M0 as per AJCC volume 8.
4. Patients must have measurable disease based on PET/CT imaging completed within 45 days +/- 1 week from date of eligibility confirmation.
5. Age ≥18 years.
6. ECOG performance status ≤2.
7. Patients must be deemed eligible for planned SOC cisplatin per treating investigators and/or treating medical oncologist.
8. Women of child-bearing potential and men must agree to use adequate contraception (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.
9. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• 1. Patients with metastatic or recurrent disease.

  2. Carcinoma of the neck of unknown primary site origin (T0 is ineligible even if p16 is positive).

  3. Prior radiotherapy resulting in overlap of radiation therapy fields.

  4. Patients who are pregnant, nursing or intended to conceive or father children during the course of the study.

  5. Patients with active autoimmune or connective tissue disease that require systemic treatment in the opinion of the Investigator.

  6. Patients who are receiving any other investigational agents. Patients who have received other investigational agents previously who are no longer receiving these investigational agents may be eligible at the discretion of the Investigator.

  7. Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous or not preferable, in the opinion of the Investigator.