This clinical trial evaluates how decreasing the dose of radiation to the elective neck (areas of lymph nodes not directly involved in the cancer) impacts treatment outcomes in patients with human papillomavirus (HPV)-related oropharyngeal cancer. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Radiation therapy plays an important role in the treatment of HPV-related oropharyngeal cancer, but it also causes significant toxicities. Given the significant toxicities associated with treatment, and the excellent outcomes of HPV-related oropharyngeal cancer, researchers are attempting to identify methods to de-escalate treatment for HPV-related oropharyngeal cancer in an effort to maintain excellent treatment outcomes while reducing the risk of toxicities. Reducing the dose of radiation therapy to the lymph nodes in the neck that aren't directly involved in the cancer may improve patient quality of life while still maintaining excellent rates of cure of disease.

PRIMARY OBJECTIVE:

I. To determine 2-year locoregional progression free survival (LRPFS).

SECONDARY OBJECTIVES:

I. To determine 2-year progression free survival (PFS). II. To determine 2-year regional failure in the low-dose elective region. III. To determine 2-year overall survival (OS). IV. To determine physician-reported toxicities at 1, 3, 12-months as measured by Common Terminology Criteria for Adverse Events (CTCAE).

V. To assess patient-reported toxicities at 1, 3, 12-months as measured by Functional Assessment of Cancer Therapy - Head & Neck Radiotherapy Index (FACT-HN-Rad).

OUTLINE:

Patients receive standard dose radiation therapy to the tumor and reduced dose radiation therapy to the elective neck lymph nodes five days per week for a total of 35 fractions over 7 weeks. Patients also undergo computed tomography (CT), positron emission tomography (PET), and nasopharyngolaryngoscopy throughout the trial.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Inclusion Criteria:

• 3.1.1 Patients must have a histologically confirmed HPV-related OPSCC, confirmed by HPV insitu hybridization.
• 3.1.2 Patients must not have received prior treatment (i.e., no induction chemotherapy).
• 3.1.3 Patients must have evaluable disease (per RECIST v1.1 response criteria). See Section 6.
• 3.3 for the evaluation of measurable disease.
• 3.1.4 Patients must be age ≥ 18 years.
• 3.1.5 Patients must have AJCC 8 th edition Stage I-II disease, as defined by a T-classification of T1-3, and N-classification of N1-2, without metastases (M0), as defined by physical examination (including nasopharyngolaryngoscopy) and positron emission tomography (PET)
• 3.1.6 Patient must receive a staging PET scan prior to registration on study.
• 3.1.7 Patients must exhibit an ECOG performance status of 0-1. Please refer to Appendix A ECOG Performance Status Scale.
• 3.1.8 Patients may be planned to undergo RT alone or RT with concurrent chemotherapy, with chemotherapy managed at the discretion of the treating medical oncologist per standard of care.
• 3.1.9 RT is known to be teratogenic to a developing human fetus. For this reason, patients of child-bearing potential (POCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from time of informed consent, for the duration of study participation (while actively receiving RT. Should a patient become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. NOTE: A POCBP is any patient (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: • Has not undergone a hysterectomy or bilateral oophorectomy • Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)
• 3.1.10 POCBP must have a negative pregnancy test prior to CT simulation or sign the Department of Radiation Oncology's pregnancy testing declination form. Note: the timing of the pregnancy test/declination form will follow the policy of the Department of Radiology and Oncology, which requires completion of pregnancy testing or signed pregnancy declination prior to CT simulation.
• 3.1.11 Patients must have the ability to understand and the willingness to sign a written informed consent document prior to registration.

Exclusion Criteria:

• 3.2.1 Patients with cT4, cN3, or cM1 disease by AJCC 8 th edition.
• 3.2.2 Patients who have had prior RT to the head/neck region that would result in overlap of RT fields. 3.2.3 Patients who have had prior major surgery to the head/neck region that could disrupt lymphatic flow.
• 3.2.4 Patients who have an uncontrolled intercurrent illness that would interfere with the receipt of RT including, but not limited to any of the following, are not eligible: • Uncontrolled connective tissue disorders (e.g. lupus, scleroderma) given potential for this to interfere with RT • Psychiatric illness/social situations that would limit compliance with study requirements • Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints