Evaluating a Decreased Dose of Radiation Therapy to the Elective Neck for the Treatment of HPV-Related Oropharyngeal Cancer, ENLIGHT Trial

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; surgical methods (e.g. tubal ligation); 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 is participating in this study, she should inform her treating physician immediately for consideration of cessation of RT. 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 standard pregnancy testing declination form. Note: the timing of the pregnancy test/declination form will follow the standard policy of the Department of Radiation 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 as determined by the PI.
* 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