Inclusion Criteria:
* Pathologically confirmed head and neck squamous cell carcinoma of the oral cavity, oropharynx, larynx, hypopharynx, sinus, or lymph nodes of the neck of unknown primary.
* Planned for curative intent postoperative radiotherapy based on pathologic risk factors.
* Patients with non-HPV-mediated oropharyngeal squamous cell carcinoma or non-oropharyngeal squamous cell carcinoma must have at least one of the following: pathologic tumor classification pT3-4, multiple lymph nodes involved with cancer, perineural invasion, lymphovascular invasion, close margins (within 2 mm for oropharyngeal cancer status post transoral resection; within 5 mm for all others) or cleared margins (initially positive, subsequently cleared in an additional specimen), extranodal extension (any extent), or positive surgical margins.
* Patients with HPV-mediated oropharyngeal squamous cell carcinoma must have at least one of the following pathologic risk factors: extranodal extension (any extent), positive surgical margins, or more than 4 lymph nodes involved with cancer.
* Complete macroscopic surgical resection with curative intent for HNSCC with an anticipated interval between the primary surgical resection and initiation of postoperative radiotherapy greater than 42 days but less than or equal to 112 days from surgery. Note: the start date of the time to initiation of PORT is the first (primary) surgical resection. This does not include diagnostic procedures (e.g., biopsy, diagnostic tonsillectomy) or any subsequent surgical interventions for any reason (e.g., wound complications).
* Age ≥ 18 years at the time of enrollment.
* ECOG performance status of 0-1.
* Ability to understand and the willingness to sign an IRB-approved informed consent document directly, in English or Spanish, and to complete study-related forms and activities.
Exclusion Criteria:
* Recurrent head and neck cancer that has recurred after prior courses of definitive RT or surgery followed by postoperative RT/CRT. Note that individuals who have been treated with surgery alone and are now recurrent are eligible.
* Second primary head and neck cancer after initial treatment of a prior head and neck cancer.
* History of prior radiotherapy to the head and neck region, such that any portion of the anticipated target volume overlaps with any region that was previously targeted.
* Active malignancy other than the head and neck cancer to be treated with PORT (excluding non-melanoma skin cancer, in situ carcinoma of any site).
* Metastatic disease from the head and neck cancer to be treated with PORT defined as distant organ involvement outside of the head and neck and/or non-regional lymph node involvement outside of the head and neck.
* Time from primary surgical resection to anticipated initiation of PORT greater than 112 days.
* 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
* Not a candidate for radiation therapy per treating clinician. For example, individuals who are pregnant or plan to become pregnant (due to the risks of the developing fetus) or any other contraindication to radiation therapy.
