This clinical trial evaluates the clinical outcome of mucosal sparing adjuvant radiotherapy after surgical exploration in HPV+ head and neck cancer of unknown primaries. The purpose of this research is to assess if radiation treatment to the neck only for tumors with unclear original locations after careful surgical evaluation will lead to historical rates of disease control while reducing side effects and toxicity from treatment.

PRIMARY OBJECTIVE:

I. To describe the rate of manifestation of an occult primary tumor in the pharyngeal axis or delayed nodal recurrence in a un-dissected and/or non-irradiated neck at 2 years after study registration in patients treated with mucosal sparing (and unilateral neck, if applicable) radiotherapy after resection using transoral surgery for head and neck cancer of unknown primaries (HNCUP).

SECONDARY OBJECTIVES:

I. To describe the rates and severity of acute and late toxicities and PEG dependence attributable to mucosal sparing radiotherapy after resection using transoral surgery by assessment of grade 3 or higher adverse events National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5.0 criteria.

II. To describe the overall survival, recurrence-free survival (manifestation of an occult primary in the pharyngeal axis, nodal recurrence in a treated (surgery/radiation therapy [RT]) neck, delayed lymph node metastasis in an untreated neck (surgery/RT), and distant failure associated with mucosal sparing radiotherapy.

III. To describe swallowing function changes (assessed via swallowing study) associated with transoral surgery and adjuvant mucosal sparing radiotherapy.

OUTLINE:

Patients who have recurrence or progression during treatment or observation have medical charts reviewed every 6 months for 5 years. Patients who complete adjuvant treatment are followed for observation 3 days after radiation therapy, 1 month after radiation therapy, every 3 months after radiation therapy for 2 years, every 6 months for 1 year, and then annually for 2 years.

Inclusion Criteria:

• Patients meet criteria for intensity-modulated proton therapy (IMPT) treatment for oropharyngeal cancer

  • If IMPT is declined by patient's insurance, they can be treated with standard of care IMRT using the same applicable standard of care procedures outlined in the procedures manual

• Meet criteria for adjuvant chemotherapy (if applicable)

• Histological confirmation of human papillomavirus (HPV)+ squamous cell carcinoma as defined by neck node pathology. HPV positivity will be defined as positive staining for p16 and HPV deoxyribonucleic acid (DNA) in situ hybridization (ISH). (If discordant, ribonucleic acid [RNA] ISH will be run for confirmatory testing)

• Clinical stage T0 N1-N3 and confirmed pathologic stage T0 N1-N2 M0 (American Joint Committee on Cancer [AJCC] 8th edition) with one of the following risk factors:

  • Lymph node >= 3 cm
  • >= 2 positive lymph nodes
  • Presence of extracapsular extension
  • > 1 nodal level involved

• Absence of distant metastases on standard diagnostic workup, prior to registration (chest computed tomography [CT], chest x-ray [CXR], or positron emission tomography [PET]/CT)

• Able to undergo pre-operative Q-clear series PET/CT head/neck for diagnostic workup of occult primary and nodal disease

• Able to undergo transoral surgery and neck dissection by their ears, nose, and throat (ENT) oncologist

  • Surgical exploration/sampling of all mucosal sites including ipsilateral wide field tonsillectomy and base of tongue resection. Additional biopsies or surgical excision at the surgeon's discretion. Any radiographic or clinically suspicious areas should be biopsied or removed. Bilateral neck dissection for high risk patients. Ipsilateral dissection only, for patients with contralateral cN0 necks and negative preoperative imaging
  • Final pathologic evaluation demonstrating all benign samplings without discernible primary

• Documented smoking history

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

• Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only

• Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 35 days prior to registration)

• Platelet count >= 100,000/mm^3 (obtained =< 35 days prior to registration)

• Hemoglobin >= 8.0 g/dL (obtained =< 35 days prior to registration)

• Creatinine =< 1.5 mg/dL or creatinine clearance >= 50 mL/min (obtained =< 35 days prior to registration)

• Total or direct bilirubin < 2 x institutional upper limit of normal (ULN) (obtained =< 35 days prior to registration)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 3 x institutional ULN (obtained =< 35 days prior to registration)

• Ability to complete questionnaire(s) by themselves or with assistance

• Able to provide written informed consent

• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)

Exclusion Criteria:

• Any patient with positive retropharyngeal nodes on imaging

• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:

  • 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

• 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

• Other active malignancy =< 5 years prior to registration. EXCEPTIONS: Non-melanotic skin cancer, breast cancer, prostate cancer, well-differentiated thyroid cancer, carcinoma-in-situ of the cervix. NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer

• Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive

• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm

• History of connective tissue disorders such as scleroderma, rheumatoid arthritis, lupus, or Sjogren's disease

• Prior history of radiation therapy to the affected site