Study of Mucosal Sparing Adjuvant Radiotherapy After Surgical Exploration in HPV+ Head and Neck Cancer of Unknown Primaries

Prior treatment

• 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
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
• Prior history of radiation therapy to the affected site

Other illness

• 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
• Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive
• History of connective tissue disorders such as scleroderma, rheumatoid arthritis, lupus, or Sjogren's disease

Age

• 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

Other

• 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

• 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)