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

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)