This clinical trial studies how well intensity modulated proton therapy (IMPT) or intensity modulated X-ray (radiation) therapy (IMRT) works after surgery in treating patients with head and neck cancer. IMPT is a type of radiation therapy that allows for the most accurate application of proton radiation to the tumor and has the potential to reduce treatment-related side effects. IMRT is a type of 3-dimensional radiation therapy that uses computer-generated images to show the size and shape of the tumor. Thin beams of x-ray radiation of different intensities are aimed at the tumor from many angles. This type of radiation therapy reduces the damage to healthy tissue near the tumor. IMPT may work as well as IMRT after surgery in treating patients with head and neck cancer.

PRIMARY OBJECTIVES:

I. To evaluate the local-regional control among subjects in each arm at 2 years after study registration.

II. To evaluate difference in MD Anderson Dysphagia Inventory (MDADI) score between patients with proton and intensity-modulated radiation therapy (IMRT) adjuvant radiation.

SECONDARY OBJECTIVES:

I. To determine overall survival, progression free survival, local, regional, distant recurrence risks, and infield and outfield recurrence in the trial at 2 years after study registration.

II. To determine the rate of grade 3+ acute adverse events (from treatment start to 30 days after radiation completion date).

III. To determine the rate and severity of late solicited toxicities. IV. To determine the incidence of secondary acute effects attributable to radiotherapy (e.g., percutaneous endoscopic gastrostomy [PEG] tube placement, duration and dose of narcotic analgesia required, weight loss, and hospitalization days).

V. To determine the impact of treatment on patient-reported quality of life. VI. To objectively quantify the severity of oral mucositis during and following radiotherapy.

EXPLORATORY OBJECTIVES:

I. To estimate direct and indirect costs of the study regimen and compare these with standard of care treatment techniques.

II. To correlate histopathologic, molecular, and tumor genetic/epigenetic alterations with clinical outcomes.

III. To correlate circulating biomarkers (micro ribonucleic acid [miRNA], circulating tumor deoxyribonucleic acid [ctDNA]) with clinical outcomes.

IV. To determine adverse events and patient reported outcomes related to abbreviated concomitant chemotherapy.

V. To qualitatively evaluate patient beliefs regarding tradeoffs of cancer control, treatment time, cost, acute side effects, and late side effects.

VI. To determine cancer outcomes, adverse events, and patient reported outcomes and compare across head and neck subsites, between those aged ≥ 65 to those age < 65 at date of enrollment, between male and female, and in the adjuvant population between time to total package completion (< 9 weeks vs ≥ weeks, surgery = day 0), and by treatment with and without chemotherapy.

VII. To evaluate the predictive relationship of linear energy transfer (LET) weighted modeling using an relative biologic enhancement (RBE)-based model and RBE-independent model with grade 3+ acute and late toxicity.

OUTLINE: Patients who already underwent surgical resection are assigned to Arm A. Patients who have undergone upfront surgical resection and need postoperative radiotherapy are assigned to Arm B or Arm C.

ARM A: Patients undergo intensity modulated proton therapy (IMPT) or IMRT for 18 sessions over 24 days in the absence of disease progression or unacceptable toxicity. Patients may receive cisplatin intravenously (IV) over 1-2 hours per standard of care. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) and positron emission tomography (PET)/CT or PET/MRI during screening and follow-up. Patients may also undergo blood sample collection throughout the trial.

ARM B: Patients undergo IMPT for 15 sessions over 19 days in the absence of disease progression or unacceptable toxicity. Patients may receive cisplatin IV over 1-2 hours per standard of care. Patients undergo CT or MRI and PET/CT or PET/MRI during screening and follow-up. Patients may also undergo blood sample collection throughout the trial.

ARM C: Patients undergo IMRT for 15 sessions over 19 days in the absence of disease progression or unacceptable toxicity. Patients may receive cisplatin IV over 1-2 hours per standard of care. Patients undergo CT or MRI and PET/CT or PET/MRI during screening and follow-up. Patients may also undergo blood sample collection throughout the trial.

After completion of study treatment, patients are followed up within 21 days and then at months 3, 6, 9, 12, 15, 18, 24, 35, 48, and 60.

Inclusion Criteria:

• Age >= 18 years

• Histological confirmation of a newly diagnosed non-human papillomavirus (HPV) associated malignant epithelial cancer in the head and/or neck. Diagnosis requires confirmation of p16 and/or HPV DNA negativity for oropharyngeal and unknown primary sites. p16 positivity in skin cancers is allowed

• Primary lesion located in the nasal cavity, paranasal sinuses, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, lymph nodes (unknown primary or metastasis from head and neck [HN]-skin primary) or skin cancer where lymph node radiation is recommended

  • NOTE: Patients with primary lesions in the larynx must have a T3 primary, bulky T2 primary (> 6 cc), and/or at least 1 regional lymph node

• Confirmation of American Joint Committee on Cancer (AJCC) 8th edition defined M0 established by positron emission tomography (PET)/computed tomography (CT) or PET/magnetic resonance imaging (MRI)

• Eastern Cooperative Oncology Group (ECOG) performance status (0-1 prior to initial treatment)

• Able to provide written informed consent

• Able to complete questionnaires independently or with assistance

• Willing to return to enrolling institution for follow up during the observation phase

Exclusion Criteria:

• 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

• Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy

  • NOTE: Patients known to be HIV positive, but without clinical evidence of immunocompromised state, are eligible for this trial

• 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

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

• Other active malignancy =< 2 years prior to registration

  • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix and prostate cancer with a Gleason score of 6 or less
  • NOTE: If there is a history or prior malignancy, they must not be receiving ongoing anticancer treatment

• History of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

• Prior radiation therapy that would have a clinically significant overlap with the intended head/neck radiation

• For Arms A and B only: Unable to receive proton therapy because of extensive metallic hardware in close proximity to treatment site, logistical circumstances, or any other reason

• Any of the following diagnoses: HPV-associated squamous cell carcinoma, germ cell tumors, hematologic malignancies, neuroendocrine malignancies, adenoid cystic carcinoma, sarcomas of bone, benign tumors