This randomized phase III trial studies the side effects and how well intensity-modulated proton beam therapy works and compares it to intensity-modulated photon therapy in treating patients with stage III-IVB oropharyngeal cancer. Radiation therapy uses high-energy x-rays, protons, and other types of radiation to kill tumor cells and shrink tumors. It is not yet known whether intensity-modulated proton beam therapy is more effective than intensity-modulated photon therapy in treating oropharyngeal cancer.

PRIMARY OBJECTIVES:

To compare the progression-free survival (PFS) between concurrent chemo-radiation strategies with IMRT and IMPT following the treatment of oropharyngeal tumors.

SECONDARY OBJECTIVES:

1. To assess and compare overall survival between IMRT and IMPT along with estimating disease-related outcomes such as: [2-year progression-free survival, patterns of failure, 2-year overall survival, 2-year distant metastasis free survival, and second primary cancers]
2. To assess acute and chronic/late side effects, and to compare the rates of Grade 3-5 toxicity between IMRT and IMPT following the treatment of oropharyngeal tumors.
3. To assess Patient Reported Outcome (PRO) measures of symptoms using MD Anderson Symptom Inventory (MDASI), MD Anderson Dysphagia Inventory (MDADI), FACT-HN, Xerostomia and Health Questionnaire (EQ-5D-3L), Work status (WPAI: SHP)
4. To assess Physician Reported Toxicity using Common Terminology Criteria for Adverse Events (CTCAE)-4.0
5. To evaluate and compare Quality-Adjusted-Life-Years (QALY) between IMPT and IMRT;
6. To perform Cost-benefit economic analysis of treatment;
7. To determine whether specific molecular profiles are associated with overall or progression-free survival;
8. To investigate associations between changes in blood biomarkers, or HPV-specific cellular immune responses, or HPV ctDNA (measured at baseline and three months and at each follow-up visit for up to 10 years) with overall or progression-free survival;
9. To bank peripheral blood at time of enrollment, weeks 2, 4, and 6 during treatment and at each follow up visits for up to 10 years to explore the ability of circulating markers to predict outcome;
10. To bank head and neck tissues to explore the ability of tissue-based markers to predict outcome;
11. To bank peripheral blood and tissues for future interrogations; Finally, all additional secondary endpoints

EXPLORATORY OBJECTIVE:

I. To assess potential differences between patients on study and patients who were considered eligible for randomized, were randomized to a treatment arm, but were denied insurance coverage for the treatment arm she/he was randomized to; or may have dropped out of the study for other reasons after being randomized. These patients will compromise Group 3: consisting of patients randomized to Protons but not treated and Group 4: consisting of patients randomized to IMRT but not treated at the designated institution. Furthermore, these patients will only be followed for recurrence and survival.(Phase III)

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo IMRT once daily (QD) five days a week for approximately 6.5 weeks.

ARM II: Patients undergo IMPT QD five days a week for approximately 6.5 weeks.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, and then every 6 months for 5 years.

Inclusion Criteria:

• Histologically documented squamous cell carcinoma of the oropharynx (American Joint Committee on Cancer [AJCC] version [v]7 stage III-IV A,B)
• Tumor tissue (primary or cervical metastasis) available for human papilloma virus (HPV) and/or p16 (in situ hybridization [ISH], immunohistochemistry [IHC] or genotyping testing); if you do not have enough leftover tumor tissue available, you will have a tumor biopsy for tumor marker testing
• Eastern Cooperative Oncology Group (ECOG) performance status = 0, 1, or 2
• Negative pregnancy test for women of child bearing potential
• Concurrent chemotherapy
• Bilateral neck radiation

Exclusion Criteria:

• Previous radiation treatment for head and neck mucosal primary cancers within the past 5 years (i.e. oropharynx, nasopharynx, hypopharynx, larynx, and oral cavity)

• Pregnant or breast-feeding females

• Clinically significant uncontrolled major cardiac, respiratory, renal, hepatic, gastrointestinal or hematologic disease but not limited to:

  • Symptomatic congestive heart failure, unstable angina, or cardiac dysrhythmia not controlled by pacer device
  • Myocardial infarction within 3 months of registration

• Distant metastases (stage IV C, any T, any N and M1)

• Previous surgical resection or neck dissection for oropharyngeal cancer, administered with therapeutic intent