A Study Comparing Personalized Radiation Therapy With Standard Radiation Therapy in People With HPV-Positive Throat Cancer

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of HPV associatedsquamous cell carcinoma of the oropharynx (tonsil, base of tongue, or oropharyngealwalls) or squamous cell carcinoma with an unknown primary. Surgical removal ofprimary site is allowed.

• Patients must test positive for both p16 expression (70% nuclear and cytoplasmexpression; Ventana Medical Systems) and mRNA HPV in situ hybridization (RNAscope® 2.5 HD Reagent kit (Advanced Cell Diagnostics, Inc, Hayward, CA). Any CLIA certifiedtesting method can be used.

• Clinical stage T0-2, N1-2c (AJCC, 7th ed.) without evidence of distant metastasisbased on FDG PET/CT. Upfront clarity in staging for both editions is needed toensure eligibility.

• ECOG Performance Status of 0-1 or KPS >/=70

• Age ≥ 18

• Adequate hematologic function within 30 days prior to registration, defined asfollows:

• White Blood Count (WBC) ≥ 2 K/mcL

• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3

• Platelets ≥ 100,000 cells/mm^3

• Hemoglobin ≥ 10.0 g/dl

• Adequate renal function within 30 days prior to registration, defined as follows: o Serum creatinine < 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min determinedby 24-hour collection or estimated by Cockcroft-Gault formula: CCr male = [(140 -age) x (wt in kg)] [(Serum Cr mg/dl) x (72)] CCr female = 0.85 x (CrCl male)

• Negative serum pregnancy test within 14 days prior to registration for women ofchildbearing potential

• The patient must provide study-specific informed consent prior to study entry

Exclusion Criteria:

• Patients with prior head and neck radiation therapy where there is >30% overlap withthe current head and neck radiation fields. Exceptions can be made if determined bythe PI/Co-PI that the patient can proceed with protocol activities

• Patients whose tumors are borderline T4 based on anterior tumor extension to theextrinsic muscles of the tongue

• Patients with simultaneous primary cancers outside of the oropharynx o Note: Exceptions can be made for patients with simultaneous primaries outside theoropharynx if determined by the PI/Co-PI the patient can proceed with protocolactivities

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease freefor 3 years or if cure rate from treatment at 5 years to be 90% or greater o Note: Exceptions can be made for patients with prior malignancies outside theoropharynx if determined by the PI/Co-PI the patient can proceed with protocolactivities.

• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for adifferent cancer is allowable

• No particle therapy

• Patients who are deemed non-compliant to all the protocol related activities

• Contraindications to receive either cisplatin or the combination ofcarboplatin/5-fluorouracil at the prescribed doses.

• Severe, active co-morbidity defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalizationwithin the last 6 months

• Transmural myocardial infarction within the last 6 months

• Acute bacterial or fungal infection requiring intravenous antibiotics at thetime of registration

• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illnessrequiring hospitalization or precluding study therapy within 30 days ofregistration

• Hepatic Insufficiency resulting in clinical jaundice and/or coagulation defects