Inclusion Criteria:

• PRE-REGISTRATION (STEP 0)
• Pathologically proven diagnosis of squamous cell carcinoma (including variants such as verrucous carcinoma, spindle cell carcinoma, carcinoma not otherwise specified [NOS]) of the head/neck (oral cavity, oropharynx, hypopharynx or larynx); clinical stage T2-T4a, N0-2, M0 or T1, N1-2, M0
• Patient has undergone total resection of the primary tumor with curative intent
• Patient must have negative human papillomavirus (HPV) status of the tumor as determined by p16 protein expression using immunohistochemistry (IHC)
• The patient must have the following assessments done within 80 days prior to randomization:
  • Examination by an Ear, Nose, and Throat (ENT)/Head & Neck Surgeon
  • Neck computed tomography (CT) scan (from skull base to clavicle) and
  • Chest x-ray (or chest CT scan or CT/positron emission tomography [PET] of the chest) to rule out distant metastatic disease
• Patients with, per the operative and/or pathology report, positive margin(s) (tumor present at the cut or inked edge of the tumor), nodal extracapsular extension, and/or gross residual disease after surgery are not eligible
• A paraffin-embedded surgical tumor tissue specimen has been located is available for shipment to Foundation Medicine, Inc. following pre-registration
• Patients with a history of a curatively treated malignancy must be disease-free for at least two years except for carcinoma in situ of cervix and/or non-melanomatous skin cancer
• Patient must not have had previous irradiation to the head and neck that would result in overlap in radiation fields for the current disease
• RANDOMIZATION (STEP 1)
• Per the operative report, the gross total resection of the primary tumor with curative intent was completed within 7 weeks prior to randomization
• Patient has Eastern Cooperative Oncology Group (ECOG) performance status 0-1 within 2 weeks prior to randomization
• Women must not be pregnant or breast-feeding; females of childbearing potential must have a blood or urine study within 2 weeks prior to randomization to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study
• Absolute neutrophil count >= 1,500/mm^3
• Platelets >= 100,000/mm^3
• Total bilirubin =< the upper limit of normal (ULN)
• Calculated creatinine clearance must be > 60 ml/min using the Cockcroft-Gault formula
• Patient must not have an intercurrent illness likely to interfere with protocol therapy