Concurrent chemotherapy and radiation therapy (chemoRT) has become the standard of care for treatment of many patients with advanced head and neck squamous cell carcinoma (HNSCC), though many clinical questions remain. Prior experience has revealed locoregional control (LRC), disease free survival (DFS) and overall survival (OS) at 3 years exceeding 80% after treatment with the use of hyperfractionated intensity modulated radiation therapy (IMRT) and concurrent weekly cisplatin chemotherapy for patients with locally advanced HNSCC. This multi-institutional phase II ZCC00204 trial resulted in an acceptable quality of life (QOL) and toxicity profile. The current trial is an attempt to maintain high LRC, while further minimizing both acute and chronic toxicities, and maximizing QOL.

Inclusion Criteria:

• Biopsy proven squamous cell carcinoma of oral cavity, oropharynx, hypopharynx, or larynx
• No surgical resection of primary site or neck dissection (excisional biopsy of lymph node is permitted)
• Human Papilloma Virus (HPV) testing of tumor performed; HPV p16 by immunohistochemistry
• Stage III or IVa disease (T1-2N1-3M0, T3-4N0-3M0) excluding T1-2N1 oral cavity and tonsil primaries and any N2C or bilateral N3 disease. Patients with T2N0 cancer of the base of tongue and hypopharynx are eligible
• ECOG performance status 0-1
• Age >18 years
• No current pregnancy
• No other invasive malignancies within the last 2 years Patients with basal cell or squamous cell skin cancers or carcinoma in situ of any site are eligible.
• No prior radiotherapy to the head and neck region
• No prior cisplatin chemotherapy
• No symptomatic coronary disease or myocardial infarction within the last 6 months
• Laboratory evaluation: ANC > 2,000/mm3, platelets >100,000/mm3, creatinine < 1.5 mg/dl, creatinine clearance > 50 ml/min, bilirubin < 1.5 mg/dl, AST or ALT < 2X upper normal limit
• Study-specific consent signed prior to entry

Exclusion Criteria:

• Second primary malignancy that is clinically detectable
• Inability or unwillingness to comply with chemoRT
• Prior radiotherapy, chemotherapy, or investigational treatment for squamous cell carcinoma of head and neck.
• Metastatic disease (M1)
• Pregnant or breast-feeding women.