Phase II Study of Concurrent C225, Cisplatin and Radiation in Stage IV Squamous Cell Carcinoma of the Head and Neck

OBJECTIVES:

Primary

• Determine 2-year progression-free survival in patients with unresectable locally advanced or regional stage IV squamous cell or undifferentiated carcinoma of the head and neck treated with cetuximab, cisplatin, and definitive radiotherapy.

Secondary

• Determine response rate and overall survival in patients treated with this regimen.
• Determine the toxic effects of this regimen in these patients.
• Correlate epidermal growth factor receptor (EGFR) expression by immunohistochemistry, EGFR phosphorylation, map kinase, Akt, signal transducer and activator of transcription 3 (STAT3), and other tissue and serum tests with toxicity of this regimen and outcomes in these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to tumor site (hypopharynx vs. oropharynx vs. oral cavity vs. larynx), primary tumor stage (T1-3 vs. T4), and nodal status (N0 vs. N1 vs. N2-3).

• Cetuximab therapy: Patients receive an initial loading dose of cetuximab IV over 2 hours on day 1. Patients then receive cetuximab IV over 1 hour on days 8, 15, 22, 29, 36, 43, 50, and 57.
• Chemoradiotherapy: Beginning on day 15 of cetuximab therapy, patients undergo radiotherapy once daily, 5 days a week, for at least 7 weeks. Patients also receive cisplatin IV over 1-2 hours on days 15, 36, and 57.
• Cetuximab maintenance therapy: After the completion of chemoradiotherapy, patients continue to receive cetuximab IV over 1 hour once weekly for 6-12 months.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 6 months for 10 years.

ACCRUAL: A total of 69 patients were accrued for this study.

Inclusion criteria

• Histologically confirmed squamous cell or undifferentiated carcinoma of the head and neck (excluding nasopharynx, paranasal sinus, and parotid gland)

• Unresectable locally advanced or regional stage IV disease
• No evidence of distant metastases
• Must have demonstrable primary tumor site
• Measurable disease
• Unresectable disease

• Meets the following criteria for unresectable disease by tumor site:

• Hypopharynx, meeting 1 of the following criteria:

• Extension across the midline of the posterior pharyngeal wall
• Any evidence of fixation to the cervical spine
• Larynx

• Direct subglottic extension (>3cm) into surrounding muscle or skin
• Oral cavity

• Lesion precluding functional reconstruction
• Base of tongue, meeting 1 of the following criteria:

• Extension into the root of the tongue
• Patient refuses total glossectomy
• Tonsillar area, meeting 1 of the following criteria:

• Extension into pterygoid area as manifested by x-ray or trismus
• Extension across midline of pharyngeal wall
• Direct extension into soft tissue of the neck
• Unilateral neck node metastases fixed to carotid artery, mastoid, base of skull, or cervical spine with any of the above tumors
• Patients requiring total glossectomy are eligible
• Age>=18 years
• ECOG Performance status of 0-1
• Adequate hematologic, renal, and hepatic function obtained <=4 weeks prior to registration

• Absolute neutrophil count ≥ 2,000/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9.0 g/dL
• Alkaline phosphatase ≤ 3 times normal
• Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤ 3 times normal
• Bilirubin ≤ 1.5 mg/dL
• Creatinine ≤ 1.2 mg/dL OR creatinine clearance ≥ 50 mL/min
• Able to tolerate fluid load
• At least 14 days since major surgery (including dental extraction) except percutaneous endoscopic gastrostomy (PEG) placement or mediport placement

Exclusion criteria

• Pregnant or nursing
• Fertile patients do not use effective contraception
• Patients who refuse surgery but whose tumors are technically resectable OR whose tumors are unresectable for medical reasons are not eligible
• Disease metastases below the clavicles or elsewhere (M1) or with a postoperative recurrence
• Prior excisional surgery of head and neck tumor
• Prior radiotherapy to the head and neck region
• Prior chemotherapy
• Prior drugs that target the epidermal growth factor receptor pathway
• Prior chimerized or murine monoclonal antibody
• Active systemic infection
• Known allergy to murine proteins
• Severe chronic obstructive pulmonary disease requiring ≥ 3 hospitalizations within the past year
• Myocardial infarction within the past 3 months
• Uncontrolled congestive heart failure
• Unstable or uncontrolled angina
• Clinically apparent jaundice
• Postoperative recurrence
• Other malignancy within the past 3 years except resected basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or other in situ tumors