Cetuximab, Cisplatin, and Radiation Therapy in Treating Patients With Stage IB, Stage II, Stage III, or Stage IVA Cervical Cancer

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose or safe biologically effective dose of cetuximab when administered in combination with cisplatin, external beam radiotherapy, and brachytherapy in patients with stage IB-IVA cervical cancer.

II. Determine the feasibility of this regimen, in terms of chronic and acute toxic effects, in these patients.

SECONDARY OBJECTIVES:

I. Determine the distribution of progression-free survival and overall survival of patients treated with this regimen at 1 year after study entry.

II. Determine the site of recurrence (locoregional vs distant) in patients treated with this regimen up to 1 year after study entry.

III. Correlate response or progression-free survival with epidermal growth factor receptor expression in tumor samples from patients treated with this regimen at 1 year after study entry.

IV. Correlate response or progression-free survival with grade of cetuximab-induced rash in patients treated with this regimen at 1 year after study entry.

OUTLINE: This is a multicenter, dose-escalation study of cetuximab. Patients are stratified according to nodal status (positive para-aortic and/or pelvic lymph nodes vs negative para-aortic and pelvic lymph nodes).

Patients receive cetuximab IV over 1-2 hours and cisplatin IV on days 1, 8, 15, 22, 29, and 36 (weeks 1-6). Patients also undergo external beam radiotherapy to the para-aortic and pelvic lymph nodes OR whole pelvis once daily on days 1-5, 8-12, 15-19, 22-26, and 29-33 (weeks 1-5). Patients then receive either 1 or 2 applications of low-dose rate brachytherapy in weeks 6-8 OR 5 applications of high-dose rate (HDR)* brachytherapy once weekly in weeks 4-8. Treatment continues in the absence of disease progression or unacceptable toxicity.

NOTE: *No external beam radiotherapy is administered on the day of HDR brachytherapy. If the majority of external beam radiotherapy has been administered, HDR brachytherapy may be administered in 2 applications per week (separated by at least 72 hours) in order to complete all treatment within 8 weeks.

Cohorts of 3-6 patients per stratum receive escalating doses of cetuximab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

After completion of study treatment, patients are followed every 3 months for 1 year.

Inclusion criteria

• Histologically confirmed cervical cancer

• Clinical stage IB-IVA disease
• Any cell type allowed
• Positive or negative pelvic and/or para-aortic lymph nodes by radiography
• Unstained sections from primary tumor available
• Performance status - GOG 0-1
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• SGOT ≤ 2.5 times ULN
• Alkaline phosphatase ≤ 2.5 times ULN
• Creatinine normal
• Creatinine clearance > 50 mL/min
• Patients with ureteral obstruction must undergo stent or nephrostomy tube placement prior to study entry
• No renal abnormality (e.g., pelvic kidney or horseshoe kidney) that would require modification of radiation fields
• No significant cardiac disease within the past 6 months, including any of the following:

• Uncontrolled hypertension
• Unstable angina
• Congestive heart failure
• Uncontrolled arrhythmia
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No sensory or motor neuropathy > grade 1
• No septicemia
• No severe infection
• No circumstance that would preclude study participation or follow-up
• No other invasive malignancy within the past 5 years except nonmelanoma skin cancer
• No uncontrolled seizure disorder
• No active neurologic disease
• No history of active collagen vascular disease
• No prior chimerized or murine monoclonal antibody therapy
• No prior cytotoxic chemotherapy for cervical cancer
• No prior pelvic or abdominal radiotherapy for cervical cancer
• No concurrent intensity modulated radiotherapy
• No prior renal transplantation
• More than 30 days since prior major surgery (excluding diagnostic biopsy)
• No other prior therapy for cervical cancer
• No prior cancer treatment that would preclude study therapy
• No other concurrent investigational agents