RATIONALE: Drugs used in chemotherapy, such as cisplatin and tirapazamine, and work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Tirapazamine may help cisplatin kill more tumor cells by making tumor cells more sensitive to the drug. Radiation therapy uses high-energy x-rays to kill tumor cells. Internal radiation uses radioactive material placed directly into or near a tumor to kill tumor cells. Cisplatin and tirapazamine may make tumor cells more sensitive to radiation therapy. It is not yet known whether giving cisplatin together with radiation therapy is more effective with or without tirapazamine in treating cervical cancer.

PURPOSE: This randomized phase III trial is studying cisplatin, radiation therapy, and tirapazamine to see how well they work compared to cisplatin and radiation therapy in treating patients with cervical cancer.

OBJECTIVES:

Primary

• Compare the progression-free survival of patients with stage IB, IIA, IIB, IIIB, or IVA carcinoma of the cervix treated with cisplatin and radiotherapy with vs without tirapazamine.

Secondary

• Compare overall survival of patients treated with these regimens.
• Compare the toxicity of these regimens in these patients.

Tertiary

• Correlate study treatment with tumor expression of carbonic anhydrase IX (CA-IX) and recurrence-free interval, overall survival, or metastasis in patients treated with these regimens.
• Correlate expression of CA-IX, hypoxia inducible factor-1α, CD-31, thrombospondin-1, CD-105, or vascular endothelial growth factor (VEGF) in primary tumor tissue with recurrence-free interval, overall survival, or metastasis in patients treated with these regimens.
• Correlate pre-treatment and/or post-treatment serum concentrations of angiogenic markers including angiogenin or VEGF with recurrence-free interval, overall survival, or metastasis in patients treated with these regimens.
• Correlate various combinations of biological markers of hypoxia and angiogenesis with recurrence-free interval, overall survival, or metastasis in patients treated with these regimens.
• Correlate levels of individual biological markers of hypoxia or angiogenesis with clinicopathological characteristics including tumor size, histologic subtype, FIGO stage, depth of invasion, pelvic node status, site of recurrence, and hemoglobin level as well as patient, age, race and performance status in patients treated with these regimens.

OUTLINE: This is a randomized, controlled, multicenter study. Patients are stratified according to FIGO stage of disease (IB2 vs IIA vs IIB vs IIIB vs IVA), brachytherapy method (low-dose rate vs high-dose rate), surgical staging of para-aortic nodes (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive cisplatin IV over 1 hour once weekly on days 1, 8, 15, 22, 29, and 36 (weeks 1-6). Patients also undergo external beam radiotherapy to the 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 and 3-5 days of parametrial boost radiotherapy** beginning after the first brachytherapy implant. Treatment continues in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive tirapazamine IV over 2 hours on days 1, 8, 10, 12, 15, 22, 24, 26, and 29 and cisplatin IV over 1 hour on days 1, 15, and 29. Patients also undergo radiotherapy and brachytherapy as in arm I. 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.

NOTE: **Not required for patients with stage IB or IIA disease.

After completion of study treatment, patients are followed for at least 5 years.

PROJECTED ACCRUAL: A total of 750 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous cell carcinoma of the uterine cervix
• Stage IB2, IIA, IIB, IIIB, or IVA disease
• Stage IIA tumors must be > 4 cm
• Primary, untreated disease
• Negative, non-suspicious para-aortic nodes by lymphangiogram, CT scan, MRI, or lymphadenectomy
• Must have been adequately clinically staged
• Suitable for treatment with radical intent using concurrent chemotherapy and pelvic radiotherapy
• No disease involvement of the lower third of the vagina
• No carcinoma of the cervical stump

PATIENT CHARACTERISTICS:

Performance status

• GOG 0-3

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• SGOT ≤ 3 times ULN
• Alkaline phosphatase ≤ 3 times ULN

Renal

• Creatinine ≤ 2.0 mg/dL

Cardiovascular

• No New York Heart Association class III-IV heart failure
• No history of myocardial infarction
• No unstable angina
• No uncontrolled hypertension

Other

• No pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No septicemia or severe infection
• No other invasive malignancy within the past 5 years except nonmelanoma skin cancer

PRIOR CONCURRENT THERAPY:

Surgery

• No prior hysterectomy
• No prior coronary artery bypass surgery

Other

• No prior cancer therapy that would preclude study treatment
• No concurrent angina medication