Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Cisplatin and Radiation Therapy With or Without Tirapazamine in Treating Patients With Cervical Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	18 and over	NCI	GOG-0219 CAN-NCIC-GOG-0219, NCT00262821

Special Category: CTSU trial

Objectives

Primary

1. 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

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

Tertiary

1. Correlate study treatment with tumor expression of carbonic anhydrase IX (CA-IX) and recurrence-free survival, overall survival, or metastasis in patients treated with these regimens.
2. 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 survival, overall survival, or metastasis in patients treated with these regimens.
3. Correlate pre-treatment and/or post-treatment serum concentrations of angiogenic markers including angiogenin or VEGF with recurrence-free survival, overall survival, or metastasis in patients treated with these regimens.
4. Correlate various combinations of biological markers of hypoxia and angiogenesis with recurrence-free survival, overall survival, or metastasis in patients treated with these regimens.
5. 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.

Entry Criteria

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 regardless of stage (all stage IIIA, IIIB and IVA with lower one-third involvement)
• No carcinoma of the cervical stump

Prior/Concurrent Therapy:

Surgery

• No prior hysterectomy or planned hysterectomy as part of initial cervix cancer therapy
• No prior coronary artery bypass surgery

Other

• No prior cancer therapy that would preclude study treatment
• No concurrent angina medication
• No concurrent intensity-modulated radiotherapy

Patient Characteristics:

Performance status

• GOG 0-3

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³

Hepatic

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

Renal

• Creatinine ≤ ULN or calculated creatinine clearance ≥ 60mL/min

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

Expected Enrollment

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

Outcomes

Progression-free survival
Overall survival
Local control

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 30-60 minutes 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: **Patients may receive a parametrial boost at the discretion of the treating radiation oncologist.]

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

Trial Contact Information

Trial Lead Organizations

Gynecologic Oncology Group

Paul DiSilvestro, MD, Protocol chair		Ph: 401-453-7520 Email: pdisilvestro@wihri.org
Bradley Monk, MD, Protocol co-chair		Ph: 714-456-7974 Email: bjmonk@uci.edu

NCIC-Clinical Trials Group

Peter Craighead, MD, Protocol chair		Ph: 403-521-3997 Email: peterch@cancerboard.ab.ca

Registry Information
Official Title		A Phase III, Randomized Trial of Weekly Cisplatin and Radiation Versus Cisplatin and Tirapazamine and Radiation in Stage IB2, IIA, IIIB and IVA Cervical Carcinoma Limited to the Pelvis
Trial Start Date		2006-02-06
Trial Completion Date		2008-07-25 (estimated)
Registered in ClinicalTrials.gov		NCT00262821
Date Submitted to PDQ		2005-11-07
Information Last Verified		2009-09-02
NCI Grant/Contract Number		CA27469

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