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

Study Overview
=================
Brief Summary
-----------------
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. Drugs used in chemotherapy, such as cisplatin and tirapazamine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. 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 OBJECTIVES: I. Compare overall survival of patients treated with these regimens. II. Compare the toxicity of these regimens in these patients. TERTIARY OBJECTIVES: I. 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. II. 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. III. 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. IV. Correlate various combinations of biological markers of hypoxia and angiogenesis with recurrence-free survival, overall survival, or metastasis in patients treated with these regimens. V. 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 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.

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

Conditions
-----------------
Cervical Adenocarcinoma, Cervical Adenosquamous Cell Carcinoma, Cervical Squamous Cell Carcinoma, Stage IB Cervical Cancer, Stage IIA Cervical Cancer, Stage IIB Cervical Cancer, Stage III Cervical Cancer, Stage IVA Cervical Cancer

Intervention / Treatment
-----------------
* Drug: cisplatin
* Drug: tirapazamine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 Performance status - GOG 0-3 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Bilirubin ≤ 1.5 times upper limit of normal (ULN) SGOT ≤ 3 times ULN Alkaline phosphatase ≤ 3 times ULN Creatinine ≤ ULN or calculated creatinine clearance ≥ 60mL/min No New York Heart Association class III-IV heart failure No history of myocardial infarction No unstable angina No uncontrolled hypertension 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 No prior hysterectomy or planned hysterectomy as part of initial cervix cancer therapy No prior coronary artery bypass surgery No prior cancer therapy that would preclude study treatment No concurrent angina medication No concurrent intensity-modulated radiotherapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (cisplatin)<br>Patients receive cisplatin IV on days 1, 8, 15, 22, 29, and 36 (weeks 1-6). | Drug: cisplatin<br>* Given IV<br>* Other names: DDP;|
| Experimental: Arm II (cisplatin, tirapazamine)<br>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. | Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Drug: tirapazamine<br>* Given IV<br>* Other names: WIN 59075;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival - Percentage of Patients Alive and Progression Free | Patients' progression status based on clinical, radiological or pathological (histological) evidence of disease after study therapy. Progression includes any death without evidence of disease progression. Progression-free Survival (PFS) is defined as time in month from study enrollment to disease progression, death or date of last contact. | From study entry until first disease progression, death or date of last contact, up to 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | The observed length of life from entry into the study to death or date of last contact. | From study entry to death or last contact, up to 6 years | 
| Adverse Events (Grade 3 or Higher) During Treatment Period | Number of participants with a maximum grade of 3 or higher during treatment period. Adverse events are graded and categorized using CTCAE v3.0. | All Adverse Events (AEs) occuring during treatment and up to 30 days after stopping the study treatment are reported |