Comparison of Immediate and Delayed Adjuvant Chemotherapy in Treating Patients Who Have Undergone a Radical Cystectomy for Stage III or Stage IV Transitional Cell Carcinoma of the Bladder Urothelium

Study Overview
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Brief Summary
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Randomized phase III trial to compare the effectiveness of immediate adjuvant chemotherapy with that of adjuvant chemotherapy given when the cancer returns in treating patients who have undergone a radical cystectomy for stage III or stage IV transitional cell carcinoma of the bladder urothelium. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug and giving them after surgery may kill any remaining tumor cells. It is not yet known if adjuvant chemotherapy is more effective when given immediately after radical cystectomy (surgery to remove the bladder) or when the cancer returns.

Detailed Description
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PRIMARY OBJECTIVES: I. Compare the overall and progression-free survival of patients with stage III or IV transitional cell carcinoma of the bladder urothelium treated with immediate versus deferred adjuvant chemotherapy after radical cystectomy. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, tumor status (pT1-2 vs pT3 vs pT4), and node status (node positive vs node negative with 15 or more nodes sampled vs node negative with less than 15 nodes sampled). Patients are randomized to one of two treatment arms. ARM I: Beginning within 90 days of radical cystectomy, patients receive a total of 4 courses of adjuvant chemotherapy. ARM II: Beginning at the time of clinical relapse, patients receive a total of 6 courses of adjuvant chemotherapy. Patients in both arms receive one of the following chemotherapy regimens to be determined by participating center: REGIMEN A (Classical M-VAC): Patients receive classical M-VAC comprising methotrexate IV on days 1, 15 and 22; vinblastine IV on days 2, 15, and 22; and doxorubicin IV and cisplatin IV on day 2. Courses repeat every 28 days. REGIMEN B (High-dose M-VAC): Patients receive high-dose M-VAC comprising methotrexate IV on day 1 and vinblastine IV, doxorubicin IV, and cisplatin IV on day 2. Patients also receive filgrastim (G-CSF subcutaneously once daily on days 4-10. Courses repeat every 14 days. REGIMEN C (Gemcitabine and cisplatin): Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 followed by cisplatin IV on day 1 or 2. Courses repeat every 28 days. Patients are followed every 3 months for 1 year, every 6 months for 5 years, and then annually thereafter. Peer Reviewed and Funded or Endorsed by Cancer Research UK and EORTC.

Official Title
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Randomized Phase III Trial Comparing Immediate Versus Deferred Chemotherapy After Radical Cystectomy in Patients With pT3-pT4, and/or N+M0 Transitional Cell Carcinoma (TCC) of the Bladder

Conditions
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Stage III Bladder Cancer, Stage IV Bladder Cancer, Transitional Cell Carcinoma of the Bladder

Intervention / Treatment
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* Drug: doxorubicin hydrochloride
* Drug: gemcitabine hydrochloride
* Drug: vinblastine sulfate
* Drug: methotrexate
* Drug: cisplatin
* Biological: filgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed transitional cell carcinoma of the bladder urothelium T3-4, N1-3, M0 No pure squamous cell or adenocarcinoma tumors No more than 90 days since prior radical cystectomy and bilateral lymphadenectomy without evidence of microscopic residual disease Performance status - WHO 0-1 WBC at least 3,500/mm^3 Platelet count at least 120,000/mm^3 SGOT/SGPT less than 2.5 times upper limit of normal (ULN) Alkaline phosphatase less than 2.5 times ULN Bilirubin normal Glomerular filtration rate greater than 60 mL/min No clinically significant cardiac arrhythmia No congestive heart failure No complete bundle branch block No New York Heart Association class III or IV heart disease Not pregnant or nursing Fertile patients must use effective contraception during and for 6 months after study Considered fit for cisplatin-containing combination chemotherapy No clinically abnormal auditory function No known hypersensitivity to E. coli-derived drug preparations No grade 2 or greater peripheral neuropathy No other prior or concurrent malignancy except adequately treated carcinoma in situ of the cervix, treated basal cell skin cancer, or treated incidental prostate cancer (pT2, Gleason score no greater than 6, and PSA less than 0.5 ng/mL) No psychological, familial, sociological, or geographical condition that would preclude study involvement No prior systemic chemotherapy No prior radiotherapy to the bladder
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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 (immediate chemotherapy)<br>Beginning within 90 days of radical cystectomy, patients receive a total of 4 courses of adjuvant chemotherapy. | Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: Adriamycin RDF;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Drug: vinblastine sulfate<br>* Given IV<br>* Other names: Velsar;Drug: methotrexate<br>* Given IV<br>* Other names: MTX;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Biological: filgrastim<br>* Given SC<br>* Other names: Neupogen;|
| Experimental: Arm II (deferred chemotherapy)<br>Beginning at the time of clinical relapse, patients receive a total of 6 courses of adjuvant chemotherapy. | Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: Adriamycin RDF;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Drug: vinblastine sulfate<br>* Given IV<br>* Other names: Velsar;Drug: methotrexate<br>* Given IV<br>* Other names: MTX;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;Biological: filgrastim<br>* Given SC<br>* Other names: Neupogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of survival | Estimated using the Kaplan-Meier technique and compared based on a two sided logrank test with retrospective stratification for the participating cooperative group, the chemotherapy regimen, the T category and the nodal status. | 5 years | 
| Duration of progression-free survival | Estimated using the Kaplan-Meier technique and compared based on a two sided logrank test with retrospective stratification for the participating cooperative group, the chemotherapy regimen, the T category and the nodal status. | 5 years |