4B951, Combination Chemotherapy in Treating Patients With Bladder Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known whether combination chemotherapy is more effective than observation alone in treating bladder cancer. PURPOSE: This randomized phase III trial is studying combination chemotherapy to see how well it works compared to observation alone in treating patients with bladder cancer.

Detailed Description
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OBJECTIVES: Compare the recurrence-free and overall survival in patients with transitional cell carcinoma of the bladder with p53 gene alterations treated with methotrexate, vinblastine, doxorubicin, and cisplatin vs observation alone. Compare the recurrence-free and overall survival in patients with or without p53 gene alterations treated with observation alone. Examine the expression of p53 and other genes, particularly RB, p21, and p16, involved in cell cycle regulation that may be involved in the response to chemotherapy in these patients. Correlate p53 mutational gene status with p53 protein expression by immunohistochemistry, outcome (recurrence-free and overall survival), response to chemotherapy, and expression of key molecules in the p53-mediated apoptotic pathway in patients treated with this regimen vs observation alone. OUTLINE: This is a randomized, multicenter study. Patients are assigned to 1 of 2 treatment groups based on the status of the p53 gene in the bladder tumor. Group A (p53 gene alteration, defined by greater than 10% nuclear reactivity): Patients are stratified according to age (under 65 vs 65 and over), stage (P1 vs P2a vs P2b), grade (1 or 2 vs 3 or 4), and p21 status. Patients are randomized to 1 of 2 treatment arms within 10 weeks after radical cystectomy and bilateral pelvic lymphadenectomy and within 2 weeks after registration. Arm I: Within 2 weeks after randomization, patients receive 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. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Arm II: Patients undergo observation for recurrence but do not receive adjuvant chemotherapy after surgery. Patients who are eligible for randomization but decline to be randomized undergo observation for recurrence. Group B (p53 gene normal, defined by less than 10% nuclear reactivity): Patients undergo observation for recurrence but do not receive adjuvant chemotherapy after surgery. Patients are followed every 6 months for 5 years and then annually thereafter. PROJECTED ACCRUAL: A total of 800 patients will be accrued for this study within 4.75 years.

Official Title
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MVAC (Methotrexate, Vinblastine, Adriamycin, and Cisplatin) in Organ-Confined Bladder Cancer Based on p53 Status

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: doxorubicin hydrochloride
* Drug: methotrexate
* Drug: vinblastine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically proven organ confined transitional cell carcinoma (TCC) of the bladder Must have undergone radical cystectomy and bilateral pelvic lymphadenectomy with pathologic stage from definitive cystectomy specimen of P1, P2a, or P2b and N0, M0 TCC with or without squamous/glandular differentiation (no adenocarcinoma, squamous cell carcinoma, or small cell carcinoma) Margins must be negative for invasive or in situ TCC In situ TCC in the urethra or ureter(s) allowed provided margins are negative Clinical stage T1, T2a, or T2b based on transurethral resection bladder tumor specimen with P0 or PIS and N0, M0 TCC allowed Incidental pT2a (Gleason score no greater than 7), pT2b (Gleason score no greater than 7), or pT2c (Gleason score no greater than 7) adenocarcinoma of the prostate allowed No invasive tumor into ureter(s) or urethra Must have potentially curable disease Must register within 9 weeks after surgery No metastatic disease by physical exam and chest x-ray or CT scan of the chest Eligible for randomization if: p53 gene alteration present Randomization occurs within 10 weeks after surgery Those who are randomized to receive (MVAC) methotrexate, vinblastine, doxorubicin, and cisplatin begin MVAC within 12 weeks after cystectomy No metastatic disease by physical exam and chest x-ray or CT scan of the chest No prohibitive medical risk for chemotherapy PATIENT CHARACTERISTICS: Age Any age Performance status ECOG 0-1 OR Karnofsky 70-100% Life expectancy Not specified Hematopoietic WBC at least 4,000/mm^3 Platelet count at least 150,000/mm^3 Hepatic SGOT or SGPT no greater than 2 times normal Alkaline phosphatase no greater than 2 times normal Bilirubin normal Renal Creatinine no greater than 1.8 mg/dL OR Creatinine clearance at least 50 mL/min Blood urea nitrogen normal Cardiovascular No serious arrhythmias No congestive heart disease with New York Heart Association class III or IV status Randomization group: Ejection fraction must be at least 50% by MUGA scan if there is a clinical concern regarding the patient's cardiac status Other No other malignancy (including synchronous papillary or invasive upper urinary tract malignancy) within the past 5 years except incidental prostate cancer (found at cystectomy), basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix No concurrent advanced medical illness or psychologic disease No prohibitive medical risk for chemotherapy Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy See Disease Characteristics No prior systemic chemotherapy for bladder cancer At least 5 years since other prior systemic chemotherapy Prior intravesical therapy allowed Randomization group: Prior intravesical therapy allowed if administered prior to cystectomy Endocrine therapy Not specified Radiotherapy No prior pelvic irradiation Surgery See Disease Characteristics

Ages Eligible for Study
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Maximum Age: 120 Years

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 |
| --- | --- |
| Experimental: Arm I: M-VAC x 3<br>Patients with altered (+) p53, reconsented to randomization, randomized to three cycles of MVAC | Drug: cisplatin<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: methotrexate<br> <br> Drug: vinblastine<br> <br> |
| No Intervention: Arm II: Observation<br>Patients with altered (+) p53, reconsented to randomization, randomized to observation | |
| No Intervention: Arm III: Observation<br>Patients with unaltered (-) p53 | |
| No Intervention: Arm IV: Observation<br>Patients with altered (+) p53, patients did not consent to randomization | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probability of Recurring | p53 positive patients randomized to MVAC (arm I) compared to p53 positive patients randomized to observation (arm II). Time from registration to the first observation of disease recurrence, censoring patients who died of unrelated causes. Probabilities of recurring were based on cumulative incidence curves. Recurrence is defined as first radiological appearance of bladder cancer, per local standard of care. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probability of Overall Survival | p53 positive patients randomized to MVAC (arm I) compared to p53 positive patients randomized to observation (arm II). Survival is calculated from registration to death due to any cause. Probabilities of survival were based on the Kaplan-Meier product-limit method. | 5 years | 
| Probability of Recurrence | Patients with tumors demonstrating alteration in p53 compared to patients with no p53 alterations. Probabilities of recurring were based on cumulative incidence curves. Recurrence is defined as first radiological appearance of bladder cancer, per local standard of care. | 5 years | 
| Probability of Overall Survival | Patients with tumors demonstrating alteration in p53 compared to patients with no p53 alterations. Probabilities of survival were based on the Kaplan-Meier product-limit method. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I bladder cancer, stage II bladder cancer, transitional cell carcinoma of the bladder