Combination Chemotherapy and Radiation Therapy With/Without Surgery In Patients With Stage II/III Bladder Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy (RT) uses high-energy x-rays to damage tumor cells. It is not yet known which regimen of combination chemotherapy plus radiation therapy with or without surgery is more effective in treating bladder cancer. PURPOSE: Randomized phase II trial to study the effectiveness of two combination chemotherapy regimens and radiation therapy with or without radical cystectomy in treating patients who have stage II or stage III bladder cancer.

Detailed Description
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OBJECTIVES: Estimate the safety and tolerability of induction paclitaxel, cisplatin, and radiotherapy or fluorouracil, cisplatin, and radiotherapy followed by consolidation chemoradiotherapy or radical cystectomy and adjuvant gemcitabine, paclitaxel, and cisplatin in patients with operable stage II or III bladder cancer. Estimate the efficacy of these regimens, in terms of complete response, in patients who have undergone prior transurethral resection (TUR). Estimate the efficacy of these regimens after TUR, in terms of preserving the native tumor-free bladder 5 years after therapy, in these patients. Estimate the function of the preserved bladder in patients treated with these regimens after TUR. Determine the value of tumor histopathologic, molecular genetic, and DNA content parameters as possible prognostic factors for initial tumor response and recurrence-free survival in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to T stage (T2 vs T3/T4 ). Patients are randomized to one of two treatment arms. Induction therapy (weeks 1-3): Arm I: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and cisplatin IV over 1 hour on days 1-3, 8-10, and 15-17. Patients also receive pelvic radiotherapy twice daily on days 1-5, 8-12, and 15-17. Arm II: Patients receive fluorouracil IV over 24 hours on days 1-3 and 15-17 and cisplatin IV over 1 hour on days 1-3, 8-10, and 15-17. Patients also receive pelvic radiotherapy as in arm I. Patients in both arms who achieve complete response after induction therapy proceed to consolidation therapy on week 8. Patients with operable pT1 or worse tumor response proceed to radical cystectomy on week 9. Consolidation therapy (weeks 8 and 9): Arm I: Patients receive paclitaxel IV over 1 hour on days 1 and 8 and cisplatin IV over 1 hour on days 1, 2, 8, and 9. Patients also receive pelvic radiotherapy twice daily on days 1-5 and 8-10. Arm II: Patients receive 5-FU IV over 24 hours on days 1-3 and 8-10 and cisplatin as in arm I. Patients also receive radiotherapy as in arm I. Adjuvant chemotherapy (weeks 21-33 or 17-29): Beginning 12 weeks after consolidation therapy or 8 weeks after radical cystectomy, patients receive gemcitabine IV over 30-60 minutes, paclitaxel IV over 1 hour, and cisplatin IV over 1 hour on days 1 and 8. Treatment repeats every 3 weeks for 4 courses. Patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 3 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 96 patients (48 per treatment arm) will be accrued for this study within 3 years.

Official Title
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A Phase II Randomized Trial for Patients With Muscle-Invading Bladder Cancer Evaluating Transurethral Surgery and BID Irradiation Plus Either Paclitaxel and Cisplatin or 5-Fluorouracil and Cisplatin Followed by Selective Bladder Preservation and Gemcitabine/Paclitaxel/Cisplatin Adjuvant Chemotherapy

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: fluorouracil
* Drug: paclitaxel
* Radiation: radiation therapy
* Drug: Gemcitabine
* Procedure: Radical cystectomy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed operable primary muscle invasive bladder cancer T2-T4a, NX or N0, M0 (stage II or III) Must have an adequate functioning bladder Must have undergone a prior transurethral resection of the bladder tumor within the past 8 weeks No evidence of tumor-related hydronephrosis No evidence of distant metastases or histologically or cytologically confirmed lymph node metastases Patients with involvement of the prostatic urethra with transitional cell cancer that was visibly completely resected are allowed No evidence of stromal invasion of the prostate PATIENT CHARACTERISTICS: Age Not specified Performance status Zubrod 0-1 Life expectancy Not specified Hematopoietic Hemoglobin at least 10 g/dL White blood cell (WBC) count at least 4,000/mm^3 Absolute neutrophil count at least 1,800/mm^3 Platelet count at least 100,000/mm^3 Hepatic Serum bilirubin no greater than 2.0 mg/dL Renal Serum creatinine no greater than 1.5 mg/dL Creatinine clearance at least 60 mL/min NOTE: If the creatinine clearance is greater than 60 mL/min, creatinine of no greater than 1.8 mg/dL is allowed at the discretion of the study chair Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other malignancy within the past 5 years except nonmelanoma skin cancer, stage T1a prostate cancer, or carcinoma in situ of the cervix Must be able to tolerate systemic chemotherapy with pelvic radiotherapy and radical cystectomy PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior systemic chemotherapy Endocrine therapy Not specified Radiotherapy No prior pelvic radiotherapy Surgery See Disease Characteristics Other No concurrent drugs that have potential nephrotoxicity or ototoxicity (e.g., aminoglycosides)

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: Pelvic RT + paclitaxel + cisplatin<br>Induction: Twice-daily pelvic radiation therapy (RT) with paclitaxel and cisplatin; Consolidation: Twice-daily pelvic radiation therapy with paclitaxel and cisplatin if tumor response is T0/Ta/Tis or radical cystectomy if tumor response is ≥ T1; Adjuvant: gemcitabine, paclitaxel, and cisplatin. | Drug: cisplatin<br>* Induction: 15 mg/m2 as a 60-minute infusion on days 1, 2, 3, 8, 9, 10, 15, 16, and 17; Consolidation: 15 mg/m2 as a 60-minute infusion on days 1, 2, 8, and 9; Adjuvant: 35 mg/m2 as a 60-minute infusion on days 1 and 8 of each 21-day cycle for 4 cycles.<br>Drug: paclitaxel<br>* Induction: 50 mg/m2 as a 60-minute infusion on days 1, 8, and 15; Consolidation: 50 mg/m2 as a 60-minute infusion on days 1 and 8; Adjuvant: 50 mg/m2 as a 60-minute infusion on days 1 and 8 of each 21-day cycle for 4 cycles.<br>Radiation: radiation therapy<br>* Induction: External beam irradiation, 1.6 Gy, will be given to the pelvis in the first treatment followed by an interfraction period of at least 4-6 hours. During the second treatment, 1.5 Gy will be delivered to the whole bladder for the first five sessions (7.5 Gy) then to the tumor plus a margin for eight sessions (12. Gy). Consolidation: Consolidation therapy will start 7-14 days following a cystoscopic re-evaluation demonstrating a complete response to the induction therapy. 1.5 Gy (per fraction) will be given to the pelvis in two treatment fractions per day, with an interfraction period of at least 4-6 hours.<br>Drug: Gemcitabine<br>* Adjuvant: 1000 mg/m2 over 30-60 minutes on days 1 and 8 of each 21-day cycle for 4 cycles.<br>Procedure: Radical cystectomy<br>* Operable patients with pT1 or worse tumor response on re-evaluation following induction therapy will have radical cystectomy.<br>|
| Experimental: Pelvic RT + fluorouracil + cisplatin<br>Induction: Twice-daily pelvic radiation therapy (RT) with fluoruracil and cisplatin; Consolidation: Twice-daily pelvic radiation therapy with fluoruracil and cisplatin if tumor response is T0/Ta/Tis or radical cystectomy if tumor response is ≥ T1; Adjuvant: gemcitabine, paclitaxel, and cisplatin. | Drug: cisplatin<br>* Induction: 15 mg/m2 as a 60-minute infusion on days 1, 2, 3, 8, 9, 10, 15, 16, and 17; Consolidation: 15 mg/m2 as a 60-minute infusion on days 1, 2, 8, and 9; Adjuvant: 35 mg/m2 as a 60-minute infusion on days 1 and 8 of each 21-day cycle for 4 cycles.<br>Drug: fluorouracil<br>* Induction: 400 mg/m2 as a 24-hour infusion on days 1, 2, 3, 15, 16, and 17; Consolidation: 400 mg/m2 as a 24-hour infusion on days 1, 2, 3, 8, 9, and 10.<br>Radiation: radiation therapy<br>* Induction: External beam irradiation, 1.6 Gy, will be given to the pelvis in the first treatment followed by an interfraction period of at least 4-6 hours. During the second treatment, 1.5 Gy will be delivered to the whole bladder for the first five sessions (7.5 Gy) then to the tumor plus a margin for eight sessions (12. Gy). Consolidation: Consolidation therapy will start 7-14 days following a cystoscopic re-evaluation demonstrating a complete response to the induction therapy. 1.5 Gy (per fraction) will be given to the pelvis in two treatment fractions per day, with an interfraction period of at least 4-6 hours.<br>Drug: Gemcitabine<br>* Adjuvant: 1000 mg/m2 over 30-60 minutes on days 1 and 8 of each 21-day cycle for 4 cycles.<br>Procedure: Radical cystectomy<br>* Operable patients with pT1 or worse tumor response on re-evaluation following induction therapy will have radical cystectomy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Completion Rate | Radiation therapy and chemotherapy per protocol or within acceptable variation guidelines based on central review. The study was designed for a two-sided binomial test with 87% power and a significance level of 0.05 with a null hypothesis of a 70% completion rate against the alternative 90% completion rate. For each arm, more than 34 out of 43 evaluable patients completing the treatment, would indicate to reject the null hypothesis for a better treatment completion rate. Fewer than 24 out 43 evaluable patients completing the treatment would indicate to reject the null hypothesis for a worse treatment completion rate. Otherwise, the conclusion would be that there is not enough evidence to reject the null hypothesis of a 70% completion rate in either direction. | From randomization to 11 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response After Induction | Complete response requires the absence of any tumor in the tumor-site biopsy specimen or elsewhere and a bimanual exam that does not indicate the presence of a tumor mass. | From randomization to eight weeks | 
| Bladder-intact Survival Rate (5 Years) | Bladder-intact survival was measured from the date of randomization to occurrence of cystectomy or death. Five-year rates were estimated using the Kaplan-Meier method. | From the date of randomization to five years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II bladder cancer, stage III bladder cancer