S0219, Combination Chemotherapy Followed By Observation or Surgery in Patients With Stage II or Stage III Cancer of the Urothelium

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 and decrease the need for surgery. PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy followed by observation or surgery to remove the bladder (cystectomy) in treating patients who have stage II or stage III cancer of the urothelium.

Detailed Description
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OBJECTIVES: Determine the pathologic complete response of patients with stage II or III transitional cell cancer of the urothelium treated with neoadjuvant gemcitabine, paclitaxel, and carboplatin followed by observation or immediate cystectomy. Determine, preliminarily, if molecular markers predict response, survival, and tumor recurrence in patients treated with these regimens. Determine recurrence rates and cystectomy-free survival of patients who choose observation after an initial response to neoadjuvant chemotherapy. Compare the survival of patients treated with neoadjuvant chemotherapy followed by cystectomy vs observation. Determine the feasibility, tolerability, and toxicity of these regimens in these patients. OUTLINE: This is a multicenter study. Patients receive gemcitabine IV over 30 minutes and paclitaxel IV over 30 minutes on days 1 and 8 and carboplatin IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks after completion of neoadjuvant chemotherapy, patients undergo a third transurethral resection of bladder tumor. Patients with T0 disease after neoadjuvant chemotherapy may choose to undergo observation. These patients undergo cystoscopies with biopsies every 3 months for 1 year, every 4 months for 1 year, and then every 6 months until disease progression. Patients with T1 disease or greater after neoadjuvant chemotherapy undergo immediate cystectomy. Patients with T0 disease may also choose this option. Patients undergoing immediate cystectomy are followed every 6 months for 2 years and then annually for 3 years. PROJECTED ACCRUAL: A total of 95 patients will be accrued for this study within 2 years.

Official Title
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A Sequential Approach to the Treatment of Muscle Invasive, Non-Metastatic Urothelial Carcinoma of the Bladder: A Phase II Trial of Neoadjuvant Gemcitabine, Paclitaxel and Carboplatin With Molecular Correlates

Conditions
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Bladder Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Urethral Cancer

Intervention / Treatment
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* Drug: carboplatin
* Drug: gemcitabine
* Drug: paclitaxel
* Procedure: surgery


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed muscle-invasive (T2-T4a), node-negative (N0) urothelial transitional cell cancer (TCC) of the bladder Focal squamous and/or adenocarcinoma differentiation, defined as ≤ 10% of tumor volume allowed The following diagnoses are not allowed: Small cell carcinoma Sarcomatoid components Disease diagnosed with an initial transurethral resection of bladder tumor (TURBT) and a second TURBT performed within 8 weeks of first with attempt to remove all tumor present Residual disease after second TURBT allowed No more than 14-56 days after second TURBT No metastatic disease by chest x-ray and CT scan or MRI of the abdomen and pelvis Fresh tumor tissue, paraffin tumor tissue, unstained slides, or cell block specimen from one or both TURBTs available PATIENT CHARACTERISTICS: Age 18 and over Performance status Zubrod 0-2 Life expectancy Not specified Hematopoietic White blood cell count (WBC) at least 3,500/mm^3 Absolute granulocyte count at least 1,500/mm^3 Platelet count at least lower limit of normal Hepatic Bilirubin no greater than 1.5 mg/dL Aspartate aminotransferase (SGOT) no greater than 2 times upper limit of normal Renal Creatinine no greater than 2.0 mg/dL AND/OR Creatinine clearance at least 60 mL/min Other No prohibitive medical risk that would preclude radical cystectomy No other serious concurrent systemic disorder that would preclude study compliance No other malignancy except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, adequately treated stage I or II cancer in complete remission, or any other cancer for which patient has been disease-free for 5 years Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy Prior intravesical immunotherapy allowed Chemotherapy No prior systemic chemotherapy for TCC of the urothelium Prior intravesical chemotherapy allowed Endocrine therapy Not specified Radiotherapy No prior radiotherapy for TCC of the urothelium No concurrent radiotherapy Surgery See Disease Characteristics

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine, Paclitaxel, Carboplatin<br>Gemcitabine, Paclitaxel, Carboplatin followed by surgery | Drug: carboplatin<br> <br> Drug: gemcitabine<br> <br> * Other names: gemcitabine hydrochloride;Drug: paclitaxel<br> <br> * Other names: Taxol;Procedure: surgery<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response Rate by Transurethral Resection of Bladder Tumor (TURBT) and Imaging Studies After Chemotherapy | Pathologic complete response (CR) is defined as absence of viable tumor in the TURBT specimen. Stable/No Response is defined as at least some disease evaluation tests were done (same tests as baseline) and status does not qualify for CR or Progression. Progression is defined as one or more of the following must occur: unequivocal progression of disease in the opinion of the treating physician. Appearance of any new lesion/site. Death due to disease without documented progression or symptomatic deterioration. | up to 12 weeks after registration (assessed within 8 weeks after completion of 3 cycles of chemotherapy ) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival is defined from the date of registration to date of death from any cause | 0-2 years | 
| Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal. | Patients were assessed for adverse events at weeks 1, 2, 4, 5, 7, 8, and following surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anterior urethral cancer, localized transitional cell cancer of the renal pelvis and ureter, posterior urethral cancer, stage II bladder cancer, stage III bladder cancer, transitional cell carcinoma of the bladder, urethral cancer associated with invasive bladder cancer, regional transitional cell cancer of the renal pelvis and ureter