S0121, Neoadjuvant Carboplatin, Paclitaxel, and Gemcitabine Followed by Cisplatin and Radiation Therapy in Treating Patients With Locally Advanced or Recurrent Carcinoma of the Urothelium

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as carboplatin, paclitaxel, gemcitabine, and cisplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Giving chemotherapy before radiation therapy, and combining chemotherapy with radiation therapy, may kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of neoadjuvant gemcitabine, paclitaxel, and carboplatin followed by cisplatin and radiation therapy in treating patients who have locally advanced or recurrent carcinoma (cancer) of the urothelium.

Detailed Description
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OBJECTIVES: Determine the overall survival of patients with locally advanced or recurrent carcinoma of the urothelium treated with neoadjuvant carboplatin, paclitaxel, and gemcitabine followed by concurrent cisplatin and radiotherapy. Determine the feasibility of administering this regimen to these patients. Determine the progression-free survival of patients treated with this regimen. Determine the qualitative and quantitative toxic effects of this regimen in these patients. Determine the response rate (confirmed and unconfirmed) of patients treated with the neoadjuvant regimen and those treated with the whole regimen. Determine the proportion of patients who qualify for concurrent cisplatin and radiotherapy after receiving the neoadjuvant regimen. Determine the potential value of suppressor gene expression analysis (p53 and retinoblastoma gene) and HER2 expression as indicators of prognosis and/or response in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients receive neoadjuvant chemotherapy comprising paclitaxel IV over 3 hours and carboplatin IV over 15 minutes on day 1 and gemcitabine IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for a maximum of 3 courses in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks after the completion of neoadjuvant chemotherapy, patients receive cisplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for a maximum of 2 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo concurrent radiotherapy 5 days a week for 6 weeks. Patients are followed every 3 months for 2 years and then every 6 months for 3 years. PROJECTED ACCRUAL: A total of 80 patients will be accrued for this study within 4 years.

Official Title
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Phase II Evaluation of Carboplatin, Paclitaxel and Gemcitabine Followed by Concurrent Cisplatin and Radiation Therapy in Patients With Locally Advanced or Recurrent Urothelial Malignancy

Conditions
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Bladder Cancer, Urethral Cancer

Intervention / Treatment
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* Drug: carboplatin
* Drug: cisplatin
* Drug: gemcitabine hydrochloride
* Drug: paclitaxel
* Procedure: neoadjuvant therapy
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed primary or recurrent invasive carcinoma of the urothelium Transitional, squamous, or mixed cell subtypes allowed Primary disease site must be the urinary bladder or urethra Disease confined to the true pelvis (T2-T4, N0-N3, M0) Must meet at least 1 of the following criteria: Nodal involvement at or below the level of the bifurcation of the iliac vessels Medically or surgically inoperable Patient refused cystectomy Measurable or nonmeasurable disease Evidence of tumor invasion of the muscularis by cystoscopy and biopsy and detailed bladder mapping within the past 56 days No extrapelvic metastases Eligible to receive radiotherapy Planned radiotherapy at a SWOG-approved facility PATIENT CHARACTERISTICS: Age 18 and over Performance status Zubrod 0-2 Life expectancy Not specified Hematopoietic Granulocyte count at least 1,500/mm^3 Platelet count at least lower limit of normal Hepatic Bilirubin no greater than upper limit of normal (ULN) SGOT or SGPT no greater than 2.5 times ULN Renal Creatinine clearance at least 60 mL/min OR Creatinine no greater than ULN Gastrointestinal No chronic diarrhea No malabsorption No extensive diverticular disease of the colon No inflammatory bowel disease No other pre-existing gastrointestinal disorders Other Not pregnant or nursing Fertile patients must use effective contraception No active infections requiring antibiotics No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer currently in complete remission PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior chemotherapy for patients with a current diagnosis of advanced bladder cancer that is also the initial diagnosis No prior systemic chemotherapy except adjuvant therapy for recurrent disease completed more than 6 months ago No prior carboplatin No prior paclitaxel No prior gemcitabine Endocrine therapy Not specified Radiotherapy See Disease Characteristics No prior pelvic radiotherapy Surgery See Disease Characteristics Recovered from prior surgery

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

| Intervention/Treatment |
| --- |
|Drug: carboplatin|*AUC=5 (by modified Calvert formula), IV, over 15 minutes; given q 21 days for a maximum of 3 cycles (1 cycle = 21 days)|
|Drug: cisplatin|75 mg/m2 (maximum dose 150 mg), IV, rapid infusion; given q 21 days for 2 cycles (1 cycle = 21 days)|
|Drug: gemcitabine hydrochloride|800 mg/m2, IV, over 30 minutes; given on Days 1 & 8, q 21 days, for a maximum of 3 cycles (1 cycle = 21 days)|
|Drug: paclitaxel|200 mg/m2, IV, over 3 hours; given q 21 days for a maximum of 3 cycles (1 cycle = 21 days)|
|Procedure: neoadjuvant therapy|Neoadjuvant chemotherapy (paclitaxel, carboplatin, and gemcitabine)|
|Radiation: radiation therapy|Radiation treatments will be delivered once daily. Treatment will be given 5 days per week at a dose of 180 to 200 cGy per day. All fields will be treated everyday.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent bladder cancer, stage III bladder cancer, squamous cell carcinoma of the bladder, stage II bladder cancer, recurrent urethral cancer, urethral cancer associated with invasive bladder cancer, distal urethral cancer, proximal urethral cancer, stage IV bladder cancer, transitional cell carcinoma of the bladder