S0337, Gemcitabine After Surgery in Treating Patients With Newly Diagnosed or Recurrent Bladder Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving gemcitabine directly into the bladder after surgery may kill more tumor cells. It is not yet known whether giving gemcitabine directly into the bladder is more effective than a placebo in treating bladder cancer. PURPOSE: This randomized phase III trial is studying gemcitabine to see how well it works when given directly into the bladder compared with a placebo after surgery in treating patients with newly diagnosed or recurrent bladder cancer.

Detailed Description
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OBJECTIVES: Primary Compare the efficacy of a single intravesical instillation of gemcitabine hydrochloride vs placebo immediately after transurethral resection of the bladder tumor (TURBT) in preventing recurrence at 2 years in patients with grade 1 or 2 superficial transitional cell cancer of the bladder. Secondary Compare whether a single instillation of intravesical gemcitabine hydrochloride can improve the time to progression to muscle invasive disease vs placebo in these patients. Compare the qualitative and quantitative toxicities of these regimens in these patients. Compare whether treatment with post-TURBT intravesical instillation of gemcitabine vs placebo results in reduced long-term morbidity in patients, as defined by requirement for fewer TURBTs, courses of traditional intravesical therapies, and surveillance cystoscopies over 4 years. Tertiary Assess whether performing a combination of molecular and/or cytologic diagnostic marker tests, including NMP-22 Bladder Chek and BTA Stat every 3 months, can predict recurrence as accurately as cystoscopy alone in these patients. OUTLINE: This is a randomized, double-blind, multicenter study. Patients are stratified according to disease status (first occurrence vs recurrent disease) and number of tumor sites (1 vs ≥ 2). Patients are randomized to 1 of 2 treatment arms. All patients undergo transurethral resection of the bladder tumor. Within 3 hours, patients receive intravesical therapy according to their randomized arm. Arm I: Patients receive intravesical gemcitabine hydrochloride over 1 hour. Arm II: Patients receive intravesical placebo over 1 hour. Urine is collected at baseline and then every 3 months for 2 years for research studies including the NMP-22 Bladder Chek and BTA Stat test. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 2 years. PROJECTED ACCRUAL: A total of 340 patients will be accrued for this study.

Official Title
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A Phase III Blinded Study of Immediate Post TURBT Instillation of Gemcitabine Versus Saline in Patients With Newly Diagnosed or Occasionally Recurring Grade I/II Superficial Bladder Cancer

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: gemcitabine hydrochloride
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of newly diagnosed or recurrent transitional cell bladder cancer meeting the following criteria: Ta or T1 primary tumor Grade 1 or 2 disease No more than 2 recurrences (except for index tumor) within the 18 months prior to the index tumor's transurethral resection of the bladder tumor (TURBT) Index tumor post-TURBT must meet the following criteria: Ta or T1 tumor without any prior tumor in situ, grade 3 (high grade) disease within 2 years prior to index tumor TURBT, or invasion of the muscularis propria (stage ≥ T2) Grade 1 or 2 disease (similar to papillary urothelial neoplasm of low malignant potential and low-grade bladder cancer) Not a candidate for a therapy other than TURBT (e.g., a series of instillations of intravesical immunotherapy [e.g., BCG] or intravesical chemotherapy, or cystectomy or partial cystectomy) Negative upper tract imaging studies within 1 year (365 days) prior to study entry Imaging studies may be performed after registration provided it is done prior to TURBT on the day of treatment No urothelial cancer of the prostate or more distal urethra (or urethra at all in women) as assessed by endoscopy Must have a negative urine culture (less than or equal to 10,000 col/mL, mixed flora-likely contamination) OR negative urine analysis for infection AND negative nitrates on reagent strip, ≤ 10 white blood cell count (WBC)/high-power field, and no rods or organisms on examination of spun urine sediment OR an automated or visual reagent strip urinalysis that is negative for leukocytes and nitrates within the past 28 days TURBT planned within the next 28 days and planned treatment within 3 hours after TURBT PATIENT CHARACTERISTICS: Zubrod performance status 0-1 Not pregnant or nursing Fertile patients must use effective contraception No other prior malignancy except for any of the following: Adequately treated basal cell or squamous cell skin cancer In situ cervical cancer Adequately treated stage I or II cancer from which patient is in complete remission Any other cancer from which patient has been disease-free for 3 years PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 145 days since prior intravesical therapy

Ages Eligible for Study
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Minimum Age: 18 Years
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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive intravesical gemcitabine hydrochloride over 1 hour. | Drug: gemcitabine hydrochloride<br>* Given intravesically<br>|
| Placebo Comparator: Arm II<br>Patients receive intravesical placebo over 1 hour. | Other: placebo<br>* Given intravesically<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Recurrence Rate | Percentage of patients who experienced a recurrence of grade 1 or 2 superficial transitional cell cancer of the bladder between the date of registration and 24 months. Disease recurrence considered to occur at date of first observation of recurrent disease subsequently confirmed by biopsy. Patients without recurrence were censored at the time of their last cystoscopy. | Up to 2 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Progression to Muscle Invasive Disease at 4 Years | From date of registration to date of diagnosis of progressive disease. Censor at date of last disease assessment for those without progression. | 4 years | 
| Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Number of patients with Grade 3 through Grade 5 adverse events that are related to study drug | Up to 4 years after Transurethral Resection of Bladder Tumor (TURBT) | 
| Rate of Disease Worsening Over 2 Years | Compare whether treatment with post-TURBT intravesical instillation of gemcitabine vs placebo results in reduced long-term morbidity in patients, as defined by requirement for fewer TURBTs, courses of traditional intravesical therapies, and surveillance cystoscopies over 4 years. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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transitional cell carcinoma of the bladder, stage 0 bladder cancer, stage I bladder cancer, recurrent bladder cancer