Bladder Cancer
Conditions
Keywords
transitional cell carcinoma of the bladder, stage 0 bladder cancer, stage I bladder cancer, recurrent bladder cancer
Brief summary
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
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.
Interventions
DRUGgemcitabine hydrochloride
Given intravesically
OTHERplacebo
Given intravesically
Sponsors
National Cancer Institute (NCI)
SWOG Cancer Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Recurrence Rate | Up to 2 Years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Progression to Muscle Invasive Disease at 4 Years | 4 years | From date of registration to date of diagnosis of progressive disease. Censor at date of last disease assessment for those without progression. |
| Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Up to 4 years after Transurethral Resection of Bladder Tumor (TURBT) | Number of patients with Grade 3 through Grade 5 adverse events that are related to study drug |
| Rate of Disease Worsening Over 2 Years | Up to 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I Patients receive intravesical gemcitabine hydrochloride over 1 hour post-TURBT.
gemcitabine hydrochloride: Given intravesically | 201 |
| Arm II Patients receive intravesical placebo over 1 hour post-TURBT.
placebo: Given intravesically | 205 |
| Total | 406 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Death prior to TURBT | 0 | 1 |
| Overall Study | Drug Delivery Issue | 2 | 2 |
| Overall Study | Incorrect Disease Status | 6 | 6 |
| Overall Study | TURBT Complication | 12 | 8 |
| Overall Study | Withdrawal by Subject | 11 | 11 |
Baseline characteristics
| Characteristic | Arm II | Arm I | Total |
|---|---|---|---|
| Age, Continuous | 66 years | 66 years | 66 years |
| Number of tumors 1 | 140 Participants | 135 Participants | 275 Participants |
| Number of tumors >= 2 | 65 Participants | 66 Participants | 131 Participants |
| Occurence status First Occurence | 128 Participants | 128 Participants | 256 Participants |
| Occurence status Recurrent | 77 Participants | 66 Participants | 143 Participants |
| Occurence status Unknown | 0 Participants | 7 Participants | 7 Participants |
| Prior intravesical therapy No | 166 Participants | 162 Participants | 328 Participants |
| Prior intravesical therapy Yes | 39 Participants | 39 Participants | 78 Participants |
| Race/Ethnicity, Customized Race Asian | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized Race Black | 9 Participants | 6 Participants | 15 Participants |
| Race/Ethnicity, Customized Race Native American | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Unknown | 4 Participants | 5 Participants | 9 Participants |
| Race/Ethnicity, Customized Race White | 185 Participants | 186 Participants | 371 Participants |
| Sex: Female, Male Female | 24 Participants | 38 Participants | 62 Participants |
| Sex: Female, Male Male | 181 Participants | 163 Participants | 344 Participants |
| Smoking history Current | 54 Participants | 49 Participants | 103 Participants |
| Smoking history Never | 46 Participants | 54 Participants | 100 Participants |
| Smoking history Prior | 101 Participants | 98 Participants | 199 Participants |
| Smoking history Unknown | 4 Participants | 0 Participants | 4 Participants |
| Zubrod Performance Status 0 | 165 Participants | 157 Participants | 322 Participants |
| Zubrod Performance Status 1 | 40 Participants | 44 Participants | 84 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 17 / 201 | 25 / 205 |
| other Total, other adverse events | 60 / 165 | 58 / 174 |
| serious Total, serious adverse events | 7 / 165 | 5 / 174 |
Outcome results
Primary
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.
Time frame: Up to 2 Years
Population: Intent-to-Treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I | Disease Recurrence Rate | 27.86 percentage of patients with recurrence |
| Arm II | Disease Recurrence Rate | 40 percentage of patients with recurrence |
p-value: 0.0195% CI: [0.48, 0.9]Log Rank
Secondary
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
Time frame: Up to 4 years after Transurethral Resection of Bladder Tumor (TURBT)
Population: All eligible patients who received instillation after TURBT and reported adverse events
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I | Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Urinary frequency/urgency | 0 Participants |
| Arm I | Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Bladder spasms | 0 Participants |
| Arm I | Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Hemorrhage, GU - Bladder | 1 Participants |
| Arm I | Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Hemorrhage, GU - Urinary NOS | 2 Participants |
| Arm I | Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Infection-Other (Specify) | 1 Participants |
| Arm I | Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Pain - Bladder | 0 Participants |
| Arm I | Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Pain - Urethra | 0 Participants |
| Arm II | Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Urinary frequency/urgency | 2 Participants |
| Arm II | Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Infection-Other (Specify) | 0 Participants |
| Arm II | Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Bladder spasms | 1 Participants |
| Arm II | Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Pain - Urethra | 1 Participants |
| Arm II | Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Hemorrhage, GU - Bladder | 0 Participants |
| Arm II | Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Pain - Bladder | 1 Participants |
| Arm II | Compare Qualitative and Quantitative Toxicities Between the Treatment Arms | Hemorrhage, GU - Urinary NOS | 1 Participants |
Secondary
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.
Time frame: Up to 2 years
Population: TURBT data after patients stopped trial was not collected.
Secondary
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.
Time frame: 4 years
Population: Intent-to-Treat Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I | Rate of Progression to Muscle Invasive Disease at 4 Years | 2.49 percentage of patients with progression |
| Arm II | Rate of Progression to Muscle Invasive Disease at 4 Years | 4.39 percentage of patients with progression |
p-value: 0.2395% CI: [0.18, 1.49]Log Rank