Bladder Cancer
Conditions
Keywords
stage I bladder cancer, stage II bladder cancer, transitional cell carcinoma of the bladder
Brief summary
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. It is not yet known whether combination chemotherapy is more effective than observation alone in treating bladder cancer. PURPOSE: This randomized phase III trial is studying combination chemotherapy to see how well it works compared to observation alone in treating patients with bladder cancer.
Detailed description
OBJECTIVES: * Compare the recurrence-free and overall survival in patients with transitional cell carcinoma of the bladder with p53 gene alterations treated with methotrexate, vinblastine, doxorubicin, and cisplatin vs observation alone. * Compare the recurrence-free and overall survival in patients with or without p53 gene alterations treated with observation alone. * Examine the expression of p53 and other genes, particularly RB, p21, and p16, involved in cell cycle regulation that may be involved in the response to chemotherapy in these patients. * Correlate p53 mutational gene status with p53 protein expression by immunohistochemistry, outcome (recurrence-free and overall survival), response to chemotherapy, and expression of key molecules in the p53-mediated apoptotic pathway in patients treated with this regimen vs observation alone. OUTLINE: This is a randomized, multicenter study. Patients are assigned to 1 of 2 treatment groups based on the status of the p53 gene in the bladder tumor. * Group A (p53 gene alteration, defined by greater than 10% nuclear reactivity): Patients are stratified according to age (under 65 vs 65 and over), stage (P1 vs P2a vs P2b), grade (1 or 2 vs 3 or 4), and p21 status. Patients are randomized to 1 of 2 treatment arms within 10 weeks after radical cystectomy and bilateral pelvic lymphadenectomy and within 2 weeks after registration. * Arm I: Within 2 weeks after randomization, patients receive methotrexate IV on days 1, 15, and 22; vinblastine IV on days 2, 15, and 22; and doxorubicin IV and cisplatin IV on day 2. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. * Arm II: Patients undergo observation for recurrence but do not receive adjuvant chemotherapy after surgery. Patients who are eligible for randomization but decline to be randomized undergo observation for recurrence. * Group B (p53 gene normal, defined by less than 10% nuclear reactivity): Patients undergo observation for recurrence but do not receive adjuvant chemotherapy after surgery. Patients are followed every 6 months for 5 years and then annually thereafter. PROJECTED ACCRUAL: A total of 800 patients will be accrued for this study within 4.75 years.
Interventions
DRUGcisplatin
DRUGdoxorubicin hydrochloride
DRUGmethotrexate
DRUGvinblastine
Sponsors
National Cancer Institute (NCI)
NCIC Clinical Trials Group
University of Southern California
SWOG Cancer Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically proven organ confined transitional cell carcinoma (TCC) of the bladder * Must have undergone radical cystectomy and bilateral pelvic lymphadenectomy with pathologic stage from definitive cystectomy specimen of P1, P2a, or P2b and N0, M0 TCC with or without squamous/glandular differentiation (no adenocarcinoma, squamous cell carcinoma, or small cell carcinoma) * Margins must be negative for invasive or in situ TCC * In situ TCC in the urethra or ureter(s) allowed provided margins are negative * Clinical stage T1, T2a, or T2b based on transurethral resection bladder tumor specimen with P0 or PIS and N0, M0 TCC allowed * Incidental pT2a (Gleason score no greater than 7), pT2b (Gleason score no greater than 7), or pT2c (Gleason score no greater than 7) adenocarcinoma of the prostate allowed * No invasive tumor into ureter(s) or urethra * Must have potentially curable disease * Must register within 9 weeks after surgery * No metastatic disease by physical exam and chest x-ray or CT scan of the chest * Eligible for randomization if: * p53 gene alteration present * Randomization occurs within 10 weeks after surgery * Those who are randomized to receive (MVAC) methotrexate, vinblastine, doxorubicin, and cisplatin begin MVAC within 12 weeks after cystectomy * No metastatic disease by physical exam and chest x-ray or CT scan of the chest * No prohibitive medical risk for chemotherapy PATIENT CHARACTERISTICS: Age * Any age Performance status * ECOG 0-1 OR * Karnofsky 70-100% Life expectancy * Not specified Hematopoietic * WBC at least 4,000/mm\^3 * Platelet count at least 150,000/mm\^3 Hepatic * SGOT or SGPT no greater than 2 times normal * Alkaline phosphatase no greater than 2 times normal * Bilirubin normal Renal * Creatinine no greater than 1.8 mg/dL OR * Creatinine clearance at least 50 mL/min * Blood urea nitrogen normal Cardiovascular * No serious arrhythmias * No congestive heart disease with New York Heart Association class III or IV status * Randomization group: * Ejection fraction must be at least 50% by MUGA scan if there is a clinical concern regarding the patient's cardiac status Other * No other malignancy (including synchronous papillary or invasive upper urinary tract malignancy) within the past 5 years except incidental prostate cancer (found at cystectomy), basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix * No concurrent advanced medical illness or psychologic disease * No prohibitive medical risk for chemotherapy * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy * Not specified Chemotherapy * See Disease Characteristics * No prior systemic chemotherapy for bladder cancer * At least 5 years since other prior systemic chemotherapy * Prior intravesical therapy allowed * Randomization group: * Prior intravesical therapy allowed if administered prior to cystectomy Endocrine therapy * Not specified Radiotherapy * No prior pelvic irradiation Surgery * See Disease Characteristics
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Probability of Recurring | 5 years | p53 positive patients randomized to MVAC (arm I) compared to p53 positive patients randomized to observation (arm II). Time from registration to the first observation of disease recurrence, censoring patients who died of unrelated causes. Probabilities of recurring were based on cumulative incidence curves. Recurrence is defined as first radiological appearance of bladder cancer, per local standard of care. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Probability of Overall Survival | 5 years | p53 positive patients randomized to MVAC (arm I) compared to p53 positive patients randomized to observation (arm II). Survival is calculated from registration to death due to any cause. Probabilities of survival were based on the Kaplan-Meier product-limit method. |
| Probability of Recurrence | 5 years | Patients with tumors demonstrating alteration in p53 compared to patients with no p53 alterations. Probabilities of recurring were based on cumulative incidence curves. Recurrence is defined as first radiological appearance of bladder cancer, per local standard of care. |
Countries
Canada, United States
Participant flow
Pre-assignment details
Patients with stage pT1/T2N0M0 urothelial cancer who had undergone a radical cystectomy within the prior 9 weeks were eligible for enrollment. Twenty-two patients who were registered were never assigned to a group after enrolling due to: missing baseline documentation (5), incorrect disease stage (13), and patient withdrawal (4).
Participants by arm
| Arm | Count |
|---|---|
| Arm I: M-VAC x 3 p53 positive, randomized to 3 cycles of adjuvant combination methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) | 58 |
| Arm II: Observation p53 positive, randomized to observation/no intervention | 56 |
| Arm III: Observation p53 negative, assigned to observation/no intervention | 227 |
| Arm IV: Observation p53 positive, refused random assignment, assigned to observation/no intervention | 158 |
| Total | 499 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 12 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Arm I: M-VAC x 3 | Arm III: Observation | Arm IV: Observation | Total | Arm II: Observation |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 21 Participants | 100 Participants | 77 Participants | 213 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 37 Participants | 127 Participants | 81 Participants | 286 Participants | 41 Participants |
| Bladder carcinoma in situ No | 16 Participants | 60 Participants | 36 Participants | 124 Participants | 12 Participants |
| Bladder carcinoma in situ Unknown | 8 Participants | 30 Participants | 23 Participants | 73 Participants | 12 Participants |
| Bladder carcinoma in situ Yes | 34 Participants | 137 Participants | 99 Participants | 302 Participants | 32 Participants |
| Grade 1 or 2 | 2 Participants | 16 Participants | 5 Participants | 24 Participants | 1 Participants |
| Grade 3 or 4 | 56 Participants | 210 Participants | 152 Participants | 473 Participants | 55 Participants |
| Grade missing | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants |
| Lymphovascular invasion No | 33 Participants | 117 Participants | 84 Participants | 259 Participants | 25 Participants |
| Lymphovascular invasion Unknown | 12 Participants | 64 Participants | 45 Participants | 138 Participants | 17 Participants |
| Lymphovascular invasion Yes | 13 Participants | 46 Participants | 29 Participants | 102 Participants | 14 Participants |
| No. of nodes identified <15 nodes | 22 Participants | 68 Participants | 64 Participants | 168 Participants | 14 Participants |
| No. of nodes identified >= 15 nodes | 36 Participants | 159 Participants | 94 Participants | 331 Participants | 42 Participants |
| p21 status Absent | 24 Participants | 35 Participants | 64 Participants | 145 Participants | 22 Participants |
| p21 status missing | 0 Participants | 2 Participants | 2 Participants | 4 Participants | 0 Participants |
| p21 status Present | 34 Participants | 190 Participants | 92 Participants | 350 Participants | 34 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 6 Participants | 1 Participants | 9 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 4 Participants | 13 Participants | 4 Participants | 22 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 3 Participants | 3 Participants | 11 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 52 Participants | 203 Participants | 150 Participants | 454 Participants | 49 Participants |
| Sex: Female, Male Female | 7 Participants | 49 Participants | 34 Participants | 99 Participants | 9 Participants |
| Sex: Female, Male Male | 51 Participants | 178 Participants | 124 Participants | 400 Participants | 47 Participants |
| Stage pT1 | 21 Participants | 87 Participants | 61 Participants | 185 Participants | 16 Participants |
| Stage pT2 and pT2a | 37 Participants | 140 Participants | 97 Participants | 314 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 12 / 58 | 9 / 56 | 41 / 227 | 36 / 158 |
| other Total, other adverse events | 35 / 46 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 46 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Probability of Recurring
p53 positive patients randomized to MVAC (arm I) compared to p53 positive patients randomized to observation (arm II). Time from registration to the first observation of disease recurrence, censoring patients who died of unrelated causes. Probabilities of recurring were based on cumulative incidence curves. Recurrence is defined as first radiological appearance of bladder cancer, per local standard of care.
Time frame: 5 years
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Arm I: M-VAC x 3 | Probability of Recurring | 0.85 probability | Standard Error 0.05 |
| Arm II: Observation | Probability of Recurring | 0.84 probability | Standard Error 0.06 |
Secondary
Probability of Overall Survival
p53 positive patients randomized to MVAC (arm I) compared to p53 positive patients randomized to observation (arm II). Survival is calculated from registration to death due to any cause. Probabilities of survival were based on the Kaplan-Meier product-limit method.
Time frame: 5 years
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Arm I: M-VAC x 3 | Probability of Overall Survival | 0.87 probability | Standard Error 0.05 |
| Arm II: Observation | Probability of Overall Survival | 0.84 probability | Standard Error 0.05 |
Secondary
Probability of Overall Survival
Patients with tumors demonstrating alteration in p53 compared to patients with no p53 alterations. Probabilities of survival were based on the Kaplan-Meier product-limit method.
Time frame: 5 years
Population: This analysis compares p53 positive patients (combined arms I, II, and IV) to p53 negative patients (arm III).
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Arm I: M-VAC x 3 | Probability of Overall Survival | 0.82 probability | Standard Error 0.03 |
| Arm II: Observation | Probability of Overall Survival | 0.84 probability | Standard Error 0.03 |
Secondary
Probability of Recurrence
Patients with tumors demonstrating alteration in p53 compared to patients with no p53 alterations. Probabilities of recurring were based on cumulative incidence curves. Recurrence is defined as first radiological appearance of bladder cancer, per local standard of care.
Time frame: 5 years
Population: This analysis compares p53 positive patients (combined arms I, II, and IV) to p53 negative patients (arm III).
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Arm I: M-VAC x 3 | Probability of Recurrence | 0.83 probability | Standard Error 0.03 |
| Arm II: Observation | Probability of Recurrence | 0.77 probability | Standard Error 0.03 |