Bladder Cancer
Conditions
Keywords
stage II bladder cancer, stage III bladder cancer
Brief summary
RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy (RT) uses high-energy x-rays to damage tumor cells. It is not yet known which regimen of combination chemotherapy plus radiation therapy with or without surgery is more effective in treating bladder cancer. PURPOSE: Randomized phase II trial to study the effectiveness of two combination chemotherapy regimens and radiation therapy with or without radical cystectomy in treating patients who have stage II or stage III bladder cancer.
Detailed description
OBJECTIVES: * Estimate the safety and tolerability of induction paclitaxel, cisplatin, and radiotherapy or fluorouracil, cisplatin, and radiotherapy followed by consolidation chemoradiotherapy or radical cystectomy and adjuvant gemcitabine, paclitaxel, and cisplatin in patients with operable stage II or III bladder cancer. * Estimate the efficacy of these regimens, in terms of complete response, in patients who have undergone prior transurethral resection (TUR). * Estimate the efficacy of these regimens after TUR, in terms of preserving the native tumor-free bladder 5 years after therapy, in these patients. * Estimate the function of the preserved bladder in patients treated with these regimens after TUR. * Determine the value of tumor histopathologic, molecular genetic, and DNA content parameters as possible prognostic factors for initial tumor response and recurrence-free survival in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to T stage (T2 vs T3/T4 ). Patients are randomized to one of two treatment arms. * Induction therapy (weeks 1-3): * Arm I: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15 and cisplatin IV over 1 hour on days 1-3, 8-10, and 15-17. Patients also receive pelvic radiotherapy twice daily on days 1-5, 8-12, and 15-17. * Arm II: Patients receive fluorouracil IV over 24 hours on days 1-3 and 15-17 and cisplatin IV over 1 hour on days 1-3, 8-10, and 15-17. Patients also receive pelvic radiotherapy as in arm I. Patients in both arms who achieve complete response after induction therapy proceed to consolidation therapy on week 8. Patients with operable pT1 or worse tumor response proceed to radical cystectomy on week 9. * Consolidation therapy (weeks 8 and 9): * Arm I: Patients receive paclitaxel IV over 1 hour on days 1 and 8 and cisplatin IV over 1 hour on days 1, 2, 8, and 9. Patients also receive pelvic radiotherapy twice daily on days 1-5 and 8-10. * Arm II: Patients receive 5-FU IV over 24 hours on days 1-3 and 8-10 and cisplatin as in arm I. Patients also receive radiotherapy as in arm I. * Adjuvant chemotherapy (weeks 21-33 or 17-29): Beginning 12 weeks after consolidation therapy or 8 weeks after radical cystectomy, patients receive gemcitabine IV over 30-60 minutes, paclitaxel IV over 1 hour, and cisplatin IV over 1 hour on days 1 and 8. Treatment repeats every 3 weeks for 4 courses. Patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 3 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 96 patients (48 per treatment arm) will be accrued for this study within 3 years.
Interventions
DRUGcisplatin
Induction: 15 mg/m2 as a 60-minute infusion on days 1, 2, 3, 8, 9, 10, 15, 16, and 17; Consolidation: 15 mg/m2 as a 60-minute infusion on days 1, 2, 8, and 9; Adjuvant: 35 mg/m2 as a 60-minute infusion on days 1 and 8 of each 21-day cycle for 4 cycles.
DRUGfluorouracil
Induction: 400 mg/m2 as a 24-hour infusion on days 1, 2, 3, 15, 16, and 17; Consolidation: 400 mg/m2 as a 24-hour infusion on days 1, 2, 3, 8, 9, and 10.
DRUGpaclitaxel
Induction: 50 mg/m2 as a 60-minute infusion on days 1, 8, and 15; Consolidation: 50 mg/m2 as a 60-minute infusion on days 1 and 8; Adjuvant: 50 mg/m2 as a 60-minute infusion on days 1 and 8 of each 21-day cycle for 4 cycles.
RADIATIONradiation therapy
Induction: External beam irradiation, 1.6 Gy, will be given to the pelvis in the first treatment followed by an interfraction period of at least 4-6 hours. During the second treatment, 1.5 Gy will be delivered to the whole bladder for the first five sessions (7.5 Gy) then to the tumor plus a margin for eight sessions (12. Gy). Consolidation: Consolidation therapy will start 7-14 days following a cystoscopic re-evaluation demonstrating a complete response to the induction therapy. 1.5 Gy (per fraction) will be given to the pelvis in two treatment fractions per day, with an interfraction period of at least 4-6 hours.
DRUGGemcitabine
Adjuvant: 1000 mg/m2 over 30-60 minutes on days 1 and 8 of each 21-day cycle for 4 cycles.
PROCEDURERadical cystectomy
Operable patients with pT1 or worse tumor response on re-evaluation following induction therapy will have radical cystectomy.
Sponsors
National Cancer Institute (NCI)
Eastern Cooperative Oncology Group
NRG Oncology
Radiation Therapy Oncology Group
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 confirmed operable primary muscle invasive bladder cancer * T2-T4a, NX or N0, M0 (stage II or III) * Must have an adequate functioning bladder * Must have undergone a prior transurethral resection of the bladder tumor within the past 8 weeks * No evidence of tumor-related hydronephrosis * No evidence of distant metastases or histologically or cytologically confirmed lymph node metastases * Patients with involvement of the prostatic urethra with transitional cell cancer that was visibly completely resected are allowed * No evidence of stromal invasion of the prostate PATIENT CHARACTERISTICS: Age * Not specified Performance status * Zubrod 0-1 Life expectancy * Not specified Hematopoietic * Hemoglobin at least 10 g/dL * White blood cell (WBC) count at least 4,000/mm\^3 * Absolute neutrophil count at least 1,800/mm\^3 * Platelet count at least 100,000/mm\^3 Hepatic * Serum bilirubin no greater than 2.0 mg/dL Renal * Serum creatinine no greater than 1.5 mg/dL * Creatinine clearance at least 60 mL/min NOTE: If the creatinine clearance is greater than 60 mL/min, creatinine of no greater than 1.8 mg/dL is allowed at the discretion of the study chair Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No other malignancy within the past 5 years except nonmelanoma skin cancer, stage T1a prostate cancer, or carcinoma in situ of the cervix * Must be able to tolerate systemic chemotherapy with pelvic radiotherapy and radical cystectomy PRIOR CONCURRENT THERAPY: Biologic therapy * Not specified Chemotherapy * No prior systemic chemotherapy Endocrine therapy * Not specified Radiotherapy * No prior pelvic radiotherapy Surgery * See Disease Characteristics Other * No concurrent drugs that have potential nephrotoxicity or ototoxicity (e.g., aminoglycosides)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Completion Rate | From randomization to 11 weeks | Radiation therapy and chemotherapy per protocol or within acceptable variation guidelines based on central review. The study was designed for a two-sided binomial test with 87% power and a significance level of 0.05 with a null hypothesis of a 70% completion rate against the alternative 90% completion rate. For each arm, more than 34 out of 43 evaluable patients completing the treatment, would indicate to reject the null hypothesis for a better treatment completion rate. Fewer than 24 out 43 evaluable patients completing the treatment would indicate to reject the null hypothesis for a worse treatment completion rate. Otherwise, the conclusion would be that there is not enough evidence to reject the null hypothesis of a 70% completion rate in either direction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response After Induction | From randomization to eight weeks | Complete response requires the absence of any tumor in the tumor-site biopsy specimen or elsewhere and a bimanual exam that does not indicate the presence of a tumor mass. |
| Bladder-intact Survival Rate (5 Years) | From the date of randomization to five years. | Bladder-intact survival was measured from the date of randomization to occurrence of cystectomy or death. Five-year rates were estimated using the Kaplan-Meier method. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pelvic RT + Paclitaxel + Cisplatin Induction: Twice-daily pelvic radiation therapy with paclitaxel and cisplatin; Consolidation: Twice-daily pelvic radiation therapy with paclitaxel and cisplatin if tumor response is T0/Ta/Tis or radical cystectomy if tumor response is ≥ T1; Adjuvant: gemcitabine, paclitaxel, and cisplatin IV. | 46 |
| Pelvic RT + Fluorouracil + Cisplatin Induction: Twice-daily pelvic radiation therapy with fluoruracil and cisplatin; Consolidation: Twice-daily pelvic radiation therapy with fluoruracil and cisplatin if tumor response is T0/Ta/Tis or radical cystectomy if tumor response is ≥ T1; Adjuvant: gemcitabine, paclitaxel, and cisplatin IV. | 47 |
| Total | 93 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | No protocol treatment received | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 1 |
Baseline characteristics
| Characteristic | Pelvic RT + Paclitaxel + Cisplatin | Pelvic RT + Fluorouracil + Cisplatin | Total |
|---|---|---|---|
| Age, Continuous | 65 years | 67 years | 66 years |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Male | 38 Participants | 40 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 46 / 46 | 47 / 47 |
| serious Total, serious adverse events | 43 / 46 | 39 / 47 |
Outcome results
Primary
Treatment Completion Rate
Radiation therapy and chemotherapy per protocol or within acceptable variation guidelines based on central review. The study was designed for a two-sided binomial test with 87% power and a significance level of 0.05 with a null hypothesis of a 70% completion rate against the alternative 90% completion rate. For each arm, more than 34 out of 43 evaluable patients completing the treatment, would indicate to reject the null hypothesis for a better treatment completion rate. Fewer than 24 out 43 evaluable patients completing the treatment would indicate to reject the null hypothesis for a worse treatment completion rate. Otherwise, the conclusion would be that there is not enough evidence to reject the null hypothesis of a 70% completion rate in either direction.
Time frame: From randomization to 11 weeks
Population: All eligible patients who started study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pelvic RT + Paclitaxel + Cisplatin | Treatment Completion Rate | 67 percentage of participants |
| Pelvic RT + Fluorouracil + Cisplatin | Treatment Completion Rate | 53 percentage of participants |
Secondary
Bladder-intact Survival Rate (5 Years)
Bladder-intact survival was measured from the date of randomization to occurrence of cystectomy or death. Five-year rates were estimated using the Kaplan-Meier method.
Time frame: From the date of randomization to five years.
Population: All eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pelvic RT + Paclitaxel + Cisplatin | Bladder-intact Survival Rate (5 Years) | 67 percentage of participants |
| Pelvic RT + Fluorouracil + Cisplatin | Bladder-intact Survival Rate (5 Years) | 71 percentage of participants |
Secondary
Complete Response After Induction
Complete response requires the absence of any tumor in the tumor-site biopsy specimen or elsewhere and a bimanual exam that does not indicate the presence of a tumor mass.
Time frame: From randomization to eight weeks
Population: All eligible patients who started study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pelvic RT + Paclitaxel + Cisplatin | Complete Response After Induction | 72 percentage of participants |
| Pelvic RT + Fluorouracil + Cisplatin | Complete Response After Induction | 62 percentage of participants |