Combination Chemotherapy and Radiation Therapy With/Without Surgery In Patients With Stage II/III Bladder Cancer

Radiation Therapy Oncology Group

Status and phase: Completed; Phase 2

Conditions: Bladder Cancer

Treatments: Drug: Gemcitabine; Radiation: radiation therapy; Procedure: Radical cystectomy; Drug: cisplatin; Drug: fluorouracil; Drug: paclitaxel

Study type: Interventional

Funder types: Other; NETWORK; NIH

Identifiers

NCT00055601

CDR0000258303

ECOG-R0233

NCI-2011-01578 (Registry Identifier)

RTOG 0233

Details and patient eligibility

About

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.

Full 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.

Enrollment: 97 patients

Sex: All

Ages: Under 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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97 participants in 2 patient groups

Pelvic RT + paclitaxel + cisplatin

Experimental group

Description:

Induction: Twice-daily pelvic radiation therapy (RT) 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.

Treatment:

Drug: cisplatin

Drug: Gemcitabine

Radiation: radiation therapy

Drug: paclitaxel

Procedure: Radical cystectomy

Pelvic RT + fluorouracil + cisplatin

Experimental group

Description:

Induction: Twice-daily pelvic radiation therapy (RT) 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.

Treatment:

Drug: cisplatin

Drug: fluorouracil

Drug: Gemcitabine

Radiation: radiation therapy

Procedure: Radical cystectomy