4B951, Combination Chemotherapy in Treating Patients With Bladder Cancer

SWOG Cancer Research Network

Status and phase: Terminated; Phase 3

Conditions: Bladder Cancer

Treatments: Drug: methotrexate; Drug: doxorubicin hydrochloride; Drug: cisplatin; Drug: vinblastine

Study type: Interventional

Funder types: Other; NETWORK; NIH

Identifiers

NCT00005047

SWOG-4B951 (Other Identifier)

CDR0000067639

CAN-NCIC-BL10 (Other Identifier)

CCCWFU-88198

LAC-USC-4B951 (Other Identifier)

NCI-G00-1715 (Other Identifier)

NYU-9852 (Other Identifier)

U10CA032102 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 521 patients

Sex: All

Ages: Under 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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521 participants in 4 patient groups

Arm I: M-VAC x 3

Experimental group

Description:

Patients with altered (+) p53, reconsented to randomization, randomized to three cycles of MVAC

Treatment:

Drug: methotrexate

Drug: vinblastine

Drug: cisplatin

Drug: doxorubicin hydrochloride

Arm II: Observation

No Intervention group

Description:

Patients with altered (+) p53, reconsented to randomization, randomized to observation

Arm III: Observation

No Intervention group

Description:

Patients with unaltered (-) p53

Arm IV: Observation

No Intervention group

Description:

Patients with altered (+) p53, patients did not consent to randomization