4B951, Combination Chemotherapy in Treating Patients With Bladder Cancer

MVAC (Methotrexate, Vinblastine, Adriamycin, and Cisplatin) in Organ-Confined Bladder Cancer Based on p53 Status

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.

Study Overview

• Status: Terminated
• Conditions: Bladder Cancer
• Intervention / Treatment: Drug: methotrexate; Drug: cisplatin; Drug: doxorubicin hydrochloride; Drug: vinblastine

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.

• Study Type: Interventional
• Enrollment (Actual): 521
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Toronto Sunnybrook Regional Cancer Centre at Sunnybrook and Women's College Health Sciences Centre
• United States
  • Arizona
    • Glendale, Arizona, United States, 85306
      • Banner Thunderbird Medical Center
    • Phoenix, Arizona, United States, 85006
      • Banner Good Samaritan Medical Center
    • Phoenix, Arizona, United States, 85006
      • CCOP - Western Regional, Arizona
  • California
    • Los Angeles, California, United States, 90089-9181
      • USC/Norris Comprehensive Cancer Center and Hospital
  • Colorado
    • Greeley, Colorado, United States, 80631
      • North Colorado Medical Center
    • Loveland, Colorado, United States, 80539
      • McKee Medical Center
  • Illinois
    • Alton, Illinois, United States, 62002
      • Saint Anthony's Hospital at Saint Anthony's Health Center
    • Maywood, Illinois, United States, 60153
      • Cardinal Bernardin Cancer Center at Loyola University Medical Center
    • Mount Vernon, Illinois, United States, 62864
      • Good Samaritan Regional Health Center
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • St. Francis Hospital and Health Centers - Beech Grove Campus
  • Kansas
    • Chanute, Kansas, United States, 66720
      • Cancer Center of Kansas, P.A. - Chanute
    • Dodge City, Kansas, United States, 67801
      • Cancer Center of Kansas, P.A. - Dodge City
    • El Dorado, Kansas, United States, 67042
      • Cancer Center of Kansas, P.A. - El Dorado
    • Kansas City, Kansas, United States, 64128
      • Veterans Affairs Medical Center - Kansas City
    • Kingman, Kansas, United States, 67068
      • Cancer Center of Kansas, P.A. - Kingman
    • Liberal, Kansas, United States, 67901
      • Southwest Medical Center
    • Newton, Kansas, United States, 67114
      • Cancer Center of Kansas, P.A. - Newton
    • Parsons, Kansas, United States, 67357
      • Cancer Center of Kansas, P.A. - Parsons
    • Pratt, Kansas, United States, 67124
      • Cancer Center of Kansas, P.A. - Pratt
    • Salina, Kansas, United States, 67401
      • Salina Regional Health Center
    • Salina, Kansas, United States, 67042
      • Cancer Center of Kansas, P.A. - Salina
    • Wellington, Kansas, United States, 67152
      • Cancer Center of Kansas, P.A. - Wellington
    • Wichita, Kansas, United States, 67214
      • CCOP - Wichita
    • Wichita, Kansas, United States, 67214
      • Via Christi Cancer Center at Via Christi Regional Medical Center
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas, P.A. - Wichita
    • Wichita, Kansas, United States, 67203
      • Associates in Womens Health, P.A. - North Review
    • Wichita, Kansas, United States, 67208
      • Cancer Center of Kansas, P.A. - Medical Arts Tower
    • Winfield, Kansas, United States, 67156
      • Cancer Center of Kansas, P.A. - Winfield
  • Louisiana
    • Shreveport, Louisiana, United States, 71130-3932
      • Feist-Weiller Cancer Center at Louisiana State University Health Sciences
    • Shreveport, Louisiana, United States, 71101
      • Veterans Affairs Medical Center - Shreveport
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0942
      • University of Michigan Comprehensive Cancer Center
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital - Royal Oak Campus
  • Missouri
    • Cape Girardeau, Missouri, United States, 63701
      • St. Francis Medical Center
    • Cape Girardeau, Missouri, United States, 63701
      • Southeast Missouri Regional Cancer Center at Southeast Missouri Hospital
    • Saint Louis, Missouri, United States, 63141
      • CCOP - St. Louis-Cape Girardeau
    • Saint Louis, Missouri, United States, 63141
      • David C. Pratt Cancer Center at St. John's Mercy
  • Montana
    • Great Falls, Montana, United States, 59405
      • Big Sky Oncology
    • Great Falls, Montana, United States, 59405
      • Sletten Regional Cancer Institute
  • New York
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
    • Dayton, Ohio, United States, 45428
      • Veterans Affairs Medical Center - Dayton
    • Dayton, Ohio, United States, 45405
      • Grandview Hospital
    • Dayton, Ohio, United States, 45406
      • Good Samaritan Hospital
    • Dayton, Ohio, United States, 45409
      • David L. Rike Cancer Center at Miami Valley Hospital
    • Dayton, Ohio, United States, 45415
      • Samaritan North Cancer Care Center
    • Dayton, Ohio, United States, 45429
      • CCOP - Dayton
    • Independence, Ohio, United States, 44131
      • Community Oncology Group at Cleveland Clinic Cancer Center
    • Kettering, Ohio, United States, 45429
      • Charles F. Kettering Memorial Hospital
    • Middletown, Ohio, United States, 45044
      • Middletown Regional Hospital
    • Troy, Ohio, United States, 45373-1300
      • UVMC Cancer Care Center at Upper Valley Medical Center
    • Wooster, Ohio, United States, 44691
      • Cleveland Clinic - Wooster
    • Xenia, Ohio, United States, 45385
      • Ruth G. McMillan Cancer Center at Greene Memorial Hospital
  • Texas
    • Fort Sam Houston, Texas, United States, 78234
      • Brooke Army Medical Center
    • Lackland Air Force Base, Texas, United States, 78236
      • Wilford Hall Medical Center
    • San Antonio, Texas, United States, 78284-7811
      • University of Texas Health Science Center at San Antonio
    • San Antonio, Texas, United States, 78229
      • Cancer Therapy and Research Center
    • San Antonio, Texas, United States, 78209
      • Veterans Affairs Medical Center - San Antonio (Murphy)
    • San Antonio, Texas, United States, 78229
      • University Hospital - San Antonio
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Sentara Cancer Institute at Sentara Norfolk General Hospital
  • Washington
    • Bellingham, Washington, United States, 98225
      • St. Joseph Hospital Community Cancer Center
    • Bremerton, Washington, United States, 98310
      • Olympic Hematology and Oncology
    • Mount Vernon, Washington, United States, 98273
      • Skagit Valley Hospital Cancer Care Center
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
    • Seattle, Washington, United States, 98101
      • CCOP - Virginia Mason Research Center
    • Seattle, Washington, United States, 98109-1024
      • Fred Hutchinson Cancer Research Center
    • Seattle, Washington, United States, 98195-6043
      • University Cancer Center at University of Washington Medical Center
    • Seattle, Washington, United States, 98104
      • Group Health Central Hospital
    • Seattle, Washington, United States, 98114
      • Swedish Cancer Institute at Swedish Medical Center - First Hill Campus
    • Sedro-Woolley, Washington, United States, 98284
      • North Puget Oncology at United General Hospital
    • Spokane, Washington, United States, 99202
      • Cancer Care Northwest - Spokane South
    • Wenatchee, Washington, United States, 98801
      • Wenatchee Valley Clinic
  • West Virginia
    • Parkersburg, West Virginia, United States, 26102
      • Community Comprehensive Cancer Center at Camden-Clark Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 120 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm I: M-VAC x 3; Patients with altered (+) p53, reconsented to randomization, randomized to three cycles of MVAC	Drug: methotrexate; Drug: cisplatin; Drug: doxorubicin hydrochloride; Drug: vinblastine
NO_INTERVENTION: Arm II: Observation; Patients with altered (+) p53, reconsented to randomization, randomized to observation
NO_INTERVENTION: Arm III: Observation; Patients with unaltered (-) p53
NO_INTERVENTION: Arm IV: Observation; Patients with altered (+) p53, patients did not consent to randomization

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	5 years
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.	5 years
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.	5 years

Collaborators and Investigators

• Sponsor: Southwest Oncology Group
• Collaborators: National Cancer Institute (NCI); University of Southern California; NCIC Clinical Trials Group
• Investigators: Study Chair: Richard J. Cote, MD, FRCPath, University of Southern California; Study Chair: Seth P Lerner, MD, Baylor College of Medicine

Publications and helpful links

General Publications

• von Rundstedt FC, Mata DA, Groshen S, Stein JP, Skinner DG, Stadler WM, Cote RJ, Kryvenko ON, Godoy G, Lerner SP. Significance of lymphovascular invasion in organ-confined, node-negative urothelial cancer of the bladder: data from the prospective p53-MVAC trial. BJU Int. 2015 Jul;116(1):44-9. doi: 10.1111/bju.12997. Epub 2015 Mar 25.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 1997
• Primary Completion (ACTUAL): March 1, 2011
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: April 6, 2000
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (ESTIMATE): January 27, 2003

Study Record Updates

• Last Update Posted (ACTUAL): June 8, 2017
• Last Update Submitted That Met QC Criteria: May 10, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: transitional cell carcinoma of the bladder; stage I bladder cancer; stage II bladder cancer
• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Antibiotics, Antineoplastic; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Cisplatin; Doxorubicin; Liposomal doxorubicin; Methotrexate; Vinblastine
• Other Study ID Numbers: CDR0000067639; U10CA032102 (U.S. NIH Grant/Contract); LAC-USC-4B951 (OTHER: USC); SWOG-4B951 (OTHER: SWOG); NCI-G00-1715 (OTHER: NCI); NYU-9852 (OTHER: NYU); CAN-NCIC-BL10 (OTHER: NCIC-CTG); CCCWFU-88198