Clinical trial NCT00005047: 4B951, Combination Chemotherapy in Treating Patients With Bladder Cancer
Official title: MVAC (Methotrexate, Vinblastine, Adriamycin, and Cisplatin) in Organ-Confined Bladder Cancer Based on p53 Status
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Bladder Cancer
Keywords: stage I bladder cancer
stage II bladder cancer
transitional cell carcinoma of the bladder
Lead sponsor: SWOG Cancer Research Network
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: NCIC Clinical Trials Group
name: University of Southern California
First posted: 2003-01-27
Enrollment: 521
Sex: ALL
Maximum age (years): 120
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Probability of Recurring
timeFrame: 5 years
Secondary outcomes:
measure: Probability of Overall Survival
timeFrame: 5 years
measure: Probability of Recurrence
timeFrame: 5 years
measure: Probability of Overall Survival
timeFrame: 5 years
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Banner Thunderbird Medical Center
state: Arizona
city: Phoenix
country: United States
facility: Banner Good Samaritan Medical Center
state: Arizona
city: Phoenix
country: United States
facility: CCOP - Western Regional, Arizona
state: Arizona
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center and Hospital
state: California
city: Greeley
country: United States
facility: North Colorado Medical Center
state: Colorado
city: Loveland
country: United States
facility: McKee Medical Center
state: Colorado
city: Alton
country: United States
facility: Saint Anthony's Hospital at Saint Anthony's Health Center
state: Illinois
city: Maywood
country: United States
facility: Cardinal Bernardin Cancer Center at Loyola University Medical Center
state: Illinois
city: Mount Vernon
country: United States
facility: Good Samaritan Regional Health Center
state: Illinois
city: Beech Grove
country: United States
facility: St. Francis Hospital and Health Centers - Beech Grove Campus
state: Indiana
city: Chanute
country: United States
facility: Cancer Center of Kansas, P.A. - Chanute
state: Kansas
city: Dodge City
country: United States
facility: Cancer Center of Kansas, P.A. - Dodge City
state: Kansas
city: El Dorado
country: United States
facility: Cancer Center of Kansas, P.A. - El Dorado
state: Kansas
city: Kansas City
country: United States
facility: Veterans Affairs Medical Center - Kansas City
state: Kansas
city: Kingman
country: United States
facility: Cancer Center of Kansas, P.A. - Kingman
state: Kansas
city: Liberal
country: United States
facility: Southwest Medical Center
state: Kansas
city: Newton
country: United States
facility: Cancer Center of Kansas, P.A. - Newton
state: Kansas
city: Parsons
country: United States
facility: Cancer Center of Kansas, P.A. - Parsons
state: Kansas
city: Pratt
country: United States
facility: Cancer Center of Kansas, P.A. - Pratt
state: Kansas
city: Salina
country: United States
facility: Cancer Center of Kansas, P.A. - Salina
state: Kansas
city: Salina
country: United States
facility: Salina Regional Health Center
state: Kansas
city: Wellington
country: United States
facility: Cancer Center of Kansas, P.A. - Wellington
state: Kansas
city: Wichita
country: United States
facility: Associates in Womens Health, P.A. - North Review
state: Kansas
city: Wichita
country: United States
facility: Cancer Center of Kansas, P.A. - Medical Arts Tower
state: Kansas
city: Wichita
country: United States
facility: Cancer Center of Kansas, P.A. - Wichita
state: Kansas
city: Wichita
country: United States
facility: CCOP - Wichita
state: Kansas
city: Wichita
country: United States
facility: Via Christi Cancer Center at Via Christi Regional Medical Center
state: Kansas
city: Winfield
country: United States
facility: Cancer Center of Kansas, P.A. - Winfield
state: Kansas
city: Shreveport
country: United States
facility: Veterans Affairs Medical Center - Shreveport
state: Louisiana
city: Shreveport
country: United States
facility: Feist-Weiller Cancer Center at Louisiana State University Health Sciences
state: Louisiana
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital - Royal Oak Campus
state: Michigan
city: Cape Girardeau
country: United States
facility: Southeast Missouri Regional Cancer Center at Southeast Missouri Hospital
state: Missouri
city: Cape Girardeau
country: United States
facility: St. Francis Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: CCOP - St. Louis-Cape Girardeau
state: Missouri
city: Saint Louis
country: United States
facility: David C. Pratt Cancer Center at St. John's Mercy
state: Missouri
city: Great Falls
country: United States
facility: Big Sky Oncology
state: Montana
city: Great Falls
country: United States
facility: Sletten Regional Cancer Institute
state: Montana
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center at Columbia University
state: New York
city: Rochester
country: United States
facility: James P. Wilmot Cancer Center at University of Rochester Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Dayton
country: United States
facility: Grandview Hospital
state: Ohio
city: Dayton
country: United States
facility: Good Samaritan Hospital
state: Ohio
city: Dayton
country: United States
facility: David L. Rike Cancer Center at Miami Valley Hospital
state: Ohio
city: Dayton
country: United States
facility: Samaritan North Cancer Care Center
state: Ohio
city: Dayton
country: United States
facility: Veterans Affairs Medical Center - Dayton
state: Ohio
city: Dayton
country: United States
facility: CCOP - Dayton
state: Ohio
city: Independence
country: United States
facility: Community Oncology Group at Cleveland Clinic Cancer Center
state: Ohio
city: Kettering
country: United States
facility: Charles F. Kettering Memorial Hospital
state: Ohio
city: Middletown
country: United States
facility: Middletown Regional Hospital
state: Ohio
city: Troy
country: United States
facility: UVMC Cancer Care Center at Upper Valley Medical Center
state: Ohio
city: Wooster
country: United States
facility: Cleveland Clinic - Wooster
state: Ohio
city: Xenia
country: United States
facility: Ruth G. McMillan Cancer Center at Greene Memorial Hospital
state: Ohio
city: Fort Sam Houston
country: United States
facility: Brooke Army Medical Center
state: Texas
city: Lackland Air Force Base
country: United States
facility: Wilford Hall Medical Center
state: Texas
city: San Antonio
country: United States
facility: Veterans Affairs Medical Center - San Antonio (Murphy)
state: Texas
city: San Antonio
country: United States
facility: Cancer Therapy and Research Center
state: Texas
city: San Antonio
country: United States
facility: University Hospital - San Antonio
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Norfolk
country: United States
facility: Sentara Cancer Institute at Sentara Norfolk General Hospital
state: Virginia
city: Bellingham
country: United States
facility: St. Joseph Hospital Community Cancer Center
state: Washington
city: Bremerton
country: United States
facility: Olympic Hematology and Oncology
state: Washington
city: Mount Vernon
country: United States
facility: Skagit Valley Hospital Cancer Care Center
state: Washington
city: Seattle
country: United States
facility: CCOP - Virginia Mason Research Center
state: Washington
city: Seattle
country: United States
facility: Group Health Central Hospital
state: Washington
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Seattle
country: United States
facility: Swedish Cancer Institute at Swedish Medical Center - First Hill Campus
state: Washington
city: Seattle
country: United States
facility: University Cancer Center at University of Washington Medical Center
state: Washington
city: Sedro-Woolley
country: United States
facility: North Puget Oncology at United General Hospital
state: Washington
city: Spokane
country: United States
facility: Cancer Care Northwest - Spokane South
state: Washington
city: Wenatchee
country: United States
facility: Wenatchee Valley Clinic
state: Washington
city: Parkersburg
country: United States
facility: Community Comprehensive Cancer Center at Camden-Clark Memorial Hospital
state: West Virginia
city: Toronto
country: Canada
facility: Toronto Sunnybrook Regional Cancer Centre at Sunnybrook and Women's College Health Sciences Centre
state: Ontario
Study officials:
affiliation: University of Southern California
name: Richard J. Cote, MD, FRCPath
role: STUDY_CHAIR
affiliation: Toronto Sunnybrook Regional Cancer Centre
name: Laurence H. Klotz, MD
role: STUDY_CHAIR
affiliation: Baylor College of Medicine
name: Seth P Lerner, MD
role: STUDY_CHAIR
References:
citation: 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.