S0337, Gemcitabine After Surgery in Treating Patients With Newly Diagnosed or Recurrent Bladder Cancer

A Phase III Blinded Study of Immediate Post TURBT Instillation of Gemcitabine Versus Saline in Patients With Newly Diagnosed or Occasionally Recurring Grade I/II Superficial Bladder Cancer

RATIONALE: Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving gemcitabine directly into the bladder after surgery may kill more tumor cells. It is not yet known whether giving gemcitabine directly into the bladder is more effective than a placebo in treating bladder cancer.

PURPOSE: This randomized phase III trial is studying gemcitabine to see how well it works when given directly into the bladder compared with a placebo after surgery in treating patients with newly diagnosed or recurrent bladder cancer.

Study Overview

• Status: Completed
• Conditions: Bladder Cancer
• Intervention / Treatment: Drug: gemcitabine hydrochloride; Other: placebo

Detailed Description

OBJECTIVES:

Primary

• Compare the efficacy of a single intravesical instillation of gemcitabine hydrochloride vs placebo immediately after transurethral resection of the bladder tumor (TURBT) in preventing recurrence at 2 years in patients with grade 1 or 2 superficial transitional cell cancer of the bladder.

Secondary

• Compare whether a single instillation of intravesical gemcitabine hydrochloride can improve the time to progression to muscle invasive disease vs placebo in these patients.
• Compare the qualitative and quantitative toxicities of these regimens in these patients.
• Compare whether treatment with post-TURBT intravesical instillation of gemcitabine vs placebo results in reduced long-term morbidity in patients, as defined by requirement for fewer TURBTs, courses of traditional intravesical therapies, and surveillance cystoscopies over 4 years.

Tertiary

• Assess whether performing a combination of molecular and/or cytologic diagnostic marker tests, including NMP-22 Bladder Chek and BTA Stat every 3 months, can predict recurrence as accurately as cystoscopy alone in these patients.

OUTLINE: This is a randomized, double-blind, multicenter study. Patients are stratified according to disease status (first occurrence vs recurrent disease) and number of tumor sites (1 vs ≥ 2). Patients are randomized to 1 of 2 treatment arms.

All patients undergo transurethral resection of the bladder tumor. Within 3 hours, patients receive intravesical therapy according to their randomized arm.

• Arm I: Patients receive intravesical gemcitabine hydrochloride over 1 hour.
• Arm II: Patients receive intravesical placebo over 1 hour. Urine is collected at baseline and then every 3 months for 2 years for research studies including the NMP-22 Bladder Chek and BTA Stat test.

After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 2 years.

PROJECTED ACCRUAL: A total of 340 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 406
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
  • California
    • Los Angeles, California, United States, 90048
      • Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center
    • Sacramento, California, United States, 95817
      • University of California Davis Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center at UC Health Sciences Center
    • Denver, Colorado, United States, 80220
      • Veterans Affairs Medical Center - Denver
    • Denver, Colorado, United States, 80211
      • Urology Center of Colorado
  • Idaho
    • Lewiston, Idaho, United States, 83501
      • St. Joseph Regional Medical Center
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Cardinal Bernardin Cancer Center at Loyola University Medical Center
  • Kansas
    • Great Bend, Kansas, United States, 67530
      • St. Rose Ambulatory and Surgery Center
    • Hays, Kansas, United States, 67601
      • Hays Medical Center
    • Hutchinson, Kansas, United States, 67502
      • Hutchinson Hospital Corporation
    • Kansas City, Kansas, United States, 66160-7357
      • Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
    • Kansas City, Kansas, United States, 66112
      • Kansas City Cancer Centers - West
    • Overland Park, Kansas, United States, 66210
      • Kansas City Cancer Centers - Southwest
    • Pittsburg, Kansas, United States, 66762
      • Mount Carmel Regional Cancer Center
    • Salina, Kansas, United States, 67401
      • Tammy Walker Cancer Center at Salina Regional Health Center
    • Shawnee Mission, Kansas, United States, 66204
      • Kansas City Cancer Center - Shawnee Mission
    • Topeka, Kansas, United States, 66606
      • St. Francis Comprehensive Cancer Center
  • Louisiana
    • Shreveport, Louisiana, United States, 71130-3932
      • Feist-Weiller Cancer Center at Louisiana State University Health Sciences
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0942
      • University of Michigan Comprehensive Cancer Center
    • Detroit, Michigan, United States, 48202
      • Josephine Ford Cancer Center at Henry Ford Hospital
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital - Royal Oak Campus
  • Missouri
    • Kansas City, Missouri, United States, 64128
      • Veterans Affairs Medical Center - Kansas City
    • Kansas City, Missouri, United States, 64108
      • Truman Medical Center - Hospital Hill
    • Kansas City, Missouri, United States, 64154
      • Kansas City Cancer Centers - North
    • Kansas City, Missouri, United States, 64131
      • Kansas City Cancer Centers - South
    • Lee's Summit, Missouri, United States, 64064
      • Kansas City Cancer Centers - East
  • Montana
    • Billings, Montana, United States, 59101
      • CCOP - Montana Cancer Consortium
    • Billings, Montana, United States, 59101
      • St. Vincent Healthcare Cancer Care Services
    • Billings, Montana, United States, 59107-7000
      • Billings Clinic - Downtown
    • Billings, Montana, United States, 59102
      • Hematology-Oncology Centers of the Northern Rockies - Billings
    • Bozeman, Montana, United States, 59715
      • Bozeman Deaconess Cancer Center
    • Butte, Montana, United States, 59701
      • St. James Healthcare Cancer Care
    • Great Falls, Montana, United States, 59405
      • Great Falls Clinic - Main Facility
    • Great Falls, Montana, United States, 59405
      • Sletten Cancer Institute at Benefis Healthcare
    • Havre, Montana, United States, 59501
      • Northern Montana Hospital
    • Helena, Montana, United States, 59601
      • St. Peter's Hospital
    • Kalispell, Montana, United States, 59901
      • Kalispell Regional Medical Center
    • Kalispell, Montana, United States, 59901
      • Glacier Oncology, PLLC
    • Kalispell, Montana, United States, 59901
      • Kalispell Medical Oncology at KRMC
    • Missoula, Montana, United States, 59807-7877
      • Montana Cancer Specialists at Montana Cancer Center
    • Missoula, Montana, United States, 59807
      • Montana Cancer Center at St. Patrick Hospital and Health Sciences Center
  • New York
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28232-2861
      • Blumenthal Cancer Center at Carolinas Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Cancer Institute
  • Oregon
    • Coos Bay, Oregon, United States, 97420
      • Bay Area Hospital
    • Portland, Oregon, United States, 97239-3098
      • Knight Cancer Institute At Oregon Health and Science University
  • Texas
    • Fort Sam Houston, Texas, United States, 78234-6200
      • Brooke Army Medical Center
    • Houston, Texas, United States, 77030-4009
      • M. D. Anderson Cancer Center at University of Texas
    • Houston, Texas, United States, 77030
      • Methodist Hospital
    • Houston, Texas, United States, 77030
      • Veterans Affairs Medical Center - Houston
    • Houston, Texas, United States, 77030
      • Baylor University Medical Center - Houston
    • Lackland Air Force Base, Texas, United States, 78236
      • Wilford Hall Medical Center
    • 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, 78229-3900
      • University of Texas Health Science Center at San Antonio
    • San Antonio, Texas, United States, 78229
      • University Hospital - San Antonio
  • Washington
    • Bellevue, Washington, United States, 98004
      • Overlake Cancer Center at Overlake Hospital Medical Center
    • Centralia, Washington, United States, 98531-9027
      • Providence Centralia Hospital
    • Everett, Washington, United States, 98201
      • Providence Regional Cancer Partnership
    • Federal Way, Washington, United States, 98003
      • St. Francis Hospital
    • Olympia, Washington, United States, 98506-5166
      • Providence St. Peter Hospital Regional Cancer Center
    • Puyallup, Washington, United States, 98372
      • Good Samaritan Cancer Center
    • Tacoma, Washington, United States, 98405-3004
      • Franciscan Cancer Center at St. Joseph Medical Center
    • Tacoma, Washington, United States, 98405
      • Allenmore Hospital
    • Tacoma, Washington, United States, 98405
      • CCOP - Northwest
    • Tacoma, Washington, United States, 98405
      • MultiCare Regional Cancer Center at Tacoma General Hospital
    • Tacoma, Washington, United States, 98499
      • St. Clare Hospital
    • Tacoma, Washington, United States, 98431
      • Madigan Army Medical Center - Tacoma

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of newly diagnosed or recurrent transitional cell bladder cancer meeting the following criteria:

  • Ta or T1 primary tumor
  • Grade 1 or 2 disease

• No more than 2 recurrences (except for index tumor) within the 18 months prior to the index tumor's transurethral resection of the bladder tumor (TURBT)

  • Index tumor post-TURBT must meet the following criteria:

    • Ta or T1 tumor without any prior tumor in situ, grade 3 (high grade) disease within 2 years prior to index tumor TURBT, or invasion of the muscularis propria (stage ≥ T2)
    • Grade 1 or 2 disease (similar to papillary urothelial neoplasm of low malignant potential and low-grade bladder cancer)
• Not a candidate for a therapy other than TURBT (e.g., a series of instillations of intravesical immunotherapy [e.g., BCG] or intravesical chemotherapy, or cystectomy or partial cystectomy)

• Negative upper tract imaging studies within 1 year (365 days) prior to study entry

  • Imaging studies may be performed after registration provided it is done prior to TURBT on the day of treatment
• No urothelial cancer of the prostate or more distal urethra (or urethra at all in women) as assessed by endoscopy
• Must have a negative urine culture (less than or equal to 10,000 col/mL, mixed flora-likely contamination) OR negative urine analysis for infection AND negative nitrates on reagent strip, ≤ 10 white blood cell count (WBC)/high-power field, and no rods or organisms on examination of spun urine sediment OR an automated or visual reagent strip urinalysis that is negative for leukocytes and nitrates within the past 28 days
• TURBT planned within the next 28 days and planned treatment within 3 hours after TURBT

PATIENT CHARACTERISTICS:

• Zubrod performance status 0-1
• Not pregnant or nursing
• Fertile patients must use effective contraception

• No other prior malignancy except for any of the following:

  • Adequately treated basal cell or squamous cell skin cancer
  • In situ cervical cancer
  • Adequately treated stage I or II cancer from which patient is in complete remission
  • Any other cancer from which patient has been disease-free for 3 years

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• More than 145 days since prior intravesical therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients receive intravesical gemcitabine hydrochloride over 1 hour.	Drug: gemcitabine hydrochloride; Given intravesically
Placebo Comparator: Arm II; Patients receive intravesical placebo over 1 hour.	Other: placebo; Given intravesically

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Recurrence Rate	Percentage of patients who experienced a recurrence of grade 1 or 2 superficial transitional cell cancer of the bladder between the date of registration and 24 months. Disease recurrence considered to occur at date of first observation of recurrent disease subsequently confirmed by biopsy. Patients without recurrence were censored at the time of their last cystoscopy.	Up to 2 Years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Progression to Muscle Invasive Disease at 4 Years	From date of registration to date of diagnosis of progressive disease. Censor at date of last disease assessment for those without progression.	4 years
Compare Qualitative and Quantitative Toxicities Between the Treatment Arms	Number of patients with Grade 3 through Grade 5 adverse events that are related to study drug	Up to 4 years after Transurethral Resection of Bladder Tumor (TURBT)
Rate of Disease Worsening Over 2 Years	Compare whether treatment with post-TURBT intravesical instillation of gemcitabine vs placebo results in reduced long-term morbidity in patients, as defined by requirement for fewer TURBTs, courses of traditional intravesical therapies, and surveillance cystoscopies over 4 years.	Up to 2 years

Collaborators and Investigators

• Sponsor: Southwest Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Edward M. Messing, MD, FACS, James P. Wilmot Cancer Center; Study Chair: Deepak M. Sahasrabudhe, MD, James P. Wilmot Cancer Center; Study Chair: Theresa M. Koppie, MD, Oregon Health and Science University; Study Chair: David P. Wood, MD, Beaumont Physician Partners

Publications and helpful links

General Publications

• Messing EM, Tangen CM, Lerner SP, Sahasrabudhe DM, Koppie TM, Wood DP Jr, Mack PC, Svatek RS, Evans CP, Hafez KS, Culkin DJ, Brand TC, Karsh LI, Holzbeierlein JM, Wilson SS, Wu G, Plets M, Vogelzang NJ, Thompson IM Jr. Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non-Muscle-Invasive Bladder Cancer on Tumor Recurrence: SWOG S0337 Randomized Clinical Trial. JAMA. 2018 May 8;319(18):1880-1888. doi: 10.1001/jama.2018.4657.

Helpful Links

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive

Study record dates

Study Major Dates

• Study Start: September 1, 2007
• Primary Completion (Actual): June 1, 2017
• Study Completion (Actual): June 1, 2017

Study Registration Dates

• First Submitted: March 7, 2007
• First Submitted That Met QC Criteria: March 7, 2007
• First Posted (Estimate): March 9, 2007

Study Record Updates

• Last Update Posted (Actual): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 8, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: recurrent bladder cancer; transitional cell carcinoma of the bladder; stage 0 bladder cancer; stage I 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; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gemcitabine
• Other Study ID Numbers: CDR0000534235; U10CA032102 (U.S. NIH Grant/Contract); S0337 (Other Identifier: SWOG)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No