S1011 Standard or Extended Pelvic Lymphadenectomy in Treating Patients Undergoing Surgery for Invasive Bladder Cancer

A Phase III Surgical Trial to Evaluate the Benefit of a Standard Versus an Extended Pelvic Lymphadenectomy Performed at Time of Radical Cystectomy for Muscle Invasive Urothelial Cancer

RATIONALE: Lymphadenectomy may remove tumor cells that have spread to nearby lymph nodes in patients with invasive bladder cancer. It is not yet known whether extended pelvic lymphadenectomy is more effective than standard pelvic lymphadenectomy during surgery.

PURPOSE: This randomized phase II trial is studying standard pelvic lymphadenectomy to see how well it works compared to extended pelvic lymphadenectomy in treating patients undergoing surgery for invasive bladder cancer.

Study Overview

• Status: Completed
• Conditions: Bladder Cancer
• Intervention / Treatment: Procedure: therapeutic conventional surgery; Procedure: therapeutic standard lymphadenectomy; Procedure: therapeutic extended lymphadenectomy

Detailed Description

OBJECTIVES:

Primary

• To compare disease-free survival (DFS) of patients with muscle-invasive urothelial carcinoma of the bladder undergoing radical cystectomy with extended pelvic lymph node dissection (PLND) or standard pelvic lymphadenectomy.

Secondary

• To compare overall survival (OS) of patients randomized to extended PLND versus those randomized to standard pelvic lymphadenectomy.
• To evaluate operative time; whether or not nerve sparing was performed, intraoperative, peri-operative and 90-day morbidity and mortality; length of hospital stay; histology (pure urothelial versus mixed); lymph node counts and lymph node density; adjuvant chemotherapy received; and local and retroperitoneal soft tissue recurrence in patients randomized to extended PLND versus those randomized to standard pelvic lymphadenectomy.
• To collect peripheral blood and two paraffin-embedded blocks of the primary tumor for translational medicine studies, including circulating tumor cells (CTCs) and markers of epithelial and mesenchymal transition, and correlate these findings with pathologic T stage and node metastasis as well as DFS and OS.

OUTLINE: This is a multicenter study. Patients are stratified according to prior neoadjuvant therapy (yes vs no), clinical stage (T2 vs T3 vs T4a), and Zubrod performance status (0-1 vs 2). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo radical cystectomy and standard pelvic lymphadenectomy.
• Arm II: Patients undergo radical cystectomy and extended pelvic lymphadenectomy.

Blood and tumor specimens may be collected periodically for translational studies.

After completion of study therapy, patients are followed up periodically for 6 years.

• Study Type: Interventional
• Enrollment (Actual): 658
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BCCA-Vancouver Cancer Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V8
      • QEII Health Sciences Centre/Capital District Health Authority
  • Ontario
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program
    • Toronto, Ontario, Canada, M5G 2M9
      • University Health Network-Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3H 2R9
      • The Research Institute of the McGill University Health Centre (MUHC)
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill University Department of Oncology
• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90033
      • Los Angeles County-USC Medical Center
    • Palo Alto, California, United States, 94304
      • Stanford Cancer Institute
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • San Francisco, California, United States, 94158
      • UCSF Medical Center-Mission Bay
    • San Francisco, California, United States, 94115
      • UCSF Medical Center-Mount Zion
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center - Anschutz Cancer Pavilion
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • Louisiana State University Health Sciences Center Shreveport
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
    • Rochester, New York, United States, 14642
      • University of Rochester
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97239
      • Portland Veterans Administration Medical Center
  • Texas
    • Dallas, Texas, United States, 75235
      • Parkland Memorial Hospital
    • Dallas, Texas, United States, 75390
      • UT Southwestern/Simmons Cancer Center-Dallas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
    • Houston, Texas, United States, 77030
      • Baylor Saint Luke's Medical Center
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
    • San Antonio, Texas, United States, 78209
      • Audie L Murphy Veterans Affairs Hospital

Participation Criteria

Eligibility Criteria

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

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed urothelial carcinoma of the bladder

  • Stage T2, T3, or T4a disease

    • No clinical stage consistent with a low-risk of node metastasis (CIS only, T1)
    • No T4b disease (fixed lesion)

  • Disease that requires primary radical cystectomy and lymph node dissection for definitive treatment

    • No laparoscopic surgery

• Predominant urothelial carcinoma with any of the following elements allowed:

  • Adenocarcinoma
  • Squamous cell carcinoma
  • Micropapillary or minor components of other rare phenotype
  • No pure squamous cell carcinoma or adenocarcinoma
• No visceral or nodal metastatic disease proximal to the common iliac bifurcation by 2-view chest x-ray and abdominal-pelvic imaging by computerized tomography or MRI of the abdomen and pelvis
• No intra-operative pelvic lymph node involvement (confirmed by frozen section) at or above the bifurcation of the common iliac vessels in any of the extended template

PATIENT CHARACTERISTICS:

• Zubrod performance status 0-2
• ALT and AST ≤ upper limit of normal (ULN)*
• Alkaline phosphatase ≤ ULN*
• Not pregnant or nursing
• Fertile patients must use an effective contraception
• No other prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or stage I or II cancer from which the patient is in complete remission for the past 5 years
• Medically suitable to undergo cystectomy, in the physician's opinion NOTE: *Levels may be ≥ ULN provided metastatic disease is excluded using dedicated liver imaging, bone scan, or biopsy.

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior partial cystectomy for invasive bladder cancer
• No prior pelvic surgery that would obviate a complete extended lymphadenectomy (e.g., aorto-femoral/iliac bypass)
• Prior neoadjuvant chemotherapy for this cancer allowed provided it has been completed and patient has recovered
• No prior pelvic irradiation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm I; therapeutic conventional surgery therapeutic standard lymphadenectomy	Procedure: therapeutic conventional surgery; Patients undergo radical cystectomy; Procedure: therapeutic standard lymphadenectomy; Patients undergo standard pelvic lymphadenectomy.
Experimental: Arm II; therapeutic conventional surgery therapeutic extended lymphadenectomy	Procedure: therapeutic conventional surgery; Patients undergo radical cystectomy; Procedure: therapeutic extended lymphadenectomy; Patients undergo extended pelvic lymphadenectomy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
5-year Disease-free Survival (DFS)	Comparing 5-year disease-free survival (DFS) in participants undergoing radical cystectomy for muscle-invasive urothelial carcinoma of the bladder (UCB) treated with radical cystectomy and extended pelvic lymph node dissection (PLND) compared to radical cystectomy and standard pelvic lymphadenectomy. Disease-free survival is defined as the time from the date of randomization to date of first documentation of relapse/recurrence or death due to any cause. Participants last known to be alive without report of relapse/recurrence are censored at date of last contact. Criteria for recurrence included measurable disease on cross-sectional imaging or plain radiography targeting lung, liver, and bone. If local pelvic recurrence was identified on digital rectal examination, biopsy was required for confirmation. Second primary tumors of the upper urinary tract or retained urethra were not considered to be recurrence.	Duration of treatment and follow-up until death or 6 years after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
5-year Overall Survival (OS)	Comparing 5-year overall survival (OS) in participants randomized to extended PLND versus those randomized to standard pelvic lymphadenectomy. Overall survival is defined as the time from date of randomization to date of death from any cause. Participants known to be alive are censored at date of last contact.	Duration of treatment and follow-up until death or 6 years after randomization
Median Operative Time	Evaluating duration of surgery in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy.	Duration of surgery
Median Days in Hospital	Evaluating duration of post-operative hospital stay in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy.	From date of operation to 90 days post-operation
Use of Nerve Preservation	Evaluating the frequency of nerve sparing surgery in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy.	Duration of surgery
Lymph Node Counts	Evaluating the number of positive lymph nodes removed during surgery as well as the total number of lymph nodes removed in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy.	Duration of surgery
Receipt of Adjuvant Chemotherapy	Evaluating the receipt of adjuvant chemotherapy in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy. Participants that reported plans to start adjuvant chemotherapy are included in these counts.	From date of operation to 90 days post-operation
Frequency of Post-Operative Local Recurrence	Evaluating the frequency of post-operative local and retroperitoneal soft-tissue recurrence in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy.	From date of operation to 90 days post-operation
Post-Operative Morbidity	Evaluating perioperative morbidity (death within 30 days of surgery) and post-operative morbidity (death within 90 days of surgery) in participants randomized to extended lymphadenectomy versus those randomized to standard lymphadenectomy.	From date of operation to 90 days post-operation

Collaborators and Investigators

• Sponsor: SWOG Cancer Research Network
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Seth P. Lerner, MD, Baylor College of Medicine

Publications and helpful links

General Publications

• Froehner M, Novotny V, Heberling U, Rutsch L, Litz RJ, Hubler M, Koch R, Baretton GB, Wirth MP. Relationship of the number of removed lymph nodes to bladder cancer and competing mortality after radical cystectomy. Eur Urol. 2014 Dec;66(6):987-90. doi: 10.1016/j.eururo.2014.07.046. Epub 2014 Aug 19.
• Kamat AM, Hahn NM, Efstathiou JA, Lerner SP, Malmstrom PU, Choi W, Guo CC, Lotan Y, Kassouf W. Bladder cancer. Lancet. 2016 Dec 3;388(10061):2796-2810. doi: 10.1016/S0140-6736(16)30512-8. Epub 2016 Jun 23. Erratum In: Lancet. 2016 Dec 3;388(10061):2742. doi: 10.1016/S0140-6736(16)31776-7.

Study record dates

Study Major Dates

• Study Start (Actual): November 25, 2011
• Primary Completion (Actual): May 1, 2024
• Study Completion (Actual): May 1, 2024

Study Registration Dates

• First Submitted: October 19, 2010
• First Submitted That Met QC Criteria: October 19, 2010
• First Posted (Estimated): October 20, 2010

Study Record Updates

• Last Update Posted (Actual): November 29, 2024
• Last Update Submitted That Met QC Criteria: November 6, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: stage III bladder cancer; transitional cell carcinoma of the bladder; stage II bladder cancer
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urologic Neoplasms; Urinary Bladder Diseases; Urinary Bladder Neoplasms
• Other Study ID Numbers: S1011; SWOG-S1011 (Other Grant/Funding Number: U10CA180888); NCI-2011-02604 (Registry Identifier: NCI)