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 and giving them after surgery may kill any remaining tumor cells. It is not yet known if adjuvant chemotherapy is more effective when given immediately after radical cystectomy (surgery to remove the bladder) or when the cancer returns.

PURPOSE: Randomized phase III trial to compare the effectiveness of immediate adjuvant chemotherapy with that of adjuvant chemotherapy given when the cancer returns in treating patients who have undergone a radical cystectomy for stage III or stage IV transitional cell carcinoma of the bladder urothelium.

Condition	Treatment or Intervention	Phase
stage III bladder cancer stage IV bladder cancer transitional cell carcinoma of the bladder	Drug: cisplatin  Drug: doxorubicin  Drug: filgrastim  Drug: gemcitabine  Drug: methotrexate  Drug: vinblastine  Procedure: adjuvant therapy  Procedure: biological response modifier therapy  Procedure: chemotherapy  Procedure: colony-stimulating factor therapy  Procedure: cytokine therapy	Phase III

Further Study Details: 

OBJECTIVES:

• Compare the overall and progression-free survival of patients with stage III or IV transitional cell carcinoma of the bladder urothelium treated with immediate versus deferred adjuvant chemotherapy after radical cystectomy.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, tumor status (pT1 or 2 vs pT3 vs pT4), and node status (node positive vs node negative with 15 or more nodes sampled vs node negative with less than 15 nodes sampled). Patients are randomized to one of two treatment arms.

• Arm I: Beginning within 90 days of radical cystectomy, patients receive a total of 4 courses of adjuvant chemotherapy.
• Arm II: Beginning at the time of clinical relapse, patients receive a total of 6 courses of adjuvant chemotherapy. Patients in both arms receive one of the following chemotherapy regimens to be determined by participating center:
• Regimen A (Classical M-VAC): Patients receive classical M-VAC comprising 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. Courses repeat every 28 days.
• Regimen B (High-dose M-VAC): Patients receive high-dose M-VAC comprising methotrexate IV on day 1 and vinblastine IV, doxorubicin IV, and cisplatin IV on day 2. Patients also receive filgrastim (G-CSF) subcutaneously once daily on days 4-10. Courses repeat every 14 days.
• Regimen C (Gemcitabine and cisplatin): Patients receive gemcitabine and cisplatin comprising gemcitabine IV over 30 minutes on days 1, 8, and 15 followed by cisplatin IV on day 1 or 2. Courses repeat every 28 days. Patients are followed every 3 months for 1 year, every 6 months for 5 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 1,344 patients (672 per treatment arm) will be accrued for this study within 5.37 years.

Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed transitional cell carcinoma of the bladder urothelium
• T3-4, N1-3, M0
• No pure squamous cell or adenocarcinoma tumors
• No more than 90 days since prior radical cystectomy and bilateral lymphadenectomy without evidence of microscopic residual disease

PATIENT CHARACTERISTICS: Age:

• Not specified

Performance status:

• WHO 0-1

Life expectancy:

• Not specified

Hematopoietic:

• WBC at least 3,500/mm^3
• Platelet count at least 120,000/mm^3

Hepatic:

• SGOT/SGPT less than 2.5 times upper limit of normal (ULN)
• Alkaline phosphatase less than 2.5 times ULN
• Bilirubin normal

Renal:

• Glomerular filtration rate greater than 60 mL/min

Cardiovascular:

• No clinically significant cardiac arrhythmia
• No congestive heart failure
• No complete bundle branch block
• No New York Heart Association class III or IV heart disease

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 6 months after study
• Considered fit for cisplatin-containing combination chemotherapy
• No clinically abnormal auditory function
• No known hypersensitivity to E. coli-derived drug preparations
• No grade 2 or greater peripheral neuropathy
• No other prior or concurrent malignancy except adequately treated carcinoma in situ of the cervix, treated basal cell skin cancer, or treated incidental prostate cancer (T1, Gleason score no greater than 6, and PSA less than 0.5 ng/mL)
• No psychological, familial, sociological, or geographical condition that would preclude study involvement

PRIOR CONCURRENT THERAPY: Biologic therapy:

• Not specified

Chemotherapy:

• No prior systemic chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy to the bladder

Surgery:

• See Disease Characteristics

Austria
      Kaiser Franz Josef Hospital, Vienna,  A-1100,  Austria; Recruiting
Belgium
      Akademisch Ziekenhuis Gent, Gent,  B-9000,  Belgium; Recruiting
      Cazk Groeninghe - Campus Maria's Voorzienigheid, Kortrijk,  B-8500,  Belgium; Recruiting
      CHU Liege - Domaine Universitaire du Sart Tilman, LIEGE,  B-4000,  Belgium; Recruiting
      Cliniques Universitaires Saint-Luc, Brussels,  1200,  Belgium; Recruiting
      Institut Jules Bordet, Brussels,  1000,  Belgium; Recruiting
      Onze Lieve Vrouw Ziekenhuis Aalst, Aalst,  B-9300,  Belgium; Recruiting
      U.Z. Gasthuisberg, Leuven,  B-3000,  Belgium; Recruiting
Canada, Alberta
      Cross Cancer Institute, Edmonton,  Alberta,  T6G 1Z2,  Canada; Recruiting
      Tom Baker Cancer Centre - Calgary, Calgary,  Alberta,  T2N 4N2,  Canada; Recruiting
Canada, British Columbia
      British Columbia Cancer Agency - Centre for the Southern Interior, Kelowna,  British Columbia,  V1Y 5L3,  Canada; Recruiting
      British Columbia Cancer Agency - Vancouver Island Cancer Centre, Victoria,  British Columbia,  V8R 6V5,  Canada; Recruiting
      British Columbia Cancer Agency, Vancouver,  British Columbia,  V5Z 4E6,  Canada; Recruiting
Canada, Manitoba
      CancerCare Manitoba, Winnipeg,  Manitoba,  R3E 0V9,  Canada; Recruiting
Canada, Nova Scotia
      Nova Scotia Cancer Centre at Queen Elizabeth II Health Sciences Centre, Halifax,  Nova Scotia,  B3H 1V7,  Canada; Recruiting
Canada, Ontario
      Cancer Care Ontario-London Regional Cancer Centre, London,  Ontario,  N6A 4L6,  Canada; Recruiting
      Cancer Centre of Southeastern Ontario, Kingston,  Ontario,  K7L 5P9,  Canada; Recruiting
      Hotel Dieu Health Sciences Hospital - Niagara, St. Catharines,  Ontario,  L2R 5K3,  Canada; Recruiting
      Margaret and Charles Juravinski Cancer Centre, Hamilton,  Ontario,  L8V 5C2,  Canada; Recruiting
      Ottawa Regional Cancer Centre at Ottawa Hospital - General Campus, Ottawa,  Ontario,  K1H 1C4,  Canada; Recruiting
      Princess Margaret Hospital, Toronto,  Ontario,  M5G 2M9,  Canada; Recruiting
      Toronto Sunnybrook Regional Cancer Centre, Toronto,  Ontario,  M4N 3M5,  Canada; Recruiting
Canada, Quebec
      Hopital Notre- Dame du CHUM, Montreal,  Quebec,  H4L 2M1,  Canada; Recruiting
      McGill Cancer Centre, Montreal,  Quebec,  H2W 1S6,  Canada; Recruiting
      Montreal General Hospital, Montreal,  Quebec,  H3G 1A4,  Canada; Recruiting
Denmark
      Aarhus University Hospital - Aarhus Sygehus - Norrebrogade, Aarhus,  DK-8000,  Denmark; Recruiting
      Herlev Hospital - University Hospital of Copenhagen, Copenhagen,  DK-2730,  Denmark; Recruiting
      Rigshospitalet, Copenhagen,  2100,  Denmark; Recruiting
France
      Centre Alexis Vautrin, Vandoeuvre-les-Nancy,  54511,  France; Recruiting
      Centre de Lutte Contre le Cancer Georges-Francois Leclerc, Dijon,  21079,  France; Recruiting
      Centre Eugene Marquis, Rennes,  35042,  France; Recruiting
      Centre Hospitalier Departemental, La Roche-sur-Yon,  F-85025,  France; Recruiting
      Centre Hospitalier General de Saint Nazaire, Saint-Nazaire,  44600,  France; Recruiting
      Centre Hospitalier Universitaire Henri Mondor, Creteil,  94010,  France; Recruiting
      Centre Leon Berard, Lyon,  69373,  France; Recruiting
      Centre Medico-Chirurgical Foch, Suresnes,  92151,  France; Recruiting
      Centre Oscar Lambret, Lille,  59020,  France; Recruiting
      Centre Paul Papin, Angers,  49036,  France; Recruiting
      Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle, Montpellier,  34298,  France; Recruiting
      Centre Regional Francois Baclesse, Caen,  14076,  France; Recruiting
      Centre Regional Rene Gauducheau, Nantes-Saint Herblain,  44805,  France; Recruiting
      CHU de la Timone, Marseille,  13385,  France; Recruiting
      Hopital Bichat - Claude Bernard, Paris,  75018,  France; Recruiting
      Hopital Clinique Claude Bernard, Metz,  57072,  France; Recruiting
      Hopital de Bicetre, Le Kremlin-Bicetre,  94275,  France; Recruiting
      Hopital Europeen Georges Pompidou, Paris,  75015,  France; Recruiting
      Hopital Saint Andre, Bordeaux,  33075,  France; Recruiting
      Hopital Tenon, Paris,  75970,  France; Recruiting
      Hopitaux Universitaire de Strasbourg, Strasbourg,  67091,  France; Recruiting
      Institut Bergonie, Bordeaux,  33076,  France; Recruiting
      Institut Claudius Regaud, Toulouse,  31052,  France; Recruiting
      Institut Gustave Roussy, Villejuif,  F-94805,  France; Recruiting
      Institut Jean Godinot, Reims,  51056,  France; Recruiting
Germany
      Klinikum Nuernberg - Klinikum Nord, Nuernberg,  D-90419,  Germany; Recruiting
Israel
      Assaf Harofeh Medical Center, Zerifin,  70300,  Israel; Recruiting
Italy
      Ospedale di Circolo e Fondazione Macchi, Varese,  21100,  Italy; Recruiting
      Ospedale S. Camillo-Forlanini, Rome,  00151,  Italy; Recruiting
      Ospedale Santa Croce, Cuneo,  12100,  Italy; Recruiting
      Universita di Palermo, Palermo,  90141,  Italy; Recruiting
Netherlands
      Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam,  1066 CX,  Netherlands; Recruiting
      University Medical Center Groningen, Groningen,  9700 RB,  Netherlands; Recruiting
      University Medical Center Nijmegen, Nijmegen,  NL-6500 HB,  Netherlands; Recruiting
      University Medical Center Rotterdam at Erasmus Medical Center, Rotterdam,  3000 CA,  Netherlands; Recruiting
Norway
      Norwegian Radium Hospital, Oslo,  N-0310,  Norway; Recruiting
Poland
      Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw,  02-781,  Poland; Recruiting
Sweden
      Uppsala University Hospital, Uppsala,  SE-75185,  Sweden; Recruiting
Switzerland
      Inselspital, Bern, Bern,  CH-3010,  Switzerland; Recruiting
Turkey
      Marmara University Hospital, Istanbul,  81190,  Turkey; Recruiting
United Kingdom, England
      Addenbrooke's Hospital at Cambridge University Hospitals NHS Foundation Trust, Cambridge,  England,  CB2 2QQ,  United Kingdom; Recruiting
      Bradford Hospitals NHS Trust, Bradford,  England,  BD9 6RJ,  United Kingdom; Recruiting
      Bristol Haematology and Oncology Centre, Bristol,  England,  BS2 8ED,  United Kingdom; Recruiting
      Cancer Research Centre at Weston Park Hospital, Sheffield,  England,  S1O 2SJ,  United Kingdom; Recruiting
      Christie Hospital N.H.S. Trust, Manchester,  England,  M20 4BX,  United Kingdom; Recruiting
      Churchill Hospital, Oxford,  England,  OX3 7LJ,  United Kingdom; Recruiting
      Derriford Hospital, Plymouth,  England,  PL6 8DH,  United Kingdom; Recruiting
      Guy's and St. Thomas' Hospitals NHS Foundation Trust, London,  England,  SE1 9RT,  United Kingdom; Recruiting
      Guy's Hospital, London,  England,  SE1 9RT,  United Kingdom; Recruiting
      Leicester Royal Infirmary, Leicester,  England,  LE1 5WW,  United Kingdom; Recruiting
      Mayday University Hospital, Croydon,  England,  United Kingdom; Recruiting
      Mount Vernon Hospital, Northwood,  England,  HA6 2RN,  United Kingdom; Recruiting
      Norfolk and Norwich University Hospital, Norwich,  England,  NR4 7UY,  United Kingdom; Recruiting
      Northern Centre for Cancer Treatment at Newcastle General Hospital, Newcastle upon Tyne,  England,  NE4 6BE,  United Kingdom; Recruiting
      Portsmouth Oncology Centre at Saint Mary's Hospital, Portsmouth Hants,  England,  PO3 6AD,  United Kingdom; Recruiting
      Princess Royal Hospital, Hull,  England,  HU8 9HE,  United Kingdom; Recruiting
      Royal Marsden NHS Foundation Trust - Surrey, Sutton,  England,  SM2 5PT,  United Kingdom; Recruiting
      Royal Shrewsbury Hospital, Shrewsbury,  England,  SY3 8XQ,  United Kingdom; Recruiting
      Royal South Hants Hospital, Southampton,  England,  SO14 0YD,  United Kingdom; Recruiting
      Saint Bartholomew's Hospital, London,  England,  EC1A 7BE,  United Kingdom; Recruiting
      Scunthorpe General Hospital, Scunthorpe,  England,  DN15 7BH,  United Kingdom; Recruiting
      St. James's University Hospital at Leeds Teaching Hospital NHS Trust, Leeds,  England,  LS9 7TF,  United Kingdom; Recruiting
      Sunderland Royal Hospital, Sunderland,  England,  SR4 7TP,  United Kingdom; Recruiting
      University Hospital of North Durham, Durham,  England,  DH1 5TW,  United Kingdom; Recruiting
      Worthing Hospital, Worthing,  England,  BN11 2DH,  United Kingdom; Recruiting
United Kingdom, Wales
      Velindre Cancer Center at Velinde Hospital, Cardiff,  Wales,  CF14 2TL,  United Kingdom; Recruiting

Study chairs or principal investigators

Cora N. Sternberg, MD, FACP,  Vincenzo Pansadoro Foundation   
Christine Theodore, MD,  Study Chair,  Institut Gustave Roussy   
Sten Nilsson, MD,  Study Chair,  Karolinska University Hospital - Solna   
Armen G. Aprikian, MD,  Study Chair,  Montreal General Hospital   
Michael Leahy, MBChB, FRACP, FRCP, FRC Path,  Study Chair,  Fremantle Hospital   
Ian Tannock, MD, PhD,  Study Chair,  Princess Margaret Hospital   

Study ID Numbers:  CDR0000069130; EORTC-30994; ACOSOG-EORTC-30994; CAN-NCIC-EORTC-30994; GETUG-EORTC-30994; JUG-EORTC-30994; NORDIC-EORTC-30994; SEUG-EORTC-30994; SWOG-EORTC-30994; UKCCCR-EORTC-30994; NCRI-BLADDER-EORTC-30994; NCT00028756
Record last reviewed:  March 2005
Last Updated:  March 15, 2005
Record first received:  January 4, 2002
ClinicalTrials.gov Identifier:  NCT00028756
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08