Surgery With or Without Combination Chemotherapy in Treating Patients With Liver Metastases From Colorectal Cancer
NCT ID: NCT00006479
Last Updated: 2011-04-18
Study Results
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Basic Information
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UNKNOWN
PHASE3
INTERVENTIONAL
2000-09-30
Brief Summary
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PURPOSE: Randomized phase III trial to compare the effectiveness of surgery with or without combination chemotherapy in treating patients who have liver metastases from colorectal cancer.
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Detailed Description
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* Compare the progression-free and overall survival of patients with resectable colorectal liver metastases treated with surgery with or without neoadjuvant and adjuvant oxaliplatin, fluorouracil, and leucovorin calcium.
* Compare the percentage of patients with total resection with these two treatments.
OUTLINE: This is a multicenter study. Patients are stratified according to participating center, prior adjuvant chemotherapy (yes vs no), plasma CEA level in ng/mL at diagnosis of liver metastases (5 or less vs 6 to 30 vs 31 or greater), serosa extension of primary cancer (absent T1 or T2 vs present T3 or T4), lymphatic spread of primary cancer (absent vs present N+), time interval between diagnosis of primary tumor to metastases (2 years or more vs fewer than 2 years), and number of metastases (1 to 3 vs 4). Patients are randomized to one of two treatment arms.
* Arm I: Patients receive oxaliplatin IV over 2 hours on day 1 and leucovorin calcium (LV) IV over 2 hours followed by fluorouracil (5-FU) IV over 22 hours on days 1 and 2. Treatment repeats every 15 days for 6 courses in the absence of disease progression or unacceptable toxicity.
At 2 to 5 weeks after chemotherapy, patients undergo liver resection. Patients with progressive disease after 3 courses of chemotherapy undergo liver resection at least 2 weeks after completion of course 3 and do not receive postoperative chemotherapy.
At 2 to 5 weeks after surgery, patients receive oxaliplatin, LV, and 5-FU as in preoperative chemotherapy.
* Arm II: Patients undergo liver resection. Patients are followed every 3 months for 2 years and then every 6 months thereafter.
Peer Reviewed and Funded or Endorsed by Cancer Research UK
PROJECTED ACCRUAL: A total of 330 patients (165 per arm) will be accrued for this study within 3 years.
Conditions
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Study Design
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TREATMENT
Interventions
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FOLFOX regimen
fluorouracil
leucovorin calcium
oxaliplatin
adjuvant therapy
conventional surgery
neoadjuvant therapy
Eligibility Criteria
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Inclusion Criteria
* Diagnosis of potentially resectable colorectal liver metastases that meets one of the following criteria:
* Metachronous metastases after complete resection of primary tumor without gross or microscopic evidence of residual disease
* Synchronous metastases after complete resection of primary tumor more than 1 month before study
* Synchronous metastases with sufficient evidence (i.e., CAT scan or diagnostic laparoscopy) that both the primary tumor and liver metastases can be completely resected during the same procedure and resection of primary may be delayed 3-4 months
PATIENT CHARACTERISTICS:
Age:
* 18 to 80
Performance status:
* WHO 0-2
* Karnofsky 60-100%
Life expectancy:
* Not specified
Hematopoietic:
* Absolute neutrophil count greater than 1,500/mm\^3
* Platelet count greater than 100,000/mm\^3
Hepatic:
* No hepatic insufficiency
Renal:
* Creatinine less than 2 times upper limit of normal
Cardiovascular:
* No uncontrolled congestive heart failure or angina pectoris
* No hypertension or arrhythmia
Other:
* No other malignancy within the past 10 years except adequately treated carcinoma in situ of the cervix or nonmelanoma skin cancer
* No peripheral neuropathy greater than grade 1
* No prior significant neurologic or psychiatric disorders
* No active infection
* Not pregnant or nursing
* Fertile patients must use effective contraception
PRIOR CONCURRENT THERAPY:
Biologic therapy:
* No concurrent biologic therapy
Chemotherapy:
* No prior chemotherapy for advanced disease
* Prior adjuvant chemotherapy for primary cancer allowed unless included oxaliplatin
* No other concurrent chemotherapy
Endocrine therapy:
* No concurrent anticancer endocrine therapy
Radiotherapy:
* No concurrent radiotherapy
Surgery:
* See Disease Characteristics
Other:
* At least 30 days since prior investigational drugs
* No concurrent investigational drugs
18 Years
80 Years
ALL
No
Sponsors
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Australasian Gastro-Intestinal Trials Group
NETWORK
Arbeitsgruppe Lebermetastasen und Tumoren
OTHER
Cancer Research UK
OTHER
Fondation Francaise de Cancerologie Digestive
OTHER
European Organisation for Research and Treatment of Cancer - EORTC
NETWORK
Principal Investigators
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Bernard Nordlinger, MD
Role:
Hopital Ambroise Pare
Euan T. Walpole, MD
Role: STUDY_CHAIR
Princess Alexandra Hospital
Wolf O. Bechstein, MD
Role: STUDY_CHAIR
Arbeitsgruppe Lebermetastasen und Tumoren
John N. Primrose, MD
Role: STUDY_CHAIR
University Hospital Southampton NHS Foundation Trust
Philippe Rougier, MD
Role: STUDY_CHAIR
Hopital Ambroise Pare
Locations
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Bankstown - Lidcombe Hospital
Bankstown, New South Wales, Australia
Institute of Oncology at Prince of Wales Hospital
Randwick, New South Wales, Australia
Royal North Shore Hospital
St Leonards, New South Wales, Australia
Newcastle Mater Misericordiae Hospital
Waratah, New South Wales, Australia
Royal Brisbane and Women's Hospital
Brisbane, Queensland, Australia
Princess Alexandra Hospital
Brisbane, Queensland, Australia
Ashford Cancer Centre
Ashford, South Australia, Australia
Flinder Medical Centres
Bedford Park, South Australia, Australia
Queen Elizabeth Hospital
Woodville, South Australia, Australia
Launceston General Hospital
Launceston, Tasmania, Australia
Frankston Hospital
Frankston, Victoria, Australia
Austin and Repatriation Medical Centre
Heidelberg West, Victoria, Australia
Mount Hospital
Perth, Western Australia, Australia
Royal Perth Hospital
Perth, Western Australia, Australia
Sir Charles Gairdner Hospital - Perth
Perth, Western Australia, Australia
Allgemeines Krankenhaus der Stadt Wien
Vienna, , Austria
Kaiser Franz Josef Hospital
Vienna, , Austria
Institut Jules Bordet
Brussels, , Belgium
Hopital Universitaire Erasme
Brussels, , Belgium
Academisch Ziekenhuis der Vrije Universiteit Brussel
Brussels, , Belgium
Universitair Ziekenhuis Gent
Ghent, , Belgium
Hopital de Jolimont
Haine-Saint-Paul, , Belgium
Cazk Groeninghe - Campus St-Niklaas
Kortrijk, , Belgium
U.Z. Gasthuisberg
Leuven, , Belgium
Centre Hospitalier - Abbeville
Abbeville, , France
Centre Hospitalier Regional et Universitaire d'Angers
Angers, , France
C.H.G. Beauvais
Beauvais, , France
CHR de Besancon - Hopital Jean Minjoz
Besançon, , France
Institut Bergonie
Bordeaux, , France
CHU Ambroise Pare
Boulogne-Billancourt, , France
C.H. Bourg En Bresse
Bourg-en-Bresse, , France
CMC Bligny
Briis-sous-Forges, , France
CHU de Caen
Caen, , France
Hopital Louis Pasteur
Colmar, , France
Centre Hospitalier Universitaire Henri Mondor
Créteil, , France
Hopital Du Bocage
Dijon, , France
CHU de Grenoble - Hopital de la Tronche
Grenoble, , France
Centre Hospitalier Departemental
La Roche-sur-Yon, , France
Clinique Du Pre
Le Mans, , France
Hopital Robert Boulin
Libourne, , France
Centre Hospital Regional Universitaire de Limoges
Limoges, , France
CHU de la Timone
Marseille, , France
Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
Montpellier, , France
Hopital Lariboisiere
Paris, , France
Hopital Europeen Georges Pompidou
Paris, , France
Hopital Cochin
Paris, , France
C.H.G. De Pau
Pau, , France
Hopital Haut Leveque
Pessac, , France
Centre Eugene Marquis
Rennes, , France
Hopital Charles Nicolle
Rouen, , France
Hopital Universitaire Hautepierre
Strasbourg, , France
Centre Hospitalier Regional de Purpan
Toulouse, , France
CHU de Tours
Tours, , France
Centre Alexis Vautrin
Vandœuvre-lès-Nancy, , France
Hopital Paul Brousse
Villejuif, , France
Helios Klinikum Berlin
Berlin, , Germany
Robert Roessle Klinik at Charite - Campus Berlin Buch im Helios Klinikum Berlin
Berlin, , Germany
Staedtisches Klinikum Dessau
Dessau, , Germany
Medizinische Klinik I
Dresden, , Germany
Department of Medicine III
Erlangen, , Germany
Kliniken Essen - Mitte
Essen, , Germany
Klinikum der J.W. Goethe Universitaet
Frankfurt, , Germany
Universitaetsklinikum Freiburg
Freiburg im Breisgau, , Germany
Klinik der Justus - Leibig - Universitaet Giessen
Giessen, , Germany
Klinikum der Friedrich-Schiller Universitaet Jena
Jena, , Germany
Knappschaft Krankenhaus
Langendreer, , Germany
Universitaet Leipzig
Leipzig, , Germany
Staedtisches Klinikum Leipzig
Leipzig, , Germany
Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg
Magdeburg, , Germany
Johannes Gutenberg University
Mainz, , Germany
Klinikum Rechts Der Isar - Technische Universitaet Muenchen
Munich, , Germany
Klinikum der Universitaet Regensburg
Regensburg, , Germany
Caritasklinik St. Theresia
Saarbrücken, , Germany
Eberhard Karls Universitaet
Tübingen, , Germany
Dr. Horst-Schmidt-Kliniken
Wiesbaden, , Germany
Universitaets-Hautklinik Wuerzburg
Würzburg, , Germany
Prince of Wales Hospital
Shatin, N.T., , Hong Kong
Ospedale San Martino/Cliniche Universitarie Convenzionate
Genoa (Genova), , Italy
Universita di Padova
Padua, , Italy
Leiden University Medical Center
Leiden, , Netherlands
Academisch Ziekenhuis Maastricht
Maastricht, , Netherlands
Christchurch Hospital
Christchurch, , New Zealand
Haukeland Hospital - University of Bergen
Bergen, , Norway
Instituto Portugues de Oncologia Centro do Porto, SA
Porto, , Portugal
Sahlgrenska University Hospital
Gothenburg (Goteborg), , Sweden
Karolinska University Hospital/Huddinge
Stockholm, , Sweden
Uppsala University Hospital
Uppsala, , Sweden
North Hampshire Hospital
Basingstoke, England, United Kingdom
Queen Elizabeth Hospital at University of Birmingham
Birmingham, England, United Kingdom
Bristol Haematology and Oncology Centre
Bristol, England, United Kingdom
Bristol Royal Infirmary
Bristol, England, United Kingdom
Addenbrooke's NHS Trust
Cambridge, England, United Kingdom
St. Luke's Cancer Center
Guildford, England, United Kingdom
Cookridge Hospital at Leeds Teaching Hospital NHS Trust
Leeds, England, United Kingdom
St. James's University Hospital
Leeds, England, United Kingdom
Leicester Royal Infirmary
Leicester, England, United Kingdom
Royal Liverpool and Broadgreen Hospitals
Liverpool, England, United Kingdom
Royal London Hospital
London, England, United Kingdom
Royal Free Hospital
London, England, United Kingdom
St. George's Hospital
London, England, United Kingdom
Clatterbridge Centre for Oncology NHS Trust
Merseyside, England, United Kingdom
Freeman Hospital
Newcastle upon Tyne, England, United Kingdom
Mount Vernon Hospital
Northwood, England, United Kingdom
Queen's Medical Centre
Nottingham, England, United Kingdom
Royal Preston Hospital
Preston, England, United Kingdom
Weston Park Hospital
Sheffield, England, United Kingdom
Royal South Hants Hospital
Southampton, England, United Kingdom
Southampton General Hospital
Southampton, England, United Kingdom
Royal Infirmary of Edinburgh at Little France
Edinburgh, Scotland, United Kingdom
Ysbyty Gwynedd
Bangor, Wales, United Kingdom
North Manchester Healthcare NHS Trust
Manchester, , United Kingdom
Countries
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References
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Sorbye H, Mauer M, Gruenberger T, et al.: Predictive factors for the effect of perioperative FOLFOX for resectable liver metastasis in colorectal cancer patients (EORTC phase III study 40983). [Abstract] J Clin Oncol 28 (Suppl 15): A-3544, 2010.
Sorbye H, Mauer M, Gruenberger T, et al.: Evaluation of carcinoembryonic antigen (CEA) as a predictive baseline factor for the benefit of perioperative FOLFOX in resectable liver metastasis from colorectal cancer (EORTC study 40983). [Abstract] American Society of Clinical Oncology 2010 Gastrointestinal Cancers Symposium, 22-24 January 2010, Orlando, Florida. A-407, 2010.
Benoist S, Nordlinger B. The role of preoperative chemotherapy in patients with resectable colorectal liver metastases. Ann Surg Oncol. 2009 Sep;16(9):2385-90. doi: 10.1245/s10434-009-0492-7. Epub 2009 Jun 25.
Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Federation Francophone de Cancerologie Digestive (FFCD). Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008 Mar 22;371(9617):1007-16. doi: 10.1016/S0140-6736(08)60455-9.
Julie C, Lutz MP, Aust D, et al.: Pathological analysis of hepatic injury after oxaliplatin-based neoadjuvant chemotherapy of colorectal cancer liver metastases: results of the EORTC Intergroup phase III study 40983. [Abstract] American Society of Clinical Oncology 2007 Gastrointestinal Cancers Symposium, 19 -21 January 2007, Orlando, Florida A-241, 2007.
Nordlinger B, Sorbye H, Collette L, et al.: Final results of the EORTC Intergroup randomized phase III study 40983 [EPOC] evaluating the benefit of peri-operative FOLFOX4 chemotherapy for patients with potentially resectable colorectal cancer liver metastases. [Abstract] J Clin Oncol 25 (Suppl 18): A-LBA5, 2007.
Gruenberger T, Sorbye H, Debois M, et al.: Tumor response to pre-operative chemotherapy (CT) with FOLFOX-4 for resectable colorectal cancer liver metastases (LM). Interim results of EORTC Intergroup randomized phase III study 40983. [Abstract] J Clin Oncol 24 (Suppl 18): A-3500, 2006.
Nordlinger B, Sorbye H, Debois M, et al.: Feasibility and risks of pre-operative chemotherapy (CT) with Folfox 4 and surgery for resectable colorectal cancer liver metastases (LM). Interim results of the EORTC Intergroup randomized phase III study 40983. [Abstract] J Clin Oncol 23 (Suppl 16): A-3528, 253s, 2005.
Tanis E, Julie C, Emile JF, Mauer M, Nordlinger B, Aust D, Roth A, Lutz MP, Gruenberger T, Wrba F, Sorbye H, Bechstein W, Schlag P, Fisseler A, Ruers T. Prognostic impact of immune response in resectable colorectal liver metastases treated by surgery alone or surgery with perioperative FOLFOX in the randomised EORTC study 40983. Eur J Cancer. 2015 Nov;51(17):2708-17. doi: 10.1016/j.ejca.2015.08.014. Epub 2015 Sep 2.
Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Mauer M, Tanis E, Van Cutsem E, Scheithauer W, Gruenberger T; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Federation Francophone de Cancerologie Digestive (FFCD). Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Nov;14(12):1208-15. doi: 10.1016/S1470-2045(13)70447-9. Epub 2013 Oct 11.
Sorbye H, Mauer M, Gruenberger T, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Van Cutsem E, Scheithauer W, Lutz MP, Nordlinger B; EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK (CRUK); Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO); Australasian Gastro-Intestinal Trials Group (AGITG); Federation Francophone de Cancerologie Digestive (FFCD). Predictive factors for the benefit of perioperative FOLFOX for resectable liver metastasis in colorectal cancer patients (EORTC Intergroup Trial 40983). Ann Surg. 2012 Mar;255(3):534-9. doi: 10.1097/SLA.0b013e3182456aa2.
Other Identifiers
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EORTC-40983
Identifier Type: -
Identifier Source: secondary_id
AGITG-EORTC-40983
Identifier Type: -
Identifier Source: secondary_id
ALM-CAO-EORTC-40983
Identifier Type: -
Identifier Source: secondary_id
CRUK-LON-EORTC-40983
Identifier Type: -
Identifier Source: secondary_id
FFCD-EORTC-40983
Identifier Type: -
Identifier Source: secondary_id
EU-20048
Identifier Type: -
Identifier Source: secondary_id
CRC-EORTC-40983
Identifier Type: -
Identifier Source: secondary_id
CDR0000068309
Identifier Type: -
Identifier Source: org_study_id
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