Clinical trial NCT00006479: Surgery With or Without Combination Chemotherapy in Treating Patients With Liver Metastases From Colorectal Cancer
Official title: Pre- and Post-Operative Chemotherapy With Oxaliplatin 5FU/LV Versus Surgery Alone in Resectable Liver Metastases From Colorectal Origin - Phase III Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Colorectal Cancer
Metastatic Cancer
Keywords: stage IV colon cancer
stage IV rectal cancer
recurrent colon cancer
recurrent rectal cancer
liver metastases
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: Australasian Gastro-Intestinal Trials Group
name: Arbeitsgruppe Lebermetastasen und Tumoren
name: Cancer Research UK
name: Fondation Francaise de Cancerologie Digestive
First posted: 2003-01-27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
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 and combining chemotherapy with surgery may kill more tumor cells. It is not yet known if surgery is more effective with or without chemotherapy for liver metastases.

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.

Detailed description: OBJECTIVES:

* 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.

Eligibility criteria: DISEASE CHARACTERISTICS:

* 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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Bankstown
country: Australia
facility: Bankstown - Lidcombe Hospital
state: New South Wales
city: Randwick
country: Australia
facility: Institute of Oncology at Prince of Wales Hospital
state: New South Wales
city: St. Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Waratah
country: Australia
facility: Newcastle Mater Misericordiae Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Ashford
country: Australia
facility: Ashford Cancer Centre
state: South Australia
city: Bedford Park
country: Australia
facility: Flinder Medical Centres
state: South Australia
city: Woodville
country: Australia
facility: Queen Elizabeth Hospital
state: South Australia
city: Launceston
country: Australia
facility: Launceston General Hospital
state: Tasmania
city: Frankston
country: Australia
facility: Frankston Hospital
state: Victoria
city: Heidelberg West
country: Australia
facility: Austin and Repatriation Medical Centre
state: Victoria
city: Perth
country: Australia
facility: Mount Hospital
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Perth
country: Australia
facility: Sir Charles Gairdner Hospital - Perth
state: Western Australia
city: Vienna
country: Austria
facility: Allgemeines Krankenhaus der Stadt Wien
city: Vienna
country: Austria
facility: Kaiser Franz Josef Hospital
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Brussels
country: Belgium
facility: Hopital Universitaire Erasme
city: Brussels
country: Belgium
facility: Academisch Ziekenhuis der Vrije Universiteit Brussel
city: Ghent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Haine Saint Paul
country: Belgium
facility: Hopital de Jolimont
city: Kortrijk
country: Belgium
facility: Cazk Groeninghe - Campus St-Niklaas
city: Leuven
country: Belgium
facility: U.Z. Gasthuisberg
city: Abbeville
country: France
facility: Centre Hospitalier - Abbeville
city: Angers
country: France
facility: Centre Hospitalier Regional et Universitaire d'Angers
city: Beauvais
country: France
facility: C.H.G. Beauvais
city: Besancon
country: France
facility: CHR de Besancon - Hopital Jean Minjoz
city: Bordeaux
country: France
facility: Institut Bergonie
city: Boulogne Billancourt
country: France
facility: CHU Ambroise Pare
city: Bourg En Bresse
country: France
facility: C.H. Bourg En Bresse
city: Briis Sous Forges
country: France
facility: CMC Bligny
city: Caen
country: France
facility: CHU de Caen
city: Colmar
country: France
facility: Hopital Louis Pasteur
city: Creteil
country: France
facility: Centre Hospitalier Universitaire Henri Mondor
city: Dijon
country: France
facility: Hopital Du Bocage
city: Grenoble
country: France
facility: CHU de Grenoble - Hopital de la Tronche
city: La Roche Sur Yon
country: France
facility: Centre Hospitalier Departemental
city: Le Mans
country: France
facility: Clinique Du Pre
city: Libourne
country: France
facility: Hopital Robert Boulin
city: Limoges
country: France
facility: Centre Hospital Regional Universitaire de Limoges
city: Marseille
country: France
facility: CHU de la Timone
city: Montpellier
country: France
facility: Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
city: Paris
country: France
facility: Hopital Lariboisiere
city: Paris
country: France
facility: Hopital Europeen Georges Pompidou
city: Paris
country: France
facility: Hopital Cochin
city: Pau
country: France
facility: C.H.G. De Pau
city: Pessac
country: France
facility: Hopital Haut Leveque
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Rouen
country: France
facility: Hopital Charles Nicolle
city: Strasbourg
country: France
facility: Hopital Universitaire Hautepierre
city: Toulouse
country: France
facility: Centre Hospitalier Regional de Purpan
city: Tours
country: France
facility: CHU de Tours
city: Vandoeuvre-les-Nancy
country: France
facility: Centre Alexis Vautrin
city: Villejuif
country: France
facility: Hopital Paul Brousse
city: Berlin
country: Germany
facility: Helios Klinikum Berlin
city: Berlin
country: Germany
facility: Robert Roessle Klinik at Charite - Campus Berlin Buch im Helios Klinikum Berlin
city: Bochum-Langendreer
country: Germany
facility: Knappschaft Krankenhaus
city: Dessau
country: Germany
facility: Staedtisches Klinikum Dessau
city: Dresden
country: Germany
facility: Medizinische Klinik I
city: Erlangen
country: Germany
facility: Department of Medicine III
city: Essen
country: Germany
facility: Kliniken Essen - Mitte
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe Universitaet
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Giessen
country: Germany
facility: Klinik der Justus - Leibig - Universitaet Giessen
city: Jena
country: Germany
facility: Klinikum der Friedrich-Schiller Universitaet Jena
city: Leipzig
country: Germany
facility: Universitaet Leipzig
city: Leipzig
country: Germany
facility: Staedtisches Klinikum Leipzig
city: Magdeburg
country: Germany
facility: Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg
city: Mainz
country: Germany
facility: Johannes Gutenberg University
city: Munich
country: Germany
facility: Klinikum Rechts Der Isar - Technische Universitaet Muenchen
city: Regensburg
country: Germany
facility: Klinikum der Universitaet Regensburg
city: Saarbrucken
country: Germany
facility: Caritasklinik St. Theresia
city: Tuebingen
country: Germany
facility: Eberhard Karls Universitaet
city: Wiesbaden
country: Germany
facility: Dr. Horst-Schmidt-Kliniken
city: Wuerzburg
country: Germany
facility: Universitaets-Hautklinik Wuerzburg
city: Shatin, N.T.
country: Hong Kong
facility: Prince of Wales Hospital
city: Genoa (Genova)
country: Italy
facility: Ospedale San Martino/Cliniche Universitarie Convenzionate
city: Padova
country: Italy
facility: Universita di Padova
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Bergen
country: Norway
facility: Haukeland Hospital - University of Bergen
city: Porto
country: Portugal
facility: Instituto Portugues de Oncologia Centro do Porto, SA
city: Gothenburg (Goteborg)
country: Sweden
facility: Sahlgrenska University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital/Huddinge
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Basingstoke
country: United Kingdom
facility: North Hampshire Hospital
state: England
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital at University of Birmingham
state: England
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
state: England
city: Bristol
country: United Kingdom
facility: Bristol Royal Infirmary
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's NHS Trust
state: England
city: Guildford
country: United Kingdom
facility: St. Luke's Cancer Center
state: England
city: Leeds
country: United Kingdom
facility: Cookridge Hospital at Leeds Teaching Hospital NHS Trust
state: England
city: Leeds
country: United Kingdom
facility: St. James's University Hospital
state: England
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool and Broadgreen Hospitals
state: England
city: London
country: United Kingdom
facility: Royal London Hospital
state: England
city: London
country: United Kingdom
facility: Royal Free Hospital
state: England
city: London
country: United Kingdom
facility: St. George's Hospital
state: England
city: Merseyside
country: United Kingdom
facility: Clatterbridge Centre for Oncology NHS Trust
state: England
city: Newcastle-Upon-Tyne
country: United Kingdom
facility: Freeman Hospital
state: England
city: Northwood
country: United Kingdom
facility: Mount Vernon Hospital
state: England
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
state: England
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
state: England
city: Southampton
country: United Kingdom
facility: Royal South Hants Hospital
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh at Little France
state: Scotland
city: Bangor
country: United Kingdom
facility: Ysbyty Gwynedd
state: Wales
city: Manchester
country: United Kingdom
facility: North Manchester Healthcare NHS Trust
Study officials:
affiliation: Hopital Ambroise Pare
name: Bernard Nordlinger, MD
affiliation: Princess Alexandra Hospital
name: Euan T. Walpole, MD
role: STUDY_CHAIR
affiliation: Arbeitsgruppe Lebermetastasen und Tumoren
name: Wolf O. Bechstein, MD
role: STUDY_CHAIR
affiliation: University Hospital Southampton NHS Foundation Trust
name: John N. Primrose, MD
role: STUDY_CHAIR
affiliation: Hopital Ambroise Pare
name: Philippe Rougier, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.