Surgery With or Without Combination Chemotherapy in Treating Patients With Liver Metastases From Colorectal Cancer

Colorectal Cancer Clinical Trial

Official title:

Pre- and Post-Operative Chemotherapy With Oxaliplatin 5FU/LV Versus Surgery Alone in Resectable Liver Metastases From Colorectal Origin - Phase III Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00006479
• Other study ID #: CDR0000068309
• Secondary ID: EORTC-40983AGITG
• Status: Active, not recruiting
• Phase: Phase 3
• First received: November 6, 2000
• Last updated: April 15, 2011
• Start date: September 2000

Study information

• Verified date: December 2000
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 0
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Study Design

Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms
• Metastatic Cancer
• Neoplasm Metastasis

Intervention

Drug:
• FOLFOX regimen

• fluorouracil

• leucovorin calcium

• oxaliplatin

Procedure:
• adjuvant therapy

• conventional surgery

• neoadjuvant therapy

Locations

Country	Name	City	State
Australia	Ashford Cancer Centre	Ashford	South Australia
Australia	Bankstown - Lidcombe Hospital	Bankstown	New South Wales
Australia	Flinder Medical Centres	Bedford Park	South Australia
Australia	Princess Alexandra Hospital	Brisbane	Queensland
Australia	Royal Brisbane and Women's Hospital	Brisbane	Queensland
Australia	Frankston Hospital	Frankston	Victoria
Australia	Austin and Repatriation Medical Centre	Heidelberg West	Victoria
Australia	Launceston General Hospital	Launceston	Tasmania
Australia	Mount Hospital	Perth	Western Australia
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	Sir Charles Gairdner Hospital - Perth	Perth	Western Australia
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	Queen Elizabeth Hospital	Woodville	South Australia
Austria	Allgemeines Krankenhaus der Stadt Wien	Vienna
Austria	Kaiser Franz Josef Hospital	Vienna
Belgium	Academisch Ziekenhuis der Vrije Universiteit Brussel	Brussels
Belgium	Hopital Universitaire Erasme	Brussels
Belgium	Institut Jules Bordet	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
France	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	Besancon
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	Creteil
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 Cochin	Paris
France	Hopital Europeen Georges Pompidou	Paris
France	Hopital Lariboisiere	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	Vandoeuvre-les-Nancy
France	Hopital Paul Brousse	Villejuif
Germany	Helios Klinikum Berlin	Berlin
Germany	Robert Roessle Klinik at Charite - Campus Berlin Buch im Helios Klinikum Berlin	Berlin
Germany	Knappschaft Krankenhaus	Bochum-Langendreer
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
Germany	Klinik der Justus - Leibig - Universitaet Giessen	Giessen
Germany	Klinikum der Friedrich-Schiller Universitaet Jena	Jena
Germany	Staedtisches Klinikum Leipzig	Leipzig
Germany	Universitaet 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	Saarbrucken
Germany	Eberhard Karls Universitaet	Tuebingen
Germany	Dr. Horst-Schmidt-Kliniken	Wiesbaden
Germany	Universitaets-Hautklinik Wuerzburg	Wuerzburg
Hong Kong	Prince of Wales Hospital	Shatin, N.T.
Italy	Ospedale San Martino/Cliniche Universitarie Convenzionate	Genoa (Genova)
Italy	Universita di Padova	Padova
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Academisch Ziekenhuis Maastricht	Maastricht
New Zealand	Christchurch Hospital	Christchurch
Norway	Haukeland Hospital - University of Bergen	Bergen
Portugal	Instituto Portugues de Oncologia Centro do Porto, SA	Porto
Sweden	Sahlgrenska University Hospital	Gothenburg (Goteborg)
Sweden	Karolinska University Hospital/Huddinge	Stockholm
Sweden	Uppsala University Hospital	Uppsala
United Kingdom	Ysbyty Gwynedd	Bangor	Wales
United Kingdom	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	Royal Infirmary of Edinburgh at Little France	Edinburgh	Scotland
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 Free Hospital	London	England
United Kingdom	Royal London Hospital	London	England
United Kingdom	St. George's Hospital	London	England
United Kingdom	North Manchester Healthcare NHS Trust	Manchester
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

Sponsors (5)

Lead Sponsor	Collaborator
European Organisation for Research and Treatment of Cancer - EORTC	Arbeitsgruppe Lebermetastasen und Tumoren, Australasian Gastro-Intestinal Trials Group, Cancer Research UK, Fondation Francaise de Cancerologie Digestive

Countries where clinical trial is conducted

Australia,  Austria,  Belgium,  France,  Germany,  Hong Kong,  Italy,  Netherlands,  New Zealand,  Norway,  Portugal,  Sweden,  United Kingdom, 

References & Publications (8)

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. Review. — View 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 Onco

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 Clinica

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 metast

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.

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 — View 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 S

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.