Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Closed 18 to 80 Other EORTC-40983 AGITG-EORTC-40983, ALM-CAO-EORTC-40983, CRUK-LON-EORTC-40983, FFCD-EORTC-40983, EU-20048, CRC-EORTC-40983, NCT00006479

Objectives

1. 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.
2. Compare the percentage of patients with total resection with these two treatments.

Entry 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

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

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/mm³
• Platelet count greater than 100,000/mm³

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

Expected Enrollment

A total of 330 patients (165 per arm) will be accrued for this study within 3 years.

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

Nordlinger B, Sorbye H, Glimelius B, et al.: 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 371 (9617): 1007-16, 2008.[PUBMED Abstract]

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.

Trial Contact Information

Trial Lead Organizations

European Organization for Research and Treatment of Cancer

Bernard Nordlinger, MD, Study coordinator		Ph: 33-14-90-95-586

Australasian Gastro-Intestinal Trials Group

Euan Walpole, MD, Protocol chair		Ph: 61-7-3240-5564 Email: Euan_Walpolee@health.qld.gov.au

Arbeitsgruppe Lebermetastasen und Tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie

Wolf Bechstein, MD, Protocol chair		Ph: 49-69-6031-5251 Email: Wolf.Bechstein@kgu.de

Cancer Research UK at Imperial College School of Medicine - London

John Primrose, MD, Protocol chair		Ph: 44-23-8079-6144 Email: j.n.primrose@soton.ac.uk

Fondation Francaise de Cancerologie Digestive

Philippe Rougier, MD, Protocol chair		Ph: 33-01-49-095-325 Email: philippe.rougier@apr.ap-hop-paris.fr

Registry Information
Official Title		Pre- and Post-Operative Chemotherapy with Oxaliplatin 5FU/LV Versus Surgery Alone in Resectable Liver Metastases from Colorectal Origin - Phase III Study
Trial Start Date		2000-09-01
Registered in ClinicalTrials.gov		NCT00006479
Date Submitted to PDQ		2000-09-27
Information Last Verified		2000-12-21

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