Combination Chemotherapy in Treating Patients With Recurrent or Metastatic Colorectal Cancer

First Line Infusional 5-Fluorouracil, Folinic Acid and Oxaliplatin for Metastatic Colorectal Cancer or Loco-Regional Recurrency - Role of Chronomodulated Delivery Upon Survival - A Multicenter Randomized Phase III Trial

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 may kill more tumor cells. It is not yet known which regimen of combination chemotherapy is more effective in treating patients with recurrent or metastatic colorectal cancer.

PURPOSE: Randomized phase III trial to study the effectiveness of combining fluorouracil, leucovorin, and oxaliplatin in different ways in treating patients with recurrent or metastatic colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: leucovorin calcium; Drug: oxaliplatin; Drug: FOLFOX regimen

Detailed Description

OBJECTIVES: I. Compare the effects of chronomodulated versus nonchronomodulated infusional administration of a 3 drug high-dose chemotherapy regimen on survival in patients with locoregionally recurrent or metastatic colorectal cancer. II. Assess the antitumor effect of the combination of fluorouracil, leucovorin calcium, and oxaliplatin given as first line chemotherapy in these patients. III. Assess the response rate and toxicity of this treatment in these patients. IV. Assess the quality of life of patients receiving this treatment.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to performance status (ECOG 0-1 vs 2), extent of liver involvement (none vs less than 25% vs 25% or greater), and institution. Patients are randomized into 2 arms: Arm I (chronotherapy): Patients receive a 4 day infusion of fluorouracil, leucovorin calcium, and oxaliplatin administered via pump using chronomodulated delivery rates. Arm II (fixed infusion rate): Patients receive leucovorin calcium and oxaliplatin as 2 hour concurrent infusions followed by fluorouracil as a 22 hour infusion on day 1. On day 2, patients receive a 2 hour infusion of leucovorin calcium followed by a 22 hour infusion of fluorouracil. For patients on both arms, courses repeat every 2 weeks until the occurrence of disease progression, severe toxicity, or complete remission for a minimum of 4 months. Quality of life is assessed prior to treatment and 2 weeks after courses 4 and 8. Patients are followed for survival.

PROJECTED ACCRUAL: A total of 554 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Anticipated): 554
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna (Wien), Austria, A-1030
    • Krankenanstalt Rudolfstiftung
• Belgium
  • Antwerpen, Belgium, 2010
    • VZW Monica Campus Eewnfeestkliniek
  • Brussels, Belgium, B-1000
    • Hopital Saint Jean
  • Brussels (Bruxelles), Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Charleroi, Belgium, 6000
    • Centre Hospitalier Notre Dame - Reine Fabiola
  • Liege, Belgium, B-4000
    • CHU Sart-Tilman
  • Liege (Luik), Belgium, B 4000
    • Les Cliniques Saint-Joseph ASBL
  • Namur, Belgium, 5000
    • Clinique Sainte Elisabeth
  • Virton, Belgium, 6762
    • Centre Hospitalier de Lorraine
• Canada
  • Ontario
    • North York, Ontario, Canada, M4N 3M5
      • Sunnybrook and Women's College Health Sciences Centre
  • Quebec
    • Rimouski, Quebec, Canada, G5L 5T1
      • Centre Hospitalier Regional De Rimouski
• France
  • Bayonne, France, 64109
    • Centre Hospitalier de la Cote Basque
  • Clermont-Ferrand, France, 63011
    • Centre Jean Perrin
  • Croix, France, 59170
    • Clinique du parc
  • Dijon, France, 21079
    • Centre de Lute Contre le Cancer,Georges-Francois Leclerc
  • Levallois-Perret, France, 92300
    • Hopital Perpetuel Secours
  • Lille, France, 59020
    • Centre Oscar Lambret
  • Limoges, France, 87042
    • Centre Hospital Regional Universitaire de Limoges
  • Metz, France, 55038
    • Hopital Notre-Dame de Bon Secours
  • Montlucon, France, 03109
    • Centre Hospitalier de Montlucon
  • Neuilly sur Seine, France, 92200
    • Clinique Hartmann
  • Paris, France, 75674
    • Hopital Cochin
  • Saint Cloud, France, 92211
    • Centre René Huguenin
  • Saint Etienne, France, 42022
    • Hopital Bellevue
  • Villejuif, France, 94804
    • Hopital Paul Brousse
• Germany
  • Jena, Germany, D-07740
    • Klinikum der Friedrich-Schiller Universitaet Jena
• Greece
  • Crete
    • Iraklion (Heraklion), Crete, Greece, 71110
      • University Hospital of Heraklion
• Italy
  • Chieti, Italy, 66100
    • Universita G.D'Annunzio Di Chieti
  • Orbassano, (Torino), Italy, 10043
    • Azienda Ospedale S. Luigi - Universita Di Torino
  • Pavia, Italy, I-27100
    • Fondazione Salvatore Maugeri
  • Pordenone, Italy, 33170
    • Azienda Ospedaliera "Santa Maria Degli Angeli"
  • RIONERO in VULTURE, Italy, I-58028
    • Ospedale Oncologico Regionale
  • Rome, Italy, 00161
    • Istituti Fisioterapici Ospitalieri - Roma
• Norway
  • Bergen, Norway, N-5021
    • Haukeland Hospital - University of Bergen
• Portugal
  • Amadora, Portugal, P-2700
    • Hospital Fernando Fonseca
  • Lisbon (Lisboa), Portugal, 1100
    • Hospital De Santo Antonio Dos Capuchos

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS: Histologically proven locoregionally recurrent or metastatic adenocarcinoma of the colon or rectum Histologic or cytologic proof of adenocarcinoma consistent with colorectal cancer in a solitary lesion if plasma carcinoembryonic antigen level is no greater than normal Metastases not limited to bone, pleural effusion, or ascites Surgically resectable metastases not eligible No symptomatic brain metastasis At least one bidimensionally measurable lesion measuring at least 20 mm in one diameter outside a previously irradiated area

PATIENT CHARACTERISTICS: Age: 18 to 75 Performance status: ECOG 0-2 Life expectancy: Not specified Hematopoietic: Absolute neutrophil count at least 2,000/mm3 Platelet count at least 100,000/mm3 Hepatic: Bilirubin no greater than 3 times upper limit of normal Renal: No uncontrolled hypercalcemia Cardiovascular: No significant cardiac disease Pulmonary: No severe respiratory illness Neurologic: No peripheral sensory neuropathy Other: No uncontrolled infection or chronic disease No second malignancy except basal cell carcinoma of the skin or in situ carcinoma of the cervix

PRIOR CONCURRENT THERAPY: Biologic therapy: No prior immunotherapy for locoregionally recurrent or metastatic colorectal cancer No concurrent prophylactic growth factor Chemotherapy: No prior chemotherapy for locoregionally recurrent or metastatic colorectal cancer At least 6 months since adjuvant chemotherapy Endocrine therapy: No prior hormone therapy for locoregionally recurrent or metastatic colorectal cancer No concurrent corticosteroids Radiotherapy: See Disease Characteristics No prior radiotherapy for locoregionally recurrent or metastatic colorectal cancer Concurrent localized analgesic radiotherapy of a bone lesion permitted unless indicative of disease progression Surgery: No prior surgery for locoregionally recurrent or metastatic colorectal cancer Other: No other concurrent investigational drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Investigators: Study Chair: Francis Levi, MD, PhD, Institut de Cancerologie et D'Immunogenetique at Hopital Paul-Brousse

Publications and helpful links

General Publications

• Efficace F, Innominato PF, Bjarnason G, Coens C, Humblet Y, Tumolo S, Genet D, Tampellini M, Bottomley A, Garufi C, Focan C, Giacchetti S, Levi F; Chronotherapy Group of the European Organisation for Research and Treatment of Cancer. Validation of patient's self-reported social functioning as an independent prognostic factor for survival in metastatic colorectal cancer patients: results of an international study by the Chronotherapy Group of the European Organisation for Research and Treatment of Cancer. J Clin Oncol. 2008 Apr 20;26(12):2020-6. doi: 10.1200/JCO.2007.12.3117.
• Giacchetti S, Zidani R, Perpoint B, et al.: Phase III trial of 5-fluorouracil (5-FU), folinic acid (FA), with or without oxaliplatin (OXA) in previously untreated patients (pts) with metastatic colorectal cancer (MCC). [Abstract] Proceedings of the American Society of Clinical Oncology 16: A805, 229a, 1997.
• Levi F, Zidani R, Misset JL. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Lancet. 1997 Sep 6;350(9079):681-6. doi: 10.1016/s0140-6736(97)03358-8.
• Mormont MC, Bleuzen P, Lellouch J, et al.: Prognostic value of circadian rhythm assessment for survival of patients with metastatic colorectal cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 16: A-956, 269a, 1997.
• Innominato PF, Giacchetti S, Moreau T, Smaaland R, Focan C, Bjarnason GA, Garufi C, Iacobelli S, Tampellini M, Tumolo S, Carvalho C, Karaboue A, Levi F; ARTBC International Chronotherapy Group. Prediction of survival by neutropenia according to delivery schedule of oxaliplatin-5-Fluorouracil-leucovorin for metastatic colorectal cancer in a randomized international trial (EORTC 05963). Chronobiol Int. 2011 Aug;28(7):586-600. doi: 10.3109/07420528.2011.597532.
• Giacchetti S, Bjarnason G, Garufi C, Genet D, Iacobelli S, Tampellini M, Smaaland R, Focan C, Coudert B, Humblet Y, Canon JL, Adenis A, Lo Re G, Carvalho C, Schueller J, Anciaux N, Lentz MA, Baron B, Gorlia T, Levi F; European Organisation for Research and Treatment of Cancer Chronotherapy Group. Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group. J Clin Oncol. 2006 Aug 1;24(22):3562-9. doi: 10.1200/JCO.2006.06.1440.
• Garufi C, Bjarnason GA, Giacchetti S, et al.: Independent prognostic value of the rest/activity circadian rhythm on overall survival (OS) in patients (pts) with metastatic colorectal cancer (MCC) receiving first line chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin: a companion study to EORTC 05963. [Abstract] J Clin Oncol 23 (Suppl 16): A-3553, 259s, 2005.
• Innominato PF, Focan C, Bjarnason GA, et al.: Quality of life (QoL) correlates with the rest/activity circadian rhythm (RAR) in patients (pts) with metastatic colorectal cancer (MCC) on first line chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin : an international multicenter study (EORTC 05963). [Abstract] J Clin Oncol 23 (Suppl 16): A-8029, 736s, 2005.
• Lévi F, Gorlia T, Tubiana N, et al.: Gender as a predictor for optimal dynamic scheduling of oxaliplatin, 5-fluorouracil and leucovorin in patients with metastatic colorectal cancer. Results from EORTC randomized phase III trial 05963. [Abstract] J Clin Oncol 23 (Suppl 16): A-3587, 267s, 2005.
• Giacchetti S, Bjarnason GA, Garufi C, et al.: First line infusion of 5-fluorouracil, leucovorin, oxaliplatin for metastatic colorectal cancer chronomodulated versus conventional delivery. A multicenter randomized trial of the EORTC chronotherapy group. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-2231, 2002.

Study record dates

Study Major Dates

• Study Start: March 1, 1998
• Primary Completion (Actual): March 1, 2002

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: January 22, 2004
• First Posted (Estimate): January 23, 2004

Study Record Updates

• Last Update Posted (Estimate): July 2, 2012
• Last Update Submitted That Met QC Criteria: June 29, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage IV rectal cancer; stage IV colon cancer; adenocarcinoma of the colon; recurrent colon cancer; recurrent rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin; Calcium; Levoleucovorin
• Other Study ID Numbers: EORTC-05963