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.

Condition	Treatment or Intervention	Phase
recurrent colon cancer Stage IV rectal cancer adenocarcinoma of the rectum recurrent rectal cancer stage IV colon cancer adenocarcinoma of the colon	Procedure: chemotherapy  Drug: drug modulation  Drug: fluorouracil  Drug: leucovorin calcium  Drug: oxaliplatin	Phase III

Further Study Details: 

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.

PROTOCOL 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.

Ages Eligible for Study:  18 Years   -   75 Years

Criteria

PROTOCOL ENTRY CRITERIA:

--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

--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

--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

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

Study chairs or principal investigators

Francis Levi,  Study Chair,  EORTC Chronotherapy Study Group   

Study ID Numbers:  CDR0000066218; EORTC-05963
Record last reviewed:  January 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00003287
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08