A multicenter evaluation of intensified, ambulatory, chronomodulated chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin as initial treatment of patients with metastatic colorectal carcinoma

BACKGROUND. The combination of 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (1-OHP) was shown to be both more active against metastatic col orectal carcinoma and better tolerated if the drug delivery rate was chrono modulated according to circadian rhythms rather than constant. This allowed the authors to intensify the three-drug chronotherapy regimen and to asses s its activity as the initial treatment of metastatic colorectal carcinoma patients in ten centers from four countries. METHODS. Patients with previously untreated and inoperable measurable metas tases from colorectal carcinoma received a daily administration of chronomo dulated 5-FU (700 mg/m(2)/day, peak delivery rate at 04:00 hours), LV (300 mg/m(2)/day, peak delivery rate at 04:00 hours), and 1-OHP (25 mg/m(2)/day, peak delivery rate at 16:00 hours) for 4 days every 14 days. Intrapatient escalation of 5-FU dose was performed if toxicity was less than World Healt h Organization (WHO) Grade 2. RESULTS. Of 90 enrolled patients, 35 had a WHO performance status of 1 or 2 ; 49 had metastases in greater than or equal to 2 organs. The liver was inv olved in 79 patients, 30 of whom had clinical hepatomegaly. The main dose-l imiting toxicities were WHO modified Grade 3 or 4 diarrhea (41% of patients , 8.2% of courses), stomatitis (30% of patients, 5.1% of courses), and Grad e 2 cumulative peripheral sensory neuropathy (19% of patients after 12 cour ses). Two patients died with severe gastrointestinal toxicity. Using the in tent-to-treat method, the overall objective response rate was 66% (95% conf idence limits, 56-76%). Surgical removal of previously inoperable metastase s was successful in 31 patients (34%). Histologic necrosis of metastases wa s >90% in 7 patients and complete in 1 patient. The median progression free survival and survival durations were 8.4 months (range, 5.9-10.9 months) a nd 18.5 months (range, 13.2-23.8 months), respectively, with 38% of the pat ients alive at 2 years of follow-up. CONCLUSIONS. The objective response rate appeared to be approximately 3-fol d as high as that achieved with current 5-FU-based regimens and translated into an approximately 50% increase in median survival. The hypothesis that this intensified, ambulatory, chronotherapy regimen can increase survival c urrently is being investigated in a multicenter randomized study conducted by the European Organization for Research and Treatment of Cancer Chronothe rapy Study Group. Cancer 1999;85:2532-40. (C) 1999 American Cancer Society.