ArticlesRandomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer
Introduction
The toxic effects of cancer chemotherapy in mice predictably vary two-fold or more according to dosing time because of the effect of circadian rhythms on cellular or proliferative activity.1 In human bone marrow, skin, and oral and rectal mucosae, DNA synthesis, a stage of the cell-division cycle associated with increased susceptibility to S-phase-specific agents, decreases by 50% or more between 0000 h and 0400 h compared with daytime.1, 2, 3 The activity of dehydropyrimidine dehydrogenase in human mononuclear cells increases by 40% around midnight.4 This enzyme brings about the intracellular catabolism of fluorouracil and contributes to improved tolerability of this drug between 0000 h and 0400 h.
We tested the clinical relevance of the chronotherapy principle in outpatients with metastatic colorectal cancer in relation to circadian dependencies of pharmacology and the long chemical stability of fluorouracil and oxaliplatin (Fournica and Hecquet, unpublished results).
1, 4, 5, 6 Chemotherapy of colorectal cancer generally combines fluorouracil with folinic acid and produces an objective response (tumour shrinkage of 50% or more) in 20–25% of patients, with an apparent dose-response relation.7, 8, 9, 10 Nevertheless, median survival generally remains at less than 12 months, although chemotherapy improves quality of life and survival.7, 8, 9, 10, 11, 12 The diaminocyclohexane platinum complex oxaliplatin achieved 10% objective responses with acceptable toxicity when given as a single drug to patients with fluorouracil refractory metastatic colorectal cancer.13, 14 Oxaliplatin has been approved in France and is currently undergoing registration procedures at the European and American agencies, among others.
5-day chronomodulated infusion regimens were first devised for fluorouracil and oxaliplatin as single agents, then both combined with folinic acid.15 We showed that high doses of this three-drug combination could be safely given to outpatients through a drug-delivery system programmable to circadian rhythms.13, 15, 16, 17 The three-drug chronotherapy regimen produced unusually high rates of objective responses (58%) and 3-year survival (17%) in a large phase II trial, which were confirmed in an international multicentre study.17, 18 Therefore, we expected a 20% difference in objective-response rate in favour of chronotherapy compared with constant-rate delivery.
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Patients and methods
The study was approved by the local internal review board and biomedical ethics committees.
From May 25, 1991, to Feb 2, 1993, patients with measurable metastases from colorectal cancer who were eligible for intial chemotherapy and satisfied admission criteria18 were invited to participate in this trial and, after acceptance, to give written informed consent.
We calculated a target size of 210 patients for the trial, assuming that the rate of objective tumour response would be 40% with
Results
The centres enrolled between ten and 62 patients each, and the treatment groups contained similar numbers (figure 2). The main difference at baseline in characteristics of patients between the two groups was in the proportion of patients with recurring metastases after previous surgical removal (p<0·005, table 1). 22 (24%) patients in the constant-rate infusion group received chronotherapy either from the start of treatment (two patients) or after maximum-response assessment to avoid excessive
Discussion
Chronotherapy with the three-drug combination substantially improved objective-response rate. Tolerability of chemotherapy was increased in comparison with constant-rate infusion, and the dose of fluorouracil could be higher.
The reliability of response assessments was established through an independent radiology review. The 29% response rate achieved with constant-rate infusion slightly exceeds the rates that are generally obtained with standard chemotherapy for colorectal cancer.7, 8, 9, 10, 20
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