Elsevier

The Lancet

Volume 350, Issue 9079, 6 September 1997, Pages 681-686
The Lancet

Articles
Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer

https://doi.org/10.1016/S0140-6736(97)03358-8Get rights and content

Summary

Background

The efficacy of chemotherapy may be affected by circadian rhythms. Therefore, we tested chronomodulated infusion (administered to coincide with relevant circadian rhythms) of oxaliplatin, fluorouracil, and folinic acid compared with a constant-rate infusion method. The combination of three drugs was delivered for 5-day courses with 16-day intervals.

Methods

We expected chronotherapy to increase objective response rate by 20% compared with constant-rate infusion. We tested this effect in a randomised multicentre trial involving patients with previously untreated metastases from colorectal cancer who were enrolled at nine institutions in three countries. 93 patients were asssigned chronotherapy and 93 were assigned constant-rate infusion via multichannel programmable ambulatory pumps. The trial was interrupted when a significant difference in main outcome was reached. All data were analysed by intention to treat.

Findings

On enrolment, we found significant imbalances in two characteristics—abdominal gland or bone metastases (constant-rate infusion two patients, chronotherapy ten patients) and relapse from surgically treated metastases (constant-rate infusion seven patients, chronotherapy 22 patients). An objective response was obtained in 47 (51%) of the chronotherapy group, and in 27 (29%) of the constant-rate group (difference 21·5% [95% CI 13·7–31·2], p=0·003). Chronotherapy reduced five-fold the rate of severe mucosal toxicity (14% vs 76%, p<0·0001) and halved that of functional impairment from peripheral sensitive neuropathy (16% vs 31%, difference 15·0% [9·5–25·7], p<0·01). Median time to treatment failure was 6·4 months on chronotherapy and 4·9 months on constant-rate infusion (p=0·006), and 24% of the patients from the constant-rate infusion group received chronotherapy after failure. With a minimum follow-up of 3 years, median survival times and 3-year survival were similar in both groups (15·9 vs 16·9 months and 22% vs 21%, respectively).

Interpretation

Chronotherapy was significantly less toxic and more effective than constant-rate infusion. The results support the concept of temporal selectivity of cancer chemotherapy.

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.

Section snippets

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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