Chronomodulation

Fig. 10.6 Cytotoxicity of chronomodulated 5-FU effect of variability of cell cycle phase durations. Shown is the cumulative cell kill when 5-FU is delivered in a circadian manner with peak at 4 a.m., in the presence of entrainment by the circadian clock, for different values of variability V indicated on...

Levi, F., Zidani, R., Vannetzel, J.M., Per-point, B., Focan, C., Faggiuolo, R., Chollet, P., Garufi, C., Itzhaki, M., Dogliotti L. Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases a randomized multi-institutional trial. J. Natl Cancer Inst. 1994, 86 1608-1617. 

Circadian rhythms exist in cell metabolism and proliferation and those of leukaemic cells differ from normal leucocytes. Evidence is increasing that the time of day at which therapy is administered does iirfluence the outcome for example, maintenance chemotherapy of some leukaemias is more effective if given in the evening (chronomodulation). 

Cure H, Chevalier V, Pezet D, Bousquet J, Focan C, Levi F, Garufi C, Chippom J, Chollet P. Phase II trial of chronomodulated infusion of 5-fluoromacil and folinic... 

It has been suggested that chronomodulated delivery of oxaliplatin might reduce the incidence of platinum-induced neurotoxicity (118,119). In a randomized, multicenter trial in patients with previously untreated metastases from colorectal cancer, 93 patients were assigned chronotherapy and 93 were assigned constant-rate infusion (120). Chronotherapy reduced the rate of severe mucositis... 

Levi F, Zidani R, Brienza S, Dogliotti L, Perpoint B, Rotarski M, Letourneau Y, Llory JF, Chollet P, Le Rol A, Focan C. A multicenter evaluation of intensified, ambulatory, chronomodulated chemotherapy with oxali-platrn, 5-fluorouracil, and leucovorin as initial treatment of patients with metastatic colorectal carcinoma. International Organization for Cancer Chronotherapy. Cancer 1999 85(12) 2532-40. 

Several investigators have recommended chronomodulating the 5-FU infusion in accordance with the circadian rhythm in 5-FU pharmacokinetics, tumor cell susceptibility, and normal cell tolerability to maximize response and minimize toxicity (54,57). These authors used a chronomodulated 5-FU infusion from 2200 to lOOOh with a peak infusion rate at 0400 h. 5-FU clinical response was greater and toxicity was less during the chronomodulated infusions versus the continuous infusions. 

At present, such techniques are being used in the circadian chronomodulation of anticancer drugs (Levi et al, 1994). These therapeutic approaches are based on the observation that the antitumoral efficacy of the drugs, as welt as their toxicity for the organism, vary with 24 h periodicity. In the case of 5-FU (see chapter 11), such observations can be related to the fact that the activity of enzymes involved in the... 

Giacchetti S, Perpoint B, Zidani R, et al (2000) Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18 136-147... 

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