[Chrono-chemotherapy and dose intensity].
Circadian (about 24 h) changes modulate cellular metabolism and proliferation in healthy tissues. As a result, the extent of toxicity of cancer chemotherapy varies by 50% or more according to dosing time in mice or rats. These experimental data led to test the principle of adapting chemotherapy delivery to circadian rhythms--so-called "chronotherapy"--in cancer patients. Clinical trials first aimed to assess toxicities and maximal tolerated dose of chronotherapy schedules. Programmable-in-time pumps became the indispensable tool for reliably testing this principle in a large enough patient population and without any need for hospitalization. Results from randomized clinical trials have indicated that chronotherapy allowed to increase dose intensity (DI, a secondary criterion in these trials) by 13 to 45% as compared to injecting the drug at another time (doxorubicin, cisplatin) or according to a flat rate (5-fluorouracil, floxuridine, oxaliplatin). A non-randomized trial further suggested this principle would also apply to cytokine delivery (interferon alpha). Two consecutive randomized trials have revealed that chronotherapy-related increase in 5-FU DI was further associated with a 20% increase in response rate of patients with metastatic colorectal cancer to the 3-drug association that was used (5-FU, folinic acid and oxaliplatin). In a subsequent phase II trial 5-FU daily dose and 3-drug treatment frequency were increased in 50 patients with this disease. Such intrapatient dose escalation protocol also disclosed a positive correlation between DI of 5-FU and response. New anticancer drugs should benefit from this approach so that both their clinical safety and patient's quality of life are improved, through ambulatory administration.
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Laboratoire Rythmes biologiques et chronothérapeutique, hôpital Paul-Brousse, Villejuif, France.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002909:Chronobiology Phenomena; D002940:Circadian Rhythm; D002945:Cisplatin / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007260:Infusion Pumps; D016898:Interferon-alpha / Q000008:administration & dosage; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D010051:Ovarian Neoplasms / Q000188:drug therapy; D000077150:Oxaliplatin; D051381:Rats
D000903:Antibiotics, Antineoplastic; D016898:Interferon-alpha; D009944:Organoplatinum Compounds; D005467:Floxuridine; D000077150:Oxaliplatin; D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil
Chronochimiothérapie et intensité de dose.