Implications of circadian clocks for the rhythmic delivery of cancer therapeutics

Implications of circadian clocks for the rhythmic delivery of cancer therapeutics

“…Chronotherapy reduced the incidence of severe mucositis fivefold, halved the incidence of functional impairment from peripheral sensory neuropathy and reduced the incidence of grade 4 toxicity requiring hospitalization by threefold when compared with the flat infusion regimen. This improvement in patient tolerability to the cancer medications was accompanied by a significant increase in the objective response rate to the cancer chemotherapy, from 29 to 51 per cent (table 1; Lévi et al 2007b).…”

“…Conversely, 40-60 per cent of the patients treated 6 or 9 hours before or after these times displayed severe toxicity, while this was the case for 80 per cent of the patients receiving peak 5-FU-LV at 16.00 and peak oxaliplatin at 04.00. Tumour response occurred in 30.4 per cent of the patients receiving either one of the best tolerated modalities, as compared to 12.5 per cent of the patients given either one of the worst tolerated modalities (table 1; Lévi et al 2007b).…”

“…This schedule has been administered with programmable-in-time multichannel electronic pumps and validated in patients with metastatic colorectal cancer registered in phase I, II and III clinical trials. (Adapted from Bjarnason et al (2001), Bjarnason & Jordan (2002), Smaaland et al (2002), Lévi (2001) and Lévi et al (2007b). )…”

“…These large differences resulted from the coordinated circadian rhythms that modify drug pharmacokinetics (PK) and pharmacodynamics (PD) across the 24 hours (Lévi & Schibler 2007). These findings led us to develop a chronomodulated circadian delivery schedule of three anti-cancer drugs that produced fivefold less severe toxicity when compared with wrongly timed or constant-rate infusion (Mormont & Lévi 2003;Lévi et al 2007b). However, gender was responsible for large differences in both the tolerability and the survival of patients on cancer chronotherapeutics (Giacchetti et al 2006).…”

Comparison of the Eight-Hour With the 22-Hour Infusion of 5-Fluorouracil, in the FOLFOX Chemotherapy of Colon Cancer: A Retrospective Study

“…This variability in 5-FU plasma concentration may affect variability in tolerance to the drug and lower therapeutic efficacy (15). Accordingly, several investigators have tried to alter the rate of a prolonged infusion in a circadian pattern, in order to improve the therapeutic index, called chronomodulation (26)(27)(28). However, previous studies have failed to find a constant circadian pattern of 5-FU plasma concentrations over prolonged drug infusion (17).…”