Title: Chronotherapy with 5-fluorouracil, oxaliplatin, and folinic acid in colorectal cancer
Abstract: Author's reply Sir—Victor Sandor acknowledges the striking and concurrent improvements in both tolerability and response rate of chemotherapy, which were brought about by chronotherapy, compared with constant-rate infusion. As far as we are aware, no randomised trial has reported any difference of such magnitude in patients with metastatic cancer, by simply altering the modality of drug delivery, especially if the chemotherapy regimen involved two or more drugs, as was the case in our trial. Sandor questions the validity of constant-rate infusion as an adequate control arm for testing chronotherapy, since the sequence of the drugs and their expected pharmacokinetics were not similar in both treatment groups. Indeed, the sequence in which two anticancer drugs are given and the time interval which separates them clearly influence cytotoxicity in in-vitro models; yet this theory failed each time it was tested in patients. We believe that one of the reasons for such failure has been the lack of consideration of a circadian regulation of cell cycle and metabolic determinants of cytotoxicity. Several experiments in tumour-bearing mice or rats have concurrently assessed the respective roles of sequence, interval, and circadian time of combination chemotherapy, and have shown a major influence of circadian dosing time for outcome (reviewed in 1Lévi F Cancer chemotherapy.in: Redfern PH Lemmer B Chronopharmacology of anticancer agents. Handbook experimental pharmacology: physiology and pharmacology of biological rhythms. Springer-Verlag, Berlin1997: 299-331Google Scholar). In any event, a sequence between oxaliplatin and 5-fluorouracil/folinic acid is only recognisable on the first infusional day in our chronotherapy schedule, in which variable rate 12-hour infusions of oxaliplatin and 5-fluorouracil/folinic acid are regularly alternated for 5 days. We feel we would have been fortunate to find by chance that 12 hours represents an ideal infusion duration for 5-fluorouracil, a drug which has been accommodated in nearly 100 schedules for the past 50 years. None of these schedules, including those in which 5-fluorouracil was combined to a platinum complex made any reference to the circadian time dependency of drug toxicity or metabolism, and none achieved any clearcut improvement in therapeutic index in randomised trials. Both constant-rate infusion and chronotherapy produced similar areas under the time-concentration curves of 5-fluorouracil, although the circadian variations in plasma concentrations were different.2Metzger G Massari C Etienne MC et al.Spontaneous or imposed circadian changes in plasma concentrations of 5-fluorouracil coadministered with folinic acid and oxaliplatin: relationship with mucosal toxicity in cancer patients.Clin Pharm Ther. 1994; 56: 190-201Crossref PubMed Scopus (66) Google Scholar In addition chronomodulated schedules with differing times of maximum delivery rate produced large differences in drug pharmacokinetics and in toxicities, as we recently reported.3Langouèt AM, Metzger G, Comisso M, et al. Plasma drug concentration control through time-programmed administration. Presented at 87th meeting of American Association of Cancer Research, Washington DC, USA, March 20–24, 1996: abstract 1253.Google Scholar, 4Gruia G, Giacchetti S, Deprés P, et al. Role of time of peak delivery of chronomodulated 5-fluorouracil (5-FU), 1-leucovirin (LV) and oxaliplatin (L-OHP) in patients with metastatic colorectal cancer. Presented at 32nd meeting of American Society of Clinical Oncology, Philadelphia, PA, USA, May 18–21, 1996: abstract 372.Google Scholar Taken together, the results show that anticancer drug metabolism and toxicities are exquisitely dependent on circadian rhythms. Our trial has established the clinical relevance of chronotherapy. We invite our colleagues to systematically investigate the circadian dimension in the design and validation of optimally sequenced drug regimens. Chronotherapy with 5-fluorouracil, oxaliplatin, and folinic acid in colorectal cancerFrances Levi and colleagues (Sept 6, p 681)1 report a difference in response rate and toxicity between colon cancer patients treated with infusional 5-fluorouracil, folinic acid, and oxaliplatin given by chronotherapy, compared with patients given a 24-hour constant-rate infusion of these agents. They take these findings to support the hypothesis that the pharmacological effects of certain chemotherapeutic agents are influenced by circadian rhythms, and that their efficacy can be improved and their toxicity diminished by appropriately timing the therapies with respect to these rhythms. Full-Text PDF
Publication Year: 1997
Publication Date: 1997-11-01
Language: en
Type: article
Indexed In: ['crossref']
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Cited By Count: 1
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