Chronomodulated Chemotherapy in Advanced Colorectal Carcinoma
Authors: Tim Price, Chris Karapetis, Virginie Chevalier, Hervé Curé, Philippe Chollet, Francis Lévi
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.02.131 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12228219 Chronomodulated Chemotherapy in Advanced Colorectal Carcinoma Tim PricexTim PriceSearch for articles by this author , Chris KarapetisxChris KarapetisSearch for articles by this author Virginie ChevalierxVirginie ChevalierSearch for articles by this author , Hervé CuréxHervé CuréSearch for articles by this author , Philippe CholletxPhilippe CholletSearch for articles by this author , Francis LévixFrancis LéviSearch for articles by this author Show More Queen Elizabeth HospitalFlinders Medical Center, Adelaide, AustraliaCentre Jean Perrin, Clermont-Ferrand, FranceHôpital Paul Brousse, Villejuif, France https://doi.org/10.1200/JCO.2002.02.131 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15092002In Reply:Chronomodulated delivery schedules have indeed pioneered the recent progress in the chemotherapy for advanced colorectal cancer. In 1992, Lévi et al1 first reported a 58% objective response rate in patients with previously untreated metastatic colorectal cancer receiving a chronomodulated infusion of oxaliplatin (l-OHP), combined with fluorouracil (5-FU) and folinic acid (FA), given as a 5 days on, 16 days off regimen. This modality of administration was chosen, because (1) conventional delivery methods had then failed to show good activity or acceptable tolerability of l-OHP and (2) preclinical studies had shown a marked circadian dependency of the toxicity and the efficacy of both oxaliplatin and 5-FU.2-4 Therefore, the exploration of chronomodulated schedules did not constitute an alternative to the use of new drugs against colorectal cancer but critically contributed to the demonstration of oxaliplatin tolerability and activity against colorectal cancer and to its availability today.Two consecutive international randomized trials have further shown a 51% objective response rate with chronomodulated 5-FU/FA/l-OHP. In both trials, the chronomodulated schedule was several fold better tolerated than constant-rate infusion.5-6 The same international group further achieved an objective response rate of 66% using an intensified scheme (4 days on, 10 days off) as first-line chemotherapy of metastatic colorectal cancer. In this trial, patients were treated near individual maximum-tolerated dose, as a result of an intrapatient dose-escalation scheme, based on individual tolerability.7In the current trial, we omitted l-OHP from the latter intensified regimen and searched for the antitumor activity of chronomodulated 5-FU/FA alone, as first-line treatment of metastatic colorectal cancer. Using independent review of computed tomography scans, we demonstrated that this two-drug chronomodulated combination achieved 41% objective responses.8 This figure ranks among those currently achieved by several schedules combining 5-FU and irinotecan or oxaliplatin. Because our goal was to treat each patient near individual maximum-tolerated dose, the occurrence of toxic events per patient is a proof of adequate protocol compliance and adequate reporting of toxic events. This strategy led to allow a large increase in dose-intensity.8 We fully agree with Price and Karapetis, however, that a definitive proof of activity increase should result from a randomized trial with conventional 5-FU/FA as a comparator yet that this trial would probably be difficult to achieve presently. Nevertheless, we also believe that this two-drug modality could also be compared at fixed doses with recent combination schedules involving l-OHP or irinotecan in metastatic or adjuvant situations. We agree with Price and Karapetis that many factors play a role on patient survival, beside first-line chemotherapy. These include second- or third-line treatment and surgery of metastases.9 Despite this limitation, the Chronotherapy Group of the European Organization for Research and Treatment of Cancer has just completed an international randomized trial addressing this issue (EORTC 05963).Chronomodulated 5-FU/FA is rather easy to administer to outpatients, using a programmable multichannel delivery pump, currently approved in Europe, the United States, and China. The patient only comes once to the hospital center to be connected to the pump, then returns home or continues his usual activities while receiving chronomodulated therapy. We are currently developing a program of outpatient distant programming and control of chronotherapy delivery through the internet. On another hand, several studies have suggested that this chronotherapy also improves quality of life as compared with conventional chemotherapy delivery.10 Thus, the available technology allows to deliver modern and complex treatments outside the hospital and without exhausting the patients.1. Levi F, Misset JL, Brienza S, et al: A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump: High antitumor effectiveness against metastatic colorectal cancer. Cancer 69:: 893,1992-900, Crossref, Medline, Google Scholar2. Boughattas N, Levi F, Fournier C, et al: Circadian rhythms in toxicities and tissues uptake of oxaliplatin in mice. Cancer Res 49:: 3362,1989-3368, Medline, Google Scholar3. Granda TG, d’Attino RM, Filipski E, et al: Circadian optimisation of irinotecan and oxaliplatin efficacy in mice with Glasgow osteosarcoma. Br J Cancer 86:: 999,2002-1005, Crossref, Medline, Google Scholar4. Peters GJ, Van Dijk J, Nadal JC, et al: Diurnal variation in the therapeutic efficacy of 5-fluorouracil against murine colon cancer. In Vivo 1:: 113,1987-117, Medline, Google Scholar5. Lévi F, Zidani R, Vannetzel JM, et al: 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 86:: 1608,1994-1617, Crossref, Medline, Google Scholar6. Levi F, Zidani R, Misset JL: Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer: International Organization for Cancer Chronotherapy. Lancet 350:: 681,1997-586, Crossref, Medline, Google Scholar7. Levi F, Zidani R, Brienza S, et al: A multicenter evaluation of intensified, ambulatory, chronomodulated chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin as initial treatment of patients with metastatic colorectal carcinoma: International Organization for Cancer Chronotherapy. Cancer 85:: 2532,1999-2540, Crossref, Medline, Google Scholar8. Cure H, Chevalier V, Adenis A, et al: Phase II trial of chronomodulated infusion of high-dose fluorouracil and l-folinic acid in previously untreated patients with metastatic colorectal cancer. J Clin Oncol 20:: 1175,2002-1181, Link, Google Scholar9. Giacchetti S, Itzhaki M, Gruia G, et al: Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 10:: 663,1999-669, Crossref, Medline, Google Scholar10. Pugliese P, Garufi C, Perrone M, et al: Quality of life and chronotherapy. 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