Abstract
The combination of hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil and oxaliplatin with intravenous cetuximab has safely achieved prolonged survival in colorectal cancer patients with extensive liver metastases and prior treatment. Systemic exposure to the drugs or their main metabolites was determined during the first course of chronomodulated triplet HAI in 11 patients and related to toxicities after one or three courses. Consistent trends were found between the area under the plasma concentration–time curve (AUC) values of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN38; a bioactive metabolite), total oxaliplatin and platinum ultrafiltrate (P-UF), on the one hand, and subsequent leukopenia severity, on the other hand. Moreover, the maximum plasma concentration (C max) and the AUC of P-UF significantly predicted grades of diarrhoea (p = 0.004 and 0.017, respectively) and anaemia (p = 0.001 and 0.008, respectively) after the first course. Systemic drug exposure helps explain both the adverse events and the low rate of extrahepatic progression—a usual drawback of HAI chemotherapy—thus supporting upfront testing of the regimen. Systems optimization of chronomodulated HAI delivery could further reduce adverse events.
Similar content being viewed by others
References
Kemeny NE, et al. Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2009;27(21):3465–71.
Bouchahda M, et al. Modern insights into hepatic arterial infusion for liver metastases from colorectal cancer. Eur J Cancer. 2011;47(18):2681–90.
Kemeny NE, et al. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol. 2006;24(9):1395–403.
Mocellin S, et al. Meta-analysis of hepatic arterial infusion for unresectable liver metastases from colorectal cancer: the end of an era? J Clin Oncol. 2007;25(35):5649–54.
Arai Y, et al. Phase I/II study of radiologic hepatic arterial infusion of fluorouracil plus systemic irinotecan for unresectable hepatic metastases from colorectal cancer: Japan Clinical Oncology Group Trial 0208-DI. J Vasc Interv Radiol. 2012;23(10):1261–7.
Sadahiro S, et al. Clinical significance of and future perspectives for hepatic arterial infusion chemotherapy in patients with liver metastases from colorectal cancer. Surg Today. 2013;43(10):1088–94.
D’Angelica MI, et al. Phase II trial of hepatic artery infusional and systemic chemotherapy for patients with unresectable hepatic metastases from colorectal cancer: conversion to resection and long-term outcomes. Ann Surg. 2015;261(2):353–60.
Maeda Y, et al. Long-term outcomes of conversion hepatectomy for initially unresectable colorectal liver metastases. Ann Surg Oncol. 2016;23(Suppl 2):S242–8.
Levi FA, et al. Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV. Ann Oncol. 2016;27(2):267–74.
Jonker DJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040–8.
Van Cutsem E, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011–9.
Bouchahda M, et al. Rescue chemotherapy using multidrug chronomodulated hepatic arterial infusion for patients with heavily pretreated metastatic colorectal cancer. Cancer. 2009;115(21):4990–9.
Ensminger WD. Intrahepatic arterial infusion of chemotherapy: pharmacologic principles. Semin Oncol. 2002;29(2):119–25.
Kerr DJ, et al. Phase I clinical and pharmacokinetic study of leucovorin and infusional hepatic arterial fluorouracil. J Clin Oncol. 1995;13(12):2968–72.
Kusunoki M, et al. Results of pharmacokinetic modulating chemotherapy in combination with hepatic arterial 5-fluorouracil infusion and oral UFT after resection of hepatic colorectal metastases. Cancer. 2000;89(6):1228–35.
van Riel JM, et al. Continuous infusion of hepatic arterial irinotecan in pretreated patients with colorectal cancer metastatic to the liver. Ann Oncol. 2004;15(1):59–63.
Kern W, et al. Phase I and pharmacokinetic study of hepatic arterial infusion with oxaliplatin in combination with folinic acid and 5-fluorouracil in patients with hepatic metastases from colorectal cancer. Ann Oncol. 2001;12(5):599–603.
Guthoff I, et al. Hepatic artery infusion using oxaliplatin in combination with 5-fluorouracil, folinic acid and mitomycin C: oxaliplatin pharmacokinetics and feasibility. Anticancer Res. 2003;23(6D):5203–8.
Ceze N, et al. An enzyme-linked immunosorbent assay for therapeutic drug monitoring of cetuximab. Ther Drug Monit. 2009;31(5):597–601.
Fracasso PM, et al. A phase 1 escalating single-dose and weekly fixed-dose study of cetuximab: pharmacokinetic and pharmacodynamic rationale for dosing. Clin Cancer Res. 2007;13(3):986–93.
Canal P, et al. Pharmacokinetics and pharmacodynamics of irinotecan during a phase II clinical trial in colorectal cancer. Pharmacology and Molecular Mechanisms Group of the European Organization for Research and Treatment of Cancer. J Clin Oncol. 1996;14(10):2688–95.
LeRoy AF, et al. Analysis of platinum in biological materials by flameless atomic absorption spectrophotometry. Biochem Med. 1977;18(2):184–91.
Christophidis N, et al. Comparison of liquid- and gas-liquid chromatographic assays of 5-fluorouracil in plasma. Clin Chem. 1979;25(1):83–6.
Levi F, et al. Circadian timing in cancer treatments. Annu Rev Pharmacol Toxicol. 2010;50:377–421.
Levi F, et al. Oxaliplatin: pharmacokinetics and chronopharmacological aspects. Clin Pharmacokinet. 2000;38(1):1–21.
Metzger G, et al. Spontaneous or imposed circadian changes in plasma concentrations of 5-fluorouracil coadministered with folinic acid and oxaliplatin: relationship with mucosal toxicity in patients with cancer. Clin Pharmacol Ther. 1994;56(2):190–201.
Lévi F. Fluoropyrimidines in cancer therapy: circadian rhythms in 5-fluorouracil pharmacology and therapeutic applications. In: Fluoropyrimidines in Cancer Therapy (Drug Discovery) Rustum YM, editor. New Jersey: Humana Press Inc.; 2003. p. 107–28.
Guichard S, et al. CPT-11 converting carboxylesterase and topoisomerase activities in tumour and normal colon and liver tissues. Br J Cancer. 1999;80(3–4):364–70.
Garufi C, et al. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. Br J Cancer. 2010;103(10):1542–7.
Assenat E, et al. Cetuximab plus FOLFIRINOX (ERBIRINOX) as first-line treatment for unresectable metastatic colorectal cancer: a phase II trial. Oncologist. 2011;16(11):1557–64.
Levi F, et al. Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): safety, efficacy and improved secondary surgical resectability. Cancer Chemother Pharmacol. 2011;67(2):339–48.
Falvella FS, et al. DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan. Br J Clin Pharmacol. 2015;80(3):581–8.
Lim AS, et al. A common polymorphism near PER1 and the timing of human behavioral rhythms. Ann Neurol. 2012;72(3):324–34.
Zhou F, et al. Functional polymorphisms of circadian positive feedback regulation genes and clinical outcome of Chinese patients with resected colorectal cancer. Cancer. 2012;118(4):937–46.
Innocenti F, et al. Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer. J Clin Oncol. 2014;32(22):2328–34.
Chabot GG. Clinical pharmacokinetics of irinotecan. Clin Pharmacokinet. 1997;33(4):245–59.
Li XM, et al. A circadian clock transcription model for the personalization of cancer chronotherapy. Cancer Res. 2013;73(24):7176–88.
Dulong S, et al. Identification of circadian determinants of cancer chronotherapy through in vitro chronopharmacology and mathematical modeling. Mol Cancer Ther. 2015;14(9):2154–64.
Xu YQ, et al. Diurnal variation of hepatic antioxidant gene expression in mice. PLoS One. 2012;7(8):e44237.
Myint K, et al. Multidrug resistance-associated protein 2 (MRP2) mediated transport of oxaliplatin-derived platinum in membrane vesicles. PLoS One. 2015;10(7):e0130727.
Zhang R, et al. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci USA. 2014;111(45):16219–24.
Okyar A, et al. Strain- and sex-dependent circadian changes in abcc2 transporter expression: implications for irinotecan chronotolerance in mouse ileum. PLoS One. 2011;6(6):e20393.
Patel VR, et al. CircadiOmics: integrating circadian genomics, transcriptomics, proteomics and metabolomics. Nat Methods. 2012;9(8):772–3.
Fustin JM, et al. Rhythmic nucleotide synthesis in the liver: temporal segregation of metabolites. Cell Rep. 2012;1(4):341–9.
Acknowledgments
The authors sincerely acknowledge the contribution of the patients who participated in this companion translational study and the nurses who performed blood sampling.
Author contributions
Francis Lévi designed the study, collected clinical and/or pharmacokinetic data, and analysed and interpreted the data. Abdoulaye Karaboué designed the study, collected clinical and/or pharmacokinetic data, and analysed and interpreted the data. Marie-Christine Etienne-Grimaldi designed the study and performed the pharmacokinetic determinations. Gilles Paintaud designed the study and performed the pharmacokinetic determinations. Christian Focan collected clinical and/or pharmacokinetic data. Pasquale Innominato designed the study, collected clinical and/or pharmacokinetic data, and analysed and interpreted the data. Mohamed Bouchahda designed the study, collected clinical and/or pharmacokinetic data, and analysed and interpreted the data. Gérard Milano designed the study and performed the pharmacokinetic determinations. Etienne Chatelut designed the study and performed the pharmacokinetics determinations. All co-authors were involved in the drafting or reviewing of the report and approval of the submitted manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The Association pour la Recherche sur le Temps Biologique et la Chronothérapie sponsored the study. Measurement of serum cetuximab concentrations were carried out within the CePiBAc platform, which is cofinanced by the European Regional Development Fund and the French Higher Education and Research Ministry (LabEx MAbImprove ANR-10-LABX-53-01). None of the authors has any conflict of interest.
Rights and permissions
About this article
Cite this article
Lévi, F., Karaboué, A., Etienne-Grimaldi, MC. et al. Pharmacokinetics of Irinotecan, Oxaliplatin and 5-Fluorouracil During Hepatic Artery Chronomodulated Infusion: A Translational European OPTILIV Study. Clin Pharmacokinet 56, 165–177 (2017). https://doi.org/10.1007/s40262-016-0431-2
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40262-016-0431-2