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Journal of Clinical Oncology, Vol 23, No 9 (March 20), 2005: pp. 2105 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.99.297
Is There a New Drug Beyond Floxuridine for Intra-Arterial Hepatic Chemotherapy in Liver Metastases From Colorectal Cancer?On behalf of the International Society of Regional Cancer Treatment and Società Italiana di Terapie Integrate Locoregionali in Oncologia, Department of Oncology, General City Hospital S.Giuseppe, Empoli (Florence), Italy To the Editor: We read with great interest the article by Kemeny et al,1 who reported the results of intra-arterial hepatic chemotherapy (HAIC) with floxuridine (FUDR) and dexamethasone in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal cancer (CRC). They found that the maximum tolerated dose (MTD) for combined systemic irinotecan and hepatic arterial infusion FUDR was 200 mg/m2 every other week, and FUDR at 0.12 mg/kg x pump volume ÷ pump flow rate in an adjuvant regimen is feasible. With a median follow-up time of 26 months, the 2-year survival rate is 89%. All 27 patients who were treated at MTD are alive. The choice of irinotecan for systemic therapy was used because lung metastases express a higher level of thymydylate synthetase (TS) than in other sites,2 and fluorouracil or FUDR (inhibitors of TS) may not be the most appropriate drug to use to control the development of disease in the lung. Instead, these drugs are active in liver metastases in which TS could be lower. This hypothesis is not totally accepted. More reports show that in liver metastasis, TS could be high.2-4 For this reason, it should be of interest to test irinotecan directly as HAIC in liver metastases from CRC to overcome the inefficiency of FUDR in about half of patients. Irinotecan is an inhibitor of nuclear enzyme topoisomerase 1. SN-38 is believed to be the active metabolite of irinotecan and is produced by the enzyme carboxylesterase (CPT-CE).5,6 Hepatic metabolism by glycuronidation and subsequent biliary excretion is the most important route of elimination of SN-38. Guichard et al7 evaluated the activity of irinotecan by converting CPT-CE in 53 CRCs, eight liver metastases, and in normal tissues adjacent to the tumors. Irinotecan CPT-CE activity was variable, with a coefficient of variation of approximately 50% in primary tumors and in normal tissues. The mean CPT-CE activity in liver metastases was 1.90 pmol/min/mg proteins, which is comparable to that observed in primary tumors (1.81 pmol/min/mg proteins). CPT-CE activity in normal liver ranged from 2.05 to 8.17 pmol/min/mg proteins and was significantly higher than in liver metastases (P = .0009). The two- to three-fold lower activity found in primary compared with normal liver suggests that a local conversion to SN-38 might occur in tumor cell. The prodrugs irinotecan and SN-38 are in two forms: the active lactonate form, and the inactive carboxylate form. In tumor cell, the paucity of CPT-CE probably causes a lower clearance than in normal tissues, with less production of the inactivate carboxylate form and more persistence of the inactive lactonate form. On this basis, irinotecan could be the new drug of choice for HAIC overcoming FUDR inability with respect to TS. In a phase I clinical study, we define the MTD of irinotecan HAIC for hepatic metastases from CRC as 200 mg/m2 every 3 weeks.8 In a subsequent phase II study, we treated 12 advanced patients obtaining four partial responses lasting 24, 15, 12, and 8 weeks, three patients with stable disease lasting more than 12 weeks, and five patients who experienced disease progression.9 Our conclusion is that probably is the time to compare HAI FUDR to the administration of irinotecan as HAIC in liver metastases from CRC in order to increase the outcome of this disease both in an adjuvant and palliative setting in combination with systemic treatment. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Kemeny N, Jarnagin W, Gonen M, et al: Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal cancer. J Clin Oncol 21:3303-3309, 2003
2. Gorlick R, Metzger R, Danenberg KD, et al: Higher levels of tymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma. J Clin Oncol 16:1465-1469, 1998
3. Davies MM, Johnston PG, Kaur S, et al: Colorectal liver metastasis thymidylate synthase staining corrlates with response to hepatic arterial floxuridine. Clin Cancer Res 5:325-328, 1999 4. Berg RW, Ferguso PJ, DeMoor JM, et al: The means to an end of tumor cell resistence to chemotherapeutic drugs targeting thymidylate sunthase: Shoot the messenger. Curr Drug Targets 3:297-309, 2002[CrossRef][Medline]
5. Gupta E, Lestingi TM, Mick R, et al: Metabolic fate of irinotecan in humans: Correlation of glucoronidation with diarrea. Cancer Res 54:3723-3725, 1994 6. Rivory LP, Robert J: Identification and kinetics of a b-glucuronide of SN-38 in human plasma after administration of the campttothecin derivative irinotecan (CPT-11). Cancer Chemother Pharmacol 36:176-179, 1995[Medline] 7. Guichard S, Hennebelle I, Chevreau, et al: CPT-11 converting carboxilesterase in tumor and in normal colon and liver tissues. Br J Cancer 80:364-370, 1999[CrossRef][Medline] 8. Fiorentini G, Ricci Lucchi S, Giovanis P, et al: Irinotecan hepatic arterial infusion chemotherapy for hepatic metastases from colorectal cancer: Results of a phase I clinical study. Tumori 87:388-390, 2001[Medline] 9. Fiorentini G, Rossi S, Dentico P, et al: Irinotecan hepatic arterial infusion chemotherapy for hepatic metastases from colorectal cancer: A phase II clinical study. Tumori 89:382-384, 2003[Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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