Hepatic activation of irinotecan predicts tumour response in patients with colorectal liver metastases treated with DEBIRI: exploratory findings from a phase II study

• DOI: 10.1007/s00280-013-2199-5
• Publication Date: 2013-06-11T13:10:57Z
• Authors: R. P. Jones; P. Sutton; R. M. D. Greensmith; A. Santoyo-Castelazo; D. F. Carr; R. Jenkins; C. Rowe; J. Hamlett; B. K. Park; M. Terlizzo; E. O’Grady; P. Ghaneh; S. W. Fenwick; H. Z. Malik; G. J. Poston; N. R. Kitteringham
• Keywords: 0301 basic medicine; Genotype; Blotting, Western; Liver Neoplasms; Reproducibility of Results; DNA, Neoplasm; Irinotecan; Antineoplastic Agents, Phytogenic; Mass Spectrometry; Neoplasm Proteins; 3. Good health; 03 medical and health sciences; Drug Delivery Systems; Liver; Microsomes; Humans; Camptothecin; Prospective Studies; Glucuronosyltransferase; Colorectal Neoplasms; Biotransformation

The response of colorectal liver metastases to the cytotoxic agent irinotecan varies widely. Attempts to correlate tumour metabolism with response have been mixed. This study investigated the hepatic metabolism of irinotecan as a potential predictor of tumour response to irinotecan-eluting beads (DEBIRI).Ten patients with colorectal liver metastases were treated with 200 mg irinotecan (as DEBIRI) as part of the PARAGON II study. Hepatic expression of key metabolising enzymes was measured using mass spectrometry-based proteomics. Serum drug concentrations and hepatic irinotecan metabolism were characterised and correlated with tumour response.Serum concentrations of irinotecan metabolites did not correlate with hepatic metabolism or pathological response. There was a strong correlation between hepatic CES-2 expression and activation of irinotecan (r (2) = 0.96, p < 0.001). Patients with a UGT1A1*28 6/7 SNP showed no difference in drug metabolism or pathological response. Hepatic CES-2 mediated activation of irinotecan clearly correlated with tumour replacement by fibrosis (r (2) = 0.54, p = 0.01).This study provides the first evidence that hepatic activation of irinotecan predicts tumour response. Delivery of liver-targeted irinotecan to normal liver tissue rather than tumour may be a more rational approach to maximise response.