Original Article

Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 2, pp 359-368

First online:

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

  • R. P. JonesAffiliated withSchool of Cancer Studies, Institute of Translational Medicine, University of LiverpoolMRC Centre for Drug Safety Science, Institute of Translational Medicine, University of LiverpoolNorthwest Hepatobiliary Unit, Aintree University Hospital Email author 
  • , P. SuttonAffiliated withSchool of Cancer Studies, Institute of Translational Medicine, University of LiverpoolMRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool
  • , R. M. D. GreensmithAffiliated withMRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool
  • , A. Santoyo-CastelazoAffiliated withMRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool
  • , D. F. CarrAffiliated withDepartment of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool
  • , R. JenkinsAffiliated withMRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool
  • , C. RoweAffiliated withMRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool
  • , J. HamlettAffiliated withMRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool
  • , B. K. ParkAffiliated withMRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool
    • , M. TerlizzoAffiliated withDepartment of Histopathology, Aintree University Hospital
    • , E. O’GradyAffiliated withDepartment of Radiology, Aintree University Hospital
    • , P. GhanehAffiliated withSchool of Cancer Studies, Institute of Translational Medicine, University of Liverpool
    • , S. W. FenwickAffiliated withNorthwest Hepatobiliary Unit, Aintree University Hospital
    • , H. Z. MalikAffiliated withNorthwest Hepatobiliary Unit, Aintree University Hospital
    • , G. J. PostonAffiliated withNorthwest Hepatobiliary Unit, Aintree University Hospital
    • , N. R. KitteringhamAffiliated withMRC Centre for Drug Safety Science, Institute of Translational Medicine, University of Liverpool

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Abstract

Purpose

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).

Methods

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.

Results

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).

Conclusion

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.

Keywords

DEBIRI Irinotecan Carboxylesterase Liver Colorectal Metastases