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Title: Transcatheter hepatic therapy with irinotecan eluting beads (DEBIRI) for the treatment of colorectal liver metastases
Author: Jones, Robert Peter
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2013
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Background There is growing interest in preoperative chemotherapy for patients with colorectal liver metastases (CRLM) but personalising treatments to maximise response and minimise toxicity remains a challenge. Transcatheter hepatic therapy with irinotecan-eluting beads (DEBIRI) allows targeted delivery of irinotecan direct to CRLM. However, the safety and efficacy of DEBIRI in a preoperative setting has not yet been defined. In addition, very little is understood about why response to DEBIRI varies between patients. Aims This thesis had 2 key aims: (1) To assess the safety and efficacy of neoadjuvant DEBIRI (2) To investigate inter-patient variations in treatment response. Methods Patients with resectable CRLM received a single treatment with DEBIRI 1 month prior to surgery (maximal dose 200mg). The primary end-point of the study was R0 tumour resectability. Hepatic parenchyma and CRLM were sampled at the time of resection. Hepatic expression of key metabolising enzymes was assessed using mass spectrometry based proteomics. Hepatic irinotecan metabolism was characterised and correlated with tumour response. Results DEBIRI was successfully administered in 40 patients. 1 patient (3%) developed post-DEBIRI pancreatitis. All 40 proceeded to surgery, with 38 undergoing resection. 30 day operative mortality was 5%, morbidity 27.5% (Clavien-Dindo 1-4). 63 discreet lesions were targeted, with 74% R0 resection rate. Histopathological examination found no residual tumour in 17% of lesions, <50% residual tumour in 59% and >50% tumour in 24%. 91% of treated lesions demonstrated stable disease by RECIST, with 9% demonstrating disease progression. RECIST was a poor predictor of pathological response or long-term outcome. At a median follow up of 293 days, fourteen patients (36%) had disease recurrence. On multivariate analysis, only tumour KRAS status was predictive of long-term outcome (p=0.02). There was a strong correlation between hepatic CES-2 expression and irinotecan activation (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 (p = 0.01). Conclusions This study demonstrates the safety and efficacy of neoadjuvant DEBIRI for CRLM, with impressive pathological response rates. Systemic exposure to irinotecan was low. The ability of hepatic tissue to activate irinotecan into SN-38 clearly correlated with tumour replacement by fibrotic tissue, suggesting that hepatic CES-2 activation is the key step in the effectiveness of DEBIRI. These preliminary data provide a pharmacological rationale for whole lobe embolisation and suggests a potential predictive biomarker of treatment efficacy for future validation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available