Multicentre prospective study of drug-eluting bead chemoembolisation safety using tightly calibrated small microspheres in non-resectable hepatocellular carcinoma

https://doi.org/10.1016/j.ejrad.2020.108966Get rights and content

Highlights

  • Tightly calibrated 100-μm DEB-TACE is safe.

  • 100-μm DEB-TACE biliary toxicity is similar to lipiodol-TACE toxicity.

  • Tightly calibrated 100-μm DEB-TACE local tumor response is better than bigger DEB.

  • Increasing the doxorubicin dose increase the complications rate of DEB-TACE.

  • Patient comorbidities are as important as tumor response for survival in HCC.

Abstract

Purpose

To assess the safety and tolerability of transarterial drug-eluting bead chemoembolisation (DEB-TACE) using tightly calibrated 100-μm microspheres in hepatocellular carcinoma (HCC).

Method

This multicentre prospective study included 131 patients with a 2-year follow-up. All patients had Child-Pugh scores ≤ B7, a good performance status, and Barcelona Clinic Liver Cancer stage A or B. Beads were loaded with 50 mg of doxorubicin per millilitre. Overall, 223 nodules were treated (mean size: 27.6 mm, average number of nodules per patient: 1.7). Toxicity was assessed using Common Terminology Criteria for Adverse Events 4.03 and response according to the modified Response Evaluation Criteria in Solid Tumours. The primary endpoint was safety. Secondary endpoints included technical success, post-embolisation syndrome (PES), local tumour response, and 2-year survival.

Results

A total of 214 DEB-TACE procedures were performed (mean per patient: 1.64), with a technical success rate of 97.6 % and a PES rate of 9.3 %. Major complications occurred in 6.8 % of patients and 4.1 % of procedures. There were no treatment-related deaths. Doxorubicin dose was an independent predictor of complications (p = 0.01). Four patients were lost to follow-up and 18 received liver transplants. Objective response rates were 74.6 %, 45.7 %, and 44.1 % at 6, 12, and 24 months, respectively. The cumulative 24-month overall survival rate was 55.96 %. Median survival was 22 months (interquartile range = 13–24). Co-morbidities and tumour response were independent predictors of survival (p = 0.0012 and 0.0052, respectively). Complications did not affect survival (p = 0.24).

Conclusions

DEB-TACE with tightly calibrated 100-μm beads is safe and not associated with increases in biliary toxicity or complications. Tumour response and survival are in the expected range for chemoembolisation therapy. (Clinical trials ID: NCT02670122).

Introduction

In randomised studies, drug-eluting bead transarterial chemoembolisation (DEB-TACE) for the treatment of hepatocellular carcinoma (HCC) has not achieved better overall survival (OS) than conventional chemoembolisation (cTACE) [[1], [2], [3]]. Nonetheless, DEB-TACE has several proven advantages such as the delivery of higher concentrations of the chemotherapy drug in the tumour, lower systemic toxicity, a need for fewer sessions, controlled and sustained release of the drug, greater efficacy in advanced-stage or large tumours, and better standardisation of the procedure itself [[4], [5], [6]].

There is no consensus on the optimal size of the microparticles for DEB-TACE treatment [7]. Animal studies have shown that small microspheres penetrate deeper and more homogenously into tumours, causing more intense ischaemia and achieving a higher intratumoural concentration of the chemotherapy [8,9]. This would imply a better objective local response. The DEBs most commonly used in current clinical practice are 100–300 μm; DEBs sized ≤100 μm are used less often, as they are considered potentially more dangerous [10].

Biliary toxicity of DEB-TACE attributed to the ischaemic injury of the peribiliary plexus, associated with local doxorubicin toxicity, has been a particular source of concern. It has been suggested that this type of toxicity may be more intense when small microspheres are used, thus placing limits on their use [11]. Several uncontrolled retrospective studies have reported significantly higher rates of biliary complications with DEB-TACE than with cTACE [12,13]. In this context, the question of the most suitable microsphere size for use in DEB-TACE remains unanswered.

The objective of this multicentre prospective study was to assess whether DEB-TACE using small microspheres (100 μm) is associated with a higher rate of complications compared with cTACE and with DEB-TACE using bigger microspheres.

Section snippets

Study design and endpoints

This was a multicentre prospective study to assess the safety and tolerability of DEB-TACE of non-resectable HCC, using 100-μm doxorubicin-loaded microspheres (Embozene Tandem™, CeloNova BioSciences, Boston Scientific, San Antonio, TX, USA). Institutional Review Board approval was obtained at all the participating institutions. All patients provided written informed consent.

The safety of selective DEB-TACE with tightly calibrated 100-μm microspheres loaded with 50 mg of doxorubicin per

DEB-TACE procedures

The results are summarised in Fig. 1. A total of 214 DEB-TACE procedures (a mean of 1.64 per patient) were performed, with 46.5 % of the patients undergoing two DEB-TACE procedures and 12.9 %, 3.8 %, and 0.7 % undergoing three, four, and six procedures, respectively. Catheterisation was super-selective in 60.8 % of the procedures and selective in 39.2 %. The endpoint of stasis was achieved in 89.2 % of cases. Doxorubicin dose, based on the volume of microspheres infused, was 50 mg in 24, 75 mg

Discussion

Since the Precision V study, many researchers have attempted to optimise the DEB-TACE procedure [1]. The size and characteristics of the DEB is a key issue. Doxorubicin disseminates a maximum of 150 μm from the surface of the microsphere, and the density of microspheres inside the tumour should be as high as possible [22]. Animal studies have confirmed that small DEBs achieve deeper intra-tumour penetration and more uniform intra-tumour coverage, improving doxorubicin distribution and tumour

CRediT authorship contribution statement

Jose Urbano: Conceptualization, Methodology, Investigation, Data curation, Validation, Writing - original draft, Writing - review & editing, Supervision, Project administration. J. Javier Echevarria-Uraga: Investigation, Data curation, Validation, Writing - original draft, Writing - review & editing. J. Jose Ciampi-Dopazo: Investigation, Data curation, Validation, Writing - original draft, Writing - review & editing. Juan A. Sánchez-Corral: Investigation, Data curation. Jorge Cobos Alonso:

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

Authors thanks Dr. Lucia Llanos-Jiménez, epidemiologist, for her kind and efficient support in the approval processes of the national drug agency, regionals IRBs and clinical trials gov documents.

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