Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study

Abstract

Transcatheter arterial chemoembolization (TACE) offers a survival benefit to patients with intermediate hepatocellular carcinoma (HCC). A widely accepted TACE regimen includes administration of doxorubicin-oil emulsion followed by gelatine sponge-conventional TACE. Recently, a drug-eluting bead (DC Bead) has been developed to enhance tumor drug delivery and reduce systemic availability. This randomized trial compares conventional TACE (cTACE) with TACE with DC Bead for the treatment of cirrhotic patients with HCC. Two hundred twelve patients with Child-Pugh A/B cirrhosis and large and/or multinodular, unresectable, N0, M0 HCCs were randomized to receive TACE with DC Bead loaded with doxorubicin or cTACE with doxorubicin. Randomization was stratified according to Child-Pugh status (A/B), performance status (ECOG 0/1), bilobar disease (yes/no), and prior curative treatment (yes/no). The primary endpoint was tumor response (EASL) at 6 months following independent, blinded review of MRI studies. The drug-eluting bead group showed higher rates of complete response, objective response, and disease control compared with the cTACE group (27% vs. 22%, 52% vs. 44%, and 63% vs. 52%, respectively). The hypothesis of superiority was not met (one-sided P = 0.11). However, patients with Child-Pugh B, ECOG 1, bilobar disease, and recurrent disease showed a significant increase in objective response (P = 0.038) compared to cTACE. DC Bead was associated with improved tolerability, with a significant reduction in serious liver toxicity (P < 0.001) and a significantly lower rate of doxorubicin-related side effects (P = 0.0001). TACE with DC Bead and doxorubicin is safe and effective in the treatment of HCC and offers a benefit to patients with more advanced disease.

Fig. 1

Flowchart of patients in the PRECISION V Trial. * For patients with bilobar disease who could not be treated superselectively in a single treatment, a second embolization was performed (procedure 1B) for the alternative lobe within 3 weeks of the first procedure: DC Bead (n = 8) vs. cTACE (n = 5)

Fig. 2

Tumor response at 6 months (LOCF) (MITT population and advanced patient group*^, **). * More advanced disease was at least one of Child-Pugh B, ECOG 1, undergone prior curative treatment (i.e., recurrent disease), and presence of bilobar disease. In accordance with the EASL criteria: complete response (CR)—complete disappearance of all known viable tumor (assessed via uptake of contrast in the arterial phase of the MRI scan) and no new lesions; partial response (PR)—50% reduction in viable tumor area of all measurable lesions; stable disease (SD)—all other cases; progressive disease (PD)—25% increase in size of one or more measurable lesions or the appearance of new lesions. Objective response (OR) was defined as CR + PR, and disease control (DC) as CR + PR + SD. ** Analysis of advanced patient subgroup: OR rate, P = 0.038; DC rate, P = 0.026; CR rate, P = 0.091 (chi-square analysis)

Fig. 3

a Complete response, objective response, and disease control rate (cumulative number [%] of patients) of all patients at 6 months. b Complete response, objective response, and disease control rate (cumulative number [%] of patients) of patients by stratification factors for advanced disease at baseline

Fig. 4

Comparison of treatment groups for-fold changes in liver enzymes by chemoembolization procedure and maximum-fold change across all procedures (mean, 95% confidence interval [CI]). Analysis using t-test for log-transformed data; results back-transformed to ratio scale for presentation. Procedure 1B not shown due to small sample size. a Alanine aminotransferase (ALT): procedures 1 and 2 and maximum across all procedures, P < 0.001; procedure 3, P = 0.004. b Aspartate aminotransferase (AST): procedure 1, P = 0.001; procedure 2 and maximum across all procedures, P < 0.001; procedure 3, P = 0.06