Systematic Review and Pharmacokinetic Meta-analysis of Doxorubicin Exposure in Transcatheter Arterial Chemoembolization and Doxorubicin-Eluted Beads Chemoembolization for Treatment of Unresectable Hepatocellular Carcinoma

Background Almost 15 years after the introduction of transarterial chemoembolization (TACE) with drug-eluting beads (DEB-TACE) for hepatocellular carcinoma (HCC) therapy, the mean peak plasma concentration ( C max ) and area under the concentration-time curve (AUC) for doxorubicin have still not been systematically reviewed or meta-analyzed. Objective To conduct a systematic review and meta-analysis of available data and establish a reference range for C max and AUC of doxorubicin DEB-TACE and TACE, as well as explore the potential influence of microspheres’ size and type on these parameters. Methods PubMed, EMBASE, and Web of Science were searched from August 1992 through December 2021. Studies measuring exposure parameters among HCC patients treated with doxorubicin DEB-TACE without restriction on language were included. Two independent reviewers extracted and unified data sets for pooled estimate analysis. The quality of the evidence was assessed via the Grading of Recommendations Assessment, Development and Evaluation framework. The ClinPK Statement checklist and Newcastle-Ottawa Scale (NOS) were used to determine the quality of studies. Results Out of 666 studies, 246 full-text were reviewed, and 8 studies entered the meta-analysis (120 patients). C max and AUC of doxorubicin were 7.52-fold (95% CI 7.65 to 7.42-fold; P < 0.0001) and 1.91-fold (95% CI 1.95 to 1.88-fold; P = 0.0001) lower with DEB-TACE compared to TACE. Significant reduction in pooled standardized mean difference (SMD) of C max and AUC was observed with DEB-TACE versus TACE in direct comparison analysis (− 2.93; 95% CI − 3.60 to − 2.26, P < 0.00001, and − 1.73 95% CI − 2.55 to − 0.91, P < 0.0001, respectively). Moreover, in DEB-TACE stratification analysis, small microspheres revealed higher C max , AUC and tumor response rate as well as lower complication rate. Limitation The heterogeneity could not be completely addressed through sensitivity and stratification analysis. Conclusion This meta-analysis provides exposure parameters of doxorubicin and justifies the advantage of DEB-TACE over TACE in terms of safety for patients with unresectable HCC. This study showed a marked association between the size of microsphere and exposure parameters of doxorubicin supporting the preference for small microspheres in DEB-TACE. The moderate and low quality of evidence is assigned to the C max and AUC, respectively.