Division of Vascular and Interventional Radiology, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
The Department of Radiology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
Eur J Drug Metab Pharmacokinet. 2022 Jul;47(4):449-466. doi: 10.1007/s13318-022-00762-z. Epub 2022 May 11.
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) and area under the concentration-time curve (AUC) for doxorubicin have still not been systematically reviewed or meta-analyzed.
To conduct a systematic review and meta-analysis of available data and establish a reference range for C and AUC of doxorubicin DEB-TACE and TACE, as well as explore the potential influence of microspheres' size and type on these parameters.
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.
Out of 666 studies, 246 full-text were reviewed, and 8 studies entered the meta-analysis (120 patients). C 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 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, AUC and tumor response rate as well as lower complication rate.
The heterogeneity could not be completely addressed through sensitivity and stratification analysis.
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 and AUC, respectively.
经导管肝动脉化疗栓塞术（TACE）联合载药微球（DEB-TACE）治疗肝细胞癌（HCC）已有近 15 年，多柔比星的平均峰血浆浓度（C）和浓度-时间曲线下面积（AUC）仍未得到系统评价或荟萃分析。
对现有数据进行系统回顾和荟萃分析，建立多柔比星 DEB-TACE 和 TACE 的 C 和 AUC 参考范围，并探讨微球大小和类型对这些参数的潜在影响。
检索 1992 年 8 月至 2021 年 12 月期间的 PubMed、EMBASE 和 Web of Science，纳入未限制语言的 HCC 患者接受多柔比星 DEB-TACE 治疗的暴露参数研究。由 2 名独立审查员提取和统一数据集进行汇总估计分析。采用 Grading of Recommendations Assessment, Development and Evaluation 框架评估证据质量。采用 ClinPK 声明清单和 Newcastle-Ottawa 量表（NOS）评估研究质量。
在 666 项研究中，246 项全文进行了审查，8 项研究进入荟萃分析（120 例患者）。与 TACE 相比，DEB-TACE 时多柔比星的 C 和 AUC 分别降低了 7.52 倍（95%CI 7.65 至 7.42 倍；P<0.0001）和 1.91 倍（95%CI 1.95 至 1.88 倍；P=0.0001）。在直接比较分析中，DEB-TACE 与 TACE 相比，C 和 AUC 的汇总标准化均数差（SMD）显著降低（-2.93；95%CI -3.60 至-2.26，P<0.00001 和-1.73；95%CI -2.55 至-0.91，P<0.0001）。此外，在 DEB-TACE 分层分析中，小粒径微球显示出更高的 C、AUC 和肿瘤反应率以及更低的并发症发生率。
通过敏感性和分层分析仍无法完全解决异质性问题。
本荟萃分析提供了多柔比星的暴露参数，并证明了 DEB-TACE 在治疗不可切除 HCC 患者时的安全性优于 TACE。本研究表明微球大小与多柔比星暴露参数之间存在显著关联，支持在 DEB-TACE 中使用小粒径微球。C 和 AUC 的证据质量分别为中等级别和低等级别。
