Comparison of drug-eluting bead transcatheter arterial chemoembolization (TACE) versus conventional TACE for hepatocellular carcinoma with portal vein thrombus

Despite advances in imaging modalities, as well as improved surveillance, many patients with hepatocellular carcinoma (HCC) present with advanced disease characterized by large tumours and concomitant portal vein tumour thrombus (PVTT). Without treatment, this population of patients with HCC and PVTT have a median survival of only 2.7 to 4 months (1,2). The American Association for the Study of the Liver Diseases (AASLD) and European Association for the study of the liver (EASL) guidelines categorize patients with HCC and PVTT as Barcelona Clinical Liver Cancer Criteria (BCLC) stage C and recommends systemic chemotherapy with sorafenib or newer systemic agents (1-4). Treatment of patients with HCC and PVTT remains somewhat controversial, however. In particular, treatment strategies for this group of patients can vary significantly in Western versus Eastern centres. For example, some data from Asian-Pacific have suggested that treatment strategies based on precise stratification of HCC with PVTT who underwent resection and removal of PVTT had acceptable long-term outcomes at centres of excellence (1). Locoregional therapy with transarterial chemotherapy (TACE) has also been suggested as a means to deliver chemotherapeutic agents directly to the tumour site and induce necrosis through embolic agents to improve long-term outcomes (5). The BCLC recommends TACE for patients with BCLC stage B for bridging/downstaging to live transplantation, or other stage disease that may not be suitable for hepatic resection as palliative treatment (1,6). Utilization of TACE patients with unresectable HCC with PVTT is more debate as there is a lack of evidence as to whether classic chemotherapy-based TACE (C-TACE), drug eluting bead TACE (DEB-TACE), or degradable starch microsphere TACE (DSM-TACE) may be preferred in the setting of PVTT (6).

The principal technique of C-TACE involves the mixture of a chemotherapeutic drug with an embolic agent with subsequent injection into the HCC feeding artery. This technique also blocks the blood flow to the tumour causing the chemotherapeutic drug to remain inside the tumour (6,7). DEB-TACE utilizes drug-eluting microspheres loaded with a chemotherapeutic drug. The drug-eluting microspheres are delivered selectively to the feeding vessels of the HCC. The principal advantage of this method is a more controlled release within the tumour and minimization of systemic exposure and consequently adverse events (8).

DSM-TACE uses chemotherapeutic drug as an embolic agent in combination with degradable starch microspheres (9). To date, the available evidence has not definitively determined which approach may be optimal, resulting in heterogenous practice patterns at different institutions. For example, Ferrer et al. and Sacco et al. reported statistically non-significant differences between the DEB-TACE and C-TACE (10,11). While there is no statistical variance between the two treatments in other options, specific treatments like immune checkpoint inhibitors (ICIs) or tyrosine kinase inhibitor (TKI) could lead to varying outcomes. Moreover, Burrel et al. noted that DEB-TACE was associated with a slightly better response rate (59.5% vs. 55.4%) (12). In another study, Schindler et al. compared data from a retrospective single-centre cohort of 192 patients to examine safety, tumour response, and progression-free survival (PFS) among patients treated with C-TACE, DEB-TACE, and DSM-TACE. Of note, there was a slight increase in the bilirubin and in lactate dehydrogenase among patients treated with DEB-TACE 4–6 weeks post-TACE, as well as more adverse events. DSM and DEB-TACE demonstrated higher disease control rates compared with conventional TACE especially in the setting of bridging/downstaging; there were no differences in PFS among the three cohorts (6). The authors concluded that DEB-TACE was associated with more adverse events and had a more profound impact on liver function. Therefore, use of DEB84 TACE among patients with impaired liver function with PVTT should be avoided. Brown et al. comparing embolisation using microspheres alone vs. chemoembolization using doxorubicin demonstrated no apparent difference. Therefore, these results challenge the use of doxorubicin (13).

In a recent report by Zhou et al. preformed a single-centre randomised controlled trial of 163 patients with HCC and PVTT in which PFS, response rate and adverse events of C-TACE and DEB-TACE were compared. The cohort consisted of 91% of men, which may have biased the results and limited the generalizability of the study findings. Of note, the strengths of Zhou et al. research was based on the fact that both intention to treat (ITT) and per protocol (PP) analysis were done throughout and the data were consistent in both directions. Notwithstanding this limitation, DEB-TACE was associated with a better PFS and overall survival, as well as response rate compared to C-TACE cohort (14). On multivariate analysis, four independent prognostic factors were associated with PFS: albumin-bilirubin (ALBI) score, distant metastasis, treatment with tyrosine kinase inhibitors, as well as utilization of DEB-TACE. The median PFS in the DEB-TACE group was 6.0 months [95% confidence interval (CI), 5.0 to 10.0] versus 4.0 months (95% CI, 3.0 to 5.0) in the C-TACE group (hazard ratio, 0.63; 95% CI, 0.42 to 0.95; P=0.02). The DEB-TACE group demonstrated a higher response rate [51 (66.2%) vs. 36 (46.8%); P=0.001] and a longer median OS [12.0 months 98 (95% CI, 9.0 to 16.0) vs. 8.0 months (95% CI, 7.0 to 11.0), P=0.03] than the C-TACE group. The most frequent adverse event was post-embolisation syndrome, which occurred with a roughly equivalent incidence among patients in the C-TACE versus DEB102 TACE groups (14). These results were somewhat at odds with data from previous studies (6,14). As note, data from Schindler et al. had suggested that DEB-TACE was more likely to be associated with adverse events among patients with HCC and PVTT, especially in the setting of abnormal liver function tests (6). The reasons for these disparate results are likely multifactorial. Importantly, the study by Schindler et al. was retrospective in nature, while the Zhou et al. report was based on prospective randomized data. As such, the level of evidence would seemingly be higher in the latter study. However, despite randomization, the clinical characteristics of patients in the Zhou et al. study remained imbalanced (14). For example, patients who had C-TACE had larger tumours, higher liver tumor burden, and more instances of hepatic vein involvement. As such, the C-TACE group had more extensive, advanced disease, which likely biased the results in favor of DEB-TACE. The authors also did a job of ensuring that the grade of portal vein invasion was similar in the C-TACE versus DEB-TACE groups. The equalization of clinicopathologic features in the two study groups (i.e., C-TACE vs. DEB-TACE) likely “failed” due to the relatively small sample size and inadequate power in the study. As such, the current evidence cannot definitively inform whether C-TACE or DEB-TACE is optimal for patients with HCC and PVTT. In turn, decisions around locoregional therapy for patients with HCC and PVTT should be individualized and be based on size of the tumor, extent of PVTT, as well as baseline liver function. In the future, multicenter randomised controlled trials are needed to define further the optimal endovascular therapeutic approach to patients with HCC and PVTT.

Acknowledgments

Funding: None.

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