Five-year outcome of conventional and drug-eluting transcatheter arterial chemoembolization in patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and the sixth most common cancer [1, 2]. Due to chronic liver infection resulting from the high incidence of hepatitis C infection and the large number of persons with metabolic syndrome, the incidence of HCC is anticipated to rise [1, 2]. A large percentage of HCC patients are diagnosed at the intermediate or advanced stage [3, 4]. Currently, no established standard of care or therapeutic possibilities exist for patients with advanced HCC. Only 30 to 40% patients with HCC are candidates for curative treatment such as liver transplant [3, 4]. Hence, most patients can only be treated with locoregional or palliative treatment [5].

Transcatheter arterial chemoembolization (TACE) is used as a palliative local therapeutic option for patients with nonresectable HCC who may be waiting for liver transplant or who are not candidates for liver transplantation. TACE is also used to decrease the tumor burden, allowing for tumor resection [6]. Conventional TACE (cTACE) involves the delivery of embolic material to the tumor plus chemotherapeutic agents such as doxorubicin, either dissolved or emulsified in lipiodol, which is noted for causing both ischemia and strong cytotoxic effects [2, 7]. Lipiodol is a lymphographic agent which is selectively deposited in HCC tumors by arterial infusion and permits the slow release of the chemotherapeutic agent into the tumor [8‐10]. In randomized controlled trials, cTACE has demonstrated a survival benefit for HCC patients with nonresectable HCC [11‐14] and is recommended as a standard treatment option for patients with Barcelona stage B (BCLC) (intermediate stage) HCC [15, 16]. However, with TACE, the tumor does not always retain the lipiodol, resulting in decreased effectiveness of therapy and risk of liver damage [17, 18].

Drug-eluting beads (DEB) have been introduced into TACE (DEB-TACE) to promote the controlled release of cytotoxic drugs for the treatment of HCC [19, 20]. The drug-eluting microspheres added to TACE result in the delivery of high concentration of chemotherapeutic drugs to the tumor. The use of DEB-TACE is associated with a better safety profile than cTACE; DEB-TACE has been observed to have a lower incidence of adverse events such as abdominal pain, fever, nausea and vomiting [21‐24]. A number of clinical studies and meta-analyses have found that DEB-TACE was associated with a significant advantage in tumor response and survival compared with cTACE [21‐24]. However, several recent studies failed to demonstrate the superiority of DEB-TACE over cTACE in treatment efficacy, although DEB-TACE was associated with a better safety profile than cTACE [25‐28].

Although DEB-TACE has shown benefits relative to TACE in some randomized controlled studies, the method is still controversial in clinical practice. Early results of our study of DEB-TACE and cTACE published in 2015 [29] showed that, at a mean follow-up of 15 months, DEB-TACE was associated with a better safety profile and more patients achieved a complete response and fewer had disease progression than cTACE. The present retrospective study evaluated the long-term benefits of DEB-TACE and cTACE on disease progression and overall survival (OS) during 5-year follow up of patients with HCC.

This retrospective study recruited consecutive patients with HCC who were treated with TACE at the National Cheng-Kung University Hospital (Tainan, Taiwan) from November 2010 to November 2011. The retrospective analysis was approved by the Ethics Committee of the institutional review board, National Cheng Kung University Hospital (IRB No: A-ER-103-311). The study was performed in accordance with the Declaration of Helsinki and the protocol was reviewed and approved by the Institutional Review Board of the hospital. All patients provided signed informed consent.

This retrospective, observational study compared clinical outcomes of treatment-naive HCC patients who underwent cTACE (conventional TACE) or DEB-TACE (drug-eluting bead TACE). The earlier published findings from the 15-month follow-up of this study population showed that DEB-TACE treatment resulted in a higher percentage of patients with complete response and a lower percentage with disease progression than patients receiving cTACE treatment [29]. In addition, DEB-TACE was associated with a better safety profile than cTACE [29]. The data presented here are those of the same study after 5-years of follow-up. Five-years after treatment, both treatments were associated with a survival time of 37 months. However, over the 5-year follow-up period, a greater percentage of patients treated with cTACE died (76.1%) than those treated with DEB-TACE (66.7%) (P = 0.045). After five-years, all surviving patients had disease progression. However, the time to disease progression differed between groups; cTACE was associated with a shorter median time to disease progression (11 months) than DEB-TACE (16.0 months) (P = 0.019). Subgroup analysis indicated that survival and disease progression were similar for both treatments in patients with BLCC stage A or stage B + C, and in patients with > 5 tumors, or if the diameter of the patient’s five largest tumors was > 7 cm. The findings of the long-term study suggest that DEB-TACE demonstrates long-term benefits in treating treatment-naive HCC patients.

Only a limited number of studies have directly compared the efficacy and safety of DEB-TACE and cTACE in treating HCC. A number of systematic reviews and meta-analyses have evaluated the effectiveness of cTACE and DEB-TACE in treating HCC [21‐24].

Similar to our findings, several of the meta-analyses found DEB-TACE to show treatment benefit and better safety profile compared with cTACE [23, 24]. A systematic review by Martin et al. [21] found DEB-TACE had a significant advantage compared with cTACE in objective response and had greater overall disease control in patients with advanced HCC (P values ≤0.038). Zhou et al. performed a meta-analysis which included nine studies and total of 830 patients [24]. The study found DEB-TACE significantly improved overall survival and increased objective response and disease control rates. Similarly, a meta-analysis performed by Huang et al. [23], which included seven clinical studies with 700 patients, found a significantly better objective response for DEB-TACE than cTACE (P = 0.004), with a relative risk difference of 0.15 (P = 0.0003). Those authors also found that patients with one- and two-year survival were significantly more with DEB-TACE than with cTACE (P values ≤0.007). However, Huang et al. found no difference between treatments for 6-month and 3-year survival (P values ≥0.11). A meta-analysis by Zou et al. [22] found DEB-TACE was associated with higher complete response (Odds ratio [OR], 1.35), overall survival rate (OR, 1.41), and survival time (WMD, 3.03). In contrast to the studies of Huang et al. and Zhou et al., Zou et al. found no difference between treatments for objective response. Those authors also found that the treatments had similar disease control rates. All four meta-analyses found that DEB-TACE was associated with fewer side effects compared with cTACE.

In contrast to the above results, a meta-analysis performed by Facciorusso et al. [25] found that DEB-TACE and cTACE had similar safety and effectiveness. Facciorusso et al. included 12 studies, four of which were randomized controlled trials. The meta-analysis included a total of 1449 patients. The observed 1-, 2- and 3-year survival times were similar between treatment groups (P values ≥0.06). Pooled data of objective response and incidence of adverse events also indicated no differences between the two therapies (P values ≥0.36). However, the study did show a non-significant trend of superiority for DEB-TACE for overall response rate (OR, 1.2), which was confirmed by subgroup and sensitivity analysis.

The difference in findings across the meta-analyses may, in part, reflect the small number of included studies and high heterogeneity in the studies overall. Moreover, the evaluation of response rate across the studies varied, with some of the included studies used EASL criteria and others using mRECIST criteria. In addition, length of follow-up was heterogeneous among the included studies and was found to be one of the main sources of heterogeneity. The present study supports the importance of follow-up in comparing studies. In an earlier phase of the present t study conducted at 15 months post-treatment, DEB-TACE treatment was associated with patients’ greater complete response and less disease progression than cTACE. However, at the 5-year follow-up, all surviving patients had disease progression but fewer patients treated with DEB-TACE had died.

In conclusion, DEB-TACE shows greater long-term benefit compared with those of cTACE in treating treatment naïve patients with HCC. At 5 years after treatment, HCC patients receiving DEB-TACE have fewer deaths and a longer time to disease progression than patients receiving cTACE. DEB-TACE is also associated with fewer treatment-related adverse events than cTACE. Results of this long-term study support the use of DEB-TACE in treating HCC.