Efficacy and safety of drug-eluting bead transarterial chemoembolization (DEB-TACE) plus apatinib versus DEB-TACE alone in treating huge hepatocellular carcinoma patients

Huge hepatocellular carcinoma (HCC), defined as tumor size above 10 cm in diameter, places a dramatic disease burden since management options are currently limited, and it usually presents with unfavorable survival [1‐6]. For instance, most huge HCC patients experience tumor invasion and intrahepatic metastasis, which misses the opportunity of surgical resection as the curative treatment [2, 5, 6]. Consequently, transarterial chemoembolization (TACE) is commonly applied in treating huge HCC patients [7‐9]. Despite displaying certain efficacy and safety, TACE may cause disease progression and result in an unfavorable survival profile in huge HCC patients due to neoangiogenesis arising from the hypoxic environment of tumor blood vessels [8‐10]. Hence, developing novel therapies to improve the prognosis of huge HCC patients is urgent and necessary.

Apatinib, a tyrosine kinase inhibitor selectively targeting vascular endothelial growth factor receptor-2 (VEGFR-2), may synergize with TACE in treating HCC patients via inhibiting angiogenesis in the tumor hypoxic environment caused by TACE [10‐13]. For instance, TACE plus apatinib achieves better short-term and long-term treatment efficacy as well as similar incidence of adverse events compared to TACE alone in treating advanced HCC patients, recurrent HCC patients, and huge HCC patients [14‐18]. Drug-eluting bead TACE (DEB-TACE), as an improved and innovated type of TACE, utilizes non-absorbable microspheres as embolic agent and drug-loaded material to the target tumor region in treating HCC patients [19]. Moreover, DEB-TACE exhibits several advantages over conventional TACE (such as improved embolic effect, less safety issue, better loading and releasing profile etc.) [19]. Few studies apply DEB-TACE plus apatinib in treating huge HCC patients.

Thus, this study aimed to compare the efficacy and safety of DEB-TACE plus apatinib versus DEB-TACE alone in huge HCC patients.

DEB-TACE is developed as an improved technique over conventional TACE since it exhibits several advantages: (a) DEB-TACE enables a controlled manner of releasing loaded drug, (b) DEB-TACE increases intratumoral concentration and achieves a better anti-tumor effect, (c) DEB-TACE realizes an improved embolic effect by using non-soluble microspheres, (d) DEB-TACE is more convenient and feasible in the clinical practice, (e) the drug-loading speed and amount of DEB-TACE is better, and (f) DEB-TACE preciously targets HCC tumor tissue and reduces the systematic cytotoxicity [19]. However, due to enhanced tumor angiogenesis from hypoxic tumor environment caused by DEB-TACE, increased risk of disease progression and tumor recurrence in HCC patients has been reported [10, 22]. The emergence of apatinib suppresses this DEB-TACE-induced angiogenetic process arising from hypoxia tumor environment, implying its ability to synergize with DEB-TACE in HCC patients. No study compares the treatment response of DEB-TACE plus apatinib with DEB-TACE alone in huge HCC patients. In the current study, we observed that DEB-TACE plus apatinib achieved a trend of higher ORR and clinical response rate but similar DCR as DEB-TACE alone in huge HCC patients, which could be explained as that (a) the sample size of the current study was limited, leading to a low statistical power; thus, these results were not statistically significant. (b) The obvious effect of apatinib on inhibiting angiogenesis might require an accumulating period of time, which implied that 6–10-week duration was relatively short for its treatment response evaluation.

Previous study illustrates that TACE plus apatinib realizes an increased OS than TACE alone, also TACE plus apatinib (vs. TACE alone) is independently correlated with longer OS in HCC patients with macroscopic vascular invasion [14]. Moreover, several studies also exhibit that TACE plus apatinib achieves a favorable survival profile compared to TACE alone in treating advanced unresectable HCC patients, while none of them applies DEB-TACE for therapy [15‐18]. Regarding DEB-TACE plus apatinib in intermediate-to-advanced HCC patients (BCLC stage B/C), DEB-TACE plus apatinib achieves a PFS of 9.5 months (95% CI: 8.1–10.9 months) and OS of 22.0 months (95% CI: 20.2–23.9 months), but it is a single-arm study which lacks a control group [23]. In the present study, we revealed that DEB-TACE plus apatinib exhibited a median PFS of 19.0 months (95% CI: 15.5–22.5 months) and median OS of 25.1 months (95%CI: 20.3–29.9 months), which were obviously favorable than DEB-TACE alone therapy in treating huge HCC patients. Also, DEB-TACE plus apatinib (vs. DEB-TACE) could independently correlate with prolonged PFS and OS, which could be explained as that (a) apatinib inhibited the angiogenesis caused by DEB-TACE, and thereby led to a synergetic effect of DEB-TACE plus apatinib in huge HCC patients [24]. Thus, DEB-TACE plus apatinib might reduce risk of disease progression and recurrence, and thereby resulted in a favorable prognosis. (b) DEB-TACE plus apatinib exhibited a numerical higher ORR than DEB-TACE alone and thus led to an improved survival profile in huge HCC patients.

Apart from the efficacy, the safety issue of TACE plus apatinib is of great attention in treating HCC patients as well. For instance, TACE plus apatinib induces a similar incidence rate of adverse events as TACE alone in advanced HCC patients (including fever, abdominal pain, nausea/vomiting, hypertension, hand-foot syndrome, diarrhea etc.) [16]. Regarding the safety of DEB-TACE plus apatinib, it induces moderate and manageable adverse events in advanced HCC patients; also, it does not influence liver function indexes [23]. In the present study, we observed that DEB-TACE plus apatinib showed a similar incidence rate of adverse events as DEB-TACE alone in huge HCC patients. ALT level was slightly elevated after therapy in huge HCC patients received DEB-TACE plus apatinib compared to those received DEB-TACE alone, which could be explained as that apatinib selectively inhibited cytochrome P450 enzyme (such as CYP2B6/2B1 and CYP2D6/2D1), which might lead to an impaired liver function and slight elevation of ALT level in huge HCC patients [25].

There were some limitations in the current study. For example, the sample size of the current study was relatively small; also, this study was a retrospective study, which might cause patient selection bias; thus, further prospective study with larger sample size to validate our findings in huge HCC patients was necessary. Moreover, apatinib-induced adverse events (such as abnormal coagulation indexes, proteinuria etc.) and the grade of adverse events were not recorded in the present study; therefore, further study could focus on this point. Furthermore, the treatment option after disease progression was not recorded since most huge HCC patients did not live in the local region requiring long-distant travelling to our hospital.

In conclusion, DEB-TACE plus apatinib achieves prolonged PFS and OS, while similar adverse event occurrence compared to DEB-TACE alone in huge HCC treatment.