Efficacy and safety profile of drug-eluting beads transarterial chemoembolization by CalliSpheres® beads in Chinese hepatocellular carcinoma patients

As the second leading cause of cancer-related deaths worldwide and the predominant histological type of primary liver cancers, hepatocellular carcinoma (HCC) has attracted increasing attention for its poor prognosis due to delay in diagnosis [1]. Although in some part of the world the incidence of HCC was declined due to the identification of high-risk population, such as patients with hepatitis B, unfortunately, the global mortality is still high [2]. What is more, prevalence and mortality were especially high in East and South-East Asia, during 2012, China alone accounted for half of the HCC cases and deaths worldwide [1]. When comes to treatment, curative treatments, including resection, transplantation and local ablative therapies, could only be conducted on patients with early stage HCC, while for patients with advanced HCC the options consist of transarterial therapy, radiotherapy and chemotherapy [3].

Transarterial chemoembolization (TACE) is one major type of transarterial therapies, and the techniques of TACE include embolism of tumor-supplying vessels, which causes ischemia and necrosis of tumors, and infusion of chemotherapy agents [4]. TACE is recommended as a standard therapy for inoperable HCC patients, and conventional TACE (cTACE) is the TACE that combined embolism particles with chemotherapy drug delivery. Although cTACE is frequently applied in clinical practice, the systemic toxicity of chemotherapy drug after treatment cannot be ignored [5, 6]. The drawbacks of cTACE led to its gradual replacement by Drug-eluting beads TACE (DEB-TACE), which is a new technique for chemoembolization using microbeads with diameter ranging from 100 μm to 900 μm, providing more constant drug delivering effect and embolization of stable tumor-supplying arteries. Moreover, DEB-TACE is reported to be more effective and tolerable compared to cTACE in clinical practice [7‐9]. In China, few studies have been performed to evaluate the efficacy and safety of DEB-TACE treatment for patient with HCC, and the strategy on which type of patients will benefit more from DEB-TAC is not well investigated either.

Therefore, our study aimed to investigate the efficacy and safety of DEB-TACE treatment by CalliSpheres® in Chinese patients with HCC as well as the predicting factors for response.

In our study, we discovered that: (1) DEB-TACE treatment for HCC patients was of good efficacy: the CR rate was 16.2%, PR rate was 59.6% and the ORR was 75.8%; (2) subgroup analysis illustrated that patients with higher BCLC stage were of lower CR and ORR, and logistic regression analysis elucidated that more than 3 nodules, higher BCLC stage and previous cTACE history might be associated with worse ORR; (3) liver function of patients recovered at 1–3 months after a rapid worsening at 1 week post treatment. And DEB-TACE was well tolerated in HCC patients, only light and moderate common adverse events in our study were observed.

Drug eluting bead (DEB) plays a crucial role in the technique of DEB-TACE, the DEBs are capable of being impregnated with anti-tumor drugs and continuously delivering the drugs, accomplishing more stable and constant drug concentration [4]. In this study, the CalliSpheres® beads were used in the DEB-TACE procedure, which is the first microbead product in China. The CalliSpheres® beads is a class of mircrobeads made of polyvinyl alcohol hydrogel with different ranges of diameters, and an in vivo experiment elucidates that the doxorubicin concentration in rabbit livers using CalliSpheres® beads was higher than using arterial infusion with a relatively greater delivery distance of 200 μm from the bead edge for over a month [14]. According to previous studies, DEB-TACE shows good efficacy in treating HCC patients, the ORR ranges from 35%~ 84% [15‐18]. A study that was conducted on patients with HCC receiving DEB-TACE therapy elucidates a CR rate of 58% and PR rate of 31%, which is of better CR rate compared to ours [15]. While in the study of Rahman FA et al., 17% patients achieve CR and 22% patients achieves PR, the ORR is 39%, which is lower than ours due to the lower PR rate [16]. And a study that was performed in Korea shows that the CR rate is 32.1%, PR rate is 28.3% and the ORR is 60.4% [18]. The difference in response rate might result from that: (1) the different stages of HCC patients enrolled; (2) DEB-TACE is used as first-line treatment in some of their studies, which might result in a higher response rate; (3) the variant sample sizes among studies may cause different response rate.

Although DEB-TACE is recommended as a standard therapy for HCC patients in BCLC B stage, due to this was an observational study in which the patients enrolled were not selected, thus there were 24% of our patients who were in BCLC stage A. Those patients did not receive DEB-TACE due to they were not qualified, for example, the patients with multiple lesions, poor liver function or financial issues. Besides, there are several studies indicate DEB-TACE could be used for HCC patients in early stage. A single-center, single-arm, retrospective study with a cohort of 421 HCC patients received DEB-TACE also includes 20.9% patients in BCLC stage A and discloses good overall response rates at 3 months (94.5%) and 6 months (99.5%) [19]. Another retrospective cohort study also enrolls 39.4% patients in BCLC stage A, who are not treated by standard treatments or alternative therapies due to ineligible for ablation and post treatment recurrence, shows that the median survival is 54.2 months for patients in BCLC stage A [20].

Personalized treatment of DEB-TACE has now become more and more concerned among oncologists. Although criteria have been made for the prognosis of HCC patients, such as BCLC stage for risk stratify and Child-pugh class for liver function staging, predictive factors for treatment response of DEB-TACE are still not well established. C-arm CT and volume perfusion CT (VPCT) for blood volume assessment have been reported by a prior study that they are able to predict the midterm tumor response of patients [21]. Furthermore, a study illustrates that tumor heterogeneity and tumor enhancement more than 50% are correlated with CR in HCC patients after DEB-TACE therapy [22]. And in the study of Kokabi N et al., they discover that the apparent diffusion coefficients (ADC) at baseline < 0.83 × 10^− 3 mm²/s is a predictive factor for both clinical response and survival of HCC patients after DEB-TACE [23]. In our study, patients with higher BCLC stage were of worse CR and ORR, patients in BCLC stage A and B both presented with impressive treatment response rates, while patients in BCLC stage C were of extremely poor response rate. The results in regard to BCLC stage in this study might be as a consequence of that BCLC staging system assesses the liver function, tumor distribution and patients’ physical status, playing a prognostic role in the management of HCC patients [24]. In the study of Kao WY et al., 1265 treatment-naive HCC patients are enrolled and the result shows that patients in stage 0 and A1 have markedly higher overall survival rates than those in stages A2-A4, however, they do not compare the efficacy among patients in different BCLC stages [25]. For the predictive value of BCLC stage for treatment response, a previous study illustrates that HCC patients with BCLC stage B and C have similar treatment response after chemoembolization therapy [26].

Besides BCLC stage, our study also observed that patients with multiple nodules and previous cTACE history had the trend of exhibiting worse ORR. Multifocal had been well established as a factor for predicting worse prognosis in patients with HCC [27‐29]. And the number of nodules > 3 has been reported as a predicting factor for poor survival of HCC patients after resection [29]. Those results discovered by former studies indicated that the number of nodules may be of good prognostic value, which is partly in line with ours. As for patients with cTACE history, those patients had worse ORR in our study might result from that patients were less sensitive to the DEB-TACE treatment after previous cTACE treatment.

Moreover, the liver function of patients deteriorated rapidly and recovered at 1–3 months after the procedure in our study. A former study has evaluated the liver damage after DEB-TACE, in their study, the liver damage is assessed by image and in 114 patients with HCC, the results validates that the number of patients occurs with global liver damage, overall biliary injuries, intrahepatic biloma and portal vein thrombosis are 42 (36.8%), 37 (32.5%), 19 (16.7%) and 5 (4.4%) [30]. Hepatic artery injury is also a common adverse event in DEB-TACE treatment, it is reported that in 54 HCC patients received DEB-TACE treatment, the number of HCC patients occurred with grade I, II and III hepatic artery injuries are 13 (24.1%), 10 (18.5%) and 31 (57.4%) [31]. Compared to those two former studies, the liver damage in our study was relatively lighter, and the difference might result from that the global liver function of patients at baseline were variant among studies. And the reason why patients had expeditious liver function damage at 1 week might be due to the liver damage caused by the operative injury. Moreover, the recovery of liver function at 1–3 months may be because that patients in our study were mostly with intermediate liver function before operation, which indicated most patients still maintained their self-repair function of livers.

DEB-TACE has been illuminated to be at least as tolerable as cTACE in previous studies, and the adverse events are mostly low grades [16, 32]. And to some extent, DEB-TACE is even better tolerated than cTACE due to no Doxorubicin related systemic toxicity has been observed among patients treated by DEB-TACE [33]. A previous study reports that 7 (13.7%) out of 51 patients that present with complications after DEB-TACE treatment, including decompensation, hepatic vein thrombosis, pancreatitis and post embolization syndrome, the incidence of complication is relatively low [17]. In this present study, the most common adverse events during and post treatment were pain, vomiting, hypertension and fever, among which most of them were light and moderate, which was in consistent with previous studies [16, 17, 32, 33]. Those results in previous studies and ours both demonstrated a good safety by DEB-TACE treatment.

Some limitations still existed in our study: (1) the follow-up time is short, thus long-term efficacy such as overall survival was not analyzed in this study. (2) Most patients (97%) in this study had treatment history, so the efficacy and safety of CalliSpheres® DEB-TACE in treatment-naïve HCC patients could not be evaluated. (3) The sample size in our study was relatively small, which is mainly due to that the DEB-TACE treatment and the new product used in our study, the CalliSpheres® beads, are still not widely applied in clinical practice in China.

In conclusion, DEB-TACE by CalliSpheres® was efficient and well tolerated in Chinese HCC patients, and BCLC stage, number of nodules and cTACE history were possibly correlated with treatment response.