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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 7  |  Page : 1582-1587

Efficacy and safety of drug-eluting bead-transcatheter arterial chemoembolization using 100–300 μm versus 300–500 μm CalliSpheres microspheres in patients with advanced-stage hepatocellular carcinoma


1 Department of Interventional Therapy, The Affiliated Hospital of Qingdao University, Qingdao, China
2 Department of Interventional Therapy, Rizhao Central Hospital, Qingdao, China
3 Department of Radiology, Qingdao Women and Children's Hospital, Qingdao, China
4 Department of Abdominal Ultrasound, The affiliated Hospital of Qingdao University, Qingdao, China
5 Qingdao Center for Disease Control and Pervention, Qingdao, China

Date of Submission28-Apr-2020
Date of Decision13-Jul-2020
Date of Acceptance01-Oct-2020
Date of Web Publication9-Feb-2021

Correspondence Address:
Yanhua Wang
Department of Interventional Medical Therapy, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_543_20

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 > Abstract 


Purpose: To evaluate the efficacy and safety of drug-eluting bead-transcatheter arterial chemoembolization (DEB-TACE) using 100–300 μm versus 300–500 μm CalliSpheres microspheres (CSMs) for treating multiple hepatocellular carcinoma (HCC) with the largest nodule measuring between 5 and 10 cm.
Methods: Eighty-one advanced-stage HCC patients treated by DEB-TACE between January 2017 and March 2020 were retrospectively analyzed. There were 48 patients in the 100–300 μm group and 33 patients in the 300–500 μm group. Treatment response, liver function tests, and complications were compared between the two groups.
Results: At 6 months, the response rates in the 100–300 μm group were higher than those in the 300–500 μm group (P < 0.05). Disease control rates in the 100–300 μm group were higher than those in the 300–500 μm group at 1, 3, and 6 months (P < 0.05). Progression-free survival (PFS) and overall survival (OS) were longer in the 100–300 μm group (P < 0.05). Visual analog score points were higher in the 300–500 μm group (P < 0.05). There were no significant differences in complications between the two groups.
Conclusion: The use of small-diameter CSMs in multiple HCC with the largest nodule size of 5–10 cm provides better treatment response and longer PFS and OS for treating advanced-stage HCC.

Keywords: Advanced-stage of hepatocellular carcinoma, CalliSpheres microspheres, drug-eluting beads, transcatheter arterial chemoembolization


How to cite this article:
Yang T, Qin W, Sun X, Wang Y, Wu J, Li Z, Ji F, Zhang L, Liu W. Efficacy and safety of drug-eluting bead-transcatheter arterial chemoembolization using 100–300 μm versus 300–500 μm CalliSpheres microspheres in patients with advanced-stage hepatocellular carcinoma. J Can Res Ther 2020;16:1582-7

How to cite this URL:
Yang T, Qin W, Sun X, Wang Y, Wu J, Li Z, Ji F, Zhang L, Liu W. Efficacy and safety of drug-eluting bead-transcatheter arterial chemoembolization using 100–300 μm versus 300–500 μm CalliSpheres microspheres in patients with advanced-stage hepatocellular carcinoma. J Can Res Ther [serial online] 2020 [cited 2021 Mar 5];16:1582-7. Available from: https://www.cancerjournal.net/text.asp?2020/16/7/1582/308769




 > Introduction Top


China has the largest number of patients with hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV) infections. HCC is the fourth most common malignancy and the second cancer-related cause of death in China.[1] Approximately, 70% of patients are diagnosed with an advanced-stage of this cancer, thus missing the chance of undergoing surgical resection.[2]

Transcatheter arterial chemoembolization (TACE) is an effective therapy for unresectable HCC.[3],[4] Conventional TACE (cTACE) usually uses emulsions of lipiodol as the significant embolization material mixed with epirubicin or other chemotherapeutics. However, considering the abundant blood supply around the HCC, emulsions of lipiodol and chemotherapeutics cannot be retained for long periods in target tissues, thus causing systemic adverse events.[5]

To improve efficacy and reduce complications, CalliSpheres microspheres (CSMs), as a new embolic material, can slowly release chemotherapeutics and permanently embolize the target vessels. Over the years, drug-eluting bead-TACE (DEB-TACE) has been widely used for treating HCC. For short-term use, the DEB-TACE is considered a better treatment compared to cTACE. Several studies have demonstrated that DEB-TACE has better efficacy and is equally tolerated compared to cTACE.[6],[7],[8] However, so far, no studies regarding DEB-TACE using CSMs for the treatment of advanced-stage HCC have been reported. CSMs with 100–300 μm and 300–500 μm are commonly used for cancer therapy. In theory, for HCC at advanced stage, 100–300 μm CSMs can embolize distal branches of the tumor-supplying vessels to achieve a better embolization effect, but this procedure is accompanied by an increased risk, complications, and cost. However, 300–500 μm CSMs can usually accomplish embolization at a smaller dosage.

This study compared the efficacy and safety of DEB-TACE using 100–300 μm versus 300–500 μm CSMs for treating patients with advanced-stage HCC.


 > Methods Top


Patients

This retrospective cohort study included 81 patients with advanced-stage HCC who underwent the therapy of DEB-TACE in the Affiliated Hospital of Qingdao University, China, between January 2017 and March 2020. The inclusion criteria were as follows: (1) patients diagnosed with poorly differentiated primary HCC confirmed by pathological findings according to the American Association for the Study of Liver Diseases guidelines; (2) Stage B or above according to the Barcelona-clinic liver cancer (BCLC); (3) with multitumor, defined as 3 or more tumor focuses, and with largest nodule size, defined as 5–10 cm at the same time; (4) those who received DEB-TACE using 100–300 μm or 300–500 μm CSMs mixed with 80 mg epirubicin.

The exclusion criteria were the following: diagnosed with secondary liver cancer or combined with other sites of the malignant tumor; received any prior treatment; incomplete or misplaced medical records during follow-up.

After sorting, 48 patients who underwent DEB-TACE using 100–300 μm CSMs were assigned to the 100–300 μm group, while 33 patients who underwent DEB-TACE using 300–500 μm CSMs were assigned to the 300–500 μm group. These patients were grouped based on preoperative liver function and imaging findings. A suitable CSM size was decided by experienced interventional radiologists. All DEB-TACE procedures were super-selective by interventional radiologists with a similar skill level. This study was approved by the Ethics Committee of the Affiliated Hospital of Qingdao University. All patients or their legal guardians provided written informed consent.

Baseline characteristics collection

Several medical records as the baseline characteristics were obtained: age and gender; history of alcohol consumption, HBV infections, and cirrhosis; disease characteristic, including focus location, focus distribution, the largest nodule size, portal vein invasion, hepatic vein invasion, extrahepatic disease, alpha-fetoprotein (AFP), blood routine indexes, liver function indexes, the Eastern Cooperative Oncology Group (ECOG) performance status, BCLC stage, and Child–Pugh stage.

Drug-eluting bead-transcatheter arterial chemoembolization procedure

After the local disinfection of the right inguinal, anesthesia was induced using 2% lidocaine. Percutaneous right femoral artery puncture intubation was performed using the modified Seldinger technique. For digital subtraction angiography guidance, a 5F RH-Catheter (Terumo, Japan) was placed into the celiac trunk through 5F vascular sheath (Terumo, Japan) to perform angiography to define the tumor locations, sizes, and numbers. Then, a 2.5F microcatheter (Boston science, America) was super-selectively introduced into the tumor-feeding artery and corresponding regional artery according to the imaging examination for angiography to identify tumor blood supply, portal vein thrombus, and hepatic arteriovenous fistula. If an arteriovenous fistula existed, a minute quantity of 150–350 μm gelatin sponge particles (Alicon, China) was used for embolizing fistula. Subsequently, CSMs (Jiangsu Hengrui Medicine Co. Ltd, Jiangsu, China) with sizes of 100–300 μm or 300–500 μm were used as embolization material and a carrier to load 80 mg epirubicin. After 30 mins of mixing, CSMs were fully loaded with epirubicin. Subsequently, CSMs were slowly and carefully injected into the tumor-feeding artery under fluoroscopic monitoring and intermittent angiography, until the blood flow is reduced with no tumor display through angiography. If the tumor was present after the injection of one bottle of CSM, 300–500 μm blank microspheres would be used as supplementary embolization. Finally, angiography was performed to evaluate the embolization of the tumor-feeding vessels.

Assessment of efficacy and safety

According to the modified Response Evaluation Criteria in Solid Tumors, treatment response and survival were evaluated by enhanced computed tomography examination 1 month after DEB-TACE and were classified as a complete response, partial response, stable disease, and progressive disease.

Patients were monitored until June 2020 with a median follow-up duration of 9.31 months (range, 1.5–27.0 months). Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were also calculated. AFP was considered a significant index to assess efficacy.

During hospitalization and 1-month follow-up after DEB-TACE, liver function indices such as albumin (ALB), total bilirubin (TBIL), total bile acid, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were used as one of the evaluation indicators. Blood routine indexes such as white blood cell, red blood cell, absolute neutrophil count, hemoglobin and platelet (PLT), blood creatinine concentration, hospital stay, complications, and adverse events (pain, fever, nausea, or vomiting) were also considered as assessment indicators.

Statistical analysis

The SPSS Statistic Package 25.0 (IBM, Chicago, IL, USA) was used for statistical analyses. All data of continuous variables were expressed as mean ± standard deviation. A comparison between groups was performed using the Chi-square test and t-test. Survival analysis was performed by the Kaplan–Meier method and the log rank test. Univariate and multivariate Cox proportional-hazards regression analysis was used to analyze the factors affecting PFS and OS. P < 0.05 was considered to be statistically significant.


 > Results Top


Baseline characteristics

There was no difference in age, gender, history of drinking, history of HBV infections, history of cirrhosis, ECOG performance status, BCLC stage, and Child–Pugh stage, with the largest nodule sizes between groups [P < 0.05, [Table 1]]. Median PLT was within the normal range (100–300 × 109 L) in both groups; however, it was lower in the 100–300 μm group compared with a 300–500 μm group (P = 0.042) The other blood routine indexes and liver function indexes were not significantly different. In summary, the baseline characteristics of the patients were nearly similar between groups.
Table 1: Baseline characteristics of patients with advanced-stage hepatocellular carcinoma

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Treatment response

As shown in [Table 2], the DCR showed better efficacy in the 100–300 μm group compared to the 300–500 μm group at M1 (87.5% vs. 75.8%, P < 0.001), M3 (66.7% vs. 42.4%, P < 0.001), and M6 (45.8% vs. 12.1%, P < 0.001). The ORR also showed that the 100–300 μm group was at a higher level at M3 (56.3% vs. 30.3%, P < 0.001) and at M6 (12.5% vs. 0%, P < 0.001). However, there was a better efficacy in total treatment response at M6 (P = 0.003). In addition, at M1, AFP decreased in the 100–300 μm group compared to the 300–500 μm group (66.7% vs. 51.5%, P = 0.218).
Table 2: Treatment response between the 100-300 and 300-500 μm groups

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Comparison of progressive-free survival and overall survival

Using the Kaplan–Meier curves and log rank tests, the 100–300 μm group showed longer PFS [271.5 vs. 128.1 days, P = 0.001, [Figure 1]a] and longer OS [664.7 vs. 334.3 days, P = 0.001, [Figure 1]b] than the 300–500 μm group. PFS and OS between groups using the Kaplan–Meier curves and log rank test are shown in [Table 3].
Figure 1: (a and b) PFS and OS between groups. The comparison was determined by Kaplan–Meier curves and log rank test. PFS and OS were favorable in the DEB-TACE group. DEB-TACE=Drug-eluting bead transcatheter arterial chemoembolization, PFS=Progression-free survival; OS=Overall survival

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Table 3: Progressive-free survival and overall survival between the 100-300 and 300-500 μm groups using the Kaplan-Meier curves and log rank test

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Comparison of changes in blood examination index after drug-eluting bead-transcatheter arterial chemoembolization and postembolization syndrome between the 100–300 μm and 300–500 μm groups

Differences in ALT and TBIL, ALT, and TBIL increased in both groups but were more pronounced in the 300–500 μm group compared to the 100–300 μm group [64.74 vs. 46.28 in ALT, P = 0.037; 13.94 vs. 23.93 in TBIL, P = 0.001, [Table 4]]. In addition, a minor reduction in ALB was observed in both groups.
Table 4: Change in blood examination index after D-transcatheter arterial chemoembolization for evaluating safety

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As for the postembolization syndrome, postprocedure pain was evaluated by the visual analog score (VAS) point [6.3 vs. 6.8, P = 0.035, [Table 5]]. However, there was no difference in the other indices between the two groups; fever was recorded after the procedure (37.61°C vs. 37.93°C, P = 0.204). During hospitalization, the patients had nausea/vomiting (31.3% vs. 30.3%, P = 0.928). The average hospital stay was recorded as 4.82 days vs. 5.11 days (P = 0.260).
Table 5: Postembolization syndrome between the 100-300 and 300-500 μm groups

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 > Discussion Top


The embolic material used in cTACE involves emulsions of lipiodol, which usually disappears from local tumor target within months, probably by tumor collateral circulation, thus decreasing efficacy.[9] Several studies have revealed that DEB-TACE achieved better short-term treatment response, higher ORR, and longer PFS compared to cTACE.[6],[10],[11] The embolic material used in this study was CSMs, which produced higher concentrations of epirubicin in targeted tissues, as shown by animal experiments. As for patients with advanced-stage HCC, short-term treatment response is of great importance.

The embolic material has several diameter-related specifications. Customary, for larger tumor size and tumor quantity, a larger size of embolization material should be used.[5] To explore whether this principle applies to D-TACE, we used two kinds of CSMs with common sizes (100–300 μm and 300–500 μm) for comparison in multiple and large (5–10 cm) HCCs, both of which proved to have certain advantages. In theory, 100–300 μm CSMs had more than 448,000 units of embolic material within one dose, which means that it could enter the branches of finer tumor vessels and achieve denser embolization. Moreover, CSM can carry more than 90% concentrations of chemotherapeutics after 30 min of absorption, which is >300 μm CSM. Meanwhile, 300–500 μm CSM has more than 25,000 units of embolic material within one dose, which displays good embolic efficacy and safety for treating abundant blood supply vessels of HCC.[12] Compared with 100–300 μm CSM, fewer doses are necessary to achieve complete embolization under the same conditions, which reduces the financial burden of patients. During this study, approximately 76.5% of lesions were embolized completely by one bottle of CSM; the observed differences were not statistically significant between groups (14 [29.2%] vs. 5 [15.2%], P = 0.144).

In this retrospective study, one of our main findings was that during 6 months of follow-up, D-TACE using the 100–300 μm CSM group had a better response than D-TACE using the 300–500 μm CSM group in advanced-stage HCC. At 6 months, the death rate was also significantly lower in the 100–300 μm CSM group than the 300–500 μm CSM group (20.8% vs. 60.6%, P < 0.05), which revealed that the denser embolization in fine branches of tumor vessels can inhibit the occurrence of new blood vessels for a longer period. Using the 100–300 μm CSM in DEB-TACE not only achieves a better embolization effect but also decreases hepatic artery injury by more selective tumor embolization. In some patients with diffuse HCC, injecting CSM in the common hepatic artery at slow speed would also get good treatment response due to tumor siphonage.[13] Simultaneously, our results revealed that ORR and DCR were similar at 1–3 months between the two groups, which might be related to the incomplete collateral circulation and recanalization of tumor vessels. Further, PFS and OS were longer in the 100–300 μm CSM group, which means that using CSM of small diameter to obtain a denser embolization in the tumor vessels is more conducive for the long-term prognosis of multiple HCC with the largest nodule size ranging between 5 and 10 cm.

In this study, we found that postembolization syndrome occurred in most patients from both groups and observed that the differences were not statistically significant, except for postembolization pain. Using 300–500 μm CSM in DEB-TACE caused higher VAS points (6.3 vs. 6.8, P = 0.035), which may be related to normal hepatic tissue ischemia by embolizing the branches of thicker vessels. Several studies revealed that the incidence of postembolization syndrome after cTACE and degradable starch microspheres TACE (DSM-TACE) was 36.1% and 73.7%, respectively.[14],[15] However, Siriwardana et al. found that large tumor size (>5 cm) and elevated serum bilirubin were the independent risk factors for acute hepatic decompensation and postembolization fever, which existed in this study.[16] Because the basic conditions of these studies were different, there is no significant comparison of results that can be analyzed. Furthermore, nausea and vomiting occurred more often in the 100–300 μm CSM group (31.3% vs. 30.3%, P = 0.928), which might be related to biliary duct injury, abdominal pain, and abdominal distension by embolism of the branches of finer tumor vessel. However, no serious complications occurred in any group. Some blood routine indexes and liver function indexes such as ALT, AST, and TBIL increased, while ALB decreased and worsened for a month. Nonetheless, these indexes recovered in most patients within 3 months.[17] Several studies have revealed that CSM, as an embolic material, could aggravate bile duct injury, especially in small-diameter CSM.[18] In our study, the indicator of bile duct injury was TBIL, which slightly increased after D-TACE. Strict indications with adequate preoperative evaluations could avoid serious complications.

This study has several limitations. First, the sample size of this study is single centered, the retrospective study was conducted on a smaller scale, and baseline characteristics such as PLT, TBIL, and mean largest nodule size were different between the two groups. Second, due to the small sample size and short follow-up time, the downstaging role of the two groups and factors affecting PFS and OS could not be accurately compared.


 > Conclusion Top


The use of small-diameter CSM in multiple HCC with the largest nodule size ranging from 5 to 10 cm provides a better treatment response and longer PFS and OS in patients with advanced-stage HCC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Wiggermann P, Sieron D, Brosche C, Brauer T, Scheer F, Platzek I, et al. Transarterial chemoembolization of child-A hepatocellular carcinoma: Drug-eluting bead TACE (DEB TACE) vs. TACE with cisplatin/lipiodol (cTACE). Med Sci Monit 2011;17:CR189-95.  Back to cited text no. 8
    
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Frédéric D, Thomas I, Stéphanie D, Nicolas T, Lambros T, Valérie N, et al. Biodegradable Pickering emulsions of lipiodol for liver trans-arterial chemo-embolization. Acta Biomaterialia 2019;87:177-86.  Back to cited text no. 9
    
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Orlacchio A, Chegai F, Roma S, Merolla S, Bosa A, Francioso S. Degradable starch microspheres transarterial chemoembolization (DSMs-TACE) in patients with unresectable hepatocellular carcinoma (HCC): Long-term results from a single-center 137-patient cohort prospective study. Radiol Med 2020;125:98-106.  Back to cited text no. 15
    
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Siriwardana RC, Niriella MA, Dassanayake AS, Liyanage CA, Upasena A, Sirigampala C, et al. Factors affecting post-embolization fever and liver failure after trans-arterial chemo-embolization in a cohort without background infective hepatitis- a prospective analysis. BMC Gastroenterol 2015;15:96.  Back to cited text no. 16
    
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