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ORIGINAL ARTICLE
Year : 2022 | Volume
: 18
| Issue : 7 | Page : 1981-1987
Comparison of 8spheres polyvinyl alcohol microsphere and gelatin sponge particle efficacy for transcatheter arterial chemoembolization in stages A to B patients with hepatocellular carcinoma
Jia Zeng1, Yufeng Wang1, Huiwen Wang2, Yingwen Hou2, Dongfeng He2
1 Department of Cancer Hospital Affiliated to Harbin Medical University, Harbin, Heilongjiang Province, China
2 Department of Interventional Radiology, Cancer Hospital Affiliated to Harbin Medical University, Harbin, Heilongjiang Province, China
Correspondence Address:
Dongfeng He
Cancer Hospital Affiliated to Harbin Medical University, Harbin, Heilongjiang Province
China
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/jcrt.jcrt_736_22
Purpose: This study aimed to compare the clinical efficacy and prognostic analysis results of 8spheres polyvinyl alcohol (PVA) microspheres (8SM) with gelatin sponge (GS) particles for transcatheter arterial chemoembolization (TACE) in patients with stages A–B hepatocellular carcinoma (HCC).
Methods: Data were collected from 172 patients who underwent TACE at Harbin Medical University Cancer Hospital from January 2014 to July 2020. Patients were divided into two groups: TACE group using 8SM plus lipiodol (8spheres PVA group, N = 89) and TACE group using GS particles plus lipiodol (the GS group, N = 83). Subsequently, we compared the liver function, blood count, alpha-fetoprotein (AFP), and other parameters of patients in each group before and after interventional embolization. We also calculated the patient's progression-free survival and overall survival in these groups.
Results: The postoperative liver function indices, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the 8spheres PVA group, were worse than in the GS group. The postoperative median survival time was 19 ± 3.06 months and no significant difference in survival time was observed in GS group (26 ± 3.19 months) (P = 0.509). Multivariate analysis showed that targeted therapy (P = 0.051), maximum tumor diameter <5 cm (P = 0.018), age ≥60 years (P = 0.018), and AFP <120.5 μg/L (P = 0.007) significantly improved the overall survival rate of patients.
Conclusion: Postoperative liver function indices of patients with HCC treated with GS particles were better than those treated with 8SM; thus, GS particles are more suitable for patients with poor liver function.
Keywords: Embolic agents, gelatin sponge, hepatocellular carcinoma, polyvinyl alcohol microsphere, transcatheter arterial chemoembolization
As hepatocellular carcinoma (HCC) accounts for 75– 85% of primary liver cancer types, making it the most common. 2018 statistics show that primary liver cancer is the sixth most frequent cancer and the fourth leading cause of cancer-related deaths worldwide.[1] In addition, the incidence of HCC in China is also increasing yearly. For patients with unresectable HCC, transcatheter arterial chemoembolization (TACE) is a proven method, with conventional TACE (cTACE) showing a good survival advantage.[2],[3] Thus, studies have reported that cTACE achieves local ischemic tumor necrosis through embolization and releases chemotherapeutic drugs to kill tumor cells, achieving the purpose of treatment. The embolic substances commonly used include iodized oil, gelatin sponge (GS), polyvinyl alcohol (PVA), absolute ethanol, etc. During an operation, GS or PVA particles are supplemented with iodized oil after embolization, with the effect being better than that of arterial chemoembolization with iodized oil alone. However, there is currently no consensus on the standard supplementary embolization agent: GS particles or PVA embolization microspheres.[4],[5] Therefore, this paper selected the most commonly used particle embolization agents to compare their clinical efficacy and safety.
Specifically, GS is a nontoxic, nonantigenic protein gelatinous substance. Therefore, it is the most commonly used embolic agent in interventional treatment. However, when exposed to water, it has excellent compressibility and re-expansion, which can cause temporary occlusion of arterial vessels and recanalization of blood vessels about 2 weeks after surgery.[6] In addition to mechanical embolism, the spongy framework of GS can be filled with erythrocytes, causing platelet aggregation and fibrin deposition in the blood vessels, favoring the quick formation of thrombus, causing a vascular spasm, and aiding blood vessel embolization. Contrastively, PVA is a permanent embolic sponge-like agent with holes of varying sizes, which can be compressed to 1/15–1/10 volume and expand rapidly in water. Compared with GS, PVA particles are characterized by good biocompatibility, nonabsorbability by the body, and slow chemical degradation, leading to permanent or semi-permanent embolization of tumors.[7] Nevertheless, due to the complete occlusion of target blood vessels, it is difficult for the catheter to super-select the collateral circulation vessels of the tumor for embolization treatment when the main vessels of the tumor are occluded again. Due to these limitations, 8spheres® microspheres are usually used as blank PVA microspheres. Based on this background, we conducted a multifactorial analysis of the prognostic impact of 8spheres PVA embolization microspheres (8SM) versus GS as a supplemental embolic agent for TACE treatment in patients with HCC.
> Material and MethodsGeneral information
This retrospective study examined data previously collected from patients with HCC treated with TACE using different embolization materials at the Harbin Medical University Cancer Hospital from January 2014 to July 2020. The inclusion criteria selected patients with the following characteristics: (1) clinical or pathological diagnosis of HCC, (2) Child–Pugh classification A or B, BCLC stage A–B, or an Eastern Cooperative Oncology Group performance score of 0–2 point, (3) no imaging evidence of vascular invasion or extrahepatic metastasis, (4) no local or systemic treatments before the operation, and (5) patients with imaging findings detecting at least one measurable lesion on CT, DSA, or MRI within 14 days before and after interventional therapy. Contrastively, the following exclusion criteria removed the following: (1) patients with drug allergy to platinum or doxorubicin and (2) those with uncontrollable ascites, hepatic encephalopathy, esophagogastric variceal bleeding, or other serious complications.
According to different treatment methods, the selected patients were divided into the 8spheres PVA microspheres group (8SM group, comprising 54 patients in stage A and 35 patients in stage B) and the GS group (GS group, comprising 83 patients in GS group, 48 in stage A and 35 in stage B).
Experimental method
After disinfection, capping, and local anesthesia of the puncture site with 2% lidocaine, the right femoral artery was punctured following the Seldinger technique, after which a 5F vascular sheath was placed. Next, the feeding artery of the tumor was determined through catheterization by placing a 5F catheter into the celiac trunk and superior mesenteric artery, then super-selectively inserting it into the tumor blood supply artery with a 7F microcatheter. Then, while the 8SM group was treated with 8spheres embolization microspheres (100–300 μm) produced by Jiangsu Hengrui Bio-pharmaceutical Company and combined with iodized oil for TACE, the GS group was treated with GS particles (150–350 μm, 350–560 μm) combined with lipiodol for transcatheter arterial chemoembolization. Notably, the iodine oil was mixed with epirubicin, lopressor, and raltitrexed to form an emulsion (the amount of iodine oil and chemotherapeutic agent used is usually chosen according to the tumor size and the contrast situation), followed by a supplemental bolus with polyethylene or GS microspheres. Besides, the embolization endpoint was a stagnation of forward blood flow in the tumor-feeding artery. Subsequently, liver function and blood tests were performed 3 days after the intervention, 2–3 months after, and 1 year after, after which enhanced CT/MRI examinations were repeated 2–3 months after the intervention. Two radiologists compared the postoperative images with baseline images, assessed the tumor response according to the modified response evaluation criteria in solid tumors (RECIST),[8] and repeated TACE treatment 1.5or 3 months after the first treatment according to the tumor response. Additionally, a subsequent TACE treatment was performed using the same embolic agent as the first TACE treatment. The primary study endpoint was the overall OS, and the secondary study endpoint was the objective remission rate, disease control rate, safety, and postoperative liver function indices.
Evaluation of tumor response
Enhanced MRI or CT examinations were performed 2–3 months after TACE, and the therapeutic effect was evaluated according to the modified RECIST. According to the results, the patients were divided into the following four categories: complete remission (CR), partial remission (PR), stable disease (SD), progressive disease (PD), objective remission rate (ORR) (PR + CR), and disease control rate (DCR) (CR + PR + SD).
Statistical methods
Statistical analysis was performed using Statistical Package for Social Sciences (v. 24.0, IBM Corp., Armonk, NY, USA). Although normally distributed continuous variables were presented as the mean value ± standard deviation, skewed distributed continuous variables were presented as the median (25th–75th), and categorized variables were expressed in percentages. Furthermore, comparison between two groups was determined using the t-test, the Wilcoxon rank-sum test, or the Chi-square test. Additionally, while survival analysis was evaluated using the Kaplan–Meier curve and logarithmic rank test, prognostic factors of progression-free survival (PFS) and overall survival (OS) were determined using multivariate Cox's proportional hazards regression analysis with the Forward Stepwise (Conditional LR) method. P value < 0.05 was considered significant.
> ResultBaseline characteristics
According to the preoperative laboratory assessment results, no statistical difference existed between the groups in gender, age, alpha-fetoprotein (AFP), total protein (TP), total bilirubin (TBIL), prothrombin time (PT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), maximum tumor diameter, Hepatitis B or C, Child–Pugh classification and BCLC stage, treatment times, lipiodol dosage, and history of targeted therapy between the two groups (P > 0.05). However, there was a statistical difference in albumin between the two groups before the intervention (P = 0.045), which showed a small difference, with an average in the normal range also being observed [Table 1]
Postoperative liver function comparison between the two groups
The liver function indices were rechecked 3 days after the intervention, then 2–3 months and 1 year after the operation. Although the results showed no significant difference in liver function between the two groups 3 days after the intervention, the ALT (P = 0.016) and AST (P = 0.020) levels in the 8SM group 2–3 months after intervention were significantly higher than those in GS group. Furthermore, no significant difference in TBIL (P = 0.391) and albumin (P = 0.190) [Figure 1] levels were observed. Unfortunately, although liver function data were missing in most patients 1 year after the intervention, there was no significant difference in liver function parameters: ALT (P = 0.687), AST (P = 0.765), total bilirubin (P = 0.991), and albumin (P = 0.995).
Figure 1: Postoperative liver function between the two groups Skewed continuous variables are expressed as the median (25th–75th). AST = aspartate aminotransferase; ALT = alanine aminotransferase; TBIL = total bilirubin; ALB = albumin; 8SM = 8Spheres polyvinyl alcohol microspheres; GS = gelatin spongeTreatment response comparison between the two groups
Based on the results of abdominal MRI or CT scans performed 2–3 months after TACE, no clear differences between the two groups in the treatment responses were observed [Table 2]
Comparison of the survival profile between the two groups
The Kaplan–Meier method and log-rank test were used to record and compare the PFS and OS of patients in the 8SM and GS groups. Investigations revealed no significant difference in OS (P = 0.588) [Figure 2] and PFS (P = 0.194) [Figure 2] between the two groups. Further analysis also showed no significant difference in OS between the two groups at stages A–B in BCLC staging (P > 0.05). Furthermore, there was no significant difference in OS between the two groups when the maximum tumor diameters were ≥5 and <5 cm (P = 0.426 and 0.807) [Table 3].
Figure 2: PFS and OS between the two groups 8SM = 8Spheres polyvinyl alcohol microspheres group; GS = gelatin sponge group; OS = overall survival; PFS = progression-free survivalAnalysis of the predictive factors for survival
Multivariate Cox's proportional hazards regression model analysis was performed to evaluate the factors affecting OS. Investigations revealed that poor OS was obtained when patients were younger than 60 years (P = 0.002), had AFP ≥120.5 ng/mL (P = 0.011), maximum tumor diameter ≥5 cm (P = 0.017), and had undergone no previous targeted therapy (P = 0.051) [Figure 3]
Figure 3: Factors affecting OS using multivariate Cox's proportional hazards regression model analysis > Discussion In this study, we discovered that the understudied HCC patients with multiple cTACE treatment histories had the following characteristics:
Increased ALT and AST levels in the 8SM group compared with GS group, and had undergone targeted therapy (P = 0.051); had maximum HCC size of <5 cm (P = 0.018); age ≥60 years (P = 0.018); and AFP <120.5 μg/L (P = 0.007), proposing these factors to be significantly indigenous in affecting prognosis.No significant difference in the OS and PFS of patients with HCC treated with TACE using 8Spheres polyvinyl microspheres compared with GS particles, and no significant difference in the OS of patients at different stages and tumor sizes.No difference in treatment response and the number of TACE treatments between the two groups.TACE is one of the preferred treatment methods for advanced primary hepatic carcinoma. The principle of TACE is to maintain local drug concentration and reduce systemic chemotherapy drug concentration on the basis of tumor-feeding artery embolization. Therefore, selecting embolization agents is particularly important in TACE. In the guidelines for the diagnosis and treatment of HCC (2019 edition),[9] it is proposed that conventional TACE, mainly composed of lipiodol emulsion with chemotherapeutic drugs, and combined with GS particles, blank microspheres, and polyethylene particles, can further improve efficacy. However, there are no clear standard and consistent conclusions on the selection of adjuvant embolic agents. Furthermore, there are presently only a few clinical studies on the standard choice of adjuvant embolizing agents. Therefore, this paper compared the clinical efficacy and safety of GS particles and PVA microspheres, the most commonly used adjuvant embolic agents in cTACE, in the hope that it will have some reference value for the selection of clinical adjuvant embolic agents. Chen et al.[10] reviewed 174 patients with unresectable HCC. The results showed that GS particles were advantageous compared with the lipiodol group in patients with BCLC stages B and C. Additionally, when the tumor diameter was greater than 5 cm, they also showed that GS particles as embolization agents in TACE treatment can significantly improve tumor response rate and reduce serious adverse events. In another study, Cun et al.[11] used drug-loaded microspheres combined with 8Spheres PVA microspheres for the TACE treatment of HCC. They observed that drug-loaded microspheres combined with 8Spheres PVA microspheres had obvious advantages in reducing the adverse reactions of advanced liver cancer after embolization. A retrospective study of 109 HCC cases[12] also showed that while GS combined with lipiodol TACE was effective for treating large-diameter tumors, the tumor control rate was significantly better than that of the simple lipiodol-treatment group. Moreover, Ali Koçyiğit et al.[4] compared GS and PVA particles as TACE embolization materials, with their results indicating that while the median postoperative survival of the PVA group was 21.8 ± 18.7 months, the median postoperative survival of the GS group was 15.9 ± 17.9 months. Nevertheless, from their results, GS or PVA as embolization agents had no significant effect on the survival rate. Here, the survival rate of the PVA group was slightly higher than that of the GS group because the number of patients with Child–Pugh A in the PVA group was more than that in the GS group. However, our results had a higher survival rate than those recorded in Ali Koçyiğit's results, which is likely because those patients had a better overall condition and were in an earlier stage. A retrospective study[13] on 81 patients treated with TACE using different embolization agents also showed that the median survival time in the GS group was about 21.9 months and that in the PVA group was about 18.8 months, indicating that the survival rate of patients with HCC treated with GS or PVA TACE was similar.
Follow-up after conventional TACE using only lipiodol showed that lipiodol emulsion was more susceptible to reduction, probably due to the fluidity of lipiodol.[14] Nevertheless, supplementing embolic particles, such as GS particles and PVA microspheres after lipiodol embolization, can make up for the defect of incomplete lipiodol embolization, continuously blocking tumor blood supply arteries, and prolonging tumor vascular embolization, which makes ischemic tumor necrosis more obvious. Simultaneously, the complete embolization of peripheral tumor vessels can reduce the probability of vascular recanalization and collateral circulation, thus reducing the risk of tumor recurrence and progression. It has also been shown that while the concentration of chemotherapeutic agents in tumor tissue samples was significantly higher in a rabbit VX2 model treated with GS pellets by TACE, the concentration of chemotherapeutic drugs in peripheral blood decreased significantly.[15] Therefore, there is a need for supplemental embolization with particle embolization after conventional TACE with lipiodol embolization. Although the clinical benefits of drug-loaded microspheres, which have been widely used recently, are broadly similar to those of conventional TACE for HCC treatment,[16],[17] new embolic materials, such as drug-loaded microspheres, have several problems, such as high therapeutic costs, making the choice of GS or PVA particles as supplementary embolic material for TACE particularly important. The current study's findings regarding survival rates are consistent with previous studies in that no significant difference was observed in survival rates between patients treated with TACE for HCC using polyethylene embolization microspheres versus GS particles. We also observed that while the AST and ALT levels of the 8spheres PVA microspheres group were increased at 2–3 months after TACE, no difference in liver function existed between the two groups three days after TACE. The reason for this observation may be that since chemotherapeutic drugs and embolic materials for 3 days after intervention can significantly impact liver function, PVA microspheres could be used as permanent embolization materials during TACE due to the reflux of the intra-tumoral embolic agent into the normal liver tissue after filling, causing increased damage to the normal liver tissue. It has also been observed that the permanent or semi-permanent embolization of tumor blood supply vessels caused by PVA can induce signal transduction in tumor cells to resist and reverse hypoxia, such as stimulating the expression of vascular endothelial growth factor. Moreover, while permanent chemoembolization agents can lead to changes in liver arteries and reduce the pathways of repeated treatment,[18] GS particles can be administered about 2 weeks after an intervention, revascularizing, alleviating the occlusion of blood vessels around, and allowing repeat surgery, thereby restoring liver function 2–3 months after surgery, with less impact on liver function. Therefore, in elderly patients, especially those with poor liver function, GS particles should be preferred as supplementary embolic material during TACE to avoid further deterioration of liver function after TACE. Contrastively, the results from the study by Lee et al.[19] showed that while PVA particles with smaller particle sizes (<100 μm) could safely embolize more micro-artery capillaries around the tumor, tumor necrosis rates were higher after TACE, rarely leaking to the nontumor hepatic sinus space and reducing the damage to the surrounding nontumor tissue. However, the diameter of blank microspheres included in this study was 100–300 μm. So, subsequent studies need to include data with different diameters and larger sample sizes to verify the effect of blank microspheres with different diameters on the prognosis of patients with HCC after TACE. In addition, although TACE induces necrosis and ischemia of the tumor cells, it leads to an upregulation of vascular endothelial growth factor and fibroblast growth factor, leading to tumor recurrence and progression.[20] Therefore, combining TACE with anti-angiogenic drug targeting agents should further be explored to solve this problem,[21],[22] thereby significantly prolonging the survival of patients with unresectable HCC.
This study has some limitations. First, since our study was not randomized, the choice of selective or nonselective procedure was determined by the tumor or liver condition. However, the patient characteristics of the two groups are similar. Second, our study may have been biased in choosing patients. Therefore, a single-center trial that will require large sample sizes, including multi-center clinical trials, should be conducted in the future. Lastly, many patients with poor compliance did not review and receive treatment on time, resulting in a poor prognosis.
Informed consent
This paper is a retrospective study, all patients provided signed informed consent before study entry.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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