Comparison of treatment response, survival profiles as well as safety profiles between CalliSpheres® microspheres transarterial chemoembolization and conventional transarterial chemoembolization in huge hepatocellular carcinoma

Abstract

Background: This study aimed to compare treatment response, survival and safety profiles between drug-eluting beads transarterial chemoembolization (DEB-TACE) with CalliSpheres^® microspheres (CSM) and conventional TACE (cTACE) in huge hepatocellular carcinoma (HCC) patients.

Methods: 71 patients with huge HCC underwent DEB-TACE or cTACE were consecutively enrolled. Treatment response was assessed at first month (M1), third month (M3) and sixth month (M6) after TACE therapy; progression free survival (PFS) and overall survival (OS) were evaluated; liver function indexes were recorded before TACE operation (M0), at first week (W1), M1 and M6 after TACE therapy; adverse events which occurred after TACE operation were recorded.

Results: DEB-TACE presented with higher objective response rate (ORR) and disease control rate (DCR) compared to cTACE. Regarding survival profiles, the short-term mortality rate was lower, and PFS as well as OS were longer in DEB-TACE group compared with cTACE group. Multivariate Cox’s regression further illustrated that DEB-TACE vs cTACE was an independent protective factor for PFS and OS. As for safety profiles, patients’ liver function injury was reduced in DEB-TACE group compared with cTACE group. The incidence of fever was lower and CINV were less severe in DEB-TACE group compared with cTACE group, while no difference in occurrence of liver abscess, increase of ascites or moderate pain between two groups was observed.

Conclusion: DEB-TACE with CSM presents with better treatment response, survival profiles as well as safety profiles compared to cTACE in treatment for huge HCC patients.

Background

Hepatocellular carcinoma (HCC) is the most common carcinoma as well as the second cause of cancer-related deaths in China, and huge HCC, accounting for around 20% of HCC cases, is defined as HCC whose nodule size is greater than 10 cm in diameter [1–3]. Although the medical treatments for HCC have developed a lot in recent decades, there is still no recognized standard treatment for huge HCC, and the most commonly used curative approach for huge HCC is surgical resection, while due to large nodule size, high risk of tumor rupture, vascular invasion as well as intrahepatic metastasis, the incidence of intraoperative death remains higher and post-operational survival is still worse in huge HCC patients compared to smaller HCC patients [4–6]. Moreover, surgical resection is not applicable in most of HCC patients due to hidden onset of diseases, loss of liver function and severe complications especially in huge HCC patients who need to resect over 80% of liver [7]. Other therapeutic approaches such as associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) and radio-frequency ablation are less commonly applied for treatment of huge HCC and are complicated with severe liver injury and risk of future liver remnant hypertrophy [8, 9]. Therefore, exploring other non-surgical therapeutic methods that both reduce the tumor size and control disease progression is necessary for treating huge HCC patients.

As one of the non-surgical therapeutic methods, transarterial chemoembolization (TACE) is the most commonly used treatment for unresectable HCC [10, 11]. Conventional TACE (cTACE) uses lipiodol as drug carrier to load and release the anti-cancer drugs, as well as gelatin sponge as embolization agents to block the blood supply to the targeted tumor, which has achieved generally good efficacy and safety profiles in treatment of huge HCC [12]. However, cTACE poses high risk of systemic drug toxicity due to poor drug loading and releasing profiles as well as infixation of agents, therefore, drug eluting microspheres, as new drug delivery and embolization agents for TACE, have been developed and realized sustained and optimized concentration of chemotherapy agents in tumor to overcome the limitations of cTACE [13, 14]. For the application of drug-eluting bead TACE (DEB-TACE) in clinical settings, there are a number of studies disclosing favorable roles of DEB-TACE with various microspheres including CalliSpheres® microspheres (CSM) (the first drug-eluting microspheres developed in China), DC® beads and HepaSpheres® on treatment in general HCC patients compared with cTACE [15–22]. Considering that DEB-TACE yielded better treatment efficacy compared to cTACE in general HCC patient, while its application in huge HCC patients was not yet investigated, we hypothesized that DEB-TACE might have promising outcomes in huge HCC patients as well.

Thus, this retrospective cohort study aimed to compare treatment response, survival and safety profiles between DEB-TACE with CSM and cTACE in huge HCC patients.

Method

Patients

Seventy-one patients with huge HCC who underwent DEB-TACE or cTACE therapy in the First Affiliated Hospital of Zhengzhou University between Jan 2016 and Dec 2017 were consecutively enrolled in this retrospective cohort study. The inclusion criteria consisted of: (1) diagnosed as primary HCC according to American Association for the Study of the Liver Diseases (AASLD) guidelines; (2) Single nodule or multiple fused nodules in diameter; (3) aged 18 to 75 years; (4) received DEB-TACE or cTACE treatment; (5) medical records were completely preserved and accessible. The exclusion criteria were as follows: (1) secondary HCC; (2) patients who had a history of malignancies except for ≥10 cm HCC; (3) patients previously received DEB-TACE and cTACE therapy in other hospital; (4) patients who switched treatment between DEB-TACE and cTACE; (5) patients who received radiofrequency ablation, microwave ablation, particle implantation or other interventional therapies after DEB-TACE or cTACE treatment; (6) patients without any response assessment data or follow-up data. Finally, 31 patients who underwent DEB-TACE therapy were included in the DEB-TACE group, and 40 patients who received cTACE treatment were included in the cTACE group. The present study was approved by Institutional Review Board of the First Affiliated Hospital of Zhengzhou University, and written informed consents were obtained from all the patients or their statutory guardians.

Baseline information collection

Patients’ baseline features were collected from electronic medical records, which included age, gender, cause of cirrhosis, largest nodule size, tumor location, portal vein tumor thrombus (PVTT), intrahepatic metastasis, extrahepatic metastasis, Eastern Cooperative Oncology Group (ECOG) performance status, Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh stage, model for end-stage liver disease (MELD) score, hepatic artery-portal venous fistula (HAPVF), ascites and splenomegaly.

Procedures of DEB-TACE

In the present study, the CSM (Jiangsu Hengrui Medicine Co., Ltd., Jiangsu Province, China) with diameters of 300-500 μm were used in the DEB-TACE procedure. Before DEB-TACE, the CSM were loaded with pirarubicin (THP) (60 mg-80 mg) (Shenzhen Main Luck Pharmaceuticals Inc., China) according to the manufacturer's directions, subsequently, the high concentration contrast agent was added into the CSM (loaded with THP) as 1:1 ratio, and then the mixture of contrast agent and CSM loaded with THP was kept still for 5 min for further use. After the completion of drug loading process, DEB-TACE was conducted as follows: firstly, local anesthesia was performed, then tumor supplying vessels were detected by digital subtraction angiography (DSA). After the tumor supplying vessel was identified and selected, the femoral artery was punctured by Seldinger technique using microcatheter with diameter of 4F or 5F (Merit Maestro, Merit Medical System, Inc., USA). Then 100 mg oxaliplatin (Jiangsu Hengrui Medicine Co., Ltd., China) was injected into the tumor supplying vessel within 30 min, subsequently, the mixture of CSM was injected at a speed of 1 mL/min until the flow of contrast agent stagnated. Five minutes later, the angiography was performed again, and if there was incomplete embolization, DEB-TACE was performed for another time using Embospheres^® (Mai Ruitong medical devices Beijing Co., Ltd., China) with diameters of 300-500 μm.

Procedures of cTACE

Suspension of 10 mL ethiodized poppyseed oil injection (EPO) (Jiangsu Hengrui Medicine Co., Ltd., China) and 20 mg THP was confected before cTACE. The processes of angiography and puncture of cTACE were performed as same as DEB-TACE procedures, and the injection of oxaliplatin was also carried out as described above. After that, the suspension of 10 mL EPO and 20 mg THP was injected into the tumor supplying vessel. If 10 mL EPO was not enough for complete embolization, gelatin sponge particles with diameters of 350-560 μm (Hangzhou Aili Pharmaceutical Technology Co., Ltd., China) were added until the stenosis of the flow occurred. In addition, the angiography was performed for another time to detect if there was incomplete embolization.

Pain management during and after TACE operation

Analgesics were prepared before operation, which consisted of dexmedetomidine (Jiangsu Hengrui Medicine Co., Ltd., China), dezocin (Yangzi River Pharmaceutical Company, China) and 0.9% sodium chloride injection. And 30 min before the initiation of the operation, the analgesics were administrated to patients by patient-controlled analgesia at a speed of 2 mL/h. Analgesics dosage was adjusted according to pain visual analogue scale (VAS) score during the operation. After operation, dezocine 5 mg+0.9% sodium chloride 2 mL were given to the patients by intravenous injection if necessary (according to pain VAS score). Furthermore, symptomatic treatments were performed for postoperative complications.

Treatment and assessment after TACE operation

Cinobufotalin was administrated to patients for antitumor therapy after TACE operations, which was given as follows: 1.2 g tid orally, 14 d per cycle, repeated every 14 d, and patients received at least 2 cycles of Cinobufotalin. Enhanced computerized tomography (CT) or enhanced magnetic resonance imaging (MRI) was performed for treatment response assessment at first month (M1), third month (M3) and sixth month (M6) after first cycle of DEB-TACE or cTACE therapy, and as for patients with deficient deposit of EPO, residual lesions or recurrence, DEB-TACE or cTACE was repeated. Treatment response was assessed according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), which included: (1) complete response (CR): disappearance of any intratumoral arterial enhancement in all target lesions; (2) partial response (PR): at least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase ) target lesions; (3) stable disease (SD): any cases that did not qualify either PR or progressive disease (PD); (4) PD: an increase of at least 20% in the sum of the diameters of the viable (enhancing) target lesions. In addition, objective response rate (ORR) was defined as the percentage of patients who achieved CR or PR, and disease control rate (DCR) was defined as proportion of patients who achieved CR, PR or SD.

Follow up

Liver function indexes including total bilirubin (TBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and albumin (ALB) were measured before TACE operation (M0), at first week after first cycle of TACE operation (W1), M1 and M6. Moreover, adverse events which occurred after TACE treatments were recorded as well including liver abscess, increase of ascites, fever, moderate pain (VAS≥4) and Chemotherapy-induced nausea and vomiting (CINV). All patients were followed up by hospitalization and phone calls, and median follow-up time was 6.1 (range: 2.8-14.7) months. Progression free survival (PFS) was defined as the duration from the time of first TACE operation to the time of disease progression or death. Overall survival (OS) was defined as the duration from the time of first TACE operation to the time of death.

Statistical analysis

Statistical analysis was performed using SPSS 22.0 statistical software (SPSS Inc., USA), and figures were made by GraphPad Prism 6.01 software (GraphPad Software Inc., USA). Count data were expressed as count (percentage); normally distributed continuous data were presented as mean ± standard deviation; skewed distributed continuous data were described as median (25^th-75^th quantiles). Comparison between two groups was determined by Chi-square test, t test or Wilcoxon rank sum test. Survival analysis was performed using Kaplan–Meier method, and difference of survival profiles between two groups was determined by log-rank test. Univariate and multivariate Cox’s proportional hazards regression analyses were used to determine prognostic factors of PFS and OS, and the multivariate Cox’s proportional hazards regression was performed using Forward Stepwise (Conditional LR) method. P value <0.05 was considered significant, and the significant results were shown in boldface.

Results

Study flow

392 HCC patients who underwent DEB-TACE or cTACE treatment were initially screened, while 294 patients were excluded including 117 patients who were without complete data, 101 patients who were with nodule <10 cm in diameter, 31 patients who received radiofrequency ablation, microwave ablation or other interventional therapies after DEB-TACE or cTACE treatment, 22 patients who switched treatment between DEB-TACE and cTACE, 12 patients who were with a history of other malignancies, 8 patients who previously received DEB-TACE or cTACE in other hospital, 3 patients who had secondary HCC (Fig. 1). Subsequently, 98 patients with huge HCC were eligible, whereas 27 of them were excluded including 22 patients who were unable to contact to obtain informed consents and 5 patients who refused to sign the informed consents. The remaining 71 patients with huge HCC were eventually included in the analysis. 31 patients who received DEB-TACE were assigned to DEB-TACE group and 40 patients who received cTACE were assigned to cTACE group.

Patients’ baseline characteristics

Huge HCC patients in DEB-TACE (N=31) and cTACE (N=40) groups were age and gender matched (Table I). The mean age was 52.7 ± 9.4 years in DEB-TACE group and 54.2 ± 11.2 years in cTACE group (P=0.557). There were 29 males and 2 females in DEB-TACE group, while 33 males and 7 females in cTACE group (P=0.304). As for other baseline characteristics, no difference was observed between DEB-TACE and cTACE groups either regarding to cause of cirrhosis (P=0.452), largest nodule size (P=0.205), tumor location (P=0.918), PVTT (P=0.214), intrahepatic metastasis (P=0.994), extrahepatic metastasis (P=1.000), ECOG performance status (P=0.826), BCLC stage (P=0.639), child-Pugh stage (P=0.824), MELD score (P=0.303), HAPVF (P=0.747), ascites (P=0.873) and splenomegaly (P=0.306).

Comparison of treatment response rate between DEB-TACE and cTACE groups Comparison of treatment response rate between DEB-TACE and cTACE groups was performed using Chi-square test. At M1 after treatment, no difference in CR, ORR or DCR was observed between two groups (All P>0.05) (Fig. 2A). At M3 after treatment, CR was similar (P>0.05) but ORR (P<0.05) and DCR (P<0.05) were higher in DEB-TACE group compared with cTACE group (Fig. 2B). At M6 after treatment, ORR was higher (P<0.05) while CR (P>0.05) and DCR (P>0.05) were similar in DEB-TACE group compared with cTACE group (Fig. 2C). These implied that DEB-TACE resulted in better treatment response in huge HCC patients compared with cTACE.

Short-term mortality and causes of death between DEB-TACE and cTACE groups

The 6-month mortality rate was 25.8% in DEB-TACE group, which was decreased compared to that in cTACE group (52.5%) (P=0.023) (Fig. 3A). The comparison of death causes revealed that no difference in distant metastasis, cachexia, liver failure, complications of diabetes or other causes of death was observed between DEB-TACE and cTACE groups (All P>0.05) (Fig. 3B). 

Comparison of PFS and OS between DEB-TACE and cTACE groups

Kaplan–Meier method was used to assess PFS and OS of huge HCC patients and difference between DEB-TACE and cTACE groups was determined by log-rank test. PFS was longer in DEB-TACE group (median PFS: 3.3 months 95%CI: 2.8-3.7 months) compared with cTACE group (median PFS: 2.1 months 95%CI: 1.7-2.5 months) (P<0.001) (Fig. 4A). Also, OS was increased in DEB-TACE group (median OS: 7.8 months 95%CI: 4.6-11.0 months) compared to cTACE group (median OS: 5.7 months 95%CI: 5.0-6.3 months) (P=0.004) (Fig. 4B).

Factors affecting PFS

Univariate Cox’s proportional hazard regression displayed that DEB-TACE vs cTACE (P=0.001) was correlated with longer PFS, while PVTT (P=0.001), intrahepatic metastasis (P=0.020), extrahepatic metastasis (P<0.001), ECOG performance status (≥2 vs <2) (P=0.009), BCLC stage (C vs B) (P=0.005), Child-Pugh stage (B vs A) (P=0.009) and HAPVF (P<0.001) were associated with shorter PFS (Table II). Further multivariate Cox’s regression with Forward Stepwise (Conditional LR) method revealed that DEB-TACE vs cTACE (P<0.001) independently predicted better PFS, while extrahepatic metastasis (P<0.001), BCLC stage (C vs B) (HR=3.205, P=0.001) and HAPVF (P=0.005) independently predicted worse PFS in huge HCC patients.

Factors affecting OS

For OS, univariate Cox’s proportional hazard regression disclosed that DEB-TACE vs cTACE (P=0.005) was associated with better OS, whereas PVTT (P<0.001), intrahepatic metastasis (P=0.018), extrahepatic metastasis (P<0.001), ECOG performance status (≥2 vs <2) (P=0.017), BCLC stage (C vs B) (P=0.003), Child-Pugh stage (B vs A) (P=0.008), HAPVF (P<0.001) and ascites (P=0.003) were correlated with worse OS (Table III). In addition, multivariate Cox’s regression with Forward Stepwise (Conditional LR) method illustrated that DEB-TACE vs cTACE (P<0.001) independently predicted longer OS, while PVTT (P=0.004), intrahepatic metastasis (P<0.001), extrahepatic metastasis (P=0.024), ECOG performance status (≥2 vs <2) (P<0.001) and HAPVF (P<0.001) independently predicted shorter OS in huge HCC patients.

Comparison of liver function indexes between DEB-TACE and cTACE groups

No difference in liver function parameters was observed between DEB-TACE and cTACE groups at M0, W1 or M1 (All P>0.05), whereas at M6, TBIL (P=0.045), ALT (P=0.007) and AST (P=0.047) were higher but ALB (P<0.001) was lower in DEB-TACE group compared with cTACE group (Table IV).

Comparison of adverse events between DEB-TACE and cTACE groups

Incidences of adverse events which occurred after TACE treatments were recorded, and comparisons of adverse events between DEB-TACE and cTACE groups were performed (Table V). The incidence of fever (P=0.034) was lower and CINV grade (P=0.001) was less severe in DEB-TACE group compared with cTACE group, whereas no difference in occurrence of liver abscess (P=1.000), increase of ascites (P=1.000) or moderate pain (P=0.946) was observed between the two groups.

Discussion

Our results disclosed that in huge HCC patients: (1) DEB-TACE with CSM yielded better treatment response compared to cTACE. (2) Short-term mortality rate (within 6 months) was lower, and PFS as well as OS were longer in DEB-TACE group compared to cTACE group. (3) Compared to cTACE, DEB-TACE resulted in decreased level of liver function injury at M6 as well as lower incidence of adverse events after TACE treatments.

Treatment is even harder and prognosis is worse for huge HCC compared to smaller HCC due to advanced and complex disease conditions, and there is no consensus on a standard treatment strategy for huge HCC [4]. Currently, surgical resection is recognized as curative therapy for huge HCC, while the success rate of surgery is much lower in huge HCC compared with smaller HCC, and the post-surgical survival is also unsatisfactory [7]. Also, ALPPS is applied for treatment of huge HCC, whereas it induces extensive future liver remnant hypertrophy and high morbidity [8]. Other therapeutic approaches such as high intensity focused ultrasound and radiofrequency ablation are increasingly investigated for huge HCC management, while their treatment outcomes are limited by complicated tumor location as well as severe complications in huge HCC [8, 9, 23]. Apart from these, cTACE has been illustrated by accumulating studies to present relatively good treatment efficacy in treating huge HCC, whereas for DEB-TACE, which overcomes several limitations of cTACE and has been reported to achieve better treatment outcomes compared with cTACE in general HCC patients, its roles in huge HCC patients are still obscure [10, 13, 14, 24, 25]. Therefore in this study, we assumed that for huge HCC patients, DEB-TACE might also possess satisfying treatment outcomes, and compared the efficacy, survival profiles as well as safety profiles between DEB-TACE with CSM and cTACE in huge HCC patients.

Drug-eluting microspheres are developed for loading and slowly releasing cytotoxic drugs into the tumor, and they also act as embolization agents to block blood supply to hypervascular tumors [26]. DEB-TACE using these microspheres have been extensively investigated regarding treatment response in HCC patients. For instance, a study in China exhibits that DEB-TACE using CSM results in better ORR compared to cTACE at second cycle of treatment in HCC patients at BCLC stage C [17]. In addition, short-term (3-6 months) ORR and DCR are higher in DEB-TACE with CSM group compared with cTACE group in general HCC patients [19]. Also, DEB-TACE with DC^® beads presents better treatment response compared with cTACE in HCC patients [27]. These previous studies imply that DEB-TACE performs better than cTACE in treatment response in general HCC patients, whereas the roles of DEB-TACE on huge HCC patients are less investigated. Therefore, we evaluated treatment response to DEB-TACE and cTACE in huge HCC patients and discovered that ORR and DCR were higher in DEB-TACE group compared with cTACE group. The possible explanations were: (1) Microspheres had better drug loading and releasing profiles than lipiodol used in cTACE, resulting in higher concentration of drug at targeted tumor, thereby more effectively killing cancer cells and inducing tumor necrosis compared with cTACE. Meanwhile, due to homogeneity of the microspheres and vascular deformability, the peripheral embolization effect of DEB-TACE was better, therefore, DEB-TACE presented better treatment response compared with cTACE. (2) Regarding stability of treatment response, the drug concentration at targeted tumors might be more stable and slowly reduced in DEB-TACE due to constant release of drugs compared to cTACE, therefore, DEB-TACE achieved more sustained treatment response compared to cTACE.

As for survival profiles of DEB-TACE and cTACE in HCC patients, discrepancy still exists in different clinical researches. Some studies state that DEB-TACE is better than cTACE in prolonging patients’ survival, whereas other voices claim that there is no difference in survival profiles between these two treatments [28-31]. Considering that these previous studies focus on general HCC patients, and information of DEB-TACE in huge HCC is limited, we compared survival profiles between DEB-TACE and cTACE in huge HCC patients and discovered that short-term mortality rate was lower, and PFS as well as OS were longer in DEB-TACE group compared to cTACE group. These could be due to that: (1) Benefiting from the drug loading and releasing profiles of microspheres, DEB-TACE was illustrated to achieve and sustain optimal drug concentration as well as retain treatment response for a longer duration compared to cTACE, therefore, patients’ survival profiles were better in DEB-TACE group compared to cTACE group [32]. (2) DEB-TACE might lead to less escape of drugs to normal liver tissue and adjacent organs, reducing the risk of liver function injury as well as the systemic cytotoxicity, thereby favoring survival profiles in huge HCC patients. Moreover, we performed multivariate Cox’s regression analysis to further screen factors that independently affected survivals of huge HCC patients and discovered that DEB-TACE vs cTACE was an independent protective factor for PFS and OS, which again supported our results that DEB-TACE yielded better survival profiles compared to cTACE.

Although TACE has achieved promising efficacy in treatment for HCC, it is also illustrated to cause embolic syndrome (with incidence exceeding 10%) including liver dysfunction, pain, ascites and CINV due to embolization of the blood transferring arteries [33]. In general HCC patients, safety profiles have been investigated between DEB-TACE and cTACE based on the symptoms of embolic syndrome. For example, a recent study comparing the short-term safety elucidates that liver function is better reserved and the incidence of drug-related complications is lower in DEB-TACE group with CSM compared with cTACE group [19]. A randomized controlled trial reveals that patients receive DEB-TACE with DC^® beads experience less procedural abdominal pain than those treated with cTACE [31]. Additionally, the ALT change from baseline to 48 h after TACE procedure is decreased indicating less liver function injury in patients underwent DEB-TACE with DC^® beads compared with cTACE [27]. These previous studies imply that DEB-TACE is relatively safe and well tolerated in treatment of general HCC patients, whereas for huge HCC patients, its safety profiles still remain unclear. In line with the previous studies, our study observed that hepatic injury was less and the incidence of adverse events was lower in DEB-TACE group compared to cTACE group in huge HCC patients. These could be explained by that: EPO that was used in cTACE might lead to fast escape and metabolization of cytotoxic drugs, hence increased the toxicity to normal liver tissues and adjacent organs, thereby aggravated liver function injury and adverse events in huge HCC patients. Whereas for DEB-TACE, it achieved stable and sustained release of drugs to the targeted tumor and less drug escape to the adjacent tissues, which reduced systemic drug toxicity, and presented with less liver function injury and lower incidence of adverse events.

There were still several limitations in our study: (1) As a retrospective study with relatively small sample size, the statistical power of our results might be mitigated, therefore, further studies preferably randomized controlled trails or prospective studies with larger sample size were needed to verify the results. (2) Analgesics were administered during and after treatment on requirement. Therefore, considering that patients might have different tolerance degree to pain and received different dose of analgesics, the result regarding pain in adverse events might be influenced. (3) Embospheres^® (with diameters of 300-500 μm) was used if embolization was not complete, which might become a cofounding factor for treatment outcomes. (4) The follow-up duration in this study was relatively short, therefore comparison of long-term efficacy between DEB-TACE and cTACE on treatment outcomes in huge HCC patients were not investigated.

Conclusions

In conclusion, DEB-TACE with CSM presents with better treatment response, survival profiles as well as safety profiles compared to cTACE in treatment for huge HCC patients.

Abbreviations

DEB-TACE, drug-eluting beads transarterial chemoembolization; CSM, CalliSpheres® microspheres; cTACE, conventional TACE; PFS, progression free survival; OS, overall survival; ORR, objective response rate; DCR, disease control rate; HCC, hepatocellular carcinoma; ALPPS, associating liver partition and portal vein ligation for staged hepatectomy; TACE, transarterial chemoembolization; PVTT, portal vein tumor thrombus; MELD, model for end-stage liver disease; HAPVF, hepatic artery-portal venous fistula; DSA, digital subtraction angiography; PR, partial response; SD, stable disease; PD, progressive disease; CINV, chemotherapy-induced nausea and vomiting

Declarations

Ethics approval and consent to participate

The present study was approved by Institutional Review Board of the First Affiliated Hospital of Zhengzhou University, and written informed consents were obtained from all the patients or their statutory guardians.

Consent to publish

Not applicable.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81401494).

Authors' Contributions

XH and JR contributed to the conception; XD, JL, HL and FL contributed to data acquisition and data analysis; SJ, XD, and JL drafted the manuscript, XH and JR revised the manuscript. All authors read and approved the final manuscript.

Acknowledgments

Not applicable.

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References

Tables

Table 1. Baseline characteristics.

Data were presented as mean value ± standard deviation, count (percentage) or median (25^th-75^th quantiles). Comparison was determined by t test, Chi-square test or Wilcoxon rank sum test. P value <0.05 was considered significant (in bold). DEB-TACE: drug-eluting bead transarterial chemoembolization; cTACE: conventional transarterial chemo-embolization; PVTT: portal vein tumor thrombus; ECOG: Eastern Cooperative Oncology Group; BCLC: Barcelona Clinic Liver Cancer; MELD: model for end-stage liver disease; HAPVF: hepatic artery-portal venous fistula.

Table 2. Factors affecting PFS by Cox’s proportional hazards regression model analysis.

Factors affecting PFS were determined by univariate and multivariate Cox’s proportional hazards regression model analyses, and the multivariate Cox’s proportional hazards regression was performed with Forward Stepwise (Conditional LR) method. P value <0.05 was considered significant (in bold). PFS: progression free survival; HR: hazard ratio; CI: confidence interval; DEB-TACE: drug-eluting bead transarterial chemoembolization; cTACE: conventional transarterial chemo-embolization; PVTT: portal vein tumor thrombus; ECOG: Eastern Cooperative Oncology Group; BCLC: Barcelona Clinic Liver Cancer; MELD: model for end-stage liver disease; HAPVF: hepatic artery-portal venous fistula. 

Table 3. Factors affecting OS by Cox’s proportional hazards regression model analysis.

Factors affecting OS were determined by univariate and multivariate Cox’s proportional hazards regression model analyses, and the multivariate Cox’s proportional hazards regression was performed with Forward Stepwise (Conditional LR) method. P value <0.05 was considered significant (in bold). OS: overall survival; HR: hazard ratio; CI: confidence interval; DEB-TACE: drug-eluting bead transarterial chemoembolization; cTACE: conventional transarterial chemo-embolization; PVTT: portal vein tumor thrombus; ECOG: Eastern Cooperative Oncology Group; BCLC: Barcelona Clinic Liver Cancer; MELD: model for end-stage liver disease; HAPVF: hepatic artery-portal venous fistula.

Table 4. Change of liver function before and after treatment.

Data were presented as mean value ± standard deviation. Comparison was determined by t test. P value <0.05 was considered significant (in bold). DEB-TACE: drug-eluting bead transarterial chemoembolization; cTACE: conventional transarterial chemo-embolization; TBIL: total bilirubin; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALB: albumin.

Table 5. Adverse events.

Data were presented as count (percentage). Comparison was determined by Chi-square test or Wilcoxon rank sum test. P value <0.05 was considered significant (in bold). DEB-TACE: drug-eluting bead transarterial chemoembolization; cTACE: conventional transarterial chemo-embolization; VAS: visual analogue scale; CINV: Chemotherapy-induced nausea and vomiting.