Abstract
Purpose: To explore the clinical efficacy and safety of CalliSpheres® microspheres drug-eluting bead transarterial chemoembolization (DEB-TACE) combined with sorafenib in the treatment of large liver cancer. Method: The study retrospectively analyzed 90 patients with large liver cancer. 42 patients who received DEB-TACE and sorafenib were included in the experimental group and 48 patients who received only DEB-TACE were included in the control group. The efficacy, TTP, OS and ARs were evaluated and further analysis was conducted on factors which might affect the prognosis. Results: As of June 2020. The median OS of the experimental group was significantly longer than that of the control group (18.6 months vs. 12.7 months), and the TTP was also longer in the experimental group (8.3 months vs. 6.9 months). Three months after the intervention, the ORR and DCR of the experimental group were significantly higher than those of the control group. The main ARs of the experimental group taking sorafenib included hand-foot syndrome, skin rash, diarrhea, fatigue, hypertension, and anorexia. And they could be alleviated through treatment of the symptoms. TACE-related ARs for both groups were fever, pain, nausea, and vomiting, and there was no significant difference. Logistic regression analysis showed that the combined sorafenib treatment was a protective factor improving the prognosis of patients with large liver cancer, and risk factors were the number of tumors and vascular invasion. Conclusion: DEB-TACE combined with sorafenib is safe and well tolerated in the treatment of large liver cancer. It can improve the tumor control rate and prolong the survival time.
Keywords: Transcatheter arterial chemoembolization, drug-eluting bead microspheres, hepatocellular carcinoma, sorafenib
Introduction
Transarterial chemoembolization (TACE) is an important treatment for unresectable liver cancer, and its combination with CalliSpheres drug-eluting bead microspheres (DEB-TACE) can achieve a high tumor response rate [1]. However, post-TACE ischemia and hypoxia can promote the increase of vascular endothelial growth factor receptor (VEGF) expression and tumor neovascularization, which can lead to tumor recurrence. This effect is particularly prominent in large liver cancers with abundant blood supply [2]. Sorafenib is a multi-kinase inhibitor that has the dual effects of anti-tumor angiogenesis and inhibiting tumor cell proliferation. It can inhibit the growth of residual tumors after TACE, thereby improving the middle and long-term efficacy of advanced liver cancer [3]. This study aims to explore the clinical efficacy and safety of DEB-TACE combined with sorafenib in the treatment of large liver cancer.
Materials and method
Participants
Patients with large liver cancer (>10 cm) who were admitted to the three centers of Linyi Tumor Hospital in Shandong Province, Zhongshan Hospital Affiliated to Dalian University, and Chang Gung Memorial Hospital Affiliated to Tsinghua University from January 2017 to June 2019 were selected. This study followed the relevant regulations in the Declaration of Helsinki and was approved by the Medical Ethics Committee of Linyi Tumor Hospital, Shandong Province [IRB Number: [2016] 078]. The enrolled patients all agreed to participate voluntarily and signed an informed consent form.
Inclusion criteria: (1) Diagnosed with primary liver cancer clinically or by liver biopsy; (2) Large liver cancer with single nodule diameter greater than 10 cm or the sum of multiple nodules greater than 10 cm; (3) BCLC stage B or C, Child classification Grade A or B, ECOG stamina score 0 to 2; (4) Age 18 to 80 years, with an estimated survival time of more than 3 months; (5) Patients who progressed after previous treatments such as c-TACE, ablation, radiotherapy and chemotherapy. Exclusion criteria: (1) Metastatic liver cancer; (2) Combined with severe dysfunction of other important organs separate from liver cancer; (3) Mental disorder, pregnancy, irregular follow-up or unable to follow-up; (4) BCLC stage A or D, Child classification Grade C, ECOG stamina score greater than 2.
Treatment
Preparation of CalliSpheres drug-eluting bead microspheres: Microspheres of 300 to 500 μm (1 g/bottle, Suzhou Hengrui Jialisheng Biomedical Technology Co., Ltd., National Instruments Note 20153771072) were used in this study. The microspheres and physiological saline were drawn out with a 20 ml syringe, and the syringe was placed vertically for 2 to 3 min. Until the microspheres were settled, the supernatant was pushed out as much as possible. In addition, 60 mg of epirubicin was dissolved with 5 ml of sterile water for injection. The syringe (20 ml) with microspheres and the syringe (5 ml) of epirubicin were connected through a three-way connection, and the epirubicin solution was slowly pushed into the syringe with the microspheres. The syringe containing the microspheres and chemotherapy drugs was then covered with a needle cap and shaken every 5 minutes for a total of 30 minutes for adsorption. Further, the microspheres carrying epirubicin and the non-ionic contrast agent iodixanol were mixed in a ratio of 1:1 and stood for 5 minutes.
Transarterial chemoembolization: Seldinger’s method was used to puncture the right femoral artery, and a catheter was introduced into the right hepatic duct for routine celiac artery and common hepatic angiography. According to the tumor location, size, and whether the tumor staining was complete, auxiliary angiography of the ectopic blood supply arteries such as the diaphragmatic artery, superior mesenteric artery, left gastric artery, and right renal artery were performed to identify all the tumor’s blood supply arteries. The microcatheter was inserted into the tumor supply artery, and 100 to 150 mg oxaliplatin was infused. Then the pre-configured drug-eluting bead microspheres were slowly injected (1 ml/min) in a pulse model, and the embolization was stopped when the flow rate of the contrast agent stopped. After pausing for 5 minutes, another angiography was performed, and the embolization was stopped when the tumor staining completely disappeared. If there was still tumor staining, additional embolization was performed, and an ordinary embolization microsphere was applied if necessary.
Oral medication: Sorafenib mesylate tablets (200 mg/tablet, Nexavar, Bayer Pharmaceuticals, Germany) were given for 3 to 5 days after the first TACE treatment. The starting dose was 400 mg twice a day. If there was an intolerable AR the dose was changed to 400 mg once a day, or stopped for about 1 week, with the full dose resumed after the symptoms were relieved. Our discontinuation criteria were disease progression or worsening, serious ARs, or decompensated liver function (Grade C).
Efficacy evaluation and adverse reaction observation: After the first TACE, a comprehensive assessment of the condition was performed every 4 to 6 weeks. The review included routine blood work, liver, and kidney function, AFp, chest CT scan and upper abdominal enhanced CT/MRI. From the imaging results, the tumor response was evaluated according to the mRECIST standard, as complete remission (CR), partial remission (PR), progressive disease, or stable disease (SD). While the tumor remained and progressed, additional interventional therapy was considered. In addition, the objective response rate (CR + PR) and disease control rate (CR + PR + SD) of the two groups of patients were evaluated at 1 and 3 months after the first intervention. Safety was assessed by following the National Cancer Institute (National Cancer Institute, NCI) Common Terminology Criteria for Adverse Events (version 3.0).
Research endpoints: The primary endpoint of this study was OS, while the secondary endpoints included ORR, DCR, TTP, and safety. OS was defined as the time from the beginning of the first interventional treatment to the death of the patient or the last follow-up. TTP was defined as the time from the beginning of the first interventional treatment to the first objective progression of the tumor.
Statistical analysis: SPSS 20.0 software was used for statistical analysis of the data. The continuous data were represented as means ± standard deviations and tested using the independent sample t test. Categorical data (baseline data, ORR, DCR) were represented as percentages and analyzed with a chi-square test. TTP, OS, and corresponding curves between the two groups were analyzed by the Kaplan-Meier method. A log-rank test was used for comparison of survival rates between the two groups. Single-factor and multivariate Cox risk regression models were used to analyze related factors, and P<0.05 was considered statistically significant.
Results
From January 2017 to June 2019, a total of 90 patients with large liver cancer who met the inclusion criteria and received DEB-TACE treatment from Linyi Tumor Hospital, Dalian University Affiliated Zhongshan Hospital, and Tsinghua University Chang Gung Memorial Hospital were selected. Among them, 78 were males and 12 were females. Forty-two patients were in the experimental group (DEB-TACE combined with sorafenib treatment) and 48 patients in the control group (only DEB-TACE treatment). There were no significant differences between the two groups of patients in terms of age, gender, Child classification, ECOG score, etiology, or BCLC staging (P>0.05), as shown in Table 1.
Table 1.
General information of 90 patients with hepatocellular carcinoma
| Clinical indicators | Experimental group (n=42) | Control group (n=48) | P value |
|---|---|---|---|
| Age (years) | 60.3±14.0 | 59.7±13.2 | 0.417 |
| Gender | 0.709 | ||
| Male | 37 | 41 | |
| Female | 5 | 7 | |
| History of liver disease | 0.915 | ||
| Hepatitis B | 33 | 38 | |
| Hepatitis C | 4 | 5 | |
| Alcoholic liver disease | 3 | 3 | |
| Others | 2 | 2 | |
| History of cirrhosis | 0.977 | ||
| Yes | 20 | 23 | |
| No | 22 | 25 | |
| Tumor diameter (cm) | 11.5±3.7 | 11.0±3.0 | 0.241 |
| Number of tumors | 0.875 | ||
| ≤3 | 30 | 35 | |
| >3 | 12 | 13 | |
| Vascular invasion | 0.975 | ||
| Yes | 13 | 15 | |
| No | 29 | 33 | |
| Extrahepatic metastasis | 0.756 | ||
| Yes | 6 | 8 | |
| No | 36 | 40 | |
| ECOG score | 0.996 | ||
| 0 | 14 | 16 | |
| 1 | 23 | 26 | |
| 2 | 5 | 6 | |
| Child classification | 0.924 | ||
| A | 31 | 35 | |
| B | 11 | 13 | |
| BCLC stage | 0.976 | ||
| B | 13 | 15 | |
| C | 29 | 33 | |
| AFP level (ng/ml) | 0.909 | ||
| ≤400 | 18 | 20 | |
| >400 | 24 | 28 | |
| Previous treatment | |||
| Yes | 7 | 8 | 1 |
| No | 35 | 40 |
Short-term efficacy evaluation
One month after the first intervention, we obtained 88 of the 90 patients’ imaging evaluations, including 42 in the experimental group and 46 in the control group. Three months after treatment, imaging evaluations were available for 85 patients, including 40 in the experimental group and 45 in the control group. According to the mRECIST1.1 evaluation standard, 1 month after the first intervention, the ORR (76.19% vs. 71.74%, χ2=0.225, P=0.635) and DCR (100% vs. 95.65%, χ2=1.868, P=0.176) of the experimental group were slightly higher than those of the control group. After three months, the ORR (80.00% vs. 57.78%, χ2=4.825, P=0.028) and DCR (97.50% vs. 84.44%, χ2=4.233, P=0.039) of experimental group were significantly higher than those of the control group, as shown in Table 2.
Table 2.
The short-term efficacy of the two groups of patients (cases, %)
| 1 month after the intervention | CR | PR | SD | PD | ORR | DCR |
|
| ||||||
| Experimental group (n=42) | 7 | 25 | 10 | 0 | 76.19 | 100 |
| Control group (n=48) | 6 | 27 | 11 | 2 | 71.74 | 95.65 |
|
| ||||||
| 3 months after the intervention | ||||||
|
| ||||||
| Experimental group (n=42) | 10 | 22 | 7 | 1 | 80.00 | 97.50 |
| Control group (n=48) | 5 | 21 | 12 | 7 | 57.78 | 84.44 |
Survival period and survival rate
Until June 2020, the follow-up period was 8 to 36 months, with an average of 28.5 months. The median survival time of the experimental group was 18.6 months (95% CL 14.035 to 23.965), while for the control group it was 12.7 months (95% CL 9.815 to 16.185). The median survival time was significantly higher in the experimental group (χ2=6.470, P=0.011). The median TTP of the experimental group was 8.3 months (95% CL 7.888 to 10.112), while it was 6.0 months in the control group (95% CL 4.768 to 7.232). There was also a significant difference between these two groups (χ2=8.271, P=0.004) in this measure. As shown in Figures 1 and 2.
Figure 1.
Comparison of overall survival curve between the two groups.
Figure 2.
Comparison of time to progression curve between the two groups.
Adverse reaction
Patients in the experimental group had unique ARs after taking sorafenib, mainly presenting as hand-foot syndrome, skin rash, diarrhea, fatigue, hypertension, and anorexia. The severity of these ARs was less than the third grade and could be alleviated after treatment of the symptoms. There were no cases of withdrawal from the study. Two patients had grade 3 blood pressure increases; after a short period of suspension from treatment, they were given medical antihypertensive treatment and then restored to the original dose. Six patients were reduced to 400 mg/day due to intolerable hand-foot syndrome and diarrhea. The main ARs of patients receiving only DEB-TACE treatment included fever, pain, nausea, and vomiting. The duration was generally 5 to 7 days, and the ARs were all alleviated after symptomatic treatment with internal medicine. No serious complications such as liver abscess, gastrointestinal perforation, liver and kidney failure occurred, as shown in Tables 3 and 4.
Table 3.
The occurrence of TACE-related adverse reactions after the first DEB-TACE in the two groups
| Adverse reactions | Experimental group (n=42) | Control group (n=42) | P value |
|---|---|---|---|
| Fever | 14 | 17 | 0.835 |
| Pain | 12 | 14 | 0.950 |
| Nausea and vomiting | 30 | 34 | 0.950 |
| Liver abscess | 0 | 0 | 1 |
Table 4.
The occurrence of adverse reactions related to sorafenib in patients of the experimental group
| Adverse reactions | Total numbers | Grade I | Grade II | Grade III | Grade IV |
|---|---|---|---|---|---|
| Hand-foot syndrome | 24 | 17 | 4 | 3 | 0 |
| Skin rash | 9 | 7 | 2 | 0 | 0 |
| Diarrhea | 15 | 9 | 4 | 2 | 0 |
| Fatigue | 11 | 10 | 1 | 0 | 0 |
| Hypertension | 5 | 1 | 2 | 2 | 0 |
| Anorexia | 5 | 2 | 3 | 0 | 0 |
Influencing factors analysis
Eleven items (age, gender, etiology, tumor number, vascular invasion, extrahepatic metastasis, ECOG score, Child classification, BCLC stage, AFP level, and treatment method) were separately analyzed with Cox single-factor analysis. The results showed that the number of tumors, vascular invasion, extrahepatic metastasis, and treatment methods were statistically significant factors (P<0.05). Multivariate Cox regression analysis showed that TACE combined with sorafenib treatment was a protective independent factor, and the number of tumors and vascular invasion were independent risk factors for the prognosis of patients (P<0.05), shown in Table 5.
Table 5.
Single-factor and multi-factor analysis of the prognosis of patients with large liver cancer
| Item | Single-factor analysis | Multi-factor analysis | |||
|---|---|---|---|---|---|
|
|
|
||||
| HR (95% CI) | P value | Regression coefficients | HR (95% CI) | P value | |
| Age | 0.976 (0.948-1.011) | 0.703 | |||
| Gender | 1.304 (0.450-3.782) | 0.915 | |||
| Etiology | 0.452 (0.045-3.237) | 0.158 | |||
| ECOG score | 1.58 (0.957-2.164) | 0.094 | |||
| Child classification | 1.601 (0.786-3.249) | 0.054 | |||
| BCLC stage | 1.792 (1.057-2.601) | 0.107 | |||
| AFP level | 1.206 (0.628-2.236) | 0.219 | |||
| Extrahepatic metastasis | 0.456 (0.248-1.339) | 0.001 | 0.760 | 2.310 (1.673-3.554) | 0.073 |
| Tumor numbers | 1.511 (0.809-2.751) | 0.043 | 0.426 | 1.960 (1.017-3.758) | 0.013 |
| Vascular invasion | 1.035 (0.573-1.676) | 0.033 | 0.806 | 1.971 (1.193-3.255) | 0.008 |
| Treatment | 0.193 (0.088-0.523) | 0.002 | -1.405 | 0.561 (0.327-0.965) | 0.001 |
Discussion
Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor in the world and the second leading cause of tumor death [4]. When the tumor diameter is more than 5 cm, it is clinically defined as large liver cancer. About 32% of patients are initially diagnosed as having large liver cancer, and another 10% to 20% of patients have tumors more than 10 cm in diameter [5]. Patients with large liver cancer are often in the middle and advanced stages of the tumor growth, and their prognosis is worse than that of patients with small liver cancer [6]. Because middle and late-stage liver cancer easily invades the blood vessels inside and outside the liver, and it is accompanied by varying degrees of liver cirrhosis, most patients cannot have radical surgery. The surgical resection rate for large liver cancer was less than 30%, and the 5-year survival rate after surgery was less than 40% [7,8].
For unresectable large liver cancer, TACE is currently recognized as the preferred treatment method [9,10]. Classical TACE (cTACE) is a mixture of iodized oil and chemotherapeutic drugs to selectively embolize tumor blood supply arteries, and cause tumor cell necrosis through cell ischemia and drug toxicity [11-13]. However, not all liver cancer tissues have a good lipiodol deposition effect, and the chemotherapeutic drugs will enter the systemic circulation due to the continuous erosion of blood flow, resulting in a decrease in the efficacy of local drugs and an increase in systemic adverse reactions (AR), which ultimately affects the degree of local chemoembolization. With the development and application of novel embolic materials, DEBs have been continuously used in TACE therapy. DEBs are an ideal embolic material to carry chemotherapeutic drugs, permanently embolize tumor blood vessels and slowly release chemotherapeutic drugs in tumors. Compared with cTACE, DEB-TACE can achieve higher local tumor control rate and better safety [14,15].
Most large liver cancers are rich in blood supply, and there are often multiple blood vessels involved in that blood supply, including the hepatic artery and portal vein. Kim et al. [16] reported the incidence of extrahepatic blood supply for tumors smaller than 4 cm to be less than 3%, and when the tumor diameter was larger than 6 cm, this incidence increased to 63%. Therefore, even with super-selective TACE it is difficult to achieve complete embolization of tumor arteries, and most of the lesions remain after surgery. Studies reported that the tumor necrosis rate for using TACE alone in the treatment of large liver cancer was only 2% [17]. Residual lesions after TACE also seriously affected the treatment effect and prognosis [18,19]. In fact, as the diameter of liver cancer tumors increases, the incidence of subclinical lesions and the incidence of portal cancer thrombi also increase. The results of this study showed that 28 patients (31.11%) were diagnosed with large liver cancer accompanied by vascular invasion, 25 (27.78%) had multiple nodules, and both of these were independent factors affecting patients’ prognoses. In addition, TACE could easily form a hypoxic microenvironment after tumor embolization, leading to changes in hypoxia-related factors and increasing the risk of tumor recurrence [20].
As a multi-kinase inhibitor, sorafenib can effectively inhibit tumor angiogenesis and tumor cell proliferation [21], and make up for the deficiency of TACE in the treatment of large liver cancer. Evidence-based medicine studies confirm that TACE combined with sorafenib can effectively control the growth of advanced HCC, improve prognosis, and prolong survival [22-24]. At present, a number of single-arm studies have confirmed that TACE combined with sorafenib was safe and effective in the treatment of patients with unresectable HCC. However, the results of randomized control trials have not yet reached a unified conclusion. In a double-blind, placebo-controlled, phase III clinical study of TACE combined with sorafenib in the treatment of unresectable HCC patients in Japan and South Korea, the results showed no difference in the primary endpoint TTP between the two groups (5.4 months vs. 3.7 months) [25]. This result was considered to be mainly related to the delay in the administration of sorafenib. Sorafenib was not used until 9 weeks after TACE, at which time new blood vessels and branches might have formed and tumor cells might have spread, resulting in no opportunity for a cumulative effect from sorafenib [26]. Another randomized, open-label, multi-center, phase II clinical study in Japan included a total of 156 patients with unresectable liver cancer. In that study, compared with TACE alone, TACE combined with sorafenib slowed the tumor invasion of blood vessels and extrahepatic metastasis and prolonged the progression-free survival of patients up to 11.7 months. The study concluded that a longer period of taking sorafenib was a key factor in the success of the treatment [24].
CalliSpheres microspheres are DEBs independently researched and developed in China. They are colored microspheres with a smooth surface and a charge, with variable elasticity. These features give the microspheres compressibility in a space smaller than their own particle size and a degree of resilience, which can produce an accumulation of effects after embolization of the target vessel, and enhance the embolization effect [27]. The efficacy of TACE combined with Callispheres drug-eluting bead microspheres is currently widely recognized in clinical practice. Liu et al. [28] performed DEB-TACE treatment and cTACE treatment on 71 cases of massive liver cancer. Three months after the first treatment, the ORR and DCR of the DEB-TACE group were 60.00% and 86.66% respectively, and the median OS was 269 days (approximately 9 months). In this study, DEB-TACE also achieved the same tumor response. Massani et al. [29] retrospectively analyzed records of 28 liver cancer patients treated with DEB-TACE (3 patients in stage A, 4 in stage B, and 21 in stage C). The tumor diameter was 6.15 (±3.45) cm, and the median survival time was 22.7 months. In this study, the median survival time of the DEB-TACE treatment group was 12.7 months, which was shorter than that of the Massani study. It might be because many of the patients with large liver cancer enrolled in this study also had intrahepatic spread and portal vein invasion. The tumor burden was high, and the overall survival (OS) time was short. Compared with cTACE, although DEB-TACE could achieve a higher tumor response rate, it still could not achieve complete tumor embolization and necrosis, and it could not overcome the problem of tumor progression and recurrence caused by the increase of VEGF levels after surgery. Therefore, for patients with large liver cancer, DEB-TACE still needed to be combined with sorafenib, a targeted anti-angiogenesis drug.
DEB-TACE combined with sorafenib is rarely reported in the treatment of liver cancer. In a randomized, double-blind, phase II clinical study of sorafenib combined with DEB-TACE in the treatment of advanced liver cancer, it was found that the combined treatment did not improve the time of disease progression [30]. The study from Johns Hopkins University showed that for unresectable HCC, continuous application of sorafenib treatment, combined with DEB-TACE, could control local tumors well and bring survival benefits to patients [31]. In this study, the ORR and DCR of the experimental group were slightly higher than those of the control group 1 month after the first treatment, but there was no significant difference. The tumor response of the experimental group was significantly better than that of the control group 3 months after the treatment. In addition, compared with the control group, the experimental group’s median OS (18.6 months vs. 12.7 months) and TTP (8.3 months vs. 6.0 months) were improved. This was consistent with the meta-analysis results of TACE combined with sorafenib in the treatment of advanced liver cancer [32]. Multivariate analysis found that using sorafenib was a protective factor for the prognosis of large liver cancer, which further suggested that the combination of sorafenib after DEB-TACE in large liver cancer patients was more meaningful for the prognosis of patients. The biggest advantage of DEB-TACE was the long-lasting chemoembolism effect, while sorafenib could reverse multi-drug chemotherapy resistance and could further improve the effect of traditional chemotherapy drugs. This advantage might be better used in combination with DEB-TACE. In addition, significant necrosis and shrinkage of tumors could occur in the short-term after DEB-TACE. A combination with sorafenib could further effectively inhibit tumor angiogenesis and inhibit tumor growth in this early period. We found that in the experimental group of patients, DSA angiography showed that the tumor blood vessels were significantly reduced, slender, and even disappeared from the tumor angiography, indirectly confirming the ability of sorafenib to inhibit the expression of VEGF receptors. The normalization of blood vessels could recreate the tumor microenvironment, and it was also considered to be the basis of the microenvironment for the treatment of malignant tumors. DEB-TACE combined with molecular targeted therapy might also achieve this goal [33,34].
Previous studies have shown that TACE combined with sorafenib might increase the possibility of liver insufficiency [35]. In this study, the main ARs related to oral sorafenib were hand-foot syndrome, skin rash, diarrhea, fatigue, hypertension, and anorexia. All of them were at or lower than grade 3, which could be alleviated after treatment of the symptoms. Grade 4 ARs were not observed in our study, showing that DEB-TACE combined with sorafenib therapy has good safety in patients with large liver cancer, consistent with the findings of related studies [36]. Wang et al. [37] suggested that practitioners treating patients with sorafenib after TACE should pay attention to evaluation of the patient’s basic condition. Good basic liver function was an important condition for improving the tolerance of sorafenib treatment and ensuring the continuity of treatment. The slow release of drugs after DEB-TACE could protect normal liver tissue to the greatest extent, especially for patients having large liver cancer with poor basic liver function.
The treatment of liver cancer has entered a new era of targeted therapy. The application of various multi-target drugs and immune checkpoint inhibitors has made liver cancer treatment more comprehensive and systematic. This study shows that CalliSpheres-TACE combined with sorafenib has a synergistic anti-tumor effect, which significantly prolongs the disease progression time and OS of patients with large liver cancer, with good safety, and tolerability. It can bring new hopes and choices to patients with large liver cancer. However, the incidence of liver cancer is greatly affected by region, with obvious differences in treatment response and prognosis. Due to economic conditions and national conditions, especially for patients with advanced liver cancer, a reasonable and economical treatment is still something front-line doctors need to consider when formulating a treatment plan. At the same time, global multi-center prospective studies are also necessary to further observe the effectiveness and safety of CalliSpheres-TACE combined with sorafenib.
Disclosure of conflict of interest
None.
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