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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 2  |  Page : 250-257

Transarterial chemoembolization combined with microwave ablation and apatinib in patients with Barcelona clinic liver cancer Stage C hepatocellular carcinoma: A propensity score matching analysis


1 Department of Minimally Invasive Interventional Therapy, Sun Yat-Sen University Cancer Center; Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou, China
2 Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China; Zhong Shan Medical School, Sun Yat-Sen University, Guangzhou, China

Date of Submission18-May-2019
Date of Decision08-Nov-2019
Date of Acceptance15-Nov-2019
Date of Web Publication28-May-2020

Correspondence Address:
Weijun Fan
Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, No. 651 Dongfeng East Road, Guangzhou, Guangzhou 510060 People's
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_345_19

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 > Abstract 

Context and Aims: Apatinib combined with transarterial chemoembolization (TACE) has shown promising results in cases of Barcelona clinic liver cancer Stage C (BCLC C) hepatocellular carcinoma (HCC). This study aimed to investigate the efficacy and safety of TACE in combination with microwave ablation (MWA) and apatinib.
Materials and Methods: A retrospective, single.center study was undertaken using a one.to.one propensity score matching (PSM) analysis design and involved BCLC C HCC patients who underwent treatment with TACE.MWA.apatinib or TACE alone between January 2013 and June 2018. The patients were recommended to administer 500mg apatinib per day, combined with MWA and TACE. The adverse effects of apatinib, MWA. and TACE.related complications, progression.free survival (PFS), and overall survival (OS) were assessed.
Results: Of the 149 patients with BCLC C HCC who underwent TACE.MWA.apatinib or TACE alone, 131 were included in our study. Among them, 21 (16.0%) received TACE.MWA.apatinib and 110 (84.0%) underwent TACE alone. After PSM, twenty pairs were enrolled into different treatment groups. Patients in the TACE.MWA.apatinib group had a significantly longer median PFS than patients in the TACE.alone group on both before (median, 8.9 vs. 1.7 months, P = 0.0002) and after PSM (median, 5.4 vs. 2.1 months, P = 0.001). They also had a significantly longer median OS than patients in the TACE.alone group on before (median, 24.4 vs. 5.8 months, P = 0.000007) and after PSM (median, 24.4 vs. 5.4 months, P = 0.00005).
Conclusions: The combination of apatinib, TACE, and MWA in BCLC C HCC patients is safe and effective. Toxicity is manageable by adjusting the apatinib dosage.

Keywords: Apatinib, Barcelona clinic liver cancer Stage C, hepatocellular carcinoma, microwave ablation, transarterial chemoembolization


How to cite this article:
Shuanggang C, Shen L, Qiu Z, Qi H, Cao F, Xie L, Fan W. Transarterial chemoembolization combined with microwave ablation and apatinib in patients with Barcelona clinic liver cancer Stage C hepatocellular carcinoma: A propensity score matching analysis. J Can Res Ther 2020;16:250-7

How to cite this URL:
Shuanggang C, Shen L, Qiu Z, Qi H, Cao F, Xie L, Fan W. Transarterial chemoembolization combined with microwave ablation and apatinib in patients with Barcelona clinic liver cancer Stage C hepatocellular carcinoma: A propensity score matching analysis. J Can Res Ther [serial online] 2020 [cited 2020 Jul 16];16:250-7. Available from: http://www.cancerjournal.net/text.asp?2020/16/2/250/285183

FNx01Chen Shuanggang, Lujun Shen, Zhiyu Qiu, contributed equally to this work.





 > Introduction Top


Transarterial chemoembolization (TACE) is an effective treatment for patients with intermediate- and advanced-stage hepatocellular carcinoma (HCC) and the one that has been recommended in cases of HCC with a limited portal vein tumor thrombus (PVTT).[1],[2] However, TACE can induce hypoxia and elevate levels of the pro-angiogenic factor and vascular endothelial growth factor (VEGF), in residual surviving HCC tissues, which may result in metastasis and recurrence.[3],[4] Therefore, theoretically, TACE combined with sorafenib could be a good treatment choice in cases of advanced HCC. However, some clinical studies have shown that such treatment produces an unsatisfactory response for HCC.[5],[6]

Local ablation, such as microwave ablation (MWA), has been recommended as a treatment method for those patients who are not suitable for curative surgical treatment.[7] However, the rate of complete ablation in HCC after single radiofrequency ablation (RFA) varies from 48% to 97%.[8] Some studies have shown that incomplete tumor ablation could be an important factor in enhancing local tumor angiogenesis and promoting the rapid progression of residual HCC.[9],[10] Yet, in contrast, an animal study has demonstrated that sorafenib can suppress HCC progression in cases of incomplete ablation.[11]

Apatinib is an oral small-molecule tyrosine kinase inhibitor (TKI) that selectively binds to and inhibits the VEGF receptor 2 (VEGFR2) and is available in Mainland China. Some clinical studies have suggested that a combination treatment of the angiogenesis inhibitor, apatinib, and TACE can significantly prolong the progression-free survival (PFS) and overall survival (OS) of patients with advanced HCC.[12],[13] Some studies have reported that TACE combined with MWA can also improve OS in advanced HCC patients, with a better efficacy than through using TACE alone.[14],[15] However, no previous studies have focused on the effect of a combination therapy using apatinib, TACE, and MWA. Therefore, we conducted a retrospective study to compare the efficacy of apatinib combined with TACE and MWA in patients with advanced Barcelona clinic liver cancer Stage C (BCLC C) HCC through propensity score matching (PSM).


 > Materials and Methods Top


Patients

We retrospectively analyzed the data of 389 patients with BCLC C HCC treated at the Sun Yat-sen University Cancer Center (SYSUCC), China, between January 2013 and June 2018. All patients provided informed consent for their inclusion before participating in the study. The study was conducted in accordance with the Declaration of Helsinki and was approved by the SYSUCC Hospital Ethics Committee. The inclusion criteria included: (1) patients (≥18 years) with an HCC diagnosis confirmed by histopathological examination or radiologic imaging studies; (2) classification as BCLC C HCC, based on the criteria of the American Association for the Study of Liver Diseases guidelines;[16] (3) a Child–Pugh score of A to B8; and (4) adequate bone marrow, renal, and cardiac function. The exclusion criteria were: (1) patients with severe coagulation disorders; (2) patients with HIV infection or an immune deficiency; (3) patients with a second primary malignancy; (4) patients who received other systemic treatments prior to cancer progression; (5) pregnant women or women who were planning to get pregnant; and (6) patients with a disease recurrence following surgical resection [Figure 1]. After the application of these criteria, a total of 131 patients were included in the study, of whom 21 patients underwent treatment with apatinib combined with TACE and MWA (the TACE-MWA–apatinib group), and 110 patients underwent treatment with TACE alone (the TACE-alone group). Within the week prior to commencing treatment (i.e., TACE or MWA), we obtained patients' data, including imaging, biochemistry, tumor markers, and routine blood test results.
Figure 1: Flow diagram of the study design. A total of 389 patients met the enrollment criteria. Twenty pairs were generated after a 1:1 propensity score matching analysis

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Transarterial chemoembolization procedure

All patients enrolled in this study, who were divided into the TACE-MWA–apatinib and TACE-alone groups according to whether they went on to receive apatinib and MWA or not, underwent at least one round of TACE treatment. In the cases where the tumor was incompletely ablated or where disease progression or recurrence was observed, undergoing repeated cycles of TACE or MWA was recommended following an evaluation of the tumor response by three experienced physicians, who formed a consensus decision using computed tomography (CT) or magnetic resonance imaging (MRI) results, according to the modified Response Evaluation Criteria in Solid (mRECIST) criteria.[17]

A super selective method that is recommended for hepatic artery administration via the femoral artery was used to administer TACE. This method allowed for the injection of lipiodol, lobaplatin, and pirarubicin (i.e., lipiodol: lobaplatin: pirarubicin = 5–15 ml: 30–50 mg: 30–50 mg, where the dosage was dependent on whether the tumor was completely embolized) directly into the tumor site; thus, it performed a dual role comprised of both an embolism and chemotherapy. The end point of the completed procedure was the complete embolization of the tumor with the stagnation of blood flow from the feeding arteries and the absence of tumor staining on an angiogram. All TACE procedures were performed by an interventional radiologist with more than 5 years of experience.

Microwave ablation procedure

The patients were recommended to undergo MWA therapy after 1–2 cycles of TACE treatment. The patients could choose whether to accept the physician's advice, according to their physical condition, and economic and/or social status. Those patients who followed the physician's recommendations underwent CT-guided percutaneous MWA under local anesthesia (5–10 ml 2% lidocaine), followed by the administration of analgesia (range, 40–100 mg meperidine). According to the location, size, and number of the lesions, physicians, who each had at least 5 years of experience of performing CT-guided percutaneous MWA, chose the number of MWA needles used, the power (range, 50–80 W) and corresponding time (range, 3–10 min/time) and whether to adjust the needle position in order to eliminate as much of the tumor as possible. For example, for tumors with a maximum diameter of <5 cm, physicians could choose a MWA needle that would best achieve the ablation end point with the adjustment of the power and time of MWA and the position of needle. However, for tumors with a maximum diameter of larger than 5 cm, physicians could choose to use two or more MWA needles and multiple-time overlapping MWA in order to achieve the ablation end point. For multiple tumors, if possible, all lesions were treated in a single procedure. A CT scan was obtained immediately after MWA. For tumors <5 cm in diameter and those capable of complete ablation, the end point of MWA was defined as having a security boundary that extended at least 5 mm beyond the tumor boundary. For tumors larger than 5 cm in diameter or that were incapable of complete ablation, the end point of MWA was defined as more than 95% of the whole lesion having been treated. Complete ablation was defined as the inability to detect enhanced lesions by contrast material-enhanced CT or MRI 1 month after MWA. All patients were routinely hospitalized for 2–3 days after MWA unless complications occurred.

Microwave ablation equipment

A microwave delivery system (FORSEA; Qinghai Microwave Electronic Institute, Nanjing, China) was used during MWA therapy. This system consisted of an MTC-3 microwave generator (FORSEA) with a frequency of 2450 MHz, a power output of 10–150 W, a flexible low-loss cable, and a 16G cooled-shaft antenna.

Apatinib management

Patients could also be recommended to take apatinib after TACE treatment. Patients could choose whether to take apatinib according to their physical condition and economic and/or social status. Patients in the TACE-MWA–apatinib group underwent at least 4 weeks of oral apatinib therapy, at a dose of 500 mg/day, after TACE treatment and until there were signs of disease progression according to the mRECIST criteria, a protocol-defined unacceptable and unrelieved toxicity occurred, there was a dose interruption of more than 1 month, or for other reasons. Dose reductions (i.e., 250 mg once daily, or 250 mg every other day) and drug interruptions were allowed in cases of Grades 3–4 drug-related adverse events (AEs), defined according to the Common Terminology Criteria for AEs version 4.0.

Follow-up, tumor response assessment, and the end point

All patients underwent a re-examination approximately 1 month after the last cycle of TACE or MWA treatment using abdominal contrast material-enhanced CT or MRI. Assessment of the treatment response was based on the mRECIST 1.1 criteria. All the contrast material-enhanced CT or MRI results were examined by at least two diagnostic radiologists, each with more than 5 years of experience, during the follow-up.

The primary end point was the patients' OS, which was defined as the interval time from the start of thefirst TACE treatment to death by any cause. The secondary end point was the patients' PFS, which was defined as the interval time from the start of thefirst TACE treatment to progression of the disease, according to the mRECIST 1.1 criteria, or death.

Statistical analysis

Unadjusted hazard ratios and the effects of baseline characteristics on efficacy were assessed using Cox proportional-hazard modeling. The PFS and OS rates for each group were estimated using Kaplan–Meier curves and compared between the two groups using a log-rank test. Categorical patient variables were compared between the two groups using either a Chi-square or Fisher's exact test. The log-rank rank test and other statistical tests of the primary end point were two sided. P <0.05 indicated statistical significance. To minimize selection bias from selecting factors related to the treatment, a PSM analysis was used. The following variables were included in the propensity model; age, sex, Child–Pugh class, alpha-fetoprotein (AFP) level, tumor size, number of tumors, PVTT, distant metastasis, and hepatitis B virus (HBV) infection. One-to-one matching between the groups was conducted using the optimal matching method. All the statistical analyses were conducted using the statistical software, SPSS version 25.0. IBM, New York, United States of America.


 > Results Top


Baseline characteristics of the transarterial chemo emboli zation-microwave ablation-apatinib and transarterial chemoembolization-alone groups before and after propensity score matching analyses

[Table 1] shows the characteristics of patients with advanced HCC, who were treated between January 2013 and June 2018, for the TACE-MWA–apatinib and TACE-alone groups, before and after PSM. Before PSM, a total of 148 patients were enrolled in this study, of whom 21 (16.0%) and 110 (84.0%) were in the TACE-MWA–apatinib and TACE-alone groups, respectively. After PSM, a total of forty patients were enrolled in this study, twenty (50%) of whom were in the TACE-MWA–apatinib group and twenty (50%) were in the TACE-alone group. Several variables, such as age (P = 0.016), PVTT (P = 0.0005), and distant metastasis (P = 0.007), were statistically significantly different between the two groups before PSM; however, these statistically significant differences were eradicated after PSM (age, P = 0.292; PVTT, P = 0.168; distant metastasis, P = 0.723). There were no significant differences between the two groups for the other variables (AFP, tumor size, number of tumors, HBV infection, Child–Pugh class, and sex) either before or after PSM [Table 1].
Table 1: Baseline characteristics of patients who received transarterial chemoembolization-microwave ablation-apatinib and transarterial chemoembolization alone

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Apatinib administration, adverse events, and complications

No treatment-related deaths occurred in either group. In the TACE-MWA–apatinib group, the median duration of apatinib administration was 2.1 months. Seven of the 21 TACE-MWA–apatinib patients had to reduce the apatinib dosage from 500 to 250 mg because of AEs; however, two patients recovered the full dosage as the AEs could be tolerated. The apatinib-related AEs are depicted, in detail, in [Table 2]. Twenty-six AEs occurred in 13 (61.9%) of the 21 patients. There were five Grade 3–4 AEs that occurred in five patients (23.8%), all of whom either reduced the dosage of apatinib from 500 to 250 mg or required a transient interruption. However, all the 21 patients persevered with the apatinib treatment, regardless of the apatinib-related AEs.
Table 2: Adverse events related to apatinib in the transarterial chemoembolization-microwave ablation-apatinib group

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A total of 118 complications were observed in 74 patients. There were no major complications in the TACE-MWA–apatinib group, but two major complications were observed in the TACE-alone group (one patient developed myelosuppression and another developed septicemia). The minor complications observed in both groups are depicted in [Table 3]. The major (P = 0.488) and minor (P = 0.053) complication rates between the two groups were not significantly different. However, the total number of complications in TACE-MWA–apatinib group was significantly less than those in TACE-alone group (P = 0.036) [Table 3].
Table 3: Complications related to microwave ablation or transarterial chemoembolization

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Progression-free survival

The median PFS was 8.9 months (95% confidence interval [CI]: 1.5–16.2 months) in the TACE-MWA–apatinib group and 1.7 months (95% CI: 1.1–2.4 months) in the TACE-alone group before PSM (P = 0.0002) [Figure 2]. After PSM, the median PFS time was 5.4 months (95% CI: 0.0–11.2 months) in the TACE-MWA–apatinib group and 2.1 months (95% CI: 1.0–3.3 months) in the TACE-alone group (P = 0.001) [Figure 3]. Ten variables (sex, age, Child–Pugh class, tumor size, number of tumors, AFP level, HBV infection, PVTT, distant metastasis, and treatment method) were included in a Cox proportional-hazards model, but univariable analyses showed that only the method of treatment (TACE-MWA–apatinib or TACE-alone), PVTT, and age were significantly associated with PFS [Table 4]. To exclude the possibility that variable interactions contributed to PFS, a multivariate analysis using the age, tumor size, number of tumors, AFP level, PVTT, distant metastasis, method of treatment, and HBV infection variables was carried out. This suggested that the method of treatment and AFP level were independent prognostic factors of PFS [Table 4].
Figure 2: Kaplan–Meier curves of progression-free survival for the transarterial chemoembolization-microwave ablation–apatinib and transarterial chemoembolization-alone groups, before one-to-one propensity score matching. Transarterial chemoembolization-microwave ablation–apatinib group: n = 21; median progression-free survival, 8.9 months; 95% confidence interval: 1.5–16.2 months. Transarterial chemoembolization-alone group: n = 110; median progression-free survival, 1.7 months; 95% confidence interval: 1.1–2.4 months (P = 0.0002)

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Figure 3: Kaplan–Meier curves of progression-free survival for the transarterial chemoembolization-microwave ablation–apatinib and transarterial chemoembolization-alone groups, after one-to-one propensity score matching. Transarterial chemoembolization-microwave ablation–apatinib group: n = 20; median progression-free survival, 5.4 months; 95% confidence interval: 0.0–11.2 months. Transarterial chemoembolization-alone group: n = 20; median progression-free survival, 2.1 months; 95% confidence interval: 1.0–3.3 months (P = 0.001)

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Table 4: Univariate and multivariate analyses of progression-free survival in the enrolled cohort

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Overall survival

The median OS was 24.4 months (95% CI: not available) for the TACE-MWA–apatinib group and 5.8 months (95% CI: 3.4–7.4 months) for the TACE-alone group before PSM (P = 0.000007) [Figure 4]. After a PSM analysis, the median OS time was 24.4 months in the TACE-MWA–apatinib group and 5.4 months in the TACE-alone group (P = 0.00005) [Figure 5]. The same ten variables that were used for the PFS Cox proportional-hazards model were included in a Cox proportional-hazards model of OS. Univariable analyses showed that the method of treatment (TACE-MWA–apatinib or TACE alone) and PVTT were the only factors significantly associated with OS [Table 5]. To exclude the possibility that interactions between variables contributed to OS, seven variables (tumor size, number of tumors, AFP level, PVTT, distant metastasis, method of treatment, and HBV infection) were analyzed using a multivariate analysis, which suggested that the method of treatment was the only independent prognostic factor of OS [Table 5].
Figure 4: Kaplan–Meier curves of overall survival for the transarterial chemoembolization-microwave ablation–apatinib and transarterial chemoembolization-alone groups, before one-to-one propensity score matching. Transarterial chemoembolization-microwave ablation–apatinib group: n = 21; median overall survival, 24.4 months; 95% confidence interval: not available. Transarterial chemoembolization-alone group: n = 110; median overall survival, 5.8 months; 95% confidence interval: 5.2–6.5 months (P = 0.000007)

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Figure 5: Kaplan–Meier curves of overall survival for the transarterial chemoembolization-microwave ablation–apatinib and transarterial chemoembolization-only groups, after one-to-one propensity score matching. Transarterial chemoembolization-microwave ablation–apatinib group: n = 20; median overall survival, 24.4 months; 95% confidence interval: not available. Transarterial chemoembolization-alone group: n = 20; median overall survival, 5.4 months; 95% confidence interval: 3.4–7.4 months (P = 0.00005)

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Table 5: Univariate and multivariate analyses of the overall survival for the enrolled cohort

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 > Discussion Top


The treatment of advanced HCC is a challenge worldwide. Previous studies have shown that the median OS time of HCC patients with PVTT was 2.7–4 months without treatment.[18]

According to the BCLC guidelines, Sorafenib is recommended as thefirst-line treatment.[19] Studies have shown that treatment with Sorafenib, in combination with a hepatectomy or local therapy, is tolerable and could significantly prolong a patient's OS time in cases of advanced liver cancer.[20],[21] For tumors that are capable of complete ablation, this may be because MWA or a hepatectomy reduces the tumor burden, whereas sorafenib reduces the likelihood of tumor recurrence. For tumors that are incapable of complete ablation, sorafenib, a multikinase inhibitor, could reduce the rapid progression of residual tumors by inhibiting the hypoxia inducible factor-1a/VEGF A pathway and tumor angiogenesis.[22],[23] Some studies have suggested that local ablation treatment combined with sorafenib can push advanced HCC into complete remission and can significantly prolong OS time and reduce recurrence in patients with early-stage or advanced HCC.[24],[25]

TACE is also a very important method of treatment in patients with BCLC C HCC. However, TACE causes local hypoxia in the residual tumor by blocking tumor-supplying arteries that, consequently, can stimulate the neovascularization of tumors by inducing high levels of VEGF expression in tissues around the residual tumor, which increases tissue invasion and metastasis. Studies have shown that sorafenib combined with TACE and RFA results in a longer PFS and better OS than a combination of just TACE and RFA in patients with medium or large and advanced, recurrent HCC.[26],[27] Apatinib, an oral small-molecule TKI available in Mainland China that is cost-effective than sorafenib, selectively binds to and inhibits VEGFR2, and has an affinity for VEGFR2 that is ten times higher than that of sorafenib.[28] Recently, studies have shown that TACE combined with apatinib can significantly prolong the PFS and improve the OS of patients with BCLC C HCC, suggesting that apatinib may be a promising oral anti-angiogenic agent in the treatment of advanced HCC.[12],[13] For example, Chen et al. reported the outcome of eighty BCLC C HCC patients receiving TACE combined with apatinib or TACE alone with, who had median OS times of 13 and 9.9 months, respectively.[13] Furthermore, a case report suggested that apatinib may effectively control the progression of HCC in patients with sorafenib resistance.[29] Although no clinical study has been published on the effect of apatinib combined with ablation treatment in humans, one study suggested that apatinib can improve the efficacy of RFA in the treatment of HCC in animals.[30] Additional studies have reported that TACE combined with MWA can improve OS in patients with advanced HCC.[14],[15] For example, Li et al. reported the outcomes of sixty advanced HCC patients receiving TACE combined with MWA treatment. These patients had 1- and 3-year OS rates of 48% and 23%, respectively, with a median 3-year OS of 13.5 months.[14],[15] We have retrospectively explored the treatment of apatinib combined with TACE and MWA in patients with BCLC C HCC.

Our study, which is based on the theory of PSM analysis, suggests that apatinib in combination with TACE and MWA is an effective and tolerable method of treatment in patients with BCLC C HCC. We also found that treatment with TACE-MWA–apatinib was a protective factor and that the OS of patients with BCLC C HCC who underwent TACE-MWA–apatinib treatment was prolonged by 79% compared to patients who underwent TACE alone, according to univariate and multivariate Cox regression analyses [Table 4]. We found that tumor size, AFP level, HBV infection, PVTT, and distant metastasis are factors that do not affect OS, although this may be due to using too small a sample size. The study also revealed that TACE-MWA–apatinib treatment in patients with BCLC C HCC was safe as there were few Grade 3–4 AEs associated with apatinib [Table 2] and no major complications associated with MWA or TACE [Table 3]. Even in cases where Grade 3–4 AEs did occur, they were effectively controlled through dose reduction and supporting therapies.

Although our findings are significant, there were several limitations to this study. First, our sample size was too small to satisfactorily reflect the effectiveness of TACE-MWA–apatinib therapy in all patients with BCLC C HCC. Second, the study was retrospective and based in a single center, which may create selection bias. Therefore, prospective and multicentric randomized controlled trials will be conducted in future.


 > Conclusion Top


This study is thefirst to reveal that combination therapy using apatinib, TACE, and MWA has a promising outcome in patients with BCLC C HCC. Patients who undergo TACE-MWA–apatinib combination therapy have a significantly longer OS than those who undergo treatment with TACE alone.

Acknowledgments

Here, we would like to especially thank Shuanggang Chen's girlfriend, Ms. Binyan Shen, for her great support for him when he has been pursuing the dream of conquering HCC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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