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Comparison of Transcatheter Arterial Chemoembolization-Radiofrequency Ablation and Transcatheter Arterial Chemoembolization Alone for Advanced Hepatocellular Carcinoma with Macrovascular Invasion Using Propensity Score Analysis: A Retrospective Cohort Study

Comparison of Transcatheter Arterial Chemoembolization-Radiofrequency Ablation and Transcatheter... Hindawi Journal of Oncology Volume 2020, Article ID 1341863, 12 pages https://doi.org/10.1155/2020/1341863 Research Article Comparison of Transcatheter Arterial Chemoembolization-Radiofrequency Ablation and Transcatheter Arterial Chemoembolization Alone for Advanced Hepatocellular Carcinoma with Macrovascular Invasion Using Propensity Score Analysis: A Retrospective Cohort Study 1 1 1 1 1 1 Yao Liu, Yuxin Li , Fangyuan Gao, Qun Zhang, Xue Yang, Bingbing Zhu, 1 2 1 3 1 Shuaishuai Niu, Yunyi Huang, Ying Hu, Wei Li , and Xianbo Wang Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 101121, China Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China Correspondence should be addressed to Wei Li; vision988@126.com and Xianbo Wang; wangxianbo022714@163.com Received 30 March 2020; Revised 8 July 2020; Accepted 13 July 2020; Published 20 August 2020 Academic Editor: San-Lin You Copyright © 2020 Yao Liu et al. 0is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. To compare the efficacies of transcatheter arterial chemoembolization (TACE) with radiofrequency ablation (RFA) (TACE + RFA) and TACE alone in patients with hepatocellular carcinoma (HCC) and macrovascular invasion (MVI). Methods. In total, 664 patients having HCC with MVI were included. Of these patients, 141 were treated with TACE + RFA, 254 with TACE alone, and 269 with supportive therapy (control group). 0e overall survival (OS) was compared among these groups. Propensity score matching (PSM) was performed for balancing the characteristics of the three groups. Results. After one-to-one PSM, the 12- month OS rates were higher in the TACE and TACE + RFA groups than in the control group (p � 0.0009 and p � 0.0017, respectively). Furthermore, higher 12-month OS rates were observed in the TACE + RFA group than in the TACE group (p � 0.0192). 0e 12-month OS rates of patients were remarkably higher in α-fetoprotein (AFP)< 400 ng/ml, tumor< 3, tumor diameter< 5 cm, or portal vein tumor thrombosis (PVTT) group who were treated with TACE + RFA than in those who were treated with TACE (p � 0.0122, p � 0.0090, p � 0112, and p � 0.0071, respectively). Conclusions. TACE + RFA provides a superior survival outcome than TACE alone in HCC patients, especially in AFP<400 ng/ml, tumor<3, tumor diameter<5 cm, or PVTT group. Cancer (BCLC) staging system, HCC accompanied by MVI is 1. Introduction defined as advanced HCC (BCLC stage C) [5–7]. Neither Globally, liver cancer is a major cause of cancer-related death, transcatheter arterial chemoembolization (TACE) with radi- and hepatocellular carcinoma (HCC) accounts for >90% of all ofrequency ablation (RFA) (TACE + RFA) nor TACE alone is primary liver cancers [1]. Approximately, 10%–40% of HCC suitable for treating these patients. Instead, the BCLC guide- patients present with macrovascular invasion (MVI) of the lines recommend sorafenib as a unique treatment for these portal and/or hepatic veins at the time of diagnosis [2–4]. MVI patients. According to two the registered trials using sorafenib, is an independent predictor of poor outcomes in patients with the median overall survival (OS) changed from 5.6 to 8.1 HCC. 0e median survival is considerably lower in HCC months [8, 9]. In contrast, two randomized controlled trials patients with MVI (2−4 months) than in those without MVI reported that HCC patients with MVI did not respond well to (10−24 months) [3]. Based on the Barcelona Clinic Liver sorafenib (response rate: 2%–3.3%). 2 Journal of Oncology Patients with BCLC stage C disease show high hetero- and TACE + RFA groups (p � 0.001 for both). 0e α-feto- geneity, and, therefore, the BCLC treatment algorithm protein (AFP) levels were significantly lower in the TACE + RFA group than in the control group (p � 0.018). cannot be applied regularly [6]. Kodama et al. retrospectively compared the effects of hepatic arterial infusion chemo- Patients who received conservative treatment had signifi- therapy plus radiotherapy with those of sorafenib mono- cantly higher Child-Pugh class, model for end-stage liver therapy in patients with portal vein tumor thrombosis disease (MELD) score, a large number of tumors, and high (PVTT) and advanced HCC. 0e patients in the hepatic BCLC stages (p< 0.001 for all). arterial infusion chemotherapy plus radiotherapy group showed remarkably longer median OS rates than those in the 2.3. Propensity Score Matching. For one-to-one comparison sorafenib monotherapy group (p � 0.002) [10]. Several between patients in the TACE and conservative treatment retrospective studies have reported that locoregional ther- groups, variables in the propensity score model included apies, such as transarterial radioembolization and TACE, GGT levels, MELD score, Child-Pugh class, white blood cell can affect PVTT progression and intravascular tumors de- counts, tumor number, and BCLC stage. For one-to-one velopments [11–13]. However, the optimal treatment for comparison between the patients in the TACE + RFA and HCC patients with MVI is unknown. control groups, the propensity score model included GGT Currently, the number of studies that directly compare levels, Child-Pugh class, AFP levels, tumor number, and the treatment effects of TACE + RFA with TACE in HCC BCLC stage as variables (Table 1). After propensity score patients with MVI is insufficient. 0erefore, in this study, a matching (PSM), the significantly related characteristics retrospective study was performed to compare the effects of were well-balanced (Table 2). For one-to-one comparison the two aforementioned therapies on advanced HCC with between patients in the TACE + RFA and TACE groups, MVI. Furthermore, propensity score matching (PSM) was variables in the propensity score model included tumor performed to correct the potentially confounding elements number, Child-Pugh class, AFP, and PVTT Vp4. After that influence the effects of these therapies. PSM was also propensity score matching (PSM), the significantly related used to reach an equilibrium on the baseline characteristics characteristics of the 139 pairs were well-balanced (Table 3). of the two aforementioned groups [14]. 2.4. Treatment Strategy. 0e appropriate treatment was 2. Materials and Methods selected by our multidisciplinary team. For the unresectable 2.1. Patients Selection. HCC was diagnosed according to the HCC patients with MVI, TACE has been the preferred American Association for the Study of Liver Diseases criteria palliative treatment. 0e following criteria were used for [5]. CT or MRI was used for assessing the presence of MVI. TACE alone: Child-Pugh A or B liver function, absent 0ese techniques were used because intraluminal masses massive ascites, or with gross classification of diffuse type. that expand into the portal vein, hepatic vein, and/or inferior Indications for TACE-RFA were Child-Pugh A or B liver vena cava show enhancement in the arterial phase, and, function, absent massive ascites, or severe hypersplenism under low-attenuation, the intraluminal masses are en- and were performed in patients with inoperative solitary or hanced in the portal phase [15, 16]. 0e requirement for multiple tumors with a diameter of 3–7 cm. 0e HCC pa- informed consent from the patients was waived because of tients with MVI in the control group were evaluated as the retrospective nature of the study. unsuitable for TACE or TACE-RFA therapy, and the pa- In total, 923 HCC patients with MVI were treated with tients with Child-Pugh A liver function gave up sorafenib TACE + RFA, TACE, or conservative therapy from October treatment on their own. 2008 to May 2016. Among these patients, those who met the Patients with HCC and MVI in the control group gave following criteria were included in this study: (i) receiving up sorafenib treatment. TACE + RFA, TACE, or conservative treatment as first-line therapy, (ii) without current or prior malignancies other 2.5. TACE Procedure. Superior mesenteric angiography and than HCC, and (iii) availability for follow-up after the in- common hepatic angiography were performed before che- tervention. Finally, we recruited 664 patients who received moembolization to assess tumor vascularity, vascular TACE + RFA (n � 141), TACE (n � 254), or conservative anatomy, and tumor range. After administering local an- treatment (n � 269) (Figure 1). esthesia to the patients, the Seldinger technique was adopted to introduce a 5F catheter into the abdominal aorta through 2.2. Characteristics of the Study Participants. 0e baseline the superficial femoral artery. During hepatic arterial an- demographic characteristics of the patients after TACE, giography, fluoroscopy was performed to introduce the TACE + RFA, or conservative treatment were compared, catheter into the celiac and superior mesenteric arteries, and the results are shown in Table 1. No significant dif- followed by identification of the feeding artery and staining ference in age distribution was seen among the three groups of the tumor and the surrounding vascular anatomy. A microcatheter was introduced into the feeding artery via the (p � 0.657). Majority of the patients were male and positive for hepatitis B virus surface antigen and had a family history catheter. A combination of ultra-fluid lipiodol (5–10 ml), lobaplatin (20–40 mg), and pirarubicin (10–30 mg) was then of HCC. 0e c-glutamyl transpeptidase (GGT) levels were significantly higher in the control group than in the TACE introduced into the tumor. If there was a significant Journal of Oncology 3 HCC patients with MVI initially treated between October 2008 and May 2016 (n = 923) 259 patients excluded: (i) 701 with MVI and/or extrahepatic metastasis (ii) 124 were not related to HBV, HCV, and/or alcohol (iii) 63 with hepatitis A, D, or E, syphilis, and/or acquired immune deficiency syndrome (iv) 112 with incomplete data or lack of follow up Pooled in the study cohort (n = 664) TACE Supportive therapy (control) TACE + RFA (n = 254) (n = 269) (n = 141) Propensity score matching Propensity score matching Control versus TACE Control versus TACE + RFA (n = 190) (n = 102) Figure 1: Flowchart of the treatments included in the study. Table 1: Baseline characteristics of patients before matching. Control TACE TACE + RFA Variables p value p value (n � 269) (n � 254) (n � 141) a) a) Median age (range) 55 (25–81) 55 (25–78) 0.695 56 (28–78) 0.241 b) b) Sex (M/F) 231/38 217/37 0.886 117/24 0.437 b) b) Family history of HCC (yes/no) 38/231 30/224 0.431 15/126 0.317 b) b) HBV related (yes/no) 248/21 233/21 0.846 129/12 0.803 c) c) GGT (IU/L) 185.3 (90.7–322.2) 125.5 (80.3–181.1) <0.001 95.2 (59.5–143.4) <0.001 9 c) c) WBC (×10 /L) 5.0 (3.6–6.6) 4.6 (3.3–5.9) 0.027 4.5 (3.5–6.5) 0.559 9 c) c) PLT (×10 /L) 108.4 (69.9–158.8) 93.1 (62.0–144.3) 0.068 112.9 (64.0–161.6) 0.747 b) b) AFP (ng/mL) (≥400/<400) 138/131 114/140 0.142 55/86 0.018 b) b) PVTT (%) 226 (84.0) 211 (83.1) 0.849 117 (83.0) 0.849 b) b) HVTT (%) 12 (4.5) 14 (5.5) 0.757 7 (5.0) 0.987 b) b) PVTT + HVTT (%) 31 (11.5) 29 (11.4) 0.844 17 (12.1) 0.979 b) b) Tumor number (≥3/<3) 160/109 111/143 <0.001 48/93 <0.001 b) b) Tumor diameter (cm) (≥5/<5) 167/102 154/100 0.733 77/64 0.143 b) b) Child-Pugh class (A/B or C) 69/200 133/121 <0.001 89/52 <0.001 c) c) MELD score 9.1 (5.3–11.9) 6.4 (3.9–8.4) <0.001 6.0 (3.0–8.3) <0.001 b) b) TNM (III/IV) 221/48 211/43 0.783 125/16 0.085 b) b) BCLC (C/D) 202/67 225/29 <0.001 129/12 <0.001 Age is presented as median (range), categorical variables as number (%), continuous variable as mean (interquartile range). a), t-test; b), chi-square test or Fisher’s exact test; c), Mann–Whitney U test. HBV, hepatitis B virus; GGT, gamma-glutamyl transferase; WBC, white blood cell count; PLT, platelet count; AFP, α-fetoprotein; PVTT, portal vein tumor thrombosis; HVTT, hepatic vein tumor thrombosis; MELD, model for end-stage liver disease; TNM, tumor, node, and metastasis staging; BCLC, Barcelona Clinic for Liver Cancer. arterioportal (AP) shunt, it is necessary to embolize gelatin 2.6. RFA Procedure. RFA was performed one week after sponge particles for occluding the shunt. Additional angi- TACE treatment session, and under conscious analgesic ography was performed before completing the operation to sedation by intravenous administration of 0.5 mg atropine, ensure full blockage of the supplying artery. 0.1 g pethidine hydrochloride, and 10 mg diazepam and 4 Journal of Oncology Table 2: Baseline characteristics of patients after matching. TACE Control TACE + RFA Control Variables p value p value (n � 188) (n � 188) (n � 102) (n � 102) a) a) Median age (range) 55 (25–78) 54 (25–81) 0.655 57 (28–78) 53 (25–80) 0.068 b) b) Sex (M/F) 164/24 160/28 0.500 84/18 90/12 0.236 b) b) Family history of HCC (yes/no) 24/164 25/163 0.878 10/92 15/87 0.286 b) b) HBV related (yes/no) 169/19 174/14 0.362 93/9 94/8 0.800 c) c) GGT (IU/L) 169.4 (86.8–190.4) 197.9 (83.2–275.3) 0.141 101.5 (59.7–156.4) 112.2 (60.4–185.3) 0.711 9 c) c) WBC (×10 /L) 5.0 (3.4–5.8) 5.1 (3.5–6.4) 0.319 4.5 (3.6–6.7) 5.2 (3.8–6.3) 0.955 9 c) c) PLT (×10 /L) 112.6 (61.7–143.8) 126.9 (70.3–162.3) 0.027 111.8 (63.1–161.5) 108.7 (69.9–164.4) 0.898 b) b) AFP (ng/mL) (≥400/<400) 90/98 88/100 0.836 44/58 41/61 0.670 b) b) PVTT (%) 154 (81.9) 147 (78.2) 0.480 83 (81.4) 85 (83.3) 0.713 b) b) HVTT (%) 11 (5.9) 12 (6.4) 1.000 6 (5.9) 6 (5.9) 1.000 b) b) PVTT + HVTT (%) 23 (12.2) 29 (15.4) 0.535 13 (12.7) 11 (10.8) 0.663 b) b) Tumor number (≥3/<3) 92/96 103/85 0.256 41/61 38/64 0.666 b) b) Tumor diameter (cm) (≥5/<5) 109/79 122/66 0.167 56/46 67/35 0.115 b) b) Child-Pugh class (A/B or C) 79/109 66/122 0.168 53/49 50/52 0.674 c) c) MELD score 6.8 (4.4–8.8) 7.7 (4.8–9.6) 0.672 6.4 (3.4–8.8) 7.4 (4.6–9.3) 0.079 b) b) TNM (III/IV) 153/35 155/33 0.789 88/14 88/14 1.000 b) b) BCLC (C/D) 160/28 162/26 0.769 92/10 87/15 0.286 Age is presented as median (range), categorical variables as number (%), continuous variable as mean (interquartile range). a), t-test; b), chi-square test or Fisher’s exact test; c), Mann–Whitney U test. HBV, hepatitis B virus; GGT, gamma-glutamyl transferase; WBC, white blood cell count; PLT, platelet count; AFP, α-fetoprotein; PVTT, portal vein tumor thrombosis; HVTT, hepatic vein tumor thrombosis; MELD, model for end-stage liver disease; TNM, tumor, node, and metastasis staging; BCLC, Barcelona Clinic for Liver Cancer. Table 3: Baseline characteristics of patients undergoing TACE or TACE + RFA before and after matching. Before matching After matching Variables TACE TACE + RFA TACE TACE + RFA p value p value (n � 254) (n � 141) (n � 139) (n � 139) a) a) Median age (range) 55 (25–78) 56 (28–78) 0.131 54 (25–78) 56 (28–78) 0.183 b) b) Sex (M/F) 217/37 117/24 0.518 112/27 117/22 0.431 b) b) Family history of HCC (yes/no) 30/224 15/126 0.725 15/124 14/125 0.844 b) b) HBV related 232/22 129/12 0.959 129/10 127/12 0.657 9 c) c) WBC (×10 /L) 4.9 (3.3–5.8) 4.5 (3.5–6.5) 0.234 4.7 (3.5–6.0) 4.6 (3.6–6.6) 0.542 9 c) c) PLT (×10 /L) 114.7 (62.0–144.5) 112.9 (64.0–161.6) 0.287 98.0 (66.0–143.3) 113.9 (65.0–161.8) 0.542 b) b) AFP (ng/mL) (≥400/<400) 114/140 55/86 0.258 54/85 54/85 1.000 b) b) PVTT (%) 211 (83.1) 117 (83.0) 1.000 119 (85.6) 119 (85.6) 1.000 b) b) Vp1 3 (1.2) 2 (1.4) 1.000 1 (0.7) 2 (1.4) 0.562 b) b) Vp2 17 (6.7) 15 (10.6) 0.323 14 (10.1) 14 (10.1) 1.000 b) b) Vp3 66 (26.0) 44 (31.2) 0.434 53 (38.1) 51 (36.7) 0.804 b) b) Vp4 125 (49.2) 56 (39.7) 0.200 64 (46.0) 65 (46.8) 0.904 b) b) HVTT (%) 14 (5.5) 7 (5.0) 0.769 7 (5.0) 6 (4.3) 0.776 b) b) PVTT + HVTT (%) 29 (11.4) 17 (12.1) 0.825 13 (9.4) 13 (9.4) 1.000 b) b) Tumor number (≥3/<3) 111/143 48/93 0.061 47/92 47/92 1.000 b) b) Tumor diameter (cm) (≥5/<5) 156/98 77/64 0.188 88/51 76/63 0.143 b) b) Child-Pugh class (A/B or C) 136/118 89/52 0.065 89/50 89/50 1.000 c) c) MELD score 6.4 (3.9–8.4) 6.0 (3.0–8.3) 0.159 5.6 (3.7–7.8) 5.1 (3.1–8.3) 0.812 b) b) TNM (III/IV) 211/43 125/16 0.136 114/25 123/16 0.128 b) b) BCLC (C/D) 225/29 129/12 0.364 126/13 128/11 0.669 Age is presented as median (range), categorical variables as number (%), continuous variable as median (interquartile range). a), t-test; b), chi-square test or Fisher’s exact test; c), Mann–Whitney U test. HBV, hepatitis B virus; GGT, gamma-glutamyl transferase; WBC, white blood cell count; PLT, platelet count; AFP, α-fetoprotein; PVTT, portal vein tumor thrombosis; HVTT, hepatic vein tumor thrombosis; MELD, model for end-stage liver disease; TNM, tumor, node, and metastasis staging; BCLC, Barcelona Clinic for Liver Cancer. application of local anesthesia (5 mL of 1% lidocaine). 6–15 years of experience. Certain needle position was de- termined by the deposition of lipiodol after TACE and the CelonPOWER RFA system (Olympus, Beckman Coulter, Inc.) with unipolar ablation electrode was used for ablation. preoperative contrast-enhanced CT (CECT) or enhanced All RFA procedures were performed percutaneously under MRI. 0e number of ablations per procedure and whether nonenhanced CT by two of the four ablation experts with the ablations were performed synchronously or in an Journal of Oncology 5 features of the recurrent tumor, liver function status, and overlapping manner was depended on the diameter, loca- tion, and shape of tumors. 0e aim was to achieve an ablative individual patient requirements. margin of at least 0.5 cm in the normal tissues surrounding the tumor, with the exception of subcapsular and peri- 2.10. Statistical Analysis. 0e continuous variables are vascular portions. Before completion of the procedure, the presented as the mean± standard deviation (if normally needle tract was ablated to avoid bleeding and tumor spread. distributed) or median and range (if nonnormally distrib- uted), and the categorical variables are presented as the 2.7. Adjunct Treatments. In the follow-up period, for pa- number and percentage. To reduce bias related to the fact tients who met the antiviral treatment standard, we applied that patients were not randomized to receive TACE + RFA, tenofovir, entecavir, lamivudine, telbivudine, or adefovir TACE, or conservative treatment, the study used logistic based on the virus replication degree and economic position. regression to generate propensity scores for all the patients. Based on the patients’ liver function, prothrombin activity, 0is was because the 3 treatment groups could have con- and plasma albumin level, we applied liver protection drugs, founding differences at baseline. 0e patients in the 3 plasma, and human albumin support treatment. Consid- treatment groups were matched with those in the control ering the patients’ condition, we applied diuretics and vi- group according to the generated PSs, with a caliper width of tamins. Antibiotics were applied to patients with 0.15 [14]. Following matching, the baseline covariates were spontaneous peritonitis. It was necessary to actively treat compared using a paired t-test or Mann–Whitney U test for some complications such as hepatorenal syndrome, hepatic continuous variables and chi-square test for categorical encephalopathy, and upper gastrointestinal bleeding. variables. 0e Kaplan–Meier method was used for analyzing the OS. All analyses were performed using the SPSS 22.0 statistical package (SPSS, Inc., Chicago, IL, USA) and RMS 2.8. Data Collection. Some prognostic factors related to the packages (R version 3.0.2). A p value <0.05 was considered estimation of patient survival were assessed, such as age, statistically significant. gender, etiology (antihepatitis C antibody, hepatitis B an- tigen, and alcohol consumption), total bilirubin, GGT levels, serum albumin levels, Child-Pugh class, model for end-stage 3. Results liver disease scores, MVI type (PVTT, hepatic vein tumor 0e median survival period for the patients after TACE was thrombosis (HVTT)), AFP levels, number of tumors, 5.3 months, TACE + RFA was 7.2 months, and control was maximum size of the tumor, and BCLC stage. 3 months before PSM and 5 months, 6.6 months, and 3 months, respectively, after PSM. 0e survival rates of TACE 2.9. Follow-Up. 0e study mainly focused on the survival of group were 72.0% at 3 months, 44.5% at 6 months, and the patients which was estimated (in months) from the date 24.9% at 1 year (Figure 2(a)); the TACE + RFA group were of initial intervention to death or final follow-up. 0ree to six 81.6% at 3 months, 57.4% at 6 months, and 34.0% at 1 year weeks after the first TACE or TACE + RFA treatment ses- (Figure 2(c)); and the control group were 42.4% at 3 sion, CT or enhanced MRI was performed to evaluate effect months, 23.8% at 6 months, and 10.0% at 1 year of treatment and detect the residual viable tumor. It is (Figure 2(a)). necessary to carry out tumor markers, CT, MRI, or ultra- sonography every 1–3 months from baseline to 12 months for detecting local recurrent lesions as well as new intra- 3.1. Survival Analysis. Before PSM, Kaplan–Meier analysis hepatic lesions in an early stage. showed that the TACE and TACE + RFA groups exhibited In the TACE group, if thick lipiodol deposition and significantly higher OS than the control group (p< 0.0001 necrosis were observed in the liver tumor, and there was no for all; Figures 2(a) and 2(c). One-to-one PSM helped in tumor enlargement or new lesions, subsequent TACE ses- obtaining 188 pairs of patients in the control versus TACE sions can be postponed. Responding to prior treatment, liver groups, and significantly higher OS rates were observed in function and changes in PS determined the frequency of the TACE group than in the control group (p � 0.0015, following TACE. Figure 2(b)). In addition, 102 pairs of patients in control In the TACE + RFA group, there are two possible types versus TACE + RFA groups (one-to-one matched) were of responses. 0e first is the complete response, in which the formed, and significantly higher OS rates were observed in CECT or enhanced MRI is not enhanced in the area where the TACE + RFA group than in the control group the tumor lies in the arterial phase. 0e second is the in- (p � 0.0017, Figure 2(d)). Furthermore, the 12-month complete response, and CECTor enhanced MRI is enhanced survival rates related to TACE + RFA and TACE treatments in the arterial stage, suggesting residual tumors [17]. It is were analyzed. Our results showed that OS rates were sig- suggested to carry out repeated TACE + RFA treatment for nificantly higher in the TACE + RFA group than in the residual tumor patients following the initial combination TACE group before and after PSM (p � 0.0080 and therapy. If a residual tumor can be observed following two p � 0.0192, respectively; Figure 3). combination therapy sessions, combination therapy has Figure 4 shows the CT images of a typical patient with failed. Patients would be switched to other treatments such massive HCC and PVTT before and after TACE + RFA as TACE alone or conservative treatment according to the treatments. 6 Journal of Oncology Pre-PSM With PSM p < 0.0001 p = 0.0015 0 369 12 0 369 12 Time in months Time in months No. at risk No. at risk Control 269 114 64 37 27 Control 188 99 56 34 25 TACE 254 183 113 77 61 TACE 188 131 77 53 40 Control Control TACE TACE (a) (b) Pre-PSM With PSM 100 100 80 80 40 40 20 20 p < 0.0001 p = 0.0017 0 0 0 369 12 0 369 12 Time in months Time in months No. at risk No. at risk Control 269 114 64 37 27 Control 102 64 36 21 16 TACE – RFA 141 97 81 63 48 TACE – RFA 102 79 54 42 32 Control TACE + RFA Control TACE + RFA (c) (d) Figure 2: Comparison of the OS of patients who were treated with TACE and TACE + RFA with that of those who received conservative treatment before and after PSM analysis. (a) OS in TACE versus control group before PSM. (b) OS in TACE versus control group after PSM. (c) OS in TACE + RFA versus control group before PSM. (d) OS in TACE + RFA versus control group after PSM. 3.2. Subgroup Analysis. We further analyzed the 12-month after TACE + RFA or TACE alone (Figures 5(b), 5(d), and OS in HCC patients with AFP <400 ng/ml or AFP ≥400 ng/ 5(f), 0.4208, p � 0.6478, and p � 0.4700, respectively). ml, tumor number <3 or tumor number ≥3, and tumor 0e 12-month OS rates of HCC patients with PVTT, HVTT, diameter <5 cm or tumor diameter ≥5 cm who underwent or PVTT + HVTT were also analyzed. Our results demonstrated TACE + RFA or TACE alone. Our results demonstrated that that TACE + RFA treatment contributed to a significantly higher the 12-month OS after TACE + RFA was significantly higher rate of 12-month survival in HCC patients with PVTTcompared than TACE alone in the AFP<400 ng/ml, tumor number<3, to those with TACE treatment (p � 0.0071, Figure 6(a)). and tumor diameter <5 cm groups (Figures 5(a), 5(c), and However, the contributions of TACE + RFA and TACE treat- 5(e), p � 0.0122, p � 0.0122, p � 0.0090, and p � 0.0112), ments to 12-month survival did not differ considerably in HCC and that the 12-month OS was similar in the AFP≥ 400 ng/ patients with HVTT (Figure 6(b)) and PVTT + HVTT ml, tumor number≥ 3, and tumor diameter≥ 5 cm groups (Figure 6(c)) (p � 0.6485 and p � 0.6959, respectively). Percent survival Percent survival Percent survival Percent survival Journal of Oncology 7 Pre-PSM With PSM 80 80 40 40 p = 0.0080 p = 0.0192 0 369 12 0 369 12 Time in months Time in months No. at risk No. at risk TACE – RFA 141 115 81 63 48 TACE – RFA 139 114 81 63 48 TACE 254 183 113 77 61 TACE 139 102 68 40 33 TACE + RFA TACE + RFA TACE TACE (a) (b) Figure 3: OS curves of patients in the TACE and TACE + RFA groups. (a) Before PSM and (b) after PSM. (a) (b) (c) (d) (e) (f) Figure 4: Images of diagnosis and follow-up of a 37-year-old patient with massive HCC and PVTT. (a) CT showing tumor and thromboses in the right branch of portal vein (arrow). (b, c) CT showing no tumor and PVTT enhancement at 1 month and 3 months after first TACE + RFA. (d) CTshowing tumor enhancement at 5 months after first TACE + RFA (arrow). (e, f) CTshowing no tumor enhancement at 2 months and 5 months after second TACE + RFA. Percent survival Percent survival 8 Journal of Oncology 100 100 80 80 60 60 40 40 20 20 p = 0.0122 p = 0.4208 0 0 0 369 12 0 369 12 Time in months Time in months No. at risk No. at risk TACE + RFA 8676605037 TACE + RFA 55 39 21 13 11 TACE 138 113 72 51 41 TACE 116 70 41 26 20 TACE + RFA TACE + RFA TACE TACE (a) (b) 100 100 80 80 60 60 40 40 20 20 p = 0.0090 p = 0.6478 0 0 0 369 12 0 369 12 Time in months Time in months No. at risk No. at risk TACE + RFA 93 78 61 48 39 TACE + RFA 48 37 20 15 9 TACE 143 106 72 50 39 TACE 111 77412722 TACE + RFA TACE + RFA TACE TACE (c) (d) 100 100 80 80 60 60 40 40 20 20 p = 0.0112 p = 0.4700 0 0 0 369 12 0 369 12 Time in months Time in months No. at risk No. at risk TACE + RFA 64 55 46 40 35 TACE + RFA 7760352313 TACE 98 79 54 41 34 TACE 156 104 59 36 27 TACE + RFA TACE + RFA TACE TACE (e) (f) Figure 5: OS of patients in the TACE + RFA group compared with the TACE group in subgroups. (a) OS in AFP< 400 ng/ml group; (b) OS in AFP≥ 400 ng/ml group; (c) OS in tumor number< 3 groups; (d) OS in tumor number≥ 3 groups; (e) OS in tumor diameter< 5 cm group; and (f) OS in tumor diameter≥ 5 cm group. Percent survival Percent survival Percent survival Percent survival Percent survival Percent survival Journal of Oncology 9 100 100 80 80 60 60 40 40 20 20 p = 0.0071 p = 0.6485 0 0 0 369 12 0 369 12 Time in months Time in months No. at risk No. at risk TACE – RFA 117 96 70 56 44 TACE – RFA 7 6432 TACE 211 156 99 66 53 TACE 14 9 6 4 3 TACE + RFA TACE + RFA TACE TACE (a) (b) p = 0.6959 0 369 12 Time in months No. at risk TACE – RFA 17 13 7 4 2 TACE 29 18 8 7 5 TACE + RFA TACE (c) Figure 6: Comparisons of the survival of TACE + RFA and TACE alone. (a) PVTT; (b) HVTT; and (c) PVTT + HVTT. p � 0.0112, and p � 0.0071, respectively); however, both 4. Discussion treatments contributed to similar OS rates in AFP≥ 400 ng/ Intermediate stage HCC is commonly treated with a com- ml, tumor number≥ 3, tumor diameter≥ 5 cm, HVTT or bination of TACE and RFA [18, 19]; however, the effec- PVTT + HVTTpatients (p � 0.4208, p � 0.6478, p � 0.4700, tiveness of this treatment, compared to that of TACE p � 0.6485, and p � 0.6959, respectively). treatment alone, in the advanced stage HCC patients is still Nowadays, effective treatments for HCC patients with unknown. 0e present study compared the effectiveness of MVI are limited and controversial. International guidelines TACE + RFA treatment and TACE treatment in HCC pa- recommend sorafenib as the only treatment for HCC pa- tients with MVI. Our results indicated that TACE + RFA tients with MVI [22, 23]. Nevertheless, patients treated with prolonged OS in HCC patients with MVI. MVI in the portal sorafenib show a median OS of 8.1 months and tend to have and hepatic veins highly correlates with the degree of tumor a low tolerance to the drug [9]. 0erefore, its curative effects malignancy [20, 21]. 0e study demonstrated that AFP have been questioned in HCC patients with MVI without <400 ng/ml, tumor number <3, tumor diameter <5 cm, or extrahepatic proliferation. However, surgery, as the first PVTTpatients who received TACE + RFA treatment showed choice, can be used to treat HCC in the early phase while for considerably higher 12-month OS rates than those who HCC, which involves the main portal vein or the main received TACE treatment (p � 0.0122, p � 0.0090, branches, surgery is not proper. According to many studies, Percent survival Percent survival Percent survival 10 Journal of Oncology with MVI. 0erefore, this study assessed the efficacy and RFA and TACE are likely to be beneficial for the unre- sectable HCC regarding local control. survival rates related to TACE + RFA method for treating advanced HCC. TACE is the preferred choice in patients with unre- sectable HCC. 0e expert consensus statement of the 2010 0ere were some limitations to this study. First, this International Hepato-Pancreato-Biliary Association defined study was conducted retrospectively and did not involve any TACE as a standard therapeutic approach for unresectable randomization of the study participants. Second, all TACE HCC, regardless of portal vein involvement (main portal and RFA procedures were performed in a single institution. vein excluded) [24]. TACE has been reported to show better 0erefore, the experiences of patients and physicians could survival rates than conservative therapy in HCC patients affect the study results. 0ird, different from those con- ducted in the United States, Japan, and Europe, the study with PVTT [25–27]. In the present study, unresectable HCC included middle and advanced tumor with poor liver found that 73% of the patients had hepatitis B virus in- fection. Hence, it is necessary to further investigate thera- function reserve, more than 3 tumor nodules that were localized to the different segment or lobe, and extrahepatic peutic strategies in HCC patients in the abovementioned areas. Fourth, no standardized treatment schemes of TACE metastases. According to our retrospective study, TACE showed better survival benefits in HCC patients with PVTT are available regarding anticancer agent dosage, treatment than conservative treatment. Despite delayed tumor pro- type, and schedule. Applying a nonstandardized treatment gression and enhanced OS due to ischemic necrosis caused scheme restricts therapeutic efficacy prediction. Fifth, the by arterial embolization, TACE could hardly achieve better OS for TACE and RFA treatment might be simply due complete necrosis in the target lesion. Following TACE, to the fact that cases subjected to RFA could have tumors incomplete embolization may result in intrahepatic or located in better position, not so close to a major portal vein, where RF would have been contraindicated; this could be extracapsular tumor invasion. Despite the safety and ef- fectiveness of TACE in chosen HCC patients with MVI, demonstrated by the fact that no differences have been shown in cases with AFP greater than 400 ng/ml where it is median survival time remains 3.8–9.5 months [25]. In ad- dition, it is reported that 27–63.2% of patients in advanced highly probable that major hepatic vessels were in close proximity to the tumors not allowing RFA. 0is possibility HCC stage saw an AP shunt [28, 29], due to PVTT [30]. AP shunts sharpen the complications presented by portal hy- might have produced a bias selection. pertension, such as refractory ascites and esophageal varices [23, 31]. Polyvinyl alcohol [32], N-butyl cyanoacrylate [33], 5. Conclusions and ethanol-soaked gelatin sponge [34] have been used for In summary, the results of our study showed that compared the treatment of AP shunts. In this study, gelatin sponge to TACE, TACE + RFA could be more effective for treating particles were used to treat AP shunts. HCC patients with MVI, especially AFP <400 ng/ml, tumor RFA is highly suitable for treating unresectable HCC and number <3, tumor diameter <5 cm, or PVTT patients be- can achieve better results, especially in HCCs with diameters cause it could hinder tumor progression and increase OS. <4 cm [29]. However, owing to failure in achieving complete However, TACE + RFA and TACE alone showed similar necrosis or optimal local tumor control, it is not suitable for effects in patients with AFP ≥400 ng/ml, tumor number ≥3, treating HCCs with diameters >5 cm [35]. Nevertheless, it tumor diameter ≥5 cm, HVTT, or PVTT + HVTT. has been reported in recent years that RFA can be used to treat HCC with PVTT [36]. Data Availability Compared to single treatment with either RFA or TACE, combining TACE with RFA provides several advantages. 0e datasets generated and analyzed during the current First, TACE can improve the ablation rates of bigger tumors study are available from the corresponding author upon by reducing the tumor burden and reducing the viable reasonable request. tumor volume prior to RFA. Moreover, TACE or repeated TACE may narrow and even occlude the major supplying Conflicts of Interest arteries to the tumor [37], adding to the difficulty of selective catheterization of the feeding artery for controlling the re- 0e authors declare that they have no conflicts of interest. sidual tumor cells. Furthermore, HCC is a tumor rich in blood supply. RFA was easily affected by blood vessel-me- Authors’ Contributions diated cooling (the heat-sink effect) [38], a significant influencing factor for hepatic malignant tumor recurrence Yao Liu and Yuxin Li contributed equally to this work. following RFA [39]. TACE can reduce or block the hepatic artery blood flow, thus reducing the heat loss during RFA Acknowledgments and may increase the volume of the zone of ablation and complete ablation rate [35, 40, 41]. Finally, subsequent RFA 0is study was supported by the Beijing Municipal Ad- would contribute to a direct ablation effect on the refractory ministration of Hospitals Clinical Medicine Development of tumors. A combination of TACE and RFA is effective for Special Funding (Grant no. ZYLX201707), the Capital’s local control of medium-sized HCCs (3–5 cm) and HCC Funds for Health Improvement and Research (Grant no. patients with PVTT [41, 42]. 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Comparison of Transcatheter Arterial Chemoembolization-Radiofrequency Ablation and Transcatheter Arterial Chemoembolization Alone for Advanced Hepatocellular Carcinoma with Macrovascular Invasion Using Propensity Score Analysis: A Retrospective Cohort Study

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Copyright © 2020 Yao Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Journal of Oncology Volume 2020, Article ID 1341863, 12 pages https://doi.org/10.1155/2020/1341863 Research Article Comparison of Transcatheter Arterial Chemoembolization-Radiofrequency Ablation and Transcatheter Arterial Chemoembolization Alone for Advanced Hepatocellular Carcinoma with Macrovascular Invasion Using Propensity Score Analysis: A Retrospective Cohort Study 1 1 1 1 1 1 Yao Liu, Yuxin Li , Fangyuan Gao, Qun Zhang, Xue Yang, Bingbing Zhu, 1 2 1 3 1 Shuaishuai Niu, Yunyi Huang, Ying Hu, Wei Li , and Xianbo Wang Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 101121, China Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China Correspondence should be addressed to Wei Li; vision988@126.com and Xianbo Wang; wangxianbo022714@163.com Received 30 March 2020; Revised 8 July 2020; Accepted 13 July 2020; Published 20 August 2020 Academic Editor: San-Lin You Copyright © 2020 Yao Liu et al. 0is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. To compare the efficacies of transcatheter arterial chemoembolization (TACE) with radiofrequency ablation (RFA) (TACE + RFA) and TACE alone in patients with hepatocellular carcinoma (HCC) and macrovascular invasion (MVI). Methods. In total, 664 patients having HCC with MVI were included. Of these patients, 141 were treated with TACE + RFA, 254 with TACE alone, and 269 with supportive therapy (control group). 0e overall survival (OS) was compared among these groups. Propensity score matching (PSM) was performed for balancing the characteristics of the three groups. Results. After one-to-one PSM, the 12- month OS rates were higher in the TACE and TACE + RFA groups than in the control group (p � 0.0009 and p � 0.0017, respectively). Furthermore, higher 12-month OS rates were observed in the TACE + RFA group than in the TACE group (p � 0.0192). 0e 12-month OS rates of patients were remarkably higher in α-fetoprotein (AFP)< 400 ng/ml, tumor< 3, tumor diameter< 5 cm, or portal vein tumor thrombosis (PVTT) group who were treated with TACE + RFA than in those who were treated with TACE (p � 0.0122, p � 0.0090, p � 0112, and p � 0.0071, respectively). Conclusions. TACE + RFA provides a superior survival outcome than TACE alone in HCC patients, especially in AFP<400 ng/ml, tumor<3, tumor diameter<5 cm, or PVTT group. Cancer (BCLC) staging system, HCC accompanied by MVI is 1. Introduction defined as advanced HCC (BCLC stage C) [5–7]. Neither Globally, liver cancer is a major cause of cancer-related death, transcatheter arterial chemoembolization (TACE) with radi- and hepatocellular carcinoma (HCC) accounts for >90% of all ofrequency ablation (RFA) (TACE + RFA) nor TACE alone is primary liver cancers [1]. Approximately, 10%–40% of HCC suitable for treating these patients. Instead, the BCLC guide- patients present with macrovascular invasion (MVI) of the lines recommend sorafenib as a unique treatment for these portal and/or hepatic veins at the time of diagnosis [2–4]. MVI patients. According to two the registered trials using sorafenib, is an independent predictor of poor outcomes in patients with the median overall survival (OS) changed from 5.6 to 8.1 HCC. 0e median survival is considerably lower in HCC months [8, 9]. In contrast, two randomized controlled trials patients with MVI (2−4 months) than in those without MVI reported that HCC patients with MVI did not respond well to (10−24 months) [3]. Based on the Barcelona Clinic Liver sorafenib (response rate: 2%–3.3%). 2 Journal of Oncology Patients with BCLC stage C disease show high hetero- and TACE + RFA groups (p � 0.001 for both). 0e α-feto- geneity, and, therefore, the BCLC treatment algorithm protein (AFP) levels were significantly lower in the TACE + RFA group than in the control group (p � 0.018). cannot be applied regularly [6]. Kodama et al. retrospectively compared the effects of hepatic arterial infusion chemo- Patients who received conservative treatment had signifi- therapy plus radiotherapy with those of sorafenib mono- cantly higher Child-Pugh class, model for end-stage liver therapy in patients with portal vein tumor thrombosis disease (MELD) score, a large number of tumors, and high (PVTT) and advanced HCC. 0e patients in the hepatic BCLC stages (p< 0.001 for all). arterial infusion chemotherapy plus radiotherapy group showed remarkably longer median OS rates than those in the 2.3. Propensity Score Matching. For one-to-one comparison sorafenib monotherapy group (p � 0.002) [10]. Several between patients in the TACE and conservative treatment retrospective studies have reported that locoregional ther- groups, variables in the propensity score model included apies, such as transarterial radioembolization and TACE, GGT levels, MELD score, Child-Pugh class, white blood cell can affect PVTT progression and intravascular tumors de- counts, tumor number, and BCLC stage. For one-to-one velopments [11–13]. However, the optimal treatment for comparison between the patients in the TACE + RFA and HCC patients with MVI is unknown. control groups, the propensity score model included GGT Currently, the number of studies that directly compare levels, Child-Pugh class, AFP levels, tumor number, and the treatment effects of TACE + RFA with TACE in HCC BCLC stage as variables (Table 1). After propensity score patients with MVI is insufficient. 0erefore, in this study, a matching (PSM), the significantly related characteristics retrospective study was performed to compare the effects of were well-balanced (Table 2). For one-to-one comparison the two aforementioned therapies on advanced HCC with between patients in the TACE + RFA and TACE groups, MVI. Furthermore, propensity score matching (PSM) was variables in the propensity score model included tumor performed to correct the potentially confounding elements number, Child-Pugh class, AFP, and PVTT Vp4. After that influence the effects of these therapies. PSM was also propensity score matching (PSM), the significantly related used to reach an equilibrium on the baseline characteristics characteristics of the 139 pairs were well-balanced (Table 3). of the two aforementioned groups [14]. 2.4. Treatment Strategy. 0e appropriate treatment was 2. Materials and Methods selected by our multidisciplinary team. For the unresectable 2.1. Patients Selection. HCC was diagnosed according to the HCC patients with MVI, TACE has been the preferred American Association for the Study of Liver Diseases criteria palliative treatment. 0e following criteria were used for [5]. CT or MRI was used for assessing the presence of MVI. TACE alone: Child-Pugh A or B liver function, absent 0ese techniques were used because intraluminal masses massive ascites, or with gross classification of diffuse type. that expand into the portal vein, hepatic vein, and/or inferior Indications for TACE-RFA were Child-Pugh A or B liver vena cava show enhancement in the arterial phase, and, function, absent massive ascites, or severe hypersplenism under low-attenuation, the intraluminal masses are en- and were performed in patients with inoperative solitary or hanced in the portal phase [15, 16]. 0e requirement for multiple tumors with a diameter of 3–7 cm. 0e HCC pa- informed consent from the patients was waived because of tients with MVI in the control group were evaluated as the retrospective nature of the study. unsuitable for TACE or TACE-RFA therapy, and the pa- In total, 923 HCC patients with MVI were treated with tients with Child-Pugh A liver function gave up sorafenib TACE + RFA, TACE, or conservative therapy from October treatment on their own. 2008 to May 2016. Among these patients, those who met the Patients with HCC and MVI in the control group gave following criteria were included in this study: (i) receiving up sorafenib treatment. TACE + RFA, TACE, or conservative treatment as first-line therapy, (ii) without current or prior malignancies other 2.5. TACE Procedure. Superior mesenteric angiography and than HCC, and (iii) availability for follow-up after the in- common hepatic angiography were performed before che- tervention. Finally, we recruited 664 patients who received moembolization to assess tumor vascularity, vascular TACE + RFA (n � 141), TACE (n � 254), or conservative anatomy, and tumor range. After administering local an- treatment (n � 269) (Figure 1). esthesia to the patients, the Seldinger technique was adopted to introduce a 5F catheter into the abdominal aorta through 2.2. Characteristics of the Study Participants. 0e baseline the superficial femoral artery. During hepatic arterial an- demographic characteristics of the patients after TACE, giography, fluoroscopy was performed to introduce the TACE + RFA, or conservative treatment were compared, catheter into the celiac and superior mesenteric arteries, and the results are shown in Table 1. No significant dif- followed by identification of the feeding artery and staining ference in age distribution was seen among the three groups of the tumor and the surrounding vascular anatomy. A microcatheter was introduced into the feeding artery via the (p � 0.657). Majority of the patients were male and positive for hepatitis B virus surface antigen and had a family history catheter. A combination of ultra-fluid lipiodol (5–10 ml), lobaplatin (20–40 mg), and pirarubicin (10–30 mg) was then of HCC. 0e c-glutamyl transpeptidase (GGT) levels were significantly higher in the control group than in the TACE introduced into the tumor. If there was a significant Journal of Oncology 3 HCC patients with MVI initially treated between October 2008 and May 2016 (n = 923) 259 patients excluded: (i) 701 with MVI and/or extrahepatic metastasis (ii) 124 were not related to HBV, HCV, and/or alcohol (iii) 63 with hepatitis A, D, or E, syphilis, and/or acquired immune deficiency syndrome (iv) 112 with incomplete data or lack of follow up Pooled in the study cohort (n = 664) TACE Supportive therapy (control) TACE + RFA (n = 254) (n = 269) (n = 141) Propensity score matching Propensity score matching Control versus TACE Control versus TACE + RFA (n = 190) (n = 102) Figure 1: Flowchart of the treatments included in the study. Table 1: Baseline characteristics of patients before matching. Control TACE TACE + RFA Variables p value p value (n � 269) (n � 254) (n � 141) a) a) Median age (range) 55 (25–81) 55 (25–78) 0.695 56 (28–78) 0.241 b) b) Sex (M/F) 231/38 217/37 0.886 117/24 0.437 b) b) Family history of HCC (yes/no) 38/231 30/224 0.431 15/126 0.317 b) b) HBV related (yes/no) 248/21 233/21 0.846 129/12 0.803 c) c) GGT (IU/L) 185.3 (90.7–322.2) 125.5 (80.3–181.1) <0.001 95.2 (59.5–143.4) <0.001 9 c) c) WBC (×10 /L) 5.0 (3.6–6.6) 4.6 (3.3–5.9) 0.027 4.5 (3.5–6.5) 0.559 9 c) c) PLT (×10 /L) 108.4 (69.9–158.8) 93.1 (62.0–144.3) 0.068 112.9 (64.0–161.6) 0.747 b) b) AFP (ng/mL) (≥400/<400) 138/131 114/140 0.142 55/86 0.018 b) b) PVTT (%) 226 (84.0) 211 (83.1) 0.849 117 (83.0) 0.849 b) b) HVTT (%) 12 (4.5) 14 (5.5) 0.757 7 (5.0) 0.987 b) b) PVTT + HVTT (%) 31 (11.5) 29 (11.4) 0.844 17 (12.1) 0.979 b) b) Tumor number (≥3/<3) 160/109 111/143 <0.001 48/93 <0.001 b) b) Tumor diameter (cm) (≥5/<5) 167/102 154/100 0.733 77/64 0.143 b) b) Child-Pugh class (A/B or C) 69/200 133/121 <0.001 89/52 <0.001 c) c) MELD score 9.1 (5.3–11.9) 6.4 (3.9–8.4) <0.001 6.0 (3.0–8.3) <0.001 b) b) TNM (III/IV) 221/48 211/43 0.783 125/16 0.085 b) b) BCLC (C/D) 202/67 225/29 <0.001 129/12 <0.001 Age is presented as median (range), categorical variables as number (%), continuous variable as mean (interquartile range). a), t-test; b), chi-square test or Fisher’s exact test; c), Mann–Whitney U test. HBV, hepatitis B virus; GGT, gamma-glutamyl transferase; WBC, white blood cell count; PLT, platelet count; AFP, α-fetoprotein; PVTT, portal vein tumor thrombosis; HVTT, hepatic vein tumor thrombosis; MELD, model for end-stage liver disease; TNM, tumor, node, and metastasis staging; BCLC, Barcelona Clinic for Liver Cancer. arterioportal (AP) shunt, it is necessary to embolize gelatin 2.6. RFA Procedure. RFA was performed one week after sponge particles for occluding the shunt. Additional angi- TACE treatment session, and under conscious analgesic ography was performed before completing the operation to sedation by intravenous administration of 0.5 mg atropine, ensure full blockage of the supplying artery. 0.1 g pethidine hydrochloride, and 10 mg diazepam and 4 Journal of Oncology Table 2: Baseline characteristics of patients after matching. TACE Control TACE + RFA Control Variables p value p value (n � 188) (n � 188) (n � 102) (n � 102) a) a) Median age (range) 55 (25–78) 54 (25–81) 0.655 57 (28–78) 53 (25–80) 0.068 b) b) Sex (M/F) 164/24 160/28 0.500 84/18 90/12 0.236 b) b) Family history of HCC (yes/no) 24/164 25/163 0.878 10/92 15/87 0.286 b) b) HBV related (yes/no) 169/19 174/14 0.362 93/9 94/8 0.800 c) c) GGT (IU/L) 169.4 (86.8–190.4) 197.9 (83.2–275.3) 0.141 101.5 (59.7–156.4) 112.2 (60.4–185.3) 0.711 9 c) c) WBC (×10 /L) 5.0 (3.4–5.8) 5.1 (3.5–6.4) 0.319 4.5 (3.6–6.7) 5.2 (3.8–6.3) 0.955 9 c) c) PLT (×10 /L) 112.6 (61.7–143.8) 126.9 (70.3–162.3) 0.027 111.8 (63.1–161.5) 108.7 (69.9–164.4) 0.898 b) b) AFP (ng/mL) (≥400/<400) 90/98 88/100 0.836 44/58 41/61 0.670 b) b) PVTT (%) 154 (81.9) 147 (78.2) 0.480 83 (81.4) 85 (83.3) 0.713 b) b) HVTT (%) 11 (5.9) 12 (6.4) 1.000 6 (5.9) 6 (5.9) 1.000 b) b) PVTT + HVTT (%) 23 (12.2) 29 (15.4) 0.535 13 (12.7) 11 (10.8) 0.663 b) b) Tumor number (≥3/<3) 92/96 103/85 0.256 41/61 38/64 0.666 b) b) Tumor diameter (cm) (≥5/<5) 109/79 122/66 0.167 56/46 67/35 0.115 b) b) Child-Pugh class (A/B or C) 79/109 66/122 0.168 53/49 50/52 0.674 c) c) MELD score 6.8 (4.4–8.8) 7.7 (4.8–9.6) 0.672 6.4 (3.4–8.8) 7.4 (4.6–9.3) 0.079 b) b) TNM (III/IV) 153/35 155/33 0.789 88/14 88/14 1.000 b) b) BCLC (C/D) 160/28 162/26 0.769 92/10 87/15 0.286 Age is presented as median (range), categorical variables as number (%), continuous variable as mean (interquartile range). a), t-test; b), chi-square test or Fisher’s exact test; c), Mann–Whitney U test. HBV, hepatitis B virus; GGT, gamma-glutamyl transferase; WBC, white blood cell count; PLT, platelet count; AFP, α-fetoprotein; PVTT, portal vein tumor thrombosis; HVTT, hepatic vein tumor thrombosis; MELD, model for end-stage liver disease; TNM, tumor, node, and metastasis staging; BCLC, Barcelona Clinic for Liver Cancer. Table 3: Baseline characteristics of patients undergoing TACE or TACE + RFA before and after matching. Before matching After matching Variables TACE TACE + RFA TACE TACE + RFA p value p value (n � 254) (n � 141) (n � 139) (n � 139) a) a) Median age (range) 55 (25–78) 56 (28–78) 0.131 54 (25–78) 56 (28–78) 0.183 b) b) Sex (M/F) 217/37 117/24 0.518 112/27 117/22 0.431 b) b) Family history of HCC (yes/no) 30/224 15/126 0.725 15/124 14/125 0.844 b) b) HBV related 232/22 129/12 0.959 129/10 127/12 0.657 9 c) c) WBC (×10 /L) 4.9 (3.3–5.8) 4.5 (3.5–6.5) 0.234 4.7 (3.5–6.0) 4.6 (3.6–6.6) 0.542 9 c) c) PLT (×10 /L) 114.7 (62.0–144.5) 112.9 (64.0–161.6) 0.287 98.0 (66.0–143.3) 113.9 (65.0–161.8) 0.542 b) b) AFP (ng/mL) (≥400/<400) 114/140 55/86 0.258 54/85 54/85 1.000 b) b) PVTT (%) 211 (83.1) 117 (83.0) 1.000 119 (85.6) 119 (85.6) 1.000 b) b) Vp1 3 (1.2) 2 (1.4) 1.000 1 (0.7) 2 (1.4) 0.562 b) b) Vp2 17 (6.7) 15 (10.6) 0.323 14 (10.1) 14 (10.1) 1.000 b) b) Vp3 66 (26.0) 44 (31.2) 0.434 53 (38.1) 51 (36.7) 0.804 b) b) Vp4 125 (49.2) 56 (39.7) 0.200 64 (46.0) 65 (46.8) 0.904 b) b) HVTT (%) 14 (5.5) 7 (5.0) 0.769 7 (5.0) 6 (4.3) 0.776 b) b) PVTT + HVTT (%) 29 (11.4) 17 (12.1) 0.825 13 (9.4) 13 (9.4) 1.000 b) b) Tumor number (≥3/<3) 111/143 48/93 0.061 47/92 47/92 1.000 b) b) Tumor diameter (cm) (≥5/<5) 156/98 77/64 0.188 88/51 76/63 0.143 b) b) Child-Pugh class (A/B or C) 136/118 89/52 0.065 89/50 89/50 1.000 c) c) MELD score 6.4 (3.9–8.4) 6.0 (3.0–8.3) 0.159 5.6 (3.7–7.8) 5.1 (3.1–8.3) 0.812 b) b) TNM (III/IV) 211/43 125/16 0.136 114/25 123/16 0.128 b) b) BCLC (C/D) 225/29 129/12 0.364 126/13 128/11 0.669 Age is presented as median (range), categorical variables as number (%), continuous variable as median (interquartile range). a), t-test; b), chi-square test or Fisher’s exact test; c), Mann–Whitney U test. HBV, hepatitis B virus; GGT, gamma-glutamyl transferase; WBC, white blood cell count; PLT, platelet count; AFP, α-fetoprotein; PVTT, portal vein tumor thrombosis; HVTT, hepatic vein tumor thrombosis; MELD, model for end-stage liver disease; TNM, tumor, node, and metastasis staging; BCLC, Barcelona Clinic for Liver Cancer. application of local anesthesia (5 mL of 1% lidocaine). 6–15 years of experience. Certain needle position was de- termined by the deposition of lipiodol after TACE and the CelonPOWER RFA system (Olympus, Beckman Coulter, Inc.) with unipolar ablation electrode was used for ablation. preoperative contrast-enhanced CT (CECT) or enhanced All RFA procedures were performed percutaneously under MRI. 0e number of ablations per procedure and whether nonenhanced CT by two of the four ablation experts with the ablations were performed synchronously or in an Journal of Oncology 5 features of the recurrent tumor, liver function status, and overlapping manner was depended on the diameter, loca- tion, and shape of tumors. 0e aim was to achieve an ablative individual patient requirements. margin of at least 0.5 cm in the normal tissues surrounding the tumor, with the exception of subcapsular and peri- 2.10. Statistical Analysis. 0e continuous variables are vascular portions. Before completion of the procedure, the presented as the mean± standard deviation (if normally needle tract was ablated to avoid bleeding and tumor spread. distributed) or median and range (if nonnormally distrib- uted), and the categorical variables are presented as the 2.7. Adjunct Treatments. In the follow-up period, for pa- number and percentage. To reduce bias related to the fact tients who met the antiviral treatment standard, we applied that patients were not randomized to receive TACE + RFA, tenofovir, entecavir, lamivudine, telbivudine, or adefovir TACE, or conservative treatment, the study used logistic based on the virus replication degree and economic position. regression to generate propensity scores for all the patients. Based on the patients’ liver function, prothrombin activity, 0is was because the 3 treatment groups could have con- and plasma albumin level, we applied liver protection drugs, founding differences at baseline. 0e patients in the 3 plasma, and human albumin support treatment. Consid- treatment groups were matched with those in the control ering the patients’ condition, we applied diuretics and vi- group according to the generated PSs, with a caliper width of tamins. Antibiotics were applied to patients with 0.15 [14]. Following matching, the baseline covariates were spontaneous peritonitis. It was necessary to actively treat compared using a paired t-test or Mann–Whitney U test for some complications such as hepatorenal syndrome, hepatic continuous variables and chi-square test for categorical encephalopathy, and upper gastrointestinal bleeding. variables. 0e Kaplan–Meier method was used for analyzing the OS. All analyses were performed using the SPSS 22.0 statistical package (SPSS, Inc., Chicago, IL, USA) and RMS 2.8. Data Collection. Some prognostic factors related to the packages (R version 3.0.2). A p value <0.05 was considered estimation of patient survival were assessed, such as age, statistically significant. gender, etiology (antihepatitis C antibody, hepatitis B an- tigen, and alcohol consumption), total bilirubin, GGT levels, serum albumin levels, Child-Pugh class, model for end-stage 3. Results liver disease scores, MVI type (PVTT, hepatic vein tumor 0e median survival period for the patients after TACE was thrombosis (HVTT)), AFP levels, number of tumors, 5.3 months, TACE + RFA was 7.2 months, and control was maximum size of the tumor, and BCLC stage. 3 months before PSM and 5 months, 6.6 months, and 3 months, respectively, after PSM. 0e survival rates of TACE 2.9. Follow-Up. 0e study mainly focused on the survival of group were 72.0% at 3 months, 44.5% at 6 months, and the patients which was estimated (in months) from the date 24.9% at 1 year (Figure 2(a)); the TACE + RFA group were of initial intervention to death or final follow-up. 0ree to six 81.6% at 3 months, 57.4% at 6 months, and 34.0% at 1 year weeks after the first TACE or TACE + RFA treatment ses- (Figure 2(c)); and the control group were 42.4% at 3 sion, CT or enhanced MRI was performed to evaluate effect months, 23.8% at 6 months, and 10.0% at 1 year of treatment and detect the residual viable tumor. It is (Figure 2(a)). necessary to carry out tumor markers, CT, MRI, or ultra- sonography every 1–3 months from baseline to 12 months for detecting local recurrent lesions as well as new intra- 3.1. Survival Analysis. Before PSM, Kaplan–Meier analysis hepatic lesions in an early stage. showed that the TACE and TACE + RFA groups exhibited In the TACE group, if thick lipiodol deposition and significantly higher OS than the control group (p< 0.0001 necrosis were observed in the liver tumor, and there was no for all; Figures 2(a) and 2(c). One-to-one PSM helped in tumor enlargement or new lesions, subsequent TACE ses- obtaining 188 pairs of patients in the control versus TACE sions can be postponed. Responding to prior treatment, liver groups, and significantly higher OS rates were observed in function and changes in PS determined the frequency of the TACE group than in the control group (p � 0.0015, following TACE. Figure 2(b)). In addition, 102 pairs of patients in control In the TACE + RFA group, there are two possible types versus TACE + RFA groups (one-to-one matched) were of responses. 0e first is the complete response, in which the formed, and significantly higher OS rates were observed in CECT or enhanced MRI is not enhanced in the area where the TACE + RFA group than in the control group the tumor lies in the arterial phase. 0e second is the in- (p � 0.0017, Figure 2(d)). Furthermore, the 12-month complete response, and CECTor enhanced MRI is enhanced survival rates related to TACE + RFA and TACE treatments in the arterial stage, suggesting residual tumors [17]. It is were analyzed. Our results showed that OS rates were sig- suggested to carry out repeated TACE + RFA treatment for nificantly higher in the TACE + RFA group than in the residual tumor patients following the initial combination TACE group before and after PSM (p � 0.0080 and therapy. If a residual tumor can be observed following two p � 0.0192, respectively; Figure 3). combination therapy sessions, combination therapy has Figure 4 shows the CT images of a typical patient with failed. Patients would be switched to other treatments such massive HCC and PVTT before and after TACE + RFA as TACE alone or conservative treatment according to the treatments. 6 Journal of Oncology Pre-PSM With PSM p < 0.0001 p = 0.0015 0 369 12 0 369 12 Time in months Time in months No. at risk No. at risk Control 269 114 64 37 27 Control 188 99 56 34 25 TACE 254 183 113 77 61 TACE 188 131 77 53 40 Control Control TACE TACE (a) (b) Pre-PSM With PSM 100 100 80 80 40 40 20 20 p < 0.0001 p = 0.0017 0 0 0 369 12 0 369 12 Time in months Time in months No. at risk No. at risk Control 269 114 64 37 27 Control 102 64 36 21 16 TACE – RFA 141 97 81 63 48 TACE – RFA 102 79 54 42 32 Control TACE + RFA Control TACE + RFA (c) (d) Figure 2: Comparison of the OS of patients who were treated with TACE and TACE + RFA with that of those who received conservative treatment before and after PSM analysis. (a) OS in TACE versus control group before PSM. (b) OS in TACE versus control group after PSM. (c) OS in TACE + RFA versus control group before PSM. (d) OS in TACE + RFA versus control group after PSM. 3.2. Subgroup Analysis. We further analyzed the 12-month after TACE + RFA or TACE alone (Figures 5(b), 5(d), and OS in HCC patients with AFP <400 ng/ml or AFP ≥400 ng/ 5(f), 0.4208, p � 0.6478, and p � 0.4700, respectively). ml, tumor number <3 or tumor number ≥3, and tumor 0e 12-month OS rates of HCC patients with PVTT, HVTT, diameter <5 cm or tumor diameter ≥5 cm who underwent or PVTT + HVTT were also analyzed. Our results demonstrated TACE + RFA or TACE alone. Our results demonstrated that that TACE + RFA treatment contributed to a significantly higher the 12-month OS after TACE + RFA was significantly higher rate of 12-month survival in HCC patients with PVTTcompared than TACE alone in the AFP<400 ng/ml, tumor number<3, to those with TACE treatment (p � 0.0071, Figure 6(a)). and tumor diameter <5 cm groups (Figures 5(a), 5(c), and However, the contributions of TACE + RFA and TACE treat- 5(e), p � 0.0122, p � 0.0122, p � 0.0090, and p � 0.0112), ments to 12-month survival did not differ considerably in HCC and that the 12-month OS was similar in the AFP≥ 400 ng/ patients with HVTT (Figure 6(b)) and PVTT + HVTT ml, tumor number≥ 3, and tumor diameter≥ 5 cm groups (Figure 6(c)) (p � 0.6485 and p � 0.6959, respectively). Percent survival Percent survival Percent survival Percent survival Journal of Oncology 7 Pre-PSM With PSM 80 80 40 40 p = 0.0080 p = 0.0192 0 369 12 0 369 12 Time in months Time in months No. at risk No. at risk TACE – RFA 141 115 81 63 48 TACE – RFA 139 114 81 63 48 TACE 254 183 113 77 61 TACE 139 102 68 40 33 TACE + RFA TACE + RFA TACE TACE (a) (b) Figure 3: OS curves of patients in the TACE and TACE + RFA groups. (a) Before PSM and (b) after PSM. (a) (b) (c) (d) (e) (f) Figure 4: Images of diagnosis and follow-up of a 37-year-old patient with massive HCC and PVTT. (a) CT showing tumor and thromboses in the right branch of portal vein (arrow). (b, c) CT showing no tumor and PVTT enhancement at 1 month and 3 months after first TACE + RFA. (d) CTshowing tumor enhancement at 5 months after first TACE + RFA (arrow). (e, f) CTshowing no tumor enhancement at 2 months and 5 months after second TACE + RFA. Percent survival Percent survival 8 Journal of Oncology 100 100 80 80 60 60 40 40 20 20 p = 0.0122 p = 0.4208 0 0 0 369 12 0 369 12 Time in months Time in months No. at risk No. at risk TACE + RFA 8676605037 TACE + RFA 55 39 21 13 11 TACE 138 113 72 51 41 TACE 116 70 41 26 20 TACE + RFA TACE + RFA TACE TACE (a) (b) 100 100 80 80 60 60 40 40 20 20 p = 0.0090 p = 0.6478 0 0 0 369 12 0 369 12 Time in months Time in months No. at risk No. at risk TACE + RFA 93 78 61 48 39 TACE + RFA 48 37 20 15 9 TACE 143 106 72 50 39 TACE 111 77412722 TACE + RFA TACE + RFA TACE TACE (c) (d) 100 100 80 80 60 60 40 40 20 20 p = 0.0112 p = 0.4700 0 0 0 369 12 0 369 12 Time in months Time in months No. at risk No. at risk TACE + RFA 64 55 46 40 35 TACE + RFA 7760352313 TACE 98 79 54 41 34 TACE 156 104 59 36 27 TACE + RFA TACE + RFA TACE TACE (e) (f) Figure 5: OS of patients in the TACE + RFA group compared with the TACE group in subgroups. (a) OS in AFP< 400 ng/ml group; (b) OS in AFP≥ 400 ng/ml group; (c) OS in tumor number< 3 groups; (d) OS in tumor number≥ 3 groups; (e) OS in tumor diameter< 5 cm group; and (f) OS in tumor diameter≥ 5 cm group. Percent survival Percent survival Percent survival Percent survival Percent survival Percent survival Journal of Oncology 9 100 100 80 80 60 60 40 40 20 20 p = 0.0071 p = 0.6485 0 0 0 369 12 0 369 12 Time in months Time in months No. at risk No. at risk TACE – RFA 117 96 70 56 44 TACE – RFA 7 6432 TACE 211 156 99 66 53 TACE 14 9 6 4 3 TACE + RFA TACE + RFA TACE TACE (a) (b) p = 0.6959 0 369 12 Time in months No. at risk TACE – RFA 17 13 7 4 2 TACE 29 18 8 7 5 TACE + RFA TACE (c) Figure 6: Comparisons of the survival of TACE + RFA and TACE alone. (a) PVTT; (b) HVTT; and (c) PVTT + HVTT. p � 0.0112, and p � 0.0071, respectively); however, both 4. Discussion treatments contributed to similar OS rates in AFP≥ 400 ng/ Intermediate stage HCC is commonly treated with a com- ml, tumor number≥ 3, tumor diameter≥ 5 cm, HVTT or bination of TACE and RFA [18, 19]; however, the effec- PVTT + HVTTpatients (p � 0.4208, p � 0.6478, p � 0.4700, tiveness of this treatment, compared to that of TACE p � 0.6485, and p � 0.6959, respectively). treatment alone, in the advanced stage HCC patients is still Nowadays, effective treatments for HCC patients with unknown. 0e present study compared the effectiveness of MVI are limited and controversial. International guidelines TACE + RFA treatment and TACE treatment in HCC pa- recommend sorafenib as the only treatment for HCC pa- tients with MVI. Our results indicated that TACE + RFA tients with MVI [22, 23]. Nevertheless, patients treated with prolonged OS in HCC patients with MVI. MVI in the portal sorafenib show a median OS of 8.1 months and tend to have and hepatic veins highly correlates with the degree of tumor a low tolerance to the drug [9]. 0erefore, its curative effects malignancy [20, 21]. 0e study demonstrated that AFP have been questioned in HCC patients with MVI without <400 ng/ml, tumor number <3, tumor diameter <5 cm, or extrahepatic proliferation. However, surgery, as the first PVTTpatients who received TACE + RFA treatment showed choice, can be used to treat HCC in the early phase while for considerably higher 12-month OS rates than those who HCC, which involves the main portal vein or the main received TACE treatment (p � 0.0122, p � 0.0090, branches, surgery is not proper. According to many studies, Percent survival Percent survival Percent survival 10 Journal of Oncology with MVI. 0erefore, this study assessed the efficacy and RFA and TACE are likely to be beneficial for the unre- sectable HCC regarding local control. survival rates related to TACE + RFA method for treating advanced HCC. TACE is the preferred choice in patients with unre- sectable HCC. 0e expert consensus statement of the 2010 0ere were some limitations to this study. First, this International Hepato-Pancreato-Biliary Association defined study was conducted retrospectively and did not involve any TACE as a standard therapeutic approach for unresectable randomization of the study participants. Second, all TACE HCC, regardless of portal vein involvement (main portal and RFA procedures were performed in a single institution. vein excluded) [24]. TACE has been reported to show better 0erefore, the experiences of patients and physicians could survival rates than conservative therapy in HCC patients affect the study results. 0ird, different from those con- ducted in the United States, Japan, and Europe, the study with PVTT [25–27]. In the present study, unresectable HCC included middle and advanced tumor with poor liver found that 73% of the patients had hepatitis B virus in- fection. Hence, it is necessary to further investigate thera- function reserve, more than 3 tumor nodules that were localized to the different segment or lobe, and extrahepatic peutic strategies in HCC patients in the abovementioned areas. Fourth, no standardized treatment schemes of TACE metastases. According to our retrospective study, TACE showed better survival benefits in HCC patients with PVTT are available regarding anticancer agent dosage, treatment than conservative treatment. Despite delayed tumor pro- type, and schedule. Applying a nonstandardized treatment gression and enhanced OS due to ischemic necrosis caused scheme restricts therapeutic efficacy prediction. Fifth, the by arterial embolization, TACE could hardly achieve better OS for TACE and RFA treatment might be simply due complete necrosis in the target lesion. Following TACE, to the fact that cases subjected to RFA could have tumors incomplete embolization may result in intrahepatic or located in better position, not so close to a major portal vein, where RF would have been contraindicated; this could be extracapsular tumor invasion. Despite the safety and ef- fectiveness of TACE in chosen HCC patients with MVI, demonstrated by the fact that no differences have been shown in cases with AFP greater than 400 ng/ml where it is median survival time remains 3.8–9.5 months [25]. In ad- dition, it is reported that 27–63.2% of patients in advanced highly probable that major hepatic vessels were in close proximity to the tumors not allowing RFA. 0is possibility HCC stage saw an AP shunt [28, 29], due to PVTT [30]. AP shunts sharpen the complications presented by portal hy- might have produced a bias selection. pertension, such as refractory ascites and esophageal varices [23, 31]. Polyvinyl alcohol [32], N-butyl cyanoacrylate [33], 5. Conclusions and ethanol-soaked gelatin sponge [34] have been used for In summary, the results of our study showed that compared the treatment of AP shunts. In this study, gelatin sponge to TACE, TACE + RFA could be more effective for treating particles were used to treat AP shunts. HCC patients with MVI, especially AFP <400 ng/ml, tumor RFA is highly suitable for treating unresectable HCC and number <3, tumor diameter <5 cm, or PVTT patients be- can achieve better results, especially in HCCs with diameters cause it could hinder tumor progression and increase OS. <4 cm [29]. However, owing to failure in achieving complete However, TACE + RFA and TACE alone showed similar necrosis or optimal local tumor control, it is not suitable for effects in patients with AFP ≥400 ng/ml, tumor number ≥3, treating HCCs with diameters >5 cm [35]. Nevertheless, it tumor diameter ≥5 cm, HVTT, or PVTT + HVTT. has been reported in recent years that RFA can be used to treat HCC with PVTT [36]. Data Availability Compared to single treatment with either RFA or TACE, combining TACE with RFA provides several advantages. 0e datasets generated and analyzed during the current First, TACE can improve the ablation rates of bigger tumors study are available from the corresponding author upon by reducing the tumor burden and reducing the viable reasonable request. tumor volume prior to RFA. Moreover, TACE or repeated TACE may narrow and even occlude the major supplying Conflicts of Interest arteries to the tumor [37], adding to the difficulty of selective catheterization of the feeding artery for controlling the re- 0e authors declare that they have no conflicts of interest. sidual tumor cells. Furthermore, HCC is a tumor rich in blood supply. RFA was easily affected by blood vessel-me- Authors’ Contributions diated cooling (the heat-sink effect) [38], a significant influencing factor for hepatic malignant tumor recurrence Yao Liu and Yuxin Li contributed equally to this work. following RFA [39]. TACE can reduce or block the hepatic artery blood flow, thus reducing the heat loss during RFA Acknowledgments and may increase the volume of the zone of ablation and complete ablation rate [35, 40, 41]. Finally, subsequent RFA 0is study was supported by the Beijing Municipal Ad- would contribute to a direct ablation effect on the refractory ministration of Hospitals Clinical Medicine Development of tumors. A combination of TACE and RFA is effective for Special Funding (Grant no. ZYLX201707), the Capital’s local control of medium-sized HCCs (3–5 cm) and HCC Funds for Health Improvement and Research (Grant no. patients with PVTT [41, 42]. 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Published: Aug 20, 2020

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