| Part 1 Polyvinyl Alcohol Chemoembolization for Hepatocellular Carcinoma With Hepatic Arteriovenous Shunts: Safety and EfficacyBackgroundHepatocellular carcinoma (HCC) frequently accompanies hepatic arteriovenous shunts (HAVS), with a reported incidence of 31.2%, including hepatic artery-portal vein shunts (A-PVS), hepatic artery-hepatic vein shunts (A-HVS) and mixed type. Of HAVS, A-PVS accounted for 76% to 92.3%, and occurred in 28.8% to 63.2% of HCC cases. HAVS is considered a poor prognostic factor for several reasons. HAVS can aggravate portal hypertension and increase the incidence of potentially life-threatening conditions, such as rupture of gastroesophageal varices, refractory ascites, portal vein steal hypohepatia, pulmonary embolism, and allergic lung damage. When HAVS appears, either subsequent chemoembolization had to be abandoned or the dose of embolic agents had to be reduced. More than that, the chemotherapeutic agents lipiodol emulsion (CALE) will be diverted instead to the portal vein or hepatic vein and thence to normal areas in the liver or lungs instead of being deposited intratumorally.To obliterate shunt, it is important to use the appropriate embolic materials and to achieve a terminal embolization. Relatively large embolic agents such as gelatin sponge and coils had been used for the embolization of HA VS. There is a consensus that proximal vessel occlusion results in near-instantaneous recruitment of intraparenchymal collateral flow, reconstituting the distal vasculature. Long-term embolic agents, such as Polyvinyl Alcohol (PVA), absolute alcohol, N-Butylcyanoacrylate (NBCA) appeare better efficacy due to its long-term effect and its low rate of recanalization. PVA is relatively effective embolic agents because of its low recanalization rate. Moreover, as a particulate embolizing agent, it is easy to handle, and is available in a wide range of sizes.PurposeThe purpose of the present study was to evaluate whether PVA chemoembolization could be performed safely and effectively in patients with HAVS of HCC.MethodsFrom January 2013 to December 2014,133 patients (121 males and 12 females; median age,51 years; range,25-77 years) underwent transarterial chemoembolization (TACE) with PVA for HCC with HAVS at Nanfang Hospital. The baseline characteristics of the slow-flow type (n= 36), intermediate-flow type (n= 58) and high-flow type (n= 39) patients revealed no different significantly among the different types (P>0.05).The diagnosis was made using the American Association for Study of Liver Diseases (AASLD) consensus guidelines for imaging diagnosis of HCC. The exclusion criteria were (i) Eastern Cooperative Oncology Group performance status (ECOG PS)>2, (ii) Child-Pugh class C, (iii) severe dysfunction of blood coagulation, (iv) severe dysfunction of heart-lung functions, (v) portal venous trunk completely blocked by tumor emboli and periportal collateral circulation undeveloped.HAVS was classified into three types according to the develop time of the arterial to venous (A-V) on arteriogram images:slow-flow HAVS:A-V>3 s; intermediate-flow HAVS:A-V=1.6-3 s; high-flow HAVS:A-V=0.5-1.5 s. According to the develop time of HAVS, the size of the PVA used was determined by the scheme: slow-flow HAVS:300-500 μm PVA; intermediate-flow HAVS:500-710 urn PVA; high-flow HAVS:710-1000 μm PVA. The cases with slow-flow and intermediate-flow HAVS were treated by 0.5-1 vial of PVA particulate following CALE. The CALE was a combination of pirarubicin (THP) 10-20 mg, oxaliplatin (L-OHP) 50-100 mg, and mitomycin C (MMC) 10 mg, dissolved in 5-15 mL contrast medium mixed with lipiodol at a 1:1 volume ratio. The high-flow type embolized by PVA-700 plus only with chemotherapeutic agents.Of the 133 patients,17 cases were treated PVA-TACE plus somfenib. Patients received sorafenib 400 mg BID on day 4 (to day 7) after the first TACE (day 1), then were interrupted on the day of next TACE, and taken sorafenib again on day 4 (to day 7) after subsequent TACE. To reduce the effect of potential confounding factors, we used a propensity score matching (PSM) method to adjust for potential confounding which randomly selected individuals in the PVA-TACE (group B, n=116) were paired with comparable individuals in the sorafenib plus PVA-TACE (group A, n=17) who fulfilled a matching criterion by 1:1.Overall survival (OS) was defined as the time interval between the initial PVA chembolization of the shunts and death or last follow-up. Patients were followed up until death or to the end of the study period (June 30,2015). Progression-free survival (PFS) was defined as the duration of time from the date of the initial PVA chemoembolization to the date of the first sign of tumor progression for patients who showed radiological evidence of disease progression or the date on which the patients died from any cause. Efficacy was assessed based on the following parameters:(1) OS, PFS; (2) tumor response, objective response rate (ORR); (3) immediate angiogram occlusion rate; (4) the characteristics of patients of pre and post-embolisation:Child-pugh class, PS score, ascites, AFP value and tumor size et al. (5) postoperative complications.Modified Response Evaluation Criteria In Solid Tumors (mRECIST) were employed to assess the tumor response on enhanced CT/MRI scans. The degree of shunts occlusion was divided into three categories:complete occlusion, nearly complete occlusion and incomplete occlusion. Angiographic complete occlusion was defined as obliteration of the shunt; nearly complete occlusion was defined as a "minor residual shunt"; and incomplete occlusion was defined as flow decrease only with one class.Continuous data are expressed as means standard deviation (x±s). One-way ANOVA analysis was was utilized to compare the measurement data. The Wilcoxon signed-rank test was employed for comparison of noncategoric variables. Survival curves were calculated by Kaplan-Meier method and compared by log-rank test. A two-tailed P value lower than 0.05 was considered statistically significant. Data were analyzed with IBM SPSS statistics version 22 and Stata 13.Results1. The efficacy of PVA chemoembolization for HCC with HAVSThe median OS of 133 patients was 9.1 months. The median OS of the slow-flow type, intermediate-flow type and high-flow type patients were 10.8 months,9.1 months and 7.3 months, respectively. The overall survival rates of the 133 patients were 73.7%,36.2%, and 10.2% at 6-month,12-month, and 24-month, respectively. The overall survival rates of the slow-flow type, intermediate-flow type and high-flow type patients were 77.8% and 42.7%,72.4% and 39.2%,69.2% and 19.0% at 6-month, and 12-month, respectively. Different HAVS of survival curves were estimated according to the Kaplan-Meier method and compared statistically by a log-rank test, revealed no different significantly among the different types (χ2= 2.865, P= 0.239).The median PFS of 113 patients with complete evaluation of imaging data was 3.7 months. The PFS rates of the 113 patients were 58.4%,31.9%, and 7.1%at 3-month,6-month, and 12-month, respectively. The median PFS of the slow-flow type (n= 36), intermediate-flow type (n= 48) and high-flow type (n= 29) patients were 3.6 months,3.7 months and 4.0 months, respectively. Different HAVS of PFS were estimated according to the Kaplan-Meier method and compared statistically by a log-rank test, revealed no different significantly among the different types (χ2= 0.926, P= 0.629).A total of 268 sessions of embolization were performed, with each patient receiving a median of two sessions (range,1-8). A total of 214 sessions of shunts embolization were performed. Of 140 sessions showed complete occlusion,40 sessions showed nearly complete occlusion and 34 cases showed incomplete occlusion. The rate of immediate angiogram occlusion were different significantly between three types of HAVS (χ2=29.096, P<0.001). The complete occlusion rate, nearly complete occlusion rate and incomplete occlusion rate were achieved in 65.4%, 18.7%,15.9%, respectively.A total of 93 patients with complete evaluation of imaging data after the embolization procedure. The ORR of 17.2%(16/93). The ORR were no different significantly among three types of HAVS (χ2=0.348, P=0.840). The OS had different significantly between group of tumor remission and group of tumor non-remission (χ2=6.601, P=0.010).2. The efficacy of sorafenib plus chemoembolization with PVA for HCC with HAVSAfter matching, the median OS of group A and group B were 12.8 months and 6.0 months, respectively. There was statistically significant difference between group A and group B (χ2=5.490, P=0.019). For group A and group B, the 6-month and 12-month survival rate of patients were 75.5% and 43.2%,47.1% and 13.7%, respectively.3. The complications of PVA chemoembolization for HCC with HAVSPostembolization syndrome developed in most patients, that was a self-limiting syndrome consisting of fever, abdominal pain, and vomiting etc. The baseline index of Child-Pugh class, ECOG PS score, total bilirubin, prothrombin time and serum albumin were significantly increased by one week after embolization (all P<0.01). The 30-day mortality was 3.8% (5/133). Gastroesophageal variceal hemorrhage rate was 1.1%(3/268), and acute hepatic failure incidence was 0.4%(1/268).Conclusions1. It is safe and effective for HCC with HAVS by the chemoembolization therapy with PVA plus chemotherapeutic agents (or PVA plus CALE).2. The efficacy of Sorafenib plus chemoembolization with PVA for HCC with HAVS is preferable to PVA-TACE alone.3. Care was taken not to reach total stasis of arterial flow to prevent acute hepatic dysfunction, especially in patients with high gastrointestinal hemorrhage risk factors, such as main portal vein thrombosis, severe liver cirrhosis, and severe gastroesophageal variceal, etc. The decision to pursue curative efficacy must be made after cautious consideration. It is advisable that embolism shunts should be separated when left and right hepatic arteries blood supply simultaneity.Part2 The Survival Prognostic Factors of Polyvinyl Alcohol Chemoembolization for Hepatocellular Carcinoma With Hepatic Arteriovenous ShuntsBackground and PurposeHepatocellular carcinoma (HCC) frequently accompanies hepatic arteriovenous shunts (HAVS), with a reported incidence of 31.2%. To avoid recanalization, it is important to use the appropriate embolic materials and to achieve a terminal embolization. Relatively large embolic agents such as gelatin sponge and coils had been used for the embolization of HAVS. There is a consensus that proximal vessel occlusion results in near-instantaneous recruitment of intraparenchymal collateral flow, reconstituting the distal vasculature. Long-term embolic agents, such as Polyvinyl Alcohol (PVA), absolute alcohol, N-Butylcyanoacrylate (NBCA) due to its long-term effect and its low rate of recanalization, which efficacy was significantly better. PVA is more likely to produce a permanent terminal occlusion because of the low frequency of recanalization. Moreover, as a particulate embolizing agent, it is easy to handle, and is available in a wide range of sizes. The purpose of this study was to identify the prognostic factors associated with survival in HCC with HAVS patients treated for PVA chemoembolization.MethodsFrom January 2013 to December 2014,133 patients (121 males and 12 females; median age,51 years; range,25-77 years) underwent transarterial chemoembolization (TACE) for HCC with HAVS at Nanfang Hospital. The baseline characteristics of the slow-flow type (n=36), intermediate-flow type (n= 58) and high-flow type (n= 39) patients revealed no different significantly among the different types (P>0.05). The exclusion criteria were (i) BCLC-D stage, (ii) severe dysfunction of blood coagulation, (iii) severe dysfunction of heart-lung functions, (iv) portal venous trunk completely blocked by tumor emboli and periportal collateral circulation undeveloped.The method of classified HAVS and PVA-TACE just as the part1 of abstract.Efficacy was assessed based on the following parameters:(1) overall survival (OS); (2) tumor response, objective response rate (ORR); (3) immediate angiogram occlusion rate. Overall survival was defined as the time interval between the initial PVA chembolization of the shunts and death or last follow-up. Patients were followed up until death or to the end of the study period (June 30,2015). Modified Response Evaluation Criteria In Solid Tumors (mRECIST) were employed to assess the tumor response on enhanced CT/MRI scans. Tumor response included complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Tumor remission included CR and PR. The degree of shunts occlusion was divided into three categories:complete occlusion, nearly complete occlusion and incomplete occlusion. Angiographic complete occlusion was defined as "complete occlusion" of the shunt; nearly complete occlusion was a small residual stagnant shunt, which was defined as a "minor residual shunt"; and incomplete occlusion was defined as flow decrease only with one class.Survival curves were calculated by Kaplan-Meier method and compared by log-rank test. Univariate analysis was performed to select potentially explanatory variables. Multivariate analysis was carried out to determine the significant prognostic factors by using the Cox proportional-hazards model. A two-tailed P value lower than 0.05 was considered statistically significant. Data were analyzed with IBM SPSS statistics version 22.Results1. The efficacy of PVA chemoembolization for HCC With HAVSThe median OS of 133 patients was 9.1 months. The median OS of the slow-flow type, intermediate-flow type and high-flow type patients were 10.8 months,9.1 months and 7.3 months, respectively. The overall survival rates of the 133 patients were 73.7%,36.2%, and 10.2% at 6-month,12-month, and 24-month, respectively. The overall survival rates of the slow-flow type, intermediate-flow type and high-flow type patients were 77.8% and 42.7%,72.4% and 39.2%,69.2% and 19.0% at 6-month, and 12-month, respectively. Different HAVS of survival curves were estimated according to the Kaplan-Meier method and compared statistically by a Log-rank test, revealed no different significantly among the different types (χ2= 2.865, P= 0.239).2. Univariate analysisThe univariate survival analysis showed statistically significant correlation with prognostic factors included:(a) initial preoperative AFP value, (b) ascites status, (c) serum albumin, (d) total bilirubin, (e) portal vein tumor thrombus, (f) multiple embolization, (g) amount of L-OHP used, (h) amount of THP used, (i) multimodality therapy and (j) tumor remission (all P<0.05). While there were no statistically significant correlation with prognostic factors included:(a) age, (b) gender, (c) ECOG PS, (d) Child-Pugh class, (e) prothrombin time, (f) gastroesophageal variceal, (g) liver cirrhosis, (h) HAVS types, (i) BCLC stages, (j) hepatic vein tumor thrombus, (k) amount of MMC and Lipiodol used (all P>0.05).3. Multivariate analysisCox multivariate survival analysis revealed that initial preoperative AFP value≥400 ng/ml (HR= 2.105, P= 0.006) was an independent risk factor. While multiple embolization (HR= 0.482, P= 0.011), tumor remission (HR= 0.431, P= 0.041) and multimodality therapy (HR= 0.416, P= 0.004) were independent protection factors.Conclusions1. It is safe and effective for HCC with HAVS by the chemoembolization therapy with PVA plus chemotherapeutic agents (or PVA plus CALE).2. HCC with HAVS patient achieves good prognosis with multiple embolization, tumor remission and multimodality therapy, while achieves poor prognosis with initial preoperative high AFP value (≥400 ng/ml). |
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