|Year : 2018 | Volume
| Issue : 2 | Page : 51-57
Safety and efficacy of low-dose transarterial chemoembolization in the hepatocellular carcinoma patients with portal vein tumor thrombosis
Won-Gyom Choe, Yong-Gun Jo, Il-Jin Sim, Guk-Song Kim, Guang-Jin Chon, U-Il Song, Yong-Jin Pong
Department of Oncology, Clinical Institute, Pyongyang Medical College, Kim Il Sung University, Pyongyang, North Korea
|Date of Web Publication||27-Nov-2018|
Dr. Won-Gyom Choe
Clinical Institute, Pyongyang Medical College, Kim Il Sung University, Taesong District, Pyongyang
Source of Support: None, Conflict of Interest: None
Aim: The aim of the study is to analyze the safety and efficacy of low-dose transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). Materials and Methods: Seventy-five HCC patients with PVTT, who were admitted to our hospital between 2011 and 2015 and underwent TACE, were analyzed. The safety and efficacy of low-dose TACE were evaluated. Results: The objective tumor response rate was 25.3%. The median overall survival time was 10.7 months (95% confidence interval [CI]: 8.2–13.2). The cumulative survival rates at 6, 12, 18, and 24 months were 65.3%, 44%, 17.3%, and 2.6%, respectively. Univariate analysis revealed that alpha-fetoprotein (heart rate [HR] = 1.307, 95% CI: 1.019–1.427,P < 0.05), Child–Pugh classification (HR = 2.984, 95% CI: 1.741–5.115, P < 0.001), PVTT (HR = 3.409, 95% CI: 2.745–4.512, P < 0.001), number of tumor (HR = 2.358, 95% CI: 1.956–3.375, P < 0.001), and size of tumor (HR = 2.301, 95% CI: 1.667–3.268, P < 0.001) were related with survival. In multivariate analysis, Child–Pugh classification (HR = 2.351, 95% CI: 1.256–4.215, P < 0.001), type of PVTT (HR = 2.749, 95% CI: 2.238–3.961, P < 0.001), number of tumor (HR = 1.795, 95% CI: 1.521–3.046, P < 0.001), and size of tumor (HR = 1.917, 95% CI: 1.379–3.057, P = 0.03) were independent predictive factors for survival rates. The incidence of complications due to procedures was 85.3%. Conclusion: The low-dose TACE may be considered selectively to HCC patients with PVTT. Child–Pugh classification, type of PVTT, number of tumor, and size of tumor were checked accurately before operation.
Keywords: Hepatocellular carcinoma, portal vein tumor thrombosis, transarterial chemoembolization
|How to cite this article:|
Choe WG, Jo YG, Sim IJ, Kim GS, Chon GJ, Song UI, Pong YJ. Safety and efficacy of low-dose transarterial chemoembolization in the hepatocellular carcinoma patients with portal vein tumor thrombosis. Muller J Med Sci Res 2018;9:51-7
|How to cite this URL:|
Choe WG, Jo YG, Sim IJ, Kim GS, Chon GJ, Song UI, Pong YJ. Safety and efficacy of low-dose transarterial chemoembolization in the hepatocellular carcinoma patients with portal vein tumor thrombosis. Muller J Med Sci Res [serial online] 2018 [cited 2019 Jan 19];9:51-7. Available from: http://www.mjmsr.net/text.asp?2018/9/2/51/246169
| Introduction|| |
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide, with the highest incidence rates reported in East Asia.,
In recent years, the Barcelona Clinic Liver Cancer (BCLC) classification has emerged as the standard classification system for clinical management of patients with HCC. According to the BCLC staging system, transarterial chemoembolization (TACE) is the current standard treatment for HCC patients with intermediate stage.
However, there are some limitations in TACE for patients with advanced liver cancer because most of them have portal vein tumor thrombosis (PVTT). The incidence of PVTT is 20%–70% of HCC patients., This is one of the negative factors for the prognosis of HCC patients. The prognosis of the HCC patients with PVTT in main branch is very poor, and the median survival of them is within 3 months without any treatment.,
Furthermore, a tumor thrombosis in the first branch or the main trunk of the portal vein may cause life-threatening complications such as variceal bleeding, ascites, and hepatic encephalopathy.,
TACE is one of the effective treatments for unresectable primary liver cancer, but it may be contraindication in case of PVTT because of the necrosis of normal liver parenchyma and liver function failure.
Ranieri et al. and Llovet et al. reported that sorafenib, a molecular-targeting drug that inhibits tumor cell proliferation and angiogenesis, improved median overall survival (OS) in patients with advanced HCC.,,
On the other hand, the study by Yau et al. showed that sorafenib did not help a survival improvement in hepatitis B endemic Asian HCC patients with PVTT.
Thus, it is very important to explore the approach for HCC with PVTT.
Many clinicians consider that TACE is a useful treatment for HCC patients with PVTT., Moreover, several studies on the safety and efficacy of TACE in HCC patients with PVTT in comparison with conservative treatment have performed.,,
More recently, Mazzaferro et al. reported that yttrium-90 radioembolization (Y90RE) was a safe and effective treatment in HCC with PVTT.
Especially, the therapeutic approaches should be designed with consideration of tumors and underlying diseases for advanced HCC treatment.
At TACE procedure, the reduction of the drug-induced toxicosis and retaining of embolization effects of lipiodol may be induced by reduction of doses of anticancer drugs.
Herein, we evaluated the safety and efficacy of low-dose TACE for HCC patients with PVTT.
| Materials and Methods|| |
About 127 HCC patients with PVTT who were admitted to our hospital between 2011 and 2015 were enrolled in this retrospective study. Among them, 52 patients were excluded from this study due to the following reasons:
(1) ≥70 years, (2) PVTT in main trunk or extrahepatic metastasis (lung and bone), (3) uncontrolled liver diseases (gastrointestinal bleeding, hepatic encephalopathy, noncurable ascites, and bacterial infection), (4) severe coagulopathy, and (5) renal function failure.
The diagnosis of HCC was confirmed using alpha-fetoprotein (AFP) value and imaging test (ultrasonogram, computed tomography [CT], and angiography) according to the European Association for the Study of Liver Disease. All patients received the detailed information about TACE and provided their written informed consent for TACE before operation. The end of follow-up was either death or December 2015.
PVTT was divided into two types in this study, Type I: tumor thrombosis involving first branches of portal vein and Type II: tumor thrombosis involving segmental branches except for main trunk or first branches of portal vein.
TACE procedure has been previously described. TACE was performed with an injection containing a mixture of chemotherapeutic agents and lipiodol.
Dose of anticancer drug
We performed TACE with one-second of the standard dose. In other words, suspension of the anticancer drug and lipiodol consists of mixture of doxorubicin and lipiodol which is calculated as 20–25 mg of doxorubicin per 10 ml of lipiodol.
The decision for additional treatment was made with the consideration of the size and the number of the tumor, liver function, and the patient's general condition.
Postembolization syndrome was fever, nausea or vomiting, and abdominal pain.
Evaluation of tumor response
Tumor response was evaluated using contrast-enhanced CT every 1–2 months after treatment. Overall tumor response was defined as the best response since the first treatment according to the modified response evaluation criteria in solid tumors (mRECIST) criteria.
Complete response (CR) is disappearance of any intratumoral arterial enhancement in target lesions; partial response (PR) is 30% decrease in the sum of the diameters of the target lesions; progressive disease (PD) is more than 20% increase in the sum of the diameters of the target lesions; and stable disease (SD) is neither PR nor PD. The objective response was defined as the sum of CR and PR.
OS was measured from the date of the first treatment to the date of death or last follow-up. The cumulative survival rates were calculated using the Kaplan–Meier method, and the differences were analyzed using the log-rank test.
Univariate and multivariate analyses were performed to evaluate the prognostic factors related to survival. Statistical analysis was performed using SPSS version 16.0 software (SPSS Inc., Chicago, IL, USA).
| Results|| |
Seventy-five HCC patients with PVTT who were treated with TACE in our hospital were analyzed. [Table 1] shows baseline characteristics of the patients.
Average age of the patients was 55.42 (range: 29–67), and majority of them were men (89.4%). Among them, 47 patients (62.6%) were in Child–Pugh classification A grade and 28 patients (37.4%) in B grade. In terms of pathology, it was mostly hepatitis B virus infection. The elevation of AFP was observed in 54.7% of all. Thirty-eight patients (50.6%) of all patients had Type I of PVTT and 37 patients (49.4%) had Type II. The number of tumor lesions was more than 2-cm lesions and less than 2-cm lesions in 29 (38.7%) and 46 patients (61.3%), respectively. The size of tumor was more than 5 cm and less than 5 cm in 44 patients (58.7%) and 31 patients (41.3%), respectively.
According to the mRECIST, tumor response after TACE was 0 (0%), 19 (25.3%), 47 (62.7%), and 9 (12.0%) in CR, PR, SD, and PD, respectively. The objective tumor response rate (CR + PR) was 25.3%.
The median OS was 10.7 months (95% confidence interval [CI]: 8.2–13.2). The cumulative survival rates at 6, 12, 18, and 24 months were 65.3%, 44%, 17.3%, and 2.6%, respectively.
The median survival time was significantly longer in Child–Pugh A patients than in Child–Pugh B patients (13.5 months vs. 6.2 months, P < 0.0001) [Figure 1]a. The median survival time in Type II PVTT patients was significantly longer than that in Type I patients (14.8 months vs. 5.8 months, P < 0.0001) [Figure 1]b. The median survival time was significantly longer in patients with more than 5-cm lesions than in patients with less than 5-cm lesions (15.6 months vs. 8.0 months, P < 0.0001) [Figure 1]c. The median survival time in patients with less than 2-cm lesions was significantly longer than that in patients with more than 2-cm lesions (12.7 months vs. 6.6 months, P < 0.05) [Figure 1]d.
|Figure 1: Comparison of overall survival in hepatocellular carcinoma patients with portal vein tumor thrombosis according to the Child–Pugh classification (a), type of portal vein tumor thrombosis (b), size of tumors (c), and number of tumors (d)|
Click here to view
Among the Child–Pugh A group, the median survival time of the patients with Type I PVTT and those with Type II PVTT was 5.8 months and 16.8 months, respectively (P < 0.001) [Figure 2]a.
|Figure 2: In Child–Pugh A grade, comparison of overall survival in hepatocellular carcinoma patients with portal vein tumor thrombosis according to the type of portal vein tumor thrombosis (a), size of tumors (b), and number of tumors (c)|
Click here to view
Among the Child–Pugh B group, the median survival time of the patients with Type I PVTT and those with Type II PVTT was 5.7 months and 10.7 months, respectively, indicating significant differences (P < 0.05).
In the Child–Pugh A group, the median survival time was significantly longer in patients with less than 5-cm lesions than in patients with more than 5-cm lesions (17.4 months vs. 8.2 months, P < 0.001) [Figure 2]b.
Among the Child–Pugh B group, there was no significant difference in the median survival time between the patients with less than 5-cm lesions and those with more than 5-cm lesions (5.8 months vs. 8.0 months) (P = 0.6).
In the Child–Pugh A group, the median survival time was significantly longer in the patients with less than 2-cm lesions than in the patients with more than 2-cm lesions (14.6 months vs. 8.2 months, P < 0.05) [Figure 2]c, but there was no significant difference in the Child–Pugh B group (5.7 vs. 6.1 months, P = 0.49).
The main complications included abdominal pain, fever, abdominal distension, nausea or vomiting, and fatigue. The incidence of complications related with the procedure was 85.3%.
Among them, 11 patients had no complication after TACE, 15 patients had one type of complication, and 49 patients had more than two types of complications.
These TACE-related complications lasted up to 10–15 days and were safely controlled by conservative treatment. Only one patient was complicated with hepatic abscess, but it was recovered by injection of antibiotics with puncture. No TACE-related death was observed.
Prognostic factors analysis
In the univariate analysis, AFP (HR = 1.307, 95% CI: 1.019–1.427, P < 0.05), Child–Pugh classification (HR = 2.984, 95% CI: 1.741–5.115, P < 0.001), type of PVTT (HR = 3.409, 95% CI: 2.745–4.512, P < 0.001), number of tumor lesions (HR = 2.358, 95% CI: 1.956–3.375, P < 0.001), and size of tumor lesions (HR = 2.301, 95% CI: 1.667–3.268, P < 0.001) were significant variables associated with survival.
In the multivariate analysis, Child–Pugh classification (HR = 2.351, 95% CI: 1.256–4.215, P < 0.001), type of PVTT (HR = 2.749, 95% CI: 2.238–3.961, P < 0.001), number of tumor lesions (HR = 1.795, 95% CI: 1.521–3.046, P < 0.001), and size of lesions (HR = 1.917, 95% CI: 1.379–3.057, P = 0.03) were the independent predictors of survival [Table 2].
| Discussion|| |
HCC patients with PVTT generally have a poor prognosis, as tumor proliferation is often extreme and accompanied by complication including intrahepatic metastasis, liver dysfunction, portal hypertension, and esophageal varices. According to the autopsy, the frequency of PVTT is about 44%~84%. More than one-third of the HCC patients are diagnosed at advanced stage with PVTT or extrahepatic metastasis.
TACE, one of nonsurgical treatments for HCC, has already been approved as an effective approach, and the rationale of TACE is based on the fact that tumor growth mostly depends on the blood supply from hepatic artery in HCC patients, whereas normal parenchyma depends on the blood supply from portal vein. Therefore, the blood supply from portal vein is main prerequisite of safety of TACE.
Theoretically, TACE is contraindication in the HCC patients with PVTT because the coexistence of portal vein and hepatic artery obstruction may induce liver failure.
The BCLC guidelines recommended sorafenib for patients with advanced HCC, with approximately 3-month survival rate.
The rationale for TACE in selected HCC patients with PVTT is that the formation of collateral vessels around the portal vein and good liver function makes the patient to tolerate the treatment.
The complications such as ascites, variceal bleeding, and hepatic encephalopathy may be appeared following embolization in the HCC patients with PVTT.
Therefore, we analyzed the safety and efficacy of low-dose TACE as an approach for unresectable HCC with PVTT. The dose reduction of chemotherapeutic agents in TACE may induce the reduction of liver dysfunction due to drug toxicity and maintenance of embolic effect of lipiodol.
In terms of efficacy, our study revealed a significantly high objective tumor response.
Although direct comparison of the tumor response was difficult due to the use of different baseline characteristics of each study and the differences of skill and drugs, the objective tumor response of 25.3% after low-dose TACE was superior to that (2.5%) of sorafenib in unresectable HCC with PVTT.,, Furthermore, it was superior to the results that objective response rates were 0%~10.5% after TACE in HCC patients with PVTT.,
In terms of survival, low-dose TACE showed the median survival of 10.7 months, which was superior to the results that the median survival of the HCC patients with PVTT is within 3 months without any treatment.,
Moreover, this result was comparable with data that median survivals were 5.5–10.2 months after hepatic arterial infusion chemotherapy (HAIC), sorafenib, Y90RE, surgery, and HAIC combined with three-dimensional conformal radiotherapy.,,,,
The target of Y90RE is more likely to be microvascular than macrovascular, and tumor necrosis is induced by radiation rather than ischemia.
Although simultaneous comparison of influences of radiation and anticancer drugs for survival is difficult in the HCC patients with PVTT, a retro-, prospective study on the safety and the efficacy of Y90RE and TACE according to Child–Pugh classification might be performed in those patients.
In terms of safety, the low-dose TACE was a therapeutic attempt to reduce the liver dysfunction due to drug toxicity but to maintain an embolic effect with lipiodolization.
In our study, although the incidence of procedure-related complications was 83.5%, these symptoms could be safely controlled by conservative treatment, and there was no procedure-related death.
These results demonstrated that low-dose TACE could be safely performed in HCC patients with PVTT.
An important limitation of our study was that the patients with poor liver function and tumor thrombosis in main trunk of portal vein were excluded because the majority of the patients with main PVTT had poor liver function, and there was a concern to produce the complication including esophageal varices due to TACE.
| Conclusion|| |
This study demonstrated that low-dose TACE could be selectively performed for HCC patients with PVTT. In other words, Child–Pugh classification, type of PVTT, size of tumor, and number of tumor lesions should be accurately checked before TACE.
In future, the comparative studies between TACE and TARE and prospective randomized controlled studies on the efficacy of combination with low-dose TACE and molecular targeting drugs might be required in HCC patients with PVTT.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533-43.
Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009;27:1485-91.
Llovet JM, BrB C, Bruix J. Prognosis of hepatocellular carcinoma: The BCLC staging classification. Semin Liver Dis 1999;19:329-38.
Cedrone A, Rapaccini GL, Pompili M, Aliotta A, Trombino C, De Luca F, et al.
Portal vein thrombosis complicating hepatocellular carcinoma. Value of ultrasound-guided fine-needle biopsy of the thrombus in the therapeutic management. Liver 1996;16:94-8.
Arii S, Tanaka J, Yamazoe Y, Minematsu S, Morino T, Fujita K, et al.
Predictive factors for intrahepatic recurrence of hepatocellular carcinoma after partial hepatectomy. Cancer 1992;69:913-9.
Llovet JM, Bustamante J, Castells A, Vilana R, Ayuso Mdel C, Sala M, et al.
Natural history of untreated nonsurgical hepatocellular carcinoma: Rationale for the design and evaluation of therapeutic trials. Hepatology 1999;29:62-7.
Villa E, Moles A, Ferretti I, Buttafoco P, Grottola A, Del Buono M, et al.
Natural history of inoperable hepatocellular carcinoma: Estrogen receptorsable hepatocellular carcinomacarcinomaDel Buono M, logy 1999;29:62-7.ial hepatectomy. Cancer 199
Cabibbo G, Enea M, Attanasio M, Bruix J, CraxC A, CammC C, et al.
Ameta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma. Hepatology 2010;51:1274-83.
Minagawa M, Makuuchi M, Takayama T, Ohtomo K. Selection criteria for hepatectomy in patients with hepatocellular carcinoma and portal vein tumor thrombus. Ann Surg 2001;233:379-84.
Ranieri G, Gadaleta-Caldarola G, Goffredo V, Patruno R, Mangia A, Rizzo A, et al.
Sorafenib (BAY 43-9006) in hepatocellular carcinoma patients: From discovery to clinical development. Curr Med Chem 2012;19:938-44.
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al.
Efficacy and safety of sorafenib in patients in the asia-pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25-34.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al.
Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90.
Yau T, Chan P, Ng KK, Chok SH, Cheung TT, Fan ST, et al.
Phase 2 open-label study of single-agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B-endemic Asian population: Presence of lung metastasis predicts poor response. Cancer 2009;115:428-36.
Omata M, Lesmana LA, Tateishi R, Chen PJ, Lin SM, Yoshida H, et al.
Asian pacific association for the study of the liver consensus recommendations on hepatocellular carcinoma. Hepatol Int 2010;4:439-74.
Georgiades CS, Hong K, D'Angelo M, Geschwind JF. Safety and efficacy of transarterial chemoembolization in patients with unresectable hepatocellular carcinoma and portal vein thrombosis. J Vasc Interv Radiol 2005;16:1653-9.
Luo J, Guo RP, Lai EC, Zhang YJ, Lau WY, Chen MS, et al.
Transarterial chemoembolization for unresectable hepatocellular carcinoma with portal vein tumor thrombosis: A prospective comparative study. Ann Surg Oncol 2011;18:413-20.
Wang JH, Changchien CS, Hu TH, Lee CM, Kee KM, Lin CY, et al.
The efficacy of treatment schedules according to barcelona clinic liver cancer staging for hepatocellular carcinoma-Survival analysis of 3892 patients. Eur J Cancer 2008;44:1000-6.
Niu ZJ, Ma YL, Kang P, Ou SQ, Meng ZB, Li ZK, et al.
Transarterial chemoembolization compared with conservative treatment for advanced hepatocellular carcinoma with portal vein tumor thrombus: Using a new classification. Med Oncol 2012;29:2992-7.
Mazzaferro V, Sposito C, Bhoori S, Romito R, Chiesa C, Morosi C, et al.
Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: A phase 2 study. Hepatology 2013;57:1826-37.
Zhao Y, Wang WJ, Guan S, Li HL, Xu RC, Wu JB, et al.
Sorafenib combined with transarterial chemoembolization for the treatment of advanced hepatocellular carcinoma: A large-scale multicenter study of 222 patients. Ann Oncol 2013;24:1786-92.
Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010;30:52-60.
Yamada K, Soejima T, Sugimoto K, Mayahara H, Izaki K, Sasaki R, et al.
Pilot study of local radiotherapy for portal vein tumor thrombus in patients with unresectable hepatocellular carcinoma. Jpn J Clin Oncol 2001;31:147-52.
Pirisi M, Avellini C, Fabris C, Scott C, Bardus P, Soardo G, et al.
Portal vein thrombosis in hepatocellular carcinoma: Age and sex distribution in an autopsy study. J Cancer Res Clin Oncol 1998;124:397-400.
Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, et al.
Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008;100:698-711.
Minagawa M, Makuuchi M. Treatment of hepatocellular carcinoma accompanied by portal vein tumor thrombus. World J Gastroenterol 2006;12:7561-7.
D'Angelo S, Germano D, Zolfino T, Sansonno D, Giannitrapani L, Benedetti A, et al.
Therapeutic decisions and treatment with sorafenib in hepatocellular carcinoma: Final analysis of GIDEON study in Italy. Recenti Prog Med 2015;106:217-26.
Zhu K, Chen J, Lai L, Meng X, Zhou B, Huang W, et al.
Hepatocellular carcinoma with portal vein tumor thrombus: Treatment with transarterial chemoembolization combined with sorafenib-a retrospective controlled study. Radiology 2014;272:284-93.
Zhang X, Wang K, Wang M, Yang G, Ye X, Wu M, et al.
Transarterial chemoembolization (TACE) combined with sorafenib versus TACE for hepatocellular carcinoma with portal vein tumor thrombus: A systematic review and meta-analysis. Oncotarget 2017;8:29416-27.
Ando E, Tanaka M, Yamashita F, Kuromatsu R, Yutani S, Fukumori K, et al.
Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: Analysis of 48 cases. Cancer 2002;95:588-95.
Fujino H, Kimura T, Aikata H, Miyaki D, Kawaoka T, Kan H, et al.
Role of 3-D conformal radiotherapy for major portal vein tumor thrombosis combined with hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma. Hepatol Res 2015;45:607-17.
Chen JS, Wang Q, Chen XL, Huang XH, Liang LJ, Lei J, et al.
Clinicopathologic characteristics and surgical outcomes of hepatocellular carcinoma with portal vein tumor thrombosis. J Surg Res 2012;175:243-50.
Sangro B, Carpanese L, Cianni R, Golfieri R, Gasparini D, Ezziddin S, et al.
Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across barcelona clinic liver cancer stages: A European evaluation. Hepatology 2011;54:868-78.
[Figure 1], [Figure 2]
[Table 1], [Table 2]