Japanese Journal of Clinical Oncology Advance Access published June 15, 2015 Japanese Journal of Clinical Oncology, 2015, 1–7 doi: 10.1093/jjco/hyv089 Original Article
Original Article
Hepatic resection versus transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with hepatic vein tumor thrombus Downloaded from http://jjco.oxfordjournals.org/ at University of Cambridge on August 8, 2015
Yong-Fa Zhang1,2,3,†, Wei Wei1,2,3,†, Zhi-Xing Guo2,3,4, Jia-Hong Wang1,2,3, Ming Shi1,2,3, and Rong-Ping Guo1,2,3,* 1
Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 2State Key Laboratory of Oncology in South China, Guangzhou, 3Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, and 4 Department of Ultrasonography, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China *For reprints and all correspondence: Rongping Guo, Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510060, P.R. China E-mail: [email protected] †
These authors contributed equally to this work and are considered co-first authors.
Received 27 February 2015; Accepted 12 May 2015
Abstract Objective: To compare the outcomes of hepatic resection and transcatheter arterial chemoembolization for resectable hepatocellular carcinoma with hepatic vein tumor thrombus. Methods: From January 2006 to November 2013, 28 patients initially diagnosed with resectable hepatocellular carcinoma combined with hepatic vein tumor thrombus received hepatic resection. These patients were compared with 56 case-matched controls (1:2 ratio) selected from a pool of 91 patients who received transcatheter arterial chemoembolization as an initial treatment during the same period. Clinical characteristics, adverse events, overall survival and survival-related factors were analyzed. Results: The 1-, 2- and 3-year overall survival rates were 66.5, 37.4 and 28.5% for the hepatic resection group and 32.3, 18.7 and 15.6% for the transcatheter arterial chemoembolization group (P = 0.015), respectively. No significant difference was found between the two groups in terms of complications and mortality. Multivariate analyses revealed combined portal vein tumor thrombosis (HR = 2.116; 95% CI: 1.26–3.57; P = 0.005) and treatment allocation (hepatic resection = 2.289; 95% CI, 1.30–4.02; P = 0.004) as risk factors for overall survival. Conclusions: Hepatic resection provides a good prognosis for hepatocellular carcinoma patients with hepatic vein tumor thrombus compared with patients undergoing transcatheter arterial chemoembolization, and the most important factor related to survival was co-existence with portal vein invasion. Key words: hepatic resection, transcatheter arterial chemoembolization, hepatocellular carcinoma, hepatic vein tumor thrombus, overall survival
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
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HR vs. TACE for HCC with HVTT
Inclusion and exclusion criteria
The prognosis of patients with advanced hepatocellular carcinoma (HCC) remains poor (1,2). Although several factors contribute to the poor prognosis associated with HCC, major vascular invasion, i.e. tumor thrombosis (TT) in the portal vein (PVTT) or hepatic vein (HVTT), is one of the most important(3–5). As a result of recent advances in surgical techniques and perioperative management, liver resection for HCC with TT has become a reasonably safe treatment option with an acceptable mortality rate (6,7). However, in the American Association for the Study of the Liver Diseases/Barcelona Clinic for Liver Cancer Staging System and treatment guidelines, major vascular invasion, including PVTT and HVTT, is regarded as indicative of an advanced stage of the disease, and sorafenib is recommended as the standard treatment (2). Unfortunately, survival among these patients remains modest, and the local tumor control rate is low (8,9). Recently, hepatic resection (HR) and transcatheter arterial chemoembolization (TACE) with or without conformal radiotherapy have been described, but there is no current credible evidence suggesting that these therapies offer survival benefits to the patients because all the studies were either case reports, had a non-controlled design, or compared HCC extending with HVTT with HCC invading the portal vein (10–20). Moreover, only a few studies have compared the outcomes of hepatic resection and TACE in the treatment of HCC involving the inferior vena cava (IVC)/right atrium (RA) (21). The survival outcomes of HCC patients with HVTT treated with HR or with TACE have not been properly compared. This study aimed to retrospectively compare the long-term survival outcomes of HCC patients with HVTT who underwent HR or TACE as their initial treatment. We also aimed to assess the factors that affected survival.
Diagnosis of HCC was based on histology or dynamic imaging (computed tomography (CT) scans or magnetic resonance imaging (MRI) according to the diagnostic criteria of the European Association for the Study of the Liver (EASL) (23).The presence of PVTT and/or HVTT was identified by preoperative Doppler ultrasonography, enhanced CT or MRI. The diagnosis of HCC with vascular invasion was also confirmed by the final pathological findings in the HR group. Patients in the HR group were enrolled using the following inclusion criteria: (i) aged between 18 and 75 years; (ii) HCC with no previous treatment; (iii) the presence of HVTT on imaging, which indicated the first branch of the hepatic vein branching from the IVC, including the right, left and middle hepatic vein, the inferior right hepatic vein or the short hepatic veins, according to the Japanese staging system (24); (iv) Eastern Co-operative Oncology Group performance status 0 (25); and (v) resectable disease defined as the complete removal of all macroscopic tumor tissue and retention of a liver remnant sufficient to sustain life, as assessed by our surgical team (26). The exclusion criteria were: (1) Child-Pugh class C or evidence of hepatic decompensation including ascites, esophageal or gastric variceal bleeding or hepatic encephalopathy; (ii) an American Society of Anesthesiologists (ASA) score of ≥3; and (iii) extrahepatic metastasis identified during preoperative imaging.
Patients and methods Study design The study involved 4713 patients who had received either HR or TACE as the initial treatment for HCC and who have been hospitalized at Cancer Center of Sun Yat-sen University between January 2006 and November 2013. Of these, 119 patients (2.5%) had been diagnosed with HCC and HVTT; 28 patients underwent resection (the HR group) and 91 patients received TACE as an initial treatment for HCC with HVTT. The patients in the HR group were matched in a 1:2 ratio with patients from the pool of 91 patients who were treated with TACE as an initial treatment (the TACE group). The patients in both groups were matched as closely as possible based on the following priority: (i) combined PVTT; (ii) tumor burden (tumor size and tumor number); (iii) liver function (Child-Pugh class and indocyanine green retention rate at 15 min; (iv) age and gender; and (v) alphafetoprotein level (AFP). Patients’ demographic, clinical and pathological data, surgical outcomes, response to TACE and survival status were recorded prospectively and analyzed retrospectively from a collective HCC database. There is no concrete evidence yet for establishing an optimal treatment strategy for HCC with HVTT (22). The patients who had an operable primary tumor (i.e. the tumor or tumors could be resected completely) and well-preserved liver function were fully informed in detail about the possible benefits and the risks of treatment with TACE or HR. The choice of treatment was ultimately determined by the patients, and a written consent was obtained from each patient prior to treatment. This study was approved by the Ethical Committee of our center.
Hepatic resection procedure The techniques for hepatic resection were performed as described previously (27). After exploration, intraoperative ultrasonography was routinely performed to estimate the location and extent of the tumor thrombus as well as to mark the parenchymal transection line. Pringle’s maneuver was routinely used with a clamp/unclamp time of 10/5 min. Anatomical hepatic resection with en bloc thrombectomy was our preferred surgical method for liver resection. As an alternative, non-anatomical resection was used in cases of where wide en bloc resection was not feasible. In terms of the thrombectomy, the tumor thrombus was either resected en bloc with the tumor or extracted out of the vascular lumen, depending on its location and extent (26). After flushing with normal saline and confirming, by intraoperative ultrasonography, that no tumor thrombus remained, the vascular incision was sutured. In this study, major hepatic resection was defined as resection of three or more Couinaud’s segments of the liver. Minor hepatic resection was defined as resection of two or fewer segments of the liver.
TACE TACE was carried out using techniques we have described previously (28) and was performed by our four radiologists, who had 7–10 years’ experience in TACE. After introducing a 5-French catheter via the femoral artery, visceral arteriograms were obtained to ascertain the locations of the tumor and the tumor-feeding arteries. Depending on the size, location and arterial supply of the tumor, the tip of the catheter was advanced into the right or left hepatic artery, or into the tumorfeeding branches. Next, we injected an embolization suspension consisting of mitomycin C 6 mg (Zhejiang Hisun Pharmaceutical Co. Ltd., China), lobaplatin 50 mg (Hainan Changan International Pharmaceutical, China), and epirubicin 50 mg (Pharmorubicin, Pfizer, USA) mixed in 10 ml of water-soluble contrast medium (Omni-paque, Winthrop Pharmaceuticals, USA). The mixture was mixed thoroughly with 10 ml of ethiodized-oil (Lipiodol; Guerbet, Aulnay-sous-Bois, France). If the tumor bearing territory showed no stagnant flow after injection of the emulsion, a maximum of 20 ml pure Lipiodol
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Introduction
Jpn J Clin Oncol, 2015 was then injected. Embolization was then performed in these patients by injecting absorbable gelatin sponge particles (Gelfoam; Hanzhou alc Ltd, China), 1–2 mm in diameter, through the angiographic catheter. This treatment regimen was used consistently in this study, regardless of tumor type and size.
Follow-up
with terminal HCC, Child-Pugh class C liver function, or an Eastern Cooperative Oncology Group score >2.
Statistical analysis Post-operative mortality was defined as any death during postoperative hospitalization or death within 30 days after treatment. According to Common Terminology Criteria for Adverse Events V3.0 (29), Grade 1–2 refers to minor complications, while major complications were defined as Grade 3 and 4. The primary outcome measure was the overall survival rate. The secondary outcome measure was procedure-related complications. For comparisons between baseline variables, we used the student’s t test for continuous variables and the χ 2 test for categorical variables. Survival curves and univariate analysis were conducted using the Kaplan–Meier method, and differences were analyzed using the log-rank test. The prognostic factors found to be significant in the univariate analysis (P < 0.1) were subjected to multivariate analysis with the Cox proportional hazards regression model. A statistically significant difference was set at P < 0.05.
Results Patients A total of 28 patients in the HR group and 56 patients in the TACE group identified as having HCC with HVTT were eventually enrolled in the study, which comprised 81 men and 3 women, with a median age of 50 (range, 25–72) years. A total of 76/84 patients had underlying chronic liver disease. The mean maximum tumor diameter for the HR and the TACE groups were 9.6. ± 3.4 cm and 9.6 ± 3.1 cm, respectively (P = 0.957). The baseline demographic data were well matched between the two groups of 84 patients except for alanine transferase (Table 1).
Outcomes after HR/TACE The surgical procedures and the operative details for the patients in the HR group are listed in Table 2. A total of 18 patients received
Table 1. Pretreatment baseline characteristics of patients Characteristic
HR (n = 28)
TACE (n = 56)
P value
Age (years)a Male/femaleb Hepatitis B carrier (±) Liver cirrhosis (yes/no) Platelet count (109/l) Prothrombin time (sec) Alanine transferase (U/l) Serum albumin (g/l) Total bilirubin (mmol/l) ICGR 15 (%) Child-Pugh class (A/B) Alpha-fetoprotein level (≤/>400) (ng/ml) Tumor size (cm) Tumor number (≤/>1) Tumor extent (unilobar/bilobar) Combined PVTT (yes/no)
47.4 ± 10.3 27/1 (96/4) 26/2 (93/7) 27/1 (96/4) 208.6 ± 77.3 12.5 ± 1.4 40.4 ± 22.0 41.7 ± 3.0 14.9 ± 7.0 4.3 ± 2.5 28/0 (100/0) 8/20 (29/71) 9.6. ± 3.4 17/11 (61/39) 20/8 (71/29) 16c/12 (57/43)
51.1 ± 10.2 54/2 (96/4) 45/11 (80/20) 49/7 (88/12) 216.9 ± 94.9 12.7 ± 1.6 69.3 ± 44.5 40.6 ± 4.7 17.3 ± 9.9 6.8 ± 5.0 53/3 (95/5) 21/35 (36/64) 9.6 ± 3.1 26/30 (46/54) 36/20 (64/36) 31d/25 (55/45)
0.124 1.000 0.203 0.259 0.688 0.484 0.000 0.168 0.245 0.094 0.547 0.417 0.957 0.217 0.513 0.876
a
Mean ± SD. Number (%); ICGR 15, indocyanine green retention rate at 15 min; PVTT, portal vein tumor thrombus; HR, hepatic resection; TACE, transcatheter arterial chemoembolization. c The degrees of PVTT for 16 patients: (the segmental branches = 4, the right/left portal vein = 10, the main portal vein = 2). d The degrees of PVTT for 31 patients: (the segmental branches = 8, the right/left portal vein = 18, the main portal vein = 5). b
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This study was censored on 30 November 2014. The routine followup protocol was uniform for patients in both the HR and TACE group, and included a serum AFP assay, abdominal ultrasonography and liver function tests every month for the first year and then at gradually increasing time intervals. In the HR group, contrast-enhanced CT was performed 1 month after hepatic resection and at 3-month intervals thereafter for surveillance. For patients in the TACE group, contrast-enhanced CT scans were obtained every 1–2 months during the first 3 months for evaluation of the tumor response. Tumor response was graded into the following four groups, according to Response Evaluation Criteria in Solid Tumors (RECIST): CR (complete response) = disappearance of all target lesions; PR ( partial response) = 30 to 99% decrease in the sum of the longest diameter of the target lesions; SD (stable disease) = neither PR nor progressive disease; and PD ( progressive disease) = more than 20% increase in the sum of the longest diameter of the target lesions. For analysis, the overall responses comprehensively take into consideration changes in target lesions, non-target lesions, and appearance of intrahepatic or extrahepatic new lesions. Recurrence was defined as the appearance of new lesions with the radiological features of HCC after HR. The choice of treatment was determined by the characteristics of the recurrent tumor, the patient’s request and the results of the discussion by our multidisciplinary team. For patients with tumor progression without contraindications for TACE, a repeat in TACE treatment was recommended. For patients whose residual tumors could not be embolized owing to technical problems, radiofrequency ablations were used to destroy the residual tumors where feasible. Conservative treatments were given to patients
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HR vs. TACE for HCC with HVTT
Table 2. Operative procedures and post-treatment outcomes for patients in the HR group Variables
HR (n = 28)
Surgical time (min) Time of Pringle maneuver (min) Intraoperative blood loss (ml) Extent of resection (R0/R1/2) Tumor differentiation Well Moderate or poor Type of hepatectomy Minor hepatectomy Major hepatectomy Minor hepatectomy + thrombectomy Major hepatectomy + thrombectomy Type of recurrence, n Intrahepatic recurrence Extrahepatic metastasis Both
233.0 ± 71.1 23.3 ± 12.9 782.1 ± 890.7 22/6 12 16 3 7 8 10
Table 3. Post-treatment outcomes of TACE for patients in the TACE group Variable Treatment sessions of TACE Overall tumor response CR PR SD PD
TACE (n = 56) 1.5 (range, 1–4) 2 13 20 21
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
hepatectomy and thrombectomy whilst 10 patients received hepatectomy only. R0 resection was achieved in 22 patients (78.6%) and the remaining 6 patients received R1 resection. During the follow-up period, 23 patients developed radiologically detectable residual disease/ tumor recurrence. Of these 23 patients, 13 received repeated TACE, 1 patient received radiofrequency ablation and the remaining patients received the most suitable supportive treatment or systemic therapy. The treatment outcomes of TACE are listed in Table 3. Fifty-six patients received a mean of 1.5 (range, 1–4) sessions of TACE. The objective tumor response rate, including CR and PR, was 26.8%. After the TACE treatment, the tumors in 12 patients were downstaged to receive HR (n = 9) or local ablative therapy (radiofrequency ablation, n = 2, or radiofrequency in combination with percutaneous ethanol injection, n = 1).
Recurrence and survival In the HR group, 23 of the 28 patients who underwent curative resection experienced post-operative recurrences. Intrahepatic recurrences occurred in 13 patients, extrahepatic metastases in 7 patients and both intrahepatic and extrahepatic recurrences in 3 patients. The median recurrence-free survival duration of the patients in the HR group was 4.0 months (95% CI: 1.6–6.4). The median progress-free survival duration of the patients in the TACE group was 3.6 months (95% CI: 2.2–5.0). At a median follow-up of 11 months (range, 1–83), the HR group had a longer median overall survival duration (15.6 months; 95%
Figure 1. The overall survival curves of patients in the HR group and patients in the TACE group (15.6 months vs. 9.1 months; P = 0.015).
CI: 9.3–21.9) than the TACE group (9.1 months; 95% CI: 7.4– 10.8). For patients in the HR group, the 1-, 2- and 3-year overall survival rates were 66.5, 37.4 and 28.5% respectively, whereas the overall survival rates in the TACE group was 32.3, 18.7 and 15.6%, respectively (P = 0.015) (Fig. 1). A subgroup analysis of HCC patients combined with or without PVTT was conducted. For the patients combined with PVTT, the median survival was better in the HR group than in the TACE group (13.6 vs. 7.4 months; P = 0.006; Fig. 2a). For the patients combined without PVTT, there was no significant difference between the two groups for median survival (26.2 vs. 14.6 months; P = 0.414; Fig. 2b). In a comparison of those patients who underwent hepatic resection with those who attained a complete or partial response after TACE, no significant difference between the two groups for median survival (15.6 vs. 18.2 months; P = 0.770; Fig. 2c).
Mortality and morbidity Table 4 shows the in-hospital mortality and the incidence of major and minor complications after undergoing hepatic resection or TACE. Two patients died of incurable hepatic failure within 30 days of TACE subsequent resection, resulting in a hospital mortality rate of 3.6% in the TACE group. One patient died of liver failure, and another died of sepsis and multi-organ failure. There was no in-hospital mortality for the HR group. Complications occurred more often in the HR group than in the TACE group (57.1 vs. 30.4%).but no significant difference was found in the incidence of complications between the two groups (P = 0.259).
Univariate and multivariate analysis of predictors of overall survival The univariate and multivariate analyses of predictors of the overall survival for all 84 patients are shown in Table 5. Sex, Child-Pugh class, combined PVTT, and treatment allocation were found to be significant risk factors for survival in the univariate analysis. After multivariate Cox proportional hazards regression analysis, combined PVTT (HR = 1.81; 95% CI: 1.26–3.57; P = 0.005) and treatment
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Table 4. Mortality and complications for patients with hepatic vein tumor thrombosis Mortality and complications In-hospital mortality Complications Minor complicationa Major complicationb
HR (n = 28)
TACE (n = 56)
0
2
13 3
10 7
P Value 0.550 0.259
a Minor complications, including mild ascites/pleural effusion (n = 18), bacteremia (n = 3), and transient liver impairment (Child’s C status for duration of hospital stay) (n = 2). b Major complications: In the HR group, post-operative hemorrhage (n = 1), pleural effusion (n = 1), and bile leakage (n = 1); In the TACE group, upper gastrointestinal hemorrhage (n = 3), and pleural effusion (n = 4).
allocation (HR = 1.66; 95% CI: 1.30–4.02; P = 0.004) were significant prognostic factors for overall survival.
Discussion To date there is no concrete evidence for establishing an optimal treatment strategy for HCC with hepatic vein invasion, and in most previous cases reports of PVTT and HVTT are mixed with cases of vascular invasion, with HVTT cases always being in the minority (10,18,21,22). The incidence of HVTT (2.5%) in our study was similar to the incidences previously reported ranging from 1.4–4.9% (5,12,14,25,30). Owing to the relatively low incidence of HVTT compared with PVTT, little is known about HVTT (14). To our knowledge, this is the first report to compare treatment outcomes among HCC patients with HVTT who were treated with different treatment modalities. Our study revealed that patients with HVTT undergoing HR have a better prognosis than those with HVTT undergoing TACE, which indicates that choosing the appropriate candidates for surgery can improve the prognosis. In addition, in a comparison of patients who underwent hepatic resection with those who attained CR/ PR after TACE, no significant difference in prognosis was found between the two groups. These results show that it may be possible to attain a similar level of efficacy with TACE as with HR for some highly selected patients with HVTT.
Due to a potential to select better risk patients with less advanced HCC to surgery, it is difficult to conduct a retrospective comparison between patients with HCC and HVTT who received hepatic resection and TACE. To minimize such a potential bias, the study was conducted as a retrospective case-matched controlled study, and the patients in this study were well matched between the HR group and the TACE group with the exception of the alanine transferase. However, alanine transferase was not found to be a significant prognostic factor both in either the univariate or multivariate analysis. Therefore, the significant difference in alanine transferase between the two groups of patients may not reduce the statistical strength and lead to bias. Some reports have documented that the results following hepatic resection for HCC combined with major vascular invasion have been disappointing (5,31). In the previous studies, the median survival time was about 6.1–11 months and the 3-year survival rate after resection was approximately 14% in HCC patients with major vascular invasion (5,10,18,20). However, in our study, hepatic resection led to an overall survival rate of 28.5% at 3 years, and 15.6 months of median survival. Our study may have yielded a better survival rate owing to the fact that previous research defined major vascular invasion contains involving the IVC(20) or PVTT (5,10,18). Our study reported that TACE led to an overall survival rate of 15.6% at 3 years, and 9.1 months of median survival, similar to previous findings (12,13). The patients with HVTT in the HR group achieved a better prognosis than the patients in the TACE group, as in previous similar studies on PVTT (26) or the IVC/RA (21) (P = 0.015). In our study, we observed a high incidence (56%) of HCC combined with PVTT. The epithelial-mesenchymal transition (EMT) (32), the mechanism of invasion in a variety of cancers, underlying the formation of both PVTT and HVTT may explain the high rate of co-existence of the two. Patients with both HVTT and PVTT had a worse prognosis than those with HVTT alone (5), owing to the high risk of intrahepatic metastasis and portal hypertension complications (5,22). In our study, HCC combined with PVTT was a significant prognostic factor in the univariate and multivariate analysis. A subgroup analysis of patients combined with PVTT, the median survival was better in the HR group than in the TACE group. However, perhaps owing to the small sample size in the HR group (n = 12), no significant survival difference was found between the two groups for
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Figure 2. (a) The overall survival curves of HCC patients combined with PVTT in the HR group and patients in the TACE group (13.6 months vs. 7.4 months; P = 0.006); (b) The overall survival curves of HCC patients combined without PVTT in the HR group and patients in the TACE group (26.2 months vs. 14.6 months; P = 0 .414); (c) The overall survival curves for a comparison of patients who underwent hepatic resection with those who attained CR/PR after TACE (15.6 vs. 18.2 months; P = 0 .770).
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HR vs. TACE for HCC with HVTT
Table 5. Univariate and multivariate analysis of risk factors for overall survival Variables
Multivariate analysis
P value Log-rank
HR
95% CI
P value Cox regression
0.655 0.085 0.671 0.322 0.372 0.289 0.560 0.307 0.691 0.061 0.923 0.783 0.113 0.772 0.022 0.015
1.81 1.66
1.26–3.57 1.30–4.02
0.005 0.004
HR, hazard ratio; HR, hepatic resection; ICGR 15, indocyanine green retention rate at 15 min; PVTT, portal vein tumor thrombus; TACE, transcatheter arterial chemoembolization; CI, confidence interval.
patients combined without PVTT. We also found that even patients combined with PVTT who had undergone HR had a worse median survival than patients without PVTT who had received TACE (13.6 vs.14.6 months). Theses survival data indicate that the co-existence of PVTT is one of the most important factors contributing to poor prognosis. There are some limitations to our study. The principal limitation of our study was its retrospective nature with all its inherent defects. Second, diagnosis of tumor thrombosis confirmed by histopathology was not accessible in the TACE group, which may have led to bias. Third, this is a single center study, and the results may not be applicable to a less specialized center. Therefore, multicenter and larger randomized studies are needed to confirm our results. In conclusion, hepatic resection provides a better prognosis for HCC patients with HVTT than for patients who receive TACE as an initial treatment, and the most important factor related to poor survival was co-existence with portal vein invasion.
Funding This study was supported by grants from the National Natural Science Foundation of China (No. 81172037/H1606), Guangzhou municipal science and technology project of China (No. 2012J4100078), and Guangdong province science and technology project of China (No.2013B021800159).
Conflict of interest statement None declared.
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Age (years), (≤/>50) Sex (male/female) Hepatitis B carrier (yes/no) Liver cirrhosis (yes/no) Prothrombin time (≤/>14), (s) Alanine transferase (≤/>40), (U/l) Serum albumin (≤/>35), (g/l) Total bilirubin (≤/>20), (mmol/l) ICGR 15 (≤/>10), (%) Child-Pugh class (A/B) Alpha-fetoprotein level (≤/>400), (ng/ml) Tumor size (≤/>10), (cm) Tumor number (≤/>1) Tumor extent (unilobar/bilobar) Combined PVTT (yes/no) Treatment allocation (HR/TACE)
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16. Xi M, Zhang L, Zhao L, et al. Effectiveness of stereotactic body radiotherapy for hepatocellular carcinoma with portal vein and/or inferior vena cava tumor thrombosis. PLoS One 2013;8:e63864. 17. Wakayama K, Kamiyama T, Yokoo H, et al. Surgical management of hepatocellular carcinoma with tumor thrombi in the inferior vena cava or right atrium. World J Surg Oncol 2013;11:259. 18. Pawlik TM, Poon RT, Abdalla EK, et al. Hepatectomy for hepatocellular carcinoma with major portal or hepatic vein invasion: results of a multicenter study. Surgery 2005;137:403–10. 19. Miyazawa M, Torii T, Asano H, et al. Does a surgery for hepatocellular carcinoma with tumor thrombus highly occupying in the right atrium have significance? A case report and review of the literature. Hepatogastroenterology 2005;52:212–6. 20. Zhang T, Huang JW, Bai YN, Wu H, Zeng Y. Recurrence and survivals following hepatic resection for hepatocellular carcinoma with major portal/hepatic vein tumor thrombus. Hepatol Res 2014;44:761–8. 21. Wang Y, Yuan L, Ge RL, Sun Y, Wei G. Survival benefit of surgical treatment for hepatocellular carcinoma with inferior vena cava/right atrium tumor thrombus: results of a retrospective cohort study. Ann Surg Oncol 2013;20:914–22. 22. Okada S. How to manage hepatic vein tumour thrombus in hepatocellular carcinoma. J Gastroenterol Hepatol 2000;15:346–8. 23. European Association For The Study Of The L, European Organisation for R, Treatment of C. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908–43. 24. Kudo M, Izumi N, Kokudo N, et al. Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by
7
Original Article
Hepatic resection versus transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with hepatic vein tumor thrombus Downloaded from http://jjco.oxfordjournals.org/ at University of Cambridge on August 8, 2015
Yong-Fa Zhang1,2,3,†, Wei Wei1,2,3,†, Zhi-Xing Guo2,3,4, Jia-Hong Wang1,2,3, Ming Shi1,2,3, and Rong-Ping Guo1,2,3,* 1
Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 2State Key Laboratory of Oncology in South China, Guangzhou, 3Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, and 4 Department of Ultrasonography, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China *For reprints and all correspondence: Rongping Guo, Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510060, P.R. China E-mail: [email protected] †
These authors contributed equally to this work and are considered co-first authors.
Received 27 February 2015; Accepted 12 May 2015
Abstract Objective: To compare the outcomes of hepatic resection and transcatheter arterial chemoembolization for resectable hepatocellular carcinoma with hepatic vein tumor thrombus. Methods: From January 2006 to November 2013, 28 patients initially diagnosed with resectable hepatocellular carcinoma combined with hepatic vein tumor thrombus received hepatic resection. These patients were compared with 56 case-matched controls (1:2 ratio) selected from a pool of 91 patients who received transcatheter arterial chemoembolization as an initial treatment during the same period. Clinical characteristics, adverse events, overall survival and survival-related factors were analyzed. Results: The 1-, 2- and 3-year overall survival rates were 66.5, 37.4 and 28.5% for the hepatic resection group and 32.3, 18.7 and 15.6% for the transcatheter arterial chemoembolization group (P = 0.015), respectively. No significant difference was found between the two groups in terms of complications and mortality. Multivariate analyses revealed combined portal vein tumor thrombosis (HR = 2.116; 95% CI: 1.26–3.57; P = 0.005) and treatment allocation (hepatic resection = 2.289; 95% CI, 1.30–4.02; P = 0.004) as risk factors for overall survival. Conclusions: Hepatic resection provides a good prognosis for hepatocellular carcinoma patients with hepatic vein tumor thrombus compared with patients undergoing transcatheter arterial chemoembolization, and the most important factor related to survival was co-existence with portal vein invasion. Key words: hepatic resection, transcatheter arterial chemoembolization, hepatocellular carcinoma, hepatic vein tumor thrombus, overall survival
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
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HR vs. TACE for HCC with HVTT
Inclusion and exclusion criteria
The prognosis of patients with advanced hepatocellular carcinoma (HCC) remains poor (1,2). Although several factors contribute to the poor prognosis associated with HCC, major vascular invasion, i.e. tumor thrombosis (TT) in the portal vein (PVTT) or hepatic vein (HVTT), is one of the most important(3–5). As a result of recent advances in surgical techniques and perioperative management, liver resection for HCC with TT has become a reasonably safe treatment option with an acceptable mortality rate (6,7). However, in the American Association for the Study of the Liver Diseases/Barcelona Clinic for Liver Cancer Staging System and treatment guidelines, major vascular invasion, including PVTT and HVTT, is regarded as indicative of an advanced stage of the disease, and sorafenib is recommended as the standard treatment (2). Unfortunately, survival among these patients remains modest, and the local tumor control rate is low (8,9). Recently, hepatic resection (HR) and transcatheter arterial chemoembolization (TACE) with or without conformal radiotherapy have been described, but there is no current credible evidence suggesting that these therapies offer survival benefits to the patients because all the studies were either case reports, had a non-controlled design, or compared HCC extending with HVTT with HCC invading the portal vein (10–20). Moreover, only a few studies have compared the outcomes of hepatic resection and TACE in the treatment of HCC involving the inferior vena cava (IVC)/right atrium (RA) (21). The survival outcomes of HCC patients with HVTT treated with HR or with TACE have not been properly compared. This study aimed to retrospectively compare the long-term survival outcomes of HCC patients with HVTT who underwent HR or TACE as their initial treatment. We also aimed to assess the factors that affected survival.
Diagnosis of HCC was based on histology or dynamic imaging (computed tomography (CT) scans or magnetic resonance imaging (MRI) according to the diagnostic criteria of the European Association for the Study of the Liver (EASL) (23).The presence of PVTT and/or HVTT was identified by preoperative Doppler ultrasonography, enhanced CT or MRI. The diagnosis of HCC with vascular invasion was also confirmed by the final pathological findings in the HR group. Patients in the HR group were enrolled using the following inclusion criteria: (i) aged between 18 and 75 years; (ii) HCC with no previous treatment; (iii) the presence of HVTT on imaging, which indicated the first branch of the hepatic vein branching from the IVC, including the right, left and middle hepatic vein, the inferior right hepatic vein or the short hepatic veins, according to the Japanese staging system (24); (iv) Eastern Co-operative Oncology Group performance status 0 (25); and (v) resectable disease defined as the complete removal of all macroscopic tumor tissue and retention of a liver remnant sufficient to sustain life, as assessed by our surgical team (26). The exclusion criteria were: (1) Child-Pugh class C or evidence of hepatic decompensation including ascites, esophageal or gastric variceal bleeding or hepatic encephalopathy; (ii) an American Society of Anesthesiologists (ASA) score of ≥3; and (iii) extrahepatic metastasis identified during preoperative imaging.
Patients and methods Study design The study involved 4713 patients who had received either HR or TACE as the initial treatment for HCC and who have been hospitalized at Cancer Center of Sun Yat-sen University between January 2006 and November 2013. Of these, 119 patients (2.5%) had been diagnosed with HCC and HVTT; 28 patients underwent resection (the HR group) and 91 patients received TACE as an initial treatment for HCC with HVTT. The patients in the HR group were matched in a 1:2 ratio with patients from the pool of 91 patients who were treated with TACE as an initial treatment (the TACE group). The patients in both groups were matched as closely as possible based on the following priority: (i) combined PVTT; (ii) tumor burden (tumor size and tumor number); (iii) liver function (Child-Pugh class and indocyanine green retention rate at 15 min; (iv) age and gender; and (v) alphafetoprotein level (AFP). Patients’ demographic, clinical and pathological data, surgical outcomes, response to TACE and survival status were recorded prospectively and analyzed retrospectively from a collective HCC database. There is no concrete evidence yet for establishing an optimal treatment strategy for HCC with HVTT (22). The patients who had an operable primary tumor (i.e. the tumor or tumors could be resected completely) and well-preserved liver function were fully informed in detail about the possible benefits and the risks of treatment with TACE or HR. The choice of treatment was ultimately determined by the patients, and a written consent was obtained from each patient prior to treatment. This study was approved by the Ethical Committee of our center.
Hepatic resection procedure The techniques for hepatic resection were performed as described previously (27). After exploration, intraoperative ultrasonography was routinely performed to estimate the location and extent of the tumor thrombus as well as to mark the parenchymal transection line. Pringle’s maneuver was routinely used with a clamp/unclamp time of 10/5 min. Anatomical hepatic resection with en bloc thrombectomy was our preferred surgical method for liver resection. As an alternative, non-anatomical resection was used in cases of where wide en bloc resection was not feasible. In terms of the thrombectomy, the tumor thrombus was either resected en bloc with the tumor or extracted out of the vascular lumen, depending on its location and extent (26). After flushing with normal saline and confirming, by intraoperative ultrasonography, that no tumor thrombus remained, the vascular incision was sutured. In this study, major hepatic resection was defined as resection of three or more Couinaud’s segments of the liver. Minor hepatic resection was defined as resection of two or fewer segments of the liver.
TACE TACE was carried out using techniques we have described previously (28) and was performed by our four radiologists, who had 7–10 years’ experience in TACE. After introducing a 5-French catheter via the femoral artery, visceral arteriograms were obtained to ascertain the locations of the tumor and the tumor-feeding arteries. Depending on the size, location and arterial supply of the tumor, the tip of the catheter was advanced into the right or left hepatic artery, or into the tumorfeeding branches. Next, we injected an embolization suspension consisting of mitomycin C 6 mg (Zhejiang Hisun Pharmaceutical Co. Ltd., China), lobaplatin 50 mg (Hainan Changan International Pharmaceutical, China), and epirubicin 50 mg (Pharmorubicin, Pfizer, USA) mixed in 10 ml of water-soluble contrast medium (Omni-paque, Winthrop Pharmaceuticals, USA). The mixture was mixed thoroughly with 10 ml of ethiodized-oil (Lipiodol; Guerbet, Aulnay-sous-Bois, France). If the tumor bearing territory showed no stagnant flow after injection of the emulsion, a maximum of 20 ml pure Lipiodol
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Introduction
Jpn J Clin Oncol, 2015 was then injected. Embolization was then performed in these patients by injecting absorbable gelatin sponge particles (Gelfoam; Hanzhou alc Ltd, China), 1–2 mm in diameter, through the angiographic catheter. This treatment regimen was used consistently in this study, regardless of tumor type and size.
Follow-up
with terminal HCC, Child-Pugh class C liver function, or an Eastern Cooperative Oncology Group score >2.
Statistical analysis Post-operative mortality was defined as any death during postoperative hospitalization or death within 30 days after treatment. According to Common Terminology Criteria for Adverse Events V3.0 (29), Grade 1–2 refers to minor complications, while major complications were defined as Grade 3 and 4. The primary outcome measure was the overall survival rate. The secondary outcome measure was procedure-related complications. For comparisons between baseline variables, we used the student’s t test for continuous variables and the χ 2 test for categorical variables. Survival curves and univariate analysis were conducted using the Kaplan–Meier method, and differences were analyzed using the log-rank test. The prognostic factors found to be significant in the univariate analysis (P < 0.1) were subjected to multivariate analysis with the Cox proportional hazards regression model. A statistically significant difference was set at P < 0.05.
Results Patients A total of 28 patients in the HR group and 56 patients in the TACE group identified as having HCC with HVTT were eventually enrolled in the study, which comprised 81 men and 3 women, with a median age of 50 (range, 25–72) years. A total of 76/84 patients had underlying chronic liver disease. The mean maximum tumor diameter for the HR and the TACE groups were 9.6. ± 3.4 cm and 9.6 ± 3.1 cm, respectively (P = 0.957). The baseline demographic data were well matched between the two groups of 84 patients except for alanine transferase (Table 1).
Outcomes after HR/TACE The surgical procedures and the operative details for the patients in the HR group are listed in Table 2. A total of 18 patients received
Table 1. Pretreatment baseline characteristics of patients Characteristic
HR (n = 28)
TACE (n = 56)
P value
Age (years)a Male/femaleb Hepatitis B carrier (±) Liver cirrhosis (yes/no) Platelet count (109/l) Prothrombin time (sec) Alanine transferase (U/l) Serum albumin (g/l) Total bilirubin (mmol/l) ICGR 15 (%) Child-Pugh class (A/B) Alpha-fetoprotein level (≤/>400) (ng/ml) Tumor size (cm) Tumor number (≤/>1) Tumor extent (unilobar/bilobar) Combined PVTT (yes/no)
47.4 ± 10.3 27/1 (96/4) 26/2 (93/7) 27/1 (96/4) 208.6 ± 77.3 12.5 ± 1.4 40.4 ± 22.0 41.7 ± 3.0 14.9 ± 7.0 4.3 ± 2.5 28/0 (100/0) 8/20 (29/71) 9.6. ± 3.4 17/11 (61/39) 20/8 (71/29) 16c/12 (57/43)
51.1 ± 10.2 54/2 (96/4) 45/11 (80/20) 49/7 (88/12) 216.9 ± 94.9 12.7 ± 1.6 69.3 ± 44.5 40.6 ± 4.7 17.3 ± 9.9 6.8 ± 5.0 53/3 (95/5) 21/35 (36/64) 9.6 ± 3.1 26/30 (46/54) 36/20 (64/36) 31d/25 (55/45)
0.124 1.000 0.203 0.259 0.688 0.484 0.000 0.168 0.245 0.094 0.547 0.417 0.957 0.217 0.513 0.876
a
Mean ± SD. Number (%); ICGR 15, indocyanine green retention rate at 15 min; PVTT, portal vein tumor thrombus; HR, hepatic resection; TACE, transcatheter arterial chemoembolization. c The degrees of PVTT for 16 patients: (the segmental branches = 4, the right/left portal vein = 10, the main portal vein = 2). d The degrees of PVTT for 31 patients: (the segmental branches = 8, the right/left portal vein = 18, the main portal vein = 5). b
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This study was censored on 30 November 2014. The routine followup protocol was uniform for patients in both the HR and TACE group, and included a serum AFP assay, abdominal ultrasonography and liver function tests every month for the first year and then at gradually increasing time intervals. In the HR group, contrast-enhanced CT was performed 1 month after hepatic resection and at 3-month intervals thereafter for surveillance. For patients in the TACE group, contrast-enhanced CT scans were obtained every 1–2 months during the first 3 months for evaluation of the tumor response. Tumor response was graded into the following four groups, according to Response Evaluation Criteria in Solid Tumors (RECIST): CR (complete response) = disappearance of all target lesions; PR ( partial response) = 30 to 99% decrease in the sum of the longest diameter of the target lesions; SD (stable disease) = neither PR nor progressive disease; and PD ( progressive disease) = more than 20% increase in the sum of the longest diameter of the target lesions. For analysis, the overall responses comprehensively take into consideration changes in target lesions, non-target lesions, and appearance of intrahepatic or extrahepatic new lesions. Recurrence was defined as the appearance of new lesions with the radiological features of HCC after HR. The choice of treatment was determined by the characteristics of the recurrent tumor, the patient’s request and the results of the discussion by our multidisciplinary team. For patients with tumor progression without contraindications for TACE, a repeat in TACE treatment was recommended. For patients whose residual tumors could not be embolized owing to technical problems, radiofrequency ablations were used to destroy the residual tumors where feasible. Conservative treatments were given to patients
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HR vs. TACE for HCC with HVTT
Table 2. Operative procedures and post-treatment outcomes for patients in the HR group Variables
HR (n = 28)
Surgical time (min) Time of Pringle maneuver (min) Intraoperative blood loss (ml) Extent of resection (R0/R1/2) Tumor differentiation Well Moderate or poor Type of hepatectomy Minor hepatectomy Major hepatectomy Minor hepatectomy + thrombectomy Major hepatectomy + thrombectomy Type of recurrence, n Intrahepatic recurrence Extrahepatic metastasis Both
233.0 ± 71.1 23.3 ± 12.9 782.1 ± 890.7 22/6 12 16 3 7 8 10
Table 3. Post-treatment outcomes of TACE for patients in the TACE group Variable Treatment sessions of TACE Overall tumor response CR PR SD PD
TACE (n = 56) 1.5 (range, 1–4) 2 13 20 21
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
hepatectomy and thrombectomy whilst 10 patients received hepatectomy only. R0 resection was achieved in 22 patients (78.6%) and the remaining 6 patients received R1 resection. During the follow-up period, 23 patients developed radiologically detectable residual disease/ tumor recurrence. Of these 23 patients, 13 received repeated TACE, 1 patient received radiofrequency ablation and the remaining patients received the most suitable supportive treatment or systemic therapy. The treatment outcomes of TACE are listed in Table 3. Fifty-six patients received a mean of 1.5 (range, 1–4) sessions of TACE. The objective tumor response rate, including CR and PR, was 26.8%. After the TACE treatment, the tumors in 12 patients were downstaged to receive HR (n = 9) or local ablative therapy (radiofrequency ablation, n = 2, or radiofrequency in combination with percutaneous ethanol injection, n = 1).
Recurrence and survival In the HR group, 23 of the 28 patients who underwent curative resection experienced post-operative recurrences. Intrahepatic recurrences occurred in 13 patients, extrahepatic metastases in 7 patients and both intrahepatic and extrahepatic recurrences in 3 patients. The median recurrence-free survival duration of the patients in the HR group was 4.0 months (95% CI: 1.6–6.4). The median progress-free survival duration of the patients in the TACE group was 3.6 months (95% CI: 2.2–5.0). At a median follow-up of 11 months (range, 1–83), the HR group had a longer median overall survival duration (15.6 months; 95%
Figure 1. The overall survival curves of patients in the HR group and patients in the TACE group (15.6 months vs. 9.1 months; P = 0.015).
CI: 9.3–21.9) than the TACE group (9.1 months; 95% CI: 7.4– 10.8). For patients in the HR group, the 1-, 2- and 3-year overall survival rates were 66.5, 37.4 and 28.5% respectively, whereas the overall survival rates in the TACE group was 32.3, 18.7 and 15.6%, respectively (P = 0.015) (Fig. 1). A subgroup analysis of HCC patients combined with or without PVTT was conducted. For the patients combined with PVTT, the median survival was better in the HR group than in the TACE group (13.6 vs. 7.4 months; P = 0.006; Fig. 2a). For the patients combined without PVTT, there was no significant difference between the two groups for median survival (26.2 vs. 14.6 months; P = 0.414; Fig. 2b). In a comparison of those patients who underwent hepatic resection with those who attained a complete or partial response after TACE, no significant difference between the two groups for median survival (15.6 vs. 18.2 months; P = 0.770; Fig. 2c).
Mortality and morbidity Table 4 shows the in-hospital mortality and the incidence of major and minor complications after undergoing hepatic resection or TACE. Two patients died of incurable hepatic failure within 30 days of TACE subsequent resection, resulting in a hospital mortality rate of 3.6% in the TACE group. One patient died of liver failure, and another died of sepsis and multi-organ failure. There was no in-hospital mortality for the HR group. Complications occurred more often in the HR group than in the TACE group (57.1 vs. 30.4%).but no significant difference was found in the incidence of complications between the two groups (P = 0.259).
Univariate and multivariate analysis of predictors of overall survival The univariate and multivariate analyses of predictors of the overall survival for all 84 patients are shown in Table 5. Sex, Child-Pugh class, combined PVTT, and treatment allocation were found to be significant risk factors for survival in the univariate analysis. After multivariate Cox proportional hazards regression analysis, combined PVTT (HR = 1.81; 95% CI: 1.26–3.57; P = 0.005) and treatment
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Table 4. Mortality and complications for patients with hepatic vein tumor thrombosis Mortality and complications In-hospital mortality Complications Minor complicationa Major complicationb
HR (n = 28)
TACE (n = 56)
0
2
13 3
10 7
P Value 0.550 0.259
a Minor complications, including mild ascites/pleural effusion (n = 18), bacteremia (n = 3), and transient liver impairment (Child’s C status for duration of hospital stay) (n = 2). b Major complications: In the HR group, post-operative hemorrhage (n = 1), pleural effusion (n = 1), and bile leakage (n = 1); In the TACE group, upper gastrointestinal hemorrhage (n = 3), and pleural effusion (n = 4).
allocation (HR = 1.66; 95% CI: 1.30–4.02; P = 0.004) were significant prognostic factors for overall survival.
Discussion To date there is no concrete evidence for establishing an optimal treatment strategy for HCC with hepatic vein invasion, and in most previous cases reports of PVTT and HVTT are mixed with cases of vascular invasion, with HVTT cases always being in the minority (10,18,21,22). The incidence of HVTT (2.5%) in our study was similar to the incidences previously reported ranging from 1.4–4.9% (5,12,14,25,30). Owing to the relatively low incidence of HVTT compared with PVTT, little is known about HVTT (14). To our knowledge, this is the first report to compare treatment outcomes among HCC patients with HVTT who were treated with different treatment modalities. Our study revealed that patients with HVTT undergoing HR have a better prognosis than those with HVTT undergoing TACE, which indicates that choosing the appropriate candidates for surgery can improve the prognosis. In addition, in a comparison of patients who underwent hepatic resection with those who attained CR/ PR after TACE, no significant difference in prognosis was found between the two groups. These results show that it may be possible to attain a similar level of efficacy with TACE as with HR for some highly selected patients with HVTT.
Due to a potential to select better risk patients with less advanced HCC to surgery, it is difficult to conduct a retrospective comparison between patients with HCC and HVTT who received hepatic resection and TACE. To minimize such a potential bias, the study was conducted as a retrospective case-matched controlled study, and the patients in this study were well matched between the HR group and the TACE group with the exception of the alanine transferase. However, alanine transferase was not found to be a significant prognostic factor both in either the univariate or multivariate analysis. Therefore, the significant difference in alanine transferase between the two groups of patients may not reduce the statistical strength and lead to bias. Some reports have documented that the results following hepatic resection for HCC combined with major vascular invasion have been disappointing (5,31). In the previous studies, the median survival time was about 6.1–11 months and the 3-year survival rate after resection was approximately 14% in HCC patients with major vascular invasion (5,10,18,20). However, in our study, hepatic resection led to an overall survival rate of 28.5% at 3 years, and 15.6 months of median survival. Our study may have yielded a better survival rate owing to the fact that previous research defined major vascular invasion contains involving the IVC(20) or PVTT (5,10,18). Our study reported that TACE led to an overall survival rate of 15.6% at 3 years, and 9.1 months of median survival, similar to previous findings (12,13). The patients with HVTT in the HR group achieved a better prognosis than the patients in the TACE group, as in previous similar studies on PVTT (26) or the IVC/RA (21) (P = 0.015). In our study, we observed a high incidence (56%) of HCC combined with PVTT. The epithelial-mesenchymal transition (EMT) (32), the mechanism of invasion in a variety of cancers, underlying the formation of both PVTT and HVTT may explain the high rate of co-existence of the two. Patients with both HVTT and PVTT had a worse prognosis than those with HVTT alone (5), owing to the high risk of intrahepatic metastasis and portal hypertension complications (5,22). In our study, HCC combined with PVTT was a significant prognostic factor in the univariate and multivariate analysis. A subgroup analysis of patients combined with PVTT, the median survival was better in the HR group than in the TACE group. However, perhaps owing to the small sample size in the HR group (n = 12), no significant survival difference was found between the two groups for
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Figure 2. (a) The overall survival curves of HCC patients combined with PVTT in the HR group and patients in the TACE group (13.6 months vs. 7.4 months; P = 0.006); (b) The overall survival curves of HCC patients combined without PVTT in the HR group and patients in the TACE group (26.2 months vs. 14.6 months; P = 0 .414); (c) The overall survival curves for a comparison of patients who underwent hepatic resection with those who attained CR/PR after TACE (15.6 vs. 18.2 months; P = 0 .770).
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HR vs. TACE for HCC with HVTT
Table 5. Univariate and multivariate analysis of risk factors for overall survival Variables
Multivariate analysis
P value Log-rank
HR
95% CI
P value Cox regression
0.655 0.085 0.671 0.322 0.372 0.289 0.560 0.307 0.691 0.061 0.923 0.783 0.113 0.772 0.022 0.015
1.81 1.66
1.26–3.57 1.30–4.02
0.005 0.004
HR, hazard ratio; HR, hepatic resection; ICGR 15, indocyanine green retention rate at 15 min; PVTT, portal vein tumor thrombus; TACE, transcatheter arterial chemoembolization; CI, confidence interval.
patients combined without PVTT. We also found that even patients combined with PVTT who had undergone HR had a worse median survival than patients without PVTT who had received TACE (13.6 vs.14.6 months). Theses survival data indicate that the co-existence of PVTT is one of the most important factors contributing to poor prognosis. There are some limitations to our study. The principal limitation of our study was its retrospective nature with all its inherent defects. Second, diagnosis of tumor thrombosis confirmed by histopathology was not accessible in the TACE group, which may have led to bias. Third, this is a single center study, and the results may not be applicable to a less specialized center. Therefore, multicenter and larger randomized studies are needed to confirm our results. In conclusion, hepatic resection provides a better prognosis for HCC patients with HVTT than for patients who receive TACE as an initial treatment, and the most important factor related to poor survival was co-existence with portal vein invasion.
Funding This study was supported by grants from the National Natural Science Foundation of China (No. 81172037/H1606), Guangzhou municipal science and technology project of China (No. 2012J4100078), and Guangdong province science and technology project of China (No.2013B021800159).
Conflict of interest statement None declared.
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Age (years), (≤/>50) Sex (male/female) Hepatitis B carrier (yes/no) Liver cirrhosis (yes/no) Prothrombin time (≤/>14), (s) Alanine transferase (≤/>40), (U/l) Serum albumin (≤/>35), (g/l) Total bilirubin (≤/>20), (mmol/l) ICGR 15 (≤/>10), (%) Child-Pugh class (A/B) Alpha-fetoprotein level (≤/>400), (ng/ml) Tumor size (≤/>10), (cm) Tumor number (≤/>1) Tumor extent (unilobar/bilobar) Combined PVTT (yes/no) Treatment allocation (HR/TACE)
Univariate analysis
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