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Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era
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ScienceDirect EJSO xx (2015) 1e9
www.ejso.com
Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era W.-C. Lee*, C.-F. Lee, C.-H. Cheng, T.-J. Wu, H.-S. Chou, T.-H. Wu, R.-S. Soong, K.-M. Chan, M.-C. Yu, M.-F. Chen Division of Liver and Transplantation Surgery, Department of General Surgery, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan Accepted 31 May 2015 Available online - - -
Abstract Aims: Surgical treatment for early-stage hepatocellular carcinoma (HCC) is toward transplantation. However, liver resection remains the major surgical treatment for HCC in Asia. This study is to examine the results of liver resection when liver transplantation became an option of treatment for early-stage HCC. Methods: In this retrospective cohort study, 1639 patients with resectable HCC were reviewed and divided into two groups. In the 1st period (2002e2005), all 679 patients received liver resection. In the 2nd period (2006e2010), 916 patients had liver resection and 44 patients jointed liver transplantation program. The results of treatment in these two periods were analyzed. Results: The characteristics of tumors were the most important factors of tumor recurrence after liver resection. Liver function reserve, characteristics of tumors, and surgeons’ endeavor were all independent factors for overall survival after liver resection. When the patients with oligo-nodular tumors or portal hypertension with low platelet count had liver transplantation rather than liver resection in the 2nd period, the survival rates in the 2nd period were improved. When the patients in the 1st period with low platelet count (105 103/ uL) were subtracted, the 5-year survival rate of the patients with one-segmentectomy for small-sized HCC in the 1st period was similar to those in the 2nd period and transplant patients. Conclusions: The outcomes of liver resection were improved while liver transplantation was performed for the patients with suspicious portal hypertension. Platelet count, 105 103/uL, could be a watershed for early stage HCC patients to undergo liver resection or liver transplantation. Ó 2015 Published by Elsevier Ltd.
Keywords: Hepatocellular carcinoma; Liver resection; Liver transplantation; Platelet; Portal hypertension; Outcomes
Introduction Hepatocellular carcinoma (HCC) is the most common primary cancer in the liver. The incidence of HCC is high in Southeast Asia because of a high prevalence of chronic
Abbreviations: HCC, hepatocellular carcinoma; BCLC, Barcelona Clinic Liver Cancer; RFA, radiofrequency ablation; UCSF, University of the San Francisco; ICG, indocyanine green; INR, international ratio; CT, computed tomography. * Corresponding author. Division of Liver and Transplantation Surgery, Department of General Surgery, Chang-Gung Memorial Hospital, 5, FuH s i n g S t r e e t , K w e i - S h a n , Ta o y u a n , Ta i w a n . Te l . : þ8 8 6 3 3281200x3366; fax: þ886 3 3285818. E-mail address: [email protected] (W.-C. Lee).
hepatitis B.1,2 The incidence is also increasing in western countries because of the infection of hepatitis C.3 It is no doubt that HCC is one of the most common malignancies in the world now.1 Substantially, HCC is an aggressive cancer disease and can be curatively treated only in Barcelona Clinic Liver Cancer (BCLC) very early/early stage.4 HCC in its very early/early stage can be treated by surgery or radiofrequency ablation (RFA). Surgery takes priority of treatment because the survival rates of surgery are superior to RFA.5,6 Recently, microwave ablation was applied to treat HCC, however, the results was inferior to surgery, either.7 Surgery for HCC includes liver resection and liver transplantation. To our knowledge, liver resection has a higher recurrent rate than liver transplantation8,9 and
http://dx.doi.org/10.1016/j.ejso.2015.05.024 0748-7983/Ó 2015 Published by Elsevier Ltd. Please cite this article in press as: Lee W-C, et al., Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.024
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the survival rate of liver resection is inferior to that of liver transplantation.10 Therefore, surgical treatment for early stage HCC is shifted from liver resection toward liver transplantation recently.11 Nevertheless, liver donation is always short and liver transplantation for HCC patients is not always available. The choice of liver transplantation as the primary treatment for HCC may also crowd-out the transplant opportunities for benign diseases. Therefore, liver resection remains the main treatment for solitary tumor or oligo-nodular tumors. In this study, we retrospectively reviewed a large cohort of patients with surgical treatments for HCC in our institute to seek whether the results of surgical treatments for HCC were improved when liver transplantation became an option of treatment and what policy of surgical treatments for very early/early stage HCC was optimal.
Liver transplantation The patients who had portal hypertension with a high ICGR15, prolonged prothrombin time, presence of varices and splenomegaly in computed tomography (CT) images or oligo-nodular HCC were suggested to have liver transplantation as an option of treatments. The patients willing to have liver transplantation would be registered in Taiwan network of organ sharing and waited for liver transplantation. If living donors were available, living donor liver transplantation was performed after complete assessments of living donors. Follow up
1639 patients who had resectable HCC from 2002 to 2010 were included in this retrospective study. In Taiwan, liver transplantation for HCC is covered by national health insurance for deceased liver transplantation if the tumors meet Milan criteria and for living donor liver transplantation if the tumors meet University of the San Francisco (UCSF) criteria since 2006.12,13 According to the time scale, this retrospective study was divided into two periods. The 1st period was from 2002 to 2005 and the 2nd period was from 2006 to 2010. The collection of clinical data was proved by local ethic committee of Chang-Gung Memorial Hospital.
For the patients having liver resection, the patients were followed up regularly. Liver function tests, measurement of a-fetoprotein, and liver ultrasonography were performed every 3 months. Dynamic CT of the liver was performed if deemed necessary. For the patients with liver transplantation, measurement of a-fetoprotein, liver ultrasonography and dynamic CT of the liver were performed every 3 months in the 1st year. Measurement of a-fetoprotein and liver ultrasonography were performed every 3 months in the following years and dynamic CT of the liver was performed if deemed necessary. Tumor recurrence was defined when CT detected tumors with typical HCC imaging pattern in the liver or extrahepatic tumors. Disease-free survival was measured from the date of surgical treatments to tumor recurrence. Overall survival was measured from the date of surgical treatments until death which was registered in Bureau of Health, Taiwan. Hospital mortality was defined that patients were not discharged and died in hospital after surgery.
Pre-operative assessment of the liver function
Biostatistics analysis
Before operation, quantitative liver function was determined by indocyanine green (ICG) test. Briefly, ICG test was performed by injecting 0.5 mg/kg of ICG into a peripheral vein and drawing a blood sample from another site 15 min later. Results were presented as 15-min retention rate of indocyanine green (ICGR15).14e16 Besides ICGR15 test, platelet counts and international ratio (INR) of prothrombin times were both collected because both parameters represented cirrhosis-associated portal hypertension and splenomegaly.17
The comparisons of categorical variables were determined by Chi-square Tests. The significance of the differences between different groups was determined by unpaired Student’s t-test. The survival rates were calculated using the KaplaneMeier method and compared between groups using the log-rank test. The statistical analyses were all performed with SigmaPlot 12.3 software for Windows (Systat Softwave, Inc., San Jose, CA, USA). P value below 0.05 was considered to be significantly different.
Materials and methods Patients
Results Surgical technique of liver resection Patients and hospital mortality During operation, intra-operative ultrasonography was performed to demarcate the tumor and identified the relationship between tumors and major vessels. Intermittent Pringle’s maneuver, 15-min clamping followed by 5min release, was applied for most of the operations. Parenchymal transection was performed by ultrasonic dissector or kellyclasy.
Among 1639 patients, 679 patients were in the 1st period and 960 patients were in the 2nd period. All patients in the 1st period had liver resections. Among the patients in 2nd period, 916 patients had liver resections and 44 patients jointed liver transplantation program. When focusing on liver resection, 22 patients (3.2%) in the 1st period and
Please cite this article in press as: Lee W-C, et al., Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.024
W.-C. Lee et al. / EJSO xx (2015) 1e9
18 patients (2.0%) in 2nd period died in hospital after liver resection. For the patients joining liver transplantation program, 34 (77.3%) patients were transplanted, 6 patients (13.6%) were dropped out and 4 patients still wait for liver transplantation now (Supplementary Fig. 1). Prognostic factors of disease-free survival for liver resection To determine the prognostic factors of disease-free survival for liver resection, the data of 1555 patients with liver resection were analyzed excluding 40 patients with hospital mortality. Univariate analysis showed that abnormal liver function, a-fetoprotein >400 ng/ml, elevation of ICGR15, blood loss >500 ml, large range of liver resection, resection margin involvement and pathological figures of tumors were all significant risk factors (Supplementary Table 1). In multivariate analysis, tumor size >5 cm in diameter, vascular invasion of tumor, presence of daughter nodules and resection margin involvement were independent risk factors (Table 1). These results showed tumor characteristics were the most important factors of tumor recurrence although surgical resection involvement also determined tumor recurrence.
3
Prognostic factors of overall survival for liver resection To determine the prognostic factors of overall survival, all patients with liver resections were included. Univariate analysis showed that abnormal liver function, a-fetoprotein >400 ng/ml, elevation of ICGR15, blood loss >500 ml, large range of liver resection, resection margin involvement and pathological figures of tumors were all significant risk factors (Supplementary Table 2). In multivariate analysis, ICGR15 >20%, range of parenchymal resection, blood loss >500 ml, resection margin involvement, vascular invasion of tumor, non-encapsulation of tumor, presence of daughter nodules were all independent risk factors (Table 1). These results showed that not only tumor characteristics but also liver function and surgical affairs determined patients’ overall survival. Difference between patients in the 1st and 2nd periods Because some patients with clinical suspicion of portal hypertension in the 2nd period chose liver transplantation as the treatment, the characteristics of the patients with
Table 1 Cox’s regression results for disease-free and overall survival. Factors
Albumin (g/dL) 3.5/>3.5 AST (U/L) >34/34 ALT (U/L) >36/36 Bilirubin (mg/dL) >1.3/1.3 Alk-p(U/L) >94/94 AFP (ng/mL) >400/400 ICG R15 (%) >20/20 No. of segmentectomy 2/1 3/1 4/1 Blood loss (ml) >500/500 Tumor size >5/5 Tumor capsule No/Yes Vascular invasion Yes/No Daughter nodules Yes/No Resection margins Positive/Negative
DFS
OS
Hazard ratio
95% C.I.
0.932
0.695e1.251
1.195
P value
Hazard ratio
95% C.I.
P value
0.640
1.174
0.808e1.707
0.400
0.958e1.491
0.115
1.053
0.786e1.412
0.729
1.072
0.864e1.331
0.525
0.978
0.737e1.300
0.880
1.091
0.823e1.448
0.544
1.198
0.828e1.734
0.338
1.139
0.941e1.379
0.182
1.017
0.785e1.317
0.898
1.190
0.981e1.443
0.077
1.171
0.909e1.509
0.222
1.263
0.920e1.736
0.149
1.752
1.159e2.648
0.008
1.143 1.228 1.203
0.916e1.427 0.935e1.611 0.889e1.629
0.236 0.139 0.231
1.209 1.524 1.470
0.870e1.679 1.039e2.234 0.969e2.230
0.258 0.031 0.070
1.117
0.910e1.371
0.290
1.300
1.001e1.689
0.049
1.332
1.081e1.641
0.007
1.324
0.992e1.768
0.057
1.218
0.993e1.493
0.059
1.407
1.073e1.846
0.014
1.768
1.457e2.145
<0.001
2.512
1.946e3.243
<0.001
1.481
1.209e1.815
<0.001
1.535
1.177e2.002
0.002
1.975
1.432e2.724
<0.001
1.647
1.086e2.498
0.019
DFS, disease-free survival; OS, overall survival. Please cite this article in press as: Lee W-C, et al., Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.024
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liver resections in the 1st and 2nd periods might be different. Therefore, liver function, surgical profiles and tumor characteristics of the patients in the 1st and 2nd periods were compared. The results showed that the patients in the 2nd period had better liver function than the patients
in the 1st period evidenced by a lower ICGR15 [7.0 (3.8e12)% versus 8.8 (5.2e13.7)%, p < 0.001] and a higher serum albumin level [4.2 (3.8e4.4) versus 4.1(3.7e4.4)g/dl, p < 0.0001] (Table 2). The tumor sizes between two groups were not different. However, the
Table 2 The characteristics of patients undergoing liver resection for HCC in two different periods. Parameters [median(Q1,Q3)]
Age (yrs) Gender (male) Platelet (x1000/uL) Albumin (g/dL) AST (U/L) ALT (U/L) Bilirubin (mg/dL) Alkaline phosphates (U/L) AFP (ng/mL) ICG R-15 min (%) Blood urea nitrogen (mg/dL) Creatinine (mg/dL) Smoking (%) No Yes Alcohol (%) No Yes HBV (%) Negative Positive HCV (%) Negative Positive Child classification (%) A B C Operation time (mins) Blood loss (mL) 1000 >1000 No. of segmentectomy (%) 1 2 3 4 Hospital mortality (%) No Yes Tumor size (cm) Tumor capsule (%) No Yes Vascular invasion (%) No Yes Daughter nodules (%) No Yes Resection margin (%) Negative Positive
Time periods 2002e2005 (n ¼ 679)
2006e2010 (n ¼ 916)
58 524 167 4.1 38.0 41.0 0.8 76.0 43.0 8.8 15.0 1.24
60 714 173 4.2 37.0 39.0 0.7 76.0 24.3 7.0 14.0 0.93
(47e67) (77.2%) (121e216) (3.7e4.4) (27.0e59.0) (26.0e68.8) (0.6e1.1) (61.0e108.0) (7.7e501.5) (5.2e13.7) (12.0e18.0) (0.90e1.20)
(50e69) (77.9%) (127e218) (3.8e4.4) (26.8e61.0) (26.0e66.0) (0.5e0.9) (62.0e97.0) (5.6e375.4) (3.8e12.0) (11.4e17.7) (0.80e1.10)
470 (69.2) 209 (30.8)
777 (84.8) 139 (15.2)
516 (76.0) 163 (24.0)
805 (87.9) 111 (12.1)
235 (35.7) 423 (64.3)
258 (33.0) 523 (67.0)
376 (64.3) 209 (35.7)
438 (61.0) 280 (39.0)
664 11 1 235 300 517 64
(98.2) (1.6) (0.1) (180e300) (150e600) (89.0%) (11.0%)
874 14 1 240 200 835 62
(98.3) (1.6) (0.1) (190e312) (100e500) (93.1) (6.9)
164 249 146 120
(24.2) (36.7) (21.5) (17.7)
329 304 141 142
(35.9) (33.2) (15.4) (15.5)
P value
Odds
95% C.I.
P Value
Ratio
Of odds ratio
0.001 0.713 0.716 <0.0001 0.837 0.983 0.006 0.829 0.129 <0.0001 0.801 0.490 <0.0001
1.014
1.004e1.024
0.008
1.284
0.993e1.660
0.057
0.815
0.639e1.038
0.097
0.979
0.963e0.994
0.008
0.486
0.348e0.685
<0.001
<0.0001
0.594
0.410e0.860
0.006
1.004 0.520
1.003e1.006 0.319e0.849
<0.001 0.009
0.565 0.425 0.410
0.414e0.771 0.289e0.623 0.265e0.634
<0.001 <0.001 <0.001
0.105 0.011
0.838
0.619e1.134
0.252
0.021
0.941
0.707e1.251
0.674
0.003
0.834
0.608e1.144
0.260
<0.0001
0.392
0.229e0.669
0.001
0.286
0.225
0.978
0.012 <0.001 0.006 <0.0001
0.107 657 (96.8) 22 (3.2) 4.0 (2.5e7.0)
898 (98.0) 18 (2.0) 3.7 (2.3e6.5)
154 (24.6) 473 (75.4)
174 (19.1) 736 (80.9)
435 (64.7) 237 (35.3)
641 (70.2) 272 (29.8)
501 (76.4) 155 (23.6)
749 (82.5) 159 (17.5)
615 (91.5) 57 (8.5)
877 (96.8) 29 (3.2)
(Q1,Q3), interquartile; HBV, hepatitis B infection; HCV, hepatitis C infection; AST, aspartate aminotransferase; ALT, alanine aminotransferase. Please cite this article in press as: Lee W-C, et al., Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.024
W.-C. Lee et al. / EJSO xx (2015) 1e9
(A) 1.0
Patients (2002-2005) Patients (2006-2010)
0.8
p<0.001 Survival (x 100%)
parenchyma resection range was more limited in the 2nd period than in the 1st period patients as our current surgical policy was minimizing liver parenchyma loss. Under such policy, 35.9% of the patients in the 2nd period had only one segment resection, compared to 24.2% of the patients in the 1st period. Although the resection range was smaller in the 2nd period, surgeons spent a longer time to perform the surgery [240 (190e312) versus 235 (180e300) minutes, p ¼ 0.012]. Simultaneously, median (interquartile) blood loss in the 2nd period was less than in the 1st period [200 (100e500) versus 300 (150e600) ml, p < 0.001]. The resection margin involvement rate (safe margin <1 mm) was lower in the 2nd period than in the 1st period (3.2% versus 8.5%, p < 0.001). Although the tumor sizes between these two group patients were almost equal, several well-known prognostic factors of tumor characteristics were different. The tumors in the 2nd period patients had higher incidence of encapsulation, and lower incidence of vascular invasion and satellite tumors than those in the 1st period patients (Table 2). For oligo-nodular tumors, 11 of 898 (1.2%) patients in the 2nd period had liver resection for two tumors, compared to 27 of 657 (4.1%) in the 1st period ( p < 0.001).
5
0.6
0.4
0.2
0.0 0
20
40
60
80
100
120
140
Months
(B) 1.0 Patients (2002-2005) Patients (2006-2010)
p<0.001
Disease-free and overall survival rates The 1-, 3- and 5-year disease-free survival rates were 73.7%, 58.3% and 53.5%, respectively, for the patients with liver resections in the 2nd period, compared to 66.1%, 41.9% and 31.6% for the patients in the 1st period ( p < 0.001, Fig. 1A). The 1-, 3- and 5-year overall survival rates were 91.3%, 79.5% and 71.6%, respectively, for the patients in the 2nd period, compared to 83.4%, 65.6% and 55.1% for the patients in the 1st period ( p < 0.001, Fig. 1B). These results clearly demonstrated that the disease-free and overall survival rates for the patients with liver resections in the 2nd period were better than in the 1st period.
Survival (x 100%)
0.8
0.6
0.4
0.2
0.0 0
Survival rates according to parenchymal resection In further analysis, disease-free and overall survival rates were calculated according to parenchymal resection ranges. The tumor sizes in different-ranged liver resections in the 1st and 2nd periods were similar (Supplementary Table 3). The disease-free and overall survival rates of limited resections were better than wide-range resection. The disease-free and overall survival rates in the 2nd period were better than in the 1st period when the same ranges of liver resections were compared (Fig. 2AeD). Clinical profiles and outcomes of patients entering liver transplant program In the 2nd period, 44 patients with Child-Pugh A cirrhosis entered liver transplantation program because of oligo-
20
40
60
80
100
120
140
Months
Figure 1. KaplaneMeier disease-free and overall survival curves. (A) The 1-, 3- and 5-year disease-free survival rates for the patients with liver resection in 2nd period were 73.7%, 58.3% and 53.5%, respectively, which were much better than those for the patients in the 1st period ( p < 0.001). (B) The 1-, 3- and 5-year overall survival rates for the patients with liver resection in 2nd period were 91.3%, 79.5% and 71.6%, respectively, which were much better than those for the patients in the 1st period, too ( p < 0.001).
nodular HCC (8/44, 18.2%) or portal hypertension with thrombocytopenia and prolonged prothrombin time. Their median (interquartile) platelet count was 77.5 (52.5e104.5) 103/uL which was lower than those with liver resection in the 1st period (167 (121e216) 103/uL, p < 0.001) or in 2nd period (173 (127e218) 103/uL, p < 0.001) (Supplementary Table 4). The median
Please cite this article in press as: Lee W-C, et al., Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.024
(A)
(B) 1.0
1 segment 2 segments 3 segments >=4 segments
1.0
Survival (x 100%)
0.8
p=0.001
Survival (x 100%)
p<0.001
0.8
1 segment 2 segments 3 segments >=4 segments
0.6
0.6
0.4
0.4 0.2 0.2 0.0 0
0.0 0
20
40
60
80
100
120
140
(C)
51.5 42.7 39.3 29.9
1 segment 2 segments 3 segments >=4 segments
(D)
85.0 71.1 63.9 60.2
80
70.8 55.8 49.0 42.6
64.9 52.9 42.8 35.8 1 segment 2 segments 3 segments >=4 segments p<0.001
1.0
p<0.001
0.8
Survival (x 100%)
0.8
Survival (x 100%)
1 2 3 >4
36.8 32.9 30.7 22.9
1.0
60
No of segmentectomy survival rate (%) 1-yr 3-yr 5-yr
No of segmentectomy survival rate (%) 1-yr 3-yr 5-yr 76.9 72.4 60.2 44.1
40
Months
Months
1 2 3 >4
20
0.6
0.4
0.6
0.4
0.2
0.2
0.0
0.0 0
20
40
60
80
100
120
140
0
20
40
Months
No of segmentectomy survival rate (%) 1-yr 3-yr 5-yr
1 2 3 >4
93.5 87.0 75.6 71.4
77.0 71.8 61.3 42.9
60
80
Months
68.3 57.4 49.6 39.0
No of segmentectomy survival rate (%) 1-yr 3-yr 5-yr 1 2 3 >4
97.0 93.9 86.9 76.4
90.8 82.1 64.1 61.0
82.5 75.6 51.4 56.4
Figure 2. KaplaneMeier disease-free and overall survival curves according to range of liver resection. (A) The disease-free survival rates for the patients in the 1st period. The less of liver parenchyma was resected, the better of the survival was achieved ( p ¼ 0.001). (B) The overall survival rates for the patients in the 1st period. The patients with limited parenchyma resection had better survival rates ( p < 0.001). (C) The disease-free survival rates for the patients in the 2nd period. The patients with limited parenchyma resection had better survival rates ( p < 0.001). (D) The overall survival rates for the patients in the 2nd period. The patients with limited parenchyma resection had better survival rates ( p < 0.001). Please cite this article in press as: Lee W-C, et al., Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.024
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(interquartile) waiting time for the patients with transplantation was 2 (1e3.3) months. The average dropped-out time after listed was 23.7 13.5 months. For all 44 patients entering into liver transplantation program, the intent-to-treatment 1-, 3- and 5-year survival rates were 95.5%, 86.3% and 76.1%, respectively. For 34 patients with liver transplantation, 1-, 3- and 5-year survival rates were 93.9%, 87.9% and 82.4%, respectively (Supplementary Fig. 2). Effect of portal hypertension on the survival of liver resection In this study, the results of liver resection in 2nd period were better than in the 1st period. The better results might be contributed due to that the patients with lower count of platelet in 2nd period chose liver transplantation as the definite treatment. To examine this hypothesis, platelet count, 105 103/uL which was the value of the 3rd interquartile in the patients entering into liver transplantation program, was chosen as the cut-off point to represent advanced cirrhosis with portal hypertension. While the patients in the 1st period were divided into two groups according to platelet count 105 103/uL, the patients with platelet count 105 103/uL had worse overall survival than the patients with platelet count >105 103/uL since 40 months after liver resection although the disease-free survival rates were similar (Supplementary Fig. 3A and B). When the patients with one-segmentectomy for transplantable tumors and without advanced cirrhosis (platelet count >105 103/uL) were selected to calculate overall survival, the 3-year survival rate was increased from 77.0% to 81% and 5-year survival rate was increased from 68.3% to 75% (Fig. 3A). These survival rates were not different from those of the patients with one-segmentectomy in the 2nd period and the patients having liver transplantation (Fig. 3B). These results showed that the overall survival of liver resection for early stage HCC would be improved if the cirrhotic patients to have liver resections were restricted to platelet count >105 103/uL. Discussion The survival rate of liver resection was improved when liver transplantation was an option of treatment for early stage HCC. This study showed that the calculated 5-year overall survival rate for the patients having liver resection in the 2nd period was much better than those in the 1st period and approached to the results of liver transplantation.12,13,18 Since 2006, living donor liver transplantation becomes an option of surgical treatments for cirrhotic patients with HCC in this institute if living donors are available and the tumors meet UCSF criteria.12 Under such circumstance, some patients with splenomegaly and low count of platelet17 or oligo-nodular tumors19 would enter liver transplantation program and chose liver transplantation rather than liver resection as the definite treatments.
Figure 3. KaplaneMeier overall survival curves for the patient with transplantable HCC. (A) The survival rates were increased when the patients with one-segmentectomy for transplantable tumors in the 1st period were limited to platelet count >105 103/ul. The 3-year survival rate was increased from 77.0% to 81% and 5-year survival rate was increased from 68.3% to 75%. (B) This survival rates were not different from those of the patients with one-segmentectomy in the 2nd period and the patients having liver transplantation ( p ¼ 0.378).
Thereafter, the patients having liver resections in the 2nd period had better quantitative liver function and a fewer incidence of oligo-nodular tumors than the patients in the 1st period. Quantitative liver function and incidence of oligo-nodular tumors were both independent prognostic factors of overall survival. Thus, the survival rate of liver resection for early stage HCC patients in the 2nd period was better than that in the 1st period. Limited resection improved the overall survival. The range of liver resection was an independent factor of overall
Please cite this article in press as: Lee W-C, et al., Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.024
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survival. In this institute, the policy of liver resection was shifted from wide resection to limited resection. Compared to the resection limited to one segment, the hazard ratio for overall survival increased 1.5 folds when resection range was beyond two segments. The damage to the liver itself was aggregated when the resection range was large. Therefore, liver parenchyma preservation during operations was important for overall survival. A higher percentage of limited liver resections in the 2nd period might contribute to the better survival rate for the patients in the 2nd period than in the 1st period. Blood loss more than 500 ml was an independent risk factor for overall survival. Surgical endeavor might contribute to the better survival for the patients in the 2nd period. In the 2nd period, we paid more attention to control bleeding during parenchyma transection to keep bloodless operation field. Ultrasonic dissector combined with intermittent Pringle’s maneuver was adopted. Intra-operatively, fluid administration was restricted.20 Hence, the operation time in the 2nd period was longer than in the 1st period, but the blood loss was less than in the 1st period. Young et al. mentioned that blood transfusion was the only risk factor for overall survival in their non-cirrhotic HCC patient receiving liver resection.21 In addition, the margin involvement rate in the 2nd period was less than in the 1st period which might be due to intra-parenchymal vascular anatomy identified easily in the bloodless operation field. These emphasize that surgeons’ endeavor contributed to patients’ survival. Tumor characteristics are important factors for both disease-free and overall survival. Tumor size, vascular invasion, non-encapsulation of tumor and presence of satellite tumors were all significant prognostic risk factors. In this study, the patients in the 2nd period had lower incidence of non-encapsulation, vascular invasion and presence of satellite tumors than the patients in the 1st period. In our previous study already showed that multiple of these risk factors worsened the survival.22 These characteristics of tumors patients might contribute to the better results of liver resection in 2nd period. Selection of liver resection or transplantation for ChildPugh A patients with transplantable HCC is still in debated.23 Randomized trials of liver resection or transplantation to treat HCC are difficult or even impossible in clinical practice. Since cirrhosis was an important factor of long-term survival for HCC patients,24 the results in this study clearly showed the survival rate of liver resection was improved if the patients were restricted to have platelet count >105 103/uL. Impliedly, liver transplantation could be restricted to the patients with advanced cirrhosis and platelet count 105 103/uL. In BCLC guideline, liver transplantation is applied to early stage HCC with portal hypertension.4 However, the watershed of portal hypertension for liver resection or liver transplantation is not clearly defined. Clinically significant portal hypertension is described as hepatic vein pressure gradient
10 mmHg, the presence of gastroesophageal varices, or using diuretics to control ascites and is also suspected when splenomegaly with platelet count is <100 103/ uL.25,26 This study showed that platelet count, 105 103/ uL, could be the watershed to undergo liver resection or liver transplantation as the 5-year survival of liver resection for the patients with platelet count >105 103/uL was similar to liver transplantation. Therefore, primary liver transplantation for HCC can be restricted to the patients with platelet count 105 103/uL to prevent to crowdout other indications of liver transplantation for benign diseases. The limitation in this study to interpret the full influence of liver transplantation on the results of liver resection for early stage HCC was the characteristics of tumors. The characteristics of tumors were better for prognosis in the 2nd period than in the 1st period. However, why the tumor characteristics were different between the patients in 1st and 2nd periods were not really known and further study was needed. In conclusion, the results of liver resection were improved while liver transplantation was applied to the patient with oligo-nodular HCC or with advanced cirrhosis. Liver resection can remain the major treatment option for the patients and the limited number of liver grafts could be reserved for the patients with platelet count <105 103/uL or oligo-nodular HCC to undergo liver transplantation. This would be the winewin policy of surgical treatment for very early/early stage HCC to achieve the best results. Conflicts of interest statement There is no conflict of interest among the authors.
Acknowledgments The authors thank Shu-Fang Huang for assistance with the statistical analysis and Muriel Kao for secretarial assistance. Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejso.2015.05.024.
References 1. Sherman M. Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis. Semin Liver Dis 2010;30:3–16. 2. Poon D, Anderson BO, Chen L-T, et al. Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009. Lancet Oncol 2009;10:1111–8. 3. Ferenci P, Fried M, Labrecque D, et al. Hepatocellular carcinoma (HCC) a global perspective. J Clin Gastroenterol 2010;44:239–45.
Please cite this article in press as: Lee W-C, et al., Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.024
W.-C. Lee et al. / EJSO xx (2015) 1e9 4. Forner A, Reig ME, de Lope CR, Bruix J. Current strategy for staging and treatment: the BCLC update and future prospects. Semin Liver Dis 2010;30:61–74. 5. Wang JH, Wang CC, Hung CH, Chen CL, Lu SN. Survival comparison between surgical resection and radiofrequency ablation for patients in BCLC very early/early stage hepatocellular carcinoma. J Hepatol 2012;56:412–8. 6. Li L, Zhang J, Liu X, Li X, Jiao B, Kang T. Clinical outcomes of radiofrequency ablation and surgical resection for small hepatocellular carcinoma: a meta-analysis. J Gastroenterol Hepatol 2012;27:51–8. 7. Sun AX, Cheng ZL, Wu PP, et al. Clinical outcome of medium-sized hepatocellular carcinoma treated with microwave ablation. World J Gastroenterol 2015;21:2997–3004. 8. Figueras J, Jaurrieta E, Valls C, et al. Resection or transplantation for hepatocellular carcinoma in cirrhotic patients: outcomes based on indicated treatment strategy. J Am Coll Surg 2000;190:580–7. 9. De Carlis L, Giacomoni A, Pirotta V, et al. Surgical treatment of hepatocellular cancer in the era of hepatic transplantation. J Am Coll Surg 2003;196:887–97. 10. Rahman A, Assifi MM, Pedroso FE, et al. Is resection equivalent to transplantation for early cirrhotic patients with hepatocellular carcinoma? A meta-analysis. J Gastrointest Surg 2012;16:1897–909. 11. Nathan H, Segev DL, Mayo SC, et al. National trends in surgical procedures for hepatocellular carcinoma: 1998e2008. Cancer 2012;118: 1838–44. 12. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394–403. 13. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–9. 14. Wakabayashi H, Ishimura K, Izuishi K, Karasawa Y, Maeta H. Evaluation of liver function for hepatic resection for hepatocellular carcinoma in the liver with damaged parenchyma. J Surg Res 2004;116: 248–52.
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15. Schneider P. Preoperative assessment of liver function. Surg Clin North Am 2004;84:355–73. 16. Fan S-T, Lo C-M, Ng IOL, Wong J. ICG clearance in assessing cirrhotic patients with hepatocellular carcinoma for major hepatic resection. Arch Surg 1995;130:198–203. 17. Giannini EG, Savarino V, Farinati F, et al. Influence of clinically significant portal hypertension on survival after hepatic resection for hepatocellular carcinoma in cirrhotic patients. Liver Int 2013;33:1594–600. 18. Zarrinpar A, Kaldas F, Busuttil RW. Liver transplantation for hepatocellular carcinoma: an update. Hepatobiliary Pancreat Dis Int 2011; 10:234–42. 19. Poon RT-P, Fan ST, Lo CM, Liu CL, Wong J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function implications for a strategy of salvage transplantation. Ann Surg 2002;235:373–82. 20. Westerkamp AC, Lisman T, Porte RJ. How to minimize blood loss during liver surgery in patients with cirrhosis. HPB 2009;11:453–8. 21. Young AL, Adair R, Prasad KR, Toogood GJ, Lodge JP. Hepatocellular carcinoma within a noncirrhotic, nonfibrotic, seronegative liver: surgical approaches and outcomes. J Am Coll Surg 2012;214:174–83. 22. Lee W-C, Jeng L-B, Chen M-F. Estimation for prognosis after hepatectomy for hepatocellular carcinoma. Br J Surg 2002;89:311–6. 23. Morris-Stiff G, Gomez D, de Liguori Carino N, Prasad KR. Surgical management of hepatocellular carcinoma: is the jury still out? Surg Oncol 2009;18:298–321. 24. Taura K, Ikai I, Hatano E, et al. Influence of coexisting cirrhosis on outcomes after partial hepatic resection for hepatocellular carcinoma fulfilling the Milan criteria: an analysis of 293 patients. Surgery 2007;142:685–94. 25. Silva MF, Sapisochin G, Strasser SI, et al. Liver resection and transplantation offer similar 5-year survival for Child-Pugh-Turcotte A HCC-patients with a single nodule up to 5 cm: a multicenter, exploratory analysis. Eur J Surg Oncol 2013;39:386–95. 26. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–36.
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Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era W.-C. Lee*, C.-F. Lee, C.-H. Cheng, T.-J. Wu, H.-S. Chou, T.-H. Wu, R.-S. Soong, K.-M. Chan, M.-C. Yu, M.-F. Chen Division of Liver and Transplantation Surgery, Department of General Surgery, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan, Taiwan Accepted 31 May 2015 Available online - - -
Abstract Aims: Surgical treatment for early-stage hepatocellular carcinoma (HCC) is toward transplantation. However, liver resection remains the major surgical treatment for HCC in Asia. This study is to examine the results of liver resection when liver transplantation became an option of treatment for early-stage HCC. Methods: In this retrospective cohort study, 1639 patients with resectable HCC were reviewed and divided into two groups. In the 1st period (2002e2005), all 679 patients received liver resection. In the 2nd period (2006e2010), 916 patients had liver resection and 44 patients jointed liver transplantation program. The results of treatment in these two periods were analyzed. Results: The characteristics of tumors were the most important factors of tumor recurrence after liver resection. Liver function reserve, characteristics of tumors, and surgeons’ endeavor were all independent factors for overall survival after liver resection. When the patients with oligo-nodular tumors or portal hypertension with low platelet count had liver transplantation rather than liver resection in the 2nd period, the survival rates in the 2nd period were improved. When the patients in the 1st period with low platelet count (105 103/ uL) were subtracted, the 5-year survival rate of the patients with one-segmentectomy for small-sized HCC in the 1st period was similar to those in the 2nd period and transplant patients. Conclusions: The outcomes of liver resection were improved while liver transplantation was performed for the patients with suspicious portal hypertension. Platelet count, 105 103/uL, could be a watershed for early stage HCC patients to undergo liver resection or liver transplantation. Ó 2015 Published by Elsevier Ltd.
Keywords: Hepatocellular carcinoma; Liver resection; Liver transplantation; Platelet; Portal hypertension; Outcomes
Introduction Hepatocellular carcinoma (HCC) is the most common primary cancer in the liver. The incidence of HCC is high in Southeast Asia because of a high prevalence of chronic
Abbreviations: HCC, hepatocellular carcinoma; BCLC, Barcelona Clinic Liver Cancer; RFA, radiofrequency ablation; UCSF, University of the San Francisco; ICG, indocyanine green; INR, international ratio; CT, computed tomography. * Corresponding author. Division of Liver and Transplantation Surgery, Department of General Surgery, Chang-Gung Memorial Hospital, 5, FuH s i n g S t r e e t , K w e i - S h a n , Ta o y u a n , Ta i w a n . Te l . : þ8 8 6 3 3281200x3366; fax: þ886 3 3285818. E-mail address: [email protected] (W.-C. Lee).
hepatitis B.1,2 The incidence is also increasing in western countries because of the infection of hepatitis C.3 It is no doubt that HCC is one of the most common malignancies in the world now.1 Substantially, HCC is an aggressive cancer disease and can be curatively treated only in Barcelona Clinic Liver Cancer (BCLC) very early/early stage.4 HCC in its very early/early stage can be treated by surgery or radiofrequency ablation (RFA). Surgery takes priority of treatment because the survival rates of surgery are superior to RFA.5,6 Recently, microwave ablation was applied to treat HCC, however, the results was inferior to surgery, either.7 Surgery for HCC includes liver resection and liver transplantation. To our knowledge, liver resection has a higher recurrent rate than liver transplantation8,9 and
http://dx.doi.org/10.1016/j.ejso.2015.05.024 0748-7983/Ó 2015 Published by Elsevier Ltd. Please cite this article in press as: Lee W-C, et al., Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.024
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the survival rate of liver resection is inferior to that of liver transplantation.10 Therefore, surgical treatment for early stage HCC is shifted from liver resection toward liver transplantation recently.11 Nevertheless, liver donation is always short and liver transplantation for HCC patients is not always available. The choice of liver transplantation as the primary treatment for HCC may also crowd-out the transplant opportunities for benign diseases. Therefore, liver resection remains the main treatment for solitary tumor or oligo-nodular tumors. In this study, we retrospectively reviewed a large cohort of patients with surgical treatments for HCC in our institute to seek whether the results of surgical treatments for HCC were improved when liver transplantation became an option of treatment and what policy of surgical treatments for very early/early stage HCC was optimal.
Liver transplantation The patients who had portal hypertension with a high ICGR15, prolonged prothrombin time, presence of varices and splenomegaly in computed tomography (CT) images or oligo-nodular HCC were suggested to have liver transplantation as an option of treatments. The patients willing to have liver transplantation would be registered in Taiwan network of organ sharing and waited for liver transplantation. If living donors were available, living donor liver transplantation was performed after complete assessments of living donors. Follow up
1639 patients who had resectable HCC from 2002 to 2010 were included in this retrospective study. In Taiwan, liver transplantation for HCC is covered by national health insurance for deceased liver transplantation if the tumors meet Milan criteria and for living donor liver transplantation if the tumors meet University of the San Francisco (UCSF) criteria since 2006.12,13 According to the time scale, this retrospective study was divided into two periods. The 1st period was from 2002 to 2005 and the 2nd period was from 2006 to 2010. The collection of clinical data was proved by local ethic committee of Chang-Gung Memorial Hospital.
For the patients having liver resection, the patients were followed up regularly. Liver function tests, measurement of a-fetoprotein, and liver ultrasonography were performed every 3 months. Dynamic CT of the liver was performed if deemed necessary. For the patients with liver transplantation, measurement of a-fetoprotein, liver ultrasonography and dynamic CT of the liver were performed every 3 months in the 1st year. Measurement of a-fetoprotein and liver ultrasonography were performed every 3 months in the following years and dynamic CT of the liver was performed if deemed necessary. Tumor recurrence was defined when CT detected tumors with typical HCC imaging pattern in the liver or extrahepatic tumors. Disease-free survival was measured from the date of surgical treatments to tumor recurrence. Overall survival was measured from the date of surgical treatments until death which was registered in Bureau of Health, Taiwan. Hospital mortality was defined that patients were not discharged and died in hospital after surgery.
Pre-operative assessment of the liver function
Biostatistics analysis
Before operation, quantitative liver function was determined by indocyanine green (ICG) test. Briefly, ICG test was performed by injecting 0.5 mg/kg of ICG into a peripheral vein and drawing a blood sample from another site 15 min later. Results were presented as 15-min retention rate of indocyanine green (ICGR15).14e16 Besides ICGR15 test, platelet counts and international ratio (INR) of prothrombin times were both collected because both parameters represented cirrhosis-associated portal hypertension and splenomegaly.17
The comparisons of categorical variables were determined by Chi-square Tests. The significance of the differences between different groups was determined by unpaired Student’s t-test. The survival rates were calculated using the KaplaneMeier method and compared between groups using the log-rank test. The statistical analyses were all performed with SigmaPlot 12.3 software for Windows (Systat Softwave, Inc., San Jose, CA, USA). P value below 0.05 was considered to be significantly different.
Materials and methods Patients
Results Surgical technique of liver resection Patients and hospital mortality During operation, intra-operative ultrasonography was performed to demarcate the tumor and identified the relationship between tumors and major vessels. Intermittent Pringle’s maneuver, 15-min clamping followed by 5min release, was applied for most of the operations. Parenchymal transection was performed by ultrasonic dissector or kellyclasy.
Among 1639 patients, 679 patients were in the 1st period and 960 patients were in the 2nd period. All patients in the 1st period had liver resections. Among the patients in 2nd period, 916 patients had liver resections and 44 patients jointed liver transplantation program. When focusing on liver resection, 22 patients (3.2%) in the 1st period and
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18 patients (2.0%) in 2nd period died in hospital after liver resection. For the patients joining liver transplantation program, 34 (77.3%) patients were transplanted, 6 patients (13.6%) were dropped out and 4 patients still wait for liver transplantation now (Supplementary Fig. 1). Prognostic factors of disease-free survival for liver resection To determine the prognostic factors of disease-free survival for liver resection, the data of 1555 patients with liver resection were analyzed excluding 40 patients with hospital mortality. Univariate analysis showed that abnormal liver function, a-fetoprotein >400 ng/ml, elevation of ICGR15, blood loss >500 ml, large range of liver resection, resection margin involvement and pathological figures of tumors were all significant risk factors (Supplementary Table 1). In multivariate analysis, tumor size >5 cm in diameter, vascular invasion of tumor, presence of daughter nodules and resection margin involvement were independent risk factors (Table 1). These results showed tumor characteristics were the most important factors of tumor recurrence although surgical resection involvement also determined tumor recurrence.
3
Prognostic factors of overall survival for liver resection To determine the prognostic factors of overall survival, all patients with liver resections were included. Univariate analysis showed that abnormal liver function, a-fetoprotein >400 ng/ml, elevation of ICGR15, blood loss >500 ml, large range of liver resection, resection margin involvement and pathological figures of tumors were all significant risk factors (Supplementary Table 2). In multivariate analysis, ICGR15 >20%, range of parenchymal resection, blood loss >500 ml, resection margin involvement, vascular invasion of tumor, non-encapsulation of tumor, presence of daughter nodules were all independent risk factors (Table 1). These results showed that not only tumor characteristics but also liver function and surgical affairs determined patients’ overall survival. Difference between patients in the 1st and 2nd periods Because some patients with clinical suspicion of portal hypertension in the 2nd period chose liver transplantation as the treatment, the characteristics of the patients with
Table 1 Cox’s regression results for disease-free and overall survival. Factors
Albumin (g/dL) 3.5/>3.5 AST (U/L) >34/34 ALT (U/L) >36/36 Bilirubin (mg/dL) >1.3/1.3 Alk-p(U/L) >94/94 AFP (ng/mL) >400/400 ICG R15 (%) >20/20 No. of segmentectomy 2/1 3/1 4/1 Blood loss (ml) >500/500 Tumor size >5/5 Tumor capsule No/Yes Vascular invasion Yes/No Daughter nodules Yes/No Resection margins Positive/Negative
DFS
OS
Hazard ratio
95% C.I.
0.932
0.695e1.251
1.195
P value
Hazard ratio
95% C.I.
P value
0.640
1.174
0.808e1.707
0.400
0.958e1.491
0.115
1.053
0.786e1.412
0.729
1.072
0.864e1.331
0.525
0.978
0.737e1.300
0.880
1.091
0.823e1.448
0.544
1.198
0.828e1.734
0.338
1.139
0.941e1.379
0.182
1.017
0.785e1.317
0.898
1.190
0.981e1.443
0.077
1.171
0.909e1.509
0.222
1.263
0.920e1.736
0.149
1.752
1.159e2.648
0.008
1.143 1.228 1.203
0.916e1.427 0.935e1.611 0.889e1.629
0.236 0.139 0.231
1.209 1.524 1.470
0.870e1.679 1.039e2.234 0.969e2.230
0.258 0.031 0.070
1.117
0.910e1.371
0.290
1.300
1.001e1.689
0.049
1.332
1.081e1.641
0.007
1.324
0.992e1.768
0.057
1.218
0.993e1.493
0.059
1.407
1.073e1.846
0.014
1.768
1.457e2.145
<0.001
2.512
1.946e3.243
<0.001
1.481
1.209e1.815
<0.001
1.535
1.177e2.002
0.002
1.975
1.432e2.724
<0.001
1.647
1.086e2.498
0.019
DFS, disease-free survival; OS, overall survival. Please cite this article in press as: Lee W-C, et al., Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.024
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W.-C. Lee et al. / EJSO xx (2015) 1e9
liver resections in the 1st and 2nd periods might be different. Therefore, liver function, surgical profiles and tumor characteristics of the patients in the 1st and 2nd periods were compared. The results showed that the patients in the 2nd period had better liver function than the patients
in the 1st period evidenced by a lower ICGR15 [7.0 (3.8e12)% versus 8.8 (5.2e13.7)%, p < 0.001] and a higher serum albumin level [4.2 (3.8e4.4) versus 4.1(3.7e4.4)g/dl, p < 0.0001] (Table 2). The tumor sizes between two groups were not different. However, the
Table 2 The characteristics of patients undergoing liver resection for HCC in two different periods. Parameters [median(Q1,Q3)]
Age (yrs) Gender (male) Platelet (x1000/uL) Albumin (g/dL) AST (U/L) ALT (U/L) Bilirubin (mg/dL) Alkaline phosphates (U/L) AFP (ng/mL) ICG R-15 min (%) Blood urea nitrogen (mg/dL) Creatinine (mg/dL) Smoking (%) No Yes Alcohol (%) No Yes HBV (%) Negative Positive HCV (%) Negative Positive Child classification (%) A B C Operation time (mins) Blood loss (mL) 1000 >1000 No. of segmentectomy (%) 1 2 3 4 Hospital mortality (%) No Yes Tumor size (cm) Tumor capsule (%) No Yes Vascular invasion (%) No Yes Daughter nodules (%) No Yes Resection margin (%) Negative Positive
Time periods 2002e2005 (n ¼ 679)
2006e2010 (n ¼ 916)
58 524 167 4.1 38.0 41.0 0.8 76.0 43.0 8.8 15.0 1.24
60 714 173 4.2 37.0 39.0 0.7 76.0 24.3 7.0 14.0 0.93
(47e67) (77.2%) (121e216) (3.7e4.4) (27.0e59.0) (26.0e68.8) (0.6e1.1) (61.0e108.0) (7.7e501.5) (5.2e13.7) (12.0e18.0) (0.90e1.20)
(50e69) (77.9%) (127e218) (3.8e4.4) (26.8e61.0) (26.0e66.0) (0.5e0.9) (62.0e97.0) (5.6e375.4) (3.8e12.0) (11.4e17.7) (0.80e1.10)
470 (69.2) 209 (30.8)
777 (84.8) 139 (15.2)
516 (76.0) 163 (24.0)
805 (87.9) 111 (12.1)
235 (35.7) 423 (64.3)
258 (33.0) 523 (67.0)
376 (64.3) 209 (35.7)
438 (61.0) 280 (39.0)
664 11 1 235 300 517 64
(98.2) (1.6) (0.1) (180e300) (150e600) (89.0%) (11.0%)
874 14 1 240 200 835 62
(98.3) (1.6) (0.1) (190e312) (100e500) (93.1) (6.9)
164 249 146 120
(24.2) (36.7) (21.5) (17.7)
329 304 141 142
(35.9) (33.2) (15.4) (15.5)
P value
Odds
95% C.I.
P Value
Ratio
Of odds ratio
0.001 0.713 0.716 <0.0001 0.837 0.983 0.006 0.829 0.129 <0.0001 0.801 0.490 <0.0001
1.014
1.004e1.024
0.008
1.284
0.993e1.660
0.057
0.815
0.639e1.038
0.097
0.979
0.963e0.994
0.008
0.486
0.348e0.685
<0.001
<0.0001
0.594
0.410e0.860
0.006
1.004 0.520
1.003e1.006 0.319e0.849
<0.001 0.009
0.565 0.425 0.410
0.414e0.771 0.289e0.623 0.265e0.634
<0.001 <0.001 <0.001
0.105 0.011
0.838
0.619e1.134
0.252
0.021
0.941
0.707e1.251
0.674
0.003
0.834
0.608e1.144
0.260
<0.0001
0.392
0.229e0.669
0.001
0.286
0.225
0.978
0.012 <0.001 0.006 <0.0001
0.107 657 (96.8) 22 (3.2) 4.0 (2.5e7.0)
898 (98.0) 18 (2.0) 3.7 (2.3e6.5)
154 (24.6) 473 (75.4)
174 (19.1) 736 (80.9)
435 (64.7) 237 (35.3)
641 (70.2) 272 (29.8)
501 (76.4) 155 (23.6)
749 (82.5) 159 (17.5)
615 (91.5) 57 (8.5)
877 (96.8) 29 (3.2)
(Q1,Q3), interquartile; HBV, hepatitis B infection; HCV, hepatitis C infection; AST, aspartate aminotransferase; ALT, alanine aminotransferase. Please cite this article in press as: Lee W-C, et al., Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.024
W.-C. Lee et al. / EJSO xx (2015) 1e9
(A) 1.0
Patients (2002-2005) Patients (2006-2010)
0.8
p<0.001 Survival (x 100%)
parenchyma resection range was more limited in the 2nd period than in the 1st period patients as our current surgical policy was minimizing liver parenchyma loss. Under such policy, 35.9% of the patients in the 2nd period had only one segment resection, compared to 24.2% of the patients in the 1st period. Although the resection range was smaller in the 2nd period, surgeons spent a longer time to perform the surgery [240 (190e312) versus 235 (180e300) minutes, p ¼ 0.012]. Simultaneously, median (interquartile) blood loss in the 2nd period was less than in the 1st period [200 (100e500) versus 300 (150e600) ml, p < 0.001]. The resection margin involvement rate (safe margin <1 mm) was lower in the 2nd period than in the 1st period (3.2% versus 8.5%, p < 0.001). Although the tumor sizes between these two group patients were almost equal, several well-known prognostic factors of tumor characteristics were different. The tumors in the 2nd period patients had higher incidence of encapsulation, and lower incidence of vascular invasion and satellite tumors than those in the 1st period patients (Table 2). For oligo-nodular tumors, 11 of 898 (1.2%) patients in the 2nd period had liver resection for two tumors, compared to 27 of 657 (4.1%) in the 1st period ( p < 0.001).
5
0.6
0.4
0.2
0.0 0
20
40
60
80
100
120
140
Months
(B) 1.0 Patients (2002-2005) Patients (2006-2010)
p<0.001
Disease-free and overall survival rates The 1-, 3- and 5-year disease-free survival rates were 73.7%, 58.3% and 53.5%, respectively, for the patients with liver resections in the 2nd period, compared to 66.1%, 41.9% and 31.6% for the patients in the 1st period ( p < 0.001, Fig. 1A). The 1-, 3- and 5-year overall survival rates were 91.3%, 79.5% and 71.6%, respectively, for the patients in the 2nd period, compared to 83.4%, 65.6% and 55.1% for the patients in the 1st period ( p < 0.001, Fig. 1B). These results clearly demonstrated that the disease-free and overall survival rates for the patients with liver resections in the 2nd period were better than in the 1st period.
Survival (x 100%)
0.8
0.6
0.4
0.2
0.0 0
Survival rates according to parenchymal resection In further analysis, disease-free and overall survival rates were calculated according to parenchymal resection ranges. The tumor sizes in different-ranged liver resections in the 1st and 2nd periods were similar (Supplementary Table 3). The disease-free and overall survival rates of limited resections were better than wide-range resection. The disease-free and overall survival rates in the 2nd period were better than in the 1st period when the same ranges of liver resections were compared (Fig. 2AeD). Clinical profiles and outcomes of patients entering liver transplant program In the 2nd period, 44 patients with Child-Pugh A cirrhosis entered liver transplantation program because of oligo-
20
40
60
80
100
120
140
Months
Figure 1. KaplaneMeier disease-free and overall survival curves. (A) The 1-, 3- and 5-year disease-free survival rates for the patients with liver resection in 2nd period were 73.7%, 58.3% and 53.5%, respectively, which were much better than those for the patients in the 1st period ( p < 0.001). (B) The 1-, 3- and 5-year overall survival rates for the patients with liver resection in 2nd period were 91.3%, 79.5% and 71.6%, respectively, which were much better than those for the patients in the 1st period, too ( p < 0.001).
nodular HCC (8/44, 18.2%) or portal hypertension with thrombocytopenia and prolonged prothrombin time. Their median (interquartile) platelet count was 77.5 (52.5e104.5) 103/uL which was lower than those with liver resection in the 1st period (167 (121e216) 103/uL, p < 0.001) or in 2nd period (173 (127e218) 103/uL, p < 0.001) (Supplementary Table 4). The median
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(A)
(B) 1.0
1 segment 2 segments 3 segments >=4 segments
1.0
Survival (x 100%)
0.8
p=0.001
Survival (x 100%)
p<0.001
0.8
1 segment 2 segments 3 segments >=4 segments
0.6
0.6
0.4
0.4 0.2 0.2 0.0 0
0.0 0
20
40
60
80
100
120
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(C)
51.5 42.7 39.3 29.9
1 segment 2 segments 3 segments >=4 segments
(D)
85.0 71.1 63.9 60.2
80
70.8 55.8 49.0 42.6
64.9 52.9 42.8 35.8 1 segment 2 segments 3 segments >=4 segments p<0.001
1.0
p<0.001
0.8
Survival (x 100%)
0.8
Survival (x 100%)
1 2 3 >4
36.8 32.9 30.7 22.9
1.0
60
No of segmentectomy survival rate (%) 1-yr 3-yr 5-yr
No of segmentectomy survival rate (%) 1-yr 3-yr 5-yr 76.9 72.4 60.2 44.1
40
Months
Months
1 2 3 >4
20
0.6
0.4
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No of segmentectomy survival rate (%) 1-yr 3-yr 5-yr
1 2 3 >4
93.5 87.0 75.6 71.4
77.0 71.8 61.3 42.9
60
80
Months
68.3 57.4 49.6 39.0
No of segmentectomy survival rate (%) 1-yr 3-yr 5-yr 1 2 3 >4
97.0 93.9 86.9 76.4
90.8 82.1 64.1 61.0
82.5 75.6 51.4 56.4
Figure 2. KaplaneMeier disease-free and overall survival curves according to range of liver resection. (A) The disease-free survival rates for the patients in the 1st period. The less of liver parenchyma was resected, the better of the survival was achieved ( p ¼ 0.001). (B) The overall survival rates for the patients in the 1st period. The patients with limited parenchyma resection had better survival rates ( p < 0.001). (C) The disease-free survival rates for the patients in the 2nd period. The patients with limited parenchyma resection had better survival rates ( p < 0.001). (D) The overall survival rates for the patients in the 2nd period. The patients with limited parenchyma resection had better survival rates ( p < 0.001). Please cite this article in press as: Lee W-C, et al., Outcomes of liver resection for hepatocellular carcinoma in liver transplantation era, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.05.024
W.-C. Lee et al. / EJSO xx (2015) 1e9
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(interquartile) waiting time for the patients with transplantation was 2 (1e3.3) months. The average dropped-out time after listed was 23.7 13.5 months. For all 44 patients entering into liver transplantation program, the intent-to-treatment 1-, 3- and 5-year survival rates were 95.5%, 86.3% and 76.1%, respectively. For 34 patients with liver transplantation, 1-, 3- and 5-year survival rates were 93.9%, 87.9% and 82.4%, respectively (Supplementary Fig. 2). Effect of portal hypertension on the survival of liver resection In this study, the results of liver resection in 2nd period were better than in the 1st period. The better results might be contributed due to that the patients with lower count of platelet in 2nd period chose liver transplantation as the definite treatment. To examine this hypothesis, platelet count, 105 103/uL which was the value of the 3rd interquartile in the patients entering into liver transplantation program, was chosen as the cut-off point to represent advanced cirrhosis with portal hypertension. While the patients in the 1st period were divided into two groups according to platelet count 105 103/uL, the patients with platelet count 105 103/uL had worse overall survival than the patients with platelet count >105 103/uL since 40 months after liver resection although the disease-free survival rates were similar (Supplementary Fig. 3A and B). When the patients with one-segmentectomy for transplantable tumors and without advanced cirrhosis (platelet count >105 103/uL) were selected to calculate overall survival, the 3-year survival rate was increased from 77.0% to 81% and 5-year survival rate was increased from 68.3% to 75% (Fig. 3A). These survival rates were not different from those of the patients with one-segmentectomy in the 2nd period and the patients having liver transplantation (Fig. 3B). These results showed that the overall survival of liver resection for early stage HCC would be improved if the cirrhotic patients to have liver resections were restricted to platelet count >105 103/uL. Discussion The survival rate of liver resection was improved when liver transplantation was an option of treatment for early stage HCC. This study showed that the calculated 5-year overall survival rate for the patients having liver resection in the 2nd period was much better than those in the 1st period and approached to the results of liver transplantation.12,13,18 Since 2006, living donor liver transplantation becomes an option of surgical treatments for cirrhotic patients with HCC in this institute if living donors are available and the tumors meet UCSF criteria.12 Under such circumstance, some patients with splenomegaly and low count of platelet17 or oligo-nodular tumors19 would enter liver transplantation program and chose liver transplantation rather than liver resection as the definite treatments.
Figure 3. KaplaneMeier overall survival curves for the patient with transplantable HCC. (A) The survival rates were increased when the patients with one-segmentectomy for transplantable tumors in the 1st period were limited to platelet count >105 103/ul. The 3-year survival rate was increased from 77.0% to 81% and 5-year survival rate was increased from 68.3% to 75%. (B) This survival rates were not different from those of the patients with one-segmentectomy in the 2nd period and the patients having liver transplantation ( p ¼ 0.378).
Thereafter, the patients having liver resections in the 2nd period had better quantitative liver function and a fewer incidence of oligo-nodular tumors than the patients in the 1st period. Quantitative liver function and incidence of oligo-nodular tumors were both independent prognostic factors of overall survival. Thus, the survival rate of liver resection for early stage HCC patients in the 2nd period was better than that in the 1st period. Limited resection improved the overall survival. The range of liver resection was an independent factor of overall
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W.-C. Lee et al. / EJSO xx (2015) 1e9
survival. In this institute, the policy of liver resection was shifted from wide resection to limited resection. Compared to the resection limited to one segment, the hazard ratio for overall survival increased 1.5 folds when resection range was beyond two segments. The damage to the liver itself was aggregated when the resection range was large. Therefore, liver parenchyma preservation during operations was important for overall survival. A higher percentage of limited liver resections in the 2nd period might contribute to the better survival rate for the patients in the 2nd period than in the 1st period. Blood loss more than 500 ml was an independent risk factor for overall survival. Surgical endeavor might contribute to the better survival for the patients in the 2nd period. In the 2nd period, we paid more attention to control bleeding during parenchyma transection to keep bloodless operation field. Ultrasonic dissector combined with intermittent Pringle’s maneuver was adopted. Intra-operatively, fluid administration was restricted.20 Hence, the operation time in the 2nd period was longer than in the 1st period, but the blood loss was less than in the 1st period. Young et al. mentioned that blood transfusion was the only risk factor for overall survival in their non-cirrhotic HCC patient receiving liver resection.21 In addition, the margin involvement rate in the 2nd period was less than in the 1st period which might be due to intra-parenchymal vascular anatomy identified easily in the bloodless operation field. These emphasize that surgeons’ endeavor contributed to patients’ survival. Tumor characteristics are important factors for both disease-free and overall survival. Tumor size, vascular invasion, non-encapsulation of tumor and presence of satellite tumors were all significant prognostic risk factors. In this study, the patients in the 2nd period had lower incidence of non-encapsulation, vascular invasion and presence of satellite tumors than the patients in the 1st period. In our previous study already showed that multiple of these risk factors worsened the survival.22 These characteristics of tumors patients might contribute to the better results of liver resection in 2nd period. Selection of liver resection or transplantation for ChildPugh A patients with transplantable HCC is still in debated.23 Randomized trials of liver resection or transplantation to treat HCC are difficult or even impossible in clinical practice. Since cirrhosis was an important factor of long-term survival for HCC patients,24 the results in this study clearly showed the survival rate of liver resection was improved if the patients were restricted to have platelet count >105 103/uL. Impliedly, liver transplantation could be restricted to the patients with advanced cirrhosis and platelet count 105 103/uL. In BCLC guideline, liver transplantation is applied to early stage HCC with portal hypertension.4 However, the watershed of portal hypertension for liver resection or liver transplantation is not clearly defined. Clinically significant portal hypertension is described as hepatic vein pressure gradient
10 mmHg, the presence of gastroesophageal varices, or using diuretics to control ascites and is also suspected when splenomegaly with platelet count is <100 103/ uL.25,26 This study showed that platelet count, 105 103/ uL, could be the watershed to undergo liver resection or liver transplantation as the 5-year survival of liver resection for the patients with platelet count >105 103/uL was similar to liver transplantation. Therefore, primary liver transplantation for HCC can be restricted to the patients with platelet count 105 103/uL to prevent to crowdout other indications of liver transplantation for benign diseases. The limitation in this study to interpret the full influence of liver transplantation on the results of liver resection for early stage HCC was the characteristics of tumors. The characteristics of tumors were better for prognosis in the 2nd period than in the 1st period. However, why the tumor characteristics were different between the patients in 1st and 2nd periods were not really known and further study was needed. In conclusion, the results of liver resection were improved while liver transplantation was applied to the patient with oligo-nodular HCC or with advanced cirrhosis. Liver resection can remain the major treatment option for the patients and the limited number of liver grafts could be reserved for the patients with platelet count <105 103/uL or oligo-nodular HCC to undergo liver transplantation. This would be the winewin policy of surgical treatment for very early/early stage HCC to achieve the best results. Conflicts of interest statement There is no conflict of interest among the authors.
Acknowledgments The authors thank Shu-Fang Huang for assistance with the statistical analysis and Muriel Kao for secretarial assistance. Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejso.2015.05.024.
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