Liver resection for hepatocellular carcinoma on cirrhosis: analysis of mortality, morbidity and survival—a European single center experience

EJSO (2005) 31, 986–993

www.ejso.com

Liver resection for hepatocellular carcinoma on cirrhosis: analysis of mortality, morbidity and survival—a European single center experience L. Capussotti, A. Muratore*, M. Amisano, R. Polastri, H. Bouzari, P. Massucco Department of Surgical Oncology, Istituto per la Ricerca e la Cura del Cancro, Turin, Italy Accepted for publication 6 April 2005 Available online 3 June 2005

KEYWORDS Hepatocellular carcinoma; Liver resection; Mortality; Post-operative complications; Survival

Abstract Aims: To evaluate short- and long-term results of liver resections and prognostic factors in cirrhotic patients with hepatocellular carcinoma. Study design: A single-unit, retrospective study analyzing 216 patients with histologically confirmed cirrhosis who underwent hepatic resection for hepatocellular carcinoma. All clinico-pathologic and follow-up data were collected prospectively. Results: Child A patients had a significantly lower in-hospital mortality rate compared to Child B–C: 4.7 vs 21.3% (pZ0.0003). Overall morbidity rate was 38.4%; multiple logistic regression analysis identified liver function, hepatic pedicle clamping time, number of nodes and transfusion rate as independent predictors for post-operative complications. Overall and disease-free 5-year survival rates were 34.1 and 25.2%. Multivariate analysis showed that Child A, radical resection, tumour size %5 cm and, absence of vascular invasion were independent prognostic factors for long-term survival. No significant differences in overall and disease-free survival were found according to the type of resection (anatomic vs non-anatomic). Conclusions: Patients with preserved liver function and small-size, single-node hepatocellular carcinomas are the best candidates for hepatic resection. Q 2005 Elsevier Ltd. All rights reserved.

* Corresponding author. Address: Istituto per la Ricerca e la Cura del Cancro, Str Provinciale 142, Km 3,95, 10060 Candiolo (TO), Italy. Tel.: C39 11 9933630; fax: C39 11 9933440. E-mail address: [email protected] (A. Muratore).

0748-7983/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2005.04.002

Long-term outcome of liver resection for hepatocellular carcinoma

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Introduction In the early 1980s, the mortality rate after liver resection for hepatocellular carcinoma (HCC) in a patient with cirrhosis was high ranging from 16 to 26%.1,2 Later studies in the same decade reported mortality rates lower than 10%, with a 3-year survival from 28 to 51%;3–5 at present, advances in surgical technique and perioperative care have reduced in-hospital death rate to 0–5%.6–8 Because of the improvement in short-term results and the shortage of transplantable livers, hepatic resection is now the first-line treatment for most patients with good liver function and a safely resectable HCC.9,10 A recent series from Queen Mary Hospital11 has reported an overall 37% rate of survival at 5 years. However, the major drawback of liver resections is the high incidence of tumour recurrence: of the 85 long-term survivors reported by Poon,11 only 45 were free of disease. Several recent studies have looked at the prognostic factors after resection in order to achieve a better selection of the patients and to improve long-term results.12–14 The aim of this study is to analyse the short- and long term results of 216 hepatic resections for HCC with cirrhosis at a single institution over the past 15 years, and to present our findings regarding those prognostic factors likely to lead to a successful outcome.

routinely performed. In the first years of our experience, liver angiography (Glipiodol injection) was used as diagnostic tool; improvements in CT equipment (triphasic helical CT) have reduced the use of angiography to few selected cases where multifocal disease had to be ruled out. Since 1988, intraoperative ultrasonography was routinely performed. Since 1998, computed tomographic estimations of remnant liver volumes were performed for all the patients undergoing a major hepatic resection (MHR). Tumour biopsy was not routinely used; when imaging techniques could not distinguish HCC from other benign or malignant conditions, biopsy was recommended if an accurate diagnosis would have altered the therapy.

Follow-up All patients were followed with liver biochemistry, AFP serum samples and abdominal ultrasonography every 4 months during the first two post-operative years and then every 6 months. A CT scan was performed every 12 months or when a recurrence was suspected. Bone metastases were assessed by scintigraphy if clinically suspected.

Statistical analyses

Material and methods From January 1985 to December 2001, 272 patients underwent liver resection for hepatocellular carcinoma in the First Department of Surgery at Mauriziano ‘Umberto I’ Hospital and (from November 1999) in the Oncological Surgical Department at Istituto per la Ricerca e la Cura del Cancro. Of the 272 patients, 216 (79.4%) had cirrhosis and are the object of this retrospective study. There were 174 men (80.6%) and 42 women with an average age of 64.3 years. Chronic viral hepatitis was present in 135 patients, alcohol abuse in 56 and hemochromatosis in two cases; aetiology was unknown in the remaining 23 cases. Child–Pugh score was A in 169 patients, B–C in 47.

Continuous variables were compared using the Student’s t-test; categorical variables were compared using the chi-square. Multiple logistic regression was used to define factors related to morbidity. Survival was calculated using the Kaplan–Meier method from the time of operation; differences between survival curves were compared using the log-rank test; a p-value !0.05 was considered significant. The multivariate analysis was performed including all the significant (p! 0.05) and borderline significant (p!0.10) factors on univariate analysis. Statistical tests were performed using Statistica for Windows (Stat Soft Inc., 1998).

Pre-operative work-up

Results

Child–Pugh classification and, in the last 3 years, indocyanine green retention test (ICG) were used to assess liver function. Alpha-fetoprotein serum samples (AFP), abdominal ultrasound and contrast-enhanced computed tomography (CT) were

Surgical technique Of the 216 patients, 156 and 52 underwent anatomical and atypical resections, respectively; in the remaining eight patients, both these

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procedures were performed at the same time. A major hepatic resection (MHR) was accomplished in 46 cases: a right hepatectomy in 24 and a left hepatectomy in 11. Seven patients underwent right trisegmentectomy whereas in two cases left hepatectomy was extended to segment 1. The last two patients had resection of segments 5–6–7. The Pringle maneuver was used in 180 cases (83.3%) with a mean and median clamping time of 43.9G 20.6 and 40G18 min, respectively. Pedicle clamping was continuous (CPC) in 96 cases (53.3%) and intermittent (IPC) in 84; mean clamping time was 47.8 min in the intermittent clamping group and 37.9 in the continuous one (pZ0.0008). Total vascular exclusion (TVE) was carried out in three cases. The resection was considered non-curative in 10 cases: microscopic infiltration of the resection margin was found in eight cases; in the remaining two, lymph node metastasis of the hepatic pedicle and neoplastic ascites were present.

Mortality Eighteen patients died, for an overall in-hospital mortality rate of 8.3%; among these, eight were Child A and 10 were Child B or C with a mortality rate of 4.7 and 21.3%, respectively (pZ0.0003). Table 1 compares clinical features of Child A and B– C patients. Eight patients died of liver failure (four Child B–C cases), four of variceal bleeding (all Child B–C patients), and three of heart attack, brain stroke (one Child B–C case) and respiratory failure, respectively. Two deaths occurred after emergency reoperation for an intra-abdominal hemorrhage (one Child B–C patient). The last patient died of sepsis, consequent to a duodenal perforation, on post-operative day 38. Among the 46 patients undergoing major hepatic resection, the overall in-hospital mortality rate was 6.5%; the causes of death were liver failure, hemoperitoneum, and sepsis. Table 1

Morbidity One hundred and fourteen post-operative complications occurred in 83 patients with an overall morbidity rate of 38.4%: 31.4% in Child A patients and 63.8% in Child B–C patients (pZ0.0001). Pulmonary complications were the most common (34.2%) followed by ascites (27.2%), hepatic insufficiency (19.3%), hemoperitoneum (9.6%) and abdominal abscess (7.9%). Other complications included variceal bleeding and abdominal wound hernia (1.8%). Fifteen patients required a reoperation: the main indication was hemoperitoneum in nine cases. In two patients with ascites refractory to medical therapies, a LeVeen peritoneo-venous shunt was positioned. The remaining patients were reoperated on for biliary fistula, portal thrombosis, duodenal perforation, and abdominal wound dehiscence. Univariate analysis of factors related to complications revealed that age !70 years, Child–Pugh B–C classification, transfusions, clamping time O40 min, and multiple nodules were significantly related to the occurrence of complications (Table 2). Multiple logistic regression analysis of these factors showed that liver function, number of nodes, hepatic pedicle clamping time, and transfusion rate were independent factors for postoperative complications (Table 3).

Long-term results The median follow-up was 28 months; the estimated Kaplan–Meier 3- and 5-year survival rates were 51.3 and 34.1%. Disease-free survival was 39.7% at 3 years and 25.2% at 5 years. By the end of follow-up, 67 patients were alive with a median survival of 30.5 months: 46 without recurrence and 21 with recurrence. At univariate analysis (Table 4), liver function, AFP serum levels, tumour size, number of nodes, Edmonson–Steiner grade, HBV or HCV infection, vascular invasion and satellite

Clinical features compared in Child A and Child B–C patients

Variables

Child A pts (169 pts)

Child B–C pts (47 pts)

p

Age (years) Gender (male/female) AST (U/l) ALT (U/l) Number nodes (single/multiple) Major resections (Y/N) Hepatic pedicle clamping (Y/N) Mean clamping time (min) Transfusion rate (blood and fresh frozen plasma)

65.4 136/33 57.1G39.6 63G47.5 135/34 45/124 141/28 40.1G24.2 49.1%

60.6 38/9 57G35.6 49.7G34.3 33/14 1/46 39/8 36.1G23.3 80.8%

0.0002 0.9 0.9 0.09 0.2 0.0003 0.6 0.3 0.0001

Long-term outcome of liver resection for hepatocellular carcinoma Table 2

989

Comparison of patients with and without complications

Factor

Number

Morbidity

Gender (M/F) Age R70 years (Y/N) Pugh A (Y/N) ASTa R2N (Y/N) ALTa R2N (Y/N) Type of resection Anatomic Wedge Combined Major liver resection (Y/N) Transfusion (fresh frozen plasmaGblood) (Y/N) Pedicle clamping (Y/N) Clamping time O40 min (Y/N) Type of clamping Intermittent/continuous HCC size O10 cm (Y/N) Single node (Y/N) Macroscopic vascular invasion (Y/N)

174/42 56/160 169/47 53/129 48/134

40.2%/30.9% 26.8%/42.5% 31.4%/63.8% 39.6%/40.3% 35.4%/41.8%

0.3 0.04 0.0001 0.9 0.4

156 52 8 46/170 121/94 180/36

37.2%/62.8% 38.5%/61.5% 62.5%/37.5% 32.6%/40% 53.7%/19.1% 39.1%/34.4%

0.9 0.2 0.4 !0.0001 0.6

99/81

53.6%/27.6%

!0.0003

84/96 13/203 168/48 16/200

40.5%/36.1% 53.8%/37.4% 32.1%/60.4% 37.5%%/37.5%

a

p

0.6 0.3 0.0004 0.6

AST/ALT R2N, serum levels two-fold or more the normal value.

tumour nodules were significantly related to survival. There was a trend toward a better long-term outcome among the patients who underwent a radical resection (R0) but the difference was not significant: survival at 5 years was 36.3% in patients who had a R0 resection and 0% in those who did not. By multivariate analysis Child–Pugh A, tumour size %5 cm, and absence of microscopic vascular invasion were independent predictive factors of 5-year survival (Table 5). Age R70 years, Child–Pugh A, AFP serum levels !20 ng/ml, tumour size less than 5 cm, single node, radical resection, Edmonson grading 1–2, absence of vascular invasion and absence of satellites nodules were significant factors associated with a better 5-year disease-free survival on univariate analysis (Table 4). Multivariate analysis identified liver function, radicality of resection, tumour size, and microscopic vascular invasion as independent prognostic factors for disease-free survival (Table 6). Eleven patients (5.1%) underwent a re-resection Table 3

with a median overall and disease-free survival (from the 2nd resection) of 21 and 20 months. Overall and disease-free survival at 3 and 5 years were 44.2, 40.5% and 22.1, 20.3%, respectively.

Features and long-term results of major hepatic resection Clinico-pathologic features of patients who did and did not undergo major hepatic resection were matched: no significant differences were observed in age, AFP serum levels, resection margin and radicality. In the major hepatic resection (MHR) group there was a higher proportion of tumours with large nodules, venous invasion, and satellite nodes; all but one of MHR-group patients were Child–Pugh A. Median and 5-year survival was not significantly different between MHR and no-MHR group: 24.1 months, 36.1% and 25.7 months, 34.9%, respectively. No significant differences were found in disease-free survival (Table 5).

Multiple logistic regression evaluating morbidity risk

Factor

Exp (B)

95% CI

p

Age (R70 years/!70 years) Pugh (A/B–C) Number nodes (1/R1) Clamping time (O40 min/%40 min) Transfusions (Y/N)

0.6 0.2 3.7 2.9 2.5

0.3–1.5 0.09–0.6 1.5–8.7 1.4–5.7 1.2–5.4

0.3 0.009 0.004 0.003 0.004

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L. Capussotti et al.

Table 4

Univariate analysis of prognostic factors

Gender (M/F) Age (R70 years/!70 years) Pugh (A/B–C) HbsAg positive (Y/N) HCV positive (Y/N) AST R2N (Y/N) ALT R2N (Y/N) AFP level (R20/!20) Tumour size %5 vs O5 cm %10 vs O10 cm Number nodes Single/multiple Satellite nodes (Y/N) Edmonson 1–2/3.4 Vascular invasion Absent Microscopic Macroscopic Resection margine Negative/positive !1 cm/R1 cm (with negative margine) Type of resection Anatomic/non Anatomic/non (with microscopic vascular invasion) Major hepatic resection (Y/N) Radical resection (Y/N) a b

N

5-year survival

p

5-year DF

p

174/42 56/160 169/47 40/175 95/56 53/129 48/134 109/104

37.3%/28.1% 44.2%/32.7% 42.9%/10.6% 14.9%/39.2% 46.5%/47.7% 33.7%/33.3% 41.6%/30.5% 27.2%/43.9%

.9 .05 !.0001 .08 .9 .4 .07 .01

29%/25.9% 35.1%/25.6% 34.4%/7.3% 15.55/30.2% 36.5%/38.5% 26.2%/26.9% 36.2%/23.8% 18.1%/39.2%

.3 .02 !.0001 .1 .9 .6 .2 .005

150/66 203/13

42.4%/19.1% 36.8%/7.7%

.002 .02

33.5%/15.8% 28.9%/7.3%

.006 .004

168/48 100/116

38.1%/24.2% 28.2%/40.9%

.03 .02

30.4%/18.4% 23.7%/31.7%

.06 .009

102/111

41.6%/29.5%

.03

33.4%/23%

.01

114 77 16

44.6% 26.8% 14.6%

.0005a

.006b

32.8% 18.5% 15.6%

208/8 107/89

37.3%/0% 34.7%/40.8%

.1 .2

29.5%/0% 29.5%/29.4%

.06 .2

164/52 58/19

33.9%/39.3% 27.9%/19.3%

.7 .1

25.9%/34.8% 18.7%/23.3%

.6 .6

46/170 206/10

36.1%/34.9% 36.8%/0%

.7 0.05

29.3%/27.5% 29.1%/0%

.9 .006

!.0001a

.008b

Absent vs microscopic. Absent vs macroscopic vascular invasion.

Discussion Short-term outcome Hepatocellular carcinoma is a frequently occurring hepatic tumour and it generally grows in a cirrhotic liver. Orthotopic liver transplantation has proved to be an appropriate treatment but, with the lack of donors and the decreased risk of hepatectomies, liver resection continues to be the treatment of choice for patients with resectable hepatocellular carcinoma (HCC) and good liver function.9,15,16 Our overall mortality rate is slightly higher than that reported in recent studies.6,8,17,18 However, our series includes 47 Child–Pugh B–C patients who underwent liver resection in the first years of our experience; their in-hospital death rate was significantly increased when compared to Child–Pugh A patients: 21.3 vs 4.7% (pZ0.0003). Moreover, multivariate analysis has confirmed Child-Pugh B–C

classification as an independent factor of morbidity. Since 1999, we have based selection of surgical patients on the results of ICG test more than Child’s classification; candidates for liver resection were Child–Pugh A patients without clinical signs of portal hypertension (esophageal varices, splenomegaly with platelet serum levels lower than 100,000 mm3): the extension of resection was tailored according to the results of the ICG test reserving major hepatectomy to retention values %10%.19 Our mortality rate has shifted from 10 to 4% in the last 3 years; a similar reduction has been reported in other series.7,8 With an overall 38.4% morbidity rate, our results are comparable to those reported in some recent series.8,14,17,20 By multivariate analysis, clamping time O40 min and transfusions were the most important predictor of morbidity. Inflow vascular control by hepatic pedicle clamping (HPC) is the simplest way to reduce blood loss and transfusion

Long-term outcome of liver resection for hepatocellular carcinoma Table 5

991

Multivariate analysis of independent predictive factors of overall survival (95% confidence intervals)

Variable

Relative risk

95.0% CI

p

Pugh (A/B–C) Tumour size (%5 cm/O5 cm) Microscopic vascular invasion (Y/N)

0.3 1.8 1.7

0.2–0.5 1.2–2.8 1.4–2.2

!0.0001 0.006 0.003

rate that are associated with adverse short-term outcomes.21,22 However, a major drawback of the Pringle maneuver is the ischemia-reperfusion damage to the hepatic parenchyma; published data suggest that HPC can be used for up to 90– 120 min in normal livers and for up to 60 min in cirrhotic livers.23–25 Moreover, in 1999 Belghiti26 has demonstrated better hepatic tolerance to intermittent (IPC) over continuous clamping (CPC), especially among patients with non-normal livers. In our series, since the early 1990s, we have started to use intermittent clamping, whenever the liver resection appeared to be technically demanding with long clamping times: 46.6% of the hepatic resections were performed under IPC. However, at univariate analysis there was not a higher rate of complications in the continuous clamping group; these results can be explained by a shorter clamping time in this subset of patients. Recent series have shown that inflow occlusion times of 40–75 min have resulted in higher hepatocellular injury and liver failure rates when the Pringle maneuver was continuous rather than intermittent.27,28

Long-term outcome With a 34.1 and 25.2% overall and disease-free 5year survival, our results are comparable to those of most recent series.8,29 However, the recurrence rate is still high and continues to be the main cause of death;12 many efforts have been made to find out which prognostic factors relate to a better outcome, but many controversies remain in this area.30 In our series, Cox regression analysis showed size %5 cm as an independent predictor of long-term outcome with a 41% survival at 5 years; a recent Western study has shown similar results.31 Another large series of 1000 patients with small HCCs undergoing resection has reported a 64.8% rate of Table 6

5-year survival.32 These findings compare favorably with the results of liver transplantation (OLT) reported by Llovet:9 in an intention-to-treat analysis including the drop-outs, the 5-year survival rate was only 54%. Thereafter, in the existing situation of donor shortage, a strategy of primary resection and rescue transplantation may be a rational way to deal with long waiting lists.15 Moreover, the age of almost 30% of our patients was more than 70 years, which is usually a contraindication to liver transplantation. Our data confirm the results of previous series indicating Child–Pugh classification as an important independent predictor of long-term outcome.13,20 Our Pugh B–C patients had a significantly worse overall and disease-free survival. This finding is presumably the result of coexisting severe fibrosis since several studies have shown that fibrosis is one of the most important prognostic factors.31,33–35 Moreover, the evaluation of fibrosis score seems to provide more prognostic information than the Child–Pugh classification; Wayne has shown that Pugh A cases with a low fibrosis score had a better long-term outcome than those with a higher score.33 A new TNM staging system incorporating the fibrosis score has been recently proposed.31 Microscopic venous invasion has been frequently reported as risk factor for recurrence after HCC resection.4,5,17,31,36,37 Our study has confirmed vascular invasion as an independent predictor of outcome with an almost two-fold risk of cancerrelated death. Since, this mode of HCC dissemination propagates tumour through the portal venous system, some authors have advocated anatomical instead of non-anatomical resections in order to completely remove the portal unit containing the tumour and to prevent liver recurrence.36 The Beaujon Hospital group has recently analysed the outcome of 64 Child–Pugh A patients with small size

Multivariate analysis of independent predictive factors of disease-free survival (95% confidence intervals)

Variable

Relative risk

95.0% CI

p

Pugh (A/B–C) Tumour size (%5 cm/O5 cm) Microscopic vascular invasion (Y/N) Radical resection (Y/N)

0.4 1.8 1.8 3.3

0.2–0.5 1.4–2.5 1.2–2.3 1.2–2.1

!0.0001 0.003 0.02 0.001

992 HCCs according to the type of resection (anatomic vs wedge); whereas morbidity and mortality rates were not statistically different, 5-year overall and disease-free survival were significantly better in the anatomic group.38 In our series, 75.9% of the patients underwent anatomic resections: the complication and survival rates were comparable. A recent study has suggested that the long-term outcome of small-size HCCs with extranodular growth was better after anatomic resection;39 this finding was presumably due to a higher rate of vascular invasion and intrahepatic metastases in this subset of patients. However, when we analysed the group of patients with microscopic vascular invasion (higher risk of intrahepatic spread), there was not a significant difference in 5-year survival: 27.9 and 19.3% in the anatomic and non-anatomic resection group, respectively. Similar results were obtained analyzing the subset of Child-Pugh A cases with small-size, microscopic vascular invasion HCCs (data not shown). Macroscopic vascular invasion is defined as a tumour thrombus in the major branches of the portal or hepatic veins. It was thought for many years to represent a contraindication to operation, be it hepatic resection or transplantation. Two years ago, Tsai37 reported the results of resective surgery on 50 patients with macroscopic venous involvement: 5-year survival was 15%. Our results are analogous with two patients alive more than 4 years after operation and a 14.6% survival rate at 5 years; when we analysed the thirteen cases undergoing radical surgery, 5-year survival was 23% (data not shown). Recently, Makuuchi40 has reported an extraordinary 42% 5-year survival rate in 18 carefully selected patients.

Results of major hepatic resection In the early 1980s, Longmire41 described the UCLA University experience with 138 patients undergoing major hepatic resection: HCC with cirrhosis was present in only seven cases with a 29% mortality rate. Ten years later, the Queen Mary Hospital42 reported similar rates. In 1994, our group analysed the short-term results of 33 patients with hepatocellular carcinoma and a histologically proven cirrhotic liver who underwent MHR: mortality and morbidity rates were 3 and 48.5%, respectively.43 The findings of the present and of other recent series confirm major hepatic resection as feasible and safe in a well-selected group of patients with liver cirrhosis; 6,44,45 moreover, despite more advanced HCCs in the MHR group, long-term survival was not significantly worse.

L. Capussotti et al.

Conclusions Liver resection may be considered an adequate treatment for patients with preserved hepatic function and small-size, single-node hepatocellular carcinomas because of the low mortality rates and the good long-term outcome. Child–Pugh classification is the most important independent predictor of outcome whereas the type or resection (anatomic vs non-anatomic) does not seem to impact long-term survival. Major hepatic resection on selected cirrhotic patients is a safe procedure with a good long-term outcome.

Acknowledgements We would like to thank Prof Marvin B. Corlette for the critical revision of our manuscript.

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