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Original Article |
1 Centre for the Study of Liver Disease, Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China
2 Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas
3 Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
4 Department of Surgery, Hôpital Beaujon, Paris, France
5 Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
6 Department of Surgery, Mayo Clinic, Rochester, Minnesota
7 Centre for the Study of Liver Disease, Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong, China
Correspondence: Address correspondence and reprint requests to: Ronnie T. Poon, MS, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China; E-mail: poontp{at}hkucc.hku.hk.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methods: The perioperative and long-term outcomes of 404 patients with small HCC (<5 cm in diameter; group 1) were compared with those of 380 patients with large or multinodular HCC (group 2). The prognostic factors in the latter group were analyzed.
Results: The postoperative complication rate (27% vs. 23%; P = .16) and hospital mortality rate (2.4% vs. 2.7%; P = .82) were similar between groups. The overall survival rates were significantly higher in group 1 than group 2 (1 year, 88% vs. 74%; 3 years, 76% vs. 50%; 5 years, 58% vs. 39%; P < .001). Among patients in group 2, five independent prognostic factors were identified to be associated with a worse overall survival: namely, symptomatic disease, presence of cirrhosis, multinodular tumor, microvascular tumor invasion, and positive histological margin.
Conclusions: Hepatic resection can be safely performed in patients with large or multinodular HCC, with an overall 5-year survival rate of 39%. Symptomatic disease, the presence of cirrhosis, a multinodular tumor, microvascular invasion, and a positive histological margin are independently associated with a less favorable survival outcome.
Key Words: Hepatectomy • Large • Multinodular • Hepatocellular • Carcinoma
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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5 cm in diameter),2 its application is limited by the shortage of organs in both Eastern and Western countries.3,4 With recent advances in surgical techniques and perioperative care, hepatic resection for HCC can now be performed with a low hospital mortality even in patients with chronic liver disease.5,6 In fact, a durable survival outcome has recently been reported in patients with cirrhosis.7
Given that HCC is associated with liver cirrhosis in most patients, the prognosis for HCC patients is affected not only by the tumor stage, but also by the functional reserve of the liver. By using different clinicopathologic parameters, several HCC prognostic classifications have been developed to predict the survival outcome of patients with different stages of disease.8–10 A recent HCC staging system from the Barcelona Clinic Liver Cancer Group (BCLC) stratifies patients with HCC into four categories: early, intermediate, advanced, and terminal10 (Table 1
). The BCLC recommends different treatment options for each stage of the disease. According to this staging system, curative hepatic resection is indicated only in patients with early-stage HCC and satisfactory liver function (a single nodule 5 cm or up to three nodules 3 cm; Okuda stage8 1 or 2; Child-Pugh class11 A or B; performance score12 of 0; no portal hypertension; and normal bilirubin level), whereas liver transplantation and local ablative therapies should be considered in patients with the same tumor stage and poor liver function (portal hypertension and increased bilirubin level). The results of hepatic resection for early-stage HCC were favorable, with 5-year survival rates ranging from 40% to 70%.13–16 However, the role of surgical resection for BCLC intermediate-stage HCC (single nodule >5 cm or multinodular tumors; Okuda stage 1 or 2; Child-Pugh class A or B; performance score of 0–2) is less well defined. Major hepatic resection is often required in patients with large or multinodular HCC because of the substantial tumor volume. This may lead to an increased risk of postoperative liver failure because of the limited liver functional reserve in patients with chronic liver disease.17 In addition, intraoperative blood loss with or without blood transfusion after major hepatectomy may contribute to unfavorable perioperative and long-term outcome of patients.18 The long-term prognosis after hepatic resection for large or multinodular HCC is often considered not favorable. Hence, several groups, including the Barcelona group, have recently recommended that large or multinodular HCC should be considered a contraindication for hepatic resection.10,19,20 Nevertheless, several other groups, on the basis of results from their individual centers, have advocated hepatic resection for large HCC, defined as HCC greater than 5 cm21–24 or even greater than 10 cm13,25–27 in diameter. Given these conflicting recommendations, the role of surgical resection in patients with large or multinodular HCC needs to be further clarified by a large-scale study.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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5 cm or up to three nodules 3 cm; Okuda stage 1 or 2; Child-Pugh class A or B; group 1), whereas 380 patients (43.4%) had intermediate-stage HCC (single nodule >5 cm or multinodular; Okuda stage 1 or 2; Child-Pugh class A or B; group 2). Ninety-one patients (10.4%) were excluded from the study because of gross vascular invasion, thereby classifying these patients as having advanced-stage HCC by the BCLC classification. All patients included in the study underwent hepatic resection with a curative intent, defined as macroscopically complete removal of the tumor.
Treatment Strategy
Preoperative diagnosis and assessment of tumor status were made by using various imaging studies, including ultrasonography, computed tomography (CT) scanning, magnetic resonance imaging, hepatic angiography, and/or post-Lipiodol (Lipiodol Ultra-Fluid, Guerbet Asia Pacific Ltd., Hong Kong, China) CT scan. An increased serum alfa fetoprotein (AFP) concentration (>400 gg/mL) was also used for diagnostic purposes. After resection, the diagnosis of HCC was subsequently confirmed by histological examination in all cases. All patients had preoperative chest radiography to rule out lung metastasis. Liver functional reserve was assessed in all patients by liver biochemistry and Child-Pugh grading11 and in two centers (The University of Hong Kong Medical Center and Kyoto University Graduate School of Medicine; n = 681) by indocyanine green (ICG) clearance test. ICG is a dye specifically excreted by the liver, and the ICG clearance test has been commonly used in assessing liver function before hepatic surgery.28 Absolute contraindications to surgery included extrahepatic metastasis, main portal vein or inferior vena cava tumor thrombus, or poor liver function (Child-Pugh class C). Tumors with invasion of the ipsilateral portal vein, hepatic vein branches, or adjacent organs were considered resectable provided that en-bloc resection of all the tumor tissue could be performed with an adequate tumor-free margin. Multiple tumors in more than one lobe were resected en bloc by extended right or left hepatectomy if the patient had adequate liver functional reserve (Child-Pugh class A). Only Child-Pugh class A patients were offered major hepatectomy, defined as the resection of three or more liver segments according to Couinaud’s classification. For selected Child-Pugh class B patients, hepatic resection was offered if the tumors were resectable by minor hepatectomy, defined as the resection of two or fewer liver segments. In centers where the preoperative ICG clearance test was available, its value provided additional guidelines for the extent of hepatic resection; i.e., major hepatectomy was limited to patients with an ICG retention rate of less than 15% at 15 minutes. Intraoperative ultrasonography was routinely performed to detect additional tumor nodules or tumor invasion of major intrahepatic portal/hepatic veins and to delineate the transection line for hepatectomy to provide an adequate tumor-free margin (at least .5 cm). Hospital mortality was defined as death during the same hospital admission after surgery. Tumor size was defined as the maximal diameter of the tumor. Resected specimens were examined histologically for pathologic staging and the presence of cirrhosis, microsatellite nodules, and microvascular invasion. Resection margins were examined for histological involvement by the tumor.
Follow-Up of Patients
All patients were followed up with regular monitoring of serum AFP concentrations and abdominal ultrasonography or CT scan to detect tumor recurrence. Suspected intrahepatic recurrence was confirmed by hepatic angiography and post-Lipiodol CT scan. In equivocal situations, pathologic diagnosis was confirmed by image-guided fine-needle aspiration cytology. Patients with intrahepatic recurrence and satisfactory liver functional reserve were offered re-resection of the recurrent tumor, if feasible. Otherwise, they were treated with transarterial chemoembolization (TACE), percutaneous ethanol injection, or radiofrequency ablation. All patients had been followed up for at least 1 year after surgery, with a median follow-up of 34.3 months (range, 12–184 months).
Statistical Analysis
All demographic and clinicopathologic data were prospectively collected in each participating center by using a computerized database. Continuous data were expressed as mean ± SD and were compared by using the unpaired t-test. Categorical data were compared by using the 
2 test with Yates’ correction or Fisher’s exact test where appropriate. The primary end point of the study was survival time after hepatic resection. The overall and disease-free survival rates were calculated by the Kaplan-Meier method and compared by using the log-rank test. Hospital deaths were included in the overall survival analysis but were excluded from the disease-free survival analysis. For patients with intermediate-stage HCC (group 2), 15 clinicopathologic variables of potential prognostic value were analyzed for their effects on overall and disease-free survival rates. Six clinical factors (age younger than or older than 60 years, sex, hepatitis B surface antigen status, hepatitis C antibody status, Child-Pugh class A or B, and asymptomatic or symptomatic disease) and eight pathologic factors (tumor size 5 or >5 cm, solitary or multiple nodules, unilobar or bilobar tumor involvement, negative or positive histologic margin, any microvascular tumor invasion, microsatellite nodules, tumor invasion of adjacent organs, and presence of cirrhosis) were categorized as binary variables. Serum AFP concentration was analyzed as a continuous variable, and the cutoff was set at the median value. Multivariate analysis was performed by using the Cox proportional hazards model to identify independent prognostic factors. All statistical analyses were performed with statistical software (SPSS 11.0 for Windows; SPSS Inc., Chicago, IL). A P value of <.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Patients in group 2 (age, 58.3 ± 11.4 years) were significantly older (P < .001) than those in group 1 (age, 53.6 ± 14.5 years). There was no significant difference in the male:female ratio between the two groups. Chronic hepatitis B infection was more prevalent in group 2 (74%) than in group 1 (66%; P = .02), whereas chronic hepatitis C infection was more common in group 1 (18%) than in group 2 (5%; P < .001). There was a higher proportion of patients with cirrhosis in group 1 (38%) than in group 2 (26%; P < .001). Patients in group 2 had better liver function than those in group 1. Symptomatic disease was more common in group 2 (55%) than in group 1 (18%; P < .001), and the serum AFP concentration was significantly higher in group 2 than in group 1 (P < .001). Concerning the pathologic characteristics of HCC in the two groups, patients in group 2 had a significantly higher proportion of tumors with bilobar tumor involvement (P < .001), tumor invasion of adjacent organs (P < .001), microvascular invasion (P < .001), and histologically positive margins (P = .007).
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). The specific complications of group 2 patients after hepatectomy are listed in Table 3.
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). Whereas patients in group 1 had a median overall survival of 83.5 months (95% confidence interval [CI], 67.9–99.1 months), group 2 patients had a median survival of 36.9 months (95% CI, 28.9–44.8 months). The cumulative 1-, 3-, and 5-year overall survival rates in group 1 were 88%, 76%, and 58%, respectively, and in group 2 they were 74%, 50%, and 39%, respectively.
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Prognostic Factors for Patients With Intermediate-Stage HCC
Patients with intermediate-stage HCC (group 2) were further analyzed with respect to the prognostic factors affecting their overall and disease-free survival. Univariate analysis revealed that 8 of the 16 evaluated factors had a significant prognostic influence on overall survival (Table 4). Hepatitis B surface antigen carrier, high serum AFP level, symptomatic disease, presence of cirrhosis, multinodular tumor, microvascular tumor invasion, tumor invasion of adjacent organs, and positive histologic margins were associated with worse overall survival. On multivariate analysis, only symptomatic disease (risk ratio [RR], 1.452; 95% CI, 1.056–1.995; P = .022), the presence of cirrhosis (RR, 1.420; 95% CI, 1.047–1.925; P = .024), multinodular tumor (RR, 1.681; 95% CI, 1.212–2.332; P = .002), microvascular tumor invasion (RR, 1.531; 95% CI, 1.130–2.074; P = .006), and positive histological margins (RR, 1.860; 95% CI, 1.171–2.954; P = .009) were independent predictors of overall survival. Patients without any prognostic risk factors had the most favorable 5-year survival rate (58%), which was significantly better than that of those with one or two risk factors (5-year survival, 37%; P < .001). Patients with three or more risk factors had the worse prognosis (5-year survival, 17%), and 88% developed recurrence within 2 years.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Although large tumor size (>5 cm) and multiple tumor nodules have been shown to be less favorable prognostic factors for patients with HCC after hepatic resection,13,36,37 surgical resection remains the only hope of cure in patients with large or multinodular HCC. The Barcelona group3s recommendation may have a significant effect on the management of patients with HCC, because many patients with HCC of intermediate stage by BCLC criteria would be excluded from surgical treatment according to the staging system. Hence, it is important to critically evaluate the outcome of hepatic resection for this group of patients to see whether surgical treatment is justified. To our knowledge, this is the largest series to date to examine the long-term survival and associated prognostic factors after hepatic resection for large or multinodular HCC. This is also the first study to specifically evaluate the surgical outcome of BCLC intermediate-stage patients who have been considered unsuitable for resection according to the BCLC recommendations. The results from an international cooperative study such as this one may lead to a more widely accepted consensus on the role of hepatic resection in large or multinodular HCC.
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Despite the older age and higher proportion of major hepatic resection in group 2 compared with group 1, the hospital mortality and postoperative complication rates were similar between groups. The low morbidity and mortality rates in this series indicate that hepatic resection for large or multinodular HCC is safe with the current surgical techniques and perioperative care in major hepatobiliary centers, provided that patients are carefully selected. In this series, major hepatectomy was offered only for patients with Child-Pugh class A liver function and/or an ICG retention rate of less than 15% at 15 minutes and for those without evidence of portal hypertension, whereas for patients with Child-Pugh class B liver function, only minor hepatectomy was considered appropriate. For patients with underlying Child-Pugh class C cirrhosis and intermediate-stage HCC or with Child-Pugh class B cirrhosis with a large tumor volume that requires major hepatectomy, surgical treatment is contraindicated.
Patients in group 2 had worse overall and disease-free survival than those in group 1. Furthermore, postoperative intrahepatic tumor recurrence occurred more frequently in group 2 than in group 1. This is expected with the more aggressive tumor biology associated with large or multinodular tumors. Large tumor size and multiple tumor nodules have previously been shown to be associated with a significantly higher risk of tumor recurrence after curative surgery.39–41 Although the survival results of surgery in group 2 were inferior to those in group 1, hepatic resection still achieved satisfactory survival rates for patients with intermediate-stage HCC in this study, with 3- and 5-year overall survival rates of 50% and 39%, respectively. It is particularly noteworthy that a substantial proportion of patients could survive disease-free for a long time after hepatic resection (3- and 5-year disease-free survival rates of 38% and 26%, respectively). Llovet et al.42 studied the natural history of untreated HCC in patients recruited in the control arm of randomized trials and found that the 3-year survival rate was only 8% in patients with untreated HCC. Two recent randomized controlled studies34,35 suggested a beneficial effect of TACE compared with conservative management, but the 3-year survival rate, even with TACE, was only 26% to 29%. These two trials included both small and large HCCs. Other studies of TACE for HCC with longer follow-up reported 5-year survival rates of only 6% to 19%.43–45 A recent meta-analysis by Llovet and Bruix46 of all the randomized clinical trials available in the literature showed that TACE provided a short-term (2-year) survival benefit (odds ratio, .42) compared with control. Whether TACE can provide a long-term survival benefit remains unclear.
Compared with the survival results of TACE reported in the literature, our study suggests that surgical resection can achieve better short-term and long-term survival results in patients with intermediate-stage HCC. Some studies have demonstrated that the tumor response rate and survival after TACE were worse in patients with large HCC (>5 cm) compared with small HCC (<5 cm) and in patients with multinodular HCC compared with solitary HCC; hence, the results of TACE for intermediate-stage HCC may be worse.44,45,47 Further clarification of the role of resection versus TACE for this group of patients requires a randomized trial, which is thus far lacking in the literature and is difficult to conduct.
Few studies have examined the long-term prognostic factors after hepatic resection for large HCC.24,26,27,48,49 Among the 380 patients with large or multinodular HCC in our study, 5 independent clinicopathologic factors were identified as adverse prognostic factors affecting survival: symptomatic disease, presence of cirrhosis, multiple tumor nodules, positive histological margins, and microvascular invasion. The prognostic effect of the ICG clearance test on patient survival was not studied because this test was not routinely performed in all centers of our study. In fact, the two centers that performed this test mainly considered the value of the test as a useful predictor for the perioperative outcome after major hepatectomy. In one previous study on the prognosis after resection of HCC in patients with cirrhosis conducted by one of the two centers, the ICG clearance rate was not found to have prognostic significance.50 Besides, tumor size per se was not a predictor of prognosis in patients with intermediate-stage HCC. Patients without risk factors had a 5-year overall survival rate of 58%, which was comparable to a 58% 5-year survival rate of patients with early-stage HCC in our series. Patients with one or two risk factors had less favorable outcomes, but their 5-year survival rate of 37% still compares favorably to the results of TACE treatment.43–45 However, patients with three or more risk factors had much worse survival results, with a 5-year survival rate of only 17%. Surgical resection is less beneficial in this subgroup of patients. Among the five prognostic risk factors, symptomatic disease and multiple tumor nodules can be identified before surgery. Cirrhosis is also often obvious in preoperative imaging. Positive histological resection margins are related to imprecise transection planes during hepatic resection. With better preoperative imaging modalities such as helical CT scan and intraoperative ultrasonography, the liver transaction plane can now be better delineated to ensure adequate tumor-free margins. Microvascular invasion by tumor is difficult to predict before surgery. Recent studies suggest that certain biological markers in the circulation may be useful in preoperative prediction of vascular invasion, but their exact clinical value requires further evaluation.51 The elucidation of prognostic factors may help to select patients with a less favorable prognosis after resection for some types of adjuvant therapy in the future.
In summary, this study shows that hepatic resection can be safely performed in patients with large or multinodular HCC, with perioperative outcomes comparable to those of patients with small HCC. Although the survival results were less favorable in patients with large or multinodular HCC, a 5-year overall survival rate of 39% and a 5-year disease-free survival rate of 26% could be achieved by surgical resection for this group of patients. These survival outcomes compare favorably to those reported in the literature that used TACE for patients with similarly staged HCC. In a selected subgroup without any adverse prognostic risk factors, the long-term survival was similar to that after resection of small HCCs. This large-scale study, which was based on a multi-institutional database, provides a strong counteraction to the BCLC group3s recommendation that large or multinodular HCC should not be treated surgically. We recommend surgical resection as an effective treatment for patients with large or multinodular HCC, provided that the liver functional reserve is acceptable for resection. It seems that this recommendation is most appropriate in the setting of a high-volume institution, such as the institutions involved in our study. In contrast, the generalized applicability of our results to low-volume centers, or even community hospitals, is less clear. Nevertheless, there is a worldwide trend in performing sophisticated surgical procedures such as major hepatectomy in high-volume institutions. A recent review using a nationally representative database suggested that patients requiring hepatectomy should be offered referral to high-volume centers because of their low mortality rate compared with that of low-volume hospitals.52 In this context, a study based on multiple high-volume centers provides useful information in guiding clinical practice. This study also identified symptomatic disease, multinodular tumor, presence of cirrhosis, positive resection margins, and microvascular tumor invasion as the independent adverse prognostic factors for survival in this group of patients. The elucidation of these factors may provide some selection criteria for better stratification of patients with large or multinodular HCC for resection or nonsurgical treatment, and it may also help in the future to select patients with a less favorable prognosis for adjuvant therapy after resection.
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ACKNOWLEDGMENTS |
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Received for publication June 1, 2004. Accepted for publication December 20, 2004.
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