© 2007 Foundation for Promotion of Cancer Research
Effectiveness of Hepatic Resection for Early-stage Hepatocellular Carcinoma in Cirrhotic Patients: Subgroup Analysis according to Milan Criteria
1 Hepatobiliary and Pancreatic Section, Gastroenterological Division, Cancer Institute Hospital, Tokyo
2 Department of Surgery, Hepato-Biliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo
3 Department of Digestive Surgery, Nihon University School of Medicine, Tokyo
4 Hepatobiliary Pancreatic Surgery Division, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
For reprints and all correspondence: Junji Yamamoto, Hepatobiliary and Pancreatic Section, Gastroenterological Division, Cancer Institute Hospital, 3-10-6, Ariake, Koto-ku, 135-8550 Tokyo, Japan. E-mail: jyamamoto{at}jfcr.or.jp
Received July 27, 2006; accepted December 16, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Background: The aim of this study was to determine the long-term post-resection outcomes for cirrhotic patients with early-stage hepatocellular carcinoma (HCC).
Methods: A total of 217 
65-year-old cirrhotic patients who underwent hepatic resection were divided into four groups in accordance with the Milan criteria: Group 1, those who met the Milan criteria (n = 130); Group 2A, those with a solitary tumor > 5 cm in size (n = 12); Group 2B, those with 2 or 3 tumors > 3 cm in size (n = 35); and Group 2C, those with 
4 tumors (n = 33). Overall and recurrence-free survival were compared between the groups.
Results: At 1, 3, 5 and 10 years, overall survival rates were 91, 67, 45 and 12%, and recurrence-free survival rates were 62, 26, 16 and 0%, respectively. Independent prognostic factors for overall survival were age, blood transfusion, tumor number, tumor size and microscopic vascular invasion; and for recurrence they were hepatitis C infection, tumor number, tumor size, microscopic vascular invasion and histological tumor grade. Group 1 patients had significantly better survival (5-year survival rate, 56%) than those of other groups (5-year survival rate, around 30%). The median tumor-free survival time was significantly shorter in Groups 2B and 2C (0.7 years and 0.6 years, respectively) than in Groups 1 and 2A.
Conclusions: Hepatic resection can confer a considerable overall survival benefit for cirrhotic patients with HCC who meet the Milan criteria. For patients with HCC who do not meet the criteria, however, hepatic resection has limited efficacy. We suggest that application of non-surgical therapy or expansion of the indications for liver transplantation may be warranted for such patient subsets.
Key Words: hepatocellular carcinoma • surgical resection • survival • recurrence
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Hepatocellular carcinoma (HCC) is the third leading cause of deaths from cancer in Japan. The frequency of HCC has reportedly also increased in recent years in other areas of the world (1, 2). HCC represents one outcome of end-stage liver disease, particularly in individuals infected with the hepatitis C virus. Owing to the development of screening programs for high-risk populations, small asymptomatic HCCs have been increasingly detected, especially in areas where the disease is endemic, such as Japan, Southeast Asia and southern Europe (3, 4). The optimal therapeutic strategy for these small HCCs remains undetermined, since non-surgical local ablation (5–7), surgery (8, 9) and liver transplantation (10, 11) have all been credited with good results. Surgical resection has generally been accepted as the treatment of choice for locally confined HCC. One of the most contentious points in the treatment of early-stage HCC arising in cirrhotic liver is whether liver transplantation represents a primary therapeutic option for patients with such tumors if a preserved hepatic reserve is available (8–11). Cirrhotic patients with early HCC have been found to have 4- or 5-year overall survival rates of > 70% after liver transplantation (10, 12–15). In the present study, in an attempt to determine the ability of partial hepatectomy to control HCC, cirrhotic patients with HCC who underwent hepatectomy were divided into groups in accordance with the Milan criteria (12), a well-established set of criteria used in patient selection for liver transplantation. The outcomes for each subgroup were examined.
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PATIENTS AND METHODS |
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Patients
From 1990 to the end of 2000, a total of 739 patients underwent initial hepatic resection for HCC at the National Cancer Center Hospital, Tokyo. Among them, 329 had cirrhosis. Case record data for these patients, including details of liver function, tumor size, tumor number and pathological findings from resected specimens, were prospectively collected in a computer database. Among these 329 patients, 30 patients were excluded because of poor prognostic factors [macroscopic vascular invasion (n = 25) or lymph node metastases (n = 4) or both (n = 1)]. Among the remaining 299 patients, 217 patients (177 men, 40 women), who were
65 years-old at treatment, were selected for further analysis. The mean patient age was 58 years (median, 59 years; range, 38–65 years). The mean duration of follow-up as of December 2004 was 66 months (median, 63 months; range, 0.3–164 months).
Collected Data
The hepatitis B (HB) and C (HC) status of patients was checked. Patients were defined as HB-positive when hepatitis B surface antigen (HBsAg) was present. Patients were defined as HC-positive when anti-HC virus antibody was present. Laboratory data gathered included serum levels of albumin, total bilirubin and prothrombin time (%) for determining Child–Pugh grading (16, 17). In addition, the 15-min retention rate for indocyanin green (ICGR15) was checked to determine the extent of resection (18). As tumor markers, serum levels of 
-fetoprotein and protein induced by vitamin K absence or antagonists-II (PIVKAII) were recorded. For all patients, surgery comprised attempted curative resection. The volume of intra-operative blood loss, intra-operative red blood cell transfusions and operative procedures were recorded. Our standard operative procedure for hepatic resection has been described in detail elsewhere (19). Resected specimens were macroscopically examined to determine the number of tumors and maximum tumor diameter. Microscopic examinations were carried out with respect to the portal or hepatic vein invasion status, presence of a fibrous capsule and histological differentiation of the tumor in accordance with the classification of Edmondson and Steiner. Fibrosis in the non-tumorous liver was evaluated and graded on a scale of 0–4, in which stages 3 and 4 were designated as cirrhosis (20, 21).
Subgroup Analyses
A summary of the clinicopathological and surgical data for the 217 patients is shown in Table 1. To examine whether certain clinical subsets of patients had different outcomes after resection, patients were stratified using the Milan criteria: Group 1 patients were those who met the Milan criteria (solitary tumor 5 cm or 2 or 3 tumors 3 cm) (n = 130); and Group 2 were those who did not meet the Milan criteria. Group 2 was further subdivided into Group 2A patients, who had solitary tumors > 5 cm in size (n = 12); Group 2B patients, who had 2 or 3 tumors > 3 cm in size (n = 35); and Group 2C patients, who had 4 tumors (n = 33).
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Statistics
Survival curves were generated using Kaplan–Meier methods and were compared using the log-rank test. Patients alive as of 31 December 2004, were censored at the time of follow-up. As for tumor recurrence, patients with no recurrence at the final follow-up were censored. Multivariate Cox regression analysis was used to identify factors independently associated with mortality. Differences in proportions were evaluated using Pearson's
2 test. Values of P < 0.05 were considered statistically significant. |
RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Clinicopathological Characteristics of Cirrhotic Patients (Table 1)
About 80% of patients were HCV-positive and 20% were HBV-positive. Hepatic functional reserve of Child–Pugh grade A was noted in > 80% of patients. However, around 60% had ICGR15 > 20%, reflecting a frequency of minor resection of > 80%. With respect to tumor characteristics, 56% of patients had multiple tumors and 54% had tumors < 3 cm in diameter. Microscopic vascular invasion was identified in 75 patients (35%), and 49 patients (25%) had tumors of Edmondson and Steiner grade 3–4.
Analysis of Post-Resection Prognostic Factors (Table 2)
Of the 217 patients, nine (4.2%) died in hospital after surgery. Overall survival rates at 1, 3, 5 and 10 years were 91, 67, 45 and 12%, respectively. Median survival time was 4.5 years. Univariate analysis revealed that serum PIVKAII level, red blood cell transfusion, tumor number, tumor size, microscopic vascular invasion and tumor differentiation were significant prognostic indicators. According to multivariate analysis, age, red blood cell transfusion, tumor number, tumor size and microscopic vascular invasion were predictive factors for post-resection patient survival (Table 3).
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During the follow-up period, 163 patients (75%) experienced recurrence. Cumulative tumor-free rates at 1, 3, 5 and 10 years were 62, 26, 16 and 0%, respectively. Median time to recurrence was 1.33 years. Univariate analysis identified red blood cell transfusion, tumor number, tumor size, microscopic vascular invasion and tumor differentiation as significant prognostic indicators. Independent prognostic factors for tumor recurrence identified by multivariate analysis were HCV infection, tumor number, tumor size, microscopic vascular invasion and histological grade of tumor (Table 3).
Comparative Subgroup Analysis of Overall Survival and Tumor-free Survival
Comparison of outcomes after hepatectomy among the four patient subsets revealed that Group 1 had significantly better survival than the other three groups (Fig. 1). Group 1 had a 5-year survival rate of > 50%, with 70 patients (53%) surviving longer than 5 years and 14 patients (11%) living for > 10 years. All other groups had 5-year survival rates of around 30% and no 10-year survivors.
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As for recurrence, Group 2A and Group 1 had comparable tumor-free survival rates after resection. The median tumor-free survival times for Groups 2B and 2C were 0.7 years and 0.6 years, respectively, indicating significantly earlier recurrence than for Groups 1 or 2A (Fig. 2).
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Pattern of Recurrence (Table 4)
At the time when recurrence was diagnosed, almost all recurrent tumors in the liver were < 3 cm in size. According to the criteria used for primary transplantation in HCC, around 70% of patients were eligible for salvage transplantation. Group 1 patients at initial resection tended to meet these criteria more frequently than those in Group 2 (P = 0.08) at the time of recurrence. Recurrence that was limited to the liver but that did not meet the Milan criteria was almost always due to multiple tumors.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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The optimal therapeutic strategy for early-stage HCCs remains to be determined, because non-surgical local ablation (5–7), surgery (8, 9) and liver transplantation (10, 11) have all been credited with good results. Comparative studies of hepatic resection and liver transplantation as initial treatments for HCC arising in cirrhotic livers have reported comparable patient survival and superior tumor-free outcomes for transplantation compared with resection (10, 11, 22, 23). The excellent survival after liver transplantation for early-stage HCCs, as initially suggested by Iwatsuki et al. (24) on the basis of experience with transplantation for patients with asymptomatic incidental tumors, was championed by Bismuth et al. (10). The Milan criteria system as proposed by Mazzaffero et al., which is based on the number and size of intrahepatic tumors, offers a simple yardstick for selecting candidates for transplantation among HCC patients with cirrhosis (12). Patient selection using these criteria yields 4- or 5-year overall survival rates of > 70%, with recurrence rates of < 15% (10, 12–15).
Our 5-year post-resection survival rate (56%) for patients meeting the Milan criteria was not particularly good compared with the rates reported in other studies (8, 9). A US group reported a 5-year survival rate of 70% after hepatic resection for patients with transplantable HCC (9). In Chinese cirrhotic patients with HCC that met the Milan criteria, a 5-year survival rate of 66% was obtained (8). Outcomes from those two series were superior to our overall survival, and are comparable to the results from liver transplantation. This discrepancy might be due to differences in patient selection for resective treatment. The US series included 22% non-cirrhotic patients and 83% patients with solitary tumors. Among the 90 Chinese patients with cirrhosis, 10 patients (11%) had oligonodular HCCs. In contrast, the 133 patients with disease who met the Milan criteria in the present series included 49 patients (37%) with 2 or 3 tumors. In addition, the rates of major hepatic resection differed, being 28% in the US series, 65% in the Chinese series and 1.5% in the present series. This might be due to differences in resection policies. However, this also suggests differences between the series in background liver disease and hepatic functional reserve. An HBsAg positivity rate of > 80% in Chinese patients (8) might mean that in cases involving HBV-related HCC, hepatic functional reserve is well preserved, even in cirrhotic liver.
With respect to the extent of resection, most of our surgical procedures (81% minor resections) are comparable to local ablative therapy approaches, such as radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI). Recent studies comparing surgical resection and local ablative therapy (5, 6) have reported comparable overall survival and recurrence-free rates for the two therapies, thus supporting the use of local ablative therapy as an equally good first treatment option. However, a detailed study in which HCCs in explanted liver were treated by RFA during the waiting time for transplantation indicated 45% viable tumor persistence after such treatment (25). Compared with surgery, local ablative therapy is an effective and less invasive treatment of small HCC in cirrhotic patients awaiting transplantation. However, in cases where there is no expectation that radical treatment in the form of transplantation will be carried out, hepatic resection is a reasonable first-line treatment for cirrhotic patients with early-stage HCC and good liver function.
In the present study, selected components of the Milan criteria were used to divide patients who did not meet the overall Milan criteria, allowing evaluation of the effectiveness of hepatic resection for each patient subset. Among three subsets of patients, recurrence-free survival for those who had large solitary tumors was comparable with those within Milan criteria, while patients with 2 or 3 tumors > 3 cm in size or 4 tumors had very short recurrence-free survival and no long-term survival. For such tumors, which exceed the ordinary criteria for local ablative therapy, transarterial chemoembolization (TACE) might be as effective as surgical resection (26, 27). Yoshimi et al. found no significant differences in the survival rates of patients who underwent hepatectomy and those who underwent TACE, although the incidence of more advanced HCC (TNM stage III or IV) was significantly higher in the TACE group than in the hepatectomy group (26). Lee et al. reported that TACE was as effective as resection in subpopulations with UICC T3N0M0 and adequate liver function (27).
Transplantation could be considered as a therapeutic modality for these subsets of patients outside Milan criteria. In analyses of patterns of recurrence, even in patients exceeding the Milan criteria, around 60% of recurrences after hepatic resection were confined to the liver and were considered transplantable using the same criteria (8, 28, 29). Several studies on cadaveric liver transplantation have reported that > 50% of patients exceeding the Milan criteria receiving transplants achieved 5-year survival (30–32). Roayaie et al. found 5-year overall and tumor-free survival rates of 44 and 48%, respectively, in transplanted patients with HCC > 5 cm in diameter (31). Kaihara et al. first reported outcomes after living donor liver transplantation for HCC patients, including 45% who did not meet the Milan criteria, with a 3-year survival rate of 55% (33). In patients exceeding the Milan criteria, Gondolesi et al. (34) reported a 3-year survival rate of 42%, and a Japanese survey of 316 patients (35) reported a 3-year overall survival of 60.4% and a recurrence-free survival rate of 52.6%, although outcomes for patients who met the Milan criteria were significantly better in both studies. Outcomes need to be reported for specific subgroups of patients in which expansion of criteria for transplantation can be applied.
The present study identified the same prognostic factors for outcome after hepatic resection as reported in many other studies (36–43). Furthermore, microscopic vascular invasion reportedly has a strong correlation with tumor size and tumor differentiation (P < 0.0001, 2 test) (15, 44, 45). The presence of larger tumors, microscopic vascular invasion and poorly differentiated tumors are also predictive of poor overall and recurrence-free survival after transplantation according to numerous studies (10, 14, 22, 45–49). These factors thus indicate a higher risk of not only intrahepatic, but also extrahepatic tumor cell spread. In the present study, elevated serum PIVKAII levels were predictive of significantly worse overall survival after surgery according to univariate analysis, but not according to multivariate analysis. Serum level of PIVKAII was significantly correlated with microscopic vascular invasion (P < 0.0001, 2 test), tumor size (P < 0.0001) and histological tumor grade (P = 0.05). Pretreatment values of PIVKAII are reportedly correlated with status of vascular invasion (49). Given that current diagnostic imaging is unable to identify microscopic vascular invasion prior to treatment and that disease extent is underestimated in about 20% of patients using conventional information (50), finding additional indicators for predicting the malignity of HCC is of pivotal importance.
HCV-positive HCCs were more frequently multiple (P = 0.02) and less invasive to the portal vein (P = 0.05) than those arising in HCV-negative liver. Such a relationship with the other potential prognostic factors may explain an independent influence on accelerated recurrence in the multivariate context although it did not reach statistical significance (P = 0.08) in the univariate analysis.
In summary, this study shows that hepatic resection can produce a considerable overall survival benefit for patients with HCC who meet the Milan criteria, although recurrence is frequent. Conversely, for patients with HCC exceeding the Milan criteria, hepatic resection has limited efficacy. We suggest that use of non-surgical therapies such as TACE, or expansion of the indications for liver transplantation may be warranted for such patient subsets.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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Acknowledgment |
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This work was supported in part by grants-in-aid for Basic Science Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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References |
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