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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2003.09.012 on September 15, 2003

Annals of Surgical Oncology 10:916-921 (2003)
© 2003 Society of Surgical Oncology
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ORIGINAL ARTICLES

Predictors of Long-Term Disease-Free Survival After Resection of Hepatocellular Carcinoma: Two Decades of Experience at Chang Gung Memorial Hospital

Chun-Nan Yeh, MD, Wei-Chen Lee, MD, Miin-Fu Chen, MD, FACS and Pei-Kwei Tsay, PhD

From the Department of General Surgery (C-NY, W-CL, M-FC), Chang Gung Memorial Hospital, Chang Gung University; and the Department of Public Health and Center of Biostatistics (P-KT), Chang Gung University, Taoyuan, Taiwan.

Correspondence: Address correspondence and reprint requests to: Chun-Nan Yeh, MD, Department of General Surgery, Chang Gung Memorial Hospital, #5, Fu-Hsing Street, Kwei-Shan, Taoyuan, Taiwan; Fax: 886-3-328-5818; E-mail: ycn{at}adm.cgmh.org.tw


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Hepatocellular carcinoma (HCC) is a common disease in Taiwan. A high incidence of recurrence after hepatectomy is the most important cause of unsatisfactory results after resection of HCC. This study aimed to determine the clinicopathologic factors for predicting survival >5 years without recurrence in HCC patients treated with hepatectomy.

Methods: The clinical features of 46 patients with surgically resected HCC who survived >5 years without recurrence (group A) were reviewed. Also, comparison was made with the clinical features and factors influencing the outcome of 1046 cases of resected HCC who survived <5 years both with and without recurrence and for >5 years with recurrence (group B).

Results: Of 1092 cases of surgically resected HCC, 46 (4.5%) survived >5 years without recurrence. Univariate analysis revealed that absence of vascular invasion, satellite lesions, low histological grading of HCC, a lower rate of underlying liver cirrhosis, wider resection margins, and an uneventful postoperative course were frequent in group A patients compared with group B patients. Moreover, multivariate stepwise logistic regression analysis identified an absence of satellite lesions and an uneventful postoperative course as the two main independently significant predictors of HCC patients undergoing hepatectomy with long-term disease-free survival. The 1-, 3-, 5-, and 10-year survival rates of group A patients were 100%, 100%, 100%, and 84.1%, whereas those of group B patients were 73.5%, 47.9%, 29.0%, and 21.2%, respectively.

Conclusions: An absence of satellite lesions and an uneventful postoperative course are the two main independent predictors for long-term disease-free survival in HCC patients undergoing hepatic resection.

Key Words: Predictors • Long-term disease-free survival • Hepatic resection • Hepatocellular carcinoma


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatocellular carcinoma (HCC) is a common disease in Taiwan, with an annual age-adjusted incidence of 28.7 per 100,000 population. HCC is the leading cause of cancer-related death among men and is second among women in Taiwan.1

Although liver transplantation has provided an alternative option for the surgical management of HCC, partial hepatic resection remains the mainstay of treatment. With advances in surgical techniques and improvements in perioperative care, surgical mortality rates in HCC patients receiving hepatectomy recently have decreased significantly. However, the prognosis of HCC after surgical resection remains poor. Five-year survival of patients undergoing surgical resection for HCC is only 30% to 40%,2–5 and a high incidence of recurrence after hepatectomy is the main cause of unsatisfactory results after surgical treatment.6–8 Chen et al.9 reported a tumor recurrence rate of up to 59% in the first year after hepatectomy. The cumulative 5-year recurrence rate was 70% to 100% from most centers.10 Postoperative recurrence is universally high and remains the main cause of late deaths. Several factors have been suggested to predispose to tumor recurrence, and Lee et al.11 proposed an estimation of prognosis after hepatectomy for HCC. However, reports on long-term disease-free survival after resection for HCC remain limited.12,13 This study attempted to determine the clinicopathologic factors that are important in predicting long-term disease-free survival after hepatectomy for HCC.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From 1982 to 2001, 1222 consecutive HCC patients underwent surgical treatment at the Department of Surgery, Chang Gung Memorial Hospital, Taipei, Taiwan. A total of 130 patients were excluded: 67 HCC patients with incomplete follow-up records and 63 HCC patients who died within 1 month after surgery (the surgical mortality rate was 5.2%; 63 of 1222). A total of 1092 HCC patients were enrolled in this study, and the clinical data were retrospectively reviewed. Among them, 46 patients (4.2%) who survived longer than 60 months without recurrence after curative surgery for HCC were classified as group A, whereas the remaining 1046 patients were classified as group B (survival <5 years both with and without recurrence and >5 years with recurrence). Laboratory tests were performed on the day before surgery. Differences in demographics, symptomatology, physical examination, laboratory data, presence of cirrhosis, Child-Pugh grade, operative findings, and pathologic features between the two groups were compared. Clinicopathologic features were conditioned as presence or absence; <1-cm versus >1-cm resection margin; and low-grade versus high-grade histological grading. Resections included segmentectomy, lobectomy, extended lobectomy, subsegmentectomy, and wedge resection. Segmentectomy is a resection of one of the four segments (lateral, medial, anterior, or posterior) of the liver, as classified by Healey and Schroy.14 Subsegmentectomy is a resection of a Couinaud segment.15 Histopathologic findings of HCC were divided into four grades according to Edmondson and Stainer’s system. Grades I and II were conditioned as low-grade HCC, and grades III and IV were conditioned as high-grade HCC.16

All data are presented as percentages of patients or mean with SD. Numerical data were compared by independent two-sample t-tests. Nominal data were compared by Pearson’s {chi}2 test or multiple forward stepwise logistic regression, when appropriate. Survival was calculated and plots were constructed according to the Kaplan-Meier method and compared with a log-rank test. All statistical analyses were performed with the SPSS computer software package (version 10.0; SPSS Inc., Chicago, IL). A value of P < .05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Group A contained 34 men and 12 women with a mean age of 50.5 ± 13.3 years (range, 18–71 years). Groups A and B displayed similar age distributions and sex ratios (Table 1). Furthermore, both groups exhibited a similar percentage of positive hepatitis B and/or C results. A lower rate of underlying liver cirrhosis was noted in the HCC patients undergoing hepatectomy with long-term disease-free survival (P = .05; Table 1) Table 2 lists the results of all preoperative laboratory tests and reveals little difference between the two groups.


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  		TABLE 1. Demographic data of 1092 HCC patients treated with hepatectomy, comparing the patients with 5 years of survival without recurrence (group A) with the remaining patients (group B)
 

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  		TABLE 2. Laboratory data of 1092 HCC patients treated with hepatectomy, comparing the patients with 5 years of survival without recurrence (group A) with the remaining patients (group B)
 
Table 3 summarizes the operative, macroscopic, and microscopic findings. Similar percentages of major hepatectomy, blood loss, blood transfusion, and tumor size were observed in both groups. Compared with patients in group B, patients in group A had a higher percentage of low-grade HCC (P = .05). Generally, the tumors in group A patients had similar capsule formation, capsular invasion, rupture percentage, and hospital stay compared with those in group B. Group A patients also exhibited less vascular invasion, an absence of satellite lesions, a wider clearance margin, and an uneventful postoperative course compared with group B patients (Table 3). Table 4 lists the postoperative complications that occurred in this study. Univariate analysis showed less underlying cirrhosis, lower histological grading of HCC, an absence of vascular invasion, an absence of satellite lesions, wider clearance margins, and fewer postoperative complications in group A patients compared with group B patients, although multivariate logistic regression analysis showed that the absence of satellite lesions and uneventful postoperative courses were the two main independent factors predicting long-term disease-free survival in HCC patients after hepatectomy (Table 5).


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  		TABLE 3. Operative, macroscopic, and microscopic findings of 1092 HCC patients treated with hepatectomy, comparing the patients with 5 years of survival without recurrence (group A) with the remaining patients (group B)
 

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  		TABLE 4. Causes of postoperative complications of 1092 HCC patients treated with hepatectomy, comparing the patients with 5 years of survival without recurrence (group A) with the remaining patients (group B)
 

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  		TABLE 5. Multiple forward stepwise logistic regression analysis of clinicopathologic features in 1092 HCC patients treated with hepatectomy, comparing the patients with 5 years of survival without recurrence (group A) with the remaining patients (group B)
 
All of the 1092 patients who underwent hepatic resection were followed up at regular intervals until their death. The duration of follow-up ranged from 1.1 to 213.5 months (median, 16.0 months). For group B patients, the 1-, 3-, and 5-year actuarial survival rates were 73.5%, 47.7%, and 29.0%, respectively. Meanwhile, for group A patients, the 5-and 10-year actuarial survival rates were 100% and 84.1%, respectively.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Demographics, symptomatology, physical findings, biochemical data, hepatitis disease status, and associated liver conditions were generally similar in the two groups. However, group A patients differed from group B patients in six respects.

Patients with long-term disease-free survival after hepatectomy had a lower rate of underlying liver cirrhosis. The effect of underlying cirrhosis in the nontumorous liver on the risk of recurrence after HCC resection is controversial. Cirrhosis has been reported to be a significant risk factor for recurrence in the remaining liver because of a predisposition to multicentric hepatocarcinogenesis.17–19 In this study, lower rates of underlying liver cirrhosis were related to long-term disease-free survival.

Low-grade HCC was related to long-term disease-free survival after hepatectomy. The prognostic significance of histological grading of HCC on the risk of recurrence is debatable. A previous Japanese study demonstrated a significantly increased recurrence rate with poorly differentiated HCC20 and confirmed that a high-grade tumor was a strong independent predictor of portal vein invasion.21 This study confirms this observation, although Shirabe et al.22 showed that well-differentiated HCC was not clinically early cancer.

An absence of vascular invasion, satellite lesions, a wider clearance margin, and fewer postoperative complications were associated with long-term disease-free survival after hepatectomy. Vascular invasion is the most consistently reported risk factor for recurrence after HCC resection.10 Intrahepatic portal vein involvement is widely accepted as the mechanism for intrahepatic recurrence for HCC. However, this study did not identify the absence of vascular invasion as an independent predictor of long-term disease-free survival for HCC after hepatic resection.

The absence of satellite lesions was identified as an independent predictor of long-term disease-free survival for HCC after hepatic resection. This observation is consistent with those of other reports.10 Satellite lesions are considered to be intrahepatic metastases and indicators of tumor invasiveness. Satellite lesions can arise from either intrahepatic metastasis or multicentric occurrence, both of which contribute to recurrence in the liver remnant.

A wider clearance margin was related to long-term survival without recurrence for HCC after hepatic resection, although this relation was not verified by multivariate analysis. A wide resection margin to ensure histological clearance is a general principle of surgical oncology. Our previous study and other Japanese reports have demonstrated that a macroscopic margin of >=1 cm is associated with reduced postoperative recurrence and improved long-term survival23,24; however, other reports have demonstrated no correlation between the surgical margin width and the incidence of recurrence.10

Here, a lower incidence of postoperative complications was an independent indicator for HCC patients after hepatectomy with long-term disease-free survival. Although this was not statistically significant, the lower percentage of hepatitis C virus infection with lower indocyanine green retention rate at 15 minutes and younger age partially contribute to the more uneventful postoperative courses of group A patients as compared with group B patients. Our previous study demonstrated that hepatitis C virus-related HCC patients were older and tended to have severe and progressive liver disease and a significantly higher indocyanine green retention rate at 15 minutes.25 Generally, septic problems occur most frequently with advanced cirrhosis and contribute heavily to the increased mortality. The increased infection rate may be partially explained by the impairment of Kupffer cell function, which reduces the intravascular clearance of the enteric organism.26 Furthermore, ascitic fluid may provide an ideal growth medium for the bacterial contaminants released during cholecystectomy.26 Overall, the relative risk of septic complications depends on the severity of cirrhosis. Numerous investigations have correlated the prevalence of sepsis with the Child-Pugh classification of the patient.26–28 In this study, ascites was the most common morbidity after hepatic resection. For hepatic surgeons, meticulous operative techniques and perioperative care are crucial to achieving an uneventful postoperative course and to preventing postoperative bleeding, bile leakage, wound infection, wound dehiscence, and intra-abdominal abscess.

On the basis of the analytical results, we conclude that the absence of satellite lesions and an uneventful postoperative course are the two main independent predictors of long-term disease-free survival in HCC patients undergoing hepatectomy.


   FOOTNOTES
 
Long-term disease-free survival in hepatocellular carcinoma patients undergoing hepatectomy was related to the absence of satellite lesions and an uneventful postoperative course.

Received for publication September 12, 2002. Accepted for publication June 9, 2003.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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