Abstract
Background and Aim: The aim of the present study was to evaluate the efficacy of liver resection for multinodular hepatocellular carcinoma (MNHCC). Patients and Methods: A total of 399 patients who underwent R0 resection for HCC from 1992 to 2011 were subjected to analysis. Out of these 399 patients, 107 patients had multinodular HCC, while 292 had a single tumor. Results: The 3- and 5-year overall survival rates of patients with MNHCC were 62.0% and 38.1% respectively. By a multivariate analysis of the survival of the 107 patients after liver resection for MNHCC, it was shown that the presence of four or more tumors and a lower serum albumin level were unfavorable prognostic factors for long-term survival. With respect to the patients with four or more HCCs, portal vein invasion was an independent unfavorable prognostic factor for long-term survival. However, in patients with four or more HCCs without portal vein invasion, overall survival rates of those with preoperative serum albumin level >4.0 mg/dl and a platelet count >105/mm3 were significantly higher than those of patients with albumin <4.0mg/dl or platelet count <105/mm3 (p=0.049). Conclusion: Liver resection can provide a survival benefit, even for patients with multiple HCCs. Even if patients have four or more tumors without portal vein invasion and with well-preserved liver function, resection for HCC may be the treatment of choice.
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and is the third leading cause of cancer-related death (1). Several studies have recently reported on improved outcomes in patients with HCC who have undergone liver resection, including not only decreases in surgical mortality and morbidity, but also favorable long-term results (2-5). However, high recurrence rates remain a major drawback of liver resection (2-4, 6). One of the most significant predictors of recurrence is the number of tumors (7, 8). It has been suggested that when the tumors result from multi-centric carcinogenesis or intra-hepatic metastases, multinodular HCC (MNHCC) may benefit from palliation with local ablative treatment or chemoembolization, rather than from hepatic resection (9). However, there have been few clinical studies to validate this recommendation.
Liver transplantation has also offered prolonged disease-free and overall survival for carefully selected patients with small HCCs, but has been limited in countries such as Japan, where cadaveric organ harvesting is very limited (10). Therefore, hepatic resection is still the mainstay of curative treatment for MNHCC.
The aim of the present study was to evaluate the efficacy of hepatic resection for MNHCC, and to identify the subgroup of patients with MNHCC who benefit most from aggressive surgical interventions.
Patients and Methods
Patients. From 1992 to 2011, a total of 434 patients diagnosed as having HCC underwent liver resection with curative intent at the Yokohama City University Graduate School of Medicine, Japan. Three patients (0.7%) died within 60 days of their operation as a result of postoperative liver failure, and another 32 patients either were unable to undergo curative hepatectomy or had concomitant extrahepatic metastases that precluded R0 resection. Accordingly, the data from the remaining 399 patients who underwent R0 resection were subjected to an analysis regarding the survival outcome. Of these 399 patients, 107 patients had MNHCC, while 292 had a single tumor.
Preoperative management. All patients underwent thorough examinations, including laboratory tests to evaluate the liver function and tumor markers such as alpha-fetoprotein (AFP). The serological presence of hepatitis B antigens or antibodies, and of hepatitis C antibodies, was considered to be evidence of hepatitis B or C exposure, respectively. Preoperative imaging for tumor staging included chest X-rays, abdominal ultrasonography (US), computed tomography (CT) and magnetic resonance imaging, if indicated.
Hepatectomy procedures. Hepatic resection was conducted as the primary treatment for HCC when tumors were considered to be resectable, and was performed according to the anatomical principles of resection. The criteria employed to determine safe hepatic resection were based on a multiple regression equation using the patient age, resection rate and indocyanine green retention at 15 min (ICG-R15), as described previously (11). When an anatomical resection was not possible, non-anatomical resections, local ablation therapy adjunctive to minor hepatic resections or hepatic resection after portal vein embolization were performed. Major hepatectomy was defined as a surgery consisting of three or more Couinaud's segmentectomies. All surgical procedures have been described previously (5). The Brisbane 2000 Terminology of the International Hepato-Pancreato-Biliary Association was used to describe the liver anatomy and resections (12). Each resected specimen was examined grossly and microscopically as described elsewhere (5).
Adjuvant therapy and patient follow-up. After liver resection, adjuvant chemotherapy was administered to patients with pathologically-confirmed satellite nodules, vascular invasion or hepatic duct invasion. Until 2000, the adjuvant therapy consisted of the transarterial administration of 20-40 mg doxorubicin combined with lipiodol. From 2001, hepatic artery infusion of 5-fluorouracil at a dose of 1,500 mg given over 24 h and cisplatin at 10 mg over 30 min through an implanted port was performed once weekly for eight weeks whenever possible. Patients underwent a monthly follow-up evaluation at our outpatient clinic. The serum levels of AFP and des-γ-carboxy prothrombin were measured monthly; CT or US was performed every three to four months and a chest roentgenogram was obtained every six months (13).
Statistical analysis. Continuous variables are expressed as the means±standard deviation, and were compared using the Mann–Whitney U-test. Categorical variables were compared using the chi-squared test or Fisher's exact test. The survival rate was calculated by the Kaplan–Meier method, and the statistical analysis of the differences in survival curves was carried out by a log-rank test. All statistical analyses were performed using the SPSS computer software package, version 10.0 for Windows (SPSS, Inc., Chicago, IL USA). Probability (p) values <0.05 were considered to be statistically significant.
Results
Clinicopathological features of patients with MNHCC. The clinicopathological findings are summarized in Table I. Out of the 107 patients with MNHCC, anatomical resection was performed in 81(75.7%). Anatomical resection with combination of partial hepatectomy was performed in 18(22.2%) of these 81 patients.
Planned reduction hepatectomy, followed by 5-fluorouracil arterial infusion and interferon therapy was performed in 27 (25.2%). Out of the remaining 80 patients, 9 (11.3%) received adjuvant transarterial administration of doxorubicin combined with lipiodol. Thirteen patients (16.3%) received adjuvant hepatic artery infusion of 5-fluorouracil and cisplatin. Recurrence of HCC was detected in 51 (63.8%) patients, with a median disease-free survival period of 13 months (range=2-106 months). Extrahepatic recurrence developed in 11 patients (13.8%), and the affected tissues were the lungs (6 patients), bones (4 patients), lymph nodes (2 patients) and adrenal gland (1 patient). Of the 51 patients with recurrence, 8 patients underwent a second hepatectomy, 1 patient underwent resection of the adrenal gland and 1 patient underwent lymph node dissection. Three patients were free from disease after multi-disciplinary therapy for recurrence.
The clinical features of 107 patients with multinodular hepatocellular carcinoma.
Survival outcomes. During the 19-year study period, the median follow-up time was 36.5 months (range=2-258 months). The 3- and 5-year overall survival rates of patients with MNHCC were 62.0% and 38.1%. The 3- and 5-year remnant liver recurrence-free survival rates of patients with MNHCC were 43.8% and 30.5%.
Prognostic factors for patients with multinodular hepatocellular carcinoma after hepatectomy.
Prognostic factors impacting survival. Table II shows the results of the univariate and multivariate analyses of survival for the 107 patients after liver resection for MNHCC, according to various prognostic parameters. In the present study, significant unfavorable prognostic factors included the presence of four or more tumors, tumors 5 cm or larger, the presence of portal vein invasion, intrahepatic metastases, a higher level of preoperative serum AFP (≥400 ng/ml) and a lower preoperative serum albumin level (≤3.5 mg/dl). Among the host factors, age, gender and the hepatitis virus status did not have a significant impact on survival. The distribution of the tumors and Union for International Cancer Control stage also did not have a major prognostic impact. With respect to treatment-related factors, the surgical procedure, including whether intraoperative ablative therapy was performed, and the surgical margins, did not influence on survival outcome. The use of neoadjuvant or adjuvant treatment for patients who underwent liver resection did not have a significant impact on survival. In the multivariate analysis, the presence of four or more tumors and a lower serum albumin level were unfavorable prognostic factors that affected the long-term survival (Table II).
The overall survival after liver resection according to the presence or absence of portal vein invasion for patients with four or more.
The results of the univariate analysis of survival for patients who underwent liver resection of four or more tumors are shown in Table III. The presence of portal vein invasion had a significant impact on the long-term outcomes. The overall survival rates in patients who underwent liver resection of tumors with portal vein invasion (34.7% at three years, 0% at five years; median survival, 26 months) were significantly worse than those in patients without invasion (76.2% at three years, 25.4% at five years; median survival, 44 months; p=0.0035) (Figure 1). Patients with a preoperative serum albumin level ≤3.5 mg/dl showed a significantly worse overall survival than those with an albumin level greater than 3.5 mg/dl (p=0.0456).
With respect to the preoperative patient variables, a platelet count less than 105/mm3 tended to be an adverse prognostic factor for the overall survival (p=0.0906). By the multivariate analysis, portal vein invasion was identified to be an independent unfavorable prognostic factor that affected the long-term survival (Table IV). In patients (N=18) who underwent liver resection of four or more tumors without portal vein invasion, the overall survival results in patients with a preoperative serum albumin level greater than 4.0 mg/dl and platelet count greater than 105/mm3 was significantly higher than in the patients with albumin level of less than 4.0 mg/dl or a platelet count lees than 105/mm3 (p=0.049) (data not shown).
Prognostic factors for patients with four or more multinodular hepatocellular carcinomas after hepatectomy identified by a univariate analysis.
Discussion
The Barcelona Clinic Liver Cancer staging system restricts hepatectomy to patients with a single HCC nodule less than 2 cm and well-preserved liver function (i.e. Child–Turcotte–Pugh class A) (14). Moreover, resection is recommended only for patients without clinical evidence of portal hypertension and with normal bilirubin levels. In such patients, resection is associated with almost no risk of posthepatectomy liver failure and an excellent long-term survival (7, 15). However, recent advances in liver surgery have rapidly improved the outcomes of surgery, especially in eastern Asia. In our series, liver resection was associated with a five-year overall survival rate of 38.1% in patients with MNHCC. The overall survival of these patients was comparable to the previous results after resection (24%-58% for patients with MNHCC) (2-4, 6, 16-18). In patients with two or three nodules, liver resection showed a good performance, with actuarial 5-year survival of 53.2% (data not shown).
Prognostic factors for patients with four or more multinodular hepatocellular carcinomas after hepatectomy identified by a multivariate analysis.
To identify which sub-group of patients would benefit the most from surgery, we investigated all of the patients who underwent hepatectomy for MNHCC. We found that those with four or more tumors or with a lower serum albumin level (≤3.5 mg/dl) had a significantly poorer outcome by the multivariate analysis. The predictors of survival for MNHCC were similar to those reported for overall HCCs. Basically, the predictors could be classified into two categories. The first category was related to tumor factors, such as AFP and des-gamma-carboxy prothrombin levels, tumor size, presence of microscopic vascular invasion and positive surgical margins. The other category was related to the underlying liver disease, and included factors such as the albumin and aspartate aminotransferase (AST) levels, viral hepatitis status and the Child–Pugh class (17, 18).
In the sub-group analysis of patients with four or more HCCs, we confirmed the prognostic significance of portal vein invasion. However, 18 out of 44 patients (40.9%) with four or more HCCs had no evidence of portal vein invasion and led to 3- and 5-year survival rates of 76.2% and 25.4%, respectively. Of these 18 patients, those with well-preserved liver functions had significantly longer survival times (median survival time=83 months) than those without (median survival time=37 months). In contrast, patients with unresectable HCCs who are treated with medical or best supportive care have a median survival of 9-12 months, with one- and three-year survival rates of 44-55% and 13-26%, respectively (3, 8, 19, 20). Furthermore, our study demonstrated that hypoalbuminemia was related to postoperative liver failure and a poor long-term outcome. Based on these findings, we believe that hepatic resection for patients with four or more tumors without portal vein invasion and with a well-preserved liver function is a justifiable therapeutic option for MNHCC.
Several studies have demonstrated that the serum albumin level was a risk factor for overall survival after hepatectomy for HCC (21, 22). Okabayashi and colleagues demonstrated that perioperative administration of a branched-chain amino acid (BCAA) for patients with HCC is clinically beneficial for reducing the morbidity associated with postoperative complications (23). Our previous study also reported that BCAA supplementation after hepatectomy promoted rapid improvement in protein metabolism and inhibited progression to liver cirrhosis (24). Muto et al. reported that administration of BCAA prevented the occurrence of HCC in cirrhotic patients (25). However, whether pre- or postoperative nutritional support for patients with HCC can directly influence the long-term survival remains unconfirmed.
Liver transplantation is generally considered the treatment of choice for patients with multiple small HCCs, because it can resolve both life-threatening complications, HCC and underlying liver cirrhosis (26). There have been a limited number of liver transplants for multiple HCCs in Japan. Therefore, we could not compare the efficacy of liver transplantation and hepatic resection for patients with multiple HCCs in our study.
In general, platelet count, which reflects the severity of portal hypertension, is a significant predictor of survival. Several studies have shown that the platelet count is a risk factor for carcinogenesis from chronic hepatitis and for patient survival and recurrence of HCC after treatment, including hepatectomy (27, 28). In the present study, neither the recurrence rate nor the rate of repeat hepatectomy as a curative treatment for remnant liver recurrence was significantly different between patients with a platelet count ≥105/mm3 and those with a platelet count less than 105/mm3 (data not shown). These data suggest that preservation of the platelet count, which reflects the liver function, might be able to improve the long-term survival of patients after aggressive liver resection
One of the major limitations of the present study was the lack of patients who received chemoembolization for MNHCC. Transcatheter arterial chemoembolization (TACE) is indicated for patients with multifocal, asymptomatic liver tumors, with Child A-B liver function, without extrahepatic spread (29). Several studies of TACE for HCC reported that the five-year survival rates were only 6%-19% (30-32). A recent meta-analysis by Llovet and Bruix of all the randomized clinical trials available in the literature showed that TACE provided a short-term (2-year) survival benefit (odds ratio=0.42) compared with the control group (33). Whether TACE can provide a long-term survival benefit remains unclear, and whether TACE can provide better outcomes than resection should be examined in future studies.
In conclusion, liver resection might be the optimal treatment for patients with four or more tumors if they have good liver function and no portal vein invasion.
Acknowledgements
We thank Dr. Nakagawa and Dr. Yabushita for their help during data collection. We also thank Dr. Masataka Taguri for his cooperation with the statistical analysis.
Footnotes
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Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received January 12, 2014.
- Revision received February 27, 2014.
- Accepted February 28, 2014.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
