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© 2000 American Society for Clinical Oncology Long-Term Prognosis After Resection of Hepatocellular Carcinoma Associated With Hepatitis B–Related CirrhosisFrom the Centre of Liver Diseases and Departments of Surgery and Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong, China. Address reprint requests to Ronnie Tung-Ping Poon, MD, Department of Surgery, Queen Mary Hospital, 102 Pokfulam Rd, Hong Kong, China; email poontp{at}hkucc.hku.hk
PURPOSE: The optimum management of hepatocellular carcinoma (HCC) associated with cirrhosis has not yet been clarified. Very few data are available in the literature regarding the prognosis after resection of HCC associated with hepatitis B virus (HBV)–related cirrhosis. This study evaluated the long-term results and prognostic factors after resection of HCC complicating HBV-related cirrhosis. PATIENTS AND METHODS: One hundred forty-six patients with HBV-related Child’s A or B cirrhosis who had undergone resection of HCC over a 10-year period were prospectively studied for long-term results. They were compared with 155 noncirrhotic patients with HBV-related HCC resected in the same period.
RESULTS: The overall survival results of cirrhotic patients after resection of HCC were comparable to those of noncirrhotic patients (5-year survival, 44.3% v 45.6%, respectively; P = .216), but the former group had significantly smaller tumors. Stratified according to tumor size, the survival results were similar between cirrhotic and noncirrhotic patients with tumors CONCLUSION: The prognosis after resection of HCCs less than 5 cm in patients with compensated HBV-related cirrhosis was comparable to that of noncirrhotic patients, which suggests that surgical resection may be considered a first-line treatment for these patients. Patients with underlying active hepatitis as indicated by a high preoperative transaminase level are less favorable candidates for resection. Further studies are needed to define the relative roles of resection and transplantation for HCC associated with hepatitis B cirrhosis.
HEPATIC RESECTION is widely regarded to be the treatment of choice for hepatocellular carcinoma (HCC) in the absence of cirrhosis.1 The role of surgical resection for HCC associated with cirrhosis is more controversial. High operative mortality rates have been reported previously,2-5 but more recent reports have demonstrated low mortality rates after resection of HCC in cirrhotic patients.6-8 Our own experience has shown that even major hepatectomy, with modern surgical management, could be well tolerated in cirrhotic patients.8 To fully justify the role of hepatic resection for HCC in cirrhotic patients, the long-term prognosis also needs to be clarified. The prognosis after resection of HCC complicating cirrhosis has been addressed by several studies from European countries and Japan, which mainly included patients with hepatitis C virus (HCV) infection or alcoholism.2,6,7,9-16 The prognosis after resection of HCC complicating cirrhosis resulting from hepatitis B virus (HBV) has not been well documented. This study evaluated the long-term survival results and prognostic factors of resection of HCC complicating HBV-related cirrhosis, with an aim to define the role of surgical resection in the treatment of patients.
Between January 1989 and December 1998, a total of 376 Chinese patients underwent curative resection of HCC at the Department of Surgery of Queen Mary Hospital in Hong Kong. Curative resection was defined as complete macroscopic removal of the tumor, including tumors with microscopic positive margin. Of these patients, 301 tested positive for hepatitis B surface antigen, eight were positive for antibody to HCV, three were seropositive for both HBV and HCV, and 49 were seronegative for both HBV and HCV; in the remaining 15, viral status was not established. Among the 301 patients with HBV infection alone, 146 had cirrhosis confirmed by histologic examination. Of the 155 patients who did not have underlying cirrhosis, 122 had histologic features of chronic hepatitis and 33 had normal livers. Hepatic resection was offered for resectable tumors irrespective of tumor size. Assessment of resectability was based on radiologic findings from chest x-ray, ultrasonography, computed tomography, and hepatic arteriography. Extrahepatic spread, bilobar multifocal disease, inferior vena cava, and main portal vein thrombosis were regarded as contraindications for resection. Preoperative liver function status was assessed by Child’s grading, liver biochemistry status, and indocyanine green (ICG) clearance test.17 Child’s C cirrhosis was considered an absolute contraindication for any hepatic resection, and we would not consider any major resection for patients with Child’s B cirrhosis. Patients with Child’s B cirrhosis with small HCCs amenable to minor resection were offered surgical treatment. An ICG retention at 15 minutes (ICG R-15) of less than 14% was considered safe for any major resection.17 The surgical techniques and perioperative care used in this study have been described previously in detail.18 Depending on the size and location of the tumor, limited resection was performed whenever possible, provided that a clear resection margin could be safely obtained. No neoadjuvant therapy was given in our center, but seven noncirrhotic (4.5%) and six cirrhotic patients (4.1%) had received transarterial chemoembolization (TACE) before referral to us. Fifteen noncirrhotic (9.7%) and 12 cirrhotic patients (8.2%) recruited in a randomized trial received postoperative adjuvant chemotherapy involving a combination of intravenous epirubicin and transarterial lipiodolized cisplatin.19 Otherwise, no adjuvant therapy was given. All patients were observed prospectively for postoperative recurrence with assessment by serum alpha-fetoprotein level, chest x-ray, and ultrasonography or computed tomography 1 month after operation and every 3 months thereafter. Patients with recurrence were managed aggressively with a multimodality approach that included reresection for resectable recurrence, TACE or percutaneous ethanol injection (PEI) for unresectable intrahepatic recurrence, and systemic chemotherapy that included intravenous epirubicin for selected patients with extrahepatic metastatic disease.20 Treatment decision was based on the pattern of recurrence and liver function reserve. Preoperative baseline clinical and laboratory parameters, intraoperative data, postoperative course, pathologic features of resected specimens, and follow-up results all have been prospectively collected in a computerized database since 1989. In the first part of the study, the overall and disease-free survival results of patients with underlying HBV-related cirrhosis were compared with those of patients with HBV-related HCC but no associated cirrhosis. In-hospital deaths after operation were not included in computing the disease-free survival rates. Tables 1, 2, and 3 show respectively the clinical, operative, and histopathologic data of patients with cirrhosis compared with noncirrhotic patients. Cirrhotic patients had significantly worse liver function parameters (platelet count, prothrombin time, and ICG R-15) but more favorable tumor status in terms of tumor size and pathologic tumor-node-metastasis (pTNM) stage. A higher proportion of cirrhotic patients underwent minor resection, but even in this group, the majority (58%) underwent major hepatectomy. There were no significant differences in blood loss, transfusion, morbidity, and hospital mortality rates between the two groups.
In the second part of the study, the prognostic factors for overall long-term survival after resection of HCC among patients with HBV-related cirrhosis were elucidated by univariate and, then, multivariate analyses. The following were analyzed: twelve clinical factors (sex, age  or > 60 years, subclinical or symptomatic presentation, Child’s grade A or B, serum bilirubin level or > 20 µmol/L, serum albumin level or > 35 g/L, platelet count or > 100 x 109 platelets/L, prothrombin time or > 12.5 seconds, serum AST level or > 100 IU/L, serum ALT level or > 100 IU/L, ICG R-15 or > 14%, and serum alpha-fetoprotein level or > 20 ng/mL), five operative or treatment factors (major or minor resection, blood loss or > 1.5 L, perioperative transfusion, preoperative chemoembolization, and postoperative adjuvant chemotherapy), and six pathologic factors (tumor size or > 5 cm, solitary or multiple tumors, macroscopic resection margin or > 1 cm, venous invasion, tumor differentiation, and encapsulation) of potential prognostic significance.
Regarding statistical analysis, continuous data are expressed as mean ± SD. Comparisons between groups were performed using the
Overall Survival Results The cumulative overall survival curves after resection of HCC in patients with and without cirrhosis are shown in Fig 1. There was no significant difference in the survival rates between cirrhotic (1-year, 75.4%; 3-year, 50.5%; 5-year, 44.3%; 10-year, 29.7%; median survival time, 43.5 months) and noncirrhotic (1-year, 79.7%; 3-year, 58.7%; 5-year, 45.6%; 10-year, 36.7%; median survival time, 50.4 months) patients (P = .216). A further analysis, after subdividing the noncirrhotic group according to liver histology, did not reveal any significant differences in the survival rates between cirrhotic patients and those with normal liver histology (1-year, 68.9%; 3-year, 56.7%; 5-year, 44.1%; 10-year, 35.3%; median survival time, 42.3 months; P = .908) or those with chronic hepatitis (1-year, 81.4%; 3-year, 60.7%; 5-year, 45.1%; 10-year, 38.7%; median survival time, 50.6 months; P = .125).
By the time of analysis, 66 patients (45%) in the cirrhotic group and 57 (37%) in the noncirrhotic group had died, including those who died in the hospital (after operation). Forty-three patients in each group died of tumor recurrence. Among cirrhotic patients, only 10 late deaths were related to cirrhotic complications such as variceal bleeding and spontaneous bacterial peritonitis. Because there was a difference in the distribution of tumor size and pTNM stage between the two groups, separate analyses were performed to assess the prognosis after stratification according to these two parameters (Table 4). The only significant difference was observed in patients who had tumors greater than 5 cm, with a worse survival outcome in the cirrhotic group (P = .034). A further analysis revealed that the survival results were comparable between cirrhotic and noncirrhotic patients who underwent minor resection for tumors greater than 5 cm (13 and 12 patients, respectively; 5-year survival rate, 38.7% v 44.4%; P = .200) but were worse in cirrhotic compared with noncirrhotic patients after major resection for tumors greater than 5 cm (65 and 102 patients, respectively; 5-year survival, 27.1% v 38.6%; P = .027).
Disease-Free Survival Results Figure 2 shows the disease-free survival curves of cirrhotic and noncirrhotic patients. The disease-free survival rates in cirrhotic patients (1-year, 51.5%; 3-year, 30.2%; 5-year, 22.0%; 10-year, 19.6%; median disease-free survival time, 12.4 months) were lower compared with those of noncirrhotic patients (1-year, 57.2%; 3-year, 41.9%; 5-year, 35.0%; 10-year, 35.0%; median disease-free survival time, 18.3 months), but the differences were not statistically significant (P = .091). By the time of analysis, recurrent disease had developed in 82 cirrhotic (60%) and 76 noncirrhotic patients (51%). In both groups, the majority of recurrent tumors occurred in the liver remnant (71 and 61 patients, respectively). Treatment modalities for recurrence were similar between cirrhotic and noncirrhotic groups (reresection, four and five patients; TACE, 44 and 39 patients; PEI, eight and seven patients; and systemic chemotherapy, 12 and 14 patients, respectively).
Table 5 shows the results of analyses of disease-free survival after stratification according to tumor size and pTNM stage, respectively. Cirrhotic patients with tumors 5 cm or stage I tumors had significantly worse disease-free survival rates compared with noncirrhotic patients with tumors of similar size or stage. No significant differences were observed between the two groups among patients with tumors of size greater than 5 cm or of stage II, IIIA, or IVA.
Prognostic Factors for Overall Survival Of a total of 23 clinical, treatment, and pathologic factors, nine were found to have prognostic influence by univariate analysis (Table 6). Preoperative serum AST level more than 100 IU/L (risk ratio [RR], 3.2661; 95% confidence interval [CI], 1.5339 to 6.9544; P = .004), perioperative transfusion (RR, 2.4670; 95% CI, 1.1895 to 5.1164; P = .015), and venous invasion (RR, 2.0822; 95% CI, 1.2594 to 3.1394; P = .001) were identified to be independent adverse prognostic factors of survival by multivariate analysis.
This is, to our knowledge, the first study that investigates in detail the long-term prognosis and prognostic factors after resection of HCC associated specifically with HBV-related cirrhosis. The 5-year survival rate in the cirrhotic group (44%) was comparable to that recently reported in some Western and Japanese studies comprising mainly patients with HCC complicating HCV-related cirrhosis7,13 and was better than 5-year survival rates of 10% to 30% reported in several other studies.10,12,14,15 However, the 5-year disease-free survival rate of this study was only 22%. Because effective adjuvant therapy to prevent recurrence is not yet available, aggressive management of recurrence is important to prolong survival time after resection of HCC. The overall survival results were similar between cirrhotic and noncirrhotic patients in this study. However, it should be noted that the former group had a significantly higher proportion of small tumors. An elaboration of the survival results stratified according to tumor size and stage helps define more precisely the role of surgical resection for HCC complicating HBV-related cirrhosis. In recent years, liver transplantation has been established as a treatment option for HCCs less than 5 cm in cirrhotic patients.22 Some centers have advocated transplantation as the treatment of choice for small HCCs complicating cirrhosis, even for patients with Child’s A cirrhosis, because of the poor survival results obtained with surgical resection.10,15,23 From recent studies that comprised mainly patients with HCV infection, 5-year survival rates after transplantation for HCCs less than 5 cm in cirrhotic patients were 60% to 70%, regardless of Child’s status.7,22,23 Previously, transplantation for HCC complicating HBV-related cirrhosis has been associated with poor outcome resulting from viral reinfection in the graft,24,25 but recently, as a result of the availability of effective antiviral therapy, it has become a viable option.26 Hence, an evaluation of the results of resection of HCC complicating HBV-related cirrhosis is important, in that it can provide a rationale for the choice of treatment for these patients. The overall survival results in our cirrhotic patients with HCCs less than 5 cm were not different from those of noncirrhotic patients, and the 5-year cumulative survival rate (61%) was comparable to that reported in studies of transplantation for HCCs less than 5 cm associated predominantly with HCV-related cirrhosis.7,22,23,27 Our data also show that, stage by stage, there were no significant differences in the overall survival rates between cirrhotic and noncirrhotic patients. No data are available to date on the long-term survival outcome after transplantation for HCC associated with HBV-related cirrhosis using new antiviral therapy. When such data become available, our data could be useful for comparison to define the relative roles of these two treatment options. Notwithstanding, our findings have justified the use of surgical resection for HCCs less than 5 cm in patients with compensated HBV-related cirrhosis. With the severe shortage of organ donors in Eastern countries, surgical resection probably should be considered the first-line treatment for these patients. However, to ensure optimum outcome, it should be offered only in institutions with surgeons who are dedicated to the surgical treatment of HCC. Our study did not show a significant difference in the survival rates between patients with Child’s A and those with Child’s B cirrhosis, but the number of patients with Child’s B cirrhosis was too small to allow a valid interpretation of the role of hepatic resection in these patients. A recent Japanese study has reported favorable results after resection of small HCCs complicating Child’s B cirrhosis.16 It seems reasonable to offer resection in selected patients with Child’s B cirrhosis with small HCCs amenable to minor resection. However, liver transplantation is now widely accepted as the treatment of choice for small HCCs associated with Child’s B or C cirrhosis.28 We regard Child’s C cirrhosis as a contraindication to hepatic resection, irrespective of the tumor size. In patients with Child’s B cirrhosis, we would not consider resection for any tumor that required a major hepatectomy. Among our cirrhotic patients with tumors greater than 5 cm, the survival results were significantly worse compared with those of noncirrhotic patients. It is clear that surgical resection is not an ideal therapeutic option for these patients. The unfavorable survival results may even suggest that these patients should not be considered as surgical candidates. Unfortunately, no other effective treatment is available for this group of patients. PEI is contraindicated because of the tumor size, and results with TACE for large HCCs associated with cirrhosis are unsatisfactory.29 Liver transplantation is also generally considered unjustified for large HCCs because of poor outcome.9,10,23,27,28,30 Hence, surgical resection may be the only reasonable option for patients with large but resectable tumors associated with Child’s A cirrhosis. A further analysis revealed that a worse outcome in cirrhotic patients with tumors greater than 5 cm was observed only in those who had undergone major resection, which suggests that minor resection may be desirable even for large tumors in cirrhotic liver, if technically possible. It is well accepted that limited resection is preferable for small HCCs in patients with cirrhosis.31 With the high incidence of intrahepatic recurrence associated with large HCCs, the preservation of liver function reserve would allow further treatment such as TACE to be possible should recurrence develop. Some authors have reported using preoperative TACE to downstage the tumor before resection for large HCCs in cirrhotic patients, and this may improve the survival in these patients.32 Neoadjuvant TACE or chemotherapy has also been used to improve the outcome of transplantation for large HCCs greater than 5 cm in some centers.32,33 The optimum management for cirrhotic patients with large HCCs remains to be clarified by further studies. The elucidation of prognostic factors provides additional information that is useful in identifying the appropriate surgical candidates among patients with HCC associated with HBV-related cirrhosis. An elevated serum AST level of more than 100 IU/L was found to be an independent adverse prognostic factor. An increase in transaminase levels indicates associated hepatitis activity in the cirrhotic liver, which has been shown to increase the risk of recurrence, although it remains uncertain whether it promotes multicentric recurrence or intrahepatic metastasis.34 Hence, cirrhotic patients with grossly elevated preoperative transaminase levels are not favorable candidates for surgical resection. New antiviral therapies such as lamivudine, which is effective in suppressing hepatitis activity associated with chronic HBV infection,35 may be useful as adjunctive treatment before and after hepatectomy in such patients. Alternatively, liver transplantation may be a more appropriate option for these patients. In conclusion, this study shows that the long-term prognosis after resection of HCCs less than 5 cm in patients with compensated hepatitis B cirrhosis was comparable to that in noncirrhotic patients. With the current shortage of organ donors, surgical resection may be considered the first-line treatment for these patients. Less favorable outcome was obtained in cirrhotic patients with large HCCs, for whom the optimum management remains to be clarified. With the availability of effective antiviral therapy, further studies are required to define the roles of resection and transplantation in the management of HCC associated with hepatitis B cirrhosis.
Supported by the Croucher Foundation and Development Fund for Area of Excellence, University of Hong Kong, Hong Kong, China.
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Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693-699, 1996 23. Figueras J, Jaurrieta E, Valls C, et al: Survival after liver transplantation in cirrhotic patients with and without hepatocellular carcinoma: A comparative study. Hepatology 25:1485-1489, 1997[Medline] 24. Wong PYN, McPeake JR, Portmann B, et al: Clinical course and survival after liver transplantation for hepatitis B virus infection complicated by hepatocellular carcinoma. Am J Gastroenterol 90:29-34, 1995[Medline] 25. Philosophe B, Greig PD, Hemming AW, et al: Surgical management of hepatocellular carcinoma: Resection or transplantation? J Gastrointest Surg 2:21-27, 1998[Medline] 26. Grellier L, Mutimer D, Ahmed M, et al: Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis. Lancet 348:1212-1215, 1996[Medline] 27. Klintmalm GB: Liver transplantation for hepatocellular carcinoma: A registry report of the impact of tumor characteristics on outcome. Ann Surg 228:479-490, 1998[Medline]
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Schlitt HJ, Neipp M, Weimann A, et al: Recurrence patterns of hepatocellular and fibrolamellar carcinoma after transplantation. J Clin Oncol 17:324-331, 1999 31. Kanematsu T, Takenaka K, Matsumata T, et al: Limited hepatic resection effective for selected cirrhotic patients with primary liver cancer. Ann Surg 199:51-56, 1984[Medline] 32. Majno PE, Adam R, Bismuth H, et al: Influence of preoperative transarterial lipiodol chemoembolization on resection and transplantation for hepatocellular carcinoma in patients with cirrhosis. Ann Surg 6:688-703, 1997 33. Stone MJ, Klintmalm GB, Polter D, et al: Neoadjuvant chemotherapy and liver transplantation for hepatocellular carcinoma: A pilot study in 20 patients. Gastroenterology 104:196-202, 1993[Medline] 34. Shirabe K, Takenaka K, Taketomi A, et al: Postoperative hepatitis status as a significant risk factor for recurrence in cirrhotic patients with small hepatocellular carcinoma. Cancer 77:1050-1055, 1996[Medline]
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Lai CL, Chien RN, Leung NW, et al: A one-year trial of lamivudine for chronic hepatitis B: Asia Hepatitis Lamivudine Study Group. N Engl J Med 339:61-68, 1998 Submitted August 2, 1999; accepted November 12, 1999. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test with Yates correction (or Fisher’s exact test, when appropriate) for nominal variables and the unpaired t test for continuous variables. Cumulative survival rates were computed according to the Kaplan-Meier method and compared between groups by the log-rank test. Significant prognostic factors found by univariate analysis were entered into a multivariate analysis by Cox proportional hazards model. All analyses were performed using statistical software (SPSS, Inc, Chicago, IL). P < .05 was considered statistically significant. 
