Impact of Antiviral Therapy on the Survival of Patients After Major Hepatectomy for Hepatitis B Virus–Related Hepatocellular Carcinoma

Objectives  To assess whether commencement of antiviral therapy after hepatectomy improves the prognosis of hepatocellular carcinoma (HCC) in preoperatively antiviral-naive patients with chronic hepatitis B virus (HBV) infection.

Design  Retrospective analysis of a prospectively collected database.

Setting  University teaching hospital.

Main Outcome Measures  Disease-free and overall survival rates.

Results  One hundred thirty-six patients received major hepatectomy for HBV-related HCC from September 1, 2003, through December 31, 2007. Among them, 42 patients received antiviral therapy (treatment group) after hepatectomy, whereas 94 did not (control group). Patient demographics, preoperative liver function, tumor characteristics, and liver function at the time of tumor recurrence were comparable between the 2 groups. Disease-free and overall survival rates were significantly prolonged in the treatment group. The 1-, 3-, and 5-year overall survival rates in the treatment group were 88.1%, 79.1%, and 71.2%, respectively; in the control group, 76.5%, 47.5%, and 43.5%, respectively (P = .005). The 1-, 3-, and 5-year disease-free survival rates in the treatment group were 66.5%, 51.4%, and 51.4%, respectively; in the control group, 48.9%, 33.8%, and 33.8%, respectively (P = .05). Subgroup analysis stratified against tumor stage and major vascular invasion showed that posthepatectomy antiviral treatment conferred a significant survival benefit in stages I and II tumors or HCCs without major venous invasion.

Conclusions  Antiviral therapy improves the prognosis of HBV-related HCC. It should be considered after hepatectomy for HBV-related HCC, especially in early-stage tumors.

Chronic hepatitis B virus (HBV) infection has become a global public health problem, with 350 million carriers worldwide.¹ In areas where HBV is highly endemic, such as the Asia-Pacific region, chronic HBV infection is present in 80% to 90% of patients with hepatocellular carcinoma (HCC). Even in Western countries where HBV infection is less prevalent, it is still found in 16% to 60% of patients with HCC.² Several studies have shown that, with the use of lamivudine, a nucleoside analogue, the risk of development of HCC and other cirrhotic-related complications was significantly reduced in those with chronic infection^3-5 and even in cirrhotic patients.⁶ However, there is a scarcity of data on the role of antiviral therapy after curative treatment for HCC.^7-9 Hepatectomy remains a standard curative treatment for HCC, but tumor recurrence is common, with approximately 50% of patients developing recurrent disease within 5 years.^10-12 Further surgical treatment was often limited by impaired function of the remnant liver,¹³ and it remains uncertain whether antiviral therapy after initial treatment for HCC would prevent the remnant liver function from further deterioration and therefore increase the chances of these patients for future treatment. The aim of our study was to evaluate whether antiviral therapy after hepatectomy would improve the overall survival of patients with HBV-related HCC.

From September 1, 2003, through December 31, 2007, 379 patients underwent hepatectomy for HCC in the Department of Surgery at our institution. Among them, 136 patients had chronic HBV infection. Preoperative clinical data, including age; sex; Child-Pugh class; serum levels of bilirubin, alanine aminotransferase, aspartate aminotransferase, albumin, and α₁-fetoprotein (AFP); platelet count; international normalized ratio; indocyanine green retention value; and the clinicopathological characteristics of the tumor, were retrieved from our prospectively collected database.

The diagnostic criteria for HCC in our center were as follows: (1) typical abnormality with arterial enhancement and contrast washout in the portal venous phase in contrast-enhanced computed tomography or magnetic resonance imaging and/or (2) an elevated serum AFP level of greater than 400 ng/mL (to convert to micrograms per liter, multiply by 1). Needle tumor biopsy was generally avoided in resectable cases to avoid the risk of needle tract seeding of tumor cells. The diagnosis of HCC was confirmed histologically in the resected specimen. The same diagnostic criterion was applied to define intrahepatic tumor recurrence. Major vascular invasion was defined as tumor thrombosis inside the major branch of the portal vein or hepatic vein macroscopically. The American Joint Committee on Cancer (AJCC) staging system for HCC was used in this study.¹⁴

All required procedures were performed by a single team of hepatobiliary surgeons (A.C.Y.C., K.S.H.C., W.K.Y., S.C.C., R.T.P.P., C.M.L., and S.T.F.). In our center, partial hepatectomy is considered the treatment of choice for patients with Child-Pugh class A cirrhosis irrespective of the tumor size¹⁵ and in selected patients with Child-Pugh class B cirrhosis. Only patients who underwent major hepatectomy, which was defined as anatomical resection of more than 2 Couinaud segments, were selected for this study. The technical details of hepatectomy have been published previously.^16,17 After hepatectomy, all patients were transferred to the intensive care unit for postoperative monitoring and were discharged home when a full diet was tolerated and the liver function had recovered.

All patients were available for follow-up. Computed tomography of the liver was performed at 1 month after hepatectomy to confirm complete tumor clearance and then every 3 months for surveillance. Blood tests for liver biochemistry values, clotting profile, complete hematological profile, and serum AFP levels were also determined at 1 month after hepatectomy and then at 3-month intervals.

Liver biochemistry findings at the time of tumor recurrence were recorded. Special tests for serum HBV DNA level were not available until recently, and the test results were not recorded in our database. Patients who had resectable intrahepatic recurrence and adequate liver function reserve were offered additional resection or radiofrequency ablation. For patients with adequate liver function reserve but anatomically nonresectable intrahepatic recurrence, transarterial chemoembolization was offered.

Initiation of antiviral therapy within 12 months after hepatectomy was based on the following criteria: (1) alanine aminotransferase level more than 2 times the upper limit of reference values, with or without a serum HBV DNA level greater than 10⁵ copies/mL; (2) serum alanine aminotransferase level greater than the upper limit of the reference value but less than 2 times the value, with serum HBV DNA level greater than 10⁵ copies/mL; or (3) liver biochemistry findings within the reference range, with serum HBV DNA levels greater than 10⁵ copies/mL only. None of the patients developed tumor recurrence before the initiation of antiviral therapy. During the early study period, lamivudine (100 mg/d) was used as our first-choice antiviral treatment; however, in recent years, we have used entecavir (0.5 mg/d) because of its high potency against HBV DNA activity. Patients who received antiviral therapy after hepatectomy were categorized as the treatment group, and those who did not were categorized as the control group.

Continuous variables were expressed in median (interquartile range) and compared using the Mann-Whitney test. Categorical variables were compared with the χ² test or Fisher exact test. We used the Kaplan-Meier method to estimate the overall and disease-free survival rates of the 2 study groups and compared them using the log-rank test. Disease-free survival was defined as the date after hepatectomy to the date of tumor recurrence or death. Overall survival was defined as the date after hepatectomy to the date of death of all causes. The last census date for this study was June 30, 2009. Twelve clinical variables were selected for univariate and then multivariate analysis by the Cox proportional hazards model to identify predictive factors for overall survival. P ≤ .05 was considered statistically significant. Statistical analysis was performed using a commercially available computer software program (SPSS, version 11.0; SPSS, Inc, Chicago, Illinois).

Antiviral therapy was started in 42 patients (lamivudine in 38 and entecavir in 4) at a median of 8 days (range, 0-12 months) after hepatectomy, whereas 94 patients did not receive any antiviral treatment. Table 1 lists the clinical demographics of our cohorts. There was no significant difference in the age, distribution of sex, and the incidence of screening-detected HCC between the 2 groups of patients. There were significantly more patients with Child-Pugh class B cirrhosis in the control group, but the preoperative liver biochemistry findings and clotting profile were largely similar between the 2 treatment groups. There was also no significant difference in the preoperative indocyanine green retention rate at 15 minutes and the proportion of patients with macroscopic cirrhosis between the groups of patients.

The pathological characteristics of HCC were similar between the patient groups (Table 2) in terms of tumor size, incidence of venous permeation, major vascular invasion, and distribution of tumor stage. Nonetheless, there was a significant prolongation of overall survival in patients given antiviral therapy after hepatectomy compared with those in the control group (Figure 1). The 1-, 3-, and 5-year overall survival rates in the treatment group were 88.1%, 79.1%, and 71.2%, respectively; in the control group, 76.5%, 47.5%, and 43.5%, respectively (P = .005). The disease-free survival was also significantly improved in the treatment group (P = .05). The 1-, 3-, and 5-year disease-free survival rates in the treatment group were 66.5%, 51.4%, and 51.4%, respectively; in the control group, 48.9%, 33.8%, and 33.8%, respectively (Figure 2).

Tumor recurrence developed in 20 patients (48%) in the treatment group and 61 patients (65%) in the control group (P = .28). Among them, 12 patients in the treatment group and 31 patients in the control group developed intrahepatic recurrence (P = .48). There was no significant difference in the serum levels of bilirubin, alanine aminotransferase, aspartate aminotransferase, or albumin or in the platelet count between groups (Table 3), suggesting that liver function was restored since the commencement of antiviral treatment after hepatectomy. For treatment of tumor recurrence, there was no significant difference in the amenability rate for a second resection or radiofrequency ablation between the treatment and control groups (5 of 16 vs 7 of 45 patients; P = .47).

Univariate analysis of the 12 baseline clinical variables revealed that the use of antiviral therapy, tumor size of no larger than 5 cm, absence of major vascular invasion, serum AFP level of no more than 400 ng/mL, serum albumin level of more than 40 g/L (to convert to grams per liter, multiply by 10), and the AJCC stages I and II were significant factors that could predict overall survival (Table 4). After multivariate analysis, the use of antiviral therapy (relative risk, 0.35; 95% confidence interval, 0.18-0.70), tumor size of no more than 5 cm (1.11; 1.05-1.17), absence of major vascular invasion (2.16; 1.19-3.90), and the AJCC stages I and II (1.51; 1.15-1.98) remained independent prognostic factors that predicted long-term survival.

When stratifying patients with and without antiviral treatment according to the 3 independent prognostic factors (ie, tumor size, status of major vascular invasion, and AJCC stage), overall and disease-free survival rates were significantly improved by antiviral treatment in patients with AJCC stage I and II tumors (Figure 3A and B) or in tumors without major vascular invasion (Figure 4A and B). The 1-, 3-, and 5-year overall survival rates of patients with stages I and II tumors after posthepatectomy antiviral treatment were 100.0%, 94.4%, and 87.1%, respectively, and those of the patients without posthepatectomy antiviral treatment were 84.8%, 65.6%, and 61.9%, respectively (P = .02). The 1-, 3-, and 5-year disease-free survival rates of patients with stages I and II tumors after posthepatectomy antiviral treatment were 83.5%, 74.9%, and 74.9%, respectively, and those of the patients without posthepatectomy antiviral treatment were 69.6%, 47.9%, and 47.9%, respectively (P = .04). For patients whose tumors were without major vascular invasion, the 1-, 3-, and 5-year overall survival rates in the treatment group were 91.9%, 83.8%, and 79.2%, and those of the patients in the control group were 84.3%, 51.2%, and 48.3%, respectively (P = .004). The 1-, 3-, and 5-year disease-free survival rates for patients whose tumors were without major vascular invasion in the treatment group were 75.6%, 55.6%, and 55.6%, respectively, and those of the patients in the control group were 54.6%, 35.2%, and 35.2%, respectively (P = .04).

For stage III tumors (Figure 3C and D) or tumors with major vascular invasion (Figure 4C and D), there was no survival benefit with the use of antiviral treatment after hepatectomy.

It is a common scenario that hepatobiliary surgeons need to decide whether antiviral therapy should be commenced after hepatectomy for HCC in HBV carriers who were antiviral-naive before their initial surgical treatment. Despite a vast amount of data on the efficacy of antiviral therapy in restoring liver function and reducing the rate of progression to cirrhosis in patients with chronic HBV infection,^3,4,18-22 the evidence about the use of antiviral therapy after surgical treatment for HCC is lacking. We believe it is in the interest of the surgeons to be aware of further treatment options for the long-term management of HCC to improve the oncological outcome of hepatectomy. Our results showed that antiviral therapy after hepatectomy confers a survival benefit in patients with HBV-related HCC. In fact, on subgroup analysis stratifying patients according to the tumor stage and status of major vascular invasion, we found that overall and disease-free survivals were improved by antiviral treatment in stages I and II tumors or in tumors without major vascular invasion. On the other hand, no survival benefit was derived from using antiviral treatment after hepatectomy for stage III tumors (Figure 3C and D) or tumors with major vascular invasion (Figure 4C and D). A lack of difference in tumor recurrence rate between the 2 groups confirmed antiviral treatment to exert no direct antitumor effect, but its main therapeutic effects are to inhibit hepatitis activity and to reduce chronic inflammation in the liver remnant that would otherwise provide a favorable environment for hepatocarcinogenesis. Hepatitis activity in the nontumorous liver has been shown to be associated with tumor recurrence after hepatectomy,^23-25 especially in late recurrence.²⁶ Recent data suggested that aggressive tumor characteristics would overshadow the effect of antiviral treatment and lead to early tumor recurrence, whereas a high viral load after hepatectomy would contribute to late tumor recurrence.²⁶ This is consistent with our findings that antiviral treatment did not reduce tumor recurrence but could delay the time to develop recurrence, especially in early-stage tumors, whereas the survival impact in advanced-stage tumors was not obvious. Another potential benefit of antiviral treatment after hepatectomy is preservation of liver function reserve that would improve the chance for further surgical treatment when intrahepatic tumor recurrence has developed. Our study showed that liver function reserve in patients with antiviral treatment was not worsened at the time of tumor recurrence when compared with the control group, who had normal liver function since hepatectomy. However, in contrast to other studies, we did not show a significantly improved treatment rate for tumor recurrence⁸ because decisions for further surgical treatment were not based solely on the liver function reserve. In fact, other clinical factors, such as tumor location, tumor proximity to bile ducts or major hepatic vessels, and size of the liver remnant after additional resection, are all important factors that determine the amenability for further resection or radiofrequency ablation for tumor recurrence.

Nonetheless, there were several limitations to our study, including small sample size, retrospective analysis, and nonstandardized selection criteria to start antiviral treatment. The higher serum AFP level in the control group implied a greater tumor load that might also confound the survival benefit of antiviral treatment. Follow-up liver biochemistry data were not available in our database until tumor recurrence; therefore, it was not feasible to evaluate the effect of antiviral treatment on the remnant liver function. Furthermore, testing for serum HBV DNA level was not available in the early phase of our study, making it impossible to evaluate any correlation between the serum HBV DNA level and the survival outcome. Recent evidence²⁶ suggested that there was a correlation between serum HBV DNA level and frequency of HCC in patients with chronic HBV infection. However, it remains uncertain whether early suppression of HBV DNA level after hepatectomy for HCC would be associated with better prognosis and whether more potent antiviral agents would have a greater survival benefit. All these issues should be further investigated in a randomized controlled trial.

In conclusion, timely commencement of antiviral therapy after hepatectomy confers survival benefits in patients with HBV-related HCC who have not received antiviral therapy before their initial treatment. The efficacy of antiviral treatment appears to be more pronounced in patients with stages I and II tumors and in the absence of major vascular invasion.

Correspondence: Albert C. Y. Chan, MBBS, FRCS, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pok Fu Lam Rd, Hong Kong Special Administrative Region (acchan@hku.hk).

Accepted for Publication: April 23, 2010.

Author Contributions:Study concept and design: A. Y. C. Chan, Chok, Yuen, S. C. Chan, Poon, Lo, and Fan. Acquisition of data: A. Y. C. Chan and Poon. Analysis and interpretation of data: A. Y. C. Chan and Poon. Drafting of the manuscript: A. Y. C. Chan. Critical revision of the manuscript for important intellectual content: A. Y. C. Chan, Chok, Yuen, S. C. Chan, Poon, Lo, and Fan. Statistical analysis: A. Y. C. Chan. Study supervision: Yuen, S. C. Chan, Poon, Lo, and Fan.

Financial Disclosure: None reported.