Effects of lamivudine on outcome after liver resection for hepatocellular carcinoma in patients with active replication of hepatitis B virus

Aim:  Patients with high serum hepatitis B virus (HBV) DNA concentrations are at high risk of tumor recurrence after liver resection for HBV-related hepatocellular carcinoma (HCC).
Methods:  Among 24 patients with high serum HBV DNA concentrations who underwent liver resection for HBV-related HCC, postoperative lamivudine therapy was chosen by 14 (lamivudine group). The other 10 patients were controls.
Results:  Clinicopathologic findings did not differ between the groups. Tumor-free survival rate after surgery was significantly higher in the lamivudine than the control group ( P  = 0.0086). By univariate analysis, multiple tumors were also a risk factor for a short tumor-free survival. By multivariate analysis, lack of lamivudine therapy and multiple tumors were independent risk factors for a short tumor-free survival. In four patients YMDD mutant viruses were detected after beginning lamivudine administration; in two of them, adefovir dipivoxil was administered because of sustained serum alanine aminotransferase elevations.
Conclusion:  Lamivudine therapy improved tumor-free survival rate after curative resection of HBV-related HCC in patients with high serum concentrations of HBV DNA, although careful follow up proved necessary for the detection of YMDD mutant viruses.     

Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma

Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related HCC.     

Lamivudine versus Entecavir for Newly Diagnosed Hepatitis B Virus-Related Hepatocellular Carcinoma

Background/AimsAntiviral therapy is a key component in the management of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. However, whether the potent drug entecavir is more effective than a less potent drug, such as lamivudine, in HBV-related HCC is not clear.MethodsA retrospective cohort of 451 newly diagnosed, HBV-related HCC patients without antiviral therapy at diagnosis, who started antiviral therapy with either entecavir (n=249) or lamivudine (n=202), were enrolled.ResultsThe median survival was longer for the entecavir group than for the lamivudine group, and lamivudine use (vs entecavir) was an independent factor for mortality (hazard ratio [HR], 1.49; p=0.002). Lamivudine use (vs entecavir) was an independent risk factor for new-onset hepatic decompensation (HR, 1.67; p=0.010) in 318 patients without previous hepatic decompensation, and it was also an independent risk factor for recurrence after curative therapy (HR, 1.84; p=0.002) in 117 patients who received curative therapy. The findings were similar in a propensity score-matched cohort.ConclusionsOverall survival, decompensation-free survival, and recurrence-free survival were better in the entecavir-treated patients than in the lamivudine treated-patients, indicating that the potent antiviral drug should be the preferred choice in HBV-related HCC patients.     

Impact of antiviral therapy on post-hepatectomy outcome for hepatitis B-related hepatocellular carcinoma

The outcome after curative resection for hepatocellular carcinoma (HCC) remains unsatisfactory due to the high recurrence rate after surgery. In patients with hepatitis B virus (HBV)-related HCC, which is the majority of patients with HCC in Asia, a high viral load is a strong risk factor for HCC recurrence. It is logical to believe that antiviral therapy may improve the post-operative outcome by promoting viral clearance and hepatocyte regeneration, as well as improving residual liver volume in HCC patients with hepatitis B. However, the effect of antiviral therapy on clinical outcomes after liver resection in patients with HBV-related HCC remains to be established. There are two main groups of antiviral treatment for HBV-oral nucleos(t)ide analogues and interferon. Interferon treatment reduces the overall incidence of HBV-related HCC in sustained responders. However, side effects may limit its long-term clinical application. Nucleos(t)ide analogues carry fewer side effects and are potent in terms of viral suppression when compared to interferon and are typically implemented for patients with more advanced liver diseases. They may also improve the outcome after curative resection for HBV-related HCC. There are increasing evidence to suggest that antiviral therapy could suppress HBV, decrease the perioperative reactivation of viral replication, reduce liver injury, preserve the liver function before and after operation, and may lower the risk of HCC recurrence. After all, antiviral therapy may improve the survival after liver resection by reducing recurrence and delaying the liver damage by the virus, resulting in a higher chance of receiving aggressive salvage therapy during HCC recurrence.     

Uracil-tegafur as an adjuvant for hepatocellular carcinoma: a randomized trial

Frequent recurrence of hepatocellular carcinoma (HCC) after surgery remains a major clinical problem. This randomized controlled trial evaluated whether postoperative adjuvant therapy with oral uracil-tegafur (UFT) prevents recurrence of HCC. A total of 160 patients who underwent curative hepatic resection for HCC were randomly assigned to receive either 300 mg/day of UFT for 1 year after surgery (n = 79, UFT group) or surgery alone (n = 80, control group). The primary endpoint was recurrence-free survival, and the secondary endpoint was overall survival. Other study variables included liver function and type of recurrence. During a median follow-up of 4.8 years (range: 0.5-7.9), recurrence-free survival curves in the groups were similar (P = .87). Overall survival was slightly but not significantly worse in the UFT group than in the control group (P = .08). The rates of recurrence-free and overall survival at 5 years were 29% and 58%, respectively, in the UFT group, as compared with 29% and 73%, respectively, in the control group. The hazard ratio for recurrence in the UFT group, relative to the control, was 1.01 (95% confidence interval: 0.84-1.22, P = .87). The proportion of patients with advanced recurrence (i.e., multiple, extrahepatic, or associated with vascular invasion) was significantly higher in the UFT group (74%, 43 of 58 patients with recurrence) than in the control group (53%, 30 of 57) (P = .02). In conclusion, our results offer no evidence to support potential benefits of adjuvant chemotherapy with UFT after surgery in patients with HCC and suggest that such treatment may even worsen overall survival.     

Antiviral therapy using lamivudine and thymosin alpha1 for hepatocellular carcinoma coexisting with chronic hepatitis B infection

BACKGROUND/AIMS: To observe the recurrence and prognosis of patients with hepatocellular carcinoma (HCC) coexisting with chronic hepatitis B infection with active virus replication after receiving antivirus therapy using lamivudine and thymosin alpha1 postoperatively. METHODOLOGY: From Jan. 2000 to Dec. 2002, 33 patients with HCC coexisting chronic hepatitis B infection with active virus replication were prospectively divided into two groups: control group (n= 17) received hepatectomy only, treatment group (n= 16) received hepatectomy and lamivudine plus thymosin alpha1 therapy postoperatively. The suppression of HBV-DNA, HBeAg seroconverted rate, recurrent tumor rate and the median survival for the two groups were observed and calculated. RESULTS: For the treatment group and control group, the one-year HBV-DNA suppression rate was 100% vs. 6% (p=0.0016); HBeAg seroconverted rate was 62.5% vs. 5.9% (p=0.0157); The median recurrent time was 7.0 vs. 5.0 months (p=0.0052); The median survival period was 10.0 vs. 7.0 months (p=0.10053), respectively. CONCLUSIONS: Antivirus therapy using lamivudine and thymosin alpha1 postoperatively may suppress the HBV reaction, delay the recurrent time and prolong the survival for HCC patients coexisting with chronic HBV infection with active virus replication.     

Overexpression of cyclooxygenase-2 in noncancerous liver tissue increases the postoperative recurrence of hepatocellular carcinoma in patients with hepatitis B virus-related cirrhosis

BACKGROUND:

Many previous studies have evaluated the histopathological features of tumours as risk factors for postoperative recurrence in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). However, there have been few large studies investigating the relationship between cyclooxygenase-2 (COX-2) expression in non-cancerous regions of the liver and postoperative recurrence in the remnant liver, especially in HBV-related HCC.

OBJECTIVE:

To evaluate the significance of COX-2 expression levels in noncancerous liver regions as a prognostic indicator of HCC in patients with HBV-related cirrhosis.

METHODS:

A total of 124 patients who underwent curative resection for HCC were reviewed retrospectively. Immunohistochemistry was used to evaluate the expression of COX-2 in noncancerous liver tissue. Clinicopathological variables were compared between patients with high COX-2 expression (n=58 [COX-2-positive group]) and patients with low COX-2 expression (n=66; [COX-2-negative group]). Univariate and multivariate analyses were performed to identify factors that affected disease recurrence.

RESULTS:

There was a significant correlation between COX-2 expression and alanine aminotransferase levels and vascular invasion. The recurrence-free survival rates in the COX-2-positive group were significantly lower than the rates in the COX-2-negative group. On multivariate analysis, the overexpression of COX-2 in noncancerous liver regions was found to be an unfavourable prognostic indicator for the recurrence of HCC.

CONCLUSIONS:

The results of the current study suggest that over-expression of COX-2 in noncancerous liver regions is an independent and significant indicator predictive of early recurrence of HCC in patients with HBV-related cirrhosis.     

Low-dose intermittent interferon-alpha therapy for HCV-related liver cirrhosis after curative treatment of hepatocellular carcinoma

AIM: To assess the efficacy of low-dose intermittent interferon (IFN) therapy in patients with hepatitis C virus (HCV)-related compensated cirrhosis who had received curative treatment for primary hepatocellular carcinoma (HCC). METHODS: We performed a prospective case controlled study. Sixteen patients received 3 MIU of natural IFN- alpha intramuscularly 3 times weekly for at least 48 wk (IFN group). They were compared with 16 matched historical controls (non-IFN group). RESULTS: The cumulative rate of first recurrence of HCC was not significantly different between the IFN group and the non-IFN group (0% vs 6.7% and 68.6% vs 80% at 1- and 3-year, P = 0.157, respectively). The cumulative rate of second recurrence was not also significantly different between the IFN group and the non-IFN group (0% vs 6.7% and 35.9% vs 67% at 1- and 3-year, P = 0.056, respectively). Although the difference in the Child-Pugh classification score between the groups at initial treatment of HCC was not signifi cant, the score was signifi cantly worse at the time of data analysis in the non-IFN group than IFN group (7.19 ± 1.42 vs 5.81 ± 0.75, P = 0.0008). The cumulative rate of deviation from objects of any treatment for recurrentHCC was also higher in the non-IFN group than IFN group (6.7% and 27% vs 0 and 0% at 1- and 3-year, P = 0.048, respectively). CONCLUSION: Low-dose intermittent IFN-alpha therapy for patients with HCV-related compensated cirrhosis after curative HCC treatment was effective by making patients tolerant to medical or surgical treatment for recurrent HCC in the later period of observation.     

Determinants of early mortality and benefits of lamivudine therapy in patients with hepatitis B virus-related decompensated liver cirrhosis

Chronic hepatitis B infection (HBV) is a major health problem worldwide. The prognosis is grave for patients with HBV-related decompensated liver cirrhosis (LC). We evaluated the effectiveness and the determinants of early mortality of lamivudine treatment in patients with HBV-related decompensated LC. Thirty patients with HBV-related decompensated LC and active viral replication were treated with lamivudine 100 mg daily for a median duration of 9 months. Among these patients, five patients died within 3 months. Two patients were lost to follow-up at week 8 and 9. One patient was treated for <6 months. Twenty-two patients were treated over 6 months. Univariate analysis revealed that the total bilirubin (P = 0.008), prothrombin time (P = 0.004), Child-Turcotte-Pugh score (P = 0.005), the model of efd-stage liver disease score (P = 0.004) and stage III hepatic encephalopathy (P = 0.001) were predictive factors of early mortality. Multivariate analysis revealed that the independent factor associated with early mortality was stage III encephalopathy. Among 22 patients, liver function improved markedly after lamivudine therapy. Of the nine hepatitis B e antigen (HBeAg)-positive patients, three had HBeAg seroconversion. Two patients had YMDD mutant and virological breakthrough at 41 and 46 weeks. One of the two had hepatocellular carcinoma and died of hepatic failure at week 125; the other received adefovir and is doing well. Lamivudine appeared to have benefits in viral suppression and significant improvement in liver function in patients with HBV-related decompensated LC. As noted in prior studies, poor baseline liver function is associated with a poor prognosis in Asian patients with decompensated HBV cirrhosis treated with lamivudine.     

Hepatitis B viral load affects prognosis of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a complex disease that is dually challenging to treat due to underlying chronic liver disease in addition to the cancer itself.The prognosis of patients with HCC is determined by intrahepatic tumor status and reserved hepatic function.Hepatitis B virus(HBV)is an established major risk factor of HCC development,and HBV viral load is being increasingly recognized as a prognostic factor in the presence of established HCC.High HBV viral load may affect the prognosis of HBV-related HCC patients in several ways.First,it is associated with more frequent recurrence of HBV-related HCC after treatment.Second,it is associated with more occurrence and severity of potentially life-threatening HBV reactivation.Last,it is associated with more worsened liver function,which limits the therapeutic options for HBV-related HCC.HBV,directly or indirectly,can induce hepatocarcinogenesis.In patients with a high HBV DNA level and subsequent active hepatitis,adhesion molecules expressed on the sinusoidal cells are up-regulated and may increase intrahepatic metastasis.HCC progression after treatment can lead to a poor prognosis by reducing number of normal functioning hepatocytes.Thus,high HBV viral load can affect the prognosis of patientswith HCC by frequent recurrence after treatment for HCC and deterioration of hepatic function associated with HCC progression.Recent meta-analysis showed that antiviral treatment reduces HCC recurrence and liver-related mortality after curative therapy of HCC.Given the strong relationship between high HBV DNA load and poor survival outcome of HCC patients due to cancer progression,it is expected that long-term antiviral therapy results in the sustained HBV suppression,control of inflammation,reduction in HCC progression,and eventually in improved overall survival.     

The current role of neoadjuvant/adjuvant/chemoprevention therapy in partial hepatectomy for hepatocellular carcinoma:a systematic review

BACKGROUND:Following curative treatment for hepato-cellular carcinoma(HCC),50%-90% of postoperative death is due to recurrent disease.Intra-hepatic recurrence is frequently the only site of recurrence.Thus,any neoadjuvant or adjuvant therapy,which can decrease or delay the incidence of intra-hepatic recurrence,or any cancer chemoprevention which can prevent a new HCC from developing in the liver remnant,will improve the results of liver resection.This article systematically reviewed the current evidence of ...     

Effect of interferon therapy on first and second recurrence after resection of hepatitis C virus-related hepatocellular carcinoma

Aim: Several investigators have shown that interferon (IFN) therapy can suppress the recurrence of hepatocellular carcinoma (HCC) after curative treatment. We investigated the effect of IFN therapy on the first and second HCC recurrence following hepatic resection of hepatitis C virus (HCV)-related HCC. Methods: Subjects included 166 patients who had undergone curative resection for a single HCV-related HCC. We analyzed the outcome after initial hepatic resection and risk factors of a second HCC recurrence following treatment for the first HCC recurrence. Results: Using multivariate analysis, a non-sustained virological response (non-SVR) was significantly associated with a high incidence of first HCC recurrence. The rate of second HCC recurrence tended to be higher in the non-SVR group than in the SVR group. In the patients with recurrence of multiple tumors or who received non-curative treatment for recurrent HCC, the second HCC recurrence rates were significantly higher. Multivariate analysis demonstrated that non-curative treatment for first HCC recurrence was an independent risk factor for a second HCC recurrence. Among the patients who received curative treatment for their first HCC recurrence, the rates of second recurrence were significantly higher in the non-SVR group than in the SVR group. Multivariate analysis also revealed that SVR was independently associated with prevention of a second HCC recurrence. Conclusions: These results suggest that on first HCC recurrence, a curative treatment should be considered in order to prevent a second recurrence if possible. In addition, IFN therapy contributes to improved prognosis after curative treatment, even in patients with recurrent HCC.     

Repeated liver resection for recurrent hepatocellular carcinoma

Background and Aim: Tumor recurrence after liver resection occurs in the majority of patients with hepatocellular carcinoma (HCC). This study was conducted to clarify the safety and effectiveness of repeated liver resection as a curative option for intrahepatic HCC recurrence. Methods: Between July 1990 and January 2009, 483 patients underwent 514 curative hepatic resections for HCC in our institution. Among this collective, 27 patients underwent 31 repeated resections due to recurrent HCC (27 s resections, three third resections and one forth resection). The outcome of these patients was retrospectively reviewed using a prospective database. Results: Perioperative morbidity and mortality was 11% (three of 27) and 0%. Six patients showed multiple liver lesions, 23 underwent minor liver resections (fewer than three segments) and five patients underwent major resections (three or more segments). The majority of the patients showed no signs of chronic liver disease (16 of 27). The median tumor free margin was 1.5 mm (range: 0 to 20 mm). The median tumor diameter was 40 mm (range: 10 to 165 mm). Tumor dedifferentiations at time of tumor recurrence were not observed. The 1‐, 3‐ and 5‐year overall survival rates after second liver resection were 96%, 70% and 42%. Conclusions: Repeated liver resection is a valid and safe curative therapy option for recurrent HCC and results in significant prolongation of survival in comparison to interventional treatment strategies in selected patients. However, due to impaired liver function, multifocal intrahepatic or extrahepatic recurrence repeated resection is only feasible in a minority of patients.     

Decompensated lamivudine-resistant hepatitis B virus-related cirrhosis treated successfully with adefovir dipivoxil allowing surgery for hepatocellular carcinoma

We describe a 64-year-old man with decompensated hepatitis B virus (HBV)-related cirrhosis who became resistant to lamivudine. He was started on adefovir at 10 mg daily while continuing lamivudine therapy. Several months later, his liver function improved and subsequently his ascites disappeared. The serum HBV-DNA level became undetectable 11 months later. Twenty months after the start of additional treatment with adefovir, one hepatocellular carcinoma (HCC) was detected, and the patient underwent a successful hepatectomy. Our findings suggest that the addition of adefovir to ongoing lamivudine therapy is useful for improving liver function in patients with decompensated lamivudine-resistant HBV-related cirrhosis, allowing surgery for HCC.     

Tenofovir versus entecavir for tertiary prevention of hepatocellular carcinoma in chronic hepatitis B infection after curative therapy: A systematic review and meta-analysis

Entecavir (ETV) and Tenofovir disoproxil fumarate (TDF) are the first-line drugs for the treatment of chronic hepatitis B virus (HBV). However, the impact of these two antiviral agents on the outcome of HBV-related hepatocellular carcinoma (HCC) after curative therapy remains to be explored. The purpose of the present study was to compare the effect of ETV and TDF on recurrence and mortality after curative treatment for HBV-related HCC. A comprehensive literature search of multiple electronic databases was conducted from 2000 to January 2022 for studies comparing ETV and TDF for HBV-related HCC patients after curative therapy. The adjusted hazard ratios (aHR) were pooled using a random-effects model. A total of nine studies with 5298 patients were included in the final meta-analysis. TDF was associated with a lower risk of HCC recurrence [aHR 0.73, 95% confidence interval (CI) 0.65–0.81] compared to HCC. TDF reduced the risk of late recurrence compared to ETV (aHR 0.58, 95% CI 0.45–0.76) but not early recurrence (aHR 0.88, 95% CI 0.76–1.02). The mortality risk was also lower with TDF compared to ETV (aHR 0.62, 95% CI 0.50–0.77). TDF was associated with a lower risk of recurrence and mortality than ETV after resection or ablation of HBV-related HCC. Further prospective randomized controlled studies are warranted to validate these results.     

Surgical treatment of HCC in a patient with lamivudine-resistant hepatitis B cirrhosis with adefovir dipivoxil

We describe a 77-year-old woman with chronic hepatitis B who became resistant to lamivudine. She was started on adefovir (10 mg daily) while still continuing lamivudine therapy. Four mo later her liver function improved and serum Hepatitis B virus (HBV)-DNA level became undetectable. Three years after the start of additional adefovir treatment, hepatocellular carcinoma (HCC) was detected and the patient underwent a successful hepatectomy. Our findings suggest that the addition of adefovir to ongoing lamivudine therapy cannot completely suppress hepatocarcinogenesis, but is useful for improving liver function in patients with lamivudine-resistant HBV-related cirrhosis, allowing HCC surgery.     

Recurrent hepatocellular carcinoma has an increased risk of subsequent recurrence after curative treatment

BACKGROUND AND AIM: Local ablation therapy has been shown to be effective for small hepatocellular carcinoma (HCC); however, HCC recurrence is very frequent even after apparently curative treatment. In particular, recurrent HCC may be more prone to subsequent recurrence, although quantitative data are lacking. The aim of this study was to evaluate the difference in the risk for subsequent recurrence, if any, between primary and recurrent cases. METHODS: A retrospective analysis was conducted of 376 patients with HCC (uninodular and 100 ng/mL, treatment other than radiofrequency ablation, HCV antibody positivity, and tumor multinodularity also remained as significant predictors. CONCLUSION: Hepatocellular carcinoma at second or later recurrence is three times as prone to subsequent recurrence as is primary HCC, when compared with adjustment for other tumor and hepatic factors.     

Effect of a new adjuvant systemic interferon alpha, 5-fluorouracil and cisplatin on advanced hepatocellular carcinoma with macroscopic portal invasion

BACKGROUND/AIMS: Despite an adequate hepatic resection, theprognosis of the patients with hepatocellular carcinoma (HCC) that have macroscopic tumor thrombus in the portal vein has still been poor. The prognosis of those patients and was investigated the significance of postoperative adjuvant therapy was discussed in this study. METHODOLOGY: Twenty five patients who had Vp2 or more portal invasion were included in this study. Those patients were retrospectively divided into 2 groups: the systemic interferon alpha, 5-Fluorouracil (FU) and cisplatin group (n = 10, IFN+ chemo group); and the no adjuvant therapy group (n = 15, control group). RESULTS: The overall survival rate was significantly higher in the IFN+chemo group compared with the control group. There was no significant difference between the 2 groups in regard to the disease-free survival rate. However, a difference in the recurrence pattern was observed between the 2 groups. In the IFN+chemo group, 3 of 6 patients with a recurrence had a single tumor in the remnant liver. While in the control group, 10 of 11 recurrent patients had either distant metastasis or multiple recurrences in the residual liver. CONCLUSIONS: Our new adjuvant systemic therapy including interferon alpha, 5FU and cisplatin for advanced HCC with macroscopic portal invasion is promising.     

Clinical analysis of patients with hepatocellular carcinoma recurrence after living-donor liver transplantation

AIM: To evaluated patterns and outcomes of hepatocellular carcinoma(HCC) recurrence after living donor liver transplantation(LDLT).METHODS: From 2001 to 2014, 293 patients underwent LDLT for HCC at our transplant center. We retrospectively reviewed 54(18.4%) patients with HCC recurrence after LDLT. We evaluated patterns and outcomes of HCC recurrence after LDLT, with particular attention to the Milan criteria at transplantation, treatments for HCC-recurrent patients, and factors related to survival after HCC recurrence. Furthermore, we evaluated the efficacy of combination treatment of sorafenib and an mT OR inhibitor.RESULTS: The 1-, 2-, and 3-year overall survival rates after HCC recurrence were 41.1%, 20.5%, and 15.4%, respectively. The median time interval between LDLT and HCC recurrence was 6.5 mo. Although recurrence rates according to the Milan criteria at LDLT were significantly different, HCC recurrence patterns and survival rates after HCC recurrence were not significantly different between the two groups. Time to recurrence 12 mo(P = 0.048), multiple recurrences at HCC recurrence(P = 0.038), and palliative treatment for recurrent tumors(P = 0.003) were significant independent prognostic factors for poor survival after HCC recurrence in a multivariate analysis. The combination treatment of sorafenib and sirolimus showedsurvival benefits in the palliative treatment group(P = 0.005).CONCLUSION: Curative treatment for recurrent HCC after LDLT is the most important factor in survival rates after HCC recurrence and combination treatments of sorafenib and an m TOR inhibitor could have survival benefits in patients with HCC recurrence after LT in the palliative treatment group.