Prevention of cancer recurrence after treatment for hepatitis C virus-related hepatocellular carcinoma by interferon therapy

The outcome of treatment for hepatitis C virus-related hepatocellular carcinoma is still unsatisfactory because of the high rate of recurrence of cancer, including intrahepatic metastasis and multicentric carcinogenesis after treatment. The rate of recurrence, especially that of multicentric carcinogenesis, is affected by persistent active hepatitis and hepatic fibrosis caused by chronic hepatitis C. Interferon therapy improves the outcome after treatment of hepatocellular carcinoma by decreasing recurrence and preserving or improving liver function when treatment is successful. Radical treatment by anatomic resection and interferon therapy can markedly improve the outcome in patients with hepatitis C virus-related hepatocellular carcinoma.     

Anti-viral therapy to reduce recurrence and improve survival in hepatitis B virus-related hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the most common malignancy and the third leading cause of cancer death worldwide.Chronic infection with hepatitis B virus(HBV)and hepatitis C virus accounts for approximately75%-80%of HCC cases worldwide.In particular,chronic HBV infection is a predominant risk factor for HCC in Asia and Africa.Hepatic resection and radiofrequency ablation are increasingly used for the curative treatment of HCC,and good local control can be achieved.However,the high rate of recurrence is a major obstacle to improving prognosis.A high viral load of HBV DNA is the most important correctable risk factor for recurrence.Furthermore,interferon and/or nucleotide analogues may decrease HBV DNA.Therefore,these drugs may decrease recurrence.In this article,treatment strategies for HBV-related HCC are described in order to reduce recurrence and improve survival.     

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.     

Alpha-fetoprotein before and after pegylated interferon therapy for predicting hepatocellular carcinoma development

AIM: To investigate factors that accurately predict hepatocellular carcinoma (HCC) development after antiviral therapy in chronic hepatitis C (CHC) patients.METHODS: CHC patients who received pegylated interferon and ribavirin were enrolled in this cohort study that investigated the ability of alpha-fetoprotein (AFP) to predict HCC development after interferon (IFN) therapy.RESULTS: Of 1255 patients enrolled, 665 developed sustained virological response (SVR) during mean follow-up period of 5.4 years. HCC was occurred in 89 patients, and 20 SVR patients were included. Proportional hazard models showed that HCC occurred in SVR patients showing AFP ≥ 5 ng/mL before therapy and in non-SVR patients showing AFP ≥ 5 ng/mL before and 1 year after therapy besides older age, and low platelet counts. SVR patients showing AFP ≥ 5 ng/mL before therapy and no decrease in AFP to < 5 ng/mL 1 year after therapy had significantly higher HCC incidence than non-SVR patients showing AFP ≥ 5 ng/mL before therapy and decreased AFP (P = 0.043). AFP ≥ 5 ng/mL before therapy was significantly associated with low platelet counts and high values of alanine aminotransferase (ALT) in stepwise logistic regression analysis. After age, gender, platelet count, and ALT was matched by propensity score, significantly lower HCC incidence was shown in SVR patients showing AFP < 5 ng/mL before therapy than in those showing AFP ≥ 5 ng/mL.CONCLUSION: The criteria of AFP < 5 ng/mL before and 1 year after IFN therapy is a benefical predictor for HCC development in CHC patients.     

Impact of direct-acting antivirals on early recurrence of HCV-related HCC: Comparison with interferon-based therapy

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Influence of interferon therapy on outcome after surgery for hepatitis C virus-related hepatocellular carcinoma.

Influence of interferon (IFN) therapy on postoperative outcomes in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is still inconclusive. Of 518 patients who underwent hepatic resection for HCV-related HCC, 312 patients with Japan integrated staging score 0-2 were included in this study. Of 50 patients underwent IFN therapy, 29 patients who obtained a normalized alanine aminotransferase (ALT) activity irrespective of disappearance of serum HCV RNA were classified as the response group, while 21 patients were classified as the non-response group because their ALT activities were not normalized and serum HCV RNA persisted. The non-IFN group included 262 patients who had not received IFN therapy. The tumor-free and the overall survival rates for patients in the response group were significantly higher than those in other groups. Only one patient in the response group died of HCC recurrence, and the proportion of deaths associated with liver disease (HCC recurrence or cirrhosis) was significantly lower in the response group than other two groups. IFN therapy can improve postoperative outcomes in patients with HCV-related HCC because of suppression of recurrence and preventing progress of cirrhosis, especially when IFN therapy has controlled their active hepatitis.     

Comparison of serum and liver hepatitis C virus quasispecies in HCV-related hepatocellular carcinoma

Background/Aims: The hepatitis C virus (HCV) genome consists of quasispecies populations of heterogeneous variants, especially in the hypervariable region. To assess the profiles of viral quasispecies in HCV-related hepatocellular carcinoma, we studied the viral population patterns in serum and liver tissues of 13 HCV-positive patients with hepatocellular carcinoma developed on cirrhotic and non-cirrhotic livers (5 and 8 cases, respectively).Methods: HCV genome heterogeneity was analyzed by polymerase chain reaction-mediated single-strand conformation polymorphism analysis, which showed multiple DNA bands representing different hypervariable region sequences.Results: The HCV populations were different between tumorous and nontumorous tissues in hepatocellular carcinomas with cirrhosis and in without cirrhosis. At least one or more than one common band was detected in both compartments in all but one case. No significant differences in the complexity of HCV quasispecies were found in hepatocellular carcinoma with or without underlying cirrhosis. Comparison of the HCV quasispecies profiles in serum and liver tissues showed a different distribution of HCV variants between these two compartments in patients. In four cases, both common and compartmentalized sequences were detected, whereas in two cases, both without cirrhosis, the HCV population in serum was completely different from that found in the liver.Conclusions: These results suggest that the complexity of HCV populations is influenced by the presence of hepatocellular carcinoma rather than by the severity of the underlying chronic liver disease. The different quasispecies patterns found in serum and liver may reflect different biological properties of circulating and intrahepatic HCV particles or the existence of extrahepatic sites of replication.     

Surgical treatment of intra hepatic recurrence of hepatocellular carcinoma

Recurrence after hepatocellular carcinoma(HCC) is frequent.Currently,there are no recommendations on therapeutic strategy after recurrence of HCC.Whereas the 5 year-recurrence rate after resection of HCC is 100%,this drops to 15% after primary liver transplantation.Repeat hepatectomy and salvage liver transplantation(SLT) could be performed in selected patients to treat recurrent HCC and enable prolonged overall survival after treatment of recurrence.Other therapies such as local ablation,chemoembolization or sorafenib could be proposed to those patients unable to benefit from resection or SLT.A clear definition of the place of SLT and "prophylactic" liver transplantation is required.Indeed,identifying risks factors for recurrence at time of primary liver resection of HCC may help to avoid recurrence beyond Milan criteria and non-resectable situations.In this review,we summarize the recent data available in the literature on the feasibility and outcomes of repeat hepatectomy and SLT as treatment for recurrent HCC.     

Long-term interferon therapy after radiofrequency ablation is effective in treating patients with HCV-associated hepatocellular carcinoma

Purpose

This study investigates the usefulness of long-term interferon (IFN) therapy following radiofrequency ablation (RFA) for HCV-associated hepatocellular carcinoma (HCC).

Methods

This is a retrospective observational study. Patients underwent pegylated IFN-α/ribavirin combination therapy for 48 weeks and then were maintained on IFN-α administration on average for 68 weeks (mean total duration 116 weeks). Patients who underwent IFN monotherapy were maintained on IFN administration on average for 78 weeks.

Results

There were biases in the background factors between the IFN and non-IFN groups. Therefore, a covariate adjustment was performed using the propensity score. An analysis of 20-matched patients from each group showed the 5-year cumulative survival rate was higher in the IFN group than in the non-IFN group (100 and 76%, respectively), and the 3-year cumulative recurrence rate was significantly lower in the IFN group than in the non-IFN group (38.0 and 64.2%, respectively). In 14 patients (i.e., IFN responders), the serum alanine aminotransferase (ALT) level remained normalized at 30 IU/mL or lower, regardless of disappearance of serum HCV RNA. In these patients, the cumulative recurrence rate was low, the hazard ratio was 0.158 (95% confidence interval = 0.045–0.561, P = 0.004), and the serum albumin level was retained.

Conclusion

These results show the importance of maintaining the liver function and suggest that long-term IFN administration after RFA inhibits recurrence and contributes to an improved outcome in patients (in particular, IFN responders) who initially develop HCC.     

直接抗病毒药物治疗后丙型肝炎相关肝细胞癌的发生与复发

丙型肝炎病毒（HCV）RNA可通过直接抗病毒药物治疗从血液循环中清除,达到持续病毒学应答（SVR）。研究表明,直接抗病毒药物治疗达到SVR后,可降低肝细胞癌（HCC）发病率,但仍需监测HCC的发生。现简要总结现有研究关于抗病毒治疗后丙型肝炎继发HCC可能原因的讨论,主要分为表观遗传学改变与DNA异常甲基化、HCV相关肝...     

Significance of plasma osteopontin in diagnosis of hepatitis C virus-related hepatocellular carcinoma

Background and study aimsAlfa fetoprotein (AFP) is widely used as a surveillance test for hepatocellular carcinoma (HCC) among patients with liver cirrhosis (LC). However, the clinical use of AFP has been shown to present some important limitations in sensitivity and specificity. Osteopontin (OPN) is a secreted matrix glycoprotein that is emerging as a significant protein in the biology of HCC. The aim of this study was to assess the diagnostic value of plasma OPN compared with that of AFP in the diagnosis of HCC among hepatitis C virus (HCV)-related LC.Patients and methodsPlasma levels of OPN and AFP were measured in 69 Egyptian patients with HCV-related LC (35 with HCC and 34 without HCC) and 20 healthy controls.ResultsBoth median AFP and OPN levels were significantly higher in the HCC group compared to LC and healthy control groups (p < 0.001 in each) and in LC compared to the control group (p < 0.001). In the HCC group, both OPN and AFP levels were significantly higher in patients with Child–Pugh class C and B compared to class A (p < 0.05 in each). There was no correlation between OPN and AFP levels. The OPN level was significantly higher in patients with multiple focal lesions than in those with single lesions (p < 0.05) and in patients with portal vein invasion compared to patients without portal vein invasion (p < 0.05). Receiver operator characteristic (ROC) curves showed that the area under the curve (AUC) for OPN and AFP was 0.824 and 0.730, respectively.ConclusionOPN is a promising tumour marker which could be used as a screening test for the diagnosis of HCC in patients with LC and, hence, improves the prognosis and survival rate of these patients. The association of OPN with the multiplicity of focal lesions and portal vein invasion suggests an additional prognostic value.     

Incidence and risk factors for hepatocellular carcinoma in 967 patients with cirrhosis

Purpose: To determine the incidence of hepatocellular carcinoma in cirrhosis and to examine the influence of age and sex, and the contribution of etiological factors. Methods: 967 patients with liver cirrhosis and free of hepatocellular carcinoma were enrolled in this longitudinal, retrospective and observational study. Monitoring for hepatocellular carcinoma was scheduled at 3- to 6-month intervals. The mean (±SD) length of follow-up was 60.3 ± 51.7 months (range 6–258). Results: During the observation period, hepatocellular carcinoma developed in 64 patients. The calculated annual incidence was 2.1%. The probability of being free of liver cancer was 92% at 5 years, 80% at 10 years, and 69% at 15 years. Age was the only independent risk factor for the development of malignancy in the multivariate analysis. There were no differences according to male sex, alcohol abuse, and chronic hepatitis B and C virus infection. Conclusions: The annual incidence of hepatocellular carcinoma was 2.1%. These results, although confirming that age is a risk factor for hepatocellular carcinoma in cirrhosis, indicate that alcohol abuse, male sex, and concurrent hepatitis B and C virus infection do not involve a higher risk of developing liver cancer.     

Prevention of hepatocellular carcinoma in chronic viral hepatitis B and C infection

Hepatocellular carcinoma(HCC)is a leading cause of cancer-related mortality worldwide,with the majority of cases associated with persistent infection from hepatitis B virus(HBV)or hepatitis C virus(HCV).Natural history studies have identified risk factors associated with HCC development among chronic HBV and HCV infection.High-risk infected individuals can now be identified by the usage of risk predictive scores.Vaccination plays a central role in the prevention of HBV-related HCC.Treatment of chronic HBV infection,especially by nucleoside analogue therapy,could also reduce the risk of HBV-related HCC.Concerning HCV infection,besides the advocation of universal precautions to reduce the rate of infection,pegylated interferon and ribavirin could also reduce the risk of HCV-related HCC among those achieving a sustained virologic response.Recently there has been mounting evidence on the role of chemopreventive agents in reducing HBV-and HCV-related HCC.The continued advances in the understanding of the molecular pathogenesis of HCC would hold promise in preventing this highly lethal cancer.     

Hepatitis-related hepatocellular carcinoma: Insights into cytokine gene polymorphisms

Hepatocellular carcinoma(HCC) is a primary liver cancer, which is one of the most prevalent cancers among humans. Many factors are involved in the liver carcinogenesis as lifestyle and environmental factors. Hepatitis virus infections are now recognized as the chief etiology of HCC; however, the precise mechanism is still enigmatic till now. The inflammation triggered by the cytokine-mediated immune response, was reported to be the closest factor of HCC development. Cytokines are immunoregulatory proteins produced by immune cells, functioning as orchestrators of the immune response. Genes of cytokines and their receptors are known to be polymorphic, which give rise to variations in their genes. These variations have a great impact on the expression levels of the secreted cytokines. Therefore, cytokine gene polymorphisms are involved in the molecular mechanisms of several diseases. This piece of work aims to shed much light on the role of cytokine gene polymorphisms as genetic host factor in hepatitis related HCC.     

Increasing hepatitis C virus-associated hepatocellular carcinoma mortality and aging: Long term trends in Japan.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) in Japan has been increasing. The aim of the study was to determine the epidemiological trends in HCC mortality in Japan. METHODS: We reviewed the medical records of all patients whose death was caused by liver disease between 1981 and 2000 at two hospitals. The courses of death were separated based on presence or absence of HCC when death ensued. Additionally, cohorts of patients with HCC were analyzed in 5-year time periods. RESULTS: The number of deaths from hepatitis C virus (HCV)-associated HCC steadily increased 2.6 times from 49 to 128 during observation period. The mean age at death from HCV-associated HCC from 1996 to 2000 was significantly higher than that in the period from 1981 to 1985 (p<0.0001). INTERPRETATION: Deaths from HCV-associated HCC increased from 1981 to 2000, consistent with the aging of the population in Japan.     

Factors predicting survival after post-transplant hepatocellular carcinoma recurrence

Background

Although factors associated with an increased risk of recurrence after liver transplantation for hepatocellular carcinoma (HCC) have been extensively studied, the history of patients with a post-transplant recurrence is poorly known.

Methods

Patients experiencing a post-transplant HCC recurrence from 1996 to 2011 in two transplant programs were included. Demographic, transplant, and post-recurrence variables were assessed.

Results

Thirty patients experienced an HCC recurrence–22 men and 8 women with a mean age of 55 ± 6 years. Sixteen (53 %) were outside the Milan criteria at the time of transplantation. Most recurrences (60 %) appeared within the first 18 months after transplantation, ranging between 1.7 and 109 months (median 14.2 months). Mean post-recurrence survival was 33 ± 31 months. On univariate analysis, total tumor volume (TTV; p = 0.047), microvascular invasion (p = 0.011), and time from transplant to recurrence (p = 0.001) predicted post-recurrence survival. On multivariate analysis, both time from transplant to recurrence (p = 0.001) and history of rejection (p = 0.043), but not the location of the recurrence or the type of recurrence treatment, predicted post-recurrence survival.

Conclusion

This study suggests that patients with early post-transplant HCC recurrence have worse outcomes. Those with a history of graft rejection have better survivals, possibly due to more active anti-cancer immunity.     

Diagnostic and therapeutic management of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is an increasing health problem, representing the second cause of cancerrelated mortality worldwide. The major risk factorfor HCC is cirrhosis. In developing countries, viral hepatitis represent the major risk factor, whereas in developed countries, the epidemic of obesity, diabetes and nonalcoholic steatohepatitis contribute to the observed increase in HCC incidence. Cirrhotic patients are recommended to undergo HCC surveillance by abdominal ultrasounds at 6-mo intervals. The current diagnostic algorithms for HCC rely on typical radiological hallmarks in dynamic contrast-enhanced imaging, while the use of α-fetoprotein as an independent tool for HCC surveillance is not recommended by current guidelines due to its low sensitivity and specificity. Early diagnosis is crucial for curative treatments. Surgical resection, radiofrequency ablation and liver transplantation are considered the cornerstones of curative therapy, while for patients with more advanced HCC recommended options include sorafenib and trans-arterial chemoembolization. A multidisciplinary team, consisting of hepatologists, surgeons, radiologists, oncologists and pathologists, is fundamental for a correct management. In this paper, we review the diagnostic and therapeutic management of HCC, with a focus on the most recent evidences and recommendations from guidelines.     

Hepatitis C impairs survival following liver transplantation irrespective of concomitant hepatocellular carcinoma

BACKGROUND/AIMS: Liver transplantation (LTX) is the only curative treatment for end-stage liver disease caused by hepatitis C (HCV). Hepatocellular carcinoma (HCC) is common in patients with HCV cirrhosis. METHODS: Two hundred and eighty-two HCV patients listed for LTX in the Nordic countries in a 17-year period were included. For comparison a group of patients with non-viral chronic liver disease (n=1552) was used. RESULTS: Two hundred and fifty-three (90%) patients received a first liver allograft. HCC was found in 38% of the explanted livers. Survival at 1, 3 and 5years was 82%, 69% and 61% vs. 85%, 80% and 76% for the comparison group (p<0.0001), this survival difference was also evident when excluding patients with HCC (p=0.007). HCV patients with HCC had 1, 3 and 5year survival of 73%, 52% and 46% compared with 88%, 80% and 71% for the HCV patients without HCC (p=0.0005). In an intention-to-treat analysis (from time of acceptance to the waiting list) HCV was also associated with an impaired survival. CONCLUSIONS: HCV cirrhosis, which is now also an important indication for LTX in the Nordic countries, and significantly impairs survival following LTX. Concomitant HCC and donor age are the two most important factors contributing to an impaired survival.     

Dermatomyositis associated with hepatocellular carcinoma in an elderly female patient with hepatitis C virus-related liver cirrhosis

A 79-year-old female patient with hepatitis C virus-related liver cirrhosis was diagnosed as having hepatocellular carcinoma (HCC) with a diameter of 2.0 cm. She refused therapy for HCC. Nine months after the diagnosis, she developed dermatomyositis when the HCC enlarged to a diameter of 6.0 cm. She underwent therapy for dermatomyositis, and then transcatheter arterial chemoembolization for HCC. Although the manifestations of dermatomyositis improved and entire tumor necrosis was achieved, she died of pneumonia 2 mo after the treatment of HCC. HCC and/or chronic hepatitis C virus infection might be involved in the pathogenesis of dermatomyositis.