Long-term clearance of hepatitis C virus following interferon α-2b or peginterferon α-2b, alone or in combination with ribavirin.

Sustained virologic response (SVR) is the standard measure for evaluating response to therapy in patients with chronic hepatitis C (CHC). The aim of this study was to prospectively assess the durability of SVR in the pivotal studies of peginterferon (PEG-IFN) α-2b or IFN α-2b. We conducted two phase 3b long-term follow-up studies of patients previously treated for CHC in eight prospective randomized studies of IFN α-2b and/or PEG-IFN α-2b. Patients who achieved SVR [undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of treatment] were eligible for inclusion in these follow-up studies. In total, 636 patients with SVR following treatment with IFN α-2b and 366 with SVR following treatment with PEG-IFN α-2b were enrolled. Definite relapse (quantifiable serum HCV RNA with no subsequent undetectable HCV RNA) was reported in six patients treated with IFN α-2b and three patients treated with PEG-IFN α-2b. Based on these relapses, the point estimate for the likelihood of maintaining response after 5 years was 99.2% [95% confidence interval (CI), 98.1-99.7%] for IFN α-2b and 99.4% (95% CI, 97.7-99.9%) for PEG-IFN α-2b. Successful treatment of hepatitis C with PEG-IFN α-2b or IFN α-2b leads to clinical cure of hepatitis C in the vast majority of cases.

High levels of HCV core+1 antibodies in HCV patients with hepatocellular carcinoma.

The core region of the hepatitis C virus (HCV) genome possesses an overlapping ORF that has been shown to encode a protein, known as the alternate reading frame protein (ARFP), F or core+1. The biological role of this protein remains elusive, as it appears to be non-essential for virus replication. However, a number of independent studies have shown that the ARFP/F/core+1 protein elicits humoral and cellular immune responses in HCV-infected individuals and interacts with important cellular proteins. To assess the significance of the core+1 humoral response in HCV-infected patients, we examined the prevalence of anti-core+1 antibodies in sera from patients with hepatocellular carcinoma (HCC) in comparison with chronically HCV-infected individuals without HCC. We produced two HCV core+1 histidine-tagged recombinant proteins for genotypes 1a (aa 11-160) and 1b (aa 11-144), as well as a non-tagged highly purified recombinant core+1/S protein (aa 85-144) of HCV-1b. Using an in-house ELISA, we tested the prevalence of core+1 antibodies in 45 patients with HCC in comparison with 47 chronically HCV-infected patients without HCC and 77 negative-control sera. More than 50 % of the serum samples from HCC patients reacted with all core+1 antigens, whereas <26 % of the sera from the non-HCC HCV-infected individuals tested positive. No core+1-specific reactivity was detected in any of the control samples. In conclusion, the high occurrence of anti-core+1 antibodies in the serum of HCC patients suggests a role for the ARFP/F/core+1 protein in the pathogenesis of HCC.

Peginterferon alpha-2a (40 kDa) and ribavirin: comparable rates of sustained virological response in sub-sets of older and younger HCV genotype 1 patients.

The average age of patients initiating therapy for HCV is increasing, with older patients exhibiting lower responses to therapy than younger patients. Identification of those older patients likely to respond needs to be addressed. Using data from 569 genotype-1 patients enrolled in two phase III studies (NV15801/NV15942) randomized to peginterferon alpha-2a (40 KDa) 180 microg/week plus ribavirin 1000/1200 mg/day for 48-weeks, we investigated factors associated with sustained virological response (SVR; undetectable HCV-RNA 24-weeks post-treatment) in patients >50 years. SVR rates among patients 50 years (52%vs 39%; P = 0.0073). Older patients with a rapid virological response (RVR; undetectable HCV-RNA at treatment week 4) or complete early virological response (cEVR; detectable HCV-RNA at week 4 but HCV-RNA <50 IU/mL at week-12) demonstrated high SVR rates (83% and 61% respectively). Older patients had lower cumulative peginterferon alpha-2a exposure and significantly lower cumulative ribavirin exposure (252 g vs 304 g in younger patients; P < 0.0001). Higher relapse rates were observed in older patients (41%vs 25%; P = 0.0042). Cumulative drug exposure and achievement of RVR or cEVR were significantly predictive of SVR by multiple logistic regression analysis in patients >50 years. Other baseline characteristics predictive of SVR in those >50 years of age were lower baseline HCV-RNA level (P = 0.0067), higher ALT-ratio (P = 0.0113) and absence of cirrhosis (P = 0.0482). Response rates were high among patients >50 years without cirrhosis who maintained adequate drug exposure and those achieving an RVR or cEVR. More frequent dose modifications of ribavirin in those >50 years likely contributed to the observed higher relapse rates.

Cellular immune responses in hepatitis B virus e antigen negative chronic hepatitis B.

The immunopathogenesis of hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) virus (HBV) infection has not been adequately investigated. We studied the cellular immune responses of peripheral lymphocytes using proliferating assays, intracellular cytokine staining (ICS) and ELISPOT interferon-gamma (IFN-gamma) assays after non-specific and specific stimulation with whole HBV proteins and synthetic peptides. Thirty patients with HBeAg negative CHB, eleven HBsAg inactive carriers, nine patients with acute hepatitis B and 22 healthy controls were included in the study. Patients with HBeAg negative CHB demonstrated an increased number of peripheral CD8+ T cells while their peripheral blood mononuclear cells showed increased proliferation after in vitro stimulation with overlapping hepatitis B core derived peptides and an envelope derived epitope (HBs 182-191 aa), similar to those observed in acute hepatitis B. Using ICS, we found an expanded population of IFN-gamma producing T lymphocytes, CD4+ and CD8+, after non-specific stimulation, in HBeAg negative CHB compared to all other groups. HBeAg negative CHB and acute hepatitis B patients had a similarly increased number of core specific T cells measured by the IFN-gamma assays. Inactive HBsAg carriers showed minimal proliferative responses overall while they exhibited an increased number of envelope specific effector T cells (measured by ICS). In conclusion, we showed that overall CD4+ T cell responses from patients with HBeAg negative CHB were comparable to those of acute hepatitis B, while inactive HBsAg carriers despite their limited proliferative capacity the effector activity of their peripheral T cells was maintained.

A partially overlapping treatment course with lamivudine and interferon in hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND: Treatment of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHBe-) with interferon or lamivudine alone is inefficient and reports of combination treatment with both drugs, equivocal so far. AIM: To investigate the efficacy of a lamivudine-interferon combination therapy in 36 patients HBeAg-negative CHBe-. METHODS: Lamivudine was administered from 1 to 12 months and interferon-alpha2b from 7 to 18 months. A historical control group of 36 CHBe- patients, matched for age and sex and treated with the same dosage of interferon-alpha2b was used. All patients were followed up for > or =12-month post-treatment. RESULTS: The biochemical response rate at the end of treatment was 78% in lamivudine-interferon and 52.8% in interferon-control group (P = 0.026) and at 12-month post-treatment 38.9% and 22.2%, respectively (P = 0.125). Alanine aminotransferase normalization and serum HBV-DNA levels < or =30 000 cp/mL were observed in 50.0% of lamivudine-interferon-treated and 30.6% of interferon-treated patients at the end of treatment (P =0.093) and in 22.2% and 13.9% of patients, respectively, at 12-month post-treatment (P = 0.358). Moreover, alanine aminotransferase normalization and undetectable serum HBV-DNA (<400 cp/mL) was observed in 30.6% of lamivudine-interferon-treated and 8.3% of interferon-treated patients at the end of treatment (P = 0.017) and in 8.3% and 0% of patients, respectively, at 12-month post-treatment (P = 0.076). CONCLUSIONS: In CHBe-, 12 months after ending a lamivudine-interferon partially overlapping 18-month combination course, 22% of patients still maintain normal alanine aminotransferase and HBV-DNA levels < or =30 000 cp/mL. However, a 12-month interferon monotherapy course may achieve similar responses.

Systematic review: cessation of long-term nucleos(t)ide analogue therapy in patients with hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND: It has been debated whether finite nucleos(t)ide analogue therapy is feasible in HBeAg-negative chronic hepatitis B. AIM: To review this issue systematically. METHODS: Using text terms HBsAg and various nucleos(t)ide analogues, PubMed was searched between 1995 and 2014 to find studies on therapy >6 months in adult HBeAg-negative chronic hepatitis B patients with off-therapy follow-up >6 months. RESULTS: Twenty-two studies with a total of 1732 patients were identified and included. The median duration of therapy, consolidation therapy and off-therapy follow-up ranged from 6 months to 8 years, 4 to 96 weeks and 6 to 80 months respectively. Patients were monitored with serum ALT and HBV DNA monthly in the first 1-3 months and every 3-6 months afterwards in most studies. The 1-year off-therapy 'virological relapse' (HBV DNA >2000 IU/mL) and 'clinical relapse' (HBV DNA > 2000 IU/mL + ALT elevation) occurred in <70% and <50% of the patients, respectively, and <40% of the patients received re-treatment. These rates were higher in patients with shorter treatment, shorter consolidation therapy and those treated with less potent nucleos(t)ide analogues. Off-therapy severe flares were rare and hepatic decompensation was reported in only one patient with cirrhosis. Biochemical relapse reflecting enhanced immune-mediated hepatocyte killing may lead to a higher chance for off-therapy HBsAg seroclearance and be possibly desirable. CONCLUSION: With an appropriate stopping rule and a proper off-therapy monitoring plan, cessation of long-term nucleos(t)ide analogue therapy prior to HBsAg seroclearance in HBeAg-negative chronic hepatitis B is a feasible alternative to indefinite treatment.

Review article: current management of chronic hepatitis B.

Chronic hepatitis B can be diagnosed in patients with increased aminotransferases, hepatitis B virus viraemia and necroinflammation with fibrosis on liver biopsy. Although, ideally, all patients with chronic hepatitis B should be treated, therapeutic intervention is currently recommended for cases with a relatively satisfactory likelihood of response and/or advanced disease. A realistic therapeutic approach aims to sustain hepatitis B e antigen (HBeAg) loss and hepatitis B e antibody (anti-HBe) seroconversion in HBeAg-positive chronic hepatitis B and to sustain biochemical and virological remission in HBeAg-negative chronic hepatitis B. Currently, three drugs are licensed for chronic hepatitis B: interferon-alpha, lamivudine and adefovir dipivoxil. In patients with HBeAg-positive chronic hepatitis B, all of these drugs achieve HBeAg loss (24-33%) and anti-HBe seroconversion (12-30%) rates significantly superior to those observed in untreated placebo controls. In patients with HBeAg-negative chronic hepatitis B, the sustained off-therapy response rate is 20-25% after a > or =12-month course of interferon-alpha and minimal (<10%), if any, after a 12-month course of lamivudine or adefovir. Long-term lamivudine induces an initial response in 70-90% of patients, but only 30-40% of patients remain in remission after the third year due to progressively increasing viral resistance. Long-term adefovir achieves a response in approximately 70% of patients at 12 months, which is maintained at 24 months with rare (<2%) drug resistance. Adefovir is also effective against lamivudine-resistant strains. Many other anti-viral agents, immunomodulatory approaches and combination therapies are currently being evaluated in chronic hepatitis B.

Effect of interferon therapy on the development of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: a meta-analysis.

BACKGROUND: The role of interferon in the prevention of hepatocellular carcinoma remains controversial. AIM: In this meta-analysis we evaluated the hepatocellular carcinoma incidence in interferon-treated and -untreated patients with hepatitis C virus-related cirrhosis. METHODS: Eleven studies with 2178 patients were found to fulfil our inclusion criteria. The pooled odds ratio (OR) and 95% confidence intervals (CI) were calculated from the raw study data. RESULTS: Hepatocellular carcinoma development was significantly more frequent in untreated (21.5%) than in interferon-treated patients (8.2%; OR: 3.0, 95% CI: 2.3-3.9). In the five studies reporting hepatocellular carcinoma incidence in patients with and without sustained response to interferon, hepatocellular carcinoma was detected at a much higher rate in patients without (9%) than with a sustained response (0.9%; OR: 3.7, 95% CI: 1.7-7.8). Moreover, hepatocellular carcinoma developed significantly more frequently in the untreated patients than in the non-sustained responders (OR: 2.7, 95% CI: 1.9-3.9). The benefit from interferon on hepatocellular carcinoma incidence was not influenced by the study type (prospective or retrospective), the follow-up duration, or the study origin. CONCLUSIONS: Interferon therapy significantly reduces the hepatocellular carcinoma risk in patients with hepatitis C virus cirrhosis. Hepatocellular carcinoma development becomes almost negligible among sustained responders, but a reduction in hepatocellular carcinoma incidence is also achieved even in the non-sustained responders.

Induction interferon therapy in naïve patients with chronic hepatitis C: increased end-of-treatment virological responses but absence of long-term benefit.

BACKGROUND AND AIMS: The low efficacy of interferon monotherapy and data from viral kinetic studies led us to evaluate the efficacy of interferon administered daily in chronic hepatitis C. PATIENTS AND METHODS: Thirty-eight naïve patients with chronic hepatitis C and active liver disease randomly received 3 or 5 MU IFN-alpha daily for 1 month, followed by the same dose three times a week for 11 months. Results were compared to a three-times-a-week scheme of 3 MU IFN-alpha for 1 year. RESULTS: At the end of the induction period, 27 out of 38 (71%) patients had cleared HCV-RNA with a significantly higher rate in the 5 MU than in the 3 MU group (17 out of 18 or 94% vs. 10 out of 20 or 50%, P=0.003). The end-of-treatment virological response rate was 66% (25 out of 38) in the induction groups and 40% (10 out of 25) in the control group (P=0.04). Six months after completion of therapy, the sustained response rate dropped to 29% (11 out of 38) compared to 28% (7 out of 25) in the standard regimen. CONCLUSIONS: In chronic hepatitis C, treatment with 5 or 3 MU IFN-alpha daily during the first month of a standard IFN regimen leads to significantly increased end-of-treatment virological responses, but long-term responses are similar to those of standard IFN monotherapy.

Immunopathogenesis of hepatitis B e antigen negative chronic hepatitis B infection.

Hepatitis B e antigen (HBeAg) negative chronic hepatitis B represents currently the predominant form of chronic hepatitis due to the hepatitis B virus (HBV) in several parts of the world. In this review, recent data regarding the process of HBeAg negative HBV strain selection during the course of chronic HBV infection are presented and the potential virus and/or host-mediated mechanisms that lead to chronic liver necroinflammation, i.e. chronic hepatitis are outlined.

HBeAg-negative hepatitis B in a previously thalassemic patient during immunosuppressive therapy for chronic GVHD.

We report the case of a 15-year-old previously thalassemic girl who, 15 months after allogeneic BMT, developed HBeAg-negative hepatitis B (variant with mu-1896). In the absence of another route of transmission, HBV reactivation is postulated. The time of emergence of the HBV variant (with mu-1896) is probably related to the development of anti-HBe immunity. This mutant strain is associated with fulminant hepatitis. The patient achieved complete remission and HBV eradication despite having moderate GVHD and receiving immunosuppressive therapy.

Splenic infarct as a late complication of liver transplantation.

Splenic infarct is a rare complication of portal hypertension. It has been reported as an early complication after successful liver transplantation when portal pressure returns to normal and the splenic size progressively declines. It has not been reported as a late complication of liver transplantation. We describe the case of a 19-year-old patient with a splenic infarct which occurred 11 months after successful orthotopic liver transplantation for decompensated cryptogenic liver cirrhosis. Following transplantation, the patient was in excellent general health, liver function tests were normal, there was no clinical evidence of portal hypertension and the splenic size had decreased significantly compared to the pre-transplantation period, although it remained increased. The patient presented with high fever, left pleuritic pain and vomiting. The splenic size had not changed and left pleuritic exudate fluid collection was detected. A hypoechoic region of the spleen was demonstrated in the ultrasound examination corresponding to a hypodense lesion in the computerized tomography scanning. The patient recovered completely, with the disappearance of the infarct in the imaging studies in 2 months time. This case report indicates that a symptomatic splenic infarct can occur late following successful liver transplantation for liver cirrhosis despite lack of any evidence of residual portal hypertension at a time that splenomegaly has not yet regressed. The differential diagnosis from a splenic abscess in transplanted patients can be difficult but the final prognosis seems to be good.

Cholestatic jaundice as a paraneoplastic manifestation of renal cell carcinoma.

Malignant diseases may cause cholestatic jaundice through either main bile duct obstruction or widespread hepatic metastasis. Renal cell carcinoma (hypernephroma, RCC) can cause a variety of paraneoplastic manifestations which can be the main presenting symptoms. Cholestasis, as a paraneoplastic syndrome, has been well described in patients with malignant lymphohyperplastic diseases. Non-metastatic nephrogenic hepatic dysfunction syndrome without jaundice has often been described in patients with hypernephroma (Stauffer's syndrome). Paraneoplastic cholestatic jaundice has not yet been described. We report, for the first time, two patients who presented with pruritus and cholestatic jaundice. During the diagnostic work-up, RCC was diagnosed. The renal tumour was an unexpected finding during computed tomographic (CT) scan. No clinical manifestations of hypernephroma, short of microscopic haematuria, were detected. Conjugated bilirubin, alkaline phosphatase and gamma-glutamyltranspeptidase were markedly increased. No hepatic metastasis or main bile duct obstruction were detected by appropriate investigations. After radical nephrectomy, liver abnormalities disappeared rapidly. We conclude that RCC should be included among neoplasms causing not only anicteric intrahepatic cholestasis but also frank jaundice as part of a paraneoplastic syndrome. The differential diagnosis from hepatic metastasis, main bile duct obstruction or other causes of jaundice is of clinical importance and of prognostic value. Patients with unexplained cholestasis should be investigated for malignant diseases including hypernephroma.

Autoimmune hepatitis associated with the antiphospholipid syndrome.

The antiphospholipid syndrome has rarely been described in patients with autoimmune hepatitis. Two cases with type I autoimmune hepatitis and antiphospholipid syndrome are presented. The first case is that of a 53-year-old Caucasian female with a history of arterial thrombosis and fetal loss who was submitted to clinical and laboratory testing due to persistent transaminasaemia and was found to have autoimmune hepatitis. Antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant) were positive. The second case is that of a 31-year-old Caucasian woman with a history of autoimmune hepatitis who was submitted to laboratory testing due to a second-trimester fetal death, revealing an increased activated partial thromboplastin time and positive antiphospholipid antibodies. In conclusion, secondary antiphospholipid syndrome may accompany autoimmune hepatitis.

Gliclazide-induced acute hepatitis.

There are few reports in the literature related to sulfonylurea-induced hepatotoxicity. We describe the case of acute hepatitis induced by gliclazide, a second generation sulfonylurea. A 60-year-old woman with diabetes mellitus (type 2) developed an acute icteric hepatitis-like illness 6 weeks after the initiation of gliclazide therapy. Other causes of acute hepatocellular necrosis were excluded. Liver histology showed marked portal inflammation with lymphocytes, monocytes and eosinophils, associated with lobular inflammation (indicative of a histological pattern consistent with drug-induced hepatitis). The drug was immediately withdrawn and the patient was given glibenclamide. The patient recovered clinically and, in less than 4 weeks, her serum bilirubin and aminotransferases returned to normal levels. We believe that this is the first description of acute hepatitis caused by an idiosyncratic adverse reaction to gliclazide or to one of its metabolites. In conclusion, this case strongly suggests that gliclazide can induce acute icteric liver necro-inflammation which may be misdiagnosed clinically as acute viral hepatitis. In patients who show abnormal liver function tests, the immediate discontinuation of gliclazide is recommended.

Fulminant hepatic failure as a presenting paraneoplastic manifestation of Hodgkin's disease.

Malignancies may uncommonly present as fulminant hepatic failure and, due to the rarity of such an occurrence, they may easily be overlooked as one of its possible causes. An unusual case of Hodgkin's disease presenting as a fulminant hepatic failure is reported. A 34-year-old man presented with an acute onset of liver failure characterized by jaundice, ascites, encephalopathy and bleeding diathesis. Chemotherapy was initiated, resulting in a dramatic improvement not only in the patient's level of consciousness, but also in prothrombin time. Unfortunately, he succumbed shortly after to disseminated candidiasis. A post-mortem needle liver sample revealed massive hepatocellular necrosis, but no liver infiltration by the neoplastic disease. We conclude that in Hodgkin's disease, involvement of the liver can be manifested as a syndrome of paraneoplastic fulminant hepatic failure. In such cases, liver transplantation is an absolute contraindication but urgent chemotherapy under antifungal surveillance can be life saving.

Epidemiology of hepatitis C virus infection in seven European Union countries: a critical analysis of the literature. HENCORE Group. (Hepatitis C European Network for Co-operative Research.

Hepatitis C is now recognized as the most common infection causing chronic liver disease in the European population. Our aim was to assess the prevalence of the antibody to hepatitis C virus (HCV), and the incidence of HCV seroconversion in the general population and the main risk groups, namely intravenous drug users, haemodialysis and transfused patients, in seven countries of the European Union, by carrying out a critical analysis of the literature. Data sources used were the Medline database and a manual search using the key words: hepatitis C, prevalence, incidence, transmission, risk factors and epidemiology. Articles published between January 1990 and March 1997 were reviewed. Articles were reviewed according to a critical analysis method regarding title, type of article, study design, period and population, tests, results and their consistency with data. The tests performed were mainly second- or third-generation serological tests. The average prevalence rate in blood donors was 1%, with a north-south gradient ranging from 0.04% to 2%. Prevalence varied from 20% to 30% in haemodialysis patients. The incidence in transfused patients was less than 1% after 1991. The prevalence in intravenous drug users was about 80%. Multicentre studies conducted in larger samples are needed to obtain more accurate and reliable results, in particular. However, the epidemiological studies available allowed us to assess the magnitude of HCV infection in Europe.

Nonparenteral transmission of viral hepatitis in Greece.

"Nonparenteral" transmission of acute viral hepatitis was implicated in 50;5 per cent of 346 patients included in this study and in 67.5 per cent of 1,235 cases reviewed for the period 169-1973. Hepatitis B surface antigen (HBs Ag) was detected in 48.3 per cent of these patients. Of 476 family contacts of HBs Ag carriers 71 per cent had HBs Ag or anti-HBs, this being true for 88.8 per cent of siblings and for 67.7 per cent of offspring. Anti-HBs was detected in 10.4 per cent to 49.3 per cent of the populations tested, its frequency correlating with that of HBs Ag and increasing with age. Significant differences in the patterns of exposure to the hepatitis Bvirus (HBV) were seen between offspring and siblings of HBs Ag carries mainly determined by the observed HBs Ag prevalence in relation to their age. It was calculated that as many as 25 per cent of all Greeks may come into familial contact with HBs Ag carriers and acquire the infection mainly by nonparenteral mechanisms. It is concluded that in Greece there is already a wide exposure to HBV before vaccination programs.

Why and how to treat chronic hepatitis C.

Chronic hepatitis C (CHC) is a major health problem worldwide, with approximately 200 million affected individuals and a significant rate of progression to end-stage cirrhosis and hepatocellular carcinoma (HCC). If hepatitis C virus (HCV) infection is left untreated in the population, then the number of liver-related deaths will soon double and the need for liver transplantation may increase to five times that seen today. Available therapies for CHC are restricted to interferon alpha (IFN alpha) monotherapy and to the combination of IFN alpha and ribavirin. Despite their high cost and side effects, both of these therapies have proved to be cost effective, particularly combination therapy. IFN alpha monotherapy for one year can induce sustained response (SR) rates of approximately 10% in naive patients infected with HCV genotype 1, and above 50% in those infected with other genotypes. Combination therapy can double or even triple the rate of SR in genotype 1 infections and may further increase the SR rate in the other HCV genotypes. Combination therapy has also been proven to be effective in approximately 50% of relapsed responders to IFN alpha monotherapy. In clinical practice, the decision to treat should be individualized and tailored on the basis of several virus- and host-related factors, particularly the grade and stage of liver disease, HCV genotype and levels of viremia. Appropriate monitoring of therapy by careful clinical evaluation, liver biochemistry and serum HCV RNA testing is mandatory. IFN alpha therapy may also prove to be effective in reducing the rate of HCC development in CHC regardless of whether a virological response is achieved, but this remains to be established.

Modern trends in the management of hepatocellular carcinoma.

No treatment of proven validity in hepatocellular carcinoma (HCC) has yet been found, with the exception of surgery in a small subset of patients. Furthermore, there is a paucity of phase I and II trials and of phase III prospective randomized trials. Radiation therapy is not considered very effective, even as a palliative procedure, but there has been renewed interest in this modality, with several ongoing trials attempting to establish optimal doses, fractionation and effectiveness. Chemotherapy, single or combination, has not increased the survival of patients with HCC, although there have been unquestionable, even spectacular, responses to chemotherapy. Adriamycin seems the most effective agent with approximately 25% objective responses. The regional administration of drugs and/or interruption of arterial supply, in this malignancy with a pattern of local confinement, yields quite high response rates but no increase in survival. Several trials with combined therapeutic modalities are now in progress. Furthermore, there have been important advances in nuclear medicine, in the totally implantable pump, in the understanding of pharmacokinetics and in microspheres, monoclonal antibodies, etc. It is remarkable that there have been so few randomized trials in such a common malignancy. To obtain valuable results any future studies should randomize patients into "treatment" and "no treatment" groups and stratify patients according to prognostic factors. It seems, however, that the combination of local and systemic treatment is the most promising answer to this virulent and fatal disease.