Hepatitis C virus relapse was suppressed by long-term self-injection of low-dose interferon in patients with chronic hepatitis C after pegylated interferon plus ribavirin treatment.

AIM: The recommended treatment for chronic hepatitis C is a combination of pegylated interferon (PEG IFN) plus ribavirin (RBV). However, the sustained virological response (SVR) rate of PEG IFN-RBV therapy was approximately 50% in patients with genotype 1b and a high viral load. Thus, we compared the efficiencies and side-effects of PEG IFN-RBV and self-injected low-dose natural (n) IFN-α in patients with hepatitis C virus (HCV). METHODS: A prospective, multicenter, open-label study was conducted in 12 Japanese institutions. A total of 129 patients with chronic hepatitis C and no detectable HCV after 24-72 weeks of PEG IFN-RBV treatment were assigned to the control (n = 82) or treated (n = 47) group. Treated patients received 3 million units of nIFN-α 2-3 times/week over 96 weeks. The groups were compared regarding treatment efficiency and side-effects. RESULTS: Significant treatment success regarding virus negativation rates was found, with 89% and 73% for the treated and control groups, respectively (P = 0.039). In contrast, there was no difference in relapse rate between the groups 24 weeks after the 96-week nIFN-α treatment (P = 0.349). However, when early viral responders and late viral responders (LVR) were separated, LVR patients responded significantly to the treatment with 90% sustained virological response, compared to 53% for the control group (P = 0.044). The side-effects of nIFN-α were less than that of PEG IFN-RBV treatment. CONCLUSION: Self-injected nIFN-α has larger benefits than prolonged PEG IFN-RBV for chronic hepatitis C patients with high viral loads of genotype 1b who fail to achieve early viral response during initial combination treatment.

Hepatocellular carcinoma in Child-Pugh C cirrhosis: prognostic factors and survival benefit of nontransplant treatments.

A retrospective multicenter study was conducted to clarify the survival benefit of nontransplant treatments for patients with hepatocellular carcinoma (HCC) associated with Child-Pugh C cirrhosis. Data on 436 patients, including 203 treated patients with HCC, were collected from 20 institutions in Japan. Cox's proportional hazards model corrected for bias by propensity score analysis clearly showed the following as significant independent prognostic factors, including all four nontransplant treatments examined: transarterial chemoembolization, hepatic arterial infusion chemotherapy, percutaneous ethanol injection therapy, radiofrequency ablation, hepatitis B virus, number of tumors, log α-fetoprotein, encephalopathy, ascites and prothrombin time. The cumulative survival rate was significantly higher in the treated group than in the untreated group. The present findings suggest that prognosis can be improved by nontransplant treatments in patients with low Child-Pugh scores. Since this study was retrospective, the possibility of selection bias cannot be ruled out. Therefore, verification by a prospective controlled study is warranted.

A randomized phase II trial of intra-arterial chemotherapy using SM-11355 (Miriplatin) for hepatocellular carcinoma.

BACKGROUND: SM-11355 is a platinum complex developed to treat hepatocellular carcinoma (HCC) via administration into the hepatic artery as a sustained-release suspension in iodized oil. We conducted a multicenter phase II trial in patients with HCC to evaluate the efficacy and safety of SM-11355, using a Zinostatin stimalamer suspension in iodized oil as a reference. METHODS: Patients with unresectable HCC were randomized 2:1 to receive administration of the SM-11355 or Zinostatin stimalamer suspension into the hepatic artery. A second injection was given 4-12 weeks later. Efficacy was evaluated by CT 3 months after treatment and categorized as therapeutic effect (TE) V to I, where TE V was defined as disappearance or 100% necrosis of all treated tumors. RESULTS: A total of 122 patients were evaluated for efficacy and toxicity (SM-11355, n = 83; Zinostatin stimalamer, n = 39). Baseline characteristics were similar in the two groups. The TE V rates were 26.5% (22/83) and 17.9% (7/39) in the SM-11355 and Zinostatin stimalamer groups, respectively. In the SM-11355 group,the most frequent drug-related adverse events (AEs) of ≥ grade 3 were elevated AST, elevated ALT, thrombocytopenia, and hyperbilirubinemia. The AEs with the largest difference between the two groups (SM-11355 vs. Zinostatin stimalamer) were hepatic vascular injury (0 vs. 48.4%) and eosinophilia (84.3 vs. 41.0%). The 2-year and 3-year survival rates were 75.9% vs. 70.3% and 58.4% vs. 48.7%, respectively. CONCLUSIONS: The results suggest that SM-11355 in iodized oil has similar efficacy to Zinostatin stimalamer and that repeated dosing of SM-11355 is possible without hepatic vascular injury in cases of relapse.

Double-Filtration Plasmapheresis plus Interferon-ß for HCV-1b Patients with Non-Sustained Virological Response to Previous Combination Therapy.

BACKGROUND AND AIMS: Double-filtration plasmapheresis (DFPP) together with interferon (IFN) administration produces a substantial reduction in the viral load during the early stages of treatment. METHODS: Based on their responses to previous pegylated IFN and ribavirin (PEG-IFN/RBV) therapy, 20 patients were divided into null virological response (NVR; n = 12) and relapse (n = 8) groups. DFPP was used in combination with IFN-ß/RBV with subsequent administration of PEG-IFN-α2a/RBV therapy (DFPP + IFN-ß/RBV then PEG-IFN/RBV). Early viral dynamics was assessed, focusing especially on complete early virological response (cEVR) associated with sustained virological response. Additionally, the interleukin 28B gene, the IFN/RBV resistance-determining region, the IFN sensitivity-determining region and the core regions were analyzed. RESULTS: Rapid virological response was achieved in 0% (0/12) of NVR and in 75% (6/8) of relapse patients, with a significant difference between the two groups (p = 0.001). Similarly, cEVR was achieved in 8% (1/12) of NVR and in 88% (7/8) of relapse patients, with a significant difference between the two groups (p = 0.037). By multivariate logistic regression analysis, interleukin-28B major was a significant determiner of cEVR (odds ratio = 24.19, p = 0.037). CONCLUSION: DFPP + IFN-ß/RBV then PEG-IFN/RBV therapy is indicated more for relapse than for NVR patients.

Effect of vitamin K2 on the recurrence of hepatocellular carcinoma.

UNLABELLED: Hepatocellular carcinoma (HCC) is characterized by frequent recurrence, even after curative treatment. Vitamin K2, which has been reported to reduce HCC development, may be effective in preventing HCC recurrence. Patients who underwent curative ablation or resection of HCC were randomly assigned to receive placebo, 45 mg/day, or 90 mg/day vitamin K2 in double-blind fashion. HCC recurrence was surveyed every 12 weeks with dynamic computed tomography/magnetic resonance imaging, with HCC-specific tumor markers monitored every 4 weeks. The primary aim was to confirm the superiority of active drug to placebo concerning disease-free survival (DFS), and the secondary aim was to evaluate dose-response relationship. Disease occurrence and death from any cause were treated as events. Hazard ratios (HRs) for disease occurrence and death were calculated using a Cox proportional hazards model. Enrollment was commenced in March 2004. DFS was assessed in 548 patients, including 181 in the placebo group, 182 in the 45-mg/day group, and 185 in the 90-mg/day group. Disease occurrence or death was diagnosed in 58, 52, and 76 patients in the respective groups. The second interim analysis indicated that vitamin K2 did not prevent disease occurrence or death, with an HR of 1.150 (95% confidence interval: 0.843-1.570, one-sided; P=0.811) between the placebo and combined active-drug groups, and the study was discontinued in March 2007. CONCLUSION: Efficacy of vitamin K2 in suppressing HCC recurrence was not confirmed in this double-blind, randomized, placebo-controlled study.

A conundrum for randomized controlled trials: experience from a small hepatocellular carcinoma trial.

OBJECTIVE: The aim of this study was to explore why patients accepted or declined to participate in a randomized clinical trial, which was subsequently discontinued because of a low recruitment rate. METHODS: Forty-one patients were invited to participate in a randomized clinical trial that aimed to compare local ablation therapies and surgery to treat small asymptomatic hepatocellular carcinomas. These patients were then asked to answer a questionnaire that assessed patient perception and reasons for accepting or declining to enroll in the randomized clinical trial. When patients had a strong preference for a specific treatment, the questionnaire assessed why, how and when they had chosen it. RESULTS: The response rate was 6/6 (100%) and 30/35 (86%) for the participant and non-participant groups, respectively. Among the 30 non-participants, 23 had a strong preference for local ablation therapies, which was less invasive and offered shorter hospitalization. Patient preference for a specific treatment often stemmed from their consultations with a clinician who referred them to a specialist hospital. Patients without strong preference for a specific treatment participated in the randomized clinical trial because of altruistic motivations. CONCLUSION: When new treatments that are innovative and less burdensome become widespread, they are difficult to compare with standard therapy utilizing a well-designed randomized clinical trial. Consequently, when an innovative treatment is developed, investigators should consider designing a randomized clinical trial as early as possible.

Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial.

BACKGROUND/AIMS: Transcatheter arterial chemoembolization (TACE) is a combination of transarterial infusion chemotherapy (TAI) and embolization, and has been widely used to treat patients with hepatocellular carcinoma (HCC). However, since the impact of adding embolization on the survival of patients treated with TAI had never been evaluated in a phase III study, we conducted a multi-center, open-label trial comparing TACE and TAI to assess the effect of adding embolization on survival. METHODS: Patients with newly diagnosed unresectable HCC were randomly assigned to either a TACE group or a TAI group. Zinostatin stimalamer was injected into the hepatic artery, together with gelatin sponge in the TACE group and without gelatin sponge in the TAI group. Treatment was repeated when follow-up computed tomography showed the appearance of new lesions in the liver or re-growth of previously treated tumors. RESULTS: Seventy-nine patients were assigned to the TACE group, and 82 were assigned to the TAI group. The two groups were comparable with respect to their baseline characteristics. At the time of the analysis, 51 patients in the TACE group and 58 in the TAI group had died. The median overall survival time was 646 days in the TACE group and 679days in the TAI group (p=0.383). CONCLUSIONS: The results of this study suggest that treatment intensification by adding embolization did not increase survival over TAI with zinostatin stimalamer alone in patients with HCC.

Validation of a new prognostic staging system for hepatocellular carcinoma: a comparison of the biomarker-combined Japan Integrated Staging Score, the conventional Japan Integrated Staging Score and the BALAD Score.

OBJECTIVES: The conventional Japan Integrated Staging (c-JIS) score has been reported to effectively stratify patients with hepatocellular carcinoma (HCC). Recently, two new staging systems, the biomarker-combined JIS (bm-JIS) score and the BALAD score, have been proposed. Both staging systems include three tumor markers: alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP and des-gamma-carboxy prothrombin specific for HCC. The aim of this study is to evaluate the performance of these three staging systems. METHODS: A total of 1,173 HCC patients were included in this study. The stratification ability and prognostic predictive power were compared between these three staging systems. RESULTS: These three staging systems effectively predicted the patient survival. When accounting for the best prognostic subgroup of each staging systems (i.e. score of 0), there were significant differences between the bm-JIS score and the BALAD score and, likewise, between the c-JIS score and the BALAD score. The likelihood ratio chi(2) test showed the highest value and the Akaike information criterion value was lowest in the bm-JIS score. CONCLUSIONS: The bm-JIS score showed good stratification ability and was thus demonstrated to be a better predictor of the prognosis than the c-JIS score and the BALAD score, especially for the patients with a good prognosis.

Diagnostic accuracy of imaging for liver cirrhosis compared to histologically proven liver cirrhosis. A multicenter collaborative study.

OBJECTIVE: To evaluate the diagnostic accuracy of liver cirrhosis by imaging modalities, including CT, MRI and US, compared to results obtained from histopathological diagnoses of resected specimens. MATERIALS AND METHODS: CT, MRI and US examinations of 142 patients with chronic liver disease who underwent surgery for complicated hepatocellular carcinoma (<3 cm in diameter) in 10 institutions were blindly reviewed in a multicenter study by three radiologists experienced in CT, MRI and US. The images were evaluated for five imaging parameters (irregular or nodular liver surface, blunt liver edge, liver parenchymal abnormalities, liver morphological changes and manifestations of portal hypertension) using a severity scale. The diagnostic imaging impression score was also calculated. Patients were histologically classified into chronic hepatitis (CH; n = 54), liver cirrhosis (LC; n = 71) and pre-cirrhosis (P-LC; n = 17) by three pathologists, independently, who reviewed the resected liver specimens. The results of the three imaging methods were compared to those from histological diagnoses, and a multivariate analysis (stepwise forward logistic regression analysis) was performed to identify independent predictive signs of cirrhosis. The diagnostic efficacies for LC and early cirrhosis were also compared among CT, MRI and US using a receiver-operating characteristic (ROC) curve analysis. RESULTS: The differences in the five imaging parameters evaluated by CT, MRI and US between LC and CH were statistically significant (p < 0.001) except for the manifestations of portal hypertension on US. Irregular or nodular surface, blunt edge or morphological changes in the liver were selected as the best predictive signs for cirrhosis on US whereas liver parenchymal abnormalities, manifestations of portal hypertension and morphological changes in the liver were the best predictive signs on MRI and CT by multivariate analysis. The predictive diagnostic accuracy, sensitivity and specificity in discriminating LC from CH based on the best predictive signs were 71.9, 77.1 and 67.6% by CT; 67.9, 67.5 and 68.3% by MRI, and 66.0, 38.4 (lower than CT and MRI, p =0.001) and 88.8% (higher than CT and MRI, p =0.001)by US. According to the imaging impression scoring system, diagnostic accuracy, sensitivity and specificity were 67.0, 84.3 and 52.9% by CT; 70.3, 86.7 and 53.9% by MRI, and 64.0, 52.4 (lower than CT and MRI, p =0.0001) and 73.5% (higher than CT and MRI, p < 0.003) by US. ROC analysis showed that MRI and CT were slightly superior to US in the diagnosis of LC but no statistically significant difference was found between them. For the pathological diagnosis of P-LC, cirrhosis was diagnosed in 59.5, 46.7 and 41.7% of the P-LC cases by US, CT and MRI, respectively, with no significant difference among these methods. CONCLUSION: US, CT and MRI had different independent predictive signs for the diagnosis of LC. MRI and CT were slightly superior to US in predicting cirrhosis, especially regarding sensitivity. Noninvasive imaging techniques play an important role in the diagnosis of cirrhosis, especially in the evaluation of P-LC.

A new prognostic staging system for hepatocellular carcinoma: value of the biomarker combined Japan integrated staging score.

OBJECTIVES: The Japan Integrated Staging (JIS) score has been reported to have good stratification ability in patients with hepatocellular carcinoma (HCC). However, the JIS score could not estimate malignant grade of HCC. The aim of this study was to evaluate the performance of a new staging system: the biomarker combined JIS (bm-JIS) which includes three tumor markers: alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP and des-gamma-carboxy prothrombin with the conventional JIS score. METHODS: A total of 1,924 HCC patients were included in this study. We compared their overall survival, the stratification ability and suitability as a prognostic model according to the bm-JIS score and the conventional JIS score. RESULTS: There were significant differences between the survival curves for all bm-JIS scores. For the conventional JIS scores of 0, 1, 2 and 3, the survival curves differed greatly according to the bm-JIS score (p < 0.0001). The independent homogenizing ability and the stratification value of the JIS score and the bm-JIS score determined by the likelihood ratio test using the Cox proportional hazard regression model showed the bm-JIS score to have a higher value(chi2 = 717.348) than the JIS score (chi2 = 668.91). CONCLUSIONS: The bm-JIS score showed superior stratification ability and thus was found to be a better predictor of the prognosis than the conventional JIS score, especially for the patients with good prognosis.

Severe complications of radiofrequency ablation therapy for hepatocellular carcinoma: an analysis of 3,891 ablations in 2,614 patients.

OBJECTIVE: To clarify information on and frequency of complications as well as mortality rate after radiofrequency ablation (RFA) for hepatocellular carcinoma. METHODS: The results of a questionnaire obtained mainly from members of the Osaka Liver Cancer Study Group at 43 departments of 38 facilities were analyzed in order to clarify the current status of RFA, and information on and frequency of complications and death occurring after RFA. RESULTS: Between January 1999 and May 2002, a total of 3,891 RFA therapies were performed percutaneously in 2,542 patients, laparoscopically in 23, and operatively in 49 (2,614 patients in total). Complications were observed in 207 of 2,614 patients (7.9%), and 9 (0.3%) died within 3 months after RFA. Among these 9 nonsurvivors, 3 had liver failure, 3 rapid progression and sarcomatous changes, 1 biliary injury, 1 gastrointestinal bleeding, and 1 acute myocardial infarction. The departments that treated larger numbers of patients per month had a smaller number of complications and deaths. CONCLUSION: It is possible that complications of RFA can be reduced by gathering experience.

Randomized, double-blind, placebo-controlled trial of bovine lactoferrin in patients with chronic hepatitis C.

Several studies have suggested that lactoferrin administration may decrease the serum level of hepatitis C virus (HCV) RNA in patients with chronic hepatitis C. The aim of the present study was to confirm the efficacy of orally administered bovine lactoferrin (bLF) in patients with chronic hepatitis C. The patients with chronic hepatitis C randomly received either oral bLF at a dose of 1.8 g daily for 12 weeks, or an oral placebo. The primary endpoint was the virologic response, defined as a 50% or greater decrease in serum HCV RNA level at 12 weeks compared with the baseline. The secondary endpoint was the biochemical response, which was defined as a 50% or greater decrease in the serum alanine aminotransferase (ALT) level at 12 weeks compared with the baseline. One hundred and ninety-eight of 199 patients were evaluable for efficacy and safety. bLF treatment was well tolerated and no serious toxicities were observed. A virologic response was achieved in 14 of 97 patients (14.4%) in the bLF group, and 19 of 101 (18.8%) in the placebo group. There was no significant difference in virologic response rates between the two groups (-4.4%, 95% confidence interval -14.8, 6.1). In addition, bLF intake did not have any favorable effect on the serum ALT level. The virologic responses were not different between two groups in any subgroup analysis. In conclusion, orally administered bLF does not demonstrate any significant efficacy in patients with chronic hepatitis C.

A proposal of the modified liver damage classification for hepatocellular carcinoma.

OBJECTIVE: The purpose of this study was to evaluate the validity of the two common classifications for assessing liver function; the Child-Pugh classification and the liver damage classification. We also examined the feasibility of the modified liver damage classification. METHODS: A total of 2306 HCC patients diagnosed between 1990 and 2002 were categorized according to the three classifications. The modified liver damage classification is calculated by summation of the scores for five variables (serum bilirubin level, serum albumin level, prothrombin activity, ICG retention rate at 15min, ascites) of the liver damage classification and classified patients into grades A-C in the similar manner as the Child-Pugh classification. The differences in distribution and survival rate of the patients in each group were compared. RESULTS: With respect to the patient distribution, 1787 (77.5%) and 469 (20.3%) patients were categorized into Child-Pugh grades A and B, respectively, whereas 1187 (51.5%) and 962 (41.7%) patients were categorized into liver damage grades A and B, respectively. As a result of this disproportionate distribution, survival rates of Child-Pugh grades A and B were lower than those of the liver damage grades A and B. Furthermore, some discrepancies were found in the distribution of patients between the liver damage classification and the modified liver damage classification. One hundred and forty-one patients of the 1187 liver damage grade A patients were categorized into grade B by the modified liver damage classification and 71 patients of the 962 liver damage grade B patients were categorized into grade C by the modified liver damage classification. The survival rates of these subgroups were similar to those of the liver damage grades B and C, respectively. CONCLUSION: The modified liver damage classification appears to be the best available tool for assessing residual liver function, for estimating the survival of Japanese HCC patients and for making decisions concerning the treatment of these patients.

Validation of a new prognostic staging system for hepatocellular carcinoma: the JIS score compared with the CLIP score.

The Japan Integrated Staging score (JIS score), which combines the Child-Turcotte-Pugh classification and tumor-node-metastasis staging, has been proposed as a better prognostic staging system for hepatocellular carcinoma (HCC) than the Cancer of the Liver Italian Program (CLIP) scoring system. In this study, validation was performed among a larger patient population. A total of 4,525 consecutive patients with HCC who had been diagnosed at five institutions were included. Stratification ability, prognostic predictive power, and reproducibility were analyzed and compared with results from the CLIP scoring system. Only 45% (1,951 of 4,525) of all patients were categorized as early stage HCC according to JIS score (0 or 1), whereas 63% (2,878 of 4,525) of the patients were categorized as having a CLIP score of 0 or 1. Significant differences in survival curves were not observed among CLIP scores 3 to 6. In contrast, survival curves showed significant differences among all the JIS scores. The same JIS scoring subgroups showed a similar prognosis, and good internal reproducibility was observed in each of the institutions. Multivariate analysis of the prognosis in all 4,525 patients proved the JIS score to be the best prognostic factor. Furthermore, the Akaike information criteria proved that the JIS scoring system was statistically a better model for predicting outcome than the CLIP scoring system. In conclusion, the stratification ability and prognostic predictive power of the JIS score were much better than that of the CLIP score and were simple to obtain and remember.

[Comparison of treatment methods for hepatocellular carcinoma--based on JIS score].

It is well known that prognosis of patients with hepatocellular carcinoma (HCC) depends not only cancer spread, but also on liver disease stage. The Japan Integrated Staging (JIS) scoring system, which combines TNM stage and Child-Pugh stage, is superior to CLIP Score in the discriminatory ability of the prognosis in 3,934 patients with HCC. Therefore, it is also useful in the comparison of the treatment results between treatment modalities or between institutions. It is thus recommended that the JIS score be used in the comparison of treatment results of patients with HCC.