Shinpei Sato

Interferon Therapy after Tumor Ablation Improves Prognosis in Patients with Hepatocellular Carcinoma Associated with Hepatitis C Virus

Context Hepatocellular carcinoma often follows hepatitis C virus infection. Currently available treatments for hepatocellular carcinoma are unsatisfactory. Percutaneous ethanol injection therapy into tumor nodules shows some promise, but recurrence rates are high. Contribution In a carefully selected group of 74 patients with multicentric hepatocellular carcinoma, mild hepatitis C, and mild cirrhosis, patients randomly assigned to receive interferon in addition to ethanol injections showed improved survival at 5 and 7 years, particularly among patients with a sustained virologic response. Cautions Combined treatment of multicentric hepatocellular carcinoma offers the possibility of enhanced survival for carefully selected patients; this study is small, however, and enrolled only patients with low virus levels and mild cirrhosis. The Editors Chronic hepatitis C virus (HCV) infection is a common, frequently asymptomatic disease. Despite the clinically quiescent course of HCV infection, it may slowly progress to cirrhosis and, eventually, to hepatocellular carcinoma (1, 2). Cirrhosis is a major risk factor for the development of hepatocellular carcinoma (3, 4), and 70% to 80% of patients with hepatocellular carcinoma in Japan have HCV infection (5). Current strategies for treating hepatocellular carcinoma include surgical resection, transarterial embolization, percutaneous ethanol injection therapy, radiofrequency wave ablation, and chemotherapy (6-9). Recent studies have shown that percutaneous ethanol injection therapy is effective for hepatocellular carcinoma when the tumors are small (<3 to 5 cm in diameter) and limited in number; survival rates are similar to those obtained with surgery (10-12). Five-year survival rates, however, are poor (30% to 60% for both hepatectomy and percutaneous ethanol injection therapy). Poor prognosis may be the result of the high incidence of tumor recurrence; the cumulative recurrence rate at 5 years is 60% to 100% (10-13). Several studies have evaluated the factors that contribute to the recurrence of hepatocellular carcinoma (12, 13). Occasionally, early recurrence develops adjacent to the treated lesion (local recurrence, 6% to 33% depending on tumor size) (14), but most tumors (80% to 90%) recur at different sites (15). Because hepatocellular carcinoma recurrence and decompensation of underlying liver disease are major problems after medical or surgical treatment, liver transplantation is another option for treating small, unresectable hepatocellular carcinomas in patients with cirrhosis. Studies report 5-year survival rates as high as 75% with liver transplantation (16-18). Interferon therapy has beneficial effects in chronic HCV infection (19, 20). In long-term follow-up studies, sustained virologic responders have remained in remission with normal liver function and improved histologic features of inflammation; in some of these responders, fibrosis even regresses (21, 22). Recently, the frequency of hepatocellular carcinoma in patients receiving interferon therapy has substantially decreased, especially in patients with sustained virologic and biochemical responses (23-25). This decreased frequency has occurred even in patients with cirrhosis (25, 26). Our study evaluated whether complete ablation of neoplastic nodules and administration of antiviral therapy could increase survival rates. Methods Study Design Our prospective study was designed by an eight-member committee in December 1992. The Ethics Committee of the University of Tokyo approved the study. We obtained informed consent from each patient in accordance with the Helsinki declaration. Patients with compensated cirrhosis, three or fewer nodules of hepatocellular carcinoma, and low HCV RNA loads were recruited after complete ablation of the lesions. Eligibility Criteria Inclusion Criteria Hepatitis C virus infection was diagnosed on the basis of identification of anti-HCV antibody using the passive hemagglutination test (Dinabbot, Tokyo, Japan) or enzyme-linked immunosorbent assay (ELISA; Ortho Diagnostic Systems, Tokyo, Japan). Hepatitis C virus RNA was identified by reverse transcriptase polymerase chain reaction (RT-PCR). The serum HCV RNA level was measured by competitive reverse transcriptase (CRT)-PCR according to the method of Kato and colleagues (27); HCV genotype was determined by the method of Okamoto and colleagues (28). Hepatocellular carcinoma was suspected on the basis of several imaging methods, including abdominal ultrasonography, dynamic computed tomography (CT), magnetic resonance imaging (MRI), and arteriography. We confirmed the diagnosis by histologic examination of tumor biopsy specimens obtained from all patients. Evaluation was based on the criteria of the International Working Party (29). In addition, we obtained and evaluated biopsy specimens from non-neoplastic lesions according to the methods of Desmet and colleagues (30). Hepatocellular carcinoma was treated with percutaneous ethanol injection therapy (7, 8, 10). Real-time linear-array scanners were used with 3.5-MHz transducers for the sonographic guidance of needles [21-gauge with a 15-cm or 20-cm needle; Hanako, Tokyo, Japan] into the tumors. Two to 10 mL of 99.5% ethanol was injected into each lesion. Ethanol injection was repeated several times at different sessions. Complete destruction of the nodules was confirmed on dynamic CT 1 month after ethanol injection according to the following criteria: 1) The destructive area was larger than the area of the tumor nodule shown on pretreatment dynamic CT and 2) dynamic CT showed no early-phase contrast enhancement of nodules (7, 8, 10). Inclusion criteria were as follows: 1) hepatocellular carcinoma with three or fewer lesions [verified by histologic examination] and dynamic CTconfirmed complete ablation of hepatocellular carcinoma lesions by percutaneous ethanol injection therapy, 2) detection of HCV RNA by RT-PCR and an HCV RNA load of 2 106 copies/mL or less by CRT-PCR (the cutoff value was based on unpublished data indicating that interferon treatment was effective in patients with HCV RNA loads of 105 copies/50 L of serum by CRT-PCR [27]], 3) platelet count of 50 109 cells/L, 4) leukocyte count of 3 109 cells/L or greater, 5) compensated cirrhosis in ChildPugh stage A, 6) age younger than 70 years, 7) no previous treatment with interferon, and 8) submission of informed consent. Exclusion Criteria Exclusion criteria were as follows: 1) liver diseases due to other causes, such as hepatitis B or primary biliary cirrhosis; 2) HCV RNA load of 2 106 copies/mL or greater by CRT-PCR; 3) severe comorbid diseases, such as heart disease, lung disease, or diabetes mellitus; 4) decompensated cirrhosis in ChildPugh stage B or C; and 5) failure to obtain informed consent. Randomization Patients who enrolled in the study were randomly assigned in a 2:1 ratio to the interferon group or the control group by the controller. We assigned patients to the treatment group or control group by using a randomization list. Interferon Therapy and Follow-up of Patients Interferon Therapy We started interferon therapy with natural interferon- (Sumitomo Pharmaceuticals, Tokyo, Japan) 2 to 3 months after tumor ablation was confirmed. Patients received 6 million U of interferon by intramuscular injection three times weekly for 48 weeks as outpatients. If patients could not tolerate this dose, the interferon dose was reduced to 3 million U. If HCV RNA in serum was still detected by RT-PCR (detection limit, 102 copies/mL) after 24 weeks of interferon therapy and serum alanine aminotransferase (ALT) levels were higher than pretreatment ALT levels, therapy was discontinued. Criteria for Interferon Response We defined the efficacy of interferon therapy virologically and biochemically. Patients who were negative for HCV RNA (as determined by RT-PCR; detection limit, 102 copies/mL) more than 6 months after the completion of interferon therapy were classified as showing a sustained virologic response. Patients with persistently normal ALT levels after the completion of interferon therapy were classified as showing a sustained biochemical response; patients with abnormal ALT levels were classified as showing a nonsustained biochemical response. Follow-up Patients attended a monthly medical consultation at the University of Tokyo Hospital outpatient clinic. Blood biochemical measures, including -fetoprotein (AFP) tumor markers, were measured every 1 to 2 months; ultrasonography was performed every 2 to 3 months; and dynamic CT was performed every 6 months. Recurrence of hepatocellular carcinoma was detected by the finding of abnormal nodules with low or high echogenic appearance on abdominal ultrasonography or by the finding of abnormal density on dynamic CT. The diagnosis was confirmed histologically through ultrasonography-guided fine-needle biopsy of the tumor. Recurrent nodules were divided into two categories [14, 15]: 1) local recurrence, in which the nodule appeared adjacent to the previously treated nodules, suggesting that residual tumor cells had not been completely ablated by percutaneous ethanol injection therapy, or 2) new foci developing at a distant site. New foci of hepatocellular carcinoma, as well as local recurrent nodules at tumor, node, metastasis (TNM) stage I, II, and III, were mainly treated by a second course of percutaneous ethanol injection therapy; local recurrent nodules at TNM stage IV were treated with transarterial chemoembolization or chemotherapy. New development of hepatocellular carcinoma and survival of the patients (tumor recurrence rate and survival rate) were analyzed in relation to the time interval after initial treatment. Statistical Analysis When estimating the sample size, we assumed that 5-year survival in the control group would be 40% according to the data of our previous unpublished study. We predicted that 5-year survival would be increased by 35% as a result of treatment

Radiofrequency ablation for hepatocellular carcinoma in so‐called high‐risk locations

We evaluated the efficacy and safety of radiofrequency (RF) ablation for hepatocellular carcinoma (HCC) in presumably high‐risk locations. Between February 1999 and December 2001, we performed RF ablation on 1,419 nodules in 636 consecutive HCC patients, of which 231 nodules in 207 patients were in high‐risk locations, defined as less than 5 mm from a large vessel or an extrahepatic organ. Eighty‐one patients had a nodule adjacent to a large vessel, 145 patients had a nodule adjacent to an extrahepatic organ, of whom 19 also had one adjacent to a large vessel. Early complications and local tumor progression were analyzed with regard to the location of each nodule. The mean nodule diameter and average number per patient were 27 mm and 2.3, respectively. Early complications, within 30 days after ablation, occurred in 12 of 207 patients (5.8 %) with a nodule in a high‐risk location and in 15 of 429 patients (3.5 %) without (P = .1776). There was no significant difference in local tumor progression rate between nodules in high‐risk locations (1 year: 2.1%, 2 years: 3.1%, 3 years: 3.1%) and those elsewhere (1 year: 0.6%, 2 years: 1.7%, 3 years: 2.5%) (P = .2745). In conclusion, HCC nodules adjacent to a large vessel or extrahepatic organ were treated with RF ablation without compromising the efficacy of the procedure. However, even though without significant difference, some complications occurred at risky locations and need to be carefully considered. (HEPATOLOGY 2006;43:1101–1108.)

Proposal of a new prognostic model for hepatocellular carcinoma: an analysis of 403 patients

Background: The prognosis of hepatocellular carcinoma (HCC) is highly dependent on tumour extension and liver function. Recently, two new prognostic scoring systems—the CLIP score, developed by Italian investigators and the BCLC score, developed in Barcelona—have been widely used to assess prognosis in patients presenting with hepatocellular carcinoma. Each system has its own relative limitations. Aims: To create a new prognostic scoring system which is simple, easy to calculate, and suitable for estimating prognosis during radical treatment of early HCC. Methods: A total of 403 consecutive patients with HCC treated by percutaneous ablation at the Department of Gastroenterology, University of Tokyo Hospital, between 1990 and 1997 were used as the training sample to identify prognostic factors for our patients and used to develop the Tokyo score. As a testing sample, 203 independent patients who underwent hepatectomy at the Department of Hepato-Biliary-Pancreatic Surgery were studied. Prognostic factors were analysed by univariate and multivariate Cox proportional hazard regression. Results: The Tokyo score consists of four factors: serum albumin, bilirubin, and size and number of tumours. Five year survival was 78.7%, 62.1%, 40.0%, 27.7%, and 14.3% for Tokyo scores 0, 1, 2, 3, and 4–6, respectively. The discriminatory ability of the Tokyo score was internally validated by bootstrap methods. The Tokyo score, CLIP score, and BCLC staging were compared by Akaike information criterion and Harrell’s c index among training and testing samples. In the testing sample, the predictive ability of the Tokyo score was equal to CLIP and better than BCLC staging. Conclusions: The Tokyo score is a simple system which provides good prediction of prognosis for Japanese patients with HCC requiring radical therapy.

Unique clinical characteristics of patients with hepatocellular carcinoma who present with high plasma des‐γ‐carboxy prothrombin and low serum α‐fetoprotein

Although the importance of α‐fetoprotein (AFP) and des‐γ‐carboxy prothrombin (DCP) in the clinical treatment of hepatocellular carcinoma (HCC) has been studied extensively, the authors examined the clinical picture of HCC with regard to the state of these two tumor markers.

Risk Assessment of Hepatocellular Carcinoma in Chronic Hepatitis C Patients by Transient Elastography

Objective The degree of liver fibrosis is the strongest indicator of risk for hepatocellular carcinoma (HCC) development. Recently developed transient elastography (Fibroscan, Echosens, France) noninvasively measures liver stiffness, and the correlation between the stiffness and liver fibrosis stage has been validated. In this cross-sectional study, we investigated the relationship between liver stiffness and HCC presence. Methods Liver stiffness was measured in chronic hepatitis C patients (85 with HCC and 180 without) by transient elastography. Multivariate logistic regression was applied to assess the association with HCC presence. We computed the receiver operating characteristics (ROC) curves concerning the prediction of HCC presence and compared the areas under ROC curve (AUROC). We also calculated stratum-specific likelihood ratios (SSLR). Results Multivariate analysis showed that HCC presence was significantly associated with liver stiffness (P<0.0001) along with age, male, and alpha-fetoprotein concentration. AUROC was 0.805, 0.741, 0.714, 0.673, 0.670, and 0.654 for liver stiffness, alpha-fetoprotein, albumin, prothrombin activity, AST-platelet ratio index, and platelet count, respectively. Other parameters showed smaller AUROC. SSLR for HCC presence by liver stiffness was 0.22 (95% confidence interval: 0.11-0.42) in <10 kPa, 0.73 (0.39 to 1.39) in 10.1 to 15 kPa, 1.30 (0.80 to 2.12) in 15.1 to 25 kPa, and 5.0 (2.96 to 8.47) in >25 kPa. Conclusions Liver stiffness measured by transient elastography is useful in demarcating chronic hepatitis C patients at a high risk for HCC, who require frequent check-up by imaging examinations.

Evaluation of transcatheter arterial embolization prior to percutaneous tumor ablation in patients with hepatocellular carcinoma: a randomized controlled trial.

Abstract: Background: Transcatheter arterial embolization (TAE) may reduce the risk of hepatocellular carcinoma (HCC) recurrence when performed before percutaneous tumor ablation (PTA), either percutaneous ethanol injection therapy (PEIT) or radiofrequency ablation (RFA). We conducted a randomized, controlled trial comparing the use of TAE combined with percutaneous ethanol injection therapy (TAE/PEIT) to the use of PEIT only to assess the effects on HCC recurrence and survival. We continued the study after the introduction of RFA and compared TAE combined with RFA (TAE/RFA) with RFA only.

Health‐related quality of life of chronic liver disease patients with and without hepatocellular carcinoma

Background and Aim:  Impaired health‐related quality of life has been reported in patients with cirrhosis and chronic hepatitis. However, only limited data are available concerning the influence of hepatocellular carcinoma.

Percutaneous ethanol injection for hepatocellular carcinoma: 20‐year outcome and prognostic factors

Ethanol injection is the best‐known image‐guided percutaneous ablation for hepatocellular carcinoma (HCC) and a well‐tolerated, inexpensive procedure with few adverse effects. However, there have been few reports on its long‐term results.

Hepatocellular Carcinoma in Elderly Patients Beneficial Therapeutic Efficacy using Percutaneous Ethanol Injection Therapy

The age of patients with hepatocellular carcinoma (HCC) has been increasing worldwide. The objective of this study was to assess the efficacy and safety of percutaneous ethanol injection therapy (PEIT) in elderly patients with HCC.

Power Doppler signals after percutaneous ethanol injection therapy for hepatocellular carcinoma predict local recurrence of tumors: a prospective study using 199 consecutive patients

BACKGROUND/AIMS This study was prospectively conducted to elucidate the relationship between pre-/post-treatment power Doppler signals of hepatocellular carcinoma (HCC) and local recurrence. METHODS One hundred ninety-nine consecutive patients with 359 HCC lesions receiving percutaneous ethanol injection therapy (PEIT) as a first-line option were enrolled. Arterial power Doppler signals in the tumor were found in 130 nodules, but not detected in 229. After confirmation of complete tumor necrosis on dynamic CT, Doppler signals in nodules were re-evaluated. Patients received periodical examinations to detect HCC recurrence. RESULTS Local HCC recurrence was observed in 36 lesions; 22%(28/130) of the pretreatment signal positive lesions, in contrast to 3.5% (8/229) of the pretreatment signal negative lesions (P < 0.01). Out of 130 signal positive nodules, signals disappeared in 120 (92%) after PEIT, but were present in ten (8%). During the 25-month follow up, local recurrence was detected in 19 (16%) from the former, in contrast to nine (90%) from the latter (P < 0.001). Uni- and multivariate Cox analysis revealed that the presence of pre-/post-treatment power Doppler signals, histological differentiation and tumor number were independent factors for local recurrence. However, 3-year recurrence rate of new lesions was 51%, but no predictors were identified. CONCLUSIONS Residual Doppler signals in tumor after PEIT were related to the local HCC recurrence.