Shuntaro Obi

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

IntroductionThe Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the management of hepatocellular carcinoma (HCC) in December 2008 to develop consensus recommendations.MethodsThe working party consisted of expert hepatologist, hepatobiliary surgeon, radiologist, and oncologist from Asian-Pacific region, who were requested to make drafts prior to the consensus meeting held at Bali, Indonesia on 4 December 2008. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively, according to the Oxford system of evidence-based approach for developing the consensus statements.ResultsParticipants of the consensus meeting assessed the quality of cited studies and assigned grades to the recommendation statements. Finalized recommendations were presented at the fourth APASL single topic conference on viral-related HCC at Bali, Indonesia and approved by the participants of the conference.

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.

Nonsurgical treatment of hepatocellular carcinoma: From percutaneous ethanol injection therapy and percutaneous microwave coagulation therapy to radiofrequency ablation

Treatment of hepatocellular carcinoma (HCC) is different from that of other solid tumors, in that surgery plays a limited role while nonsurgical therapies are very instrumental. At our institute, 90% of previously untreated patients have received image-guided percutaneous tumor ablations, such as percutaneous ethanol injection therapy (PEIT), percutaneous microwave coagulation therapy (PMCT) and radiofrequency ablation (RFA). We performed PEIT in 756 patients with HCC. Their survival rates were 89% at 1 year, 64% at 3 years, 39% at 5 years, and 18% at 10 years. With PMCT, survival rates of 122 new patients with HCC were 90% at 1 year, 87% at 2 years, and 68% at 3 years. We performed RFA in 324 patients. RFA required fewer treatment sessions and a shorter hospital stay than PEIT or PMCT to achieve complete necrosis of the lesions. By virtue of their local curability, minimal effect on liver function, and easy repeatability for recurrence, image-guided percutaneous tumor ablations, especially RFA, will be increasingly important in the treatment of HCC.

Prediction of recurrence of hepatocellular carcinoma after curative ablation using three tumor markers

Three tumor markers for hepatocellular carcinoma (HCC) are available in daily practice in Japan: alpha‐fetoprotein (AFP), des‐gamma‐carboxy prothrombin (DCP), and lens culinaris agglutinin‐reactive fraction of alpha‐fetoprotein (AFP‐L3). To elucidate the predictability of these tumor markers on HCC recurrence after curative ablation, we enrolled 416 consecutive patients with naïve HCC who had been treated by percutaneous ablation at our department from July 1997 to December 2002. Tumor marker levels were determined immediately before and 2 months after the treatment. Complete ablation was defined on CT findings as nonenhancement in the entire lesion with a safety margin. Tumor recurrence was also defined as newly developed lesions on CT that showed hyperattenuation in the arterial phase with washout in the late phase. We assessed the predictability of recurrence via tumor markers in multivariate analysis, using proportional hazard regression after adjusting for other significant factors in univariate analysis. Until the end of follow‐up, tumor recurrence was identified in 277 patients. Univariate analysis revealed the following factors to be significant for recurrence: platelet count; size and number of tumors; AFP, AFP‐L3, and DCP preablation; and AFP and AFP‐L3 postablation. Multivariate analysis indicated that AFP >100 ng/mL and AFP‐L3 >15%, both pre‐ and postablation, were significant predictors. The positivity of AFP and AFP‐L3 preablation that turned negative postablation was not significant. In conclusion, tumor markers pre‐ and post‐ablation were significant predictors for HCC recurrence and can complement imaging modalities in the evaluation of treatment efficacy. (HEPATOLOGY 2006;44:1518–1527.)

Neoplastic seeding after radiofrequency ablation for hepatocellular carcinoma.

BACKGROUND:Neoplastic seeding reportedly occurs in up to 12.5% of patients treated with radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). The aim of this study is to assess the incidence, risk factors, and prognosis of neoplastic seeding after RFA among a large number of patients with a long-term follow-up.METHOD:From February 1999 to December 2004, 1,031 patients underwent a total of 1,845 treatments with RFA for a total of 3,837 HCC nodules. The following variables were assessed to elucidate the risk factors of neoplastic seeding: age, sex, positivity for viral markers, tumor size, number of tumor nodules, number of RFA sessions, tumor location, percutaneous biopsy prior to RFA, alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP) and lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) levels, and the degree of tumor differentiation.RESULTS:Neoplastic seeding was detected in 33 patients (3.2% per patient) at intervals of 4.8–63.8 (median, 15.2) months after RFA. On multivariate logistic regression analysis, only the poor differentiation degree was associated with the risk of neoplastic seeding (P = 0.012). Of tumor factors, tumor size, and AFP, DCP, and AFP-L3 levels were significantly associated with the poor differentiation degree. The cumulative survival rates 1 and 2 yr after the detection of neoplastic seeding were 86% and 47%, respectively.CONCLUSION:Poor differentiation degree was the risk factor of neoplastic seeding after RFA for HCC. The surrogate markers for poor differentiation degree were larger tumor size and elevated tumor marker levels. Indication for RFA should be carefully considered for HCC patients under these conditions.

Absence of PIK3CA hotspot mutations in hepatocellular carcinoma in Japanese patients

A recent study revealed that the p110α (PIK3CA), catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is somatically mutated in many types of cancer. For example, PIK3CA is mutated in an estimated 35.6% of hepatocellular carcinoma (HCC) cases. To measure the frequency of PIK3CA hotspot mutations in Japanese HCC patients, exons 9 and 20 of the PIK3CA gene were sequenced in 47 clinical HCC samples. Contrary to expectations, no hotspot mutations were found any of the HCC samples. In addition, we found abnormally migrating waves near the end of exon 9 in the PCR chromatograms from 13 of the 47 samples. PCR amplification and subsequent cloning and sequencing revealed that these chromatograms contained two distinct sequences, the wild-type p110α sequence and a different sequence found on human chromosome 22q11.2, the Cat Eye Syndrome region, which contains a putative pseudogene of PIK3CA. These abnormally migrating waves were also found in noncancerous liver tissue, indicating that this was not a result of HCC-associated mutations. Therefore, it is likely that the percentage of hotspot mutations in the PIK3CA gene of Japanese HCC patients is lower than was previously reported.

Extrahepatic metastasis of hepatocellular carcinoma: incidence and risk factors

Background: Extrahepatic metastasis of hepatocellular carcinoma (HCC) is of growing importance as the survival of patients has been improved owing to advances in treatments to intrahepatic lesions.

Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update

There is great geographical variation in the distribution of hepatocellular carcinoma (HCC), with the majority of all cases worldwide found in the Asia–Pacific region, where HCC is one of the leading public health problems. Since the “Toward Revision of the Asian Pacific Association for the Study of the Liver (APASL) HCC Guidelines” meeting held at the 25th annual conference of the APASL in Tokyo, the newest guidelines for the treatment of HCC published by the APASL has been discussed. This latest guidelines recommend evidence-based management of HCC and are considered suitable for universal use in the Asia–Pacific region, which has a diversity of medical environments.