Hobyung Chung

Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score)

A clinical staging system for cancer patients provides guidance for patient assessment and making therapeutic decisions. It is useful in deciding whether to treat a patient aggressively, and in avoiding the overtreatment of patients who would not tolerate the treatment or patients whose life expectancy rules out any chance of treatment. Clinical staging is also an essential tool for comparison between groups in therapeutic trials and for comparison between different studies. The current classifications most commonly used for hepatocellular carcinoma (HCC) are the Okuda stages, the Child-Pugh staging system, tumor node metastasis (TNM) staging, and the Cancer of the Liver Italian Program (CLIP) score. Among these, the CLIP score is currently the most commonly used integrated staging score, including both tumor stage and liver disease stage. Although the CLIP score has been well validated by many authors in terms of its prognostic value in HCC patients, this score has some problems and limitations when applied to currently diagnosed HCC patients, who are diagnosed in the early stage of disease. First, the CLIP score can discriminate score 0- to 3-patient populations, but it is not able to discriminate score 4- to 6-patient groups. Second, the definition of tumor morphology in the best prognostic group is too advanced, i.e., uninodular and a tumor extent of less than 50% of the liver. As a result, the prognosis of the CLIP system best prognostic group is not so good. In other words, this system cannot identify the best prognostic group who would benefit from curative and aggressive treatment. Third, nearly 80% of the patient population is classified as having a CLIP score of 0–2, as confirmed by many studies, which shows poor stratification ability. In contrast, a new staging system based on the Liver Cancer Study Group of Japan (LCSGJ), the Japan Integrated Staging (JIS) score is currently proposed in Japan. This staging system combines Child-Pugh grade (grade A, score 0; grade B, score 1; grade C, score 2) and TNM staging by the LCSGJ criteria (stage I, score 0; stage II, score 1; stage III, score 2; stage IV, score 3). The stratification ability of the JIS scoring system is much better than that of the CLIP scoring system. The JIS scoring system also performed better than the CLIP scoring system in selecting the best prognostic patient group. The cumulative 10-year survival rates of the best prognostic groups in the CLIP staging system (CLIP score 0) and JIS staging system (JIS score 0) were 23% and 65%, respectively (P < 0.01). All scoring systems arise as a compromise between simplicity and discriminatory ability. We confirmed that the JIS score increases predictive efficacy, while remaining simple compared with the CLIP score. Because the JIS score is quite easily obtained and is objective, we strongly propose it for widespread use as a prognostic staging system for HCC in clinical practice.

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. (HEPATOLOGY 2004; 40:1396–1405.)

Changing trends in hepatitis C infection over the past 50 years in Japan.

In Japan, hepatocellular carcinoma (HCC) is the fourth leading cause of death in males and the fifth in females. Hepatitis C virus (HCV) is a major cause of HCC in Japan, with 70% of cases being HCV related. HCV genotype 1b, the most prevalent subtype in Japan, started to spread in the 1930s among injecting drug users (IDUs) during and after World War II or through medical procedures such as blood transfusion and use of contaminated syringes. The prevalence of HCV infection is much lower in the current younger generation compared with that in the older generation, particularly those aged >55 years (0.1–0.2% vs. ≧ 2%). Therefore, the total number of patients with HCV infection is estimated to decrease, even though sporadic HCV transmission is mainly seen among young IDUs. Of note, HCV genotype 2 seems to be spreading among IDUs, but the response to antiviral therapy in these patients seems to be better than that in older patients, irrespective of the genotype. Although the number of patients who die because of HCC has steadily increased over the last 50 years, the incidence of HCC is now decreasing, mainly because of the decreased prevalence of HCV-related HCC.

Differential Diagnosis of Hepatic Tumors: Value of Contrast-Enhanced Harmonic Sonography Using the Newly Developed Contrast Agent, Sonazoid

Objective: To clarify the value of contrast-enhanced harmonic ultrasonography (US) with Sonazoid, a second-generation US contrast agent, in the differential diagnosis of liver tumors compared to dynamic CT. Methods: A total of 249 hepatic nodules in 214 patients were studied; these included 177 hepatocellular carcinomas (HCCs), 42 liver metastases, 20 liver hemangiomas, 6 dysplastic nodules and 4 focal nodular hyperplasias (FNHs). After the injection of Sonazoid, nodules were scanned using real-time contrast-enhanced harmonic US in the vascular phases, i.e. the early and late vascular phases, and the Kupffer phase. Results: Six enhancement patterns were identified to be significant for the differential diagnosis of hepatic tumors. In HCCs, the presence of intratumoral vessels supplied from the periphery and fast washout (sensitivity, 96.6%; specificity, 94.4%) were the most typical characteristics. In metastases, the presence of rim-like enhancement with peripheral tumor vessels (sensitivity, 88.1%; specificity, 100%) was the typical pattern. In hemangiomas, the presence of intratumoral hypoperfusion images with globular or cotton wool-like pooling, which continue to the late vascular phase (sensitivity, 90.0%; specificity, 99.6%), was typical. In dysplastic nodules, the presence of portal enhancement without arterial supply in the early vascular phase and the presence of intratumoral uptake in the Kupffer phase (sensitivity, 83.3%; specificity, 100%) were the most typical patterns. In FNHs, the presence of a spoke-wheel pattern in the early vascular phase with dense staining in the late vascular phase, and positive uptake within the nodule in the Kupffer phase (sensitivity, 100%; specificity, 100%) were the most typical patterns. Conclusion: Contrast-enhanced harmonic US with Sonazoid allowed intimate vascular and Kupffer imaging and, therefore, is useful for the differential diagnosis of hepatic tumors.

Noninvasive Evaluation of Hepatic Fibrosis Using Serum Fibrotic Markers, Transient Elastography (FibroScan) and Real-Time Tissue Elastography

Objective: The aim of this study was to investigate the accuracy of noninvasive tests, e.g. serum fibrotic markers, transient elastography and real-time tissue elastography, in the diagnosis of hepatic fibrosis, and to determine whether they can replace liver biopsy. Methods: 119 patients with chronic liver disease were included in this study. Serum fibrotic markers including hyaluronic acid, type IV collagen, type IV collagen 7S domain and type III procollagen-N-peptide were measured. Aspartate aminotransferase (AST) and platelet counts were also measured to calculate the AST to platelet ratio index (APRI). Liver stiffness was measured using FibroScan and real-time tissue elastography. Results: The fibrotic stage, determined by histopathological diagnosis of a liver biopsy sample, did not correlate as well with serum fibrotic markers although it was useful to diagnose liver cirrhosis. However, the stage of hepatic fibrosis correlated well with liver stiffness measured by FibroScan. FibroScan was also a much better predictor of liver cirrhosis than APRI. Furthermore, the levels of liver strain measured by real-time tissue elastography correlated well with liver stiffness (p < 0.05). Conclusion: Serum fibrotic markers and FibroScan are useful for distinguishing liver cirrhosis (F4) from chronic hepatitis (F1–F3). In addition, real-time tissue elastography is a novel and promising method to determine the stage of hepatic fibrosis.

Radiofrequency ablation of hepatocellular carcinoma: value of virtual CT sonography with magnetic navigation.

OBJECTIVE Virtual CT sonography with magnetic navigation yields cross-sectional images of CT volume data that correspond to the angle of the transducer in the magnetic field in real time. The purpose of this study was to evaluate the efficiency and feasibility of virtual CT sonography for radiofrequency ablation of hypervascular hepatocellular carcinoma poorly defined on B-mode sonography. MATERIALS AND METHODS One hundred one patients enrolled in the study were separated into two groups. Fifty-one patients with 65 hepatocellular carcinomas underwent prospective virtual CT sonography as guidance for radiofrequency ablation. Fifty patients with 63 hepatocellular carcinomas managed with B-mode sonographic guidance were retrospectively selected under the same conditions as the virtual CT sonography group to act as a historical control group. RESULTS In the virtual CT sonography group, technically successful ablation was achieved in a single session in 92% (47/51) of the patients and in two sessions in 8% (4/51). In the B-mode sonography group, technical success was achieved in a single session in 72% (36/50) of the patients, in two sessions in 24% (12/50), and in three sessions in 4% (2/50). Treatment analysis showed that the technical success rate after a single treatment session was significantly (p = 0.017) higher for the virtual CT sonography group. The number of treatment sessions was significantly (p = 0.021) lower for the virtual CT sonography group (mean, 1.1 +/- 0.1 vs 1.3 +/- 0.3 sessions). CONCLUSION Virtual CT sonographically assisted radiofrequency ablation is an efficient treatment of patients with hepatocellular carcinoma that is poorly defined on B-mode sonography.

Prognostic value of pretreatment levels of tumor markers for hepatocellular carcinoma on survival after curative treatment of patients with HCC

BACKGROUND/AIMS We evaluated the prognostic value of the pretreatment elevation of tumor markers for hepatocellular carcinoma (HCC) in patients who underwent curative treatment. METHODS We studied 801 patients who had been diagnosed as initial HCC and fulfilled the following criteria: maximum tumor size, < or = 3 cm; number of tumors, < or = 3; remnant liver function, Child-Pugh class A or B; treated by hepatectomy or locoregional thermal ablation (LTA); and alpha-fetoprotein (AFP), Lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3), and des-gamma carboxy prothrombin (DCP) were measured at diagnosis. We analyzed the effects of elevated tumor markers on patient survival in these 2 distinct groups with different types of treatment, i.e. hepatectomy and LTA. RESULTS By multivariate analysis in 345 patients who underwent hepatectomy, no tumor marker significantly affected decreased survival rate. In the 456 patients who underwent LTA, the elevation of AFP-L3 (p=0.0171) and DCP (p=0.0004) significantly affected decreased survival rate; DCP elevation had the strongest effect on patient survival. CONCLUSIONS The prognostic value of pretreatment tumor marker elevation was different in patients who underwent the curative treatment according to the type of treatment. Pretreatment elevation of AFP-L3 and DCP had prognostic values only in patients treated with LTA.

Initial Treatment Response Is Essential to Improve Survival in Patients with Hepatocellular Carcinoma Who Underwent Curative Radiofrequency Ablation Therapy

Objective: This study was undertaken to assess the outcome of potentially curative radiofrequency ablation (RFA) therapy for early-stage hepatocellular carcinoma (HCC) in patients with Child-Pugh stage A cirrhosis. Methods: This study retrospectively evaluated clinical outcomes in a cohort of 171 Child-Pugh stage A cirrhotic patients who received RFA for naïve HCC within the Milan criteria. The median follow-up period was 36.7 months. Results: Cumulative survival rates estimated by the Kaplan-Meier method for all patients were 98.8, 91.1 and 76.8% at 1, 3 and 5 years, respectively. Cumulative probabilities of local tumor recurrence at 1, 2 and 3 years were 9.0, 14.1 and 17.7%, respectively. Cumulative survival rates in patients without local tumor recurrence were 96.6, 94.6 and 84.4% at 1, 3 and 5 years, respectively, compared with patients with local tumor recurrence (96.6, 74.8 and 42.1% at 1, 3 and 5 years, respectively; p = 0.0002). Cox regression analysis showed that low serum albumin (p = 0.009, RR 3.04, CI 1.32–6.98), high range of PIVKA-II (prothrombin induced by vitamin K absence or agonist II) (p = 0.025, RR 2.57, CI 1.13–5.89), with multiple (less than 3) nodules (p = 0.021, RR 2.61, CI 1.15–5.91), and with local tumor recurrence (p = 0.004, RR 3.62, CI 1.51–8.69) were significant risk factors for death. Conclusion: Initial complete response of curative RFA therapy in patients with Child-Pugh stage A cirrhosis and early-stage HCC is associated with improved survival. Therefore, clinicians should aim to achieve complete ablation of all detectable HCC nodules with adequate safety margins.

Contrast Harmonic Sonography-Guided Radiofrequency Ablation Therapy Versus B-Mode Sonography in Hepatocellular Carcinoma: Prospective Randomized Controlled Trial

OBJECTIVE The purpose of this study was to evaluate the effectiveness of contrast harmonic sonographic guidance in radiofrequency ablation of locally progressive hepatocellular carcinoma poorly depicted with B-mode sonography. SUBJECTS AND METHODS A series of 40 patients with hepatocellular carcinoma with local tumor progression poorly depicted with B-mode sonography were randomly treated with radiofrequency ablation guided by either contrast harmonic sonography (n = 20) or conventional B-mode sonography (n = 20). Unpaired Students t tests were performed to compare numbers of treatment sessions. RESULTS Treatment analysis showed that the complete ablation rate after a single treatment session was significantly higher in the contrast harmonic sonography group than in the B-mode sonography group (94.7% vs 65.0%; p = 0.043) and that the number of treatment sessions was significantly lower in the contrast harmonic sonography group (mean, 1.1 +/- 0.2 vs 1.4 +/- 0.6; p =0.037). CONCLUSION Contrast harmonic sonography-guided radiofrequency ablation is an efficient technique for guiding further ablation of local tumor progression not clearly demarcated with B-mode sonography.

Long-Term Interferon Maintenance Therapy Improves Survival in Patients with HCV-Related Hepatocellular Carcinoma after Curative Radiofrequency Ablation

Objective: To assess whether low-dose, long-term maintenance interferon (IFN) therapy inhibits recurrence after complete ablation of hepatocellular carcinoma (HCC) and improves patient survival. Methods and Patients: From June 1999 through May 2006, a total of 127 HCC cases that met the requirements of both tumor diameter 3 cm or less, and number of tumors three or fewer, were curatively treated by radiofrequency ablation therapy (RFA). Among them, 43 patients received three million IU of IFN-α2b twice per week or pegylated IFN-α2a 90 µg once per week or once per 2 weeks without discontinuation (IFN maintenance group). The remaining 84 patients, whose sex, age, and platelet counts were randomly matched to those of the IFN maintenance group, did not receive IFN treatment (control group). Results: Cumulative first, second, and third recurrence rates were significantly reduced in the IFN maintenance group compared with the control group by Kaplan-Meier estimate. The 5-year survival rate was 66% for the control group and 83% for the IFN maintenance group (p = 0.004). Multivariate analysis using the Cox proportional hazards model identified IFN maintenance therapy as an independent risk factor for survival, and the risk ratio was 0.21 (95% CI: 0.05–0.73). In conclusion, low-dose, long-term maintenance IFN therapy after curative RFA therapy of HCC significantly inhibits recurrence, and consequently improves patient survival.