Emi Ishikawa

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.

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.

Non-Invasive Evaluation of Hepatic Fibrosis for Type C Chronic Hepatitis

Objective: The aim of this study was to investigate liver fibrosis using non-invasive Real-time Tissue Elastography® (RTE) and transient elastography (FibroScan®) methods. Methods: RTE, FibroScan and percutaneous liver biopsy were all performed on patients with chronic liver disease, particularly hepatitis C, to investigate liver fibrosis. Results: FibroScan and RTE were compared for fibrous liver staging (F stage), which was pathologically classified using liver biopsy. In FibroScan, significant differences were observed between F1/F3 and F2/F4, but no such differences were observed between F1/F2, F2/F3 and F3/F4. In RTE, significant differences were observed between F1/F2, F2/F3 and F2/F4. But for F3/F4, no significant differences were observed. Conclusion: FibroScan and RTE correlated well with F staging of the liver. In particular RTE was more successful than FibroScan in diagnosing the degree of liver fibrosis.

Hepatic Arterial Infusion Chemotherapy Using Low-Dose 5-Fluorouracil and Cisplatin for Advanced Hepatocellular Carcinoma

Background: Although hepatic arterial infusion chemotherapy (HAIC) using low-dose 5-fluorouracil (5-FU) and cisplatin (low-dose FP) is commonly used for advanced hepatocellular carcinoma (HCC) with vascular invasion in Japan, few reports have investigated the efficacy and safety of this approach. We investigated the efficacy and toxicity of HAIC using low-dose FP for patients with advanced HCC as a phase II trial. Methods: Low-dose FP consisted of a continuous arterial infusion of 5-FU (250–500 mg/day, 5 days/week, for the first 2 weeks) and cisplatin (10 mg/day, 5 days/week, for the first 2 weeks). Then, 5-FU (1,000 mg/body for 5 h) and cisplatin (10 mg/body) were administered once weekly. Results: In these patients treated with low-dose FP, the response rate was 38.5%, the median time to progression was 4.1 months (95% CI 2.1–6.1 months) and the median survival time was 15.9 months (95% CI 9.8–22.0 months). The most frequent adverse events were myelosuppression such as neutropenia or thrombocytopenia. Conclusions: HAIC using low-dose FP is an effective treatment option for locally advanced HCC. However, it is not well tolerated hematologically because of potent pancytopenia and poor hepatic reserve. Therefore, this regimen should be performed carefully with regular monitoring of hematological function.

Response evaluation of transcatheter arterial chemoembolization in hepatocellular carcinomas: the usefulness of sonazoid-enhanced harmonic sonography.

Background: The purpose of this study was to investigate if Sonazoid-enhanced harmonic ultrasonography (US) could be used to evaluate the responses of hepatocellular carcinomas (HCCs) to treatment with transcatheter arterial chemoembolization (TACE). Patients and Methods: Forty-three HCCs that had been treated by TACE were evaluated by Sonazoid-enhanced harmonic US and dynamic computed tomography (CT) approximately 1 week after their treatment. The detection rates of residual tumor blood supply using the two modalities were compared. Two months after chemoembolization, 16 of the 43 HCCs, which had no additional local treatment, were followed up with dynamic CT. The results of contrast-enhanced harmonic US and dynamic CT 1 week after chemoembolization were analyzed and compared with follow-up dynamic CT results. Results: The detection rates of positive enhancement with Sonazoid-enhanced harmonic US and dynamic CT 1 week after TACE were 25 (58.1%) of 43 lesions and 17 (39.5%) of 43 lesions, respectively. Sonazoid-enhanced harmonic US was significantly more sensitive than dynamic CT in depicting the residual tumor blood supply to HCCs 1 week after TACE (p < 0.01; χ2 test). The Sonazoid-enhanced harmonic US results of the 16 lesions 1 week after chemoembolization were consistent with the follow-up results of dynamic CT 2 months after chemoembolization. Conclusions: Sonazoid-enhanced harmonic US appears to be a highly sensitive and accurate modality for evaluating responses of HCCs shortly after TACE.

Des-γ-Carboxyprothrombin May Be a Promising Biomarker to Determine the Therapeutic Efficacy of Sorafenib for Hepatocellular Carcinoma

Objective: The purpose of this study was to evaluate the role of des-γ-carboxyprothrombin (DCP) as a marker for the efficacy of sorafenib therapy for hepatocellular carcinoma (HCC). Methods: Patients with advanced HCC treated with sorafenib were retrospectively evaluated, focusing on DCP levels and clinical characteristics. Results: 50 patients with advanced HCC were treated with sorafenib alone. In 25 of these patients, the serum levels of DCP were evaluated twice (pretreatment and within 2 weeks after starting therapy). The time to progression was significantly longer in patients in whom the DCP level at 2 weeks after starting sorafenib was ≧2-fold higher than the pretreatment levels, as compared with patients without an increase in DCP (p = 0.0296). Conclusions: The serum level of DCP is a surrogate marker for tissue hypoxia and can be a predictive marker to assess the tumor response to sorafenib therapy.

Imaging of Hepatocellular Carcinoma: Qualitative and Quantitative Analysis of Postvascular Phase Contrast-Enhanced Ultrasonography with Sonazoid

Purpose: To evaluate the usefulness of vascular phase images of contrast-enhanced ultrasonography (CE-US) with Sonazoid for hepatocellular carcinomas (HCCs), a retrospective, comparative study was conducted of images of HCCs obtained by CE-US and superparamagnetic iron oxide (SPIO) magnetic resonance imaging (MRI) and evaluated qualitatively and quantitatively. Methods: Seventy-seven patients with 88 HCCs who received CE-US and SPIO-MRI were reviewed. The ratio of the echogenicity of the tumor and nontumor areas was calculated with postvascular phase CE-US (postvascular phase ratio). The ratio of the intensity of the nontumor to tumor areas on SPIO-enhanced MRI (SPIO intensity index) was also calculated. The Pearson correlations were calculated for all values between the postvascular phase ratio and SPIO intensity index for quantitative comparison. These images were also compared qualitatively for the detection rate of the tumors. Results: The sensitivities of CE-US and SPIO-MRI in detecting tumors were 98 and 95%, respectively (nonsignificant, χ2 test). The postvascular phase ratio correlated with the SPIO intensity index for HCCs (Pearson r = 0.803, p < 0.05). The image conformity of the result from the liver parenchymal phase CE-US and SPIO-MRI was 92%. Dedifferentiation spots of nodule-in-nodule HCCs were detected in 4 (80%) of 5 on postvascular phase images of CE-US, and in 2 (40%) of 5 on SPIO-MRI (nonsignificant, χ2 test). Conclusions: Postvascular phase images of CE-US with Sonazoid appear promising as an alternative to SPIO-enhanced MRI. Further study cases are needed to confirm the usefulness of postvascular phase images of CE-US compared to SPIO-MRI for the detection of dedifferentiation foci in hepatic tumors.

Oral Branched-Chain Amino Acid Granules Reduce the Incidence of Hepatocellular Carcinoma and Improve Event-Free Survival in Patients with Liver Cirrhosis

Background: It has been reported that branched-chain amino acid (BCAA) supplementation can improve nutritional status and prevent liver-related complications in patients with decompensated cirrhosis. We investigated the effects of oral BCAA supplementation on the incidence of hepatocellular carcinoma (HCC) and liver-related events in patients with compensated and decompensated cirrhosis. Methods: We enrolled 211 patients with cirrhosis including 152 patients with Child-Pugh A cirrhosis, but no history of HCC. Of these, 56 received oral administration of 12 g/day BCAA for ≧6 months (BCAA group), and 155 were followed-up without BCAA treatment (control group). The HCC occurrence and event-free survival rates were compared between the two groups. We used a propensity score analysis to overcome selection bias of this retrospective analysis. Results: The HCC occurrence rate was significantly lower and event-free survival rate was significantly higher in the BCAA group than in the control group. Multivariate analyses showed BCAA supplementation was significantly associated with reduced incidence of HCC (hazard ratio (HR) 0.416, 95% confidence interval (CI) 0.216–0.800, p = 0.0085). BCAA supplementation also reduced the incidence of liver-related events in patients with Child-Pugh A cirrhosis, although the difference did not reach statistical significance (HR 0.585, 95% CI 0.336–1.017, p = 0.0575). Conclusions: Oral BCAA supplementation is associated with reduced incidence of HCC in patients with cirrhosis and seems to prevent liver-related events in patients with Child-Pugh A cirrhosis.

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: α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP and des-γ-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(χ2 = 717.348) than the JIS score (χ2 = 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.

Radiofrequency Ablation for Hepatocellular Carcinoma: Assistant Techniques for Difficult Cases

Purpose: To confirm the safety and effectiveness of techniques to assist radiofrequency ablation (RFA) for difficult cases, we retrospectively evaluated successful treatment rates, early complications and local tumor progressions. Patients and Methods: Between June 1999 and April 2009, a total of 341 patients with 535 nodules were treated as difficult cases. Artificial pleural effusion assisted ablation was performed on 64 patients with 82 nodules. Artificial ascites-assisted ablation was performed on 11 patients with 13 nodules. Cooling by endoscopic nasobiliary drainage (ENBD) tube-assisted ablation was performed on 6 patients with 8 nodules. When the tumors were not well visualized with conventional B-mode ultrasonography (US), contrast-enhanced US-assisted ablation with Levovist® or Sonazoid® or virtual CT sonography-assisted ablation was performed. Contrast-enhanced US-assisted ablation was performed on 139 patients with 224 nodules and virtual CT sonography-assisted ablation was performed on 121 patients with 209 nodules. Results: In total, complete ablation was achieved in 514 of 535 (96%) nodules in difficult cases. For RFA with artificial pleural effusion, artificial ascites and ENBD, complete response was confirmed in all cases. For contrast-enhanced US- and CT sonography-assisted ablation, complete response was 95%. Early complications were recognized in 24 cases (4.5%). All cases recovered with no invasive treatment. Local tumor recurrence was investigated in 377 nodules of 245 patients, and 69 (18%) nodules were positive. Tumor recurrences in each assisted technique were 14.7% in artificial pleural effusion cases, 7% in artificial ascites, 12.5% in ENBD tube cases, 31% in virtual CT sonography, and 8.5% in contrast-enhanced US. Conclusion: Although local tumor progression needs to be carefully monitored, assisted techniques of RFA for difficult cases are well tolerated and expand the indications of RFA.