Masashi Kono

Effectiveness of Sorafenib in Patients with Transcatheter Arterial Chemoembolization (TACE) Refractory and Intermediate-Stage Hepatocellular Carcinoma

Background and Aims: Patients with intermediate-stage hepatocellular carcinoma (HCC) refractory to transcatheter arterial chemoembolization (TACE) are considered to be candidates for sorafenib. The aim of this study was to evaluate the superiority of conversion of treatment to sorafenib on overall survival (OS) for cases refractory to TACE. Methods: This was a retrospective cohort study carried out on 497 patients with HCC who were treated with TACE therapy at our hospital between January 2008 and December 2013. Fifty-six patients were diagnosed as refractory to TACE during their clinical course and they were divided into two cohorts, (1) those who switched from TACE to sorafenib and (2) those who continued TACE. The overall survival (OS) after the time of being refractory to TACE was evaluated between the two groups. Results: After refractoriness to TACE therapy was confirmed, 24 patients continued with TACE (TACE-group) and 32 patients underwent treatment conversion to sorafenib (sorafenib-group). The median OS was 24.7 months in the sorafenib-group and 13.6 months in the TACE-group (p=0.002). Conclusions: Conversion to sorafenib significantly improves the OS in patients refractory to TACE therapy with intermediate-stage HCC. Administration of sorafenib is therefore recommended in such circumstances of TACE treatment failure.

Validation of the Criteria of Transcatheter Arterial Chemoembolization Failure or Refractoriness in Patients with Advanced Hepatocellular Carcinoma Proposed by the LCSGJ

Background: Transcatheter arterial chemoembolization (TACE) failure or refractoriness is an indication for sorafenib therapy in patients with advanced hepatocellular carcinoma. The study evaluated the validity of the definition of TACE failure or refractoriness as proposed by the Liver Cancer Study Group of Japan (LCSGJ) through a retrospective analysis of sorafenib treatment. Methods: Out of 265 patients with advanced hepatocellular carcinoma who were treated with sorafenib at our hospital, 45 experienced TACE failure or refractoriness and were included in this study and retrospectively analyzed. Results: Multivariate analysis only identified the number of ineffective TACE procedures performed before starting sorafenib treatment as significant factors. Overall survival (OS) after starting sorafenib was statistically longer in patients treated with ≤2 consecutive ineffective TACE procedures before sorafenib administration than in patients treated with ≥3 consecutive ineffective TACE procedures (p < 0.005). This result matched the LCSGJ criteria. Conclusion: In patients treated with sorafenib, OS was extended with ≤2 consecutive ineffective TACE procedures compared to that with ≥3 consecutive ineffective TACE procedures. Thus, if tumors are uncontrolled, TACE should not be repeated. The result of this study supports the definition of TACE failure or refractoriness proposed by the LCSGJ.

Validation of a Modified Substaging System (Kinki Criteria) for Patients with Intermediate-Stage Hepatocellular Carcinoma

Introduction: Barcelona Clinic Liver Cancer (BCLC) stage B, an intermediate stage, includes various conditions of hepatocellular carcinoma (HCC). This heterogeneity of the patients with intermediate-stage HCC makes it difficult to predict their survival rates. In the present study, we examined the validity of the modified Bolondi classification (Kinki criteria) as a subclassification of patients with BCLC stage B HCC. Methods: Of 906 patients who underwent conventional transarterial chemoembolization at Kinki University Hospital, 753, who met the inclusion criteria, were examined. Of these 753 patients, 425 (56.4%) with BCLC stage B were subclassified using the Kinki criteria to examine the survival rate. Results: According to the Kinki criteria, 158 (37.2%) were subclassified into subclass B1, 236 (55.5%) into B2, and 31 (7.3%) into B3. The comparison of the survival rates showed that the median overall survival was 3.9 years (95% CI, 3.2-4.6) in the BCLC subclass B1 group, 2.5 years (95% CI, 2.2-3.1) in the B2 group, and 1.1 years (95% CI, 0.6-1.5) in the B3 group (p < 0.001). Conclusion: When the BCLC stage B patients were subclassified according to the Kinki criteria, survival curves were stratified with significant differences, suggesting that the Kinki criteria were suitable for the subclassification of the intermediate-stage HCC patients.

Radiofrequency Ablation for Hepatocellular Carcinoma Measuring 2 cm or Smaller: Results and Risk Factors for Local Recurrence

Objective: The purpose of this study was to evaluate the risk factors for local recurrence with radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) measuring ≤2 cm. Methods: This study involved 234 patients with 274 HCCs measuring ≤2 cm who had undergone RFA as the initial treatment. The mean tumor diameter was 1.478 cm. The median follow-up period was 829 days. We evaluated the post-RFA cumulative local recurrence rate and analyzed the risk factors contributing to clinical outcomes. Results: Cumulative local recurrence rates were 9, 19 and 19% at 1, 2 and 3 years, respectively. Among the 145 cases with a complete safety margin (SM) after RFA, only 4 developed local tumor recurrence and the cumulative rates of local tumor recurrence at 1, 2 and 3 years were 2, 3 and 3%, respectively. Among the 129 cases with incomplete SM, local tumor recurrence developed in 34 and the cumulative rates of local tumor progression at 1, 2 and 3 years were 14, 36 and 36%, respectively. In multivariate analysis, significant risk factors were tumor location (liver surface), irregular gross type and SM <5 mm. Conclusion: Even with HCC measuring ≤2 cm, location and gross type of tumor should be carefully evaluated before RFA is performed.

Removal of diminutive colorectal polyps: A prospective randomized clinical trial between cold snare polypectomy and hot forceps biopsy

AIM To compare the efficacy and safety of cold snare polypectomy (CSP) and hot forceps biopsy (HFB) for diminutive colorectal polyps. METHODS This prospective, randomized single-center clinical trial included consecutive patients ≥ 20 years of age with diminutive colorectal polyps 3-5 mm from December 2014 to October 2015. The primary outcome measures were en-bloc resection (endoscopic evaluation) and complete resection rates (pathological evaluation). The secondary outcome measures were the immediate bleeding or immediate perforation rate after polypectomy, delayed bleeding or delayed perforation rate after polypectomy, use of clipping for bleeding or perforation, and polyp retrieval rate. Prophylactic clipping after polyp removal wasn’t routinely performed. RESULTS Two hundred eight patients were randomized into the CSP (102), HFB (106) and 283 polyps were evaluated (CSP: 148, HFB: 135). The en-bloc resection rate was significantly higher with CSP than with HFB [99.3% (147/148) vs 80.0% (108/135), P < 0.0001]. The complete resection rate was significantly higher with CSP than with HFB [80.4% (119/148) vs 47.4% (64/135), P < 0.0001]. The immediate bleeding rate was similar between the groups [8.6% (13/148) vs 8.1% (11/135), P = 1.000], and endoscopic hemostasis with hemoclips was successful in all cases. No cases of perforation or delayed bleeding occurred. The rate of severe tissue injury to the pathological specimen was higher HFB than CSP [52.6% (71/135) vs 1.3% (2/148), P < 0.0001]. Polyp retrieval failure was encountered CSP (7), HFB (2). CONCLUSION CSP is more effective than HFB for resecting diminutive polyps. Further long-term follow-up study is required.

Clinical Factors Predicting the Effect of Tolvaptan for Refractory Ascites in Patients with Decompensated Liver Cirrhosis.

Objective: Refractory ascites reduces the quality of life of liver cirrhosis patients. Albumin preparation and diuretics, such as furosemide, have been used to treat refractory ascites, but the effect was poor in many patients. In this study, we analyzed patients treated with tolvaptan (TLV) at our hospital and investigated predictors of the effect. Methods: The subjects were 70 patients for whom TLV was introduced to treat refractory ascites who could be analyzed between November 2013 and March 2015 at our hospital. Patient background before initiation of oral TLV treatment, the dose of diuretics, and each item of biochemical tests of blood and urine were investigated, and factors correlated with the treatment effect were analyzed. An increase of ≥1,000 ml in the daily urine volume from the day before oral treatment or a decrease of ≥1 kg in the body weight within 7 days as an early effect was observed in 33 patients and not observed in 37 patients. TLV treatment was continued for 60 days or longer in 12 of the 37 patients in whom no early effect was observed, and the presence or absence of a delayed effect and predictors of the effect were investigated. A decrease in ascites on abdominal CT with improvement of subjective symptoms at 60 days was defined as a delayed effect. Results: When early predictors of the effect were investigated by univariate analysis, serum blood urea nitrogen (BUN) and serum creatinine (Cr) were significantly higher in the non-responder group (BUN: p = 0.03, Cr: p = 0.04), but no factor independently associated with the treatment effect was extracted on multivariate analysis. The delayed effect was noted in 4 (33.3%) of the 12 patients, but no predictor of the effect before treatment was identified. However, reactions, such as an increase in serum Na and reduction of urinary osmotic pressure, were observed early after TLV administration in some patients in whom the delayed effect was observed. Conclusions: The diuretic effect of TLV may decrease in renal hypofunction patients. Since the delayed effect was noted in a specific ratio of patients, continuation of TLV administration is an option even though the early treatment effect is poor unless ascites aggravates or adverse effects develop.

Evaluation of ART Scores for Repeated Transarterial Chemoembolization in Japanese Patients with Hepatocellular Carcinoma

Objective: Transarterial chemoembolization (TACE) is recommended as a first-line therapy for hepatocellular carcinoma (HCC) patients ineligible for curative therapy and without portal invasion. The Assessment for Retreatment with TACE (ART) scoring system was recently proposed for identifying patients who would not show sufficient survival benefit from repeated TACE. We reevaluated the performance of ART in HCC patients treated in Japan, where selective TACE is commonly used. Methods: Between 2000 and 2013, 988 patients with HCC underwent TACE at Kinki University Hospital, and 627 received ≥2 sessions of TACE. Seventy-six patients who underwent ≥2 TACE sessions within 90 days were investigated for their performance of the ART score in the context of overall survival (OS). Results: Only 12% (76/627) of patients underwent ≥2 TACE sessions within 90 days. Of those, 52 patients showed a low ART score (0-1.5), and 24 had a high ART score (≥2.5); the median OS was 20.2 and 37.6 months, respectively (p = 0.8207). Conclusion: The ART scoring system did not demonstrate a sufficiently predictive impact on OS among the patients who underwent ≥2 TACE sessions within 90 days. Application of the ART score should be carefully considered because differences in TACE procedures and post-TACE treatment can affect the results while evaluating OS.

US-US Fusion Imaging in Radiofrequency Ablation for Liver Metastases

Objective: Radiofrequency ablation (RFA) induces gas bubbles in ablation zones, and the ablative margin cannot be evaluated accurately on ultrasound (US) during and immediately after RFA. This study assessed the usefulness of US-US fusion imaging to visualize the ablative margin of RFA for liver metastasis. Methods: RFA guided by US-US fusion imaging was performed on 12 targeted tumors in 10 patients. Secondary hepatic malignancies included patients with colorectal cancer (n = 4), breast cancer (n = 2), lung cancer (n = 1), gastrointestinal stromal tumor (n = 1), pancreatic neuroendocrine tumor (n = 1), and adrenocortical carcinoma (n = 1). The maximal diameter of the tumors ranged from 0.8 to 4.0 cm (mean ± SD 1.6 ± 0.9 cm). Results: The mean number of electrode insertions was 1.6 per session (range 1-3). Technically, effective ablation was achieved in a single session in all patients, and safety ablative margins were confirmed on contrast-enhanced CT for early assessment of tumor response. There were no serious adverse events or procedure-related complications. During the follow-up period (median 220 days, range 31-417 days), none of the patients showed local tumor progression. Conclusion: US-US fusion imaging could show the tumor images before ablation and the ablative area on US in real time. The image overlay of US-US fusion imaging made it possible to evaluate the ablative margin three dimensionally according to the US probe action. Therefore, US-US fusion imaging can contribute to RFA therapy with a safety margin, that is, the so-called precise RFA.

Decreased blood flow after sorafenib administration is an imaging biomarker to predict overall survival in patients with advanced hepatocellular carcinoma.

Background: Sorafenib is a multikinase inhibitor targeting Raf and protein tyrosine kinases, which are involved in cell growth and tumor angiogenesis. Sorafenib administration induces temporary inhibition of tumor growth and a decrease in arterial blood flow in a considerable number of hepatocellular carcinoma (HCC) patients. We retrospectively evaluated the association between decreased blood flow and the overall survival (OS) of HCC patients after the initiation of sorafenib therapy. Patients and Methods: Therapeutic responses of 158 advanced HCC patients with hypervascular tumors who had received sorafenib for more than 1 month were analyzed. To assess their therapeutic response, patients underwent radiological evaluation before and every 4-6 weeks after the initiation of sorafenib treatment. After the classification of patients into three groups based on the change in arterial enhancement during treatment (no change, decrease and disappearance), the OS of each group was compared using the Kaplan-Meier method. Results: Statistically significant differences in OS were observed among the three groups (p < 0.001). A decrease or disappearance of arterial enhancement was significantly associated with improved OS compared to patients with no change in arterial enhancement; the median OS was 19.9 months (95% confidence interval, CI, 16.4-24.5 months) and 6.0 months (95% CI, 4.0-8.8 months), respectively (p < 0.001). However, there was no difference in OS between the decrease and disappearance groups (p = 0.88). Conclusion: We conclude that decreased arterial enhancement during sorafenib treatment was associated with the longest OS and could therefore reflect an effective response.

Duration of Stable Disease Is Associated with Overall Survival in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib

Background: Sorafenib is a molecular-targeting agent showing improved overall survival (OS) for advanced hepatocellular carcinoma (HCC). Although tumor dormancy, characterized by stable tumor status or stable disease (SD) without tumor regression, is a unique feature of sorafenib treatment, the contribution of SD to OS remains debatable. This study aimed to clarify the correlation between SD periods and OS in patients with HCC treated with sorafenib. Methods: From May 2009 to January 2013, 269 patients with advanced-stage HCC were treated with sorafenib at the Kinki University Hospital. The antitumor response of sorafenib was evaluated in 158 patients using the modified Response Evaluation Criteria in Solid Tumors, and patients with SD were divided into two subgroups according to the median duration of SD: short SD (<3 months) and long SD (≥3 months). The relationship between the duration of SD and OS was analyzed among patients with complete (CR) and partial response (PR), and long and short SD using the Kaplan-Meier method. Results: The median OS was 5.7 months in the short SD, 20.8 months in the long SD and 17.9 months in the CR + PR group. Although the duration of OS was significantly longer in the long SD group than the short SD group, no difference in OS was detected between the patients with CR + PR and patients with long SD. The impact of long SD on OS could be as strong as that of CR + PR. Conclusion: Achievement of long SD is one of the important goals for improving survival in patients with HCC treated with sorafenib.