Targeted DNA and RNA sequencing of fine-needle biopsy FFPE specimens in patients with unresectable hepatocellular carcinoma treated with sorafenib.

The multi-kinase inhibitor sorafenib is now used as standard therapy for advanced hepatocellular carcinoma (HCC). Predictive biomarkers of response to sorafenib are thus necessary. The purpose of this study was to assess the feasibility of using targeted DNA and RNA sequencing to elucidate candidate biomarkers of sorafenib response using fine-needle biopsy, formalin-fixed paraffin-embedded (FFPE) specimens in patients with HCC. Targeted DNA and RNA deep sequencing were feasible for the evaluation of fine-needle biopsy FFPE specimens obtained from 46 patients with HCC treated with sorafenib. Frequent mutations of suppressor genes, such as CTNNB1 (34.8%) and TP53 (26.1%), were detected in the HCC tumors. After excluding these suppressor genes, the average numbers of detected oncogene mutations differed significantly between the non-PD and PD groups (P = 0.0446). This result suggests that the oncogene mutational burden in the tumor might be associated with the clinical response to sorafenib. We have identified candidate gene expression (TGFa, PECAM1, and NRG1) in tumor for the prediction of sorafenib response and PFS by RNA sequencing. Our findings provide new insights into biomarkers for sorafenib therapy and allow us to discuss future therapeutic strategies.

Clinical features associated with radiological response to sorafenib in unresectable hepatocellular carcinoma: a large multicenter study in Japan.

BACKGROUND & AIMS: There have been no established predictive factors of responders to sorafenib in patients with unresectable hepatocellular carcinoma (HCC). This study aimed to investigate the factors predicting a good response to sorafenib in Japanese patients with HCC. METHODS: A total of 465 patients with unresectable HCC in the Japanese Red Cross Liver Study Group were treated with sorafenib between January 2008 and August 2013, and 316 patients with sufficient clinical data were analysed. To determine the factors predicting a good response, the relationships between radiological response and the following clinicopathological factors were analysed: age, gender, performance status, liver function, tumour status and decrease in serum alpha-foetoprotein (AFP) level after 1 month. RESULTS: This study included 259 males and 57 females with a median age of 70 years (range, 37-90 years), of which 191 (60.4%) were classified as Barcelona Clinic Liver Cancer stage C, and 271 (85.8%) had Child-Pugh class A liver function. The median overall survival time was 307 days and progression-free survival time was 109 days. According to the modified Response Evaluation Criteria In Solid Tumours, four patients achieved a complete response, 51 achieved a partial response, 136 had stable disease and 125 had progressive disease. Multivariate analysis identified female gender (P = 0.003) and decreased serum AFP level after 1 month (P = 0.042) as independent predictors of a complete or partial response. CONCLUSION: Our results suggest female gender and a decrease in serum AFP level are independent predictors of good response to sorafenib.

Comparison of standard-dose and half­dose sorafenib therapy on clinical outcome in patients with unresectable hepatocellular carcinoma in field practice: A propensity score matching analysis.

The aims of the present study were to examine whether unresectable hepatocellular carcinoma (HCC) patients treated with initial dose of sorafenib of 400 mg/day (half-dose group) had comparable treatment efficacy, safety and survival merit as compared with those treated with initial dose of sorafenib of 800 mg/day (standard-dose group) in a multicenter large study. For reducing the bias in patient selection, we compared clinical outcomes of these two groups using propensity score matching analysis. A total of 465 patients were treated with sorafenib at fourteen hospitals in Japanese Red Cross Liver Study Group from 2008 to 2013. After propensity score matching, 139 matched HCC patients were selected for analysis in both groups. We retrospectively compared overall survival (OS), progression-free survival (PFS), best treatment response and sorafenib related serious adverse events (SAEs) in the two groups. There were no relevant differences in terms of OS (median OS intervals: 9.2 months in the standard-dose group and 9.7 months in the half­dose group, P=0.350), PFS (median PFS intervals: 3.4 months in the standard-dose group and 3.2 months in the half-dose group, P=0.729) and best treatment efficacy (objective response rate: P=0.416; disease control rate: P=0.719). Grade 3 or more SAEs were observed in 37 patients (26.6%) in the standard-dose group and 33 patients (23.7%) in the half-dose group (P=0.580). Furthermore, in all subgroup analyses according to Child-Pugh classification and Barcelona Clinic Liver Cancer stage, there were no significant differences in the two groups. In conclusion, unresectable HCC patients treated with initial half­dose sorafenib had comparable prognosis compared with those treated with initial standard-dose sorafenib.

Comparison of systems for assessment of post-therapeutic response to sorafenib for hepatocellular carcinoma.

BACKGROUND: To test the hypothesis that use of the response evaluation criteria in cancer of the liver (RECICL), an improved evaluation system designed to address the limitations of the response evaluation criteria in solid tumors 1.1 (RECIST1.1) and modified RECIST (mRECIST), provides for more accurate evaluation of response of patients with hepatocellular carcinoma (HCC) to treatment with sorafenib, a molecularly targeted agent, as assessed by overall survival (OS). METHODS: The therapeutic response of 156 patients with advanced HCC who had been treated with sorafenib therapy for more than 1 month was evaluated using the RECIST1.1, mRECIST, and RECICL. After categorization as showing progressive disease (PD), stable disease (SD), or objective response, the association between OS and categorization was examined using the Kaplan-Meier method to develop survival curves. The 141 cases categorized as PD or SD by the RECIST1.1, but objective response by the mRECIST and RECICL, were further analyzed for determination of the association between OS and categorization. RESULTS: Only categorization using the RECICL was found to be significantly correlated with OS (p = 0.0033). Among the patients categorized as SD or PD by the RECIST1.1, reclassification by the RECICL but not the mRECIST was found to be significantly associated with OS and allowed for precise prediction of prognosis (p = 0.0066). CONCLUSIONS: Only the use of the RECICL allowed for identification of a subgroup of HCC patients treated with sorafenib with improved prognosis. The RECICL should, therefore, be considered a superior system for assessment of therapeutic response.

Comparison of transcatheter arterial chemoembolization and transcatheter arterial chemotherapy infusion for patients with intermediate-stage hepatocellular carcinoma.

The aim of the present study was to compare clinical outcomes in patients with intermediate-stage hepatocellular carcinoma (HCC) who underwent the following treatments: transcatheter arterial chemoembolization (TACE) using an epirubicin-mitomycin-lipiodol (EML) emulsion at initial therapy (TACE group; n=145), and transcatheter chemotherapy infusion (TACI) using an EML emulsion at initial therapy (TACI group; n=81). Overall survival (OS) and treatment efficacy in the TACE and TACI groups were retrospectively compared. Prognostic factors associated with OS were examined using univariate and multivariate analyses. Treatment-related mortality was also calculated. The median observation periods were 1.8 years (range, 0.2-9.0 years) in the TACE group and 2.0 years (range, 0.2-8.7 years) in the TACI group. The median survival time and the 1-, 2-, 3- and 5-year cumulative OS rates were 2.68 years and 81.5, 63.4, 43.9 and 32.7%, respectively, in the TACE group, and 2.64 years and 85.0, 60.0, 43.2 and 26.0%, respectively, in the TACI group (P=0.691). The objective response rate was significantly higher in the TACE group compared to the TACI group (80.0 vs. 66.7%; P=0.009). Using multivariate analysis, the Child-Pugh classification (P=0.017), tumor number ≤5 (P=0.045) and des-γ-carboxy prothrombin level >100 mAU/ml (P=0.002) were found to be significant predictors linked to OS. In all subgroup analyses involving Child-Pugh classification, maximum tumor size and tumor distribution, the differences in the two groups did not reach statistical significance in terms of OS. Treatment mortality was 0% in the two groups. In conclusion, patients with intermediate-stage HCC had a comparable prognosis when treated with TACI or TACE.

Radiofrequency ablation for hepatocellular carcinoma: the relationship between a new grading system for the ablative margin and clinical outcomes.

BACKGROUND: In our previous study, we classified the radicality (R grading) of percutaneous radiofrequency ablation (RFA) therapy for single hepatocellular carcinoma (HCC) according to the extent of the ablated margin, and demonstrated that this grading system was useful for predicting local tumor progression (LTP) after RFA. The aim of this study was to measure the overall survival (OS), the recurrence free survival (RFS), and the distant recurrence (DR) rate for each R grade (A-D), and to examine the relationship between clinical outcome and R grading. METHODS: This study involved 368 patients with solitary HCC who had undergone RFA. The mean tumor diameter was 2.0 ± 0.7 cm. We calculated the post-RFA cumulative OS, RFS, and DR rate for each R grade and analyzed the factors contributing to clinical outcomes. RESULTS: In the multivariate analysis, significant factors were as follows: tumor size >2 cm, serum albumin >3.5 g/dL, prothrombin time >70 %, HCC recurrence within 1 year, and R grading (grade A) in OS; cause of liver disease (hepatitis B), gamma glutamyl transpeptidase (GGT) >80 IU/L, platelet count >10 × 10(4)/mm(3), and R grading (grade A or B) in RFS; GGT >80 IU/L, platelet count >10 × 10(4)/mm(3), and R grading (grade A or B) in DR. In patients with sufficient Lipiodol accumulation (n = 219), very similar results were obtained. However, in patients with grade A and B (n = 232), R grade was not a significant independent factor linked to OS, although grade A patients had lower LTP rate. CONCLUSIONS: Our proposed R grading system appears to be useful for predicting clinical outcomes after RFA.

Transcatheter arterial infusion chemotherapy prior to radiofrequency thermal ablation for single hepatocellular carcinoma reduces the risk of intrahepatic distant recurrence.

The aim of the present study was to elucidate the effectiveness of transcatheter arterial infusion chemotherapy (TAI) of the whole liver using an epirubicin-mitomycin-lipiodol emulsion, prior to radiofrequency thermal ablation (RFA), in preventing intrahepatic distant recurrence (IDR) from single hepatocellular carcinoma (HCC). Of the 269 consecutive patients who underwent RFA in our institute for single HCC, a total of 182 patients were analyzed in the present study. The primary endpoint was comparison of the post-RFA IDR-free survival rates in patients treated using TAI with an epirubicin-mitomycin-lipiodol emulsion via the proper hepatic artery (TAI-EML) prior to RFA, and patients that received lipiodol infusion-alone prior to RFA. The secondary endpoints were local tumor progression (LTP) and overall survival (OS). Lipiodol infusion-alone prior to RFA was performed in 88 patients and TAI-EML prior to RFA in 94 patients. The mean tumor size was 2.06 cm (range, 0.9-3.2 cm) in the TAI group and 1.97 cm (range, 0.9-3.3 cm) in the lipiodol-alone group, respectively. The cumulative IDR-free survival rates at 1, 2 and 3 years were 74.0, 50.8 and 34.9%, respectively, in the lipiodol-alone group, and 90.8, 74.8 and 70.0%, respectively, in the TAI group (P<0.001). In terms of the OS, there was a significant difference between these two groups (P=0.048), although there was no significant difference in terms of the LTP (P=0.145). We concluded that TAI-EML prior to RFA appears to be useful in reducing post-RFA IDR and may contribute to improved survival rates.

Complete response of advanced hepatocellular carcinoma with multiple lung metastases treated with sorafenib: a case report.

Sorafenib, an oral multikinase inhibitor, has demonstrated clinical efficacy in patients with advanced hepatocellular carcinoma (HCC). However, in the SHARP trial (Sorafenib HCC Assessment Randomized Protocol trial) and the Asia-Pacific trial (conducted in the Asia-Pacific region), no cases of complete response (CR) were reported. Thereafter, only a relatively small number of CR cases were reported worldwide for sorafenib therapy. We herein report a case of CR in a patient treated with sorafenib for 4 months. The patient had advanced HCC with multiple lung metastases, and there has been no recurrence after 8 months following cessation of administration. To our knowledge, this is the first time a female treated with sorafenib alone for HCC has had a CR.