RESUMO
BACKGROUND: Although sorafenib-regorafenib sequential therapy improves the prognosis of patients with hepatocellular carcinoma (HCC), many patients abandon sequential therapy due to worsening hepatic reserve function. Thus, it is important to clarify which patients can be treated using regorafenib. The albumin-bilirubin score is a good biomarker for hepatic reserve function. The aim of this study was to determine whether patient albumin-bilirubin scores at the start of sorafenib treatment could be used to identify candidates for subsequent regorafenib therapy. METHODS: This is a retrospective cohort study. From 2009 to 2017, 267 hepatocellular carcinoma patients treated with sorafenib were enrolled. After sorafenib therapy, 138 progressive disease patients were analyzed. The patients were divided in two groups: (i) regorafenib candidate group (Child-Pugh class A, Eastern Cooperative Oncology Group Performance Status ≤1, and maintained sorafenib tolerance); and (ii) regorafenib non-candidate group. The primary endpoint was the albumin-bilirubin score. We assessed retrospectively whether albumin-bilirubin scores were useful for predicting regorafenib treatment regimen candidacy. RESULTS: For the 138 analyzed patients, the median overall survival duration was 15.6 months in the regorafenib candidate group and 6.8 months in the regorafenib non-candidate group (P < 0.01). Using univariate analysis, etiology, aspartate aminotransferase ≥40 IU/L, prothrombin time ≥85% and albumin-bilirubin score <-2.53 at the start of sorafenib treatment were identified as predictors. Using multivariate analysis, albumin-bilirubin score <-2.53 was the only significant predictor. CONCLUSIONS: Based on the multivariate analysis results, albumin-bilirubin score at the start of sorafenib therapy is a useful marker for identifying candidate patients for starting regorafenib therapy.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Sorafenibe/uso terapêutico , Idoso , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Compostos de Fenilureia/farmacologia , Prognóstico , Piridinas/farmacologia , Estudos Retrospectivos , Sorafenibe/farmacologiaRESUMO
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.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Análise de Sequência de DNA , Análise de Sequência de RNA , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Biomarcadores Tumorais/metabolismo , Biópsia por Agulha Fina , Carcinoma Hepatocelular/tratamento farmacológico , Feminino , Formaldeído/química , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mutação , Neuregulina-1/genética , Niacinamida/uso terapêutico , Inclusão em Parafina , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Sorafenibe , Fator de Crescimento Transformador alfa/genética , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , beta Catenina/genéticaRESUMO
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.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/diagnóstico , Intervalo Livre de Doença , Feminino , Humanos , Japão , Neoplasias Hepáticas/diagnóstico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Niacinamida/uso terapêutico , Prognóstico , Estudos Retrospectivos , Sorafenibe , Tomografia Computadorizada por Raios X , Resultado do Tratamento , alfa-Fetoproteínas/metabolismoRESUMO
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.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Prognóstico , Idoso , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Pontuação de Propensão , Sorafenibe , Resultado do TratamentoRESUMO
A 69 years old man was admitted to our hospital for further examinations of the liver tumor October, 2003. No underlying liver disease was found. Two tumors in the liver, 2cm in diameter respectively, were detected by abdominal ultrasonography and MRI scan. Ultrasonogram-guided needle biopsy from the liver tumor showed diffuse infiltration of CD20 positive, small lymphocytes. A distinct single band demonstrating clonal JH gene rearrangement was detected by southern blot analysis using tissues by needle biopsy. Thus, the patient was diagnosed with primary hepatic MALT lymphoma in the normal liver. These tumors were treated with percutaneus radiofrequency ablation (RFA), followed by Rituximab administration. No relapse has been noted until September, 2005.