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Survival of Hepatocellular Carcinoma Patients Treated with Sorafenib beyond Progression.

ABSTRACT: Background/Aim:Sorafenib leads to improved survival in advanced hepatocellular carcinoma (HCC) patients. Continuation of sorafenib beyond progression has been a possible treatment strategy when further approved therapeutic agents are lacking. Methods:We performed a retrospective analysis of all HCC patients at our institution with documented disease progression under treatment with sorafenib. Overall survival (OS) from start of sorafenib treatment was compared between patients who received sorafenib for > 3 weeks beyond progression (group 1) and those who discontinued sorafenib ?3 weeks after progression (group 2). Group 1 was further subdivided into those patients who received sorafenib for > 3 months (group 1a) and those who received it for ?3 months (group 1b). Results:A total of 71 patients were analyzed. Median OS for all patients was 15.4 months. OS in group 1 (15.6 months) and 2 (13.0 months) was similar (p = 0.90). Patients in group 1a showed significantly prolonged median OS (19.7 months) compared to that of patients in group 1b (13.6 months, p = 0.004), and they showed a trend towards prolonged OS compared to group 2 (p = 0.126). For patients with a poor prognosis according to their Child-Pugh stage, performance status, alpha-fetoprotein, and response to prior sorafenib treatment, OS was significantly prolonged in group 1 versus group 2 (12.1 vs. 6.4 months, p = 0.019). Conclusion:In HCC patients, continuing sorafenib beyond progression for > 3 months is associated with improved survival compared to discontinuing sorafenib within 3 months. Furthermore, patients with a poor prognosis who continue sorafenib beyond progression in general show significantly prolonged survival.

SUBMITTER: Apostolidis L

PROVIDER: S-EPMC6288626 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Survival of Hepatocellular Carcinoma Patients Treated with Sorafenib beyond Progression.

Apostolidis Leonidas L Pfeiffenberger Jan J Gotthardt Daniel D Radeleff Boris B Mehrabi Arianeb A Schemmer Peter P Jäger Dirk D Schirmacher Peter P Stremmel Wolfgang W Schulze-Bergkamen Henning H Springfeld Christoph C Weiss Karl Heinz KH

Gastrointestinal tumors 20180411 1-2

<h4>Background/aim</h4>Sorafenib leads to improved survival in advanced hepatocellular carcinoma (HCC) patients. Continuation of sorafenib beyond progression has been a possible treatment strategy when further approved therapeutic agents are lacking.<h4>Methods</h4>We performed a retrospective analysis of all HCC patients at our institution with documented disease progression under treatment with sorafenib. Overall survival (OS) from start of sorafenib treatment was compared between patients who ...[more]

PMID: 30574480

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Project description:To investigate in greater detail the efficacy and safety of sorafenib for the treatment of hepatocellular carcinoma (HCC) in patients with established cirrhosis.From October 2009 to July 2012 patients with an established diagnosis of cirrhosis and HCC treated with sorafenib were consecutively enrolled. According to the Barcelona Clinic Liver Cancer (BCLC) classification, patients were in the advanced stage (BCLC-C) or in the intermediate stage (BCLC-B) but unfit or unresponsive to other therapeutic strategies. Treatment was evaluated performing a 4-phase computed tomography or magnetic resonance imaging scan every 2-3 mo, and analyzed according to the modified Response Evaluation Criteria in Solid Tumors. Sorafenib was administered at 800 mg/d, until radiological progression or occurrence of unacceptable adverse events (AEs). Univariate and multivariate analyses identified predictors of 16-wk clinical benefit and overall survival.Forty-four patients were enrolled, 15 had intermediate HCC and 14 a Child-Pugh score of B7. AEs caused treatment interruption in 19 patients (43%), and median treatment duration was shorter in this subset (5 wk vs 19 wk, P < 0.001) and in the BCLC-C subgroup (13 wk vs 40 wk, P = 0.015). No significant differences in the reason for treatment interruption or in treatment duration were found comparing patients in Child-Pugh class A vs B or in patients older or younger than 70 years. After 16 wk of treatment, 18 patients (41%) had stable disease or partial response. Patients with viral infection or BCLC-C were at higher risk of disease progression. ECOG, extrahepatic spread, macrovascular invasion, alpha-fetoprotein or alkaline phosphatase levels at admission were independent predictors of overall survival.In patients with cirrhosis and HCC treated with sorafenib, AEs are a common cause of early treatment withdrawal. Vascular invasion and extrahepatic spread condition early response to treatment and survival. Baseline biochemical parameters may be helpful to identify patients at higher risk of shorter overall survival.

Project description:Sorafenib is a multiple receptor tyrosine kinase inhibitor known to prolong overall survival in patients with advanced hepatocellular carcinoma (HCC). Predicting this drug's survival benefits is challenging because clinical responses are rarely measurable during treatment. In this study, we hypothesized that serum cytokines levels could predict the survival of advanced HCC patients, as sorafenib targets signaling pathways activated in the tumor stromal microenvironment and potentially affects serum cytokine profiles.Of 143 patients with advanced-stage HCC, 104 who were recruited between 2003 and 2007 received hepatic arterial infusion chemotherapy (HAIC) that mainly targets tumor epithelial cells at S-phase (cohort 1); additionally, 39 recruited between 2010 and 2012 received sorafenib, which primarily targets the stromal vascular endothelial cells. Serum samples were collected and aliquoted prior to the treatment. Serum EGF, bFGF, HGF, IFN-?, IL-10, IL-12, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10, MIG, PDGF-BB, SCF, SDF1, TGF-?, TGF-?, TNF-?, and VEGF-A were measured via enzyme-linked immunosorbent assays. The Modified Response Evaluation Criteria in Solid Tumors were used to assess tumor responses.The median survival time of HCC patients in cohorts 1 (HAIC-treated) and 2 (sorafenib-treated) were 12.0 and 12.4 months, respectively. Kaplan-Meier analysis revealed no significant survival differences between the 2 groups. Patients who survived more than 2 years after sorafenib treatment exhibited higher serum levels of IL-10, IL-12, TNF-a, IL-8, SDF-1, EGF, PDGF-BB, SCF, and TGF-?. Furthermore, cohort 2 patients with higher serum IL-5 (>12 pg/mL), IL-8 (>10 pg/mL), PDGF-BB (>300 pg/mL), and VEGF-A (>50 pg/mL) levels achieved longer survival; cohort 1 patients did not. Hierarchical cluster analysis of 6 cytokines robustly enriched for comparison analysis between cohorts 1 and 2 (IL-5, IL-8, TGF-?, PDGF-BB, CXCL9, and VEGF-A) revealed that elevation of these cytokines correlated with better survival when treated with sorafenib but not with HAIC.Patients who exhibited survival benefits owing to sorafenib treatment tended to present higher serum cytokines levels, potentially reflecting the activation of stromal signaling in the tumor microenvironment. Our study thus introduces novel biomarkers that may identify advanced HCC patients who may experience survival benefits with sorafenib treatment.

Project description:Background and aimsInflammation affects progression of hepatocellular carcinoma (HCC). We therefore postulate that systemic inflammatory markers could help to predict prognosis in HCC patients receiving sorafenib therapy.MethodsOverall survival (OS) of HCC patients receiving palliative sorafenib treatment was correlated with the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), C-reactive protein to albumin ratio (CAR), Glasgow prognostic score (GPS) and the modified GPS (mGPS) along with clinicopathological parameters. Predictors of OS were assessed by multivariable Cox regression and receiver operating characteristics and area under the curve (ROC-AUC) analyses.ResultsPatients receiving sorafenib (n = 120) for advanced HCC (Barcelona Clinic Liver Cancer stage C) were explored by retrospective analysis. Findings were subsequently validated by a second HCC cohort (n = 113) receiving sorafenib at two independent treatment centers. Multivariable assessment across these HCC cohorts confirmed a stable association of CAR (p ≤ 0.001), GPS (p ≤ 0.01) and mGPS (p ≤ 0.004) with OS. This study also identified Eastern Cooperative Oncology Group (ECOG) performance score (p < 0.001) and portal thrombosis (p = 0.002) as prognostic factors and uncovered an inconsistent OS association of NLR and PLR in HCC patients. Additional combined analysis of ECOG, portal thrombosis and GPS within an extended score (GPS-EP) was associated with OS (p = 0.021), which was confirmed within the validation cohort (p = 0.001). In sorafenib-treated HCC, the ROC-AUC value for the prediction of 12-month survival was 0.761 (CAR >/≤0.37 cut-off, p < 0.001), 0.766 (GPS, p < 0.001) and 0.754 (mGPS, p < 0.001), respectively. In comparison to this, GPS-EP achieved a higher AUC of 0.826 (0.746-0.907) for the 12-month survival prediction, resulting in a 64.4% sensitivity and 83.3% specificity at a > 2 point cut-off.ConclusionsInflammatory scores obtained before sorafenib treatment initiation are associated with OS in advanced HCC. Their combination with other risk factors improves prediction of 3- and 12-month survival, which could guide treatment decisions in selected patient subgroups.

Dataset Information

Survival of Hepatocellular Carcinoma Patients Treated with Sorafenib beyond Progression.

Publications

Survival of Hepatocellular Carcinoma Patients Treated with Sorafenib beyond Progression.

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