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Dose age affect the efficacy of molecular targeted agents in the treatment of hepatocellular carcinoma: a systematic review and meta-analysis.

ABSTRACT: Currently, whether the impact of age on efficacy of molecular targeted agents (MTAs) in the treatment of hepatocellular carcinoma (HCC) patients remains undetermined. We searched databases and abstracts presented at ASCO meeting to identify relevant studies. The endpoints were overall survival (OS) and progression-free survival (PFS). Data were examined using age cutoffs of 65 years. A total of 4,231 HCC patients from eight RCTs were included for analysis, with 1,607 patients aged ≥ 65 years and 2,624 patients aged < 65 years. The pooled results demonstrated that the use of MTAs in patients < 65 years significantly improved PFS (HR 0.69, 95% CI: 0.51-0.95, p = 0.023) and OS (HR 0.79, 95% CI: 0.69-0.89, p < 0.001) when compared to controls. For HCC patients aged ≥ 65 years, the use of MTAs significantly improved PFS (HR 0.66, 95% CI: 0.53-0.84, p = 0.001) but not for OS (HR 0.94, 95% CI: 0.81 -1.09, p = 0.41). No publication bias was detected by Begg's and Egger's tests for OS. Therefore, the treatment effect of MTAs on OS might be different in younger and older HCC patients undergoing first-line or second-line treatment, but not for PFS benefit.

SUBMITTER: Du J

PROVIDER: S-EPMC5731966 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Dose age affect the efficacy of molecular targeted agents in the treatment of hepatocellular carcinoma: a systematic review and meta-analysis.

Du Jing J Mao Ye Y Liu Ming M Tie Yan Y Huang Hai H Zhao Jian J Xiang Zhongzheng Z Luo Di D

Oncotarget 20171019 60

Currently, whether the impact of age on efficacy of molecular targeted agents (MTAs) in the treatment of hepatocellular carcinoma (HCC) patients remains undetermined. We searched databases and abstracts presented at ASCO meeting to identify relevant studies. The endpoints were overall survival (OS) and progression-free survival (PFS). Data were examined using age cutoffs of 65 years. A total of 4,231 HCC patients from eight RCTs were included for analysis, with 1,607 patients aged ≥ 65 years and ...[more]

PMID: 29254256

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Project description:AimIndications of drug therapies to elderly patients with hepatocellular carcinoma (HCC) should be carefully determined. The current study assessed the safety and efficacy of molecular targeted agents (MTAs) in the elderly patients with HCC, and identified factors associated with prognosis in a real-world clinical setting.MethodsIn a retrospective observational study, clinical data of patients with unresectable HCC treated with sorafenib or lenvatinib as first-line treatment at our hospital between 2011 and 2022, were investigated. Clinical parameters, therapeutic effects, adverse events (AEs), and prognosis were evaluated separately for the non-elderly (<75 years old) and elderly patients (≥75 years old).ResultsOverall, 111 patients were enrolled, including 59 non-elderly and 52 elderly patients. Compared to the non-elderly patients, the elderly patients had significantly lower skeletal muscle mass and a significantly lower percentage of patients in poor general condition with performance status 2 or higher, but there were no differences in parameters related to liver function or nutritional status. There were no significant differences in the incidence of severe AEs and therapeutic effects between the groups. No significant difference in progression-free survival was observed in the elderly and non-elderly patients; however, overall survival (OS) for sorafenib treatment was shorter in the elderly patients than in the non-elderly patients. Elderly patients consumed lower doses of both the drugs, and relative dose intensity (RDI) 4 weeks after treatment (4W-RDI) was associated with OS. Further, OS in the elderly patients was significantly longer in the subgroup with high 4W-RDI as compared to that in the subgroup with low 4W-RDI.ConclusionsMTAs can be safely administered to elderly patients with HCC. Furthermore, 4W-RDI is associated with longer OS. Maintaining RDI in the early phase is crucial in predicting the success of treatment with MTAs, especially in the elderly patients.

Project description:Background & aimsCombination immunotherapy refers to the use of immune checkpoint inhibitors (ICI) and molecular-targeted agents (MTA), which have recently been approved for the treatment of advanced hepatocellular carcinoma (HCC). Owing to its relatively low antitumor effect (up to 30%), sequential therapy following ICIs treatment is required in patients with HCC. This study aimed to determine the impact of MTAs on the tumor immune microenvironment (TIME).MethodsWe established immune syngeneic orthotopic HCC mouse models using Hep-55.1C and Hep-53.4, and treated them with MTAs (lenvatinib, sorafenib, regorafenib, cabozantinib, and DC101 as anti-vascular endothelial growth factor receptor-2 antibodies, and AZD4547 as a fibroblast growth factor receptor (FGFR)-1/2/3/4 inhibitor) for 2 weeks. Subsequently, alterations in the TIME caused by MTAs were evaluated using immunohistochemistry (antibodies for CD3, CD8, Foxp3, Granzyme B, Arginase-1, NK1.1, F4/80, CD11c, PD-1, and PD-L1). We conducted RNA-seq analysis using lenvatinib- and AZD4547-treated tumors. To confirm the clinical relevance of these findings, we analyzed the transcriptome data of human HCC cells (MHCC-97H) treated with various concentrations of lenvatinib for 24 h using RNA-seq data from the Gene Expression Omnibus database.ResultsThe number of Foxp3- and F4/80-positive cells in the TIME was decreased in many MTAs. Cabozantinib increased the numbers in NK1.1-, Granzyme B, and CD11c-positive cells. Lenvatinib and AZD4547 increased the number of CD8, Granzyme B, and PD-L1-positive cells. Gene ontology enrichment analysis revealed that lipid metabolism-related genes were downregulated by lenvatinib and AZD4547. In total, 161 genes downregulated by FGFR inhibition in rodent models overlapped with those downregulated by lenvatinib in human HCC cells.ConclusionsIn this study, we showed that cabozantinib activated the innate immune system, and lenvatinib and AZD4547, which commonly inhibit FGFR signaling, altered TIME to a hot immune state by downregulating lipid metabolism-related genes. These findings support the therapeutic use of combination immunotherapies.

Dataset Information

Dose age affect the efficacy of molecular targeted agents in the treatment of hepatocellular carcinoma: a systematic review and meta-analysis.

Publications

Dose age affect the efficacy of molecular targeted agents in the treatment of hepatocellular carcinoma: a systematic review and meta-analysis.

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