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Treatment of Advanced Hepatocellular Carcinoma after Failure of Sorafenib Treatment: Subsequent or Additional Treatment Interventions Contribute to Prolonged Survival Postprogression.

ABSTRACT: BACKGROUND:Sorafenib is a first-line treatment option for advanced hepatocellular carcinoma (HCC) patients; however, survival predictors upon progression have not been well characterized. In the present study, we aimed to show the efficacy of multidisciplinary therapy for patients who had failed to respond to sorafenib treatment. METHODS:Among 146 BCLC stage B or C HCC patients treated with sorafenib monotherapy between July 2009 and August 2014, the first radiological progression according to the modified RECIST was identified in 71 patients; factors predicting overall survival (OS) and survival postprogression (SPP) were analyzed in these patients. RESULTS:The median OS and SPP for patients who failed to respond to sorafenib treatment were 10.5 and 6.2 months, respectively, and the SPP was strongly correlated with the OS (r = 0.982, P < 0.01, and R2 = 0.965). The independent predictors of OS and SPP were identical. The predictors of SPP were des-gamma-carboxy prothrombin, progression of portal vein thrombosis, and subsequent second-line or additional treatment. CONCLUSIONS:SPP is closely associated with OS and might be notable in patients who have failed to respond to initial sorafenib treatment. Furthermore, interventions consisting of other treatment options upon the appearance of progression might prolong OS.

SUBMITTER: Kondo M

PROVIDER: S-EPMC5498900 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Treatment of Advanced Hepatocellular Carcinoma after Failure of Sorafenib Treatment: Subsequent or Additional Treatment Interventions Contribute to Prolonged Survival Postprogression.

Kondo Masaaki M Numata Kazushi K Hara Koji K Nozaki Akito A Fukuda Hiroyuki H Chuma Makoto M Maeda Shin S Tanaka Katsuaki K

Gastroenterology research and practice 20170622

<h4>Background</h4>Sorafenib is a first-line treatment option for advanced hepatocellular carcinoma (HCC) patients; however, survival predictors upon progression have not been well characterized. In the present study, we aimed to show the efficacy of multidisciplinary therapy for patients who had failed to respond to sorafenib treatment.<h4>Methods</h4>Among 146 BCLC stage B or C HCC patients treated with sorafenib monotherapy between July 2009 and August 2014, the first radiological progression ...[more]

PMID: 28717362

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Project description:BackgroundCurrently, there are a few treatment options for unresectable hepatocellular carcinoma (HCC) after progression following sorafenib (SOR) therapy, but with limited benefit. The purpose of this study was to investigate the efficacy and safety of tyrosine kinase inhibitors (TKIs) combined with immune checkpoint inhibitors (ICIs) as second-line treatment.MethodsFrom May 2018 to May 2021, a total of 93 HCCs who failed SOR treatment were included in this study and divided into TKI group (n = 37) and TKI-ICI group (n = 56). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety were estimated among the two groups. In addition, univariate and multivariate Cox regression analyses were performed for OS and PFS to identify possible prognostic factors.ResultsWith a median follow-up time of 13.7 months, the median age of patients was 56 (range, 50-64) years and most were male. All of the patients were hepatitis virus-related HCC. Both median OS (7.63 months vs 19.23 months, P < 0.001) and median PFS (2.97 months vs 8.63 months, P < 0.001) were significantly improved in the TKI-ICI group compared to the TKI group. A significant increase in DCR was demonstrated in the TKI-ICI group compared to the TKI group (83.9% vs 45.9%, P = 0.0003), although no significant difference in ORR was reported (21.4% vs 8.1%, P = 0.1552). Multivariate Cox regression analysis of OS and PFS revealed that second-line regimen was an independent protective factor affecting death and progression in HCCs after SOR failure. In addition, Child-Pugh B7 was an independent risk factor of OS. Finally, there was no significant difference in the incidence of any grade or grade 3/4 adverse events (AEs) between the two groups, and no treatment-related deaths were observed.ConclusionThis real-world study suggests that the combination of TKIs and ICIs benefits more than mono-TKIs and is well tolerated in HCCs with hepatitis virus infection after SOR failure.

Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.

Dataset Information

Treatment of Advanced Hepatocellular Carcinoma after Failure of Sorafenib Treatment: Subsequent or Additional Treatment Interventions Contribute to Prolonged Survival Postprogression.

Publications

Treatment of Advanced Hepatocellular Carcinoma after Failure of Sorafenib Treatment: Subsequent or Additional Treatment Interventions Contribute to Prolonged Survival Postprogression.

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