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Strategies to improve sorafenib efficacy during image-guided treatment of hepatocellular carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is the third most frequent source of deaths associated with cancer after lung cancer in the world despite recent innovative treatment techniques. Liver transplantation, hepatic resection, and percutaneous ablation techniques hold great promise as potentially curative treatments for patients at early stages. Nevertheless, most of the patients are not suitable for these curative treatments due to their advanced disease stages at the time of diagnosis. Food and Drug Administration (FDA) approved tyrosine kinase inhibitor, sorafenib is a standard therapy for advanced-stage HCC patients which extends overall survival for several months. However, its therapeutic efficacy is restricted by adverse events and drug resistance which limits the number of patients benefiting from this systemic chemotherapeutic drug. During the last decade, novel approaches including but not limited to immunotherapies, ablation methods, and chemotherapeutic drugs were proposed to enhance sensitivity to sorafenib, improve therapeutic efficacy, and prohibit adverse events through novel delivery routes, utilization of nanoparticle carriers, and combination with other therapeutic agents. However, studies are still being conducted to optimize the efficiency of sorafenib and reduce its adverse events. In this review paper, we examine research studies evaluating novel delivery methods to reduce drug-related cytotoxicity to improve patient tolerance to sorafenib and its therapeutic efficacy in patients with HCC. Moreover, therapeutic approaches with the synergistic potential to combine with sorafenib are briefly summarized.

SUBMITTER: Eresen A

PROVIDER: S-EPMC8743717 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Efficacy of Sorafenib for the Treatment of Post-Transplant Hepatocellular Carcinoma Recurrence.

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| S-EPMC6209769 | biostudies-literature

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| S-EPMC10899070 | biostudies-literature

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| S-EPMC9251699 | biostudies-literature

Effective treatment strategies other than sorafenib for the patients with advanced hepatocellular carcinoma invading portal vein.

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| S-EPMC4462693 | biostudies-literature

Efficacy of sorafenib monotherapy versus sorafenib-based loco-regional treatments in advanced hepatocellular carcinoma.

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| S-EPMC3796498 | biostudies-literature

Comparative efficacy of treatment strategies for hepatocellular carcinoma: systematic review and network meta-analysis.

Project description:OBJECTIVE:Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. We conducted network meta-regression within a Bayesian framework to compare and rank different treatment strategies for HCC through direct and indirect evidence from international studies. METHODS AND ANALYSES:We pooled the OR for 1-year, 3-year and 5-year overall survival, based on lesions of size ? 3?cm, 3-5?cm and ?5?cm, using five therapeutic options including resection (RES), radiofrequency ablation (RFA), microwave ablation (MWA), transcatheter arterial chemoembolisation (TACE) plus RFA (TR) and percutaneous ethanol injection (PEI). RESULTS:We identified 74 studies, including 26?944 patients. After adjustment for study design, and in the full sample of studies, the treatments were ranked in order of greatest to least benefit as follows for 5?year survival: (1) RES, (2) TR, (3) RFA, (4) MWA and (5) PEI. The ranks were similar for 1- and 3-year survival, with RES and TR being the highest ranking treatments. In both smaller (<3?cm) and larger tumours (3-5?cm), RES and TR were also the two highest ranking treatments. There was little evidence of inconsistency between direct and indirect evidence. CONCLUSION:The comparison of different treatment strategies for HCC indicated that RES is associated with longer survival. However, many of the between-treatment comparisons were not statistically significant and, for now, selection of strategies for treatment will depend on patient and disease characteristics. Additionally, much of the evidence was provided by non-randomised studies and knowledge gaps still exist. More head-to-head comparisons between both RES and TR, or other approaches, will be necessary to confirm these findings.

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Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma.

Project description:Sorafenib, the unique drug as first-line treatment for advanced hepatocellular carcinoma (HCC), has opened a window of hope after searching for effective agents to combat HCC for decades. However, the overall outcomes are far from satisfactory. One of the explanations is the genetic heterogeneity of HCC, which has led to identifying predictive biomarkers for primary resistance to sorafenib, and then applying the concept of personalized medicine, or seeking therapeutic strategies such as combining sorafenib with other anticancer agents. Some of the combinations have demonstrated a better effectiveness than sorafenib alone, with good tolerance. The acquired resistance to sorafenib has also drawn attention. As a multikinase inhibitor, sorafenib targets several cellular signaling pathways but simultaneously or sequentially the addiction switches and compensatory pathways are activated. Several mechanisms are involved in the acquired resistance to sorafenib, such as crosstalks involving PI3K/Akt and JAK-STAT pathways, hypoxia-inducible pathways, epithelial-mesenchymal transition, etc. Based on the investigated mechanisms, some other molecular targeted drugs have been applied as second-line treatment for treat HCC after the failure of sorafenib therapy and more are under evaluation in clinical trials. However, the exact mechanisms accounting for sorafenib resistance remains unclear. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms and help to find effective strategies for overcoming sorafenib resistance in HCC.

| S-EPMC3724962 | biostudies-literature

Synergistic anti-tumor efficacy of sorafenib and fluvastatin in hepatocellular carcinoma.

Project description:Drug resistance to sorafenib is common in patients with hepatocellular carcinoma(HCC). We examined the effects of a combination of sorafenib and fluvastatin on HCC using in vitro and in vivo models. The dual treatment induced apoptosis and reduced cellular viability in HCC more effectively than either drug alone. The combination treatment also inhibited activation of hepatic stellate cells, whereas single drug treatments did not. On a molecular level, combined treatment inhibited activation of the MAPK and NF-κB pathways via Toll-like receptor 4 in HCC cells. Combined treatment also inhibited expression of stromal cell-derived factor 1α in HCC cells, which further inhibited the MAPK pathway in hepatic stellate cells. These results suggest that a combination of sorafenib and fluvastatin may be a promising therapeutic strategy for patients with advanced HCC.

| S-EPMC5410302 | biostudies-literature

Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study.

Project description:Sorafenib improves outcomes in adult hepatocellular carcinoma; however, hand foot skin reaction (HFSR) is a dose limiting toxicity of sorafenib that limits its use. HFSR has been associated with sorafenib systemic exposure. The objective of this study was to use modeling and simulation to determine whether using pharmacokinetically guided dosing to achieve a predefined sorafenib target range could reduce the rate of HFSR. Sorafenib steady-state exposures (area under the concentration curve from 0 to 12-h [AUC0->12 h ]) were simulated using published sorafenib pharmacokinetics at either a fixed dosage (90 mg/m2 /dose) or a pharmacokinetically guided dose targeting an AUC0->12 h between 20 and 55 h µg/ml. Dosages were either rounded to the nearest quarter of a tablet (50 mg) or capsule (10 mg). A Cox proportional hazard model from a previously published study was used to quantify HFSR toxicity. Simulations showed that in-target studies increased from 50% using fixed doses with tablets to 74% using pharmacokinetically guided dosing with capsules. The power to observe at least 4 of 6 patients in the target range increased from 33% using fixed dosing with tablets to 80% using pharmacokinetically guided with capsules. The expected HFSR toxicity rate decreased from 22% using fixed doses with tablets to 16% using pharmacokinetically guided dosing with capsules. The power to observe less than 6 of 24 studies with HFSR toxicity increased from 51% using fixed dosing with tablets to 88% using pharmacokinetically guided with capsules. Our simulations provide the rationale to use pharmacokinetically guided sorafenib dosing to maintain effective exposures that potentially improve tolerability in pediatric clinical trials.

| S-EPMC8604221 | biostudies-literature

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