lenvatinib and Liver-Cirrhosis

This study aimed to investigate the incidence rate and risk factors for hepatic encephalopathy (HE) among unresectable hepatocellular carcinoma (uHCC) patients with liver cirrhosis who received sorafenib or lenvatinib treatment.. uHCC patients with cirrhosis who received first-line sorafenib or lenvatinib treatment between September 2014 and February 2021 were continually reviewed in our single-center retrospective study. The Hepatic Encephalopathy Scoring Algorithm was used to evaluate the occurrence and grade of HE during treatment, and logistic regression models were used to further explore the risk factors for HE.. A total of 454 eligible patients were enrolled in our study, with 214 and 240 patients in the sorafenib and lenvatinib groups, respectively. At time of data cut-off (2021-12), the incidence of HE in sorafenib group (4.2%, 95% CI:2-7%) was significantly lower than that in lenvatinib group (11.3%,95% CI:7-15%) (p = 0.006), with alcoholic cirrhosis [OR: 5.857 (95% CI: 1.519-22.591)], Child-Pugh >7 [OR: 3.023 (95% CI: 1.135-8.053)], blood ammonia ≥38.65 μmol/L [OR: 4.693 (95% CI: 1.782-12.358)], total bile acid ≥29.5 μmol/L [OR: 11.047 (95% CI: 4.414-27.650)] and duration of treatment ≥5.6 months [OR: 4.350 (95% CI: 1.701-11.126)] to be risk factors for the occurrence of HE during first-line systemic therapy.. In our study, for off-label uHCC patients (Child-Pugh >7) with alcoholic cirrhosis, hyperammonemia, hypercholesterolemia, and estimated longer duration of treatment, the application of lenvatinib has to be cautious, which needs to be confirmed in future clinical trials.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Hepatic Encephalopathy; Humans; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Neoplasms; Phenylurea Compounds; Quinolines; Retrospective Studies; Risk Factors; Sorafenib

Hepatocellular carcinoma (HCC) is an aggressive liver tumor that occurs due to chronic liver disease, and it has a high mortality rate and limited treatment options. Immune checkpoint inhibitors have been successfully introduced and used in cancer therapy, among which inhibitors of programmed death ligand-1 (PD-L1) and its receptor programmed death-1 (PD-1) are commonly administered for HCC as combination therapy, including combined anti-angiogenic and immunotherapy combination therapy. We report a case of a primary massive HCC patient with portal hepatic vein tumor thrombus who had a good response to atezolizumab in combination with bevacizumab, following progression of disease on combined immunotherapy with pembrolizumab and lenvatinib. This case demonstrates for the first time that an HCC patient who is resistant to anti-PD-1 antibody immunotherapy can benefit from anti-PD-L1 antibody immunotherapy, providing a potentially promising strategy for the treatment of HCC.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Bevacizumab; Carcinoma, Hepatocellular; Drug Substitution; Female; Hepatitis B, Chronic; Humans; Immune Checkpoint Inhibitors; Liver Cirrhosis; Liver Neoplasms; Middle Aged; Phenylurea Compounds; Portal Vein; Programmed Cell Death 1 Receptor; Quinolines; Salvage Therapy; Tomography, X-Ray Computed; Venous Thrombosis

Hepatocellular carcinoma (HCC) arises in a cirrhotic, pro-angiogenic microenvironment. Inhibiting angiogenesis is a key mode of action of multikinase inhibitors and current non-cirrhotic models are unable to predict treatment response. We present a novel mouse cirrhotic model of xenotransplant that predicts the natural biology of HCC and allows personalized therapy.. Cirrhosis was induced in NOD Scid gamma mice with 4 months of thioacetamide administration. Patient derived xenografts (PDXs) were created by transplant of human HCC subcutaneously into non-cirrhotic mice and intra-hepatically into both cirrhotic and non-cirrhotic mice. The applicability of cirrhotic PDXs for drug testing was tested with 16 days of either sorafenib or lenvatinib. Treatment response was evaluated by MRI.. 8 out of 19 (42%) human HCC engrafted in the cirrhotic model compared with only 3 out of 19 (16%) that engrafted in the subcutaneous non-cirrhotic model. Tumor vasculature was preserved in the cirrhotic model but was diminished in the non-cirrhotic models. Metastasis developed in 3 cirrhotic PDX lines and was associated with early HCC recurrence in all 3 corresponding patients (100%), compared with only 5 out of 16 (31%) of the other PDX lines, P = .027. The cirrhotic model was able to predict response and non-response to lenvatinib and sorafenib respectively in the corresponding patients. Response to lenvatinib in the cirrhotic PDX was associated with reduction in CD34, VEGFR2 and CLEC4G immunofluorescence area and intensity (all P ≤ .03).. A clinically relevant cirrhotic PDX model preserves tumor angiogenesis and allows prediction of response to multikinase inhibitors for personalized therapy.

Topics: Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Disease Models, Animal; Female; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Neovascularization, Pathologic; Phenylurea Compounds; Precision Medicine; Prognosis; Protein Kinase Inhibitors; Quinolines; Sorafenib; Thioacetamide; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays

Molecular targeted agents are pharmacologically used to treat liver fibrosis and have gained increased attention. The present study examined the preventive effect of lenvatinib on experimental liver fibrosis and sinusoidal capillarization as well as the in vitro phenotypes of hepatic stellate cells. LX-2, a human stellate cell line, was used for in vitro studies. In vivo liver fibrosis was induced in F344 rats using carbon tetrachloride by intraperitoneal injection for 8 weeks, and oral administration of lenvatinib was started two weeks after initial injection of carbon tetrachloride. Lenvatinib restrained proliferation and promoted apoptosis of LX-2 with suppressed phosphorylation of extracellular signal-regulated kinase 1/2 and AKT. It also down-regulated COL1A1, ACTA2 and TGFB1 expressions by inhibiting the transforming growth factor-β1/Smad2/3 pathway. Treatment with lenvatinib also suppressed platelet-derived growth factor-BB-stimulated proliferation, chemotaxis and vascular endothelial growth factor-A production, as well as basic fibroblast growth factor-induced LX-2 proliferation. In vivo study showed that lenvatinib attenuated liver fibrosis development with reduction in activated hepatic stellate cells and mRNA expression of profibrogenic markers. Intrahepatic neovascularization was ameliorated with reduced hepatic expressions of Vegf1, Vegf2 and Vegfa in lenvatinib-treated rats. Collectively, these results suggest the potential use of lenvatinib as a novel therapeutic strategy for liver fibrosis.

Topics: Animals; Capillaries; Carbon Tetrachloride; Cells, Cultured; Hepatic Stellate Cells; Liver; Liver Cirrhosis; Male; Neovascularization, Pathologic; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Rats; Rats, Inbred F344

Topics: Aged; Carcinoma, Hepatocellular; Cardiac Catheterization; Endothelin Receptor Antagonists; Hepatitis B, Chronic; Humans; Hypertension, Portal; Liver Cirrhosis; Liver Neoplasms; Male; Medication Therapy Management; Phenylurea Compounds; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pulmonary Arterial Hypertension; Pyrimidines; Quinolines; Sulfonamides; Tomography, X-Ray Computed; Treatment Outcome

Lenvatinib is a multikinase inhibitor approved for systemic first line treatment of hepatocellular cancer (HCC) in patients with compensated liver cirrhosis (LC) and unaltered liver function. We aimed to evaluate the efficiency and tolerability of lenvatinib in patients with HCC in a real world setting, also including patients with advanced LC and impaired liver function.. Retrospectively, 35 patients with HCC BCLC stages B, C and D were screened. After drop-out and exclusion of patients not receiving active treatment for > 2 weeks, 28 patients (27 male; median age 64.7) with advanced HCC and LC were included in the analysis.. Fourteen patients (male, median age 62.7) treated had Child-Pugh class B LC, while the other 12 patients had a good liver function Child-Pugh class A (male, median age 68.8). Two patients had advanced Child-Pugh class C LC. The patients received an escalating dosing scheme of lenvatinib up to 12 mg/d. The tolerability of lenvatinib was similar in most of the patients, with no significant difference between the subgroups. Median survival was better in patients with Child-Pugh A LC (p=0.003). More than 60% of the patients with Child-Pugh A were still on treatment at the time of data analysis with a median follow-up of 274 ± 117.5 days compared with 153 days (95%CI: 88.3 - 217.7) in patients with Child-Pugh B and 30 days in Child-Pugh C. The survival benefit correlated significantly with less impaired liver function (p=0.003).. Tolerability and toxicity of lenvatinib are similar in patients withChild-Pugh class A and class B LC, but patients with less impaired liver function have a better survival benefit.

Topics: Aged; Carcinoma, Hepatocellular; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Phenylurea Compounds; Quinolines; Retrospective Studies

The present study aimed to assess the clinical features of patients who received lenvatinib treatment for unresectable hepatocellular carcinoma (HCC).. The clinical characteristics, adverse events, and radiological responses were evaluated for 51 consecutive patients.. Of the study subjects, 37 patients had Child-Pugh class A (CPA) liver function, and 14 patients had Child-Pugh class B (CPB) liver function. The overall response rates in the CPA and CPB groups were 42.9% and 25.0%, respectively, and disease control rates were 82.9% and 83.3%, respectively, without significant difference (p = 0.2621 and 0.9697). There was no significant difference between CPA and CPB groups regarding the incidence of adverse events, except for hepatic coma. No significant difference was observed in the relative dose intensity between the CPA and CPB groups, for the first month, 1-2 months, or 2-3 months (p = 0.2368, 0.9368, and 0.9293).. The comparable outcomes between the CPA and CPB groups suggest the acceptability of lenvatinib treatment in patients with impaired liver function, at least in the acute phase. With careful follow-up, the dose can be relatively intensified, even in patients with impaired liver function and this may contribute to offering comparable treatment.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Liver Cirrhosis; Liver Neoplasms; Phenylurea Compounds; Quinolines