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Objective: To investigate the therapeutic effect and mechanism of lenvatinib on regorafenib-resistant hepatocellular carcinoma cells. Methods: CCK-8 and clone formation assay were used to observe the inhibitory effect of lenvatinib on the growth of hepatocellular carcinoma cells. Flow cytometry was used to detect the apoptosis of regorafenib-resistant hepatocellular carcinoma cells treated with lenvatinib. The expression levels of related proteins were detected by western blot and immunohistochemical staining. The inhibitory effect of lenvatinib on the tumor formation ability of regorafenib-resistant hepatocellular carcinoma cells in vivo was observed by subcutaneous tumor formation experiment in mice. Results: CCK-8 and clone formation assay showed that lenvatinib could inhibit the proliferation of regorafenib-resistant hepatocellular carcinoma cells. The number of clones of HepG2, SMMC7721 and regorafenib-resistant HepG2, SMMC7721 cells in lenvatinib group (120.67±11.06, 53.00±11.14, 55.00±9.54, 78.67±14.64) were all lower than those in control group (478.00±24.52, 566.00±27.87, 333.67±7.02, 210.00±12.77, all P<0.05). Flow cytometry showed that lenvatinib could promote apoptosis of regorafenib-resistant hepatocellular carcinoma cells, the apoptosis rates of HepG2, SMMC7721 and regorafenib-resistant HepG2, SMMC7721 cells in lenvatinib group [(12.30±0.70)%, (9.83±0.38)%, (15.90±1.32)%, (10.60±0.00)%] were all higher than those in control group [(7.50±0.87)%, (5.00±1.21)%, (8.10±1.61)%, (7.05±0.78)%, all P<0.05]. The apoptosis-related protein levels suggested that apoptosis was increased in the treatment of lenvatinib. The animal study showed that lenvatinib can inhibit the growth of regorafenib-resistant cells in vivo. Immunohistochemistry and western blot results showed that lenvatinib could down-regulate the abnormally activated IGF1R/Mek/Erk signaling pathway in regorafenib-resistant cells. Conclusion: Lenvatinib can reverse regorafenib resistance in hepatocellular carcinoma, possibly by down-regulating IGF1R/Mek/Erk signaling pathway.
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Animals , Mice , Humans , Apoptosis , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Proliferation , Liver Neoplasms/pathology , Signal TransductionABSTRACT
Objective:To evaluate the efficacy and safety of quadruple therapy involving radiotherapy (RT), lenvatinib, anti-PD-1 antibody and GEMOX (oxaliplatin and gemcitabine) chemotherapy (quadruple therapy) in treatment cohort of patients with unresectable intrahepatic cholangiocarcinoma (ICC).Methods:The patients with recurrent, metastatic, or unresectable ICC underwent quadruple therapy at Zhongshan Hospital, Fudan University between September 2018 and May 2022 were selected. The data about efficacy and safety of quadruple therapy were collected in the hospital electronic medical record system. All patients were followed up regularly to obtain the long-term prognostic data until December 31, 2022. The efficacy, prognosis, and toxicity data were collected and analyzed.Results:A total of 41 patients were included in the analysis. After a median follow-up period of 15 months, disease progression was diagnosed in 36 patients (18 patients died), while 3 patients were lost to follow-up. The causes of death included liver failure induced by intrahepatic tumor progression ( n=6), distant metastases (lungs or brain, n=6), abdominal lymph node metastases ( n=3), cancer cachexia ( n=2), and unknown cause ( n=1). The median progression-free survival (PFS) was 11 months (95% CI: 9.2-12.8), and the median overall survival (OS) was 35 months (95% CI: 17.0-52.0). All patients experienced treatment-related adverse events (AEs) during the study treatment period. Of the 41 patients, 13 patients experienced at least once grade 3 or worse treatment-related AE, but all were manageable with symptomatic treatment. No treatment-related deaths were reported during the follow-up period. Conclusions:Radiotherapy (RT), lenvatinib, anti-PD-1 antibody and GEMOX in the treatment of unresectable ICC shows significant efficacy and good safety, which is worthy of clinical application.
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Lenvatinib mesylate is an oral receptor tyrosine kinase inhibitor against targets of vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor α, stem cell growth factor receptor, and rearranged during transfection, et al. Lenvatinib has been approved by the National Medical Products Administration of China on September 4,2018, for the first-line treatment of patients with unresectable hepatocellular carcinoma who have not received systematic treatment before. Up to February 2023, Lenvatinib has been listed in China for more than 4 years, accumulating a series of post-marketing clinical research evidences. Based on the clinical practice before and after the launch of lenvatinib and referring to the clinical experience of other anti-angiogenesis inhibitors, domestic multidisciplinary experts and scholars adopt the Delphi method to formulate the Chinese Expert Guidance on Overall Application of Lenvatinib in Hepatocellular Carcinoma after repeated discussions and revisions, in order to provide reference for reasonable and effective clinical application of lenvatinib for clinicians.
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Objective: To investigate the effect of 1-acyl-sn-glycerol-3-phosphate acyltransferaseδ (APGAT4) on the growth and lenvatinib resistance of hepatocellular carcinoma (HCC), and provide novel targets for HCC treatment. Methods: Using the bioinformatics methods to screen out upregulated genes in lenvatinib resistant cell lines from GEO dataset and survival related genes from TCGA dataset. Immumohistochemical staining was used to detect the expression AGPAT4 in HCC tissues, and its correlation with patients' survival. CCK8, EdU, cell cycle, and cell apoptosis assays were used to investigate the impact of role AGPAT4 on the proliferation and lenvatinib reistance of HCC cells. AGPAT4 stable knockdown cell line and subcutaneous nude mouse model were established to test the therapeutic effects of Lenvatinib. Analysis of variance was used to compare the differences between data sets. Results: APGAT4 was the common factor that predicted poor survival and Lenvatinib resistance. The mRNA and protein levels of APGAT4 were significantly upregulated in HCC tissues compared to the para-tumor tissues (P < 0.05). Using siRNA could significantly knocked down the mRNA and protein expression of APGAT4 in HCC cell lines Hep3B and HCCLM3. Compared with the control group, the proliferation ability of HCC cell lines (Hep3B and HCCLM3) in APGAT4 knockdown group was significantly inhibited, and the cell cycle was arrested in G2/M phase (P < 0.05). In addition, compared to the control group, HCC cell lines (Hep3B and HCCLM3) in APGAT4 knockdown group showed significant decrease in the Lenvatinib half maximal inhibitory concentration, and were more sensitive to lenvatinib-induced apoptosis (P < 0.05). In HCC subcutaneous nude mouse model, compared to the control group, the growth of tumor in APGAT4 knockdown group was significantly suppressed, and more apoptosis cells were induced (P < 0.05). Conclusion: APGAT4 promotes the growth and Lenvatinib resistance of HCC, which is a potential target for HCC treatment. Targeting APGAT4 treatment is conducive to inhibit the growth and Lenvatinib resistance of HCC.
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Animals , Mice , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Mice, Nude , Cell Line, Tumor , Cell Proliferation , RNA, Messenger , Gene Expression Regulation, NeoplasticABSTRACT
ObjectiveTo investigate the efficacy and safety of 125I intraluminal irradiation combined with lenvatinib in the treatment of progressive extrahepatic cholangiocarcinoma. MethodsA retrospective analysis was performed for 25 patients with progressive extrahepatic cholangiocarcinoma who attended Department of Interventional Radiology， The First Affiliated Hospital of Zhengzhou University， from January 2018 to November 2021， and according to the treatment modality， they were divided into combination group with 13 patients （125I intraluminal irradiation combined with lenvatinib） and control group （125I intraluminal irradiation alone）. The two groups were compared in terms of technical success rates， changes in liver function， stent patency， survival time， and incidence rates of adverse events. The independent－samples t test was used for comparison of normally distributed continuous data between two groups， and the Wilcoxon rank－sum test was used for comparison of continuous data with skewed distribution between two groups； the Fisher’s exact test was used for comparison of categorical data between groups. The Kaplan－Meier method and the log－rank test were used to evaluate survival time and stent patency. ResultsAll patients had successful implantation of biliary stents and 125I particles， with a technical success rate of 100%. After 1 month of treatment， both groups had significant improvements in the serum levels of total bilirubin， direct bilirubin， alanine aminotransferase， and aspartate aminotransferase （all P<0.05）. There were significant differences between the control group and the combination group in the duration of stent patency （7.0 months vs 9.5 months， P=0.022） and median survival time （11.5 months vs 15.6 months， P=0.008）. There were no intolerable adverse events in the combination group during treatment. ConclusionCompared with 125I intraluminal irradiation alone， 125I intraluminal irradiation combined with lenvatinib has better efficacy and is a safe and effective treatment regimen for progressive extrahepatic cholangiocarcinoma.
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The article reported one case of renal damage caused by lenvatinib in the treatment of advanced primary liver cancer. The patient was a 63-year-old male who was admitted to the hospital due to "liver cancer for 4 years, blood pressure elevation for nearly 2 years, and edema for 7 months". During the treatment of liver tumors with atezolizumab combined with lenvatinib, blood pressure increased and renal insufficiency aggravated progressively. Pathological light microscopy of renal biopsy showed endothelial cell lesion and tubulointerstitial damage, and electron microscopy showed moderate proliferation of mesangial cells and deposition of mesangial matrix. There were many agglomerated low-electron density deposits in the mesangial area, and a small amount of electron dense deposits in the subendothelium. The pathological diagnosis was endothelial cell disease (thrombotic microangiopathy) and secondary focal segmental glomerulosclerosis. Renal injury was considered as secondary to lenvatinib. After discontinuing lenvatinib and giving angiotensin receptor antagonist treatment, blood pressure was normal, urine protein turned negative, and renal function improved significantly after 8 months of outpatient follow-up.
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Objective:To study the safety and treatment outcomes of portal vein embolization (PVE) combined with lenvatinib plus an anti-programmed death-1(PD-1) antibody to treat patients with initially unreasectable hepatocellular carcinoma (uHCC).Methods:This study retrospectively analyzed the data of six patients with uHCC who received first-line combined systemic therapy with lenvatinib plus an anti-PD-1 antibody, and then underwent pre-hepatectomy PVE at the Department of Liver Surgery at Zhongshan Hospital, Fudan University from May 2019 to November 2020. All enrolled patients were males, aged (54.6±6.2) (ranged 46 to 63) years. Tumor response and liver volume were evaluated by medical imagings once every 2 months (±2 weeks) and evaluated using the Response Evaluation Criteria in Solid Tumours (version 1.1). Patients were followed-up by outpatient interviews or by phone calls to record their survival and tumor outcome status.Results:Three of the six enrolled patients had Barcelona Clinic Liver Cancer stage A and three had stage B disease. One patient achieved a partial response and five patients had stable diseases. The mean ± s. d. future liver remnant (FLR) percentage was (29.0±8.9) % before PVE and the combination therapy, and was (41.3±10.8) % before the last evaluation for liver surgery ( t=10.79, P<0.001). Hepatectomy was carried out in five patients, and one patient who failed to develop significant FLR hypertrophy did not undergo hepatectomy. Grade B post-hepatectomy liver failure and major postoperative complications (i.e. pleural effusion requiring additional percutaneous drainage) occurred in one patient. After a median post-operative follow-up of 4.5 (range: 1.0-12.3) months, all five patients were alive and were tumor free. Conclusion:PVE followed by hepatectomy is feasible in a uHCC patients receiving systemic therapy with lenvatinib and an anti-PD-1 antibody.
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Objective:To investigate the clinical efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib plus PD-1 inhibitor (TACE+Len+PD-1) versus TACE combined with lenvatinib (TACE+Len) for patients with unresectable intermediate-advanced hepatocellular carcinoma (HCC).Methods:The data of 94 patients with intermediate-advanced HCC who received TACE+Len+PD-1 (One week after TACE, the patient were treated with lenvatinib and PD-1 inhibitor. lenvatinib, 8 or 12 mg/d, orally; PD-1 inhibitor, 200 mg/3 weeks, iv) or TACE+Len (One week after TACE, the patient were treated with lenvatinib.lenvatinib, 8 or 12 mg/d, orally) in the Second Affiliated Hospital of Guangzhou Medical University from June 2019 to February 2021 were collected and retrospectively analyzed. Among these patients, 44 were in the TACE+Len+PD-1 group and 50 were in the TACE+Len group. Tumor responses were evaluated according to modified response evaluation criteria in solid tumors. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse events (AEs) were compared between the two groups. The potential prognostic factors for PFS and OS were determined.Results:The ORR of TACE+Len+PD-1 group and TACE+Len group was 72.8% (32/44) and 52.0% (26/50) (χ2=4.25, P=0.039), respectively. The DCR of TACE+Len+PD-1 group and TACE+Len group was 86.4% (38/44) and 62.0% (31/50) (χ2=7.12, P=0.008), respectively. The median PFS and median OS in TACE+Len+PD-1 group were significantly longer than those in TACE+Len group (PFS, 7.9 vs. 5.6 months, χ2=7.91, P=0.005; OS, 18.5 vs. 13.6 months, χ2=4.40, P=0.036). Multivariate Cox regression analyses showed that TACE+Len (HR=2.184,95%CI 1.366-3.493), incomplete tumor capsule (HR=2.002,95%CI 1.294-3.209) and extrahepatic metastasis (HR=1.765,95%CI 1.095-2.844) were the independent risk factors for PFS, while TACE+Len (HR=2.081,95%CI 1.097-3.948) and BCLC stage C (HR=7.325,95%CI 2.260-23.746) were the independent risk factors for OS. The incidence of ≥grade 3 AEs in TACE+Len+PD-1 group was similar to that in TACE+Len group (χ2=0.45, P=0.501). Conclusion:Compared with TACE+Len, TACE+Len+PD-1 resulted in a better tumor response and a longer PFS and OS in patients with intermediate-advanced HCC.
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Objective To compare curative effect between lenvatinib combined with locoregional therapy and locoregional therapy on PD-L1-positive hepatocellular carcinoma patients with type Ⅰ-Ⅲ portal vein tumor thrombus according to Cheng's classification. Methods The patients in lenvatinib combined with locoregional therapy group received orally-administered lenvatinib at a dose of 12 mg qd for patients≥60 kg or 8 mg qd for patients < 60 kg. The locoregional therapy group only received locoregional therapy. We retrospectively analyzed the clinical data and prognosis of two groups. Results The CR+PR were 78.1% and 53.6% in the combination group and locoregional therapy group, respectively (P < 0.05). The response rate, disease control rate and overall survival of the combination group were higher than those in the locoregional therapy group (P < 0.05). Conclusion The curative effect and overall survival of lenvatinib combined with locoregional therapy is better than locoregional therapy on PD-L1-positive hepatocellular carcinoma patients with type Ⅰ-Ⅲ portal vein tumor thrombus according to Cheng's classification.
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Objective To investigate the efficacy and safety of lenvatinib combined with sintilimab as the second-line therapy for advanced intrahepatic cholangiocarcinoma (ICC). Methods A retrospective analysis was performed for the clinical data of the patients with advanced ICC who were admitted to Beijing Ditan Hospital from October 31, 2019 to October 31, 2021 and could not undergo surgery or experienced metastasis after surgery. All patients were treated with lenvatinib combined with sintilimab as the second-line therapy. The patients were followed up, and the RECIST1.1 criteria were used to assess treatment outcome. The primary endpoint was time to progression (TTP), and the secondary endpoints were tumor objective response rate (ORR), disease control rate (DCR), overall survival (OS) time, and safety. The Kaplan-Meier method was used to plot survival curves, and the log-rank test was used for comparison between groups. Results A total of 27 patients were enrolled, among whom there were15 male patients (55.6%) and 12 female patients (44.4%), with a median age of 58 years (range 33-73 years). The median TTP for these patients was 5.5 (95% confidence interval [ CI ]: 1.7-9.3) months, and 13 patients (48.1%) died of disease progression, with a median OS time of 11.2 (95% CI : 5.0-17.4) months. The overall ORR and DCR were 40.7% and 70.3%, respectively. Of all patients, 66.7% experienced varying degrees of adverse events, and among these patients, 44.4% had an increase in alanine aminotransferase, 44.4% had an increase in aspartate aminotransferase, 37.0% had hypertension, 29.6% had an increase in bilirubin, 29.6% experienced diarrhea, and 25.9% each experienced proteinuria, anorexia, and weakness. No treatment-related death was observed, and only 1 patient developed grade Ⅳ immune-related hepatotoxicity and was relieved without sequelae after corticosteroid therapy, resulting in permanent withdrawal of sintilimab. The patients with lymph node metastasis had a significantly shorter median TTP than those without lymph node metastasis (4.5 months vs 18.8 months, P =0.035), and the patients who achieved disease remission had a significantly longer median TTP [11.6 months (95% CI : 5.6-17.6) vs 2.8 months (95% CI : 1.8-3.8), P < 0.001]; the patients with lymph node metastasis had a shorter median OS time [9.6 months (95% CI: 7.9-11.3) vs 21.9 months (95% CI : 0-44.9), P =0.053], and the patients who achieved disease remission had a significantly longer median OS time [16.6 months (95% CI : 9.0-24.2) vs 6.9 months (95% CI : 3.6-10.2), P =0.011]. Conclusion Lenvatinib combined with sintilimab has a marked clinical effect and a low incidence rate of serious adverse events as the second-line therapy for advanced ICC, and therefore, it is a safe and effective treatment regimen.
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Objective To investigate the efficacy and safety of lenvatinib in patients with unresectable hepatocellular carcinoma (HCC) previously treated with tyrosine kinase inhibitor (TKI). Methods A retrospective analysis was performed for the clinical data of 76 patients with unresectable HCC who were treated with lenvatinib in Beijing Ditan Hospital, Capital Medical University, from January 2019 to January 2020, and according to the treatment method, they were divided into TKI previously untreated group with 49 patients and TKI treatment-experienced group with 27 patients. The patients were observed till one year after enrollment, adjustment of treatment regimen, tumor progression, or death. The two groups were compared in terms of progression-free survival (PFS) time, objective response rate (ORR), disease control rate (DCR), and incidence rate of adverse events. The t -test or the Wilcoxon rank-sum test was used for comparison of continuous data between two groups, and the chi-square test or the Wilcoxon rank-sum test was used for comparison of categorical data between two groups; the Kaplan-Meier method was used for survival analysis, and the log-rank test was used for comparison between groups. Results There were no significant differences between the TKI previously untreated group and the TKI treatment-experienced group in median PFS time (115 days vs 72 days, P =0.148), ORR (36.7% vs 18.5%, P =0.098), DCR (65.3% vs 55.6%, P =0.402), and incidence rates of grade ≥3 adverse events (24.5% vs 18.5%, P =0.550). Conclusion Patients with unresectable HCC previously treated with TKI can benefit from lenvatinib and have good safety, with similar results to those treated with TKI for the first time.
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El cáncer papilar de tiroides es el tumor tiroideo más común en la infancia. En estadios avanzados, puede presentarse con cuadro de insuficiencia respiratoria. El tratamiento de elección es la tiroidectomía total y iodo radiactivo. En tumores irresecables, se debería considerar terapia con inhibidores multicinasa.Niña de 10 años de edad derivada por insuficiencia respiratoria progresiva. Se realizó el diagnóstico de cáncer papilar de tiroides con metástasis pulmonares. Por presentar un tumor irresecable no pasible de cirugía, se indicó el uso compasivo de lenvatinib, que mostró una rápida y favorable respuesta clínica con resolución de la insuficiencia respiratoria al noveno día del tratamiento.El diagnóstico temprano de cáncer papilar de tiroides previene la grave morbilidad respiratoria ocasionada por diagnósticos tardíos. Podría considerarse el uso de lenvatinib como alternativa previa a las terapias de primera línea (cirugía e iodo radiactivo) en casos de enfermedad con gran compromiso local y a distancia.
Papillary thyroid cancer is the most common thyroid tumor in childhood. In advanced stages, it can present with respiratory failure. The treatment of choice is total thyroidectomy and radioactive iodine. In cases of unresectable tumors, therapy with multikinase inhibitors should be considered. A 10-year-old girl was referred for progressive respiratory failure. A diagnosis of papillary thyroid cancer with pulmonary metastases was made. Due to the presence of an unresectable tumor not subject to surgery, the compassionate use of lenvatinib was indicated, showing a rapid and favorable clinical response with resolution of respiratory failure on the ninth day.Early diagnosis of papillary thyroid cancer prevents severe respiratory morbidity caused by late diagnoses. The use of lenvatinib should be considered as a previous step towards first-line therapies (surgery and radioactive iodine) in cases with great local and distant involvement.
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Humans , Female , Child , Thyroid Cancer, Papillary/drug therapy , Respiratory Insufficiency , Combined Modality Therapy , Thyroid Cancer, Papillary/diagnosis , Neoplasm Metastasis , Antineoplastic Agents/therapeutic useABSTRACT
Objective: Lenvatinib is an oral multitarget tyrosine kinase inhibitor (mTKI) and is recommended for patients with advanced hepatocellular carcinoma (HCC) with Child-Pugh A liver function, who are not amenable to surgical resection, locoregional treatment, or transcatheter arterial chemoembolization. Hepatogastric fistula is a rare complication with a poor prognosis in patients with HCC. Previous reports on fistula formation during mTKI therapy for HCC were all associated with sorafenib. Here, we report the first case of recurrent hepatogastric fistula during lenvatinib therapy for advanced HCC managed using an over-the-scope clip (OTSC).Patient: We present the case of a 73-year-old man with alcoholic liver cirrhosis who was treated for multiple HCC for 7 years. HCC was treated using repetitive transcatheter arterial chemoembolization, radiofrequency ablation, and sorafenib. Owing to disease progression, lenvatinib treatment was started. During lenvatinib treatment, recurrent hepatogastric fistulas developed. An OTSC was useful for fistula closure and prevention of recurrence.Results: The major cause of fistula formation is considered to be the direct invasion of HCC; however, HCC treatment might also be a contributing factor in our case. In addition, OTSC was useful for fistula closure.Conclusion: Clinicians should be aware of the fatal complications during HCC treatment.
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ObjectiveTo investigate the efficacy and safety of sequential lenvatinib therapy after stereotactic body radiotherapy (SBRT) in the treatment of advanced primary liver cancer. MethodsA total of 18 patients with advanced primary liver cancer who were admitted to The Fifth Medical Center of Chinese PLA General Hospital from October 2018 to May 2019 were enrolled, among whom there were 4 patients with BCLC stage B liver cancer and 14 patients with BCLC stage C liver cancer. The prescribed dose of planning target volume was 48-55 Gy (median 50 Gy) in 6-9 fractions, and the median of single dose was 6 (5-9) Gy per fraction. Oral administration of lenvatinib was given since 1 week after SBRT was finished, with a median medication time of 9.5 (3.6-25.8) months. Follow-up was performed once a month for the first 3 months after treatment and once every 3 months after 3 months of treatment. The Kaplan-Meier method was used to calculate overall survival (OS) rate, progression-free survival (PFS) rate, and local control (LC) rate, and the incidence rates of adverse reactions and complications were also observed. ResultsUp to the follow-up on November 30, 2020, a total of 8 patients died, among whom 3 died of liver failure, 3 died due to tumor progression, 1 died of perforation of gallbladder, and 1 died of gastrointestinal bleeding. At 3, 6, 9, 12, and 18 months of treatment, the OS rates were 100%, 94%, 83%, 72%, and 67%, respectively, the PFS rates were 100%, 67%, 50%, 22%, and 17%, respectively, and the LC rates were 100%, 94%, 94%, 94%, and 94%, respectively; the median OS time was ＞18 months, and the median PFS time was 9 months. Of all patients, 1 (6%) had a grade 3 adverse reaction during SBRT and 2 (11%) experienced a grade 3 adverse reaction during lenvatinib treatment, and no fatal adverse reaction was observed. ConclusionIt is preliminarily proved that sequential lenvatinib therapy after SBRT is an effective and safe treatment method for advanced primary liver cancer.
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ObjectiveTo investigate the clinical effect of domestic programmed cell death-1 (PD-1) inhibitor combined with lenvatinib in the treatment of advanced primary liver cancer and related adverse events. MethodsA retrospective analysis was performed for the clinical data of 24 patients with advanced primary liver cancer who were treated with domestic PD-1 inhibitor combined with lenvatinib in Beijing Ditan Hospital, Capital Medical University, from January 1, 2019 to April 2, 2020, with 15 patients in the Camrelizumab+lenvatinib group, 7 patients in the Sintilimab+lenvatinib group, and 2 patients in the Toripalimab+lenvatinib group. During follow-up, Modified Response Evaluation Criteria in Solid Tumors was used to evaluate the treatment outcome of intrahepatic lesions, and RECIST1.1 was used to evaluate extrahepatic metastatic lesions. The Kaplan-Meier method was used to evaluate survival time. ResultsAmong the 24 treatment-experienced patients, 11 achieved partial response, 7 achieved a stable disease, and 6 had disease progression, resulting in an objective response rate of 45.8% and a disease control rate of 75.0%. The median time to disease progression was 8.4 (95% confidence interval: 6.89-9.91) months. The incidence rate of adverse events was 54.17%, and the most common adverse events were fatigue (29.17%) and hypertension (25.00%). ConclusionPD-1 inhibitor combined with lenvatinib has a marked clinical effect in the treatment of advanced primary liver cancer, with a low incidence rate of serious adverse events, and thus it is a safe and effective treatment regimen.
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@#Lenvatinib mesylate (LF), a multi-target tyrosinase inhibitor mainly used in the treatment of a variety of cancers, has low oral bioavailability mainly due to its gelation during the dissolution process. In the current study, in order to enhance dissolution and eliminate gelation of LF, a supramolecular coamorphous system of LF-baicalein (BAI) (molar ratio, 1∶1) was prepared by rotary evaporation and characterized by PLM, PXRD, DSC and FTIR. Results indicated the formation of coamorphous system with a single Tg of 118 °C. Different from original LF crystal, no gelation phenomenon was observed during the dissolution of coamorphous LF-BAI. In addition, the dissolution rate of LF was increased by 2.2-fold after coamorphization. Meanwhile, the dissolution rate of the co-former BAI was also enhanced by more than 25.4-fold. Stability test showed that the prepared coamorphous system had a good physical stability for at least 90 days under 25 °C/ 60%RH and 40 °C /75%RH conditions.
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【Objective】 To investigate the effect of Polymerized human cord hemoglobin (PolyCHb) on the sensitivity of hepatocellular carcinoma grafts to lumvalatinib in nude mice. 【Methods】 Hep3B hepatoma cells were subcutaneously transplanted in 18 nude mice to establish tumor graft model. Mice were randomly divided into 3 groups: control group (the saline 90 mg·kg-1·d-1), monotherapy group (Lenvatinib10 mg·kg-1·d-1), and sensitized group (Lenvatinib mg·kg-1·d-1, polyCHB 600 mg/kg twice a week) for 28 days. The tumor volume was measured regularly and the growth curve was drawn. On day 29, the nude mice were sacrificed, the tumor was stripped and weighed, and the pathomorphological differences of each group were evaluated by HE section staining. The expression levels of hypoxia-inducing factor (HIF-1α), CD34, VEGF, CD44, MMP-9, and Glut-1 in tumor tissues of each group were determined by immunohistochemistry. The content of reactive oxygen species (ROS) in tumor tissues of each group was determined by dihydroethyl ingot method. 【Results】 The tumor growth rate and tumor volume in the sensitized group decreased significantly compared with the control group and the solo drug group. On day 29, the tumor volumes of the control group, the monotherapy group and the sensitization group were (2 076.46±350.25)mm3, (1 035.96±84.16)mm3 and (892.66±104.46)mm3, respectively. Tumor weight was (1.61±0.52)g, (0.45±0.10)g, and (0.34±0.13)g, respectively. Immunohistochemical score of HIF-1α was 75±23 vs 45±18 vs 18±11, VEGF was 52±8 vs 67±16 vs 35±4, CD34 was 40±7 vs 50±13 vs 28±7, CD44 was 37±15 vs 30±7 vs 15±3, Glut-1 was 74±41 vs 51±30 vs 14±18, MMP-9 was 51±7 vs 62±20 vs 33±3, respectively(P<0.05). The malignant degree of the sensitized group was decreased by HE section staining, which was significantly lower than that of the solo drug group and the control. The ROS content in the sensitized group was higher than that in the solo drug group and the control. 【Conclusion】 PolyCHb can reduce the expression of HIF-1α and its downstream pathway related molecules by increasing oxygenation of hepatocellular carcinoma tissues in nude mice, delay tumor growth and reduce tumor volume in a certain period, thus increase the therapeutic effect of lenvalatinib on hepatocellular carcinoma grafts in tumor bearing nude mice models.
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Lenvatinib hasapplicationsin thyroid and hepatocellular carcinomas. When lenvatinib wasapproved for hepatocellular carcinoma in Japan, the manufacturer noted an increase of 5% in the incidence of side effects than those observed in thyroid cancer, based on the clinical-trial data. The monitoring of side effectsisimportant during chemotherapy. It isdifficult to confirm all the side effects within a single practice, and it is important to consider the incidence and severity of side effects before prescribing a particular treatment regimen. An antineoplastic agent is often used for different diseases, and it may be difficult to confirm a specific side effect. Because clinical conditions vary among different diseases, it is likely that the onset of side effects also differs. We investigated the difference between the onset of side effects in thyroid and hepatocellular carcinomas using the Japanese Adverse Drug Event Report database. The main side effects reported for thyroid cancer included bleeding, hypertension, cardiac disorders, myelosuppression,acute cholecystitis, delayed wound healing, infection, gastrointestinal perforation, fistula formation, and pneumothorax. In addition,patients with hepatocellular carcinoma experienced liver damage and hepatic encephalopathy. A significant strong correlation was observed between the drug dose and number of reports of the varied side effects. We compared the side effects in patients with thyroid cancer to those with hepatocellular carcinoma; although the same drug was used, there was varied expression of the side effects. Thisneedsto be taken into account when determining which drugsare to be used for the treatment of a particular cancer type.
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ObjectiveTo investigate the symptoms and symptom clusters in patients with advanced hepatocellular carcinoma (HCC) receiving molecular-targeted therapy with lenvatinib, as well as the clinical significance of the management of symptoms and symptom clusters in reducing lenvatinib-related grade 3 or above adverse events (AEs) and AEs leading to treatment termination. MethodsA total of 98 patients with advanced HCC who were treated with lenvatinib in The Fifth Medical Center of Chinese PLA General Hospital from May 2017 to December 2018 were enrolled. The AEs associated with lenvatinib were observed according to National Cancer Institute Common Toxicity Criteria, and the primary endpoint was the number of cases with a reduced dose or interruption of lenvatinib or treatment termination due to lenvatinib-related AEs after the management of symptoms or symptom clusters. ResultsAll 98 patients completed the whole procedure. As for the lenvatinib-related AEs with an incidence rate of ＞20%, hypertension had the highest incidence rate of 42.9%, followed by diarrhea (33.6%), hepatic encephalopathy (30.6%), anorexia (30.6%), proteinuria (25.5%), fatigue (25.5%), hand-foot syndrome (22.4%), hoarseness (20.4%), and weight loss (20.4%). The incidence rate of grade 3 or 4 AEs was 55.1% (54/98); the most common grade 3 AEs were hypertension (8.2%) and hepatic encephalopathy (6.1%), and grade 4 AE was observed in 1 patient (1%). The most common symptom clusters included hypertensive proteinuria (56.1%), digestive tract syndrome (50%), and pain syndrome (36.7%). Among the 98 patients, 41 (41.8%) had a reduced dose or interruption of lenvatinib due to lenvatinib-related AEs after the management of symptoms and symptom clusters and 4(4.1%) experienced treatment termination, which was lower than the percentages of 52.9% and 8.8% in the REFLECT study. ConclusionHypertension and diarrhea are common AEs associated with lenvatinib. Hypertensive proteinuria, digestive tract syndrome, and pain syndrome are the main symptom clusters. Symptom cluster management is an effective means to reduce lenvatinib-related AEs leading to treatment termination.
ABSTRACT
BACKGROUND/OBJECTIVES: Although anaplastic thyroid carcinoma (ATC) is rare, it is one of the deadliest forms of thyroid cancer. The fatality rate for ATC is high, and the survival rate at one year after diagnosis is <20%. The present study aimed to investigate the anti-tumor activities of paclitaxel, radiation, and tyrosine kinase inhibitor (TKI) combined therapy in anaplastic thyroid cancer cells both in vitro and in vivo and explore its effects on apoptotic cell death pathways.MATERIALS #SPCHAR_X0026; METHODS: ATC cell line was exposed to TKI, lenvatinib in the presence or absence of paclitaxel with radiation, and cell viability was determined by MTT assay. Effects of the combined treatment on cell cycle and intracellular signaling pathways were assessed by flow cytometry and western blot analysis. The ATC cell line xenograft model was used to examine the anti-tumor activity in vivo.RESULTS: Our data revealed that the combined administration of paclitaxel, TKI, and radiation decreased cell viability in ATC cells, and also significantly increased apoptotic cell death in these cells, as demonstrated by the cleavage of caspase-3 and DNA fragmentation. This combination therapy reduced anti-apoptotic factor levels in ATC cells, while significantly decreasing tumor volume and increasing survival in ATC xenografts.CONCLUSION: These results indicate that administering the combination of paclitaxel, TKI, and radiation therapy may exert significant anticancer effects in preclinical models, potentially suggesting a new clinical approach for treating patients with ATC.