ObejectiveTo establish the lenvatinib-resistant model of hepatocellular carcinoma (HCC) in vitro in order to study the effect of disulfiram combined with copper ions on the proliferation and apoptosis of lenvatinib-resistant Huh7 cells.MethodsThe half-inhibitory concentration (IC50) of Huh7 cells treated with lenvatinib was detected by the CCK8 method, and the resistance of Huh7 cells to lenvatinib was induced by increasing concentration method. The cell treatment of each group: The Huh7 cells cultured with common culture medium and with 10 μmol/L lenvatinb in the control group and lenvatinib sensitive group, respectively; The lenvatinib-resistant Huh7 cells cultured with 10 μmol/L lenvatinb, with 10 μmol/L lenvatinib+1 μmol/L disulfiram+0.5 μmol/L copper ions, and with 10 μmol/L lenvatinib+10 μmol/L Akt inhibitor MK2206 in the lenvatinib-resistant group, combined drugs group, and inhibitor group, respectively. The cell survival and apoptosis rates were detected by the CCK8 and flow cytometry, respectively. The Western blot method was used to detect the expressions of phospho-protein kinase B (p-Akt), cysteine aspartic acid specific protease (caspase-9), and B-cell lymphoma-2 (Bcl-2) proteins. The Transwell assay was used to detect the cell invasiveness.ResultsThe lenvatinib-resistant cell line was successfully established. The concentrations of 10, 20, 40, 60, 80 and 160 μmol/L leventinib were applied to the Huh7 cells for 48 h, and the IC50 was calculated to be 12.35 μmol/L. The cell survival rate of the lenvatinib-resistant group was significantly higher than that of the lenvatinib sensitive group (P<0.01), which in the combined drugs group was significantly lower than that of the lenvatinib-resistant group (P<0.01), which in the inhibitor group was significantly lower than that of the lenvatinib-resistant group (P<0.05). The apoptosis rate of the combined drugs group was significantly higher than that of the lenvatinib-resistant group (P<0.01). Compared with the lenvatinib-resistant group, the expression of p-Akt protein was significantly decreased (P<0.01) and caspase-9 expression was significantly increased (P<0.01) in the combined drugs group, while the difference of Bcl-2 protein between the lenvatinib-resistant group and the combined drugs group was not statistically significant (P>0.05). The invasive cells were more in the combined drugs group as compared with the lenvatinib-resistant group (P<0.01). ConclusionThe combination of disulfiram and copper ion could increase the sensitivity of lenvatinib to lenvatinib-resistant Huh7 cells, the cell inhibition rate is significantly increased, it’s mechanism might be related to the inhibiting p-Akt expression and promoting caspase-9 expression.
Objective To investigate the prediction of baseline neutrophil-lymphocyte ratio (NLR) on the prognosis of unresectable hepatocellular carcinoma (uHCC) treated with transarterial chemoembolization (TACE) + lenvatinib + camrelizumab. Method The clinical data of 58 patients treated with TACE + lenvatinib + camrelizumab in the Department of Liver Surgery of West China Hospital of Sichuan University from June 2020 to May 2021 were analyzed retrospectively. Results Among the 58 cases included, 7 cases were complete response (CR), 37 cases were partial response (PR), 11 cases were stable disease (SD), and 3 cases were progressive disease (PD). All cases had different degrees of adverse events, including 58 cases of grade 1, 36 cases of grade 2, 35 cases of grade 3, and 1 case of grade 4. The overall response rate (ORR) and disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) were 75.9% (44/58) and 94.8% (55/58), respectively. The hepatectomy rate was 31.0% (18/58) and the conversion success rate was 37.9% (22/58). Multivariate logistic regression analysis showed that NLR was an independent risk factor for ORR (OR=0.093, P=0.008). All cases were followed up for 16–60 weeks, with a median follow-up of 34 weeks. Overall survival situation (χ2=4.163, P=0.041) and progression free survival situation (χ2=10.626, P=0.001) in the low NLR group were better than those of the high NLR group. Conclusion NLR has clinical significance in predicting the prognosis of uHCC cases underwent TACE + lenvatinib + camrelizumab, which is worthy of further study.
ObjectiveTo explore the safety and effectiveness of transarterial chemoembolization (TACE) combined with lenvatinib and programmed cell death protein-1 (PD-1) antibody in the conversion resection for intermediate and advanced unresectable hepatocellular carcinoma (HCC), and to provide new treatment strategies for the treatment of intermediate and advanced unresectable HCC. MethodThirty-eight intermediate and advanced unresectable HCC patients treated at West China Hospital of Sichuan University from October 2020 to June 2021 were prospectively included in our study, all patients treated with TACE + lenvatinib + PD-1 antibody, and the clinical data of these 38 patients were summarized. ResultsThe last evaluation time for the 38 patients was October 20, 2021. According to the mRECIST standard for tumor efficacy evaluation, the objective response rate was 84.2% (32/38), the disease control rate was 94.7% (36/38); the conversion success rate based on imaging was 55.3% (21/38), the actual conversion resection rate was 52.6% (20/38). The incidence of adverse events was 100%, of which 22 patients had grade 3 adverse events, and there was no ≥ grade 4 adverse events. All patients were followed up, the follow-up time was 16–52 weeks, and the median follow-up time was 33.5 weeks. During the follow-up period, only two patients had tumor progression, of which one patient died due to disease progression, and there was no postoperative recurrence. ConclusionsLenvatinib combined with TACE and PD-1 antibody is safe for the treatment of intermediate and advanced unresectable HCC. Triple therapy can achieve satisfactory conversion resection rate of intermediate and advanced unresectable HCC, which will provide a new treatment strategy for it.
Objective To summarize the effect of lenvatinib + transarterial chemoembolization (TACE) + programmed cell death protein-1 (PD-1) antibody in the treatment of hepatocellular carcinoma with main portal vein tumor thrombus and cavernous transformation. Methods In this study, we reported the clinical data of four patients with hepatocellular carcinoma with main portal vein tumor thrombus and cavernous transformation who received conversion therapy with lenvatinib combined with TACE and PD-1 antibody in West China Hospital. Results Among the four patients, two patients achieved complete response and two achieved partial response; tumor markers were significantly decreased after combination treatment. However, all four patients failed to undergo hepatectomy. ConclusionsLenvatinib + TACE + PD-1 antibody is effective for hepatocellular carcinoma with main portal vein tumor thrombus and cavernous transformation. However, there are still many problems worthy of further discussion.
Objective To explore the safety and efficacy of lenvatinib in combination with transarterial chemoembolization (TACE) and programmed death receptor 1 (PD-1) antibody in the treatment of recurrent liver cancer. Method The clinical data of 22 patients with unresectable recurrent liver cancer admitted to Department of Liver Surgery and Liver Transplantation Center, West China Hospital, Sichuan University and received the conversion therapy of lenvatinib+TACE+PD-1 antibody between January 2019 and January 2022 were retrospectively analyzed. Results All 22 patients experienced some degree of adverse events, with a grade 3 adverse event rate of 18.2% (4/22) and no grade 4 or higher adverse events. At 4 months of treatment, according to the modified response evaluation criteria solid tumors (mRECIST), 2 cases were in complete response (CR), 5 cases were in partial response (PR), and 6 cases were in stable disease (SD), 9 cases were in progressive disease (PD), and the objective response (CR+PR) rate (ORR) was 31.8% (7/22). At the last follow-up, there was 1 case in CR, 5 cases in PR, 1 case in SD, and 15 cases in PD, with an ORR of 27.3% (6/22). The 1-year overall survival (OS) rate was 83.8% and the 1-year progression-free survival (PFS) rate was 38.2%. In the subgroup analysis, the 1-year OS rate for patients with recurrent liver cancer with intrahepatic lesions (n=16) only was 86.2% [95%CI (77.1%, 95.3%)], the 1-year PFS rate was 46.9% [95%CI (34.0%, 59.8%)], and the ORR based on mRECIST criteria was 43.8% (7/16). Patients with intrahepatic combined with extrahepatic lesions (n=6) had a 1-year OS rate of 75.0% [95%CI (53.3%, 96.7%)] and a 1-year PFS rate of 16.7% [95%CI (15.0%, 31.9%)], and the ORR based on mRECIST criteria was 0% (0/6). There were no significant differences in OS (P=0.864) and PFS (P=0.125) between the two subgroups. The ORR of intrahepatic combined with extrahepatic lesions group was worse compared to the intrahepatic lesion group (P=0.049). Conclusion Lenvatinib in combination with TACE and PD-1 antibody is safe and effective in the treatment of unresectable recurrent liver cancer, but there are still many issues that deserve further exploration.
ObjectiveTo evaluate systematically the effectiveness and safety of transcatheter arterial chemoembolization (TACE) in combination with lenvatinib (LEN) in the treatment of intermediate and advanced primary liver cancer (PLC). MethodsThe relevant literature was comprehensively searched in the CNKI, VIP, Ovid, Schopus, PubMed, and other databases from the establishment of the databases to March 14, 2023. The literature was obtained according to the search strategy and the inclusion and exclusion criteria, and the data were extracted and the literature quality was evaluated. The Revman 5.4 software and Stata 15.1 software were used to conduct the meta-analysis to evaluate the effect of TACE+LEN regimen on the objective response rate (ORR), disease control rate (DCR), overall survival (OS), as well as secondary outcome indicators such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alpha fetoprotein (AFP), and hypertension, diarrhea, hand-foot disease, fatigue, proteinuria, and fever for the patients with PLC. ResultsA total of 15 relevant literature was included, including 1 219 patients with PLC, 591 of whom treated with TACE+LEN and 628 treated with TACE alone. The meta-analysis results showed that the TACE+LEN regimen could increase ORR and DCR and prolong OS (P<0.01), as well as effectively decrease AFP level (P<0.01). However, TACE+LEN regimen increased the risks of hypertension, diarrhea, hand-foot disease, fatigue, and proteinuria as compared with TACE alone treatment (P<0.05). However, there were no statistical impacts on AST and ALT, or the risk of fever (P>0.05). ConclusionFrom the results of this meta-analysis, TACE+LEN regimen has a certain efficacy in treatment of intermediate and advanced PLC, but prevention of its related complications is paid attention to.
ObjectiveTo investigate the effects of lenvatinib combined with transarterial chemoembolization (TACE) and programmed death protein-1 (PD-1) monoclonal antibody (Abbreviated as LEN-TAP regimen) on residual liver volume and surgical safety in intermediate and advanced hepatocellular carcinoma (HCC). MethodsThe clinicopathologic data of patients with intermediate and advanced HCC were collected retrospectively, who underwent the LEN-TAP conversion therapy and surgical resection in the Department of Liver Surgery, West China Hospital, Sichuan University from October 2020 to December 2021. The total liver volume, tumor volume, and residual liver volume of the patients before and after conversion therapy were analyzed. ResultsA total of 48 patients were included, 26 of whom had partial remission and 22 had stable disease, the objective response rate was 54.2% (26/48) according to the Response Evaluation Criteria in Solid Tumours 1.1 after conversion therapy. Before and after conversion therapy, the total liver volumes including tumor were (1 607.15±712.22) mL and (1 558.03±573.89) mL [mean difference (MD) and 95% confidence interval (CI)=–57.42(–134.30, 19.46), t=–1.503, P=0.140], the total liver volumes excluding tumor tissue were (1 095.28±227.60) mL and (1 260.31±270.71) mL [MD(95%CI)=165.03(128.13, 201.93), t=8.997, P<0.001], the tumor volumes were 260.25(107.75, 699.50) mL and 121.73 (33.00, 332.88) mL [MD(95%CI)=–222.45(–296.46, –148.44), Z=–5.641, P<0.001], and the residual liver volumes were (493.62±154.51) mL and (567.83±172.23) mL [MD(95%CI)=74.21(54.64, 93.79), t=7.627, P<0.001], respectively. The increase rates of tumor volume and residual liver volume after conversion therapy were (–53.34±33.05)% and (16.34±15.16)%, respectively. The conversional resections were successfully completed in all patients, with 13 (27.1%) cases experiencing postoperative complications and without occurrence of postoperative liver failure. ConclusionThe data analysis results of this study indicate that the LEN-TAP conversion therapy can shrink tumor volume and increase the residual liver volume for patients with intermediate and advanced HCC, which helps to improve the safety of conversion resection.