Efficacy And Safety Of Small-sized Drug-eluting Beads Transcatheter Arterial Chemoembolization Combined With Lenvatinib In The Treatment Of Unresectable Hepatocellular Carcinoma:A Real-world Study

Objectives: Transcatheter arterial chemoembolization(TACE)has been the main treatment for advanced hepatocellular carcinoma.With the emergence of small molecule targeted drugs,the combination therapy has become a research hotspot.The objective of this study was to explore the efficacy and safety of drug-eluting beads transcatheter arterialchemoembolization(DEB-TACE)combined with lenvatinib in the treatment of patients with unresectable hepatocellular carcinoma.Materials and methods: This is a real-world,single-center,retrospective study.We evaluated the efficacy of 49 patients with advanced hepatocellular carcinoma treated with DEB-TACE in combination with lenvatinib between April 2019 and June 2022.All enrolled patients were embolized with small-size drug-eluting beads(Hepasphere 30-60μm)and treated with lenvatinib 3-7 days after DEB-TACE(Body weight < 60 kg,8mg;Body weight ≥60kg,12 mg,once daily).The medical history,age,sex,pathological type,and stage of Barcelona Clinic Liver Carcinoma(BCLC),Eastern Cooperative Oncology Group Performance Status(ECOG PS),Child-Pugh grade,number of intrahepatic lesions and maximum tumor diameter,alpha fetoprotein(AFP),presence of vascular invasion or extrahepatic metastasis were collected before DEB-TACE.Radiographic follow-up,including preoperative contrast enhancement computed tomography(CT)or magnetic resonance image(MRI),was performed every 8-12 weeks.Clinical indicators were followed up at 4-week intervals.Adverse events,response to treatment,time to progression and date of death were recorded.If the patient’s lesion is not completely necrotic,repeat embolization as needed based on the clinician’s assessment.The modified Response Evaluation Criteria in Solid Tumors(m RECIST)were applied to evaluate the best tumor response.Adverse Events of DEB-TACE and lenvatinib were evaluated using The NCI Common Terminology Criteria for Adverse Events(NCI-CTCAE 5.0).Survival curves of progression-free survival(PFS)and overall survival(OS)were plotted according to Kaplan-Meier method.Differences between groups were assessed using the log-rank test.COX univariate analysis was used to screen the influencing factors related to OS/PFS,and the factors with univariate p < 0.1 were included in COX multivariate proportional risk regression model for testing.Patients’ modified Albumin-Bilirubin(m ALBI)scores were calculated before surgery,3 days after surgery,and at 1,3,and 6 months after DEB-TACE.Paired sample t-test was used to compare liver function changes before DEB-TACE,3 days post-procedure,and 1,3,and 6 months post DEB-TACE.Results: The median follow-up time of the entire population was 21.6 months(95%CI:17.5-25.7 months).Among 49 patients with advanced hepatocellular carcinoma,36 patients developed progression and 25 patients died.Median PFS were 8.8 months(95% CI:7.0-10.6 months)and median OS was 18.2 months(95% CI:14.4-22.0 months).Univariate analysis showed that BCLC stage,maximum tumor diameter group,and vascular invasion were correlated with PFS,while no independent influencing factors related to PFS were observed in multivariate analysis.Univariate analysis showed that Child-Pugh grade,number of intrahepatic lesions,maximum tumor diameter,AFP and vascular invasion were correlated with OS,and multivariate analysis showed Child-Pugh grade A(HR=2.63;95% CI,1.01-6.89;p=0.048),maximum tumor diameter < 7cm(HR=2.82;95% CI,1.09-7.30;p=0.033)had significantly prolonged OS.Among the 49 patients,a total of 4(8.2%)patients achieved complete response(CR),among which 2 patients underwent surgical resection.Partial response(PR)was 28 cases(57.1%).Stable disease(SD)was 6 cases(12.2%).Progressive disease(PD)was 11 cases(22.4%).The objective response rate(ORR)was 65.3%,and the disease control rate(DCR)was 77.5%.Common adverse events in treatment with lenvatinib included hypothyroidism(42.9%),hypertension(40.8%),albuminuria(36.7%),fatigue(34.7%)and diarrhea(30.6%).Adverse events related to DEB-TACE included fever(53.1%),elevated aspartate aminotransferase(53.1%),elevated alanine aminotransferase(44.9%),abdominal pain(46.9%),constipation(38.8%),and elevated total bilirubin(36.7%).No grade 4 or above adverse events were found.Compared with the liver function of patients before surgery and 3 days after surgery,there was a brief deterioration,with statistical difference(p = 0.000).Compared with 3 days post-procedure,liver function was significantly improved at 1 month after DEB-TACE(p = 0.004).There was no significant difference in liver function 3 days post-procedure(p = 0.061)and 6 months after operation(p = 0.483).The liver function at 1,3 and 6 months after DEB-TACE was worsened to a certain extent(p < 0.05).Conclusions: Small-sized DEB-TACE combined with lenvatinib is effective and safe treatment for patients with unresectable hepatocellular carcinoma,with high ORR and good prognosis.Child-pugh B and maximum tumor diameter ≥7cm are independent risk factors for OS in patients.The overall adverse events of the patients were controllable,and no grade 4 or above adverse events occurred.Small-sized DEB-TACE showed decreased liver function 3 days after DEB-TACE,but recovered within a short time.The addition of lenvatinib did not affect the long-term liver function performance of patients.