Clinical Efficacy And Safety Of Apatinib Mesylate In Second-line Treatment Of Advanced Cholangiocarcinoma

Background and ObjectiveAs the second most common primary hepatocellular carcinoma with a high degree of malignancy,cholangiocarcinoma(CCA)is derived from the biliary epithelial cells.Depending on the anatomic site,it is classified as intrahepatic cholangiocarcinoma(iCCA)and extrahepatic cholangiocarcinoma(eCCA),which can be further divided into perihilar cholangiocarcinoma cholangiocarcinoma(pCCA)and distal cholangiocarcinoma(dCCA).Despite the low incidence rate of cholangiocarcinoma,the incidence rate and mortality rate of cholangiocarcinoma are increasing in recent years,and the degree of malignancy is high,and the prognosis is poor.Due to the hidden character of cholangiocarcinoma and the early clinical manifestations are not specific,most patients are in the advanced stage at the time of diagnosis,which is why 5-year survival rate is very poor.The treatment of cholangiocarcinoma includes surgical resection,liver transplantation,radiotherapy,chemotherapy,targeted therapy and immunotherapy.Surgical resection is the only curable method for CCA patients.But the tumor would be able to recur and metastasize quickly.Most of the patients were in advanced stage at the time of discovery and could only be treated with systemic or palliative treatment.The standard first-line chemotherapy for advanced cholangiocarcinoma is gemcitabine plus platinum,but its efficacy is not ideal.The median overall survival(mOS)of patients is less than 1 year,and there is no standard second-line treatment.Due to the heterogeneity of cholangiocarcinoma and the change of tumor microenvironment,the treatment of cholangiocarcinoma is limited,but it also provides opportunities for molecular targeted therapy.In recent years,antiangiogenic therapy has become an important treatment strategy for patients with malignant tumor.As a small-molecule VEGFR-2 tyrosine kinase inhibitor,apatinib inhibits angiogenesis,reduces tumor microvascular density and then inhibit the growth and proliferation of tumor cells by blocking the combination of endothelial growth factor(VEGF)and VEGFR.A large number of clinical studies have shown that apatinib has antitumor activity on a variety of cancers,and the toxicity is controllable.In October 2014,apatinib was approved by China Food and Drug Administration(CFDA)for advanced gastric adenocarcinoma or esophagogastric junction adenocarcinoma following disease progression or recurrence after at least two previous systematic chemotherapy regimens.However,the clinical efficacy and safety of apatinib in the treatment of advanced cholangiocarcinoma are not clear.In vivo and in vitro studies have shown that apatinib can inhibit the proliferation and invasion of cholangiocarcinoma cells,induce apoptosis of cholangiocarcinoma cells,and inhibit the growth of xenograft tumor in mice.Therefore,we conducted an single arm,open,prospective phase Ⅱ clinical study to evaluate the clinical efficacy and safety of apatinib as a second-line treatment for advanced cholangiocarcinoma.MethodsFrom November 2017 to November 2018,patients with advanced cholangiocarcinoma after failure of gemcitabine first-line chemotherapy were enrolled.All of the patients were treated with apatinib mesylate at 500mg orally daily,administered half an hour after the meal,for a cycle of 28 days until significant disease progression or drug intolerance or the patient ask to quit.Grade 3-4 drug-related adverse events resulted in dosage reduction to 250mg per day or interruption for several days until symptoms resolved to grade 1-2 and stabilized.The patients underwent CT or MRI and estimation of tumor marker to evaluate tumor’s response to treatment every seven to nine weeks during maintenance treatment,and adverse events(AEs)were collected at the same time.In addition,the safety evaluation is conducted every two weeks.The overall survival(OS)was followed up once a month for the PD subjects who withdrew from the study and the non PD subjects who completed the follow-up.Our primary endpoints were ORR and DCR,secondary research endpoints were mPFS and mOS.All data were statistically analyzed by SPSS 21.0 software.The efficacy and adverse were evaluated respectively using Response Evaluation Criteria in Solid Tumors version 1.1(RECIST 1.1)and National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.0(NCI-CTCAE 4.0).Kaplan-Meier method was used for survival analysis.Log rank test was used to analyze the factors affecting survival benefit.P<0.05 was considered statistically significant.ResultA total of 26 patients who met the screening criteria were enrolled and treated with apatinib mesylate in the First Affiliated Hospital of Zhengzhou University from November 2017 to November 2018.The follow-up continued until all the patients met PFS and OS,and the median duration of follow-up was 8.3(range:0.9-28.0)months.Of 26 patients,2 patients were lost to follow-up.24 of 26 patients could be evaluated Short-term and Long-term efficacy,1 patient(4%)showed complete response(CR),4 patients(17%)showed partial response(PR),10 patients(41.7%)had stable disease(SD),and 9 patients(37.5%)had progressive disease(PD).Meanwhile,apatinib therapy achieved an objective response rate(ORR)of 20.8%(95%confidence interval[CI]:9.24-40.47%)and a disease control rate(DCR)of 20.8%(95%CI:42.71-78.84%).The median progressive free survival(mPFS)was 95 days(95%CI:79.70-154.34 days),and the median overall survival(mOS)was 250 days(95%CI:112.86-387.14 days).Furthermore,univariate analysis revealed that age and tumor’s anatomic location significantly affected PFS(P<0.05).There were no significant associations of survival benefit with gender,Eastern Cooperative Oncology Group(ECOG)performance status,or CA199 level(P>0.05).The most common clinically adverse events(AEs)included myelosuppression(18/26,69.2%),hypertension(15/26,57.7%),proteinuria(12/26,46.2%)and hand-foot syndrome(10/26,38.5%).Other adverse events included anemia(7/26,26.9%),fatigue(7/26,26.9%),elevated transaminase(7/26,26.9%),elevated bilirubin(5/26,19.2%),anorexia(6/26,23.1%),oral mucositis(3/26,11.5%)and rash(1/26,8%).Most patients had mild adverse events,mainly grade 1 or 2,which could be relieved after symptomatic treatment,and no treatment-related death occurred.Conclusion1.Apatinib monotherapy for advanced cholangiocarcinoma after failure of gemcitabine based first-line chemotherapy had certain curative effect and controllable adverse events,which is expected to become a second-line treatment option for patients with advanced cholangiocarcinoma.2.The efficacy of apatinib monotherapy is limited,so it is necessary to carry out large sample,multi center,randomized controlled trials to further explore the efficacy and safety of combined therapy of apatinib for advanced cholangiocarcinoma,so as to determine the best comprehensive treatment mode.