Efficacy And Safety Of Apatinib In The Treatment Of Advanced Malignancies

Background:Cancer is one of the leading causes of human death.Through many years of development,great progress has been made in the treatment of malignancies.At present,treatments of cancer perform a tendency of diversification,including surgery,chemotherapy,radiotherapy,targeted therapy,immunotherapy,biological therapy,and traditional Chinese medicine treatment.However,metastasis and drug resistance of malignancies are still the main reasons for the failure of tumor treatment.Thus,searching for effective anti-tumor drugs has become the key to tumor treatment.Angiogenesis,as a therapeutic target,has gradually become an important field in the study of anti-tumor.Novel targeted drug-apatinib can suppress tumor growth due to its efficiency of anti-angiogenesis.It is a micro-molecule tyrosine kinase inhibitor which selectively binds to the intracellular site of ATP of vascular endothelial growth factor receptor-2 and inhibits the phosphorylation of VEGFR-2 thus blocks downstream signal transmission to suppress the proliferation,invasion,and metastasis of tumor cells.Now,apatinib is widely used in many kinds of tumors including gastric cancer,lung cancer,breast cancer,hepatocellular carcinoma,sarcoma,colorectal cancer,etc.This article systematically analyzed the efficacy and safety of apatinib post-line monotherapy in patients with advanced malignancies.Methods:Literatures published on PubMed,medline,and CNKI(China national Knowledge Internet)were searched(from inception to April 20,2019)for eligible trials using the search term:apatinib.Inclusion criteria were as follows:prospective or retrospective studies that evaluated efficacy and safety of apatinib as post-line monotherapy in patients with advanced malignancies;primary outcomes included at least one of these:objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),overall survival(OS),or adverse event(AE);number of cases in the study was no less than 10.RStudio-3.5.1 was used to count pooled ratios of ORR,DCR,PFS,OS and AE.Results:A total of 130 studies(86 studies in Chinese,44 studies in English)were involved in this pooled analysis including 45 studies of gastric cancer(n=3275),42 studies of lung cancer(n=1567),15 studies of breast cancer(n=600),8 studies of colorectal cancer(n=246),7 studies of sarcoma(n=189),4 studies of ovarian cancer(n=82),2 studies of esophageal cancer(n=122),2 studies of non-Hodgkin's lymphoma(n=52),2 studies of thyroid cancer(n=20),2 studies of head and neck adenocarcinoma(n=42),1 study of hepatocellular carcinoma(n=53).The pooled ORR of apatinib post-line monotherapy in advanced gastric cancer,non-small cell lung cancer,small cell lung cancer,breast cancer,sarcoma,colorectal cancer,ovarian cancer,esophageal cancer,non-Hodgkin's lymphoma,thyroid cancer,and head and neck adenocarcinoma were:18.6%(95%CI:0.151?0.221),12.9%(95%CI:0.111?0.146),13.9%(95%CI:0.081?0.197).33.2%(95%CI:0.243?0.421),25.1%(95%CI:0.188?0.315),7.2%(95%CI:0.027?0.117),43.8%(95%CI:0.331?0.545),23.8%(95%CI:0.162?0.313),38.0%(95%CI:0.249?0.510),84.0%(95%CI:0.684?0.996),and 39.1%(95%CI:0.242?0.540).The pooled DCR of apatinib post-line monotherapy in advanced gastric cancer,non-small cell lung cancer,small cell lung cancer,breast cancer,sarcoma,colorectal cancer,ovarian cancer,esophagus cancer,non-Hodgkin's lymphoma,thyroid cancer,and head and neck adenocarcinoma were:61.6%(95%CI:0.559?0.673),68.9%(95%CI:0.650?0.729),77.0%(95%CI:0.699?0.842),69.5%(95%CI:0.604?0.787),81.6%(95%CI:0.718?0.914),61.6%(95%CI:0.488?0.744),73.3%(95%CI:0.637?0.828),75.5%(95%CI:0.678?0.831),59.5%(95?CI:0.370?0.821),97.0%(95%CI:0.867?1.000),and 90.1%(95%CI:0.809?0.994).The pooled PFS survival ratios of 3,6,9,and 12 months of apatinib post-line monotherapy in advanced gastric cancer were:56.0%(95%CI:0.489?0.630),16.8%(96%CI:0.105?0.230),5.9%(95%CI:0.036?0.082),and 5.3%(95%CI:0.022?0.084);pooled OS survival ratios of 3,6,9,12,and 15 months were:80.6%(95%CI:0.733?0.879),40.2%(95%CI:0.274?0.530),20.1%(95%CI:0.104?0.298),19.7%(95%CI:0.109?0.284),and 13.8%(95%CI:0.094?0.183).The pooled PFS survival ratios of 3,6,9,and 12 months of apatinib post-line monotherapy in advanced non-small cell lung cancer were:60.3%(95%CI:0.520?0.686),24.1%(95%CI:0.177?0.306),20.7%(95%CI:0.108?0.305),and 4.6%(95%CI:0.000?0.092);pooled OS survival ratios of 3,6,9,12,and 15 months were 87.2%(95%CI:0.839?0.905),53.4%(95%CI:0.433?0.636),37.7%(95?CI:0.275?0.480),27.3%(95%CI:0.154?0.392),and 25.3%(95%CI:0.199?0.308).The pooled PFS survival ratios of 3,6,9,and 12 months of apatinib post-line monotherapy in advanced breast cancer were:60.9%(95%CI:0.537?0.681),31.3%(95%CI:0.200?0.425),15.3%(95%CI:0.072?0.234),and 7.0%(95%CI:0.016?0.125);pooled OS survival ratios of 3,6,9,12,and 15 months were:88.5%(95%CI:0.818?0.952),67.0%(95%CI:0.531?0.809),49.2%(95%CI:0.358?0.626),37.9%(95%CI:0.308?0.450),and 34.2%(95%CI:0.157?0.527).The pooled PFS survival ratios of 3,6,9,and 12 months of apatinib post-line monotherapy in advanced sarcoma were:81.1%(95%CI:0.749?0.872),52.5%(95%CI:0.378?0.673),29.3%(95?CI:0.137?0.449),and 16.0?(95%CI:0.015?0.305);pooled OS survival ratios of 3,6,9,12,and 15 months were:99.5%(95%CI:0.976?1.000),78.0%(95%CI:0.711?0.849),65.7%(95%CI:0.491?0.823),41.2%(95%CI:0.215?0.608),and 33.2%(95%CI:0.114?0.550).The pooled PFS survival ratios of 3,6,and 9 months of apatinib post-line monotherapy in advanced colorectal cancer were:62.0%(95%CI:0.451?0.789),23.5%(95%CI:0.108?0.362),and 18.4%(95%CI:0.068?0.301);pooled OS survival ratios of 3,6,9,and 12 months were:94.9%(95%CI:0.873?1.000),77.2%(95%CI:0.591?0.952),53.3%(95%CI:0.443?0.622),and 30.1%(95%CI:0.033?0.569).The pooled PFS survival ratios of 3,6,and 9 months of apatinib monotherapy in advanced non-Hodgkin's lymphoma were:87.3%(95%CI:0.783?0.963),69.9%(95%CI:0.575?0.823),and 54.0%(95%CI:0.406?0.675);pooled OS ratios of 3,6,9,and 12 months were:99.1%(95%CI:0.952?1.000),88.7%(95%CI:0.801?0.973),69.8%(95%CI:0.575?0.822),and 65.5%(95%CI:0.526?0.784).The common adverse events of apatinib post-line monotherapy in advanced malignancies were hypertension,hand-foot syndrome,proteinuria,leukopenia,abnormal liver function,fatigue,neutropenia,thrombocytopenia,nausea/vomiting,hemoglobin reduction,mucositis,bleeding,and diarrhea,et al with the pooled incidence ratios of 40.2%(95%CI:0.359?0.446),32.6%(95%CI:0.281?0.371),29.9%(95%CI:0.260?0.338),29.9%(95%CI:0.257?0.342),27.9%(95%CI:0.219?0.339),25.3?(95%CI:0.219?0.287),23.7%(95%CI:0.190?0.283),20.5%(95%CI:0.179?0.231),19.4%(95%CI:0.154?0.234),20.0%(95%CI:0.155?0.246),18.9%(95%CI:0.152?0.225),13.0%(95%CI:0.088?0.171),and 12.6%(95%CI:0.105?0.148)et al.The pooled incidence ratios of grade 3/4 hypertension,hand-foot syndrome,proteinuria,leukopenia,abnormal liver function,fatigue,neutropenia,thrombocytopenia,nausea/vomiting,hemoglobin reduction,mucositis,bleeding,and diarrhea were:9.9%(95%CI:0.083?0.114),5.7%(95%CI:0.049?0.065),5.3%(95%CI:0.042?0.065),3.1%(95%CI:0.020?0.043),4.3%(95%CI:0.032?0.055),2.6%(95%CI:0.017?0.034),3.8%(95%CI:0.026?0.051),3.7?(95%CI:0.026?0.047),2.9%(95%CI:0.014?0.044),3.0%(95%CI:0.019?0.041),3.9%(95%CI:0.024?0.054),2.2%(95%CI:0.012?0.032),and 2.0%(95%CI:0.011?0.028).Conclusion:1.Single apatinib post-line treatment was effective to patients with advanced tumors,especially breast cancer,sarcoma,esophageal cancer,ovarian cancer,non-Hodgkin's lymphoma,head and neck adenocarcinoma,and thyroid cancer.2.The incidences of adverse reactions of apatinib were comparatively high,especially hypertension,hand-foot syndrome and proteinuria;incidences of severe(grade 3/4)adverse events of apatinib were relatively low.3.Apatinib was an option of the patients who experienced progress after first-line or more treatments.Objective:Chemotherapy-based comprehensive treatments are used for recurrent or metastatic esophageal cancer patients with poor efficacy and unbearable toxicities.This study was aimed to assess the efficacy and safety profiles of apatinib in the treatment of advanced EC patients who failed with fist-line or more treatments.Methods:We retrospectively reviewed EC patients experiencing progression after fist-line or more treatments who had received single apatinib agent as post-line treatment at department of oncology of SuBei hospital affiliated to Yangzhou University between March 2017 to December 2019.Patients were treated with oral apatinib 500/425/250mg daily,every 4 weeks for a cycle.Responding and stable patients continued the treatment until progression or intolerable toxicity.Follow-up time was until the death of the patient or the end day of the study.The Objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),overall survival(OS)and adverse effects of the drug were evaluated.The efficacy and safety were evaluated by RECIST1.1 and NCI-CTCAE4.0.Kaplan-Meier method was performed for survival analysis.Results:A total of 31 patients were retrospectively enrolled.The ORR and DCR were 22.6%and 67.7%.The median PFS and median OS were 2.5 months and 5.5 months.The most common adverse events were hypertension,hand-foot syndrome,proteinuria,and mucositis with the incidence rates of 25.8%(8/31),22.6%(7/31),16.1%(5/31),and 12.9%(4/31).The incidence of treatment-related grade 3/4 toxicities was 12.9%(4/31).Conclusion:Apatinb showed efficacy and safety in advanced esophageal patients and could be a treatment option for them who experienced progression after firs-line or more treatments.