The Efficacy And Safety Of TKIs Targeting VEGFR In Ovarian Cancer:A META-analysis

BackgroundOvarian cancer mortality in woman malignant tumors is in the first place.Due to lack of effective monitoring method and early clinical symptoms,most patients with ovarian cancer are at advanced stages when diagnosis is made.The conventional debulking operation followed by platinum-paclitaxel based chemotherapy or radiotherapy can achieve comforting results,but with the progress of the course,the chemo-resistance will be inevitable,at which time effective alternative chemotherapy schemes are extremely limited.New effective treatments are urgently needed.Target therapy has been the hotspot for the past decades,among which anti-angiogenic therapy has been most comprehensively studied.Bevacizumab is a monoclonal antibody aimed at the vascular endothelial growth factor(VEGF),which is designed to inhibit the formation of blood vessels in the tumor tissue,and thus inhibit its growth.Based on several positive large-scale clinical trials,bevacizumab was approved by FDA for the treatment of recurrent platinum-resistant ovarian cancer.The encouraging results secured by bevacizumab make people naturally think of another kind of agents,which target the intracellular tyrosine domain of VEGF receptor(VEGFR),namely tyrosine kinase inhibitor(TKI),and raise the question of whether or not this kind of agents can be equally effective or even better.So far,many relevant studies have been conducted and some have already been finished.To comprehensively analysis the efficacy and safety of this kind of agents,the author performed this meta-analysis.PurposeThe purpose of this research is to comprehensively analysis the efficacy and safety of the TKIs targeting VEGFR in ovarian cancer.MethodPubmed,Embase,and Web of Science were searched through October 5,2016 for randomized controlled trials.The pooled hazard ratios(HR)of progression-free survival(PFS)and overall survival(OS)with 95%confidence interval(95%CI)were calculated based on the Inverse-Variance method to evaluate the efficacy.Subgroup analyses by agent and treatment setting were performed.The pooled risk ratios of grade?3 adverse events(AE)with 95%CI were computed based on theMantel-Haenszel method to evaluate the safety.The software adopted was Review Manager 5.3.Results11 randomized controlled trials were selected,with 3806 patients and 5 agents(cediranib,nintedanib,pazopanib,sorafenib,and vandetanib)involved.Overall improvement was significant for PFS(HR=0.73,95%Cl 0.62-0.85),not for OS(HR=0.90,95%CI 0.78-1.04).For cediranib,nintedanib,and pazopanib,improvement of PFS was significant(HR=0.54,95%CI 0.43-0.68;HR=0.81,95%Cl 0.69-0.96;and HR=0.73,95%CI 0.55-0.97,respectively).None of the agents were able to prolong OS.Pazopanib presented non-significant PFS improvement(HR=1.09,95%Cl 0.80-1.49),and detrimental effect on OS(HR=1.71,95%Cl 1.01-2.89)in East Asians.Stratified by treatment setting,both of PFS and OS improvement was significant in the recurrent setting(HR=0.63,95%CI 0.50-0.78;and HR=0.74,95%CI 0.61-0.91,respectively).Grade?3 AEs with a significantly increased incidence included fatigue,rash,headache,anorexia,abdominal discomfort,diarrhea,hypertension,liver dysfunction,and bone marrow suppression.ConclusionBased on this META analysis,the following conclusion can be drawn:1.Overall,TKIs targeting VEGFR were effective for ovarian cancer patients,but the efficacies were not equal among them.Cediranib,nintedanib and pazopanib produced significant PFS improvement at the price of an increased incidence of grade?3 AEs(Common AEs include fatigue,diarrhea,hypertension,liver dysfunction and bone marrow suppression,etc).The clinical practice should accommodate the choosing will of the patients after informing them the pros and cons.2.Possibly for some factors unable to be controlled in the trials,pazopanib failed to show efficacy in East Asian patients.Based on the current results,pazopanib seemed an inappropriate choice for them.3.The OS for those patients with recurrent disease were shorter,and thus the PFS benefit was more likely to translate into OS improvement for them.Therefore,TKIs targeting VEGFR might be more meaningful for recurrent ovarian cancer patients.