Anti-Angiogenic Therapy In Ovarian Cancer Patients:An Updated Meta-Analysis

BackgroundOvarian cancer remains the eighth most common cancer and the leading cause of gynecologic cancer deaths wordwide,responsible for 225,000 new cases and 140,200 deaths per year.Lacking effective screening and diagnostic methods,more than 70%patients with this disease were diagnosed at advanced stages.Standard first-line treatment for this disease involves initial surgical cytoreduction followed by six cycles of systematic adjuvant chemotherapy with carboplatin and paclitaxel.In spite of initially high response rates to surgery and first-line chemotherapy,approximately 75%of patients will eventually relapse because of drug resistance.It has been a great challenge for gynecologists to treat recurrent ovarian cancer.Over the last decades,survival rates in patients with ovarian cancer have remained largely unchanged.The 5-year survival rate in women diagnosed with advanced ovarian cancer(FIGO stage III or IV)is less than 30%-40%.With the development of modern biology,targeted therapy has become a promising approach to overcome ovarian cancer and within which anti-angiogenic therapy has made an amazing anti-tumor activity.Angiogenesis plays critical roles in ovarian cancer growth,invasion,and metastasis.The poor prognosis is closely related to intensive new blood vessels which provide a promising target for the treatment of ovarian cancer.Anti-angiogenic agents exert their anti-tumor activity via inhibiting the formation of neuvascular and the possible mechanism is increasing the effects of chemotherapy by normalizing tumor vasculature,relieving the tumor hypoxia and enhancing the delivery of cytotoxic drugs.Recently,there are several randomized clinical trials assessing the efficacy and tolerance of the use of anti-angiogenic drugs in ovarian cancer patients,however the results of these trials are inconsistent.ObjectiveThis meta-analysis was designed to assess the efficacy of anti-angiogenesis therapy in patients with ovarian cancer.Metarials and methodsElectronic database of PUBMED,MENLINE,EMBASE and Cochrane Central Register of Controlled Trials were searched to identify relevant clinical randomized controlled trials(RCT)that evaluated the therapeutic value of anti-angiogenesis therapy in ovarian cancer(the final search was current to Sep.31th 2016).The articles written only in English were considered.Progression free survival(PFS),overall survival(OS)and objective response rate(ORR)were obtained from eligible RCT.The Hazard ratios(HR)for time-to-event variables and Odds ratios(OR)for dichotomous outcomes with their 95%confidence intervals(CI)were used for this meta-analysis.All the statistical analyses were carried out by Stata 11.0 software using a fixed or random-models according to heterogeneity of included studies.ResultsA total of 15 studies including 10 phase III trials and 5 phase II trials were recruited into this meta-analysis,with a population of 9359 patients.The overall analysis revealed that the incorporation of anti-angiogenic therapy was significantly associated with a longer PFS(HR=0.71,95%CI,0.62-0.81;P=0.000;random-effect)and a longer OS(HR=0.92,95%CI,0.86-0.98;P=0.008;fixed-effect)as well as a higher ORR(OR=1.74,95%CI:1.27-2.39;P=0.001;random-effect)in the total population.The results of further subgroup analyses are as follows:?stratified by treatment setting:compared with placebo,the incorporation of anti-angiogenic agents to ovarian cancer patients exhibited a statistically significant longer PFS in both primary setting(HR=0.88,95%CI:0.79-0.98;P=0.020)and recurrent setting(HR=0.58,95%CI:0.52-0.65;P<0.001);in contrast,an improved OS was gained only in the recurrent setting(HR=0.84,95%CI:0.76-0.92;P<0.001).Furthermore,we investigated survival benefit of anti-angiogenic angents between platinum-sensitive and platinum-resistant recurrent ovarian cancer patients.The results revealed a clear longer PFS and OS in both platinum-sensitive recurrent patients(HR=0.56,95%CI:0.48-0.64;P<0.001;randomized-effect for PFS;HR=0.86,95%CI:0.76-0.98;P=0.027;fixed-effect;for OS)as well as platinum-resistant recurrent cases(HR=0.54,95%CI:0.41-0.71;P<0.001;randomized-effect;for PFS;HR=0.84,95%CI,0.71-0.98;P=0.029;fixed-effect;for OS).?stratified by treatment strategy:throughout therapy of anti-angiogenic agents was associated with a statistically significant improved PFS(HR=0.66,95%CI,0.57-0.76;P<0.001;randomized-effect)and OS(HR=0.89,95%CI,0.83-0.96;P=0.001;fixed-effect).However the maintenance therapy of anti-angiogenic agents was irrelevant to a longer PFS or OS.?stratified by the functional mechanisms of anti-angiogenic agents:the incorporation of all 3 kinds of anti-angiogenic agents was associated with a statistically longer PFS(Bev group:HR=0.64,95%CI:0.50-0.82;P<0.001;AMG386 group:HR=0.68,95%CI,0.59-0.78;P=0.000;and TKI group:HR=0.76,95%CI:0.62-0.93;P=0.000).Otherwise,a longer OS was gained only in Bev group(HR=0.91,95%CI,0.84-0.99;P=0.025)and AMG386 group(HR=0.81,95%CI:0.67-0.99;P=0.036).ConclusionThe present updated meta-analysis indicated that the administration of anti-angiogenic agents to patients with ovarian cancer resulted in a clear longer PFS and OS as well as a higher ORR when compared with placebo or chemotherapy alone.Furthermore,our subgroup analyses exhibited that different strategy of anti-angiogenic agents resulted in different survival benefit,indicating the importance of proper use and patients selection for gynecologists.In future,further studies are wanted to guide the use of anti-angiogenic agents and identify the specific subgroup of patients who are most likely to benefit from anti-angiogenic therapy.