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four randomized trials have been reported in three specific clinical settings that clearly document both the biological and clinical impact of bevacizumab , a human recombinant monoclonal antibody directed against vascular endothelial growth factor ( table 1 ) [ 1 - 4 ] . however , while there has been a documented improvement in progression - free survival ( pfs ) in each of the studies , they have failed to reveal superior overall survival for patients managed on the bevacizumab - containing treatment arm .
bev , bevacizumab ; gog , gynecologic oncology group ; icon 7 , international collaborative ovarian neoplasm group ; oceans , ovarian cancer study comparing the efficacy and safety of chemotherapy and anti - angiogenic therapy in platinum - sensitive recurrent disease ; pfs , progression - free survival .
while it is recognized that not all agree on the interpretation of these findings , it is the opinion of this commentator that it is highly likely the failure to convert a statistically significant improvement in pfs to superior overall survival is a direct result of the fact that the large majority of ovarian cancer patients receive multiple anti - neoplastic agents ( including possibly bevacizumab ) previously demonstrated to have both biological and clinical activity in ovarian cancer after they complete treatment on the study , which may favorably impact their ultimate survival . despite the solid evidence - based results of these multiple phase 3 randomized trials ( and perhaps at least partly because of them ) ,
there remain many quite relevant unanswered questions regarding the optimal utilization of bevacizumab in the management of ovarian cancer ( table 2 ) .
hopefully , future clinical trials will help resolve the uncertainties surrounding the use of this important anti - neoplastic agent .
the urgency in providing these answers is heightened when one recognizes the major financial impact associated with the routine administration of bevacizumab .
specific treatment setting ( e.g. , primary chemotherapy ; recurrent platinum - sensitive disease ; platinum - resistant disease ) administered as a single agent ( e.g. , maintenance therapy ) or in combination with cytotoxic chemotherapy appropriate dose ( e.g. , 7.5 mg / kg [ employed in icon7 trial ] or 15 mg / kg [ employed in gog218 and oceans trials ] ) establishment of a reliable and clinically useful biomarker to predict the patient population who will benefit or ( conversely ) who will not benefit from bevacizumab administration treatment with bevacizumab during more than a single treatment episode ( e.g. , recurrent platinum - sensitive and platinum - resistant disease ) overall safety of abdominal surgery performed shortly before or after drug delivery ( e.g. , risks of delayed wound healing , bowel perforation , vascular events ) overall safety of drug delivery in the presence of extensive intra - abdominal cancer in the setting of chemoresistant disease development of longer - term toxicities ( e.g. , vascular , cardiac , renal ) associated with prolonged delivery in patients who experience extended survival cost , economics , etc .
gog , gynecologic oncology group ; icon7 , international collaborative ovarian neoplasm group ; oceans , ovarian cancer study comparing the efficacy and safety of chemotherapy and anti - angiogenic therapy in platinum - sensitive recurrent disease .
a preliminary report of the results of a phase 3 trial examining a potential role for pazopanib employed as a  maintenance 
strategy following the completion of primary cytotoxic chemotherapy has revealed that the administration of this agent ( compared to placebo ) improves pfs ( median 17.9 months versus 12.3 months ; p = 0.0021 ; hazard ratio [ hr ] 0.766 ) .
although data on overall survival remain immature , the initial reported data do not suggest this strategy improves overall survival .
similar to the previously discussed situation with bevacizumab , this outcome is highly likely to be a result of the multiple anti - neoplastic agents delivered to patients once they have completed treatment on this trial .
data from phase 3 trials examining several additional anti - angiogenic drugs ( nintedanib ; cediranib ; trebananib ) in ovarian cancer management are eagerly awaited .
phase 2 trials have previously demonstrated the clinical activity of single - agent olaparib , a poly(adp - ribose ) polymerase ( parp ) inhibitor , in ovarian cancer patients with a germline brca 1 or brca 2 mutation .
as pre - clinical data revealed similarities in the molecular profiles of brca mutation - positive ovarian cancers and non - mutant - positive high - grade serous ovarian tumors , investigators conducted a phase 2 randomized trial ( n = 265 patients ) comparing olaparib to  placebo  employed as a single - agent  maintenance  strategy in women with high - grade serious ovarian cancers who had achieved a response or exhibited stable disease following a second - line platinum - based chemotherapy regimen .
the study revealed a highly statistically significant improvement in pfs ( median 8.4 months versus 4.8 months ; p  <  0.001 ; hr 0.35 ) in favor of the olaparib strategy .
again , there was no difference in overall survival between the study groups . in a preliminary report of a re - evaluation of this study population ,
the investigators were able to examine 218 ( of the original 265 ) patients for the presence of germline brca mutations .
this analysis revealed an even greater impact of olaparib ( compared to placebo ) on pfs ( median 11.2 months versus 4.1 months ; p  <  0.001 ; hr 0.17 ) in patients with a germline brca mutation .
it was also noted that of the 37 patients with a known germline brca mutation who were treated with  placebo  in this trial , 13 subsequently received a parp inhibitor ( in addition to other biologically active agents this group of patients may have also received following completion of the trial ) , potentially seriously compromising an analysis of an overall survival endpoint in this study .
despite the enthusiasm for the development of novel anti - neoplastic agents in ovarian cancer , it must be remembered that classical 
anti - neoplastic agents ( e.g. the  platinums  , the  taxanes  ) remain the cornerstone in disease management .
furthermore , clinical research designed to optimize the utilization of such agents remains active in the gynecologic oncology investigative community .
for example , a phase 3 randomized trial revealed the superiority ( pfs endpoint ) of a second - line regimen of carboplatin plus pegylated liposomal doxorubicin compared to carboplatin plus paclitaxel in recurrent , potentially platinum - sensitive , ovarian cancer , possibly due to a provocative , essentially unexplained , and striking reduction in carboplatin - associated hypersensitivity reactions when this agent is delivered with pegylated liposomal doxorubicin in the second - line setting .
there has been a particular focus on strategies designed to optimize the method of paclitaxel administration in ovarian cancer .
the japanese gynecologic oncology group reported the results of a phase 3 trial demonstrating the superiority ( pfs and overall survival ) associated with administering paclitaxel on a weekly ( 80 mg / m per week ) schedule compared to the  standard  every-3-week regimen . in this program ,
the carboplatin was delivered every 3 weeks . in a preliminary report of a multi - institutional phase 3 randomized trial
, investigators explored a quite different  weekly strategy  with both the paclitaxel ( 60 mg / m per week ) and carboplatin ( auc 2/week ) administered by this novel approach . compared to  standard 
every-3-week carboplatin plus paclitaxel , the weekly ( paclitaxel and carboplatin ) schedule was revealed to produce equivalent efficacy but with substantially reduced side effects .
whether the differences in efficacy and toxicity outcomes between these two studies relate to the weekly dose of paclitaxel delivered , the approaches to the administration of carboplatin , unique genetic or environmental backgrounds of the patient populations , or a combination of these factors remains unknown and worthy of future investigative efforts .
i would list potential  conflicts of interest  to include participation in medical advisory boards for : genentech , glaxo - smith kline , amgen , boehringer - ingelheim , celgene , novartis .
over the past several years , there have been a number of relevant evidence - based randomized trials that have the potential to change the standard management paradigm in the malignancy of ovarian cancer and ( most importantly ) enhance clinically relevant outcomes . 
 this commentary will briefly review these trials .