Bevacizumab and its Role in Ovarian Cancer Therapy
Ovarian cancer (OC) ranks seventh in the world  and fifth in the United States  as the cause of cancer death. About 90% of the ovarian cancers are epithelial ovarian cancers (EOC). Unlike other gynecological cancers, the cause of EOC is unknown . The lack of specific symptoms for EOC leads to a delay in diagnosis and results in women presenting with advanced stages of the disease. The five year survival rate of advanced stage III or IV disease is estimated to be 20% . Currently surgery is the most effective treatment option for early stage I-IIA ovarian cancers with 90% 5 year survival rate . For woman with advanced stage disease, the standard treatment includes surgical debulking followed by adjuvant platinum – taxane based chemotherapy [6,7]. Nonetheless, the overall survival (OS) is poor  and drug resistance emerges within 5 years in patients with advanced stage (OC) . Recurrent ovarian cancer is classified into two groups based on platinum based therapy 1.) platinum resistant – if the cancer relapses within 6 months or 2.) platinum sensitive – if the cancer relapses after more than 6 months after completing platinum based chemotherapy . Targeted therapy might improve the outcomes of advanced stage ovarian cancer.
Angiogenesis plays an important role in the progression of OC and is perfect target for targeted therapy strategies [11, 12]. Angiogenesis mediated by vascular endothelial growth factor (VEGF) is critical for the normal ovarian function . The link between VEGF overexpression, enhanced angiogenesis and the development and progression of ovarian cancer has been well-established. This makes anti-angiogenic agents directed against VEGF attractive drug candidates. Bevacizumab is a recombinant, humanized, monoclonal antibody which binds to VEGF and neutralizes activation of its receptors . Phase II trials of bevacizumab has shown tumor regression and delayed disease progression in women with ovarian cancer [15 -17].
Until now 4 Phase III randomized clinical trials have been conducted to determine the efficacy of combining bevacizumab with standard chemotherapy. The first two ctrials GOG-0218 and ICON7 tested the efficacy of bevacizumab plus standard chemotherapy followed by bevacizumab maintenance therapy as front-line treatment [18, 19]. The other two efficacy trials OCEANS and AURELIA tested the efficacy of bevacizumab plus standard chemotherapy followed by bevacizumab maintenance therapy in platinum sensitive recurrent ovarian cancer setting [20, 21]. A statistically significant improvement in the progression free survival (PFS) and objective response rate (ORR) was observed in all the four studies. However, it is important to note that there is no significant improvement in the OS in all these studies. A recent meta-analysis of the four trials has confirmed these results . Without significant improvement in the OS use of bevacizumab as frontline therapy or in recurrent ovarian cancer setting is not cost effective [22, 23]. Notably, AURELIA showed improvement in patient-related outcomes (PROs) unlike the other 3 trials . GO 0218 trial did not show improvement in PROs, ICON7 showed slight worsening in PROs and OCEANS trial did not include PROs as end point [18-20].
The use of molecular profiling to predict responders vs non-responders to bevacizumab therapy is of importance as it would help decide which patients should receive the drug. In a preliminary analysis by Dr. Dowdy et al from Mayo clinic molecular sequencing was used to predict and identify patients who can benefit from bevacizumab treatment . These researchers used gene expression arrays to analyze the tissue form the ICON7 trial to determine the gene expression patterns of the ovarian tumors and use this data to predict the response to bevacizumab treatment . BRCA might also have a predictive value, as patients with BRCA mutations and recurrent ovarian cancer have shown single agent activity of olaparib . Patients who are BRCA negative and have platinum sensitive recurrent OC also exhibited response to olaparib therapy . The
potential role of VEGF-A as a biomarker has also been examined in bevacizumab studies. The association between high VEGF expression and disease progression  and poor OS  in platinum resistant OC has been observed in two separate phase II trials. Further research is needed to detect predictive markers of response to bevacizumab. Identification of these biomarkers would allow selection of patients who would benefit from this drug and reduce toxicity.
Interpreting the results from the trials mentioned earlier is complicated as these studies are different. The end points were evaluated using GCIG CA125 and RECIST criteria in GOG-0218 trial and only RECIST criteria in the ICON7 trial. The ICON 7 is a randomized two arm study and GOG-0218 is a randomized 3 arm study. Another important difference is, unlike other trials AURELIA is an open labelled study with no placebo control. Nevertheless, some key take home points from these studies are 1.) The dosage range in these trials was 7.5mg/kg – 15mg/Kg and in high risk OC patients there was no difference in PFS between patients receiving 15mg/Kg and 7.5mg/Kg. Therefore it is likely that the 7.5mg/Kg dose would give less toxicity and also be more cost effective. 2.) The data from OCEANS and AURELIA trials suggests that, scheduling the administration of beavcizumab until the disease progression is optimal and 3.) The data in these phase III trials does not give a compelling evidence for the use of bevacizumab as a front-line therapy but supports the use of bevacizumab plus chemotherapy in patients with platinum-resistant recurrent OC.
The GOG-0218, ICON7, OCEANS and AURELIA trials have generated a wealth of information and these studies will be road maps for future studies/clinical trials towards a cure for OC. Trials are underway to test optimal duration, dosage and efficacy of different chemotherapeutic agents by themselves and anti-angiogenic agents plus chemotherapeutic agents. Positive results with bavacizumab led to testing of other targeted anti-angiogenic agents directed against platelet derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), epidermal growth factor receptor (EGFR) and insulin growth factor 1(IGF 1) which are showing promising results. Another area of intensive research is the discovery of biomarkers with predictive and prognostic value in response to the therapeutic agents. The predictive biomarkers will help select patient population who would respond to the treatment and make the targeted therapy more cost effective which is otherwise expensive. Overall this is a promising period in ovarian cancer research as it ushers new hopes towards a cure for this notoriously challenging disease.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare no conflicts of interest in preparing this article.
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