Angiogenesis has been implicated in the pathogenesis and progression of ovarian cancer
potentially due to the promotion of tumor growth, ascites, and metastases 5]. Therefore, therapies based on angiogenesis-specific pathway are being extensively
studied in ovarian cancer 6], 7]. Our present meta-analysis was based on a pool of 8 phase III and 4 phase II clinical
trials and thus differed from the two existing meta-analyses, which included only
clinical trials involving bevacizumab 20], 21]. Namely, these two meta-analyses indicated that the addition of bevacizumanb to chemotherapy
led to significant improvement in PFS and also increased the occurrence of adverse
events including gastrointestinal events, hypertension, proteinuria, and aterial thromboembolism
20], 21]. The present meta-analysis revealed that the incorporation of anti-angiogenesis therapy
was significantly associated with improvements in PFS and OS of ovarian cancer patients.
The pooled findings were further confirmed by one-way sensitivity analyses. More interestingly,
the subgroup analyses revealed that the patients with recurrent ovarian cancer derived
greater OS benefit from the anti-angiogenesis agents. In contrast, anti-angiogenesis
therapy in the primary setting conferred no significant OS benefit to ovarian cancer
patients. These pooled results do not indicate that the recurrence setting is ideal
for the incorporation of anti-angiogenesis into the treatment of ovarian cancer. In
the front-line setting, although the ICON7 and GOG218 trial failed to identify significant
differences in the OS benefits for patients according to whether bevacizumab was added
to the treatment across the entire populations of those studies, the addition of bevacizumab
to front line therapy does confer an OS improvement for patients who are at a high
risk for progression 10], 11]. This finding raised a question regarding patient selection that that led to the
use of individualized treatment regimens. Unfortunately, there is still a paucity
of reliable biomarkers to predict the clinical benefit of anti-angiogenesis therapy
22]. This paucity inspired us to identify specific biomarker signatures that can be used
to stratify patients with ovarian cancer according to the expected benefit of anti-angiogenesis
therapy 22], 23]. Possible serum biomarkers including mesothelin, FLT4, AGP, and CA-125 were investigated
24]. Additionally, the utilities of adiposity measurements and dynamic contrast-enhanced
magnetic resonance imaging (DCE-MRI) results as clinical biomarkers for anti-angiogenesis
therapy are also currently under investigation 25], 26]. More recently, miR-378 and its downstream targets, ALCAM and EHD1, have been proven
to be potential biomarkers of the response to anti-angiogenic therapy in ovarian cancer
27]. The challenge ahead is to validate these biomarkers and implement their use in clinical
practice with the goal of providing improved guidance regarding the use of anti-angiogenic
agents.
Another intriguing finding of present study is that trebananib seems to be active
in the treatment of recurrent ovarian cancer. Improvements in both PFS and OS were
observed in the patients who were treated with trebananib in the recurrent setting.
Another phase 3 trial assessing the potential benefit of trebananib in the recurrent
setting is underway (TRINOVA-2; NCT01281254). Moreover, the clinical benefit of the
addition of trebananib to front-line chemotherapy is also currently under investigation
in a phase 3 study (TRINOVA-3; NCT01493505). Notably, the mechanism by which trebananib
blocks angiogenesis and its associated toxicity profile are distinct from those of
VEGF pathway inhibitors 12]. Thus, trebananib provides a non-VEGF anti-angiogenesis option for the treatment
of ovarian cancer and raises the possibility that trebananib could be combined with
the VEGF pathway inhibitors, e.g., bevacizumab, in the treatment of ovarian cancer.
Certain limitations must be considered when interpreting the pooled findings. First,
our meta-analysis primarily focused on the PFS and OS. Indeed, the value of the PFS
for assessing the clinical benefit of new drugs for ovarian cancer has been controversial.
Additionally, it is not appropriate to simplify the clinical benefits of new drugs
to improvements in OS, particularly when the OS benefit of a drug is marginal, but
the side effects of that drug are life threatening. Thus, appropriately designed and
executed randomized trials that consider the quality of life are needed 28]. Such trials should balance the efficacy, safety, toxicity and cost. Second, significant
heterogeneity was found in our study. We deduced that variability in definitions of
end point, measurements, experimental design, sample size, patient characteristics,
and severity of the disease, may all represent a source of heterogeneity in our meta-analysis.
Publication bias is another concern. We attempted to identify all of the relevant
studies, but unavoidably, some studies could still be missing. As the additional high-quality
clinical trials related to anti-angiogenesis therapy that are underway are completed,
further analyses can be performed to validate the trends observed here.