Angiogenesis inhibitors, in particular, bevacizumab, are one of the most well studied target agents in cancer treatment. The formation of new vasculature is a key component to the spread and proliferation of cancer. Angiogenesis may be mediated along several different pathways, including VEGF, PDGF, EGFR, and tyrosine kinase inhibitors. Promising studies have added bevacizumab, a VEGF inhibitor, to standard treatment regimens with carboplatin and paclitaxel.
One study by the Gynecologic Oncology Group (GOG218) randomized patients with advanced EOC after debulking surgery into one of three treatment groups: standard paclitaxel, carboplatin, and placebo; paclitaxel, carboplatin and bevacizumab added on cycle 2 with placebo maintenance; or paclitaxel, carboplatin, and bevacizumab, followed by 15 months of maintenance bevacizumab.69
Arm 3 showed an improvement of 4 months in progression-free survival compared with arm 1, and demonstrated that the addition of bevacizumab showed benefit over conventional chemotherapy. Although the results may be statistically different, their clinical relevance may be tempered by the potential high costs related to bevacizumab therapy.70
In addition, there was no significant difference in overall survival between the three arms, but it should be noted that the study was not powered for overall survival.69
Another Phase III trial has also supported the use of bevacizumab in the upfront setting. A Phase III trial by the Gynecologic Cancer Intergroup (ICON7) randomized patients with stage II–IV EOC to carboplatin, paclitaxel and placebo, or to carboplatin, paclitaxel, and bevacizumab, with additional maintenance bevacizumab after primary therapy.71
This study found a 1.5-month improvement in progression-free survival in patients treated with bevacizumab compared with the control arm (hazard ratio for progression or death 0.81; 95% confidence interval: 0.70–0.94; P
= 0.004). Overall survival data were not mature at the time of reporting.
In both GOG218 and ICON7, bevacizumab was well tolerated and the rates of bowel perforation were not statistically different between the controls and bevacizumab-containing arms. It was interesting to note that the progression-free survival curves for both studies seem to converge after bevacizumab was discontinued and suggests that prolonged bevacizumab maintenance therapy may benefit patients. Further studies are needed to address this finding. An additional question that remains is whether the routes of administration of chemotherapy (ie, intravenous versus intraperitoneal) matter. Studies already show the benefits of the intraperitoneal route, though its toxicity remains higher than with conventional intravenous administration. Some researchers have analyzed the cost-effectiveness of intraperitoneal chemotherapy because of potential longer-term hospital stays for serious toxicity.72
Others argue that if overall survival is increased with intraperitoneal administration, then it may prove to be a good value.73
A recently closed Gynecologic Oncology Group study (GOG-252) was designed to compare intravenous carboplatin with intraperitoneal carboplatin and cisplatin along with the addition of bevacizumab. In the first phase of the study, patients are randomized into three treatment arms: weekly intravenous paclitaxel + intravenous carboplatin every 3 weeks + intravenous bevacizumab starting cycle 2; weekly intravenous paclitaxel + intraperitoneal carboplatin + intravenous bevacizumab starting cycle 2; or intravenous paclitaxel cycle 1 + intraperitoneal cisplatin + intraperitoneal paclitaxel cycle 2 + intravenous bevacizumab starting cycle 2. The second phase of the trial will maintain all three groups on intravenous bevacizumab starting on cycle 7.74
Other studies involving bevacizumab as well as other antiangiogenesis agents in first-line therapy for EOC are noted in .
Summary of current clinical trials of first-line targeted therapies for ovarian cancer*
Few other targeted agents have been designed as initial therapy for advanced EOC, primary peritoneal cancer, and fallopian tube cancer. In a Phase II trial by Konner et al, cetuximab, a monoclonal antibody synthetically designed to block tyrosine kinase inhibitors, was added to paclitaxel and carboplatin, and patients were then continued on weekly cetuximab for 6 months.75
However, while treatment was generally well tolerated, cetuximab had only limited efficacy compared with conventional chemotherapy.75
Another Phase II trial led by Vasey et al added erlotinib, a tyrosine kinase inhibitor, to docetaxel and carboplatin.76
The overall response rate was 52%, with five of 24 patients having a complete response for at least 6 months. The results are encouraging and future studies are necessary. Current first-line therapy with PARP inhibitors and PI3K/mTOR inhibitors are ongoing ().