Recently closed and current large-scale trials span the trajectory of ovarian cancer as shown in .x,xi,xii, xiii
The single-agent activity of bevacizumab in non-randomized phase II trials among women with ovarian cancer had lead to the evaluation of the addition of this agent to standard chemotherapy in two upfront-phase III trials (ICON 7, GOG 218) and three trials for women with recurrent disease (GOG 213, OCEANS, AURELIA). Both front-line trials (GOG 218 and ICON 7) and GOG 213 are also evaluating the impact maintenance bevacizumab may have in patients without progression following chemotherapy. The GOG reported a significant 4-month improvement in PFS associated with the addition of concurrent and maintenance bevacizumab in GOG 218. xiv
In addition, phase I and II trials have demonstrated that bevacizmab can be safely combined with relevant intraperitoneally-administered chemotherapeutics, such as cisplatin, carboplatin, and paclitaxel. The GOG has launched a new trial, GOG252, which compares IV chemotherapy with carboplatin and weekly paclitaxel to two different IV/IP regimens, includes bevacizumab in all three arms. In addition, as the mature analysis of the PFS endpoint for GOG 218 demonstrates a statistically significant benefit for the bevacizumab triplet followed by maintenance bevacizumab (Arm III), the GOG is opening a new trial in women with suboptimal primary cytoreduction, which will investigate the role of weekly paclitaxel. Both arms of this trial will include bevacizumab during primary and maintenance treatment phases.
Phase II studies have also demonstrated activity for several other agents targeting angiogenesis, including sorafenib, sunitinib, cediranib, and aflibercept. Of these, cediranib and pazopanib is currently under evaluation in phase III trial (ICON 6, AGO-OVAR-16). Phase II trials evaluating combinations of anti-angiogenesis agents, as well as anti-angiogenesis agents with other biologic agents, are currently underway. In addition, the EORTC has undertaken a phase III trial evaluating the role of erlotinib, which targets epidermal growth factor receptor (EGFR) as consolidation therapy after primary chemotherapy (EORTC 55041)
The Japan Gynecologic Oncology Group (JGOG) recently reported demonstrated statistically significant improvements in both progression-free survival (PFS) and overall survival (OS) associated with weekly paclitaxel compared with paclitaxel given every 3 weeks.xv
Women on both arms received carboplatin every 3 weeks. The Italian MITO group has since opened a study comparing weekly carboplatin/ paclitaxel to the same agents given every 3 weeks(MITO 7). The UK NCRI has proposed a three-arm phase III trial comparing carboplatin/paclitaxel given every three weeks to the same drugs given weekly to the combination of carboplatin given every three weeks and paclitaxel given weekly (ICON 8). Unanswered questions include the optimal dosing for paclitaxel in dose-dense treatments, as well as the efficacy of a dose-dense approach when used in combination with anti-angiogenesis agents or when the RAF-1 pathway is impaired.
Another key issue is the timing of primary surgical cytoreduction.xvi
The consensus in the United States continues to support primary surgery, for staging and cytoreduction, followed by chemotherapy, with neoadjuvant chemotherapy reserved for those women deemed unfit for initial surgery. This opinion is based primarily on the results of GOG 152, which showed no survival benefit associated with interval cytoreduction.xvii
To date, North American investigators have not undertaken a phase III trial randomizing patients to primary surgery followed by chemotherapy versus neoadjuvant chemotherapy followed by interval cytoreduction. Based on data from EORTC 55971, many investigators have advocated neoadjuvant chemotherapy for 3 cycles, followed by surgical cytoreduction, then additional chemotherapy. Both sides agreed, however, on the need to stratify for the timing of surgery in those trials which ask a chemotherapeutic rather than a surgical question.
Multiple randomized phase III trials suggest that a combination of intraperitoneal and intravenous chemotherapy significantly improves survival among women with optimally debulked epithelial ovarian cancer. Current trials seek to evaluate the efficacy and toxicity of regimens of IP/IV chemotherapy which include dose-dense paclitaxel and intravenous bevacizumab (GOG 252), as well as the role of IP/IV chemotherapy after neoadjuvant chemotherapy (NCIC CTG OV 21). The JGOG has proposed a trial comparing IP to IV carboplatin, both given with weekly IV paclitaxel (JGOG 3019).
Meta-analysis of cooperative group data has confirmed clinical observations, namely that women with advanced-stage mucinous and clear cell epithelial ovarian cancer experience less benefit from standard chemotherapy and poorer survival than those with serous and endometrioid ovarian cancer.xviii
As mentioned above, recent developments in molecular biology have shown clear differences in genetic profiles between mucinous, clear cell, and serous/endometrioid adenocarcinomas of the ovary. As shown in , separate phase III trials have now been developed for both clear cell and mucinous epithelial carcinomas, as well as a randomized phase II trial for women with chemotherapy-naïve sex-cord and stromal ovarian tumors. In addition, the GOG has undertaken phase II trials in such less common ovarian histologies as recurrent low-grade serous cancers (AZD 6244, a MEK inhibitor), and clear cell cancer (sunitinib).