Bevacizumab in ovarian cancer: unanswered questions.

Under the term ‘epithelial ovarian cancer’ or EOC, we usually include a group of malignancies arising from extrauterine Mullerian epithelium (fallopian tube, primary peritoneal and ovarian cancer), which are characterized by peritoneal spread and by their common clinical presentation at advanced stages. Over the past 3 decades, therapeutic strides against these malignancies have been made, not from the use of early detection strategies, but rather following the introduction of the very active platinum compounds and aggressive surgical cytoreduction. Although great efforts are ongoing on the molecular characterization of these tumours, to date, drugs directed to molecular targets have not played a major part in treatment approaches. While carboplatin +paclitaxel chemotherapy regularly achieves eradication of post-surgery residual disease (assessed by non-invasive means), the average durability of these clinical responses barely exceeds 18 months. This remains the major challenge being addressed by our current clinical trials and new drug development. Upon clinical recurrence, particularly if ‘platinum resistant’, the disease is mostly ‘held at bay’ through the sequential application of a multitude of second-line drug regimens that may prolong survival through chronic administration, with variable patient benefit and acceptability. Now enter bevacizumab y After publication of bevacizumab’s activity against EOC in a Gynecologic Oncology Group (GOG) phase II study chaired by Robert Burger, interest in an anti-angiogenic strategy as part of the treatment for this disease markedly increased. A danger of bowel perforation in certain settings was recognized early. Nevertheless, such catastrophic events could be minimized with better patient selection, and trials were soon launched to examine the role of this agent when added to chemotherapy after initial diagnosis (first line) or at recurrence (second line). Furthermore, most oncologists dealing with gynaecological cancer developed experience with this agent by itself or in combination with other drugs either as part of pilot studies or in management of their patients. A picture emerged of a generally well tolerated drug that could ensure at least disease stability for several months (and often longer) in about 25% of patients, even after several lines of therapy (for a brief overview of the use of bevacizumab in this indication, please see the paper by Dhillon in this issue). Therefore, entry into well designed phase III clinical trials by the GOG (GOG-0218) and by a European/Canadian (International Collaborative Ovarian Neoplasm; ICON7) group of investigators was brisk: the results of the first-line trials were recently published by the New England Journal of Medicine. This was followed by the EuropeanMedicines Agency approval of a new indication for bevacizumab and the results being highlighted in an optimistic editorial. In fact, these two trials and the secondline phase III trial – presented at the American Society of Clinical Oncology 2011 annual meeting but not yet published – document clear effects of the drug in prolonging time to relapse or progression-free survival (PFS). Rather than celebrating the achievement of positive results, so far falling short of survival advantages, it is important to discuss the questions raised and discussions provoked from these clinical trials on how one is to apply these findings. COMMENTARY Drugs 2012; 72 (7): 931-936 0012-6667/12/0007-0931/$55.55/0