Preclinical investigations have provided strong support for the hypothesis that angiogenesis is a potent driver of epithelial ovarian cancer progression. Phase II data have revealed the activity of single-agent bevacizumab in previously treated and clinically defined platinum-resistant ovarian cancer. Several reported phase III randomized trials, involving primary and both ‘platinum-sensitive’ recurrent and platinum-resistant disease, have demonstrated the addition of bevacizumab to a cytotoxic chemotherapy regimen improves progression-free survival compared with chemotherapy alone. While there continues to be considerable debate regarding the optimal dose, timing, and duration of bevacizumab administration in ovarian cancer, the existing data provide strong support for an important role for this agent in the overall management paradigm for this malignancy.
Ovarian cancer, bevacizumab, anti-angiogenic therapy, antineoplastic therapy
Maurie Markman, MD, has served as a member of medical advisory boards for Genentech, Celgene, Amgen, GlaxoSmithKline, and Boehringer-Ingelheim.
August 09, 2013 Accepted:
August 30, 2013
Maurie Markman, MD, 1425 Stockton Road, Meadowbrook, PA, 19046, US. E: email@example.com
Epithelial ovarian cancer has long been recognized as being highly sensitive to cytotoxic chemotherapy, with anticipated objective response to platinum-based chemotherapy of approximately 70-85%1
. Furthermore, overall survival (OS) for women presenting with advanced disease has been documented to have improved over the past few decades,2
although unfortunately the majority of responding patients ultimately experience recurrence of their disease process and die of complications associated with progression of the malignancy.
As a result, there is a critical need to find novel antineoplastic agents that have the potential to improve the outcome in this difficult illness.
Administration of Anti-angiogenic Agents in Epithelial Ovarian Cancer Preclinical Rationale
As the fundamental biologic process of new blood vessel formation (angiogenesis) has been well-documented to play a crucial role in normal reproductive physiology,3
it should perhaps not come as a surprise that laboratory investigative efforts have demonstrated the strong association between high levels of expression (within the tumor or circulation) of vascular endothelial growth factors (VEGFs) and poor survival outcomes in ovarian cancer.4–7
These provocative observations subsequently led to an intensive search for antineoplastic agents that might interfere with the growth promoting effects of these potent angiogenic factors in ovarian cancer. As a result, a number of drugs with anti-angiogenic properties have been explored in clinical trials in the management of this malignancy.7
Nonrandomized Experience with Bevacizumab in the Treatment of Ovarian Cancer
Bevacizumab, a monoclonal antibody inhibitor of VEGF, has demonstrated activity in a number of tumor types and specific clinical settings, and is widely employed in routine cancer management.7
Several nonrandomized phase II studies have confirmed both the biologic and clinical activity of single agent bevacizumab (15–20% response rate) in previously treated patients with ovarian cancer.8,9
As anticipated, the most common side effect was hypertension, but in one experience a disquieting incidence (10%) of bowel perforation was observed.9
This outcome has been speculated to have resulted from the recognized negative impact of anti-angiogenic agents on the tissue-repair process, particularly in the setting of carcinomatosis. Furthermore, the observation has led to the suggestion that bevacizumab should be administered with great caution (if at all) in the presence of extensive intra-abdominal disease or when there is evidence of bowel dysfunction (e.g. symptoms of partial small bowel obstruction).
Additional reported retrospective experiences and phase II trial data have confirmed both the safety and potential utility of bevacizumab when combined with cytotoxic agents in ovarian cancer. However, in the absence of randomized study data, the specific contribution of the anti-angiogenic (or of the cytotoxic) to a particular suggested favorable outcome remained unknown.10–12
1. Hennessy B, Coleman RL, Markman M, Ovarian cancer, Lancet, 2009;374:1371–82.
2. Markman M, Ovarian cancer survival: Steady improvement, despite rhetoric to the contrary, Current Oncology Reports, 2013;15(5):433–5.
3. Ferara N, Role of vascular endothelial growth factor in regulation of physiological angiogenesis, Am J Physio, 2001;280:1358–66.
4. Raspollini MR, Amunni G, Villanucci A, et al., Prognostic significance of microvessel density and vascular endothelial growth factor expression in advanced serious carcinoma, Int J Gynecol Cancer, 2004;14:815–23.
5. Smerdel MP, Steffensen KD, Waldstrom M, et al., The predictive value of serum VEGF in multiresistant ovarian cancer patients treated with bevacizumab, Gynecol Oncol, 2010;118:167–71.
6. Yoneda J, Kuniyasu H, Crispens MA, et al., Expression of angiogenesis-related genes and progression of human ovarian carcinoma in nude mice, J Natl Cancer Inst, 1998;90:447–54.
7. Burger RA, Overview of anti-angiogenic agents in development for ovarian cancer, Gynecol Oncol, 2011;121:230–38.
8. Burger RA, Sill M, Monk BJ, et al., Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: A Gynecologic Oncology Group study, J Clin Oncol, 2007;25:5165–71.
9. Cannistra SA, Matulonis UA, Person RT, et al., Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer, J Clin Oncol, 2007;25:5180–86.
10. Garcia AA, Hirte H, Fleming G, et al., Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: A trial of the California, Chicago and Princess Margaret Hospital Phase II Consortia, J Clin Oncol, 2008;26:76–82.
11. Wright JD, Hagemann A, Rader JS, et al., Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: A retrospective analysis, Cancer, 2006;107:83–9.
12. Micha JP, Goldstein BH, Rettenmaier MA, et al., A phase II study of outpatient first-line paclitaxel, carboplatin, and bevacizumab for advanced-stage epithelial ovarian, peritoneal, and fallopian tube cancer, Int J Gynecol Cancer, 2007;17:771–6.
13. Burger RA, Brady MF, Bookman MA, et al., Incorporation of bevacizumab in the primary treatment of ovarian cancer, N Engl J Med, 2011;365:2473–83.
14. Perren TJ, Swart AM, Pfisterer J, et al., A phase 3 trial of bevacizumab in ovarian cancer, N Engl J Med, 2011;365:2484–96.
15. Broglio KR, Berry DA, Detecting an overall survival benefit that is derived from progression-free survival, J Natl Cancer Inst, 2009;101:1642–49.
16. Aghajanian C, Blank SV, Goff BA, et al., OCEANS: A randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer, J Clin Oncol, 2012;30:2039–45.
17. Pujade-Lauraine E, Hilpert F, Weber B, et al., AURELIA: A randomized phase III trial evaluating bevacizumab plus chemotherapy for platinum-resistant ovarian cancer, J Clin Oncol, 2012;30:(Suppl. LBA5002).
18. Katsumata N, Yasuda M, Takahashi F, et al., Dose-dense paclitaxel once a week in combination with carboplatin every 3-weeks for advanced ovarian cancer: A phase 3, open-label, randomized controlled trial, Lancet, 2009;374:1331–8.
19. Markman M, Liu PY, Wilczynski S, et al., Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trial, J Clin Oncol, 2003;21:2460–65.