Initial Experiences with Bevacizumab in Recurrent Ovarian Cancer: Ouch!
Abstract & Commentary
By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D., Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman is on the speaker's bureau for GlaxoSmithKline, Bristol-Myers Squibb, and Ortho Biotech.
Synopsis: Combination bevacizumab therapy demonstrated activity in heavily pretreated women with ovarian cancer. Gastrointestinal perforations were identified in 9%. Despite the toxicity of the regimen, prospective studies, particularly in less heavily pretreated patients, are warranted.
Source: Wright JD, et al. Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: a retrospective analysis. Cancer. 2006;107:83-89.
Bevacizumab is a fully humanized, monoclonal antibody targeting the proangiogenic factor, vascular endothelial growth factor or VEGF. Animal models documented this agent's efficacy in several solid tumors including ovarian cancer and phase III clinical investigation has confirmed its activity in some solid tumors. Given the relationship of angiogenesis and ovarian cancer, there has been great interest in the use of bevacizumab for ovarian cancer therapy. The authors of the current study reviewed their experience of bevacizumab, administered in combination with cytotoxic(s), to women with recurrent ovarian cancer. In this retrospective analysis, 23 patients were identified with at least assessable disease. The median number of prior regimens was 7, including a median 3 prior platinum regimens.
Overall, 8 patients achieved a response (all partial) for a response rate of 35%. Stable disease was observed in another 10. The median time to progression for responders was over 5 months and for those with stable disease over 2 months. Severe or life-threatening toxicity was observed in 4 (17%) patients including 2 patients with gastrointestinal perforation. In addition, 2 responding patients were found with chylous ascites, a rare complication in gynecologic malignancies. One patient also experienced a hypertensive encephalopathy. Despite these observed and unusual toxicities, the authors suggest the agent should be studied further in larger prospective trials of less heavily pretreated patients.
Commentary
Clearly one of the most promising recent developments in solid tumors cancer management has been the discovery of agents targeting cell signaling and the tumor microenvironment. In a previous issue of OB/GYN Clinical Alert (June 2006), I reviewed the emerging strategy of angiogenesis targeting, which in tumors arising in the colon, kidney, breast and lung have been positively confirmed through the use of agents targeting the proangiogenic factor, VEGF. The agent furthest along in clinical development in this regard is bevacizumab, which has just begun phase III study in front-line ovarian cancer and, in the near future, recurrent ovarian cancer. As is frequently the case with many new therapeutics, initial experience is reported across a variety of tumors and clinical scenarios outside of the clinical study setting. While inference from these types of retrospective studies is limited, early warning signs of potential problems can emerge. The current study joins now 3 other completed trials in the literature—all in patients with heavily pretreated ovarian cancer.1-3 With the exception of the Gynecologic Oncology Group (GOG) study, each has reported significant and/or life-threatening toxicity, particularly gastrointestinal toxicity in a sizeable proportion of treated patients. The GOG study, reported at the American Society of Clinical Oncology annual meeting in 2005, included patients with one or two prior regimens, and by design, were less heavily pretreated. The authors report just the second trial where bevacizumab has been administered in combination with a cytotoxic regimen. The response rates in their cohort are impressive, particularly given the amount of pretreatment their patients had endured. In the laboratory setting, synergistic effects of combination anti-angiogenic and cytotoxic therapy can be clearly confirmed in ovarian cancer models. It is unfortunately unknown to what degree toxicity will be similarly affected. The current environment reminds one of the early experience with paclitaxel, where unexpected bowel necrosis was observed. It is likely future work with help to identify risk factors and situations (like bowel impending bowel obstruction) where the agent should be avoided. Currently we are very much in a "two steps forward, one step back" milieu, hopefully to be solidified with current and planned clinical investigation.
References
- Hu L, et al. Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in a human ovarian cancer model. Clin Cancer Res. 2005;11:6966-6971.
- Hollingsworth HC, et al. Tumor angiogenesis in advanced stage ovarian carcinoma. Am J Pathol. 1995;147:33-41.
- Gerber HP, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res. 2005;65:671-680.
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