Incidence and management of bevacizumab-associated gastrointestinal perforations in patients with recurrent ovarian carcinoma☆
Introduction
In 2009, approximately 21,550 women will be diagnosed with ovarian carcinoma and more than 15,000 women will die from this disease [1]. Most of these women will be treated with an aggressive cytoreductive surgery followed by platinum and taxane-based chemotherapy. Despite treatment, most of these patients will recur and ultimately yield to their disease [2], [3]. In an effort to improve clinical outcomes, investigators have looked beyond conventional cytotoxic chemotherapy to biological agents. Angiogenesis appears to play a central role in the pathogenesis and clinical behavior of epithelial ovarian carcinoma. Vascular endothelial growth factor A (VEGF-A) is an important mediator of angiogenesis and is expressed in the majority of tumor specimens from patients with epithelial ovarian cancer [4], [5], [6], [7], [8]. These observations suggest that VEGF-A may be an important therapeutic target in patients with ovarian carcinoma.
Bevacizumab, a humanized IgG1 targeting VEGF-A, has been extensively studied in phase III clinical trials and is now approved in combination with chemotherapy by the U.S. Food and Drug Administration (FDA) and the European Medicine Agency (EMEA) for the treatment of metastatic colorectal cancer, non-small cell lung cancer, breast cancer, renal cell carcinoma, and recurrent glioblastoma [9], [10], [11], [12], [13], [14]. The role of bevacizumab in ovarian carcinoma was initially explored in two single-agent phase II trials in recurrent disease, one of which showed objective responses and prolongation of progression-free survival (PFS) when compared to historical controls [15]. The other trial, the ORBIT trial, was closed prematurely due to an unexpectedly high number of gastrointestinal (GI) perforations (5/44 [11%]), which were fatal in 3 patients (7%) [16]. The real assessment of the safety and efficacy of bevacizumab added to standard chemotherapy in first-line treatment following optimal surgical debulking can only come from large randomized trials that are currently ongoing [17], [18].
Based on the complications seen in the initial trials and our own experience with bevacizumab in the treatment of ovarian carcinoma we performed a review of our experience with bevacizumab-associated GI perforations. The objective of our study was to examine the incidence and management of bevacizumab-associated GI perforations in patients with recurrent ovarian carcinoma.
Section snippets
Methods
We retrospectively identified all women with recurrent ovarian carcinoma who received bevacizumab treatment at our institution from August 2004 to April 2009. Patients were identified using an institutional, electronic pharmaceutical database for bevacizumab. All patients were treated at a single institution. Patients who received bevacizumab on protocol were excluded from this analysis. During this time period, only patients who presented at the time of first recurrence would have been
Results
One hundred sixty patients with recurrent ovarian carcinoma who had been treated with bevacizumab were identified from our database. One hundred twenty-seven (79%) received bevacizumab in combination with a cytotoxic chemotherapy agent. Six (4%) patients experienced a GI perforation. Demographic and baseline characteristics of these two groups are presented in Table 1. There was no statistical difference in age, histology, International Federation of Gynecology and Obstetrics (FIGO) tumor
Discussion
Bevacizumab, a recombinant humanized monoclonal antibody directed against VEGF, has demonstrated anti-angiogenic activity in solid tumors, including renal, breast, colon, lung, and ovary [10], [12], [13], [15], [18], [19]. Phase II clinical trials and retrospective reports have shown that bevacizumab is active in ovarian carcinoma with a response rate ranging from 16% to 35% [15], [16], [18], [20], [21]. Bevacizumab is generally well tolerated and has an acceptable toxicity profile consisting
Conflicts of interest
John P. Diaz, MD: no conflicts
William P. Tew, MD: no conflicts
Oliver Zivanovic, MD: no conflicts
Jason Konner, MD: no conflicts
Paul J. Sabbatini, MD: no conflicts
Lisa A. dos Santos, MD: no conflicts
Nadeem R. Abu-Rustum, MD: no conflicts
Dennis S. Chi, MD: Speaker for Genzyme
Carol Aghajanian, MD: no conflicts
Richard R. Barakat, MD: no conflicts
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This research was initially presented as a poster presentation at the 2009 Annual SGO meeting.