Introduction
The response rate of advanced epithelial ovarian carcinoma treated with standard first-line platinum/taxane-based chemotherapy is ~80% (1–5). However, the majority of patients will relapse within 18–24 months (2–5). Decision-making regarding the treatment of recurrent ovarian cancer has been a continuous challenge. Since 1990, treatment selection has been based on whether patients have platinum-sensitive or platinum-resistant disease (6,7). For patients relapsing >6 months after the completion of the initial platinum-based chemotherapy, platinum-containing regimens are given, as long as the patients have platinum-sensitive disease (8). By contrast, for patients with platinum-resistant or platinum-refractory disease, single-drug regimens, including pegylated liposomal doxorubicin, gemcitabine or topotecan are indicated (9).
In addition to cytotoxic drugs, the development of molecular-targeted agents has emerged based on the increasing knowledge of key biological pathways driving tumor progression (10). Among the several targeted therapies investigated, the most promising approach for treating ovarian cancer is the inhibition of angiogenesis by bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor (VEGF). Accordingly, the level of VEGF expression in ovarian cancer has been associated with ascites formation and poor prognosis (11–15).
Promising data regarding efficacy have emerged from trials that have evaluated bevacizumab, alone or in combination, for the management of patients with recurrent ovarian cancer (16–20). Two phase III trials were recently conducted and led to the approval of bevacizumab by the European authorities for treating the first recurrence of platinum-sensitive or platinum-resistant ovarian cancer (21,22).
It is well known that the administration of bevacizumab is frequently associated with adverse events (AEs), including hypertension and proteinuria. In patients who are extensively pretreated or who exhibit pelvic disease or bowel obstructive symptoms, bevacizumab may also result in bowel perforation or fistula formation (17).
Importantly, the toxicities associated with the use of bevacizumab may also be observed outside of clinical trials and may be prominent, particularly when the drug is used in non-approved regimens. To date, limited data are available regarding the safety of this treatment in daily clinical practice (23–30). Thus, the present study was designed to assess the tolerance of bevacizumab in the management of recurrent ovarian cancer in routine clinical practice. A retrospective analysis was conducted using data from patients who were treated for ovarian cancer in five French referral centers. The safety of the treatment and its outcomes were evaluated from a cohort of heavily pretreated patients, the majority of whom were ineligible for inclusion in clinical trials.
Discussion
The present multi-center observational retrospective study, designed to analyze the safety profile of bevacizumab in relapsed ovarian cancer, identified predictive factors for the development of severe AEs during bevacizumab treatment. The results presented here are of particular interest, as this study included patients treated with bevacizumab in clinical practice. Indeed, data regarding treatment and outcomes of patients outside of clinical trials remains scarce, even though it may more accurately reflect the events that occur in the management and outcomes of patient with ovarian cancer in normal clinical practice.
Patients included in the current study, in contrast to those selected for clinical trials, did not conform to strict mandatory inclusion criteria, diagnostic procedures, management and follow-up protocols. The patients had a heterogeneous profile according to their previous medical history, lines of treatment prior to bevacizumab introduction and number of relapses. However, the clinical profiles of the patients at relapse were relatively homogeneous with regard to the sites of relapse and the general conditions of the patients. A majority of them had platinum-sensitive disease, and a low fraction exhibited GI obstructive disease.
The primary aim of the present study was to describe the safety profile of bevacizumab in routine practice. The most common AEs observed were hypertension, proteinuria and epistaxis, which are known side effects of bevacizumab treatment. The risk of the occurrence of such events may be dose-associated, as indicated by the multivariate Cox regression analysis and by previously published data (35–37).
Hypertension is a frequent side effect of anti-VEGF therapy (38). However, the impact of baseline hypertension on the development of high-grade hypertension during bevacizumab therapy is less well documented. For instance, in a phase III trial of bevacizumab treatment in ovarian cancer (39), and the studies included in the meta-analyses conducted by Zhu et al (35) and by Ranpura et al (40), an increased risk of high-grade hypertension associated with bevacizumab treatment was reported; however, the histories of the hypertensive patients were not analyzed. The OCEANS 20 trial reported similar findings (21). Indeed, while the baseline incidence of hypertension in enrolled patients was similar in the different groups of the study (37.6 vs. 39.7% for placebo and bevacizumab arms, respectively), and while grade ≥3 was only reported for 1 patient in the placebo arm (compared to 43 patients in the bevacizumab arm) the increased incidence of hypertension observed during bevacizumab treatment was not analyzed with regard to the hypertensive history of the patients.
In the current study, the incidence of history of hypertension for the entire cohort was 19.5%. On multivariate analysis, this feature was identified as an independent predictive risk factor for the development of high-grade hypertension during treatment. Therefore, previous history of hypertension must be taken into account for the management of patients receiving bevacizumab treatment for recurrent ovarian cancer.
All treatment-related mortalities in the current cohort occurred in patients who were previously treated with ≥4 lines of chemotherapy. This observation confirms that heavy pretreatment is an important factor involved in the occurrence of serious and fatal AEs, in clinical practice or in clinical trials (17,41).
GI perforation has been associated with the use of bevacizumab in various types of cancer (36,37,42). In trials where only ovarian cancer patients experiencing a first relapse (21) or patients treated with ≤2 regimens (43) were included, GI perforation were reported. In the present study, the rates of GI perforation (<1%) and GI fistula (3.2%) were low compared with that of other studies conducted in relapsed patients heavily pretreated with bevacizumab (17,44). This is likely due to the good performance status and relatively low incidence of pre-existing obstructive disease at the time of bevacizumab introduction in the current patients. Indeed, obstructive disease and peritoneal relapse have been reported to be the primary risk factors for GI perforation (45,46). Thus, the present results reveal that treating physicians are considering these known risk factors for bevacizumab toxicity before introducing the drug. Accordingly, multivariate analysis indicated peritoneal relapse as an independent predictive factor for grade 3–5 AEs.
The secondary endpoints for the present study included PFS and OS rates. Median PFS and OS were better for patients with platinum-sensitive disease compared with those having platinum-resistant disease. Accordingly, multivariate analysis revealed that patients who benefitted the most from bevacizumab were those treated in the second or third lines with the antibody, and who presented a platinum-sensitive disease.
In summary, as previously reported by clinical trials and other retrospective studies, the current findings confirm the impact of heavy pre-treatment on the occurrence of serious and fatal adverse events in patients treated with bevacizumab in daily practice. Notably, the present study demonstrated that a medical history of hypertension is an independent predictive risk factor for the development of high-grade hypertension during bevacizumab treatment. The current findings confirm the feasibility and toxic acceptability of the use of bevacizumab for treating relapsed ovarian cancer patients. Although these results are of importance and contribute to improved understanding of the management of adverse events attributable to the use of bevacizumab in ovarian cancer, more studies in this field are required. In particular, studies aimed at characterizing and applying biomarkers that could contribute to safer administration of bevacizumab, through the identification of patients with ovarian cancer most likely to benefit from the treatment, should be performed. Thus, retrospective analysis of patient cohorts may be of interest to validate such biomarkers and to determine whether they can be applied in clinical trials.