Bevacizumab increases risk for severe proteinuria in cancer patients

Abstract

Treatment with the chemotherapeutic agent bevacizumab, a humanized mAb that neutralizes vascular endothelial growth factor, can lead to proteinuria and renal damage. The risk factors and clinical outcomes of renal adverse events are not well understood. We performed a systematic review and meta-analysis of published randomized, controlled trials to assess the overall risk for severe proteinuria with bevacizumab. We analyzed data from 16 studies comprising 12,268 patients with a variety of tumors. The incidence of high-grade (grade 3 or 4) proteinuria with bevacizumab was 2.2% (95% confidence interval [CI] 1.2 to 4.3%). Compared with chemotherapy alone, bevacizumab combined with chemotherapy significantly increased the risk for high-grade proteinuria (relative risk 4.79; 95% CI 2.71 to 8.46) and nephrotic syndrome (relative risk 7.78; 95% CI 1.80 to 33.62); higher dosages of bevacizumab associated with increased risk for proteinuria. Regarding tumor type, renal cell carcinoma associated with the highest risk (cumulative incidence 10.2%). We did not detect a significant difference between platinum- and non-platinum-based concurrent chemotherapy with regard to risk for high-grade proteinuria (P = 0.39). In conclusion, the addition of bevacizumab to chemotherapy significantly increases the risk for high-grade proteinuria and nephrotic syndrome.

Figure 1.

Selection process for RCTs included in the meta-analysis.

Figure 2.

RR for high-grade proteinuria with bevacizumab compared with control. Both fixed- and random-effects models are used to calculate RR. (A) Overall RR for high-grade proteinuria is reported using the random-effects model. (B and C) Summary RRs for high-grade proteinuria for patients who received bevacizumab at 2.5 mg/kg per wk (B) or 5 mg/kg per wk (C) are reported using the fixed-effects model. The incidence of high-grade proteinuria is compared between patients who were treated with bevacizumab in combination with chemotherapy (bevacizumab) and chemotherapy alone (control) in each study. RR for each study is displayed numerically on the left and graphically on the right. Total events and sample sizes are also displayed for each study. For study name, the first author's name is used to represent each trial. When the same first author is involved in two trials, the publication year is also included to identify the trial. Reference number for each study is listed in brackets. For each trial, the position of the square denotes the value of RR, horizontal lines represent 95% CI, and diamond plot represents overall results of the included trials. Low-dosage bevacizumab arm of one trial is excluded from RR analysis because of zero events in the treatment and control groups.