Bevacizumab-related toxicities in the National Cancer Institute malignant glioma trial cohort

Bevacizumab is an antiangiogenic agent approved for recurrent glioblastoma due to high response rates. Prior reviews focused on severe or cardiovascular bevacizumab toxicities. We performed a comprehensive review of toxicities experienced among 210 patients enrolled in 3 phase II bevacizumab trials for recurrent malignant gliomas at the National Cancer Institute. No bevacizumab toxicities were experienced by 20 % patients, 40.2 % on monotherapy versus ≤9.5 % on combination therapy. Hypertension and proteinuria occurred in ~25 %. Fatigue, hypophosphatemia, aspartate aminotransferase elevation, rashes were common. Low grade headache, hoarseness, myalgias/arthralgias, liver enzyme elevation, azotemia and electrolyte abnormalities were noted. Rare severe toxicities, including thrombosis, hemorrhage, wound complications and colonic perforations, occurred at rates seen in other diseases. Leukopenia and neutropenia occurred solely with combination therapy, while thrombocytopenia occurred in 12.5 % on bevacizumab monotherapy. Thrombocytopenia was generally mild, but severe in (1.4 %) and increased in frequency with prolonged or combination therapy. Bevacizumab-related deaths occurred in 4 (1.9 %) patients, including brain ischemia (n = 1) and sudden unexplained deaths (n = 2). Prior hypertension increased the odds of hypertension by ≥3.4-fold (p < 0.001) and grade 3+ hypertension by ≥11.2 (p < 0.001). Prior hypertension increased the odds of hypophosphatemia by 2.4-fold (p = 0.011), but failed to predict proteinuria or azotemia. Age did not greatly impact toxicity. Hypertension, proteinuria and hypophosphatemia often occurred concurrently, more frequently and severely with prolonged use. Our study shows bevacizumab monotherapy is well tolerated, but toxicity increases with combination therapy. Balancing the risks and benefits of bevacizumab requires understanding the spectrum of bevacizumab toxicities and predisposing factors.