Treatment of Patients Excluded from Eastern Cooperative Oncology Group 4599 and AVAiL Studies: Focus on Brain Metastasis and Squamous Histology

Bevacizumab is the first molecularly targeted agent associated with improved outcomes in combination with chemotherapy in previously untreated patients with non–small-cell lung cancer (NSCLC). The addition of bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), to carboplatin and paclitaxel resulted in a significant improvement in overall survival compared with chemotherapy alone; however, bevacizumab is associated with increased risk of severe complications, including hemoptysis, neutropenic fever, and gastrointestinal perforation. Based on the initial observations that patients with squamous cell carcinoma treated with bevacizumab are at high risk for severe and fatal hemoptysis, these patients were not included in subsequent phase III clinical trials involving this agent. Patients with known brain metastases from lung cancer were excluded because of concern for intracranial bleeding. Consequently, nearly half the patients with newly diagnosed metastatic NSCLC are not treated with bevacizumab because of squamous histology or the presence of brain metastasis. This review provides a brief overview of the very limited data available regarding the safety and efficacy of bevacizumab and other VEGF inhibitors in patients with squamous cell histology or brain metastasis and current ongoing research efforts.