Dose/dense metronomic chemotherapy with fractioned cisplatin and oral daily etoposide enhances the anti-angiogenic effects of bevacizumab in advanced non-small-cell-lung cancer patients

Background: We designed a translational clinical trial to investigate whether a dose/dense chemotherapy regimen is able to enhance in patients with non-small-cell-lung-cancer, the anti-angiogenic, and anti-tumor activity of bevacizumab, a murine/human monoclonal antibody to the vasculo-endothelial-growth-factor (VEGF) Patients and Methods: Forty-eight patients (42 males and 6 females) with stage IIIB/IV non-small-cell-lung-cancer, a mean age of 68 years, and ECOG ≤ 2 were enrolled in the study. They received every three weeks fractioned cisplatinum (30 mg/sqm, days 1-3) and oral etoposide (50 mg, days 1-15) and were divided in 5 cohorts receiving different bevacizumab dosages [0; 2.5; 5; 7.5; and 10 mg/kg] on the day 3. Results: The combined treatment was able of inducing a significant decline in the blood-perfusion of primary tumor (NMR-study); in serum levels of VEGF, angiopoietin-1, thrombospondin-1; and in the number of VEGF-transporting cells. In the group of 40 patients who received bevacizumab there was an objective response and a disease stabilization rate of 77.5% (95% CI, 75.63-93.17) and 15% respectively, with a time to progression of 7.6 months. Grade I-II hematological toxicity was the most common adverse event. Four early deaths within three months, three cases of pneumonia, and six cases of mood depression at higher bevacizumab dosage were observed. The most active biological and maximum tolerated dose were 5 and 7.5 mg/kg, respectively. Conclusion: The combination of bevacizumab with a dose/dense chemotherapy regimen resulted moderately safe but showed significant anti-angiogenic, and anti-tumor activity.