Metronomic antiangiogenetic biochemotherapy of non-small cell lung cancer patients with fractionated cisplatimum, oral etoposide, and bevacizumab

Background: Chemotherapy efficacy in advanced non small cell lung cancer (NSCLC) patients may be augmented if combined with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF) with anti-angiogenetic activity. Metronomic chemotherapy is a newest approach which employs cytotoxic drugs at lower doses with very close and regular administrations, which has shown anti-angiogenetic effects, epigenetic attenuation of cancer phenotype and immune-modulation. Metronomic chemotherapy with cisplatinum and oral etoposide (mPE) has been tested in NSCLC patients with promising results. We have thus investigated a newest biochemotherapy regimen with mPE + bevacizumab (mPEBev regimen) in advanced NSCLC patients. Methods: This is a phase IB/II trial designed to evaluate toxicity, anti-tumor and biological activity of bevacizumab given at escalating doses in combination with mPE chemotherapy. Twenty-six patients with inoperable NSCLC and an ECOG≤2 were enrolled in the study and received every 21 days, iv. cisplatinum (30 mg/sqm, days 1-3), oral etoposide (50 mg/sqm, days 1-15) and bevacizumab (day 3) at different dose levels (no antibody/control group; 2.5; 5; 7.5; and 10 mg/kg). Results: The treatment resulted very active in those patients who received bevacizumab with a 95% objective response rate (19/20), with a median time to progression of 7.55 months. There were two early deaths at higher bevacizumab dosages: one due to a cardiovascular accident (7.5 mg/kg) and another to lung hemorrhage (10mg/kg). We reported also 4 cases of psychic depression and 4 cases of pneumonia which evolved into lung cavitation. A magnetic resonance monitoring showed a significant treatment-related blood perfusion reduction in the tumor site. It was also observed a progressive decrease in VEGF, thrombospondin-1 levels which were not dependent upon bevacizumab dose and were not observed in the controls. Conclusions: mPEBev regimen resulted very active in advanced NSCLC patients. Our metronomic biochemotherapy regimen with lower bevacizumab doses (2.5-5 mg/Kg) deserves to be investigated in further phase II-III trials.