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

作者：Correale Pierpaolo; Remondo Cinzia; Carbone Salvatore Francesco; Ricci Veronica; Migali Cristina; Martellucci Ignazio; Licchetta Antonella; Addeo Raffaele; Volterrani Luca; Gotti Giuseppe; Rotundo Maria Saveria; Tassone Pierfrancesco; Sperlongano Pasquale; Abbruzzese Alberto; Caraglia Michele; Tagliaferri Pierosandro; Francini Guido^*

来源：Cancer Biology and Therapy, 2010, 9(9): 685-693.

DOI：10.4161/cbt.9.9.11441

• cisplatin
• etoposide
• bevacizumab
• NSCLC
• metronomic therapy

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 (NSCLC) the anti-angiogenic effects of bevacizumab, a murine/human monoclonal antibody to the vasculo-endothelial-growth-factor (VEGF). We also evaluated the antitumor activity of this combination.
Results: The combined treatment induced 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 an objective response and a disease stabilization rate of 77.5% (95% CI, 75.63-93.17) and 15%, respectively, were recorded with a time to progression of 7.6 mo. Grade I-II hematological toxicity was the most common adverse event. Four early deaths within 3 mo, 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.
Patients and Methods: Forty-eight patients (42 males and six females) with stage IIIB/IV NSCLC, a mean age of 68 y, and ECOG <= 2 were enrolled in the study. They received every 3 w fractioned cisplatinum (30 mg/sqm, days 1-3) and oral etoposide (50 mg, days 1-15) and were divided in five cohorts receiving different bevacizumab dosages (0; 2.5; 5; 7.5; and 10 mg/kg) on day 3.
Conclusion: The combination of bevacizumab with a dose/dense chemotherapy regimen resulted moderately safe but showed significant anti-angiogenic and antitumor activity.

• 出版日期2010-5-1