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.
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.


METHODS
Forty-eight patients (42 males and six females) with stage III B/IV NSCLC, a mean age of 68 y, and ECOG <or=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.


CONCLUSIONS
The combination of bevacizumab with a dose/dense chemotherapy regimen resulted moderately safe but showed significant anti-angiogenic and antitumor activity.
Correale
Pierpaolo
P
Translational Immuno-Oncology Unit, Medical Oncology Section, Department G. Segre of Pharmacology, Siena University School of Medicine, Siena, Italy.
Remondo
Cinzia
C
Carbone
Salvatore Francesco
SF
Ricci
Veronica
V
Migali
Cristina
C
Martellucci
Ignazio
I
Licchetta
Antonella
A
Addeo
Raffaele
R
Volterrani
Luca
L
Gotti
Giuseppe
G
Rotundo
Maria Saveria
MS
Tassone
Pierfrancesco
P
Sperlongano
Pasquale
P
Abbruzzese
Alberto
A
Caraglia
Michele
M
Tagliaferri
Pierosandro
P
Francini
Guido
G
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042683:Angiopoietin-1 / Q000097:blood; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D002945:Cisplatin / Q000008:administration & dosage; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011446:Prospective Studies; D015996:Survival Rate; D019699:Thrombospondins / Q000097:blood; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D042683:Angiopoietin-1; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019699:Thrombospondins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D005047:Etoposide; D002945:Cisplatin