title: Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer.
abstract: Addition of anti-VEGF antibody therapy to standard chemotherapies has improved survival and is an accepted standard of care for advanced non-small cell lung cancer (NSCLC). However, the mechanisms by which anti-VEGF therapy increases survival remain unclear. We evaluated dynamic CT-based vascular parameters and plasma cytokines after bevacizumab alone and after bevacizumab plus chemotherapy with carboplatin and nab-paclitaxel in advanced NSCLC patients to explore potential biomarkers of treatment response and resistance to this regimen. Thirty-six patients were enrolled in this study. The primary end point was 6-mo progression-free survival rate, which was 74% (95% CI: 57, 97). This regimen has a promising overall response rate of 36% and median time to progression of 8.5 (6.0, 38.7) mo and overall survival of 12.2 (9.6, 44.1) mo. We found that anti-VEGF therapy led to a sustained increase in plasma PlGF, a potential pharmacodynamic marker. We also found that higher levels of soluble VEGFR1 measured before starting bevacizumab with chemotherapy were associated with worse survival, supporting its potential role as biomarker of treatment resistance. Our imaging biomarker studies indicate that bevacizumab-based treatment-while reducing blood flow, volume, and permeability in the overall population-may be associated with improved survival in patients with improved tumor vasculature and blood perfusion after treatment. This hypothesis-generating study supports the notion that excessively decreasing vascular permeability and pruning/rarefaction after bevacizumab therapy may negatively impact the outcome of combination therapy in NSCLC patients. This hypothesis warrants further dose-titration studies of bevacizumab to examine the dose effect on tumor vasculature and treatment efficacy.
authors.affiliation: Departments of Medicine, rheist@partners.org jain@steele.mgh.harvard.edu.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Heist
authors.affiliation: Radiation Oncology, and.
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.affiliation: Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Dushyant V
authors.initials: DV
authors.lastname: Sahani
authors.affiliation: Radiation Oncology, and.
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.affiliation: Department of Medical Oncology, University of Arizona Cancer Center at Dignity, Phoenix, AZ 85013;
authors.forename: Panos
authors.initials: P
authors.lastname: Fidias
authors.affiliation: Departments of Medicine.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.affiliation: Departments of Medicine.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Temel
authors.affiliation: Departments of Medicine.
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.affiliation: Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH 44195;
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Pennell
authors.affiliation: Department of Medicine, Division of Oncology, Stanford University/Stanford Cancer Institute, Palo Alto, CA 94305;
authors.forename: Joel W
authors.initials: JW
authors.lastname: Neal
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115; and.
authors.forename: Leena
authors.initials: L
authors.lastname: Gandhi
authors.affiliation: Department of Medical Oncology, Yale Cancer Center, New Haven, CT 06520.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lynch
authors.affiliation: Departments of Medicine.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.affiliation: Radiation Oncology, and rheist@partners.org jain@steele.mgh.harvard.edu.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000418:Albumins / Q000008:administration & dosage; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000097:blood; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D016190:Carboplatin; D017239:Paclitaxel
keywords: antiangiogenesis; bioimaging; lung cancer