title: Monitoring the effects of bevacizumab beyond progression in a murine colorectal cancer model: a functional imaging approach.
abstract: Clinical studies have shown that bevacizumab beyond progression to first line therapy is beneficial for overall survival in advanced stage colorectal cancer. We studied the utility of several functional imaging modalities to assess the efficacy of bevacizumab beyond progression (BBP). All BALB/c mice with s.c. LS174T xenografts were treated with capecitabine, oxaliplatin and bevacizumab combination therapy. Tumor volume was assessed using caliper measurements. Increase of 1.5 times the initial volume on two subsequent measurements, was considered progression. In half of the mice bevacizumab treatment was continued (n = 13) after progressive disease was established, while the others received saline injections (n = 12). Within 3 days after progression, multi-modal imaging was performed using FDG-PET, diffusion weighted imaging, T2* and dynamic contrast enhanced MRI. Measurements were repeated 7 and 10 days after the first measurements. Afterwards, tumors were analyzed for expression of carbonic anhydrase IX, glucose transporter 1, 9 F1 to stain the vasculature and Ki67 to assess proliferation. In the BBP group tumor growth after progression was reduced compared to the control group (p < 0.01). FDG-PET showed a trend towards lower FDG uptake in the BBP group (p = 0.08). DWI, T2* and DCE-MRI parameters were not significantly different between both groups. The immunohistochemical analyses showed higher CAIX-positive fraction (p < 0.01) and lower Ki67 expression (p = 0.06) in the BBP group. The relative vascular area was significantly lower in the BBP group (p = 0.03). GLUT-1 expression and vascular density did not significantly differ between both groups. Bevacizumab after progression resulted in significant changes in the tumor proliferation and microenvironment compared to discontinuation of bevacizumab. FDG-PET may be sensitive to BBP-induced effects.
authors: Department of Medical Oncology 452, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. L.Heijmen@onco.umcn.nl
authors: L
authors: L
authors: Heijmen
authors: C J A
authors: CJ
authors: Punt
authors: E G W
authors: EG
authors: Ter Voert
authors: L F
authors: LF
authors: de Geus-Oei
authors: A
authors: A
authors: Heerschap
authors: J
authors: J
authors: Bussink
authors: C G J
authors: CG
authors: Sweep
authors: V
authors: V
authors: Zerbi
authors: W J G
authors: WJ
authors: Oyen
authors: P N
authors: PN
authors: Span
authors: O
authors: O
authors: Boerman
authors: H W M
authors: HW
authors: van Laarhoven
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D019788:Fluorodeoxyglucose F18; D019394:Ki-67 Antigen / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D049268:Positron-Emission Tomography; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019394:Ki-67 Antigen; D019788:Fluorodeoxyglucose F18; D000068258:Bevacizumab