155P - Effect of bevacizumab on tumour 5-fluorouracil concentration and microcirculatory parameters obtained by dynamic contrast-enhanced MRI in a hepatoce...

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Basic Science
Hepatobiliary Cancers
Presenter Szymon Mikulski
Authors S. Mikulski1, L. Wang2, S. Hartono3, L. Martarello4, T.S. Koh5, B.C. Goh2, C.H. Thng5, Q.S. Ng6
  • 1Student Affairs Department, Duke-NUS, Singapore/SG
  • 2Cancer Science Institute Of Singapore, National University of Singapore, Singapore/SG
  • 3School Of Electronic & Electrical Engineering, Nanyang Technological University, Singapore/SG
  • 4Roche Translational Medicine Hub, SingHealth, Singapore/SG
  • 5Department Of Oncologic Imaging, National Cancer Centre, Singapore/SG
  • 6Department Of Medical Oncology, National Cancer Centre, Singapore/SG

Abstract

Introduction

Vascular endothelial growth factor (VEGF) is expressed by tumours to promote angiogenesis. Clinical trials of anti-VEGF therapy combined with chemotherapy demonstrate improvement in survival. We investigate the effect of bevacizumab (bev), a humanized monoclonal antibody that inhibits VEGF-A, on tumour 5-fluorouracil (5FU) concentration in a hepatocellular carcinoma (HCC) xenograft model, together with changes in tumour microcirculatory parameters obtained by dynamic contrast-enhanced (DCE) MRI.

Methods

48 immunodeficient mice implanted with subcutaneous HCC xenografts were first injected with bev (1mg/kg or 10mg/kg) or omalizumab (control). 1 day later, they received 5FU and were sacrificed. Tumour and plasma 5FU concentration was measured by liquid chromatography-mass spectrometry. A subset of 17 mice underwent DCE MRI with gadolinium contrast at baseline and one day after bev/omalizumab injection. Scans employed a three-dimensional spoiled gradient recalled sequence with tracer concentration estimated using variable flip-angle technique. Data analysis employed a conventional two-compartment tracer kinetic model.

Results

Tumour 5FU concentration (µg/g) was significantly lower 1 day after bev (10mg/kg) compared to control (8.4 vs 21.6, p = 0.027). However, there was no significant difference in plasma 5FU concentration between the bev and control groups. Following bev (10mg/kg), DCE MRI measurements of tumour intravascular blood volume reduced by 38.3% (p = 0.01); there was no significant change in DCE-MRI parameters in the control group. Following bev (1mg/kg), tumour permeability-surface area product (ml/100ml/min) correlated with tumour 5FU concentration (r2 = 0.84, p = 0.01).

Conclusion

Bev causes vascular shutdown consistent with its anti-angiogenic mode of action. Reduced tumour 5FU concentration suggests that the reported synergism between anti-VEGF and chemotherapy may not be attributable to improved drug delivery at this early time point. DCE-MRI may play a role as a biomarker for tumour drug concentration following anti-VEGF therapy.

Disclosure

All authors have declared no conflicts of interest.