Imaging liver metastases of colorectal cancer patients with radiolabelled bevacizumab: Lack of correlation with VEGF-A expression
Introduction
In order to grow and metastasise, tumours need a constant supply of oxygen and nutrients. For their growth beyond the size of 1–2 mm tumours are dependent on angiogenesis: the formation of new blood vessels from the existing ones.1 Angiogenesis is a complex and dynamic process regulated by pro- and anti-angiogenic factors. Vascular endothelial growth factor A (VEGF-A) plays a pivotal role in angiogenesis. It promotes endothelial cell proliferation and migration, and enhances the vascular permeability of tumour vessels.2 VEGF-A is frequently upregulated in tumours that are subject to hypoxia, but genetic factors may also contribute to enhanced VEGF-A expression.3, 4
Since 2004, the humanised anti-VEGF-A monoclonal antibody (mAb), bevacizumab, derived from the murine mAb A4.6.1. has been approved for first-line treatment of patients with metastatic colorectal cancer in combination with 5-fluorouracil-based chemotherapy.5 Bevacizumab binds all VEGF-A isoforms, which prevents interaction with the VEGF-A receptors VEGFR-1 and VEGFR-2, and thus inhibits VEGF-mediated effects on the tumour vascular network.5, 6
In previous studies in murine tumour models, we and others have shown that radiolabelled bevacizumab specifically accumulates in VEGF-expressing tumours and that In-111-labelled bevacizumab allowed non-invasive detection of VEGF-A-expression.7
In this study, we investigated the potential of In-111-labelled bevacizumab to image the expression of VEGF-A in liver metastases of 12 patients with colorectal cancer. After scintigraphic imaging the liver metastases were resected. The VEGF-A expression in these resected liver metastases was determined by in situ hybridisation and ELISA.
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Patients and study design
After informed consent, a total of 12 patients with colorectal liver metastases were enroled in this single centre study at the Radboud University Nijmegen Medical Centre. The study protocol was approved by the Institutional Review Board of the hospital. All patients were scheduled for resection of the colorectal liver metastases within 6 weeks after entering the study. Primary tumours had been removed at least 11 weeks before inclusion.
Exclusion criteria were pregnancy, lactation, any extra
Patient and tumour characteristics
Patient and tumour characteristics are listed in Table 1. A total of 12 patients were enroled in this study. The study population consisted of 6 males and 6 females with a median age of 64 years (range 50–75 years). The mean number of metastases in the liver was 1.7 ± 0.7. Five of the 12 patients had a solitary liver metastasis. Six patients had two lesions and one patient had three lesions. The mean diameter of the largest metastasis was 3.2 ± 1.0 cm, the mean volume of the largest liver metastases
Discussion
The primary aim of this study was to determine the correlation between tumour accumulation of In-111-bevacizumab and VEGF-A expression in patients with colorectal liver metastases using.
Bevacizumab, a humanised monoclonal antibody, inhibits the activity of VEGF-A on the tumour vascular network by binding and neutralising all VEGF-A isoforms. In combination with intravenous 5-fluorouracil-based chemotherapy, bevacizumab is indicated for first- or second-line treatment of patients with metastatic
Conflict of interest statement
None declared.
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2014, Molecular OncologyCitation Excerpt :Several studies investigated the feasibility to visualize tumor VEGF expression in patients using molecular imaging techniques, and some even tried to link this to bevacizumab (or other angiogenesis inhibitors) response (Figure 3). 111In-bevacizumab SPECT visualized VEGF expression in various malignancies, including CRC, RCC and melanoma and 89Zr-bevacizumab PET visualized primary BC (Desar et al., 2010; Gaykema et al., 2013; Nagengast et al., 2011; Scheer et al., 2008). There was however no straightforward correlation between radiolabeled bevacizumab uptake and tumor VEGF-A expression as determined by conventional methods (in situ hybridization/ELISA), suggesting that other factors play a role in bevacizumab targeting, such as vascular volume, vascular permeability and/or interstitial fluid pressure.
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