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Title: Imaging biomarkers of the tumour microenvironment to assess early response in patients treated with anti-angiogenic therapy
Author: Horsley, Laura
ISNI:       0000 0004 5364 0634
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2015
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Background: Angiogenesis is the process by which new blood vessels develop from existing vasculature and is a critical step in all tumours to facilitate growth beyond a few millimetres. As this process is largely inactive in physiological circumstances in adults, it represents an attractive therapeutic target in oncology. Drugs that target the angiogenic process are classified as anti-angiogenic agents. The first anti-angiogenic drug to be approved by the FDA was bevacizumab; a recombinant humanized monoclonal antibody against VEGF. Randomised studies in colorectal cancer (and other solid malignancies) have reported prolonged progression free survival and overall survival for bevacizumab. However, standard radiological criteria, Response Evaluation Criteria In Solid Tumours (RECIST), although widely employed to assess response to therapy in clinical trials, are generally insensitive to the predominantly cytostatic effects of anti-angiogenic and other targeted therapies. Alternative methods of predicting or assessing early response to such agents are needed, particularly given the cost and toxicity implications of such treatments. However, biomarkers to aid selection of patients for anti-angiogenic therapies, including bevacizumab, remain elusive. Purpose: To investigate Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI), Diffusion Weighted Imaging (DWI) and circulating angiocytokines, measured using an ELISA multiplex, as prognostic markers in patients with metastatic colorectal cancer treated with bevacizumab and chemotherapy. Results: Seventy patients were treated. DCE-MRI and DWI parameters showed good reproducibility with coefficient of variation between 3.7 to 23% for parameters. The median progression free survival, the primary end point of the trial, was 9.3 months. The overall response rate was 44%. The clinical variables which were significant for progression free survival on univariate analysis were: performance status (p=0.005), CEA (p=0.04) and serum LDH (p=0.005). Biomarkers which were significant for progression free survival on univariate analysis were serum VEGF-A (p=0.02), serum HGF (p=0.005), sVEGFR-2 (p=0.02). In each case, low values of the biomarker were associated with improved outcome. Multivariate analysis identified Ktrans (p=0.015), performance status (p=0.008) and serum HGF (p=0.003) as the most significant predictors of progression free survival. A prolonged progression free survival was associated with a good ECOG performance status, high Ktrans and low serum HGF.Conclusions: Whilst these results are encouraging, future work is required to establish whether HGF and Ktrans are prognostic markers for metastatic colorectal cancer and their precise role in the prediction of patients likely to benefit from treatment with bevacizumab.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: biomarker ; angiogenesis ; imaging ; DCE-MRI ; DWI-MRI ; circulating angiocytokines ; clinical trial ; bevacizumab