Mandeville, H.C.; (2011) Exploration of the clinical interaction between vascular targeting agents and radiotherapy. Doctoral thesis , UCL (University College London).

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Abstract

Preclinical studies of vascular disruptive and anti-angiogenic agents, combined with radiation, have demonstrated the potential for enhanced anti-tumour activity. However, the optimal strategy and scheduling for combining these treatments with radiotherapy remains uncertain. In this thesis, combretastatin-A4-phosphate (CA4P) given concurrently with fractionated radiotherapy has been studied using preclinical models, in addition to assessing the impacts of adding the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine (L-NNA), or the anti-EGFR monoclonal antibody, cetuximab, to this combination. As part of an ongoing phase Ib clinical trial, the combination of CA4P and radiotherapy was investigated in patients with non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), where concurrent cetuximab was also given. Functional imaging techniques, such as dynamic contrast enhanced (DCE)-CT and positron emission tomography (PET), provide non-invasive biomarkers, which can be harnessed to aid diagnosis, determine response to treatment and also offer prognostic information. The use of volumetric DCE-CT parameters as biomarkers of tumour hypoxia and angiogenesis in NSCLC has been explored here, with significant negative correlations demonstrated between DCE-CT parameters and immunohistochemical staining of intra-tumoural hypoxia. This illustrates the potential ability of volumetric DCE-CT to quantify whole tumour hypoxia in NSCLC. The translational research described in this thesis, has established that the vascular disruptive effects of CA4P can be safely used in combination with fractionated radiotherapy in the clinical setting, producing demonstrable tumour vascular effects. However, despite promising preclinical tumour growth delay effects, the addition of cetuximab produced dose-limiting cardiotoxicity. In patients receiving CA4P and radiotherapy, DCE-CT and circulatory biomarkers, including cytokines (VEGF, VEGFR-1, G-CSF and SDF-1), were utilised to assess treatment-induced changes in tumour vascularity and vasculogenesis. The findings in this thesis provide further information to guide future studies combining vascular targeted therapies and radiation, highlighting the role of DCE-CT and functional imaging in such work.

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