Photodynamic therapy in head and neck carcinomas : clinical and in vitro studies
Despite the advances in diagnostic and therapeutic techniques, the outcome and survival of patients suffering from head and neck cancer has remained poor, primarily due to late detection, and the tendency of the disease to develop loco-regional metastasis. A key to its control is early detection and treatment and prevention of recurrence and metastasis. Tumour metastases can be considered as complex multi-step molecular events which involve the interplay between several processes including changes in cell survival, adhesion, proteolysis, and angiogenesis. Based on these considerations, a positive correlation between tumour invasiveness and expression/suppression of these processes would be expected. Photodynamic Therapy (PDT) is a novel treatment modality for a variety of malignant tumours, including head and neck cancer. The technique is based on the combination of a photosensitive drug and visible light to disrupt cell function and induce cytotoxicity, but there is little agreement on its efficacy. Furthermore, PDT is indicated for early tumour without metastases, yet it is crucial to determine its influence on the metastasis process. The aims of the study were: (i) to explore, using an in vitro model, the influence of PDT, alone or in combination with either chemotherapy or small molecules, on cell toxicity, expression of α5β1 and αvβ6 integrins and epidermal growth factor receptor (EGFR), production of matrix metalloproteinases, MMP-2, MMP-9 and MMP-13, urokinase plasminogen activator (uPA) and vascular endothelial growth factor (VEGF); (ii) to clinically evaluate the potential of PDT as a tool for head and neck cancer treatment; (iii) to clinically evaluate the ability of an optical system, based on fluorescence and elastic scattering spectroscopy, to distinguish between normal, potentially malignant and malignant tissues and to develop an applicable algorithm that can be used as a standard for the subsequent analysis of "unknown" lesions; (iv) to monitor the sensitiser photobleaching during PDT in patients with superficial basal cell carcinoma (BCC), and compare this to clinical outcome. It was found that, using a series of human oral squamous cell carcinoma cell lines, a marked decrease of tumour invasion and migration is evident after PDT this was associated with the downregulation of MMP-9, -2 and -13, uPA and VEGF. Moreover, this migratory inhibition was further enhanced when PDT was combined with either cisplatin chemotherapy or tyrosine kinase inhibitors. Clinically, a complete response with excellent cosmetic results was achieved on patients treated with PDT. Both fluorescence and elastic scattering spectroscopy have shown a great potential to both non-invasively identify dysplastic changes at an early stage and to be used as a screening tool for the detection of subsequent primary lesions. This thesis has demonstrated that, PDT and its related optical system together are able to detect, treat and reduce invasion and metastasis of head and neck carcinoma.