Clinical pharmacology of anticancer agents with focus on neuro-oncology and biomarker assessment

Abstract

PhD Defence: Clinical pharmacology of anticancer agents with focus on neuro-oncology and biomarker assessment Patients with leptomeningeal metastases have a poor prognosis with a one year survival rate of 16-24%. Metastases to the leptomeninges, the lining of the brain and spinal cord, surrounded by cerebrospinal fluid (CSF), are difficult to detect with the currently used techniques. New methods to detect circulating tumour cells in CSF are presented. Circulating tumour cells in CSF were isolated via magnetism and subsequently stained. The cells were counted one by one with a laser and a detector. In addition we were able to analyse the cells genetically which opens possibilities for targeted therapies. In patients with an epithelial tumor (e.g. breast- or lung cancer) and a clinical suspicion on leptomeningeal metastases circulating tumour cells were found in the CSF of 94% of the patients who were finally diagnosed with the disease. The diagnosis could be made in 76% of the patients with the method used in clinical practice, viz. microscopic examination of the CSF by the pathologist. The clinical pharmacology of anticancer agents is described in part II. Generally it is assumed that large molecules like antibodies cannot penetrate and pass the blood brain barrier. However, encouraging results have been reported for immunotherapy with the antibodies nivolumab and ipilimumab in patients with melanoma brain metastases. We could detect nivolumab in the CSF and gave a perspective on the pharmacology of nivolumab and ipilimumab in melanoma brain metastases. Finally, potential novel drugs and novel combinations of drugs were investigated in phase I clinical trials and are described in this thesis.