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dc.contributor.authorHarris, Benjamin
dc.date.accessioned2019-08-01
dc.date.available2019-08-01
dc.date.issued2018-12-31
dc.identifier.urihttp://hdl.handle.net/2123/20833
dc.description.abstractLung cancer is a leading cause of cancer-related mortality and non-small cell lung cancer (NSCLC) is the most common subtype. Gold standard first-line treatment for advanced NSCLC is platinum-based doublet chemotherapy. Carboplatin is a readily accessible platinum-based drug however, it has a narrow therapeutic index despite dose optimisation. Given the poor 5-year survival rate for people with NSCLC, the gold standard requires improvement. Increased systemic inflammation is associated with worse clinical outcomes. Easily obtainable inflammatory biomarkers, including the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio, could inform dosing. This thesis aimed to assess the role of inflammation on pharmacokinetics, clinical endpoints and drug utilisation in prospectively collected and community-based NSCLC cohorts using biostatistical and pharmacometric methods. Additionally, pre-clinical experiments investigated inflammatory-mediated drug transporter expression, cytotoxicity and cell proliferation. Results showed up to half of advanced NSCLC patients have elevated systemic inflammation and this associated with poorer survival and early chemotherapy cessation in trial and community-settings. Inflammation influenced carboplatin pharmacokinetics and a new dosing model incorporating inflammatory markers was proposed that may limit carboplatin overexposure. Pre-clinical results suggested inflammation alters drug transporter gene expression and platinum drug sensitivity in-vitro but not cell proliferation. This thesis helped establish the value of inflammatory markers in predicting clinical outcomes. Relationships between inflammation and carboplatin pharmacokinetics have been identified and a carboplatin dosing model proposed. Pre-clinical studies provided potential mechanistic understanding but need further investigation. When taken together, these results may help improve the gold standard towards a more optimised ‘platinum’ standard.en_AU
dc.publisherUniversity of Sydneyen_AU
dc.publisherFaculty of Medicine and Healthen_AU
dc.publisherSchool of Medical Scienceen_AU
dc.publisherDiscipline of Pharmacologyen_AU
dc.rightsThe author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.en_AU
dc.subjectbiostatistics,chemotherapyen_AU
dc.subjectpharmacokineticsen_AU
dc.subjectinflammationen_AU
dc.subjectcarboplatinen_AU
dc.subjectnon-small cell lung canceren_AU
dc.subjectchemotherapyen_AU
dc.titleTowards the platinum standard: investigating systemic inflammation to optimise platinum-based doublet chemotherapy in non-small cell lung canceren_AU
dc.typePhD Doctorateen_AU
dc.type.pubtypeDoctor of Philosophy Ph.D.en_AU
dc.description.disclaimerAccess is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.en_AU


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