Towards the platinum standard: investigating systemic inflammation to optimise platinum-based doublet chemotherapy in non-small cell lung cancer

Abstract

Lung 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.