VALIDATING NON-INVASIVE THERAPEUTIC LUNG CANCER BIOMARKERS

UoM administered thesis: Phd

Abstract

Lung cancer is the leading cause of cancer death and a priority research area. There is an unmet need to develop biomarkers to enable patient selection and stratification in future lung cancer trials. This thesis aimed to validate non-invasive therapeutic lung cancer biomarkers. The investigated biomarkers were derived from imaging techniques used in routine healthcare (computed tomography and [18F]fludeoxyglucose (FDG) positron emission tomography (PET)) and research-domain imaging methods of hypoxia (multi-parametric magnetic resonance imaging (MRI) and [18F]fluoroazomycin arabinoside (FAZA) PET) and proliferation ([18F]fluorothymidine (FLT) PET), along with circulating biomarkers. These biomarkers were derived from one randomized controlled trial and 3 prospective pilot studies. I report for the first time the outcome of early limited stage (LS)- small cell lung cancer (SCLC), staged using the tumour, node and metastasis (TNM) staging system, within a randomized controlled trial. Early (TNM stage I-II) LS-SCLC patients achieve long-term survival with minimal acute side-effects following chemoradiotherapy and prophylactic cranial irradiation. This study guides patient management and benchmarks achievable outcomes in the era of modern radiotherapy. I report on the effects of different [18F]FAZA PET acquisition and analysis procedures on image parameters, comparing hypoxic volumes and fractions using fixed (>1.4, >1.2) and image-derived thresholds in non-small cell lung cancer (NSCLC) patients. I also investigate, for the first time, image repeatability and compare findings with a tissue-based hypoxia assessment in a patient subset, thus providing new [18F]FAZA PET validation data for the optimal application of this modality to derive potential hypoxia biomarkers. I present the world first oxygen-enhanced (OE) MRI clinical study to evaluate repeatability and show pharmacodynamic treatment effect, providing new technical and biological validation data for OE-MRI NSCLC hypoxia biomarkers. These results suggest that OE-MRI is feasible, well-tolerated, repeatable and has potential clinical utility as a biomarker in future NSCLC hypoxia-targeted therapy trials and radiotherapy dose painting studies. I present a pilot study that evaluated, to my knowledge, the largest blood biomarker panel in lung cancer patients. I show that baseline IL-1b and neutrophil count and early-treatment CYFRA 21-1 predict lung cancer radiotherapy response. CYFRA 21-1 and VCAM-1 correlated with [18F]FLT PET, highlighting for the first time a potential role of blood biomarkers as imaging surrogates. A trial proposal to investigate nimorazole (a hypoxic radiosensitizer) in TNM stage II-III NSCLC patients is presented. One of the trial aims is to validate (and ultimately qualify) [18F]FAZA PET, building on the thesis results. In summary, this thesis presents important new validation data for a range of therapeutic lung cancer biomarkers.

Details

Original languageEnglish
Awarding Institution
Supervisors/Advisors
Award date1 Aug 2018