Background:Cell-free DNA (cfDNA) circulating in the blood holds a possible prognostic value in malignant diseases. Under malignant conditions, the level of cfDNA increases but the biological mechanism remains to be fully understood. We aimed to examine the correlation between cfDNA and total tumour burden defined by positron emission tomography (PET) parameters.Methods:Patients with advanced non-small cell lung cancer (NSCLC) were enrolled into a prospective biomarker trial. Before treatment, plasma was extracted and the level of cfDNA was determined by qPCR. An 18 F-fluorodeoxyglucose (18 F-FDG) PET/computed tomography (CT) scan was performed and evaluated in terms of metabolic tumour volume (MTV) and total lesion glycolysis (TLG). Tumour contours were delineated semi-automatically by a threshold standardised uptake value (SUV) of 2.5. The primary end point was correlation among cfDNA, MTV and TLG. The secondary end point was overall survival (OS) according to cfDNA, MTV and TLG.Results:Fifty- three patients were included. There were no correlations between cfDNA and MTV (r=0.1) or TLG (r=0.1). cfDNA >75th percentile was correlated with shorter OS (P=0.02), confirmed in a multivariate analysis. MTV>the median was associated with a significantly shorter OS (P=0.02). There was no significant difference in OS according to TLG (P=0.08).Conclusion:Cell-free DNA may not be a simple measure of tumour burden, but seems to reflect more complex mechanisms of tumour biology, making it attractive as an independent prognostic marker.