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Improved radiotherapy (RT) outcomes may be facilitated through monitoring of physiological processes implicated in radio-resistance such as proliferation. To this end, we studied 16 patients with non-small cell lung cancer with dynamic 3'-deoxy-3'-fluorothymidine (FLT) PET-CT before and after a week of radical RT. In absence of changes in primary tumour volume manually delineated on CT, RT induced a significant, moderately variable decrease in maximum and mean standard uptake values (SUVmax and SUVmean) of the order of 25%. Metastatic nodes showed a larger relative decrease in uptake approximating 40% associated with volumetric regression and only partially accountable by partial volume effect. Implementation of different segmentation approaches including manual delineation by a second operator and PET-based semi-automatic algorithms [two fixed thresholds, 2/3-cluster Fuzzy C-means (FCM-2, FCM-3) and 2/3-cluster fuzzy locally adaptive Bayesian algorithm (FLAB-2, FLAB-3)] yielded substantially different volumes and SUVs but consistent SUV responses. Reproducibility comparison favoured manual delineation, while thresholding delivered poor volumetric robustness and no apparent SUV reproducibility advantage over SUVmax or SUVpeak. FCM-2/FLAB-2 demonstrated intermediate reproducibility. In contrast to anatomical volumes, metabolic volumes exhibited significant increases with treatment, which for FLAB-2 correlated with changes of intratumoural uptake heterogeneity quantified by the coefficient of variation. Normal tissue analysis revealed an anterior-posterior gradient of lung uptake and an association of baseline marrow SUV with type/timing of neo-adjuvant chemotherapy. RT induced a dramatic (≈-76%), sharply demarcated marrow SUV decline in response to a minimum of 5Gy and a small (≈-20%), consistent decline in normal lung SUV. Kinetic analysis revealed a significant increase in the tumour delivery constant K1 (+32%) and a decrease in Ki/K1, larger (-36%) and more variable than the Ki (-26%) and SUV responses. Furthermore, despite baseline independence, we found a strong negative correlation between Ki/K1 and K1 at the response level. Kinetic analysis of the most uptake-avid tumour cluster extracted with FCM-3 yielded similar results with attenuated changes in delivery and retention. Overall, we found that RT induces early measurable changes in lung tumour FLT uptake. Spatial analysis indicated a variable dissociation of anatomical and metabolic volumes, while temporal analysis showed a variable antagonistic effect on delivery and phosphorylation, indicating that SUV analysis may misrepresent the magnitude and variability of RT anti-proliferative effect.