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Background: Concomitant chemo-radiotherapy is the reference treatment for non-resectable locally-advanced Non-Small Cell Lung Cancer (NSCLC). Increasing radiotherapy total dose in the whole tumour volume has been shown to be deleterious. Functional imaging with positron emission tomography (PET/CT) offers the potential to identify smaller and biologically meaningful target volumes that could be irradiated with larger doses without compromising Organs At Risk (OAR) tolerance. This study investigated four scenarios, based on 18 FDG and 18 F-miso PET/CT, to delineate the target volumes and derive radiotherapy plans delivering up to 74Gy., Method: Twenty-one NSCLC patients, selected from a prospective phase II trial, had 18 FDG- and 18 F-miso PET/CT before the start of radiotherapy and 18 FDG PET/CT during the radiotherapy (42Gy). The plans were based planned on a standard plan delivering 66 Gy (plan 1) and on three different boost strategies to deliver 74Gy total dose in pre-treatment 18 FDG hotspot (70% of SUV max ) (plan 2), pre-treatment 18 F-miso target (SUV max  > 1.4) (plan 3) and per-treatment 18 FDG residual (40% of SUV max ). (plan 4)., Results: The mean target volumes were 4.8 cc (± 1.1) for 18 FDG hotspot, 38.9 cc (± 14.5) for 18 F-miso and 36.0 cc (± 10.1) for per-treatment 18 FDG. In standard plan (66 Gy), the mean dose covering 95% of the PTV (D95%) were 66.5 (± 0.33), 66.1 (± 0.32) and 66.1 (± 0.32) Gy for 18 FDG hotspot, 18 F-miso and per-treatment 18 FDG. In scenario 2, the mean D95% was 72.5 (± 0.25) Gy in 18 FDG hotspot versus 67.9 (± 0.49) and 67.9 Gy (± 0.52) in 18 F-miso and per-treatment 18 FDG, respectively. In scenario 3, the mean D95% was 72.2 (± 0.27) Gy to 18 F-miso versus 70.4 (± 0.74) and 69.5Gy (± 0.74) for 18 FDG hotspot and per-treatment 18 FDG, respectively. In scenario 4, the mean D95% was 73.1 (± 0.3) Gy to 18 FDG per-treatment versus 71.9 (± 0.61) and 69.8 (± 0.61) Gy for 18 FDG hotspot and 18 F-miso, respectively. The dose/volume constraints to OARs were matched in all scenarios., Conclusion: Escalated doses can be selectively planned in NSCLC target volumes delineated on 18 FDG and 18 F-miso PET/CT functional images. The most relevant strategy should be investigated in clinical trials., Trial Registration: (RTEP5, NCT01576796 , registered 15 june 2012).