BACKGROUND:The authors studied growth and progression of untreated nonsmall cell lung cancer (NSCLC) by comparing diagnostic and radiotherapy (RT) planning fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scans before proposed radical chemo-RT. METHODS: Patients enrolled on a prospective clinical trial were eligible for this analysis if they underwent 2 pretreatment whole body FDG-PET/CT scans, >7 days apart. Scan 1 was performed for diagnosis/disease staging and scan 2 for RT planning. Interscan comparisons included disease stage, metabolic characteristics, tumor doubling times, and change in treatment intent. RESULTS: Eighty-two patients underwent planning PET/CT scans between October 2004 and February 2007. Of these, 28 patients (61% stage III, 18% stage II) had undergone prior staging PET/CT scans. The median interscan period was 24 days (range, 8-176 days). Interscan disease progression (TNM stage) was detected in 11 (39%) patients. The probability of upstaging within 24 days was calculated to be 32% (95% confidence interval [CI], 18%-49%). Treatment intent changed from curative to palliative in 8 (29%) cases, in 7 because of PET. For 17 patients who underwent serial PET/CT scans under standardized conditions, there was a mean relative interscan increase of 19% in tumor maximum standardized uptake value (SUV) (P ¼ .022), 16% in average SUV (P ¼ .004), and 116% in percentage injected dose (P ¼ .002). Estimated doubling time of FDG avid tumor was 66 days (95% CI, 51-95 days). CONCLUSIONS: Rapid tumor progression was detected in patients with untreated, predominantly stage III, NSCLC on serial FDG-PET/CT imaging, highlighting the need for prompt diagnosis, staging, and initiation of therapy in patients who are candidates for potentially curative therapy. Cancer 2010;116:5030-7.