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Introduction Anatomical change of tumor during radiotherapy contributes to target missing. However, in the case of tumor shrinkage, adaptation of volume could result in an increased incidence of recurrence in the area of target reduction. This study aims to investigate the incidence of failure of the adaptive approach and, in particular, the risk for local recurrence in the area excluded after replanning. Methods In this prospective study, patients with locally advanced NSCLC treated with concomitant chemoradiation underwent weekly chest computed tomography simulation during treatment. In the case of tumor shrinkage, a new tumor volume was delineated and a new treatment plan outlined (replanning). Toxicity was evaluated with the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale. Patterns of failures were classified as in field (dimensional and/or metabolic progression within the replanning planning target volume [PTV]), marginal (recurrence in initial the PTV excluded from the replanning PTV), and out of field (recurrence outside the initial PTV). Results Replanning was outlined in 50 patients selected from a total of 217 patients subjected to weekly simulation computed tomography in our center from 2012 to 2014. With a median follow-up of 20.5 months, acute grade 3 or higher pulmonary and esophageal toxicity were reported in 2% and 4% of cases and late toxicity in 4% and 2%, respectively. Marginal relapse was recorded in 6% of patients, and 20% and 4% of patients experienced in-field and out-of-field local failure, respectively. Conclusions The reduced toxicity and the documented low rate of marginal failures make the adaptive approach a modern option for future randomized studies. The best scenario to confirm its application is probably in neoadjuvant chemoradiation trials.