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Background  To investigate the potential impact of fractionation regimes and overall treatment time (OTT) on lymphopenia during definitive radiotherapy (RT) and its associations with patient outcomes in non-small cell lung cancer (NSCLC).    Methods  Subjects consisted of 115 patients who had received definitive chemoradiation therapy (CRT) with different doses and fractions for unresectable stage III NSCLC. Clinical and laboratory records were reviewed to assess the changes in total lymphocyte counts (TLCs) during definitive RT. The associations of the TLCs with the clinical and treatment features, and outcomes were analyzed.    Results  The median reduction of TLCs in the entire cohort was 1300 cells/μL (interquartile range [IQR], 950–1510 cells/μL). Of all patients, 63 (54.8%) experienced severe lymphopenia (SL) (TLC nadir < 500 cells/μL), which occurred at a median of the 5th week following RT initiation, not at the completion of RT or upon treatment with maximal doses. SL risk was increased over the first 5 weeks (odds ratio [OR] = 3.455,  P  = 0.007), after which, no increased risk was observed (OR = 0.562,  P  = 0.216). The median TLCs remained low and failed to recover to the initial normal values of their pre-RT level after 2 months of RT completion. Patients without SL exhibited significantly improved progression-free survival (hazard ratio [HR] = 0.544,  P  = 0.010) and overall survival (HR = 0.463,  P  = 0.011) after controlling for confounding variables in multivariate analyses. The incidence of SL was significantly lower (71.1% reduction in risk (OR = 0.289,  P  = 0.007)) in patients who received hypofractionated RT with an OTT within 4 weeks, compared to those who had an OTT of more than 4 weeks (32.1% vs 62.1%,  P  = 0.006). Multivariate analyses revealed that OTT within 4 weeks (OR = 0.322,  P  = 0.032) was significantly associated with a decreased risk of developing SL after controlling for confounding factors.    Conclusions  Hypofractionated RT was significantly associated with a decreased risk of SL and improved survival during definitive radiotherapy for unresectable stage III NSCLC.    Electronic supplementary material  The online version of this article (10.1186/s13014-019-1287-z) contains supplementary material, which is available to authorized users.

Treatment-duration is related to changes in peripheral lymphocyte counts during definitive radiotherapy for unresectable stage III NSCLC