BackgroundTo explore the hematological toxicity (HT) induced by neoadjuvant chemoradiotherapy (nCRT) compared with neoadjuvant chemotherapy (nCT) and to identify the appropriate vertebral body (VB) dosimetric parameters for predicting HT in patients with locally advanced gastric cancer (GC).MethodsIn the phase III study, 302 patients with GC from an ongoing multi-center randomized clinical trial (NCT 01815853) were included. Patients from two major centers were grouped into training and external validation cohorts. The nCT group received three cycles of XELOX chemotherapy, while the nCRT received the same dose-reduced chemotherapy plus 45 Gy radiotherapy. The complete blood counts at baseline, during neoadjuvant treatment, and in the preoperative period were compared between the nCT and nCRT groups. The VB was retrospectively contoured and the dose-volume parameters were extracted in the nCRT group. Patients’ clinical characteristics, VB dosimetric parameters, and HTs were statistically analyzed. Instances of HT were graded according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE v5.0). The receiver operating characteristic (ROC) curves were generated to identify the optimal cut-off points for dosimetric variables and verify the prediction efficiency of the dosimetric index in both training and external validation cohorts.ResultsIn the training cohort, 27.4% Grade 3 + HTs were noted in the nCRT group and 16.2% in the nCT group (P= 0.042). A similar result was exhibited in the validation cohort, with 35.0% Grade 3 + HTs in the nCRT group and 13.2% in the nCT group (P= 0.025). The multivariate analysis of the training cohort revealed that V5was associated with Grade 3 + leukopenia (P= 0.000), Grade 3 + thrombocytopenia (P= 0.001), and Grade 3 + total HTs (P= 0.042). The Spearman correlation analysis identified a significant correlation of V5with the white blood cell nadir (P= 0.0001) and platelet nadir (P= 0.0002). The ROC curve identified the optimal cut-off points for V5and showed that V5< 88.75% could indicate a decreased risk of Grade 3 + leukopenia, thrombocytopenia, and total HTs in the training as well as the external validation cohorts.ConclusionsCompared with nCT, nCRT could increase the risk of Grade 3 + HT in patients with locally advanced GC. Dose constraints of V5< 88.75% in irradiated VB could reduce the incidence of Grade 3 + HT.