Interaction Between Neutrophil-to-Lymphocyte Ratio, Radiotherapy Fractionation/Technique, and Risk of Development of Distant Metastasis in Locally Advanced Rectal Cancer Patients.

Purpose/Objective(s) There is a paucity of data studying the significance of neutrophil-to-lymphocyte ratio (NLR) in peripheral blood of patients with locally advanced rectal cancer (LARC) planning to undergo preoperative RT. We aimed to investigate the prognostic impact of NLR in patients with LARC and whether there are modifiable factors in RT which influencing the level of NLR. Materials/Methods We studied 1366 patients treated with neoadjuvant RT with concurrent or sequential chemotherapy for LARC from 2006 to 2019. Most (97.8%) were treated with long-course RT (50-50.4 Gy in 25-28 fractions) with 3DCRT (n = 851) or helical tomotherapy (n = 504). Short-course RT (25 Gy in 5 fractions, followed by 6-week XELOX) was used in 30 cases (NCT03676517). The absolute neutrophil and lymphocyte counts were obtained from the sample collected at the time of initial diagnosis, before and during the course of preoperative RT and before surgery. The primary endpoint was distant metastasis-free survival (DMFS). Results With the median follow-up time of 61.3 months (4.1-173.7 months), the 5-year DMFS was 80.1%. 5-year DMFS was significantly associated with the level of NLR after RT, but not with the level of NLR before RT. In Cox multivariate model, post-RT NLR greater than 4 was independently correlated with worse DMFS (HR 1.37, 95% CI, 1.08-1.73), along with higher icT stage, ypT stage and ypN stage. The 5-year OS of patients with post-RT NLR > 4.0 was 83.2%, compared to 94.4% in post-RT NLR ≤ 4 patients (P 4.0) was more frequently developed after long-course RT (OR, 2.77, P = 0.032) or helical tomotherapy (OR, 1.29, P .05). Conclusion Elevation of NLR after neoadjuvant RT is associated with increased risk of DM development and poor OS in LARC. Development of high NLR following RT is directly related to RT fractionation and delivery modality, and tumor characteristics. Incorporation of SCRT with 3D-CRT or active bone marrow sparing-IMRT may be a modifiable factor that can indirectly affect DMFS by means of attenuating NLR in LARC patients, which needs further investigations.