Radiation-induced severe lymphopenia predicts distant metastasis in rectal cancer: dosimetric implications for immune-sparing radiotherapy

BACKGROUND: Lymphopenia is a frequent complication of pelvic radiotherapy and may impair systemic immune surveillance. This study aimed to evaluate the prognostic impact of acute severe lymphopenia (ASL) in rectal cancer and to identify dosimetric predictors relevant to immune-sparing radiotherapy. METHODS: Patients with non-metastatic rectal cancer treated with radiotherapy between 2018 and 2022 were retrospectively reviewed. Clinical variables, serum biomarkers (CEA and NLR), lymphocyte counts, and pelvic bone marrow dosimetry were analyzed. Associations between ASL, distant metastasis-free survival (DMFS), overall survival (OS), and dosimetric metrics were assessed using multivariable models. RESULTS: A total of 161 patients were included, with 69.6% developing ASL. Patients with ASL had inferior 3-year DMFS (72.6% vs. 84.7%; p = 0.034), and ASL remained an independent predictor of poorer DMFS (p = 0.027). ECOG performance status ≥ 1 (p = 0.005), clinical N2 stage (p = 0.016), and baseline CEA > 5 ng/mL (p = 0.041) were also associated with worse DMFS, while adjuvant chemotherapy was protective (p < 0.001). Predictors of ASL included lower baseline absolute lymphocyte count (OR 0.87, 95% CI 0.81–0.93 per 0.1 × 10⁹/L increase; p < 0.001), higher clinical T stage (OR 2.38, 95% CI 1.01–5.56; p = 0.046), and greater low-dose irradiation to the lower pelvis—V5 (OR 1.06, 95% CI 1.02–1.11 per 1% increase; p = 0.005), for which the optimal predictive cut-off was 88%. CONCLUSION: ASL was associated with increased risk of distant metastasis. As baseline immunity and disease burden are non-modifiable, minimizing lower pelvic V5 using as low as reasonably achievable (ALARA)–based planning constraints may help reduce ASL risk and support immune-sparing radiotherapy in rectal cancer.