Analysis of Lymphopenia in Patients with Stage III Non-small Cell Lung Cancer Treated with Chemoradiotherapy and Consolidation Immunotherapy

Background Chemoradiotherapy (CRT) followed by durvalumab is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). Radiation-induced lymphopenia (RIL) may impair anti-tumor immunity and reduce immunotherapy efficacy. This study evaluated circulating lymphocyte kinetics in relation to dosimetric parameters and their impact on survival. Materials and Methods We conducted a multicenter retrospective study across three hospitals. Patients had unresectable stage III NSCLC and received CRT followed by durvalumab. Absolute lymphocyte counts (ALC) were collected at baseline, radiotherapy initiation and completion, and 6- and 12-months post-radiotherapy. RIL was graded using CTCAE V5.0. Tumoral, nodal and total planning target volumes (PTV) and lung and heart dosimetric parameters were analyzed. Survival was assessed using landmark analysis. Results Seventy-six patients were included. All patients developed lymphopenia, severe (grade ≥3) for 51% (n=39/76). Median ALC nadir was 490/mm 3 at 45 days from radiotherapy initiation. ALC remained reduced at 1 year (1249/mm 3 ; ± 586). Patients with severe RIL had lower baseline ALC (p = 0.03). Severe RIL was associated with larger nodal PTV (p = 0.001) and total PTV (p=0.02). Lung volume receiving 5 Gy (V5) (p < 0.01) and nodal PTV (p < 0.01) independently predicted severe RIL. Total PTV>335 cm 3 and nodal PTV>181 cm 3 significantly increased severe RIL risk. CRT plus durvalumab toxicity was not associated with lymphopenia severity (p = 0.2). No differences in overall survival or progression-free survival were observed between patients with or without severe RIL. Conclusion RIL is a frequent and prolonged toxicity associated with nodal PTV and lung V5. Optimizing radiotherapy dosimetry may help to preserve immune function.