Delayed elective nodal irradiation in head-and-neck cancer radiotherapy reduces acute lymphocyte damage, lymphopenia, and modulates immune signatures.

Authors

Justus Kaufmann, Ahmed Salah, Federico Marini, Sophia Drabke, Nina Gercek, Stephanie Breinich, Laura Oebel, Heinz Schmidberger, Sebastian Zahnreich

Published in

Clinical and translational radiation oncology. Volume 62. Pages 101315. Epub Oct 08, 2026.

Abstract

Elective nodal irradiation (ENI) for locally advanced head-and-neck squamous cell carcinoma (LA-HNSCC) contributes to hematotoxicity and may impair radiotherapy-immunotherapy synergy. We investigated whether delayed ENI, using an upfront boost to gross disease and involved nodes followed by standard ENI, reduces radiation-induced lymphocyte DNA damage and lymphopenia (RIL) while modulating peripheral immune signaling compared with standard ENI.
Twenty-eight LA-HNSCC patients assigned for adjuvant (n = 13) or definitive (n = 15) (chemo)radiotherapy were randomized to standard or delayed ENI (upfront boost: adjuvant: 2 × 2 Gy, n = 6/15; definitive: 5 × 2 Gy, n = 7/13). Blood was collected pre-treatment, 15 min and 24 h after the first fraction, and (definitive only) before fraction six and at treatment end. Primary endpoints: DNA damage in lymphocytes via γH2AX and 53BP1 foci (n = 25, pre-therapy, post-first and pre-sixth fraction) and dicentric chromosomes (n = 9, pre-therapy and pre-sixth fraction). Secondary endpoints: exploratory leukocyte transcriptomics (n = 4; pre-therapy, pre-sixth fraction and end of therapy), lymphocyte counts, and RIL (n = 28; pre-therapy and weekly during therapy).
Delayed ENI reduced initial planning target volume and whole-body dose by 9.9- and 4.4-fold (both p < 0.001), resulting in 3-4-fold lower DNA damage marker frequencies (p < 0.001) and fewer radiation-damaged lymphocytes (~11% vs. ~23%, p < 0.001). Baseline lymphocyte counts were preserved during the first treatment week, delaying RIL onset, whereas standard ENI induced an immediate decline in lymphocyte counts and RIL. Week 1 lymphocyte counts inversely correlated with planning target volume, whole-body dose, and DNA damage (all p < 0.01). Exploratory transcriptomic profiling revealed enhanced interferon and metabolic signaling with delayed ENI, whereas standard ENI preferentially activated inflammatory and damage-associated pathways.
These findings suggest that delaying elective nodal irradiation may help preserve circulating immune cells during radiotherapy and provide a mechanistic rationale for future prospective studies evaluating whether this strategy can enhance radiotherapy-immunotherapy synergy in LA-HNSCC.

PMID:
42893008
Bibliographic data and abstract were imported from PubMed on 18 Oct 2026.

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