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Treatment-associated regression of tumors outside the irradiated field has occasionally been reported, but the underlying mechanisms remain unclear, particularly in the context of central nervous system (CNS)-directed therapy. Glioblastoma (GBM) is commonly treated with radiotherapy and temozolomide, both of which may influence tumor biology and the systemic environment. We report a patient with synchronous primary GBM and early-stage lung adenocarcinoma who underwent craniotomy followed by intensity-modulated radiotherapy with concurrent temozolomide for GBM. During GBM-directed chemoradiotherapy, the untreated pulmonary lesion demonstrated progressive regression without any lung-specific therapy, temporally coinciding with CNS-targeted treatment. Although comprehensive immunophenotyping was not feasible, longitudinal changes in the proportion of peripheral blood lymphocytes were observed during therapy. These findings represent a clinical observation characterized by a temporal association between CNS-directed treatment and regression of a distant, non-irradiated tumor. However, the underlying mechanism remains uncertain, and a contribution from systemic temozolomide exposure cannot be excluded. While treatment-related systemic effects may be considered, no specific causal mechanism can be established based on this single case. This case highlights an unusual clinical observation that may warrant further investigation. Further studies are needed to clarify the relationship between CNS-directed therapies and systemic tumor behavior.