Lymphocyte Kinetics and Outcomes After Comprehensive Involved-Site Radiotherapy for Oligometastases

Lymphopenia is a common adverse event following radiotherapy, but its prognostic relevance following comprehensive involved-site radiation (ISRT) for oligometastatic disease is unknown. We evaluated lymphocyte kinetics after ISRT for oligometastases and tested whether treatment-related lymphopenia was associated with overall survival (OS) and modified progression-free survival (mPFS).

We performed a single-institution registry study of consecutive patients with 1 to 5 distant metastases treated with comprehensive ISRT by a single radiation oncologist from 2014 to 2023. Systemic therapy was administered at clinician discretion. Absolute lymphocyte count (ALC) was collected at baseline, during radiation and at 1, 3 and 12 months after radiotherapy. Lymphopenia was graded using CTCAE v5.0 (grade 1, ALC < 1000 cells/µL; grade ≥ 3, ALC < 500 cells/µL). OS and mPFS (defined as death or metastatic progression not salvageable with further local therapy) were estimated by the Kaplan-Meier method. Associations were evaluated using univariable and multivariable Cox proportional hazards models.

Among 177 patients, the 5-year OS was 39.6% and the median OS was 42.8 months. Median ALC declined from 1400 cells/µL at baseline to 800 cells/µL during radiotherapy (p < 0.01) and 700 cells/µL at a median of 0.7 months after radiation (p < 0.01). Partial recovery was observed at 1000 cells/µL at 3 months (p < 0.001) and 1000 cells/µL at 1 year (p < 0.01). Baseline ALC <1000 cells/µL was associated with worse OS on univariable analysis (p = 0.04) but not on multivariable analysis. Although 27% developed grade ≥ 3 lymphopenia within 3 months of radiation, the 5-year overall survival was 41.4% without lymphopenia versus 31.9% with lymphopenia (p = 0.60). On multivariable analysis, ECOG performance status (HR 1.9, p < 0.01), age (HR 1.04, p < 0.01), albumin (HR 0.6, p = 0.03), and pre-radiation chemotherapy (HR 3.1, p < 0.01) independently predicted overall survival.

Comprehensive ISRT for oligometastatic disease was associated with a sustained decrease in median ALC. Treatment-related lymphopenia was not independently associated with OS in this heterogeneous cohort. The disease control benefit of metastasis-directed therapy may outweigh potential detrimental immunologic effects of radiation-induced lymphopenia.