Inflammatory and immune marker dynamics following intratumoral alpha dart for pancreatic cancer.

Abstract

771 Background: Immune markers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic inflammatory index (SII; NLR*platelet) are adverse prognostic factors in pancreatic ductal adenocarcinoma (PDAC). External beam radiotherapy (EBRT) and stereotactic body radiotherapy (SBRT) have limited role in PDAC and are known to typically worsen these inflammatory indices via radiation-induced lymphopenia. Diffusing Alpha-emitters Radiation Therapy (Alpha DaRT) delivers highly localized intratumoral alpha radiation with minimal systemic exposure. Whether Alpha DaRT alters systemic inflammatory markers in PDAC remains unknown. Methods: In a pilot analysis of 32 PDAC patients treated with EUS-guided intratumoral Alpha DaRT (NCT04002479), 23 with complete laboratory data were analyzed. Demographics, baseline and 30-day post-treatment hematologic and immune markers (SII, NLR, PLR, IL-6, CD4/CD8 ratio, CRP) were collected. Pre- vs post-treatment medians were compared using Wilcoxon signed-rank tests. Logistic regression evaluated baseline, post-treatment, and delta (Δ) NLR/PLR for association with disease control (DC = CR/PR/SD) vs progression (PD). Results: Median age was 73 years (40–91); 8 men (34.8%), 15 women (65.2%). All patients had successful source placement. Median pre- vs post-treatment values: NLR 3.0 vs 3.1 (p=0.22), PLR 127.1 vs 125.0 (p=0.82), IL-6 614.0 vs 5.9 pg/mL (p<0.000001), CD4/CD8 ratio 2.21 vs 2.39 (p=0.35). CRP changes from pre- to post-treatment were not statistically significant (mean 6.7 → 14.5 mg/L; median change 0 mg/L, IQR –3.5 to +8.8). The first two undertreated patients showed numerically higher post-treatment NLR (3.76 vs 2.75) and IL-6 (13.1 vs 5.7), not significant. Logistic regression did not identify baseline NLR or PLR as predictors, though both trended toward association (p=0.14–0.17; pseudo R²=0.54). Lower post-treatment NLR (p=0.09), and lower post PLR (p=0.18) favored DC. SII decreased from pre 886.9 to post 501.1, associated with a DC odds ratio of 0.72 (95% CI: 0.41 – 1.25), p = 0.238. Conclusions: Unlike EBRT and SBRT, which worsen systemic inflammatory indices in PDAC, Alpha DaRT did not increase NLR or PLR 30-day post-treatment and induced a marked IL-6 reduction without significantly altering CD4/CD8 ratio or CRP, indicating an anti-inflammatory immune preserving effect. Regression analyses suggest lower post-treatment NLR, PLR and SII may be associated with DC. The immune-preserving, potentially immune-promoting profile of Alpha DaRT supports further evaluation as a complement to novel immune strategies, such as RNA-based vaccines and novel checkpoint inhibitors, while avoiding the immunosuppression of conventional radiation. Clinical trial information: (ClinicalTrials.gov Identifier NCT04002479 .