C-X-C Motif Chemokine Receptor 4 (CXCR4)-Targeted Biologically Guided Proton Spatially Fractionated Radiotherapy for Bulky Limited-Stage Small Cell Lung Cancer.

Abstract

To evaluate the feasibility and dosimetric safety of integrating C-X-C motif chemokine receptor 4 (CXCR4)-targeted tracer 18F-AlF-NOTA-QHY-04 positron emission tomography imaging with biologically guided proton spatially fractionated radiotherapy (BG-pSFRT) for bulky limited-stage small cell lung cancer. Among 30 patients with bulky limited-stage small-cell lung cancer, a threshold range of 35%-40% of the maximum standard uptake value (SUVmax) showed optimal spatial correspondence with the computed tomography-based gross tumor volume (GTV). The median SUVmax was 6.96, and the Dice similarity coefficient ranged from 0.707 to 0.723. CXCR4-avid sub-volumes within GTV were characterized against the sub-targets of stereotactic body radiotherapy based partial tumor irradiation targeting hypoxic segments (SBRT-PATHY) and stereotactic centralized ablative radiation therapy (SCART). Dosimetric comparisons were performed between the BG-pSFRT and SCART plans (15-24 Gy per fraction in three fractions). CXCR4-defined sub-volumes with low thresholds in BG-pSFRT demonstrated spatial concordance with putative hypoxic sub-volumes in SBRT-PATHY, whereas higher SUVmax thresholds yielded multifocal distributions that exhibited spatial discordance relative to SCART, and these multifocal imaging-defined sub-volumes were targeted in BG-pSFRT for dose escalation. Compared to proton SCART, BG-pSFRT achieved greater high-dose (V80%), GTV coverage but slightly lower sub-volume conformity (89.04% vs. 95.55%; P < 0.001), and higher V5Gy and dose per fraction (P < 0.001). All organ-at-risk doses met the standard 3-fraction SBRT constraints. CXCR4-targeted BG-pSFRT may be a dosimetrically feasible strategy for bulky limited-stage small cell lung cancer and demonstrates distinct dosimetric characteristics. The current research findings are limited to the dosimetric level and further clinical trials are required for verification.