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

Abstract Background and Purpose To evaluate the feasibility and dosimetric safety of integrating C–X–C motif chemokine receptor 4 (CXCR4)‐targeted tracer 1 8 F‐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. Materials and Methods Among 30 patients with bulky limited‐stage small‐cell lung cancer, a threshold range of 35%–40% of the maximum standard uptake value (SUV max ) showed optimal spatial correspondence with the computed tomography‐based gross tumor volume (GTV). The median SUV max 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). Results CXCR4‐defined sub‐volumes with low thresholds in BG‐pSFRT demonstrated spatial concordance with putative hypoxic sub‐volumes in SBRT‐PATHY, whereas higher SUV max 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 (V 80% ), GTV coverage but slightly lower sub‐volume conformity (89.04% vs. 95.55%; P < 0.001), and higher V 5Gy and dose per fraction ( P < 0.001). All organ‐at‐risk doses met the standard 3‐fraction SBRT constraints. Conclusions 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.