Spatially Fractionated Induction Radiotherapy to Widen the Therapeutic Window in Locally Advanced Non-Small-Cell Lung Cancer (SPARROW): Study Protocol of a Multicenter, Randomized, Open-Label Seamless Phase I/II Trial.

BACKGROUND: Inoperable, locally advanced non-small-cell lung cancer (LA-NSCLC) remains associated with high rates of locoregional failure despite concurrent chemoradiotherapy and consolidation immunotherapy. Uniform dose escalation has failed to improve outcomes. We propose to address intra- and interindividual tumor heterogeneity by spatially fractionated radiotherapy (SFRT) and stereotactic body radiotherapy (SBRT). PATIENTS & METHODS: SPARROW is a prospective, multicenter, open-label seamless phase I/II randomized clinical trial. In phase I, up to 32 patients with inoperable LA-NSCLC receive induction SFRT (Lattice or central boost, 1 × 18 Gy), followed by a 4-week interval and adaptive consolidation radiotherapy (25 × 2.4 Gy). Tumor volume reduction (primary endpoint), safety, and feasibility guide selection of the optimal SFRT approach. A "backup arm" allows SBRT of small primary tumors with mediastinal fractionated radiotherapy (25 × 2.4 Gy). In phase II, 100 patients are randomized (1:1) to this personalized treatment (induction SFRT or SBRT of the primary) versus standard fractionated radiotherapy (30-35 × 2 Gy). Both treatment arms employ intensity-modulated and adaptive radiation techniques. The primary endpoint is progression-free survival (PFS). Secondary and translational endpoints include overall survival, locoregional control, patient-reported outcomes, circulating tumor DNA and immune profiling. DISCUSSION: SPARROW investigates whether personalized and novel radiotherapy techniques can overcome tumor heterogeneity and radioresistance in LA-NSCLC. The embedded translational program aims to characterize potential antitumor immune responses. Thus, SPARROW could redefine dose concepts in radiation oncology beyond lung cancer. TRIAL REGISTRATION: https://www.drks.de:DRKS00037163.