Bronchoscopic deployment and implantation of Diffusing alpha-emitters Radiation Therapy into the lung and mediastinum for treatment of lung cancer: a pre-clinical safety and feasibility study

**Background:** Lung cancer is the leading cause of cancer death globally, and many patients present with advanced disease or are not candidates for surgery or stereotactic ablative radiotherapy (SABR) due to toxicity concerns. Diffusing alpha-emitters Radiation Therapy (Alpha DaRTs) are stainless-steel tubes (0.37 mm diameter, 10 mm length) loaded with Ra-224 (half-life 3.6 days) that release alpha-emitting atoms into tissue over an effective range of ~4–5 mm. Alpha radiation has high relative biological effectiveness and is independent of tumor oxygenation. This study assessed the feasibility, usability, and safety of bronchoscopic Alpha DaRT deployment in a large animal (swine) model.

**Methods:** The study was conducted in two phases: Phase I (inert Alpha DaRTs, n=3 swine) and Phase II (active Ra-224-loaded Alpha DaRTs, n=2 swine). A total of 158 Alpha DaRTs were inserted (51 active, 107 inert) into lung parenchyma (n=134) and mediastinum (n=24) using bronchoscopy guided by radial endobronchial ultrasound (EBUS) and fluoroscopy. Alpha DaRTs were placed individually or in clusters with a maximum spacing of 4 mm. In Phase I, inert Alpha DaRTs were placed in right lung and mediastinum (session 1, day 0) and left lung (session 2, day 33); follow-up included fluoroscopy and CT scans up to day 38. In Phase II, active Alpha DaRTs were placed in bilateral lung and mediastinum (session 1, day 0) with CT scans, blood/urine tests, and necropsy at days 0, 7, and 28. Movement was assessed by CT registration using Coherent Point Drift and Munkres assignment. Operator usability was rated on a 5-point Likert scale. Safety was evaluated by daily health monitoring, hematology, serum chemistry, urinalysis, gross pathology, and histopathology.

**Key Results:** All 158 Alpha DaRTs were successfully deployed. Clusters achieved ≤4 mm spacing. Operator usability was rated as “Very Easy” (score 1) for most tasks, with slight challenge in deeper parenchyma (score 2). No Alpha DaRTs fell out during navigation. In Phase I, mean movement ± total error was 1.33±2.6 mm in mediastinum and 3.2±2.73 mm in parenchyma over 5 days. In Phase II, mean movement over 28 days was 3.1±1.7 mm in mediastinum and 4.7–6.9±2.5–2.8 mm in parenchyma. No migration to other organs was observed. No adverse events or clinically significant hematologic abnormalities occurred. Mild intermittent coughing was noted in one swine (swine #4) for two days, resolving without treatment. Serum creatine phosphokinase (CPK) elevations were attributed to intramuscular injections. Histopathology at day 28 showed mild to moderate interstitial pneumonitis, focal fibrosis, dystrophic mineralization with giant cells, and eosinophilic infiltrates around Alpha DaRT sites. No necrosis or damage to adjacent organs was observed.

**Clinical Implications:** This study demonstrates that bronchoscopic Alpha DaRT deployment is feasible, precise, and safe in a large animal model, with minimal movement and no migration. The mild local inflammatory response and absence of serious adverse effects support the potential for clinical translation. Alpha DaRTs may offer a bronchoscopic ablative option for lung cancer patients who are not candidates for surgery or SABR, particularly those with tumors near vital structures or prior radiation. The synergy with immunotherapy warrants further investigation. Limitations include single-investigator design, lack of tumor model, and short follow-up (28–38 days). Further studies are needed to assess long-term effects and inter-operator variability.