Personalized Ultra-Fractionated Stereotactic Adaptive Radiotherapy (PULSAR) for Patients with Lung Tumors and Severe Pulmonary Disease

<b>Background/Objectives:</b> Patients with early-stage non-small cell lung cancer (NSCLC) or limited lung metastases and compromised lung function, such as those with interstitial lung disease (ILD) or chronic obstructive pulmonary disease (COPD), or other factors rendering them high-risk for surgery or medically inoperable, face increased risks of treatment-related toxicity from stereotactic ablative radiation therapy (SABR). This study evaluated a novel treatment approach to mitigate these risks. <b>Methods:</b> We investigated Personalized Ultra-Fractionated Stereotactic Adaptive Radiotherapy (PULSAR), delivered as pulsed radiation every three weeks, in patients with <5 cm lung tumors and ILD, COPD, or prior therapy. Treatment occurred between 2022 and 2024. Online adaptive radiotherapy (o-ART) was employed in 20 patients (80%) to modify treatment plans when anatomical changes warranted replanning. Primary outcomes included volumetric tumor response, changes in dose to organs at risk (OARs) and acute events, while secondary outcomes included local and tumor control, and overall survival. <b>Results:</b> Twenty-three patients received PULSAR treatment at doses between 40 Gy and 60 Gy in 5 fractions and one patient received 54 Gy in 3 fractions, with a median follow-up time of 16.2 months. Approximately half of treated patients demonstrated volumetric tumor response, with median residual volume of 70% (range 36-100%) at maximal response. Among the 20 patients (80%) who underwent online adaptive replanning, significant reductions in OAR dosimetry were observed for all organs assessed including the Dmax for heart (<i>p</i> = 0.0053), bronchus (<i>p</i> = 0.0003), esophagus (<i>p</i> = 0.0005), spinal cord (<i>p</i> = 0.025), and the lung V20 Gy and V12.5 Gy (<i>p</i> < 0.0001). Treatment-related toxicity included two grade 1-2 adverse events and six grade 3 events consisting of pneumonitis, dyspnea or lung infection, with no grade 4 or 5 events. Median progression-free survival was 21.1 months, with 1-year overall survival of 74% and 1-year local control of 100%. <b>Conclusions:</b> PULSAR shows promise as a feasible treatment option for high-risk patients with NSCLC or lung metastases, demonstrating no grade 5 events and complete tumor control. Additional research is needed to fully evaluate the safety profile of PULSAR in the high-risk subgroups and whether PULSAR's treatment intervals and adaptive planning advantages lead to improved long-term outcomes compared to conventional, uninterrupted SABR regimens.