Implications for Functional Lung Avoidance Radiation Therapy (FLART): Airway Dysfunction and Ventilation Defect Reversibility
Abstract
Purpose
Functional lung avoidance radiation therapy (FLART) uses pre-treatment ventilation imaging to spare high-functioning lung from radiation. The FLAIR trial, the first randomized controlled trial of this approach, found no quality-of-life benefit in ex-smokers with non-small cell lung cancer. While underpowered, these results question FLART's core assumption: that ventilation defects represent fixed functional loss. CT mucus-plugs are prevalent in 41-67% of ever-smokers with COPD and correlate with ventilation defects. At the participant level, mucus-plugs demonstrate intervention-independent transience (16% resolving, 20% newly forming over five years). However, plug-level dynamics and correspondence with ventilation have not been examined. We quantified mucus-plug transience and its relationship with ventilation in ex-smokers with and without COPD.
Methods
Ex-smokers with (n=54) and without (n=39) COPD underwent same-day thoracic CT and hyperpolarized 129Xe MRI (3T, 1L dose, 3D FGRE acquisition) at baseline and 2.6-year follow-up (NCT02279329). Ventilation defect percent (VDP) was quantified using an automatic segmentation algorithm; CT mucus-plugs were scored by two observers using a validated approach. Spearman correlations evaluated mucus–VDP relationships; longitudinal VDP change was adjusted for emphysema progression (ΔRA950).
Results
Mucus-score correlated with VDP at baseline (ρ=.43, p<.001) and 2.6-years (ρ=.37, p<.001). Across 93 participants, 289 plugs were identified at baseline and 287 at 2.6-years; only 94 (33%) persisted while 195 (67%) resolved and 193 newly appeared. In ex-smokers without COPD, where emphysema progression was minimal, participants with mucus clearance demonstrated VDP improvement (ΔVDP=−0.3%), with 8/11 (73%) showing concordant improvement. In ex-smokers with COPD, greater emphysema progression (ΔRA950: +4%, p<0.001) obscured this relationship; after correction, 12/20 (60%) with mucus decrease showed relative VDP improvement.
Conclusion
Ventilation defects identified during FLART planning may reflect reversible airway obstruction rather than fixed functional loss. Incorporating automatic CT mucus-plug detection into pre-treatment evaluation may help distinguish transient from persistent defects, informing which regions warrant sparing from radiation.