Accounting for Serial and Parallel Functionality of the Lung May Minimize Post-Radiotherapy Loss of Respiratory Function in Lung Cancer Patients.

Purpose/objective(s) Functional lung avoidance (FLA) radiotherapy (RT) aims to minimize post-RT respiratory function loss. Current FLA approaches spatially map lung function and preferentially avoid dose to high-functioning lung (HFL). However, current FLA methods do not adequately consider the conducting architecture responsible for gas exchange (airways/vasculature). Previously, we showed that excessive toxicity to airways results in airway collapse, leading to functional loss within downstream lung sub-volumes. We proposed the functionally weighted airway sparing (FWAS) method to spare airways connected to HFL. Here, we propose a novel method that combines both FLA and FWAS to minimize post-RT functional loss. Materials/methods We estimated post-RT decline in regional airflow and ventilation as a combined measure of functional loss. High-res breath-hold CTs (BHCTs) and simulation 4DCTs from seven lung SAbR patients were analyzed retrospectively. Three functional avoidance IMRT strategies were compared to conventional IMRT planning: (i) FLA - a 4DCT-based ventilation map was used to delineate the HFL, defined as the functional regions of the lung above the mean intensity in the map. FLA plans were optimized such that mean dose and V13.5 in HFL were as low as reasonably achievable while meeting clinical dose constraints. (ii) FWAS - a virtual bronchoscopy software was used to autosegment 12 airway generations on the BHCT. Each terminal airway was connected to a lung sub-volume and assigned a functional weight based on the relative ventilation contribution of the sub-volume based on the ventilation map. For non-terminal airways, the weight was calculated in terms of the cumulative ventilation supported by corresponding downstream airways. These weights were used in the optimization along with airway dose constraints, estimated as a function of airway diameter and 5% probability of collapse. (iii) FLA+FWAS - the two strategies were combined to reduce the dose to both HFL and corresponding upstream airways. Results Overall, FLA+FWAS provided the highest ventilation preservations with an average improvement, compared to conventional plans, of 12%, followed by FWAS (8%), and FLA (3%). In all cases, clinical objectives for planning target volume and organs at risk were met. Generalized estimated equations with identity link and normal distribution and exchangeable correlation matrix showed that all these improvements were statistically significant (P Conclusion These initial results suggest that it is crucial to consider the serial as well as the parallel nature of the lung, being airway sparing likely more critical to minimize post-RT functional loss.