Functional lung avoidance for individualized radiotherapy (FLAIR): study protocol for a randomized, double-blind clinical trial

Abstract

BackgroundAlthough radiotherapy is a key component of curative-intent treatment for locally advanced, unresectable non-small cell lung cancer (NSCLC), it can be associated with substantial pulmonary toxicity in some patients. Current radiotherapy planning techniques aim to minimize the radiation dose to the lungs, without accounting for regional variations in lung function. Many patients, particularly smokers, can have substantial regional differences in pulmonary ventilation patterns, and it has been hypothesized that preferential avoidance of functional lung during radiotherapy may reduce toxicity. Although several investigators have shown that functional lung can be identified using advanced imaging techniques and/or demonstrated the feasibility and theoretical advantages of avoiding functional lung during radiotherapy, to our knowledge this premise has never been tested via a prospective randomized clinical trial.Methods/DesignEligible patients will have Stage III NSCLC with intent to receive concurrent chemoradiotherapy (CRT). Every patient will undergo a pre-treatment functional lung imaging study using hyperpolarized 3He MRI in order to identify the spatial distribution of normally-ventilated lung. Before randomization, two clinically-approved radiotherapy plans will be devised for all patients on trial, termed standard and avoidance. The standard plan will be designed without reference to the functional state of the lung, while the avoidance plan will be optimized such that dose to functional lung is as low as reasonably achievable. Patients will then be randomized in a 1:1 ratio to receive either the standard or the avoidance plan, with both the physician and the patient blinded to the randomization results. This study aims to accrue a total of 64 patients within two years. The primary endpoint will be a pulmonary quality of life (QOL) assessment at 3 months post-treatment, measured using the functional assessment of cancer therapy–lung cancer subscale. Secondary endpoints include: pulmonary QOL at other time-points, provider-reported toxicity, overall survival, progression-free survival, and quality-adjusted survival.DiscussionThis randomized, double-blind trial will comprehensively assess the impact of functional lung avoidance on pulmonary toxicity and quality of life in patients receiving concurrent CRT for locally advanced NSCLC.Trial registrationClinicaltrials.gov identifier: NCT02002052.

Regional Lung Function Profiles of Stage I and III Lung Cancer Patients: An Evaluation for Functional Avoidance Radiation Therapy

“…The idea is that if functional portions of the lung received less dose the probability of developing thoracic radiation related side-effects (radiation pneumonitis for example) would decrease [11, 14]. The development of prospective clinical trials is underway to use hyperpolarize-helium MRI for functional avoidance and to evaluate 4DCT-ventilation as a functional imaging modality for functional avoidance [15]. …”

Estimating lung ventilation directly from 4D CT Hounsfield unit values

“…CTVI provides a highly accessible alternative to clinical ventilation imaging such as 99m Tc SPECT, 5 as well as more experimental techniques like 68 Ga PET ("Galligas PET") 6 and hyperpolarized 3 He gas MRI, 7 which are not typically included in lung cancer RT imaging outside a small number of clinical trials. 8,9 A major focus of CTVI research has been clinical validation. CTVI has exhibited good voxel-wise correlations with contrast enhanced (Xe) CT in sheep (Spearman r ∼ 0.8) 10 and with ex vivo imaging of fluorescent microspheres inhaled by rats (r ∼ 0.9), 11 in both cases with the animals mechanically ventilated.…”

Inclusion of functional information from perfusion SPECT improves predictive value of dose–volume parameters in lung toxicity outcome after radiotherapy for non-small cell lung cancer: A prospective study

“…Several other techniques, beside SPECT, potentially facilitate the delineation of regional pulmonary function for curative RT of NSCLC, including hyperpolarised 3 He and 129 Xe magnetic resonance imaging (MRI) and 4D-CT [37][38][39]. Recent developments in high-resolution pulmonary ventilation and perfusion PET/CT technology allowed for functionally adapted IMRT planning in lung cancer [40].…”