title: Functional lung avoidance for individualized radiotherapy (FLAIR): study protocol for a randomized, double-blind clinical trial.
abstract: BACKGROUND
  Although 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
  Eligible 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.
  
  
  CONCLUSIONS
  This 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.
  
  
  BACKGROUND
  Clinicaltrials.gov identifier: NCT02002052.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Hoover
authors.forename: Dante Pi
authors.initials: DP
authors.lastname: Capaldi
authors.forename: Khadija
authors.initials: K
authors.lastname: Sheikh
authors.forename: David A
authors.initials: DA
authors.lastname: Palma
authors.forename: George B
authors.initials: GB
authors.lastname: Rodrigues
authors.forename: A Rashid
authors.initials: AR
authors.lastname: Dar
authors.forename: Edward
authors.initials: E
authors.lastname: Yu
authors.forename: Brian
authors.initials: B
authors.lastname: Dingle
authors.forename: Mark
authors.initials: M
authors.lastname: Landis
authors.forename: Walter
authors.initials: W
authors.lastname: Kocha
authors.forename: Michael
authors.initials: M
authors.lastname: Sanatani
authors.forename: Mark
authors.initials: M
authors.lastname: Vincent
authors.forename: Jawaid
authors.initials: J
authors.lastname: Younus
authors.forename: Sara
authors.initials: S
authors.lastname: Kuruvilla
authors.forename: Stewart
authors.initials: S
authors.lastname: Gaede
authors.forename: Grace
authors.initials: G
authors.lastname: Parraga
authors.affiliation: Department of Radiation Oncology, London Regional Cancer Program, 790 Commissioners Rd, E, London, Ontario N6A 4L6, Canada. brian.yaremko@lhsc.on.ca.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Yaremko
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy / Q000009:adverse effects / Q000379:methods*; D004311:Double-Blind Method; D006801:Humans; D008168:Lung / Q000528:radiation effects*; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D008279:Magnetic Resonance Imaging / Q000379:methods; D057285:Precision Medicine; D011446:Prospective Studies; D011788:Quality of Life; D011880:Radiotherapy Planning, Computer-Assisted / Q000379:methods*; D016019:Survival Analysis