CT Ventilation Image-Guided Lung Functional Avoidance Radiotherapy: A Single-Arm Prospective Pilot Clinical Trial

Abstract

Lung functional avoidance radiotherapy (RT) that preferentially avoids irradiating functionally normal lung regions has the potential to reduce pulmonary toxicity after RT. The primary objective of this single-arm prospective pilot clinical trial (NCT02308709) was to assess the safety and feasibility of computed tomography (CT) ventilation image-guided functional avoidance RT. We herein report on the feasibility and dosimetric results. Patients with primary lung cancer or metastatic disease to the lungs to be treated with either conventionally fractionated RT (CFRT) or stereotactic body RT (SBRT) were eligible for this trial. All patients underwent 4-dimensional (4D) CT ventilation imaging during RT simulation based on a 4D CT scan, deformable image registration, and image analysis to quantify regional volume changes as surrogates for ventilation. Each patient required clinically-approved intensity-modulated RT plans for both standard anatomic RT and CT ventilation image-guided functional avoidance RT without compromising target coverage or adherence to constraints of organs at risk (OARs). The lung dose-function metrics were compared between the two plans using the paired two-tailed t test. The primary endpoint was the rate of grade ≥3 toxicities that occurred within 12 months after treatment, to be compared with predefined acceptable rates determined based on published toxicity data. Between May 2015 and November 2019, 34 patients were enrolled (25 patients with stage II-III NSCLC to be treated with CFRT with concurrent chemotherapy and 9 patients with stage I-II NSCLC to be treated with SBRT). One patient died before initiating RT. Of 33 evaluable patients, 32 patients received full dose (CFRT 60 Gy in 2 Gy daily fractions; SBRT 54 Gy in 3 fractions or 55 Gy in 5 fractions) and 1 patient chose to discontinue concurrent chemoradiotherapy due to grade 4 esophagitis. Compared with standard RT planning, functional avoidance RT planning significantly reduced the functional mean lung dose by 0.9 Gy (95% confidence interval [CI] 0.6-1.2 Gy; P < 0.01) (relative reduction 5.2%; 95% CI 3.5-6.8%) and the percentage of total lung function receiving ≥20 Gy by 4.2% (95% CI 3.0-5.4%; P < 0.01) (relative reduction 13.2%; 95% CI 10.5-15.9%) without compromising target coverage or adherence to constraints of OARs in patients treated with CFRT. In patients treated with SBRT, functional avoidance RT planning also significantly reduced the functional mean lung dose by 0.9 Gy (95% confidence interval [CI] 0.7-1.1 Gy; P < 0.01) (relative reduction 9.6%; 95% CI 6.6-12.7%). This pilot study demonstrates the feasibility of CT ventilation image-guided functional avoidance RT that significantly reduces the dose to functionally normal lung regions. Final toxicity results will be reported upon completion of the follow-up phase.