Daily Adaptive vs. Non-Adaptive External Beam Radiation Therapy with Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer (NSCLC): A Prospective Randomized Trial of an Individualized Approach for Toxicity Reduction (ARTIA-Lung)

Abstract

Radiotherapy (RT) with concurrent chemotherapy is a standard treatment for Stage III NSCLC. However, radiation pneumonitis incidence increases rapidly with volume of lung irradiated, and esophagitis increases with dose to the esophagus. Both conditions can have adverse impacts on patients' quality of life. Daily online adaptive RT (ART) may allow for reduced normal tissue doses due to smaller margins around the target, as well as target size reduction with tumor response. This prospective, randomized controlled trial tests the hypothesis that the proportion of study participants who experience score ≥3 PRO-CTCAE cough, dyspnea, or dysphagia will be at least 20% lower with daily ART than with non-adapted RT. Enrollment goals are 244 subjects at up to 10 cancer centers worldwide. Eligibility criteria include stage IIIA-IIIC (AJCC v8) NSCLC; baseline grade 0-2 dyspnea, cough, and dysphagia; and no contralateral hilar or supraclavicular/cervical lymph node involvement. Subjects will be randomized (1:1) to CBCT-based daily ART or non-adapted RT using IMRT or VMAT delivering 60-66 Gy in 30-33 fractions with concurrent platinum doublet chemotherapy. Adjuvant immunotherapy with durvalumab is permitted. Follow-up for study participants will be for 1-year post-completion of chemoRT. Study endpoints include: frequency of PRO-CTCAE score ≥3 cough, dyspnea, or dysphagia from randomization to 30 days post-chemoRT; patient-reported quality of life (FACT-L and EQ-5D-5L questionnaires); percentage of lung receiving ≥20 Gy; mean doses to lung, heart, and esophagus; primary tumor response on CT or PET-CT (RECIST v1.1); local disease progression; and incidence of grade ≥2 pneumonitis within 1 year. Stratification factors are the treating institution and the presence of contralateral mediastinal lymph node metastases (associated with increased volume of irradiated lung). Interim analyses for futility and superiority will be performed when the primary endpoint data have been collected for 50% of evaluable participants. This study opened to enrollment on 20 October 2022 and is expected to be completed in approximately 3 years. This prospective, randomized clinical trial rigorously evaluates the impacts of daily online ART on radiation pneumonitis, esophagitis, and quality of life in patients with advanced NSCLC. It will collect standard tumor response and disease progression metrics to assure that reduced margins do not have an adverse impact on outcomes. Online ART is emerging as an innovative approach enabling increased sparing of normal tissues. The results of this clinical study will support evidence-based clinical decisions around ART technologies.