Esophageal toxicity after dose-escalated radiation therapy for stage II-III non-small cell lung cancer: a secondary analysis of the phase 2 randomized ARTFORCE PET-boost trial
Cooke, S. A. Belderbos, J. S. A. Stam, B. Reymen, B. Lambrecht, M. Fredberg Persson, G. Faivre-Finn, C. Dieleman, E. M. T. van Diessen, J. de Ruysscher, D.
Cooke, S. A.
Belderbos, J. S. A.
Stam, B.
Reymen, B.
Lambrecht, M.
Fredberg Persson, G.
Faivre-Finn, C.
Dieleman, E. M. T.
van Diessen, J.
de Ruysscher, D.
Abstract
PURPOSE: We previously reported unexpected high rates of severe esophageal toxicity (ET) in patients with stage II-III non-small cell lung cancer treated in the randomized ARTFORCE PET-Boost dose-escalation trial (clinicaltrials.gov: NCT01024829). The aim of this study is to evaluate clinical factors and dose metrics associated with ET in patients treated within the trial. METHODS AND MATERIALS: Patients received 24 fractions of 3.0-5.4 Gy, planned isotoxically to the primary tumor as a whole (>4 cm) or to an (18)F-FDG-PET defined subvolume within the primary tumor. Lymph nodes received 24 × 2.75Gy. Radiation therapy was combined with concurrent or sequential chemotherapy, or given alone. We evaluated the incidence and time to grade ≥ 3 (G ≥ 3) ET, and patient-reported symptoms. Follow-up time was estimated using the reverse Kaplan-Meier method. Uni- and multivariable logistic regression analyses with Firth's penalization were performed to assess the associations between clinical variables, dose parameters, and the incidence of G ≥ 3 ET. RESULTS: Median follow-up was 73.3 months. Of 107 patients randomized, 24(22.4%) experienced G ≥ 3 ET. There were 3 (2.8%) ET-related deaths, all esophageal fistulas. Median esophagus mean dose and D0.1% (EQD2) were 25.2 Gy (IQR, 18.9-33.2), and 69.5Gy (IQR, 66.4-75.4), respectively. G ≥ 3 ET occurred less frequently (19/54[35.2%] vs 5/53[9.4%]; P = .001) after a dose constraint for esophagus + 5 mm was introduced mid-trial (D0.1% < 70 Gy EQD2). Concurrent platinum-doublet chemotherapy, (compared with concurrent daily low-dose cisplatin or sequential/no chemotherapy) and higher esophageal doses, especially volume receiving >50 Gy, near maximum doses, and the equivalent uniform dose, were significantly associated with G ≥ 3 ET in multivariable regression. CONCLUSIONS: Concurrent platinum-doublet chemotherapy, as well as high doses to the esophagus, was independently associated with risk of severe ET. Stricter dose constraints led to significant reduction in G ≥ 3 ET. Future dose-escalation studies should lower doses to the esophagus, especially when combined with concurrent chemotherapy.
Description
Date
2025
Publisher
Collections
Keywords
Type
Article
Citation
Cooke SA, Belderbos JSA, Stam B, Reymen B, Lambrecht M, Fredberg Persson G, et al. Esophageal Toxicity After Dose-Escalated Radiation Therapy for Stage II-III Non-Small Cell Lung Cancer: A Secondary Analysis of the Phase 2 Randomized ARTFORCE PET-Boost Trial. International journal of radiation oncology, biology, physics. 2025 Aug 1;122(5):1227-37. PubMed PMID: 40156600. Epub 2025/03/29. eng.