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

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 ¹⁸F-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.