Assessment of a Contralateral Esophagus-Sparing Technique in Locally Advanced Lung Cancer Treated With High-Dose Chemoradiation: A Phase 1 Nonrandomized Clinical Trial

Abstract

Importance: Severe acute esophagitis occurs in up to 20% of patients with locally advanced lung cancer treated with chemoradiation therapy to at least 60 Gy once daily and represents a dose-limiting toxic event associated with poor outcomes.

Objective: To assess whether formalized sparing of the contralateral esophagus (CE) is associated with reduced risk of severe acute esophagitis.

Design, setting, and participants: This single-center phase 1 nonrandomized clinical trial assessing an empirical CE-sparing technique enrolled patients from July 2015 to January 2019. In total, 27 patients with locally advanced non-small cell lung carcinoma (with or without solitary brain metastasis) or limited-stage small cell lung carcinoma with gross tumor within 1 cm of the esophagus were eligible.

Interventions: Intensity-modulated radiation therapy to 70 Gy at 2 Gy/fraction concurrent with standard chemotherapy with or without adjuvant durvalumab. The esophageal wall contralateral to gross tumor was contoured as an avoidance structure to guide a steep dose falloff gradient. Target coverage was prioritized over CE sparing, and 99% of internal and planning target volumes had to be covered by 70 Gy and at least 63 Gy, respectively.

Main outcomes and measures: The primary end point was the rate of at least grade 3 acute esophagitis as assessed by Common Terminology Criteria for Adverse Events, version 4.

Results: Of 27 patients enrolled, 25 completed chemoradiation therapy. Nineteen patients had non-small cell lung carcinoma, and 6 had small cell lung carcinoma. The median age at diagnosis was 67 years (range, 51-81 years), and 15 patients (60%) were men. Thirteen patients (52%) had stage IIIA cancer, 10 (40%) had stage IIIB cancer, and 2 (8%) had stage IV cancer. The median CE maximum dose was 66 Gy (range, 44-71 Gy); the median volume of CE receiving at least 55 Gy was 1.4 cm3 (range, 0-5.3 cm3), and the median volume of CE receiving at least 45 Gy was 2.7 cm3 (range, 0-9.2 cm3). The median combined percentage of lung receiving at least 20 Gy was 25% (range, 11%-37%). The median follow-up was 33.3 months (range, 11.1-52.2 months). Among the 20 patients who had treatment breaks of 0 to 3 days and were thus evaluable for the primary end point, the rate of at least grade 3 esophagitis was 0%. Other toxic events observed among all 25 patients included 7 (28%) with grade 2 esophagitis, 3 (12%) with at least grade 2 pneumonitis (including 1 with grade 5), and 2 (8%) with at least grade 3 cardiac toxic event (including 1 with grade 5). There was no isolated local tumor failure. The 2-year progression-free survival rate was 57% (95% CI, 33%-75%), and the 2-year overall survival rate was 67% (95% CI, 45%-82%).

Conclusions and relevance: This phase 1 nonrandomized clinical trial found that the CE-sparing technique was associated with reduced risk of esophagitis among patients treated uniformly with chemoradiation therapy (to 70 Gy), with no grade 3 or higher esophagitis despite tumor within 1 cm of the esophagus. This technique may be translated into clinical practice.

Trial registration: ClinicalTrials.gov Identifier: NCT02394548.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Kamran reported having an immediate family member who is an employee of Sanofi Genzyme. Dr Gainor reported receiving personal fees from Agios, Alexo, Amgen, Array, Ariad/Takeda, AstraZeneca, Blueprint, Bristol Myers Squibb, EMD Serono, Genentech/Roche, Gilead, Incyte, Loxo/Lilly, Merck & Co, Moderna, Novartis, Oncorus, Pfizer, and Regeneron; receiving research support from Ariad/Takeda, Genentech/Roche, and Novartis; receiving institutional research support from Adaptimmune, Alexo Array, Biopharma, Blueprint, Bristol Myers Squibb, Jounce, Merck & Co, Moderna, Novartis, and Tesaro; and having an immediate family member as an employee of Ironwood Pharmaceuticals with equity outside the submitted work. Dr Keane reported receiving personal fees from AstraZeneca, OncLive, and UpToDate. No other disclosures were reported.

Figures

Figure.. Axial Computed Tomographic Images Illustrating the Contralateral Esophageal–Sparing Technique

A, Contralateral esophagus (shaded blue), esophagus (green), and target contouring. Left, clinical target volume (pink) and associated planning target volume (purple) treated to 44 Gy. Right, boost internal target volume (red) and associated planning target volume (dark red) treated to 26 Gy. B, Four additional cases with different anatomical tumor locations. C, Two participants with isodose distributions for internal target volume treated to 70 Gy (orange) and planning target volume treated to a minimum of 63 Gy (light green).