Impact of Lung and Heart Radiation Dose during Preoperative Chemoradiation on Overall Survival (OS) in Esophageal Cancer (EC) – Secondary Analysis of CALGB 80803 (Alliance)

Abstract

<h3>Purpose/Objective(s)</h3> In CALGB 80803, patients with locally advanced EC received PET-directed neoadjuvant therapy consisting of induction chemotherapy followed by chemoradiation and then surgical resection. Historically, radiotherapy has been delivered using techniques with limited ability to minimize doses to the heart and lungs, potentially leading to increased risk of peri-operative and late cardiopulmonary toxicities with significant morbidity and mortality. We evaluated the relationship between OS and radiation dose to the heart and lungs, and the impact of intensity-modulated radiation therapy (IMRT) and adherence to protocol-specified dose constraints in CALGB 80803. <h3>Materials/Methods</h3> Protocol-specified dose constraints were based on standard of care guidelines: total lung V_{10 Gy} ≤ 40%, V_{20 Gy} ≤ 20%, V_{30 Gy} ≤ 15%, V_{40 Gy} ≤ 10%; heart V_{30 Gy} ≤ 30%. Optimal dose cutpoints for each volumetric constraint were calculated that best differentiated OS. Each cutpoint was dichotomized and the Kaplan-Meier method was used to evaluate its impact on OS. The significance threshold was <i>p</i><0.05 and a Holm multiple comparisons correction was applied. <h3>Results</h3> There were 226 patients (n) included in the analysis, 60.3% were treated with IMRT. Rates of adherence were high for each of the protocol-specified dose constraints: 74.8%, 84.1%, 98.7%, 99.1%, and 73.0% for total lung V_{10 Gy}, V_{20 Gy}, V_{30 Gy}, V_{40 Gy}, and heart V_{30 Gy}, respectively. See the table for calculated dose cutpoints for each dosimetric variable as well as treatment and survival data. For heart V_{30 Gy}, 90.6% and 68.2% with V₃₀ Gy > 21% received three-dimensional conformal radiation therapy (3D-CRT) vs IMRT, respectively, while 9.4% and 31.8% with V_{30 Gy} > 21% received 3D-CRT vs IMRT, respectively (<i>p</i> < 0.001). Mean heart V_{30 Gy} was significantly lower in the IMRT vs 3D-CRT group (24.7% vs 35.5%; <i>p</i> < 0.001). On univariable Cox regression, lung V_{10 Gy} > 41% (hazard ratio [HR]: 1.87; <i>p</i> = 0.002) and heart V_{30 Gy} > 21% (HR: 1.77; <i>p</i> = 0.017) were significant poor prognostic factors for OS. <h3>Conclusion</h3> The majority of patients on CALGB 80803 were treated with IMRT plans that met the protocol-specified dose constraints for total lung and heart_. Minimizing volume of low dose to the lungs (V_{10 Gy}) was associated with a significant survival benefit, as was a lower heart V_{30 Gy}. Total lung V_{10 Gy} ≤ 41% and heart V_{30 Gy} ≤ 21%, and the use of IMRT over 3D-CRT, should be considered when designing radiation plans for EC patients. <b>Support:</b> U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. <b>ClinicalTrials.gov ID:</b> NCT01333033