Abstract
Purpose:Recent studies of radiotherapy (RT) for stage III non-small-cell lung cancer (NSCLC) have associated high dose to the heart with cardiac toxicity and decreased overall survival (OS). We used advanced statistical techniques to account for correlations between dosimetric variables and more accurately determine the range of heart doses which are associated with reduced OS in patients receiving RT for stage III NSCLC.Methods:From 2006 to 2013, 119 patients with stage III NSCLC received definitive RT at our institution. OS data was obtained from institutional tumor registry. We used multivariate Cox model to determine patient specific covariates predictive for reduced overall survival. We examined age, prescription dose, mean lung dose, lung V20, RT technique, stage, chemotherapy, tumor laterality, tumor volume, and tumor site as candidate covariates. We subsequently used novel statistical techniques within multivariate Cox model to systematically search the whole heart dose-volume histogram (DVH) for dose parameters associated with OS.Results:Patients were followed until death or 2.5 to 81.2 months (median 30.4 months) in those alive at last follow up. On multivariate analysis of whole heart DVH, the dose of 51 Gy was identified as a threshold dose above which the dose volume relationship becomes predictive for OS. We identified V55Gy (percentage of the whole heart volume receiving at least 55 Gy) as the best single DVH index which can be used to set treatment optimization constraints (Hazard Ratio = 1.044 per 1% increase in heart volume exposed to at least 55 Gy, P = 0.03). Additional characteristics correlated with OS on multivariate analysis were age, stage (IIIA/IIIB), and administration of chemotherapy.Conclusion:Doses above 51 Gy, applied to small volumes of the heart, are associated with worse OS in stage III NSCLC patients treated with definitive RT. Higher stage, older age and lack of chemotherapy were also associated with reduced OS.
Highlights
Late cardiac effects years to decades after thoracic radiotherapy (RT) have been well-described [1]
We used advanced statistical techniques to account for correlations between dosimetric variables and more accurately determine the range of heart doses which are associated with reduced overall survival (OS) in patients receiving RT for stage III non-small-cell lung cancer (NSCLC)
Three patient-specific variables were associated with OS in all models: age before RT, disease stage, and receipt of chemotherapy
Summary
Late cardiac effects years to decades after thoracic radiotherapy (RT) have been well-described [1]. Recent prospective studies in lung cancer have identified radiation-related cardiac events occurring on an earlier timeframe of months to years. The Radiation Therapy Oncology Group (RTOG) 0617 trial demonstrated decreased OS in patients randomized to higher dose radiotherapy for locally advanced non-small-cell lung cancer (NSCLC) [7]. Dose-volume analysis is one of the primary tools used in phenomenological modelling of clinical toxicity in radiation therapy. Dose volume analysis reflects the basic clinical and radiobiological insight that the likelihood of clinical toxicity depends on both the dose level and the volume to which the dose is applied. Irradiating a volume of tissue with a dose level “D” can lead to one of the three categories of outcomes: a) The SF may be high enough that the tissue can compensate for lost cells and there is no clinical toxicity observed
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