Incidental dose to cardiac subvolumes does not improve prediction of radiation pneumonitis in Stage 3 NSCLC patients

Purpose: Conflicting results have been reported for the combined effect of heart and lung irradiation on the development of radiation pneumonitis (RP) [1, 2]. The reported studies based on 3D conformal radiotherapy considered the whole heart as an organ-at-risk, thereby not distinguishing between dose to the cardiac ventricles and atria. We assessed whether inclusion of incidental dose to these cardiac subvolumes improved the prediction of Grade ≥3 RP.
Material and methods: We retrospectively assessed 188 consecutive patients with stage III non-small cell lung cancer (NSCLC) having undergone (chemo-)radiotherapy (≥60 Gy) using intensity-modulated radiation therapy (until 2011) or volumetric-modulated arc therapy (starting in 2011). Most patients (n=182) received 66 Gy in 33 (once-daily) fractions to the primary tumour and involved hilar/mediastinal lymph nodes based on FDG-PET/CT. The lungs and heart (ventricles and atria separately in 156 patients that received a contrast enhanced planning CT) were re-contoured to generate accurate dose-volume histogram (DVH) data. RP was assessed using the Radiation Therapy Oncology Group scoring criteria for pulmonary toxicity. Since high multicollinearity was observed between the DVH parameters, those with the highest Spearman correlation coefficient (Rs) were selected for the modelling procedure. Using a bootstrap approach, clinical parameters (such as age, gender, performance, smoking status, forced expiratory volume in 1 second, and cardiac comorbidity, i.e., medical history of myocardial infarction, heart failure, valvular heart disease, cardiac arrhythmias and/or hypertension) and DVH parameters of lungs and heart (assessing atria and ventricles separately and combined) were evaluated for RP prediction.
Results: After a median follow-up of 18.4 months, 26 patients (13.8%) developed RP. Only the median mean lung dose (MLD) differed between groups (15.3 Gy vs 13.7 Gy for the RP and non-RP group, respectively; p=0.004). Most Rs of the lung DVH parameters exceeded those of the heart DVH parameters and only some of the lung DVH parameters were significantly correlated with RP [See Figure 1; highest Rs for MLD (0.21; p<0.01)]. Only cardiac comorbidity was borderline associated with RP (p=0.066) on univariate logistic regression analysis. After bootstrap modelling, heart DVH parameters were seldom included in the model predicting Grade ≥3 RP. The optimal model consisted of: MLD (Odds ratio (OR) 1.28 per Gy increase; p=0.03) and cardiac comorbidity (OR 2.45 in case of cardiac comorbidity; p=0.04). The area under the receiver operator characteristic curve was 0.71, with good calibration of the model.
Conclusion: Incidental dose to the cardiac atria and ventricles did not improve RP risk prediction in our cohort of stage III NSCLC patients as the DVH parameters for lung outperformed those for the heart. The multivariable model containing the variables cardiac comorbidity and MLD is the optimal model for RP prediction in this cohort.
References
1. Huang, E.X., et al., Heart irradiation as a risk factor for radiation pneumonitis. Acta Oncol, 2011. 50(1): p. 51-60.
2. Tucker, S.L., et al., Is there an impact of heart exposure on the incidence of radiation pneumonitis? Analysis of data from a large clinical cohort. Acta Oncol, 2014. 53(5): p. 590-6.