Impact of Cardiac Dose on Overall Survival in Lung Stereotactic Body Radiotherapy (SBRT) Compared to Conventionally Fractionated Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC)

Purpose/Objective(s) To examine possible association between heart irradiation and overall survival (OS) in lung SBRT patients and to compare observed associations with cardiac toxicity models previously derived in LA-NSCLC patient studies. Materials/Methods 197 Patients treated with lung SBRT at Mayo Clinic Arizona were selected for this IRB approved study. Multivariate Cox model with Akaike Information Criterion (AIC) was used to select patient specific covariates associated with OS. Heart dosimetry was represented by indices, which is a percentage of volume exposed to dose D or greater. A multivariate Cox models with patient specific covariates and single index per model was used to find a range of doses which were predictive for OS. A digital subdivision of the heart was further used to determine spatial distribution of doses which were predictive for OS. A coarse subdivision divided hearts into 4 segments, while fine subdivision divided hearts into 64 segments. Knowledge constrained Fused Lasso operator was used to derive a more complete model which correlated heart dosimetry with OS. Results of statistical analysis were compared to predictions of a model of cardiac toxicity in LA-NSCLC patients. Results Higher age (p<0.001), higher stage (p<0.001) and squamous cell histology (p=0.001) were associated with reduced OS. Whole heart DVH analysis did not reveal associations between heart irradiation and reduced OS. Coarse subdivision of the heart into four segments revealed that the irradiation of two inferior segments of the heart with low doses was associated with reduced OS, in the right-inferior segment (HR = 1.012/1%, p=0.02), and in the left-inferior segment (HR = 1.01/1%, p=0.04). Maximum dose in the right-inferior segment of the heart was also associated with reduced OS (HR = 1.02/Gy, p=0.02). Fine subdivision of the heart into 64 segments revealed that approximately 25% of heart volume in the inferior part of the heart (15/64 segments), when irradiated to doses in the 1Gy – 5Gy range, were predictive for reduced OS (HR=1.01/1%, p=0.01). A previously derived model of cardiac toxicity in LA-NSCLC patients did not predict a reduction of OS due to heart irradiation in lung SBRT patients, because of relatively low doses to the heart in most lung SBRT patients. Conclusion Doses lower than 5Gy in the inferior segments of the heart may be associated with reduced overall survival in patients treated for lung lesions with SBRT. Stage and histology of the disease, as well as patients age, were also associated with overall survival. Comparisons of cardiac toxicity patterns in LA-NSCLC patients and lung SBRT patients suggest different etiology of cardiac toxicity in the two groups. To examine possible association between heart irradiation and overall survival (OS) in lung SBRT patients and to compare observed associations with cardiac toxicity models previously derived in LA-NSCLC patient studies. 197 Patients treated with lung SBRT at Mayo Clinic Arizona were selected for this IRB approved study. Multivariate Cox model with Akaike Information Criterion (AIC) was used to select patient specific covariates associated with OS. Heart dosimetry was represented by indices, which is a percentage of volume exposed to dose D or greater. A multivariate Cox models with patient specific covariates and single index per model was used to find a range of doses which were predictive for OS. A digital subdivision of the heart was further used to determine spatial distribution of doses which were predictive for OS. A coarse subdivision divided hearts into 4 segments, while fine subdivision divided hearts into 64 segments. Knowledge constrained Fused Lasso operator was used to derive a more complete model which correlated heart dosimetry with OS. Results of statistical analysis were compared to predictions of a model of cardiac toxicity in LA-NSCLC patients. Higher age (p<0.001), higher stage (p<0.001) and squamous cell histology (p=0.001) were associated with reduced OS. Whole heart DVH analysis did not reveal associations between heart irradiation and reduced OS. Coarse subdivision of the heart into four segments revealed that the irradiation of two inferior segments of the heart with low doses was associated with reduced OS, in the right-inferior segment (HR = 1.012/1%, p=0.02), and in the left-inferior segment (HR = 1.01/1%, p=0.04). Maximum dose in the right-inferior segment of the heart was also associated with reduced OS (HR = 1.02/Gy, p=0.02). Fine subdivision of the heart into 64 segments revealed that approximately 25% of heart volume in the inferior part of the heart (15/64 segments), when irradiated to doses in the 1Gy – 5Gy range, were predictive for reduced OS (HR=1.01/1%, p=0.01). A previously derived model of cardiac toxicity in LA-NSCLC patients did not predict a reduction of OS due to heart irradiation in lung SBRT patients, because of relatively low doses to the heart in most lung SBRT patients. Doses lower than 5Gy in the inferior segments of the heart may be associated with reduced overall survival in patients treated for lung lesions with SBRT. Stage and histology of the disease, as well as patients age, were also associated with overall survival. Comparisons of cardiac toxicity patterns in LA-NSCLC patients and lung SBRT patients suggest different etiology of cardiac toxicity in the two groups.