Is mean heart dose a relevant surrogate parameter of left ventricle and coronary arteries exposure during breast cancer radiotherapy: a dosimetric evaluation based on individually-determined radiation dose (BACCARAT study)

Abstract

BackgroundIntra-individual heterogeneity of cardiac exposure is an issue in breast cancer (BC) radiotherapy that was poorly considered in previous cardiotoxicity studies mainly based on mean heart dose (MHD). This dosimetric study analyzes the distribution of individually-determined radiation doses to the heart and its substructures including coronary arteries and evaluate whether MHD is a relevant surrogate parameter of dose for these substructures.MethodsData were collected from the BACCARAT prospective study that included left or right unilateral BC patients treated with 3D-Conformal Radiotherapy (RT) between 2015 and 2017 and followed-up for 2 years with repeated cardiac imaging examinations. A coronary computed tomography angiography (CCTA) was performed before RT for all patients. Registration of the planning CT and CCTA images allowed delineation of the coronary arteries on the planning CT images. Using the 3D dose matrix generated during treatment planning and the added coronary contours, dose distributions were generated for whole heart and the following substructures: left ventricle (LV), left main coronary artery (LMCA), left anterior descending artery (LAD), left circumflex artery (LCX) and right coronary artery (RCA). A descriptive analysis of the physical doses in Gray (Gy) was performed, Dmean was the volume-weighted mean dose.ResultsDose distributions were generated for 89 left-sided BC patients (MHD = 2.9 ± 1.5 Gy, Dmean_LAD = 15.7 ± 3.1 Gy) and 15 right-sided BC patients (MHD = 0.5 ± 0.1 Gy; Dmean_RCA = 1.2 ± 0.4 Gy). For left-sided BC patients, the ratio Dmean_LAD/MHD was around 5. Pearson correlation coefficients between MHD and Dmean for delineated substructures were all statistically significant. However, for all substructures, the coefficient of determination R2 indicated that the proportion of the variance in Dmean of the substructure predictable from MHD was moderate to low (in particular R2 = 0.45 for LAD). Among left-sided BC patients with MHD < 3Gy, 56% of patients could nevertheless receive LAD doses above 40Gy (V40 > 0).ConclusionOur study illustrates that MHD is not enough to predict with confidence individual patient dose to the LV and coronary arteries, in particular the LAD. For precise radiotherapy-induced cardiotoxicity studies it would be necessary to consider the distribution of doses within these cardiac substructures rather than just the MHD.Trial registrationClinicalTrials.gov: NCT02605512, Registered 6 November 2015 - Retrospectively registered.

Analysis of cardiac motion without respiratory motion for cardiac stereotactic body radiation therapy

“…However, it is shown that doses to the substructures such as left ventricle and coronary arteries are better predictors to adverse cardiac events, and mean heart doses do not correlate the substructure doses well. [14][15][16][17] It is, therefore, important to limit doses to heart substructures when they are spared as OARs. There is increase in dosimetric uncertainty due to the nonhomogeneous cardiac motion coupled with the respiratory motion.…”

“…Recent studies showed that the doses to the substructures of heart, especially the left ventricle and the left anterior descending artery, were predictive to radiotherapy related cardiac toxicity. [14][15][16][17] The traditional treatment planning constraint, mean dose to whole heart, is not as good a predictor and does not correlate with the doses to the substructures. Therefore, studying the motion of the heart substructures is essential to the safety of cardiac SBRT treatment.…”

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

“…While in previous clinical studies, mean heart dose was related to the likelihood of RIHD [12], and the risk of major coronary events in breast cancer patients increased linearly by approximately 4-16% for each 1 Gy in mean heart dose received [6,9,10], other studies have shown that dose to the coronary arteries may also be an indicator of risk of developing coronary artery stenosis, an important aspect of RIHD [73]. Thus, there is a need for irradiation of small segments of the heart in pre-clinical models, which may include key sections of coronary arteries, to accurately predict risk factors and successfully develop interventions in RIHD [64,[74][75][76][77][78]. Partial heart irradiation in small animals may also be used to elucidate ways in which high-dose radiation treatment of segments of the heart can decrease ventricular tachycardia events in patients [79].…”

Hierarchical clustering applied to automatic atlas based segmentation of 25 cardiac sub-structures

“…Cardiac toxicity has surfaced relatively recently as an issue to be considered in breast radiotherapy (RT), with very basic dose-volumetoxicity relationships having been proposed so far [1], though preliminary data suggest that some cardiac sub-structures may be more problematic than others, particularly highlighting coronary arteries [2,3] and ventricular walls [4]. As recently illustrated by Jacob et al [5], within the framework of the BACCARAT study, the mean heart dose (MHD) is not enough to analyze the correlation between cardiac sub-structures (especially the left anterior descending artery) exposure to therapeutic radiation and resulting toxicity; moreover, the dose distribution in the heart is not homogeneous, neither for traditional tangent irradiation, nor for more recent Intensity Modulated Radiation Therapy (IMRT) approaches [6]. Highest cardiac radiation doses can be observed in the apex and in the apical-anterior segment for tangents and some hot spots > 50 Gy may be applied to some parts of the heart, particularly with tangent treatments, while, with IMRT, typically larger volumes of the heart are exposed to low and intermediate doses.…”