Early detection of subclinical left ventricular dysfunction after breast cancer radiation therapy using speckle-tracking echocardiography: association between cardiac exposure and longitudinal strain reduction (BACCARAT study).

BACKGROUND: Breast cancer (BC) radiotherapy (RT) can induce cardiotoxicity, with adverse events often observed many years after BC RT. Subclinical left ventricular (LV) dysfunction can be detected early after BC RT with global longitudinal strain (GLS) measurement based on 2D speckle-tracking echocardiography. This 6-month follow-up analysis from the BACCARAT prospective study aimed to investigate the association between cardiac radiation doses and subclinical LV dysfunction based on GLS reduction. METHODS: The patient study group consisted of 79 BC patients (64 left-sided BC, 15 right-sided BC) treated with RT without chemotherapy. Echocardiographic parameters, including GLS, were measured before RT and 6 months post-RT. The association between subclinical LV dysfunction, defined as GLS reduction > 10%, and radiation doses to whole heart and the LV were performed based on logistic regressions. Non-radiation factors associated with subclinical LV dysfunction including age, BMI, hypertension, hypercholesterolemia and endocrine therapy were considered for multivariate analyses. RESULTS: A mean decrease of 6% in GLS was observed (- 15.1% ± 3.2% at 6 months vs. - 16.1% ± 2.7% before RT, p = 0.01). For left-sided patients, mean heart and LV doses were 3.1 ± 1.3 Gy and 6.7 ± 3.4 Gy respectively. For right-sided patients, mean heart dose was 0.7 ± 0.5 Gy and median LV dose was 0.1 Gy. Associations between GLS reduction > 10% (37 patients) and mean doses to the heart and the LV as well as the V20 were observed in univariate analysis (Odds Ratio = 1.37[1.01-1.86], p = 0.04 for Dmean Heart; OR = 1.14 [1.01-1.28], p = 0.03 for Dmean LV; OR = 1.08 [1.01-1.14], p = 0.02 for LV V20). In multivariate analysis, these associations did not remain significant after adjustment for non-radiation factors. Further exploratory analysis allowed identifying a subgroup of patients (LV V20 > 15%) for whom a significant association with subclinical LV dysfunction was found (adjusted OR = 3.97 [1.01-15.70], p = 0.048). CONCLUSIONS: This analysis indicated that subclinical LV dysfunction defined as a GLS decrease > 10% is associated with cardiac doses, but adjustment for non-radiation factors such as endocrine therapy lead to no longer statistically significant relationships. However, LV dosimetry may be promising to identify high-risk subpopulations. Larger and longer follow-up studies are required to further investigate these associations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02605512, Registered 6 November 2015 - Retrospectively registered.

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).

BACKGROUND: Intra-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. METHODS: Data 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. RESULTS: Dose 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). CONCLUSION: Our 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 REGISTRATION: ClinicalTrials.gov: NCT02605512 , Registered 6 November 2015 - Retrospectively registered.

Early detection and prediction of cardiotoxicity after radiation therapy for breast cancer: the BACCARAT prospective cohort study.

BACKGROUND: Radiotherapy (RT) for breast cancer presents a benefit in terms of reducing local recurrence and deaths resulting from breast cancer but it can lead to secondary effects due to the presence of neighboring cardiac normal tissues within the irradiation field. Breast RT has been shown to be associated with long-term increased risk of heart failure, coronary artery disease, myocardial infarction and finally cardiovascular death more than 10 years after RT. However, there is still a lack of knowledge for early cardiotoxicity induced by breast RT that can appear long before the onset of clinically significant cardiac events. Based on a 2-year follow-up prospective cohort of patients treated with breast RT, the BACCARAT (BreAst Cancer and CArdiotoxicity Induced by RAdioTherapy) study aims to enhance knowledge on detection and prediction of early subclinical cardiac dysfunction and lesions induced by breast RT and on biological mechanisms potentially involved, based on functional and anatomical cardiac imaging combined with simultaneous assessment of multiple circulating biomarkers and accurate heart dosimetry. METHODS/DESIGN: BACCARAT study consists in a monocentric prospective cohort study that will finally include 120 women treated with adjuvant 3D CRT for breast cancer, and followed for 2 years after RT. Women aged 50 to 70 years, treated for breast cancer and for whom adjuvant 3D CRT is indicated, without chemotherapy are eligible for the study. Baseline (before RT) and follow-up data include measurements of functional myocardial dysfunction including strain and strain rate based on 2D-speckle tracking echocardiography, anatomical coronary lesions including description of plaques in segments of coronary arteries based on Coronary computed tomography angiography, and a wide panel of circulating biomarkers. The absorbed dose is evaluated for the whole heart and its substructures, in particular the coronary arteries. Analysis on occurrence and evolution of subclinical cardiac lesions and biomarkers will be performed and completed with dose-response relationship. Multivariate model of normal tissue complication probability (NTCP) will also be proposed. DISCUSSION: Tools and results developed in the BACCARAT study should allow improving prediction and prevention of potential lesions to cardiac normal tissues surrounding tumors and ultimately enhance patients' care and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02605512.

Coronary stenosis risk analysis following Hodgkin lymphoma radiotherapy: A study based on patient specific artery segments dose calculation.

BACKGROUND AND PURPOSE: The dose effect-effect relationship for cardiac diseases following radiotherapy suffers from uncertainties. Three dimensional coronary artery (CA) dose calculation after mediastinal Hodgkin lymphoma radiotherapy was performed, using the patient's coronary CT angiography (CCTA), and the relationship between the coronary arteries' radiation doses and the risk of stenosis was estimated. MATERIALS AND METHODS: Radiotherapy simulation CT scans and CCTAs of patients treated for a mediastinal Hodgkin lymphoma were used to merge thoracic and detailed cardiovascular anatomies. Radiation treatment parameters were used to estimate CA radiation doses. Twenty-one patients without coronary stenosis (controls) were matched with twelve patients with stenosis (cases). CA segments were considered as sub-volumes of interest. Radiation doses to stenotic segments were compared with those received by normal segments (from cases and controls) using a logistic regression. RESULTS: In eleven cases out of twelve, the highest of the coronary dose distribution was on a damaged segment. Logistic regression with CA segments yielded an odds ratio associated with the risk of coronary stenosis of 1.049 per additional gray with the CA segment median dose (95% confidence interval, 1.004-1.095; p-value <0.05). CONCLUSION: The CA segment dose significantly increased the risk of stenosis on the segment. Such personalized CA dose calculations on larger cohorts are expected to improve the understanding of the cardiovascular radiation dose-effect relationship.

Dependence of coronary 3-dimensional dose maps on coronary topologies and beam set in breast radiation therapy: a study based on CT angiographies.

PURPOSE: In left-side breast radiation therapy (RT), doses to the left main (LM) and left anterior descending (LAD) coronary arteries are usually assessed after delineation by prior anatomic knowledge on the treatment planning computed tomography (CT) scan. In this study, dose sensitivity due to interindividual coronary topology variation was assessed, and hot spots were located. METHODS AND MATERIALS: Twenty-two detailed heart models, created from heart computed tomography angiographies, were fitted into a single representative female thorax. Two breast RT protocols were then simulated into a treatment planning system: the first protocol comprised tangential and tumoral bed beams (TGs_TB) at 50 + 16 Gy, the second protocol added internal mammary chain beams at 50 Gy to TGs_TB (TGs_TB_IMC). For the heart, the LAD, and the LM, several dose indicators were calculated: dose-volume histograms, mean dose (Dmean), minimal dose received by the most irradiated 2% of the volume (D2%), and 3-dimensional (3D) dose maps. Variations of these indicators with anatomies were studied. RESULTS: For the LM, the intermodel dispersion of Dmean and D2% was 10% and 11%, respectively, with TGs_TB and 40% and 80%, respectively, with TGs_TB_IMC. For the LAD, these dispersions were 19% (Dmean) and 49% (D2%) with TGs_TB and 35% (Dmean) and 76% (D2%) with TGs_TB_IMC. The 3D dose maps revealed that the internal mammary chain beams induced hot spots between 20 and 30 Gy on the LM and the proximal LAD for some coronary topologies. Without IMC beams, hot spots between 5 and 26 Gy are located on the middle and distal LAD. CONCLUSIONS: Coronary dose distributions with hot spot location and dose level can change significantly depending on coronary topology, as highlighted by 3D coronary dose maps. In clinical practice, coronary imaging may be required for a relevant coronary dose assessment, especially in cases of internal mammary chain irradiation.

Potential of hybrid computational phantoms for retrospective heart dosimetry after breast radiation therapy: a feasibility study.

PURPOSE: Current retrospective cardiovascular dosimetry studies are based on a representative patient or simple mathematic phantoms. Here, a process of patient modeling was developed to personalize the anatomy of the thorax and to include a heart model with coronary arteries. METHODS AND MATERIALS: The patient models were hybrid computational phantoms (HCPs) with an inserted detailed heart model. A computed tomography (CT) acquisition (pseudo-CT) was derived from HCP and imported into a treatment planning system where treatment conditions were reproduced. Six current patients were selected: 3 were modeled from their CT images (A patients) and the others were modelled from 2 orthogonal radiographs (B patients). The method performance and limitation were investigated by quantitative comparison between the initial CT and the pseudo-CT, namely, the morphology and the dose calculation were compared. For the B patients, a comparison with 2 kinds of representative patients was also conducted. Finally, dose assessment was focused on the whole coronary artery tree and the left anterior descending coronary. RESULTS: When 3-dimensional anatomic information was available, the dose calculations performed on the initial CT and the pseudo-CT were in good agreement. For the B patients, comparison of doses derived from HCP and representative patients showed that the HCP doses were either better or equivalent. In the left breast radiation therapy context and for the studied cases, coronary mean doses were at least 5-fold higher than heart mean doses. CONCLUSIONS: For retrospective dose studies, it is suggested that HCP offers a better surrogate, in terms of dose accuracy, than representative patients. The use of a detailed heart model eliminates the problem of identifying the coronaries on the patient's CT.