Validation and Modification of a Prediction Model for Acute Cardiac Events in Patients With Breast Cancer Treated With Radiotherapy Based on Three-Dimensional Dose Distributions to Cardiac Substructures

Abstract

Purpose A relationship between mean heart dose (MHD) and acute coronary event (ACE) rate was reported in a study of patients with breast cancer (BC). The main objective of our cohort study was to validate this relationship and investigate if other dose-distribution parameters are better predictors for ACEs than MHD. Patients and Methods The cohort consisted of 910 consecutive female patients with BC treated with radiotherapy (RT) after breast-conserving surgery. The primary end point was cumulative incidence of ACEs within 9 years of follow-up. Both MHD and various dose-distribution parameters of the cardiac substructures were collected from three-dimensional computed tomography planning data. Results The median MHD was 2.37 Gy (range, 0.51 to 15.25 Gy). The median follow-up time was 7.6 years (range, 0.1 to 10.1 years), during which 30 patients experienced an ACE. The cumulative incidence of ACE increased by 16.5% per Gy (95% CI, 0.6 to 35.0; P = .042). Analysis showed that the volume of the left ventricle receiving 5 Gy (LV-V5) was the most important prognostic dose-volume parameter. The most optimal multivariable normal tissue complication probability model for ACEs consisted of LV-V5, age, and weighted ACE risk score per patient (c-statistic, 0.83; 95% CI, 0.75 to 0.91). Conclusion A significant dose-effect relationship was found for ACEs within 9 years after RT. Using MHD, the relative increase per Gy was similar to that reported in the previous study. In addition, LV-V5 seemed to be a better predictor for ACEs than MHD. This study confirms the importance of reducing exposure of the heart to radiation to avoid excess risk of ACEs after radiotherapy for BC.

Fig 1.

Comparison of the mean dose distribution parameters of patient cases (patients who experienced an acute coronary event [ACE]) and noncases (those who did not) and calculation of the differences. NOTE. All data are given as the relative volumes (%) of the cardiac substructures that received (x) Gy or more in bins of 5 Gy. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Fig 2.

Excess risk of an acute coronary event (ACE) depending on the mean heart dose (MHD) in volume percentage calculated per age category and (A) absence or (B) presence of cardiac risk factors.

Fig 3.

Excess risk of an acute coronary event (ACE) depending on the mean V5 of the left ventricle (LV-V5) in volume percentage calculated per age category and risk factor: (A) no cardiac risk factors, (B) diabetes, (C) hypertension, and (D) ischemic cardiac event. For example, a patient age 70 years with an LV-V5 of 50% and no cardiac risk factors has an excess risk of 2.52% of developing an ACE within 9 years after radiotherapy. If the same patient had a history of ischemic heart disease, with a similar value for LV-V5, the excess risk would increase to 8.42%.

Fig A1.

Study population flowchart. ACE, acute coronary event; BC, breast cancer; CT, computed tomography; RT, radiotherapy.

Fig A2.

Distribution of mean heart dose (MHD) for the entire population (N = 910; median MHD, 2.37; standard deviation, 2.26; range, 0.51 to 15.25).

Fig A3.

Distribution of mean heart dose (MHD) for left-sided breast cancer (n = 451; median MHD, 4.44; standard deviation, 2.12; range, 0.99 to 15.25).

Fig A4.

Distribution of mean heart dose (MHD) for right-sided breast cancer (n = 459; median MHD, 1.31; standard deviation, 0.72; range, 0.51 to 6.87).

Fig A5.

Relationship between mean heart dose (MHD) and percentage of acute coronary events (ACEs) based on univariable analysis (ie, not corrected for age or presence of cardiovascular risk factors). The linear trend line crosses the y-axis, indicating ACEs not related to radiotherapy. Vertical bars indicate 95% CIs.

Fig A6.

Cumulative incidence of acute coronary events (ACEs) in the entire population; vertical bars indicate 95% CIs. RT, radiotherapy.