Cardiac Effects of Modern Breast Radiation Therapy in Patients Receiving Systemic Cancer Therapy

Abstract

Background: Radiation therapy (RT) improves breast cancer outcomes, but cardiac morbidity remains a concern.

Objectives: This study sought to evaluate changes in cardiac function after RT and the relationship between cardiac dose metrics and echocardiography-derived measures of function.

Methods: In a longitudinal cohort study of women with breast cancer, radiation cardiac dose metrics and core lab quantitated echocardiographic measures of cardiac function were evaluated. Dose metrics included the whole heart, left ventricle, right ventricle, and left anterior descending artery (LAD). Echocardiographic measures included left ventricular ejection fraction (LVEF), longitudinal strain, circumferential strain, E/e' (ratio of early diastolic mitral inflow velocity to early diastolic mitral annular tissue velocity), Ea/Es (ventricular arterial coupling; ratio of effective arterial elastance to end systolic elastance), and right ventricular fractional area change. The mean change in echocardiographic measures over time and the association between cardiac dose metrics and echocardiographic measures were estimated by repeated-measures multivariable linear regression via generalized estimating equations.

Results: The cohort included 303 participants (median age 52 years, 33.3% African American) who received adjuvant RT (2010-2019) with a median mean heart dose of 1.19 Gy (Q1-Q3: 0.75-2.61 Gy), were followed over a median of 5.1 years (Q1-Q3: 3.2-7.1 years). Across all participants, there was a modest increase in LVEF (52.1% pre-RT to 54.3% at 5 years; P < 0.001) but a worsening in sensitive measures of function, such as circumferential strain (-23.7% pre-RT to -21.0% at 5 years; P = 0.003). Among left-sided/bilateral breast cancer participants, changes in cardiac function were observed across all parameters (P < 0.05). The maximum LAD dose was associated with a modest worsening in LVEF, longitudinal strain, circumferential strain, and E/e'.

Conclusions: Over a median of 5.1 years, modest changes in cardiac function were observed with RT. Maximum LAD dose was associated with a worsening in systolic and diastolic function parameters.

Keywords: breast cancer; cardiac toxicity; cardio-oncology; cardiotoxicity; diastolic function; echocardiography; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; radiation cardiotoxicity; radiation physics; radiation therapy; ventricular-arterial coupling.

Graphical abstract

Central Illustration

Change in Echocardiogram Parameters Over Time in the Entire Cohort Plots correspond to the predicted mean change in echocardiogram parameter over time from baseline (time = 0, pre–radiation therapy [pre-RT]) and at 0.5, 1, 2, 3, 4, and 5 years and were estimated by repeated-measures linear regression via generalized estimating equations. The model was adjusted for the following covariates: age, cancer stage (1 and 2 vs 3 and 4), body mass index, smoking status, systolic blood pressure, race, baseline hypertension, baseline diabetes, baseline cardioprotective medications (beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins), time since last chemotherapy exposure to start of radiation, systemic cancer therapy (anthracycline, trastuzumab, anthracycline + trastuzumab), time since initiation of radiation, treatment site (left/bilateral vs right), and baseline echocardiographic measure of interest. Lines within bars represent 95% CIs. Along the y-axis, a bold red arrow is placed to indicate the directionality of a detriment in cardiovascular function relative to baseline. The x-axis represents the years since radiation therapy initiation. E = early diastolic mitral inflow velocity; e′ = early diastolic mitral annular tissue velocity; Ea = systemic arterial load; Ees = left ventricular contractile function; FAC = fractional area change; LVEF = left ventricular ejection fraction; RT = radiation therapy; VA = ventricular-arterial.

Figure 1

Change in Echocardiogram Parameters Over Time, by Treatment Site Plots are stratified by treatment sites bilateral or left chest wall (orange) and right breast or chest wall only (green) and correspond to the predicted mean change in echocardiogram parameter over time from baseline (time = 0, pre–radiation therapy [pre-RT]) and at 0.5, 1, 2, 3, 4, and 5 years and were estimated by repeated-measures linear regression via generalized estimating equations. The model was adjusted for the following covariates: age, cancer stage (1 and 2 vs 3 and 4), body mass index, smoking status, systolic blood pressure, race, baseline hypertension, baseline diabetes, baseline cardioprotective medications (beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins), time since last chemotherapy exposure to start of radiation, systemic cancer therapy (anthracycline, trastuzumab, anthracycline + trastuzumab), treatment site (left/bilateral, right), time since initiation of radiation, and baseline echocardiographic measure of interest. Lines within bars represent 95% CIs. E = peak early diastolic transmitral blood flow; e′ = peak early mitral annular tissue velocity; Ea = systemic arterial load; Ees = left ventricular contractile function; FAC = fractional area change; LVEF = left ventricular ejection fraction.