The Effect of Breast Irradiation on Cardiac Disease in Women Enrolled on BCIRG-001 at 10-Year Follow-up

Abstract

Radiation therapy (RT) for breast cancer has been shown to increase the risk of long term cardiac morbidity. Modern techniques such as 3D-CRT and IMRT decrease cardiac dose from RT. This study investigated cardiac toxicity associated with breast RT at 10 year follow-up in BCIRG-001, a phase III trial comparing adjuvant anthracycline chemotherapy (FAC) with anthracycline-taxane chemotherapy (TAC) in women with lymph node (LN) positive early breast cancer. Prospectively collected data from all 746 patients in the control arm (FAC) of BCIRG-001 at 10 year follow up was analyzed from Project Data Sphere. Cardiac toxicities examined were grade 3 or 4 congestive heart failure (CHF), myocardial infarction (MI), and LVEF decrease of >20% from baseline. Toxicities were compared between patients who did and did not receive RT, left sided versus right sided RT, left sided versus no RT, and left internal mammary nodal (IMN) versus no RT. Statistical comparisons of categorical data were completed using the chi-square test and Fisher exact test, and multivariate analysis was performed using binomial logistic regression in the R statistical package. Of the 746 patients, 538 (72%) received RT to a median dose of 50 Gy (25-65 Gy). Among the RT patients, 266 (49%) received left sided RT, 393 (69%) received regional nodal irradiation (RNI), and 51 (13% of RNI group) were treated to the IMNs (31% left-sided). There was no significant difference in age, KPS, menopausal status, ER/PR, or HER2 status, tumor grade, history of diabetes, MI, obesity, hyperlipidemia, hypertension, or arrhythmia, between patients receiving RT and those that did not. Per protocol, nearly all patients who underwent lumpectomy received RT; 241/439 (55%) of patients who underwent mastectomy received RT. There was thus fewer RT patients (versus non-RT patients) who underwent mastectomy (55% vs. 95%, P < 0.001) and more RT patients with >3 positive LN (42% vs 28%, P = 0.001). MI occurred in 6 RT patients versus 8 patients non-RT patients (1% vs 4%, P = 0.8). No patient treated with left sided or left IMN RT experienced MI. Grade 3/4 CHF was seen in 14 RT patients versus 3 non-RT patients (3% vs. 1.5%, P = 0.9). Four of 14 RT patients (29%) died of complications of CHF versus no non-RT patients. Evaluable baseline echocardiograms were available in 270 patients. Among these, 35/198 RT patients had LVEF decrease of >20% baseline versus 6/72 who did not receive RT (18% vs. 8.3%, P = 0.09). There was no difference between LVEF decreases in right-sided versus left-sided RT. On multivariate logistic regression, MI is significantly associated with previous history of MI, obesity, and older age. There is no significant increase in risk of MI at 10 years in LN positive women treated with breast RT and uniform adjuvant doxorubicin-based chemotherapy in this modern prospective study with long-term cardiac outcomes. The higher incidence of CHF morbidity and mortality warrants further study with a larger randomized cohort.