Cardiac side-effects of adjuvant radiotherapy for early breast cancer

Abstract

It is well established that adjuvant radiotherapy (RT) reduces loco-regional recurrences in breast cancer. The effect on overall survival on the other hand is much debated. Some randomized radiation therapy trials with more than 10 years follow-up as well as an overview of all unconfounded randomized trials show, in fact, a reduced survival among irradiated patients compared to the surgical controls. In an updated overview the increased mortality was suggested to be due to cardiac deaths. This excess mortality was balanced by a decreased mortality from breast cancer. Since the introduction of the term "radiation-induced heart disease (RlHD)" the existence of radiation-induced coronary artery disease has been a debated question. The papers in this thesis all investigate the possible connection between RT and cardiac diseases, particularly coronary artery disease.

In a prospective study the incidence of pericardial irritation-signs was found to be about 40% in symptom-free patients mostly after postmastectomy RT including the ipsilateral internal mammary nodes. Thus, it was shown that the effect of adjuvant RT on the heart was detectable in a number of breast cancer patients. In another study, survivors from the first Stockholm Breast Cancer Trial were examined for signs of ischemic heart disease (IHD). In 25% of the survivors treated for a left sided breast cancer with tangential 60Co fields, scintigraphy signs of IHD were found, while none of the controls exhibited such findings. All defects affected the anterior wall of the left ventricle, which indicated a possible correlation between the former radiotherapy and the observed findings.

Mortality of patients from the first Stockholm Breast Cancer Trial from ischemic heart disease, from cardiovascular disease, together with mortality and morbidity from acute myocardial infarction were analyzed in the next study. Data after a median of 20 years follow-up showed that mortality from ischemic heart disease may be positively correlated with the cardiac dose-volume. The lack of a significant increase of the incidence of myocardial infarction in the highest dose-volume group indicated that another form of radiation-induced cardiac disease may also be involved. The difference in cardiovascular mortality between the subgroups with different cardiac dose-volume was established after 4-5 years of randomization The curves continued to diverge up to about 10 years, when there appeared no further divergence. No excess risk was observed among patients who had received intermediate or low dose-volumes.

From 1993 onwards, signs of cardiac damage were assessed in 31 selected patients in whom it was impossible to exclude the heart completely from the significantly irradiated volume. The results show that of the 19 patients who underwent both a base-line and a control examination, 12 developed new, significant, irreversible, anteriorly located defects on scintigraphy. Almost all of the partially mastectomized. Stage I breast cancer patients (9/10), but only a few of those operated with modified radical mastectomy for more locally advanced cancer (3/9) developed such defects. The defects correlated well with the irradiated area of the left ventricle, and are likely to represent radiation-induced microvascular perfusion damage of the myocardium.

Based on the above findings, an estimation was made of the proportion of l patients at risk of significant cardiac irradiation among 100 node-negative left-sided breast cancer patients treated with breast-conserving surgery and irradiated to the breast only. Data were compared with the irradiated heart volumes estimated for patients treated with left-sided deep tangential 60Co fields in the first Stockholm Breast Cancer Trial. This technique was found to be associated with a significant increase of cardiac mortality. The majority of the patients with T1N0M0 breast cancer were not found to receive irradiation to a heart volume large enough to seem potentially harmful. Six percent of the patients however, received at least 25 Gy to 15-21% of the volume of the heart, which is close to the mean irradiated heart volume (25%) received by the mentioned patients in the Stockholm Trial. In conclusion, these studies illustrate that RlHD may be clinically significant problem in subgroups of breast cancer patients, mainly for those with left-sided disease also with modern radiation therapy techniques in the postmastectomy as well as the conservative surgery setting.