University of Groningen
Radiation-induced cardiac toxicity in breast cancer patients
van den Bogaard, Veerle
DOI:
10.33612/diss.144684776
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Publication date: 2020
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van den Bogaard, V. (2020). Radiation-induced cardiac toxicity in breast cancer patients. University of Groningen. https://doi.org/10.33612/diss.144684776
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GENERAL INTRODUCTION AND
OUTLINE OF THE THESIS
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INCIDENCE OF BREAST CANCER
Breast cancer (BC) is the most common form of cancer in women in the Netherlands. Approximately 15,000 women are diagnosed with invasive BC each year and the incidence of an in situ carcinoma is about 2,300 patients.1,2 The incidence is
rapidly growing (figure 1). The reasons are manifold, but reflect both the aging and growth of the population, as well as advances in diagnostic imaging. Early detection, particularly through national BC screening, combined with improved systemic treatment and more accurate radiotherapy, have substantially improved BC survival rates. Consequently, the prevalence of patients cured is increasing and those BC survivors are at increased risk of treatment-related late side effects.
STANDARD TREATMENT FOR BREAST CANCER
The current standard treatment for early stage BC is breast-conserving surgery followed by radiotherapy. Depending on patient age and pathologic risk factors, other adjuvant treatments may be recommended, such as chemotherapy, endocrine treatment and targeted agents. A meta-analysis of individual patient data for approximately 11,000 women showed that radiotherapy for early stage BC can reduce the rates of recurrence and death from BC.3 The 10-year risk of any
first recurrence was 19.3% for BC patients treated with radiotherapy and 35.0% for patients treated with only breast-conserving surgery. The 15-year absolute risk reduction of BC death was 3.8% in favour of patients treated with radiotherapy (from 25.2% to 21.4%).
Figure 1. Incidence of women diagnosed with breast cancer in the Netherlands over time.1,2
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INCIDENTAL CARDIAC IRRADIATION
Studies in which BC patients were treated with outdated radiotherapy, with exposure to much larger cardiac volumes with higher dose levels than today, showed that BC survivors are at risk of radiation-induced cardiac diseases, such as ischemic heart disease, cardiomyopathy, valvular heart disease, pericarditis, arrhythmias, and conduction disturbances.4,5,6,7,8,9,10 Over the past 2 decades,
changes in radiotherapy techniques has led to a significant reduction in radiation exposure to the heart.11,12 However, studies assessing BC patients treated with more
modern radiotherapy planning techniques, such as 3D conformal radiotherapy, or intensity modulated radiotherapy, still show higher cardiac dose levels prescribed for some patients. This could be due to their anatomy, or when deep inspiration breath hold is not possible or effective.13,14,15,16 Additionally, cardiac doses are
generally higher when the internal mammary chain is irradiated.17 Thus, although
modern radiation techniques have been refined, there are BC patients that receive considerable cardiac radiation doses, and hence are at risk for radiation-induced cardiac diseases.
DOSE-EFFECT RELATIONSHIP BETWEEN DOSE
TO THE HEART AND ACUTE CORONARY
EVENTS
Although BC treatment increases the risk of cardiac diseases, the benefits of radiotherapy and systemic therapy outweigh the risks for many patients. However, it remains important to reduce radiation exposure to the heart while maintaining appropriate target coverage. Finding this balance is challenging. Many questions remain to be answered, such as the magnitude of the risk after a given dose to the heart or its substructures, the time to develop radiation-related cardiac diseases, or the influence of other cardiac risk factors or cardiotoxic chemotherapy. Information on the relationships between dose to the heart, and its substructures and cardiac toxicity, could be helpful to identify patients at high risk for developing radiation-induced cardiac toxicity. Furthermore, such information may also provide targets for treatments that help to avoid or delay cardiac events. Patients at high risk could benefit from primary preventive measures such as optimisation of photon radiotherapy treatment plans or selection for proton therapy. Concerning secondary preventive measures, BC patients who have been treated and are at high risk of future cardiac events could be offered individualised cardiac screening programs. Thus, with better identification of BC patients at risk for cardiac damage due to radiotherapy, long-term outcomes and quality of life could be greatly improved.
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The risk of radiation induced acute coronary events has been investigated in detail. In 2013, a large cohort study showed a significant relationship between radiation dose to the heart and the rate of ischemic heart diseases.18 The rate of
major acute coronary events increased linearly with the mean dose to the heart by 7.4% per gray (Gy) over the entire follow-up period of more than 20 years. There was no apparent threshold below which there was no increased risk of acute coronary events. Confining the analysis to the first 9 years after radiation exposure, a relative increase of approximately 16% per Gy was found. Even within 5 years after radiotherapy exposure, radiation-related increase in the risk of acute coronary events was observed. However, this study had some important limitations. First, patients were treated with radiotherapy between 1958 and 2001, meaning that radiotherapy techniques were outdated and fractionation schemes were different from those currently used. Second, because patients were treated well before computed tomography (CT) based simulation became common practice, cardiac volumes and dose distributions had to be calculated based on reconstructed radiotherapy regimens and dose could not be measured individually.19 The investigators examined only the mean dose to the heart and
left anterior descending coronary artery (LAD), other possibly important dose-volume histogram (DVH) parameters were not examined. Due to these limitations, the question arises as to whether these results can be translated to the breast cancer population treated today. Therefore validation in an independent cohort, with modern radiotherapy techniques, is necessary. Furthermore, it would be relevant to investigate whether other DVH-parameters could better predict the risk of acute coronary events after radiotherapy, compared with the parameter representing the mean dose to the heart.
OTHER FACTORS RELEVANT FOR
RADIATION-INDUCED CARDIAC DISEASES
Next to the cardiotoxic effect of radiotherapy, some patients will have co-morbidities or receive other cardiotoxic treatments, such as chemotherapy, that may contribute to a higher risk of radiation-induced cardiac diseases, which may adversely affect the quality of life of cancer survivors.20
A limited numbers of studies has reported on the effects of cardiovascular risk factors or co-morbidities on radiation-related cardiac diseases. One study found that smoking and radiotherapy together were associated with a more than additive effect on risk of myocardial infarction.4 Another study found an interaction
between the risk of developing coronary artery disease and hypertension at the start of radiotherapy.21 In contrast, two studies found that cardiovascular
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of radiation-related cardiac diseases, but they did increase the absolute risk due to radiotherapy.18,22
In addition to radiation dose to the heart, the administration of certain chemotherapeutic agents form an additional risk factor of cardiac toxicity.23
Anthracyclines are one of the most widely used chemotherapeutic agents for the treatment of breast cancer.24 However, the cumulative anthracycline dose is
a well-recognised risk factor for development of, both acute and late, cardiac toxicity, mostly characterised by congestive heart failure.25,26,27,28,29 Therefore, it
is essential to take into account the effect of co-morbidity and other cardiotoxic cancer treatments on the dose-effect relationship.
OUTLINE OF THE THESIS
The overall objective of this thesis was to evaluate the relationship between radiation dose to the heart and cardiac substructures, and acute coronary events, in female BC patients treated with radiotherapy after breast-conserving surgery. Furthermore, other variables that potentially can contribute to the development of acute coronary events, such as cardiac risk factors and chemotherapy, were investigated, which may improve the identification of BC patients at high risk of radiation-induced cardiac toxicity.
As mentioned, in 2013 a large cohort study demonstrated a dose-effect relationship based on the mean dose to the whole heart and the rate of acute coronary events.18 The main aim of chapter 2 was to validate these findings with
an independent cohort of patients with BC based on individual three-dimensional dose distributions derived from CT-planning scans. Furthermore, we wanted to investigate whether other dose-distribution parameters of the heart or its substructures could better predict the excess risk of acute coronary events after radiotherapy for individual BC patients compared with MHD.
Another important treatment-related cardiac disease of BC therapy is heart failure.4,5,6,7,8 The left ventricular ejection fraction (LVEF) by echocardiography is
the cornerstone of LV systolic function assessment in clinical practice. However it can underestimate actual cardiac damage because of the compensatory reserve of the myocardium that enables adequate ventricular outcome, even in the presence of dysfunctional myocytes. So, cardiac dysfunction can remain sub-clinical for a long time because of its gradual onset and presentation with vague symptoms. Therefore, it becomes increasingly important to assess not only clinical cardiac dysfunction, but also the sub-clinical functional effects. The global longitudinal systolic strain (GLS) is an echocardiographic technique that detects and quantifies sub-clinical and subtle disturbances in LV systolic function. In chapter 3 we assessed the relationship between radiation dose to the left ventricle and radiation dose to the coronary arteries and left ventricle
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systolic function, GLS and left ventricle diastolic function in BC survivors treated with radiotherapy.
As several studies indicate that the excess risk induced by radiotherapy depends on baseline cardiovascular risk factors, it becomes increasingly important for radiation oncologists to identify which baseline factors are important for BC patients.18,4,21,22 The amount of coronary artery calcium (CAC), as determined from
CT, is a well-established and reliable early predictor of acute coronary events in the general population. However, its predictive value in BC patients in unknown. The main objective of chapter 4 was to test if pre-treatment CAC scores, based on planning CT scans, were associated with the cumulative incidence of acute coronary events among BC patients treated with post-operative radiotherapy. If the CAC score is a reliable predictor of acute coronary events, it could be used as an important baseline cardiovascular risk factor.
Understanding the underlying mechanisms behind radiation-induced cardiac diseases is still lacking. However, some studies have highlighted the importance of the coronary arteries in the pathogenesis of radiation-induced cardiac toxicity in cancer patients, in particular the left anterior descending coronary artery (LAD).30,31 The problem of manually contouring the LAD is that it is time consuming,
susceptible to intra- and inter-observer variation and often challenging due to the lack of intravenous contrast-enhancement in planning CT scans. These problems limit large scale contouring tasks necessary for research projects. Therefore in chapter 5 we developed and evaluated an automatic segmentation tool for the LAD in non-contrast planning CT-scans based on anatomical landmarks.
Armed with the knowledge about dose-effect relationships in chapter 2, and the importance of dose to the coronary arteries in chapter 3, we wanted to understand more about a possible mechanism behind the radiation-induced acute coronary events. Darby et al. showed that particularly older patients developed acute coronary events, mainly in the first 5 to 10 years.18 As age is an
important factor in developing higher calcium scores in the coronary arteries,32
we hypothesised that radiation dose to pre-existing atherosclerotic plaques in the coronary arteries leads to subsequent inflammatory reactions and an increased risk of acute coronary events, possibly due to plaque rupture and thrombosis. With the available calcium scores in chapter 4 and the development of an auto-segmentation tool for the LAD in chapter 5, we were able to investigate this hypothesis. Therefore, in chapter 6we tested a hypothesis that radiation dose to atherosclerotic plaques is more important for the development of acute coronary events than radiation dose to the whole heart or LAD, for a cohort of BC patients treated with 3D conformal radiotherapy. The findings of this thesis are summarised and discussed in chapter 7.
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