|Year : 2017 | Volume
| Issue : 2 | Page : 186-192
Cardiotoxic effects of radiotherapy and strategies to reduce them in patients with breast cancer: An overview
Department of Family Practice, Medical University of Silesia, Katowice-Zabrze, Poland
|Date of Web Publication||23-Jun-2017|
3 Maja Street 13/15, 41-800 Zabrze
Source of Support: None, Conflict of Interest: None
Cardiotoxicity of various anticancer therapies, including radiotherapy (RT), can lead to cardiovascular (CV) complications, and their severity depends on many factors, including the site of action, the applied dose, the method of administration, the presence of pre-existing CV diseases, or CV risk factors, the individual patient characteristics, and the current or previous use of antineoplastic therapies. Cardiotoxicity can occur immediately upon administration of the anticancer therapy or it may have a delayed onset (months or years after the treatment). For an oncology treatment team, it is essential that the patients with cancer are in their best cardiac condition before they initiate anticancer therapy, during remission, and after its termination, and thus, a collaboration with cardiologists is of utmost importance. This article reviews cardiotoxicity associated with RT, focusing on patients with breast cancer. In addition, it outlines the main management strategies to assess, monitor, reduce, or possibly prevent RT-induced cardiotoxicity, based on the current research evidence. Medline literature review relating to this subject was performed, using the electronic search for the keywords “radiotherapy” and “cardiotoxicity” on PubMed for inclusion of the previous publications, and further search of reference articles on the detection and management of radiation-related heart disease in patients with breast cancer was conducted.
Keywords: Breast cancer, cardiotoxicity, cardiovascular diseases, coronary heart disease, radiotherapy
|How to cite this article:|
Rygiel K. Cardiotoxic effects of radiotherapy and strategies to reduce them in patients with breast cancer: An overview. J Can Res Ther 2017;13:186-92
| > Introduction|| |
With enormous progress that has been made in reducing the morbidity and mortality from a variety of malignancies, a large number of cancer survivors are now at a risk of both cardiac disease and cancer recurrence. The main therapeutic options for patients with cancer include a combination of surgical procedures, radiotherapy (RT), and chemotherapy (CHT). Except surgery, these anticancer treatments have several potential adverse cardiac effects. Until recently, the heart has been viewed as a radio-resistant organ that would not be affected by RT doses below 30 Gy. However, over the last decade, some new evidence has emerged, according to which, the radiation-induced heart disease (RIHD) can occur, following even lower radiation doses (e.g., mean cardiac doses of 3–17 Gy in breast cancer patients treated with RT postmastectomy). Moreover, at doses above 30 Gy, the RIHD can occur within 2 years from exposure, and its risk is magnified by a higher RT dose, younger age of patients undergoing RT, and pre-existing cardiovascular diseases (CVD) or traditional CV risk factors. At lower RT doses (below 30 Gy), the usual latency period is longer (over a decade), and symptoms are often nonspecific. The spectrum of RIHD includes coronary heart disease (CHD), pericardial disease (acute pericarditis, delayed pericarditis, pericardial effusion, and constrictive pericarditis), congestive heart failure (CHF), valvular heart disease, cardiomyopathy, and arrhythmias. For oncologists and cardiologists, who participate in the management of such patients, it is critical to limit the cardiotoxic effects of antineoplastic therapies. However, there are relatively few established clinical guidelines designed to facilitate the cardiac care of oncology patients.
This article reviews cardiotoxicity associated with RT, focusing on patients with breast cancer. It presents the current management strategies to assess, monitor, reduce, or possibly prevent RT-induced cardiotoxicity, based on recent research evidence. It also outlines the importance of close collaboration between oncologists and cardiologists that is necessary for the patient safety, improvement of clinical outcomes, and quality of life. Medline literature review relating to this subject was performed using the electronic search for the keywords “radiotherapy” and “cardiotoxicity” on PubMed for inclusion of the previous publications, and then, further search of reference articles on the prevention and management of radiation-related heart disease in patients with breast cancer was conducted. The main timeframe for this search was set from 2000 to 2015.
| > Radiation-Induced Cardiovascular Complications|| |
It has been documented that RT, used in the treatment of different malignancies, including breast cancer can cause CVD, including the pericardium, myocardium, heart valves, and CHD. Moreover, the incidence of RIHD was higher in patients, who received high doses of RT, or in those, who were treated with RT and concurrent anthracycline-based CHT. It should be highlighted that patients with pre-existing CHD have been particularly vulnerable to RT-induced cardiac damage, involving endothelial cells. Although an accurate incidence of RT-induced atherosclerosis is difficult to determine, coronary artery lesions have been documented in patients without prior CHD diagnosis or conventional CV risk factors. Vascular injury and myocardial damage from RT can be silent, and in about a half of asymptomatic patients, new myocardial perfusion defects can develop. Clinical manifestations of RIHD include symptoms such as chest pain (angina pectoris), shortness of breath (dyspnea on exertion and orthopnea), pedal edema, fatigue, and irregular heart rhythm. In addition, it has been suggested that sudden cardiac death that might occur in patients treated with RT could have been caused by hyperplasia of the intima, in all coronary arteries, or by a significant left main coronary artery stenosis.
| > Radiation-Induced Heart Disease – clinical Manifestations and Management|| |
Radiation-related pericardial, valvular, and myocardial diseases are less common today than in the past, due to modifications in RT techniques, resulting in lower radiation doses applied to the heart. CV problems that can arise from RT are presented below.
CHD from radiation-related damage has a similar vascular pathology to CHD from atherosclerosis. In both instances, ischemic heart disease can be manifested clinically as stable angina pectoris, unstable angina, myocardial infarction, or chronic ischemic heart disease. It should be emphasized that thoracic RT has now been established as a risk factor for CHD. However, RT-related CHD is usually not detected until at least 10 years postexposure, and the relative risk of CHD increases with higher RT doses, younger age at irradiation, as well as the presence of conventional risk factors for CHD. In general, RT-related CHD has been managed with pharmacotherapy, nonpharmacological (e.g., lifestyle modification such as nutrition and physical activity) approaches, control of risk factors, and revascularization procedures, including percutaneous coronary interventions, or coronary artery bypass grafting (CABG), according to the indications from a specialistic cardiology–cardiosurgery team. It should be noted that any cardiosurgical procedure can be technically challenging because of a possible mediastinal scarring and frail blood vessels (e.g., the left internal mammary artery). Moreover, it has been reported that in cases, in which previously irradiated internal mammary arteries were selected as conduits for CABG, a postprocedure restenosis rate was increased.
Radiation-related pericarditis is characterized by an exudate (pericardial effusion) containing protein-rich fluid within the pericardial sac. Rapid accumulation of this fluid can cause potentially life-threatening cardiac tamponade. In addition, accumulation of fibrin on the mesothelial lining of the epicardium or the parietal pericardium can lead to pericardial fibrosis, consisting of collagen deposition, which replaces the peripheral adipose layer and increases the thickness of the fibrous layer. This in consequence results in a rigid pericardial sac that can cause constriction, often accompanied by effusion.
Although acute pericarditis is now rarely diagnosed, some patients can still present with symptoms of pleuritic chest pain, tachycardia, fever, pericardial rub, and with characteristic electrocardiographic (ECG) abnormalities, within a few weeks after cardiac irradiation. These signs and symptoms are transient, and they usually resolve upon treatment with nonsteroidal anti-inflammatory medications. Only a small number of patients develop chronic pericarditis, up to 10 years post-RT, and the disease incidence is related to the volume of irradiated pericardium, acute phase of the effusion, and the RT dose. The severity varies from asymptomatic pericardial thickening to cardiac tamponade that requires pericardiocentesis. In case of recurrent effusion, a subtotal pericardiectomy to prevent the development of severe constrictive pericarditis has been recommended.
Myocardial fibrosis consists of a proliferation of collagen bands, separating and replacing myocytes, in the anterior wall of the left ventricle (LV). This can, in some cases, lead to cardiac ischemia, and at times to CHF. Radiation-related myocardial fibrosis often remains asymptomatic, and can be discovered incidentally on echocardiography (ECHO), over 10 years after RT. Clinically significant ventricular dysfunction leading to cardiomyopathy is uncommon; however, it can occur, especially in the context of the combination of high doses of RT (above 30 Gy) applied to large volumes of the heart, especially with the concurrent use of anthracycline-based CHT. The management of radiation-related cardiomyopathy is consistent with the current cardiology guidelines for the therapy of heart failure.
Valvular heart disease associated with RT has been related with mediastinal radiation doses above 30 Gy, younger age at irradiation, and with a latency period of over 20 years. Aortic valve disease usually consists of mixed stenosis and regurgitation and it is more common than mitral and right-sided valvular diseases. These valvular lesions are characterized by fibrosis and calcification.,
In addition to these cardiac abnormalities induced by RT, a plethora of arrhythmias and conduction blocks has been observed, as well as some autonomic nervous system dysfunctions, including a persistent nonvariable tachycardia. Moreover, RT-induced carotid artery disease can contribute to atherosclerotic lesions, which are more extensive than the ones that are typical for carotid bifurcation stenosis. The RT-induced atherosclerotic plaques are often located in long segments of the carotid artery, posing an increased risk for stroke.
| > Radiation-Induced Heart Disease in Patients With Breast Cancer – insights from the Past Clinical Trials|| |
Breast cancer represents the most common cancer in women worldwide (with the overall 5-year survival rate of 90%), and for many of them, RT has been used. In breast cancer, majority of the data relevant to the effect of RT on CVD has been derived from a long-term follow-up of women enrolled into trials, in which all patients received similar treatment in terms of surgery and CHT, and then half of them were randomized to receive adjuvant RT. A meta-analysis from 1987, of randomized clinical trials of postoperative adjuvant RT in breast cancer, revealed that survival beyond 10 years was significantly worse in patients receiving RT. However, it was still not possible to determine which factors were predominantly responsible for this negative impact on survival. According to the results of a meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), published in 2005, it was shown that the mortality from heart disease was increased by 27% in the patients randomized to surgery plus RT compared with the patients randomized to surgery alone. Certain aspects of the RT techniques, used in the earlier trials, which particularly contributed to the increased cardiac mortality included a field placement near the heart (e.g., anterior fields used to treat the internal mammary nodes), orthovoltage radiation (delivery of high doses of RT to the anterior part of the heart), large daily fractions, and high total RT doses.
| > Cardiac Risk in Women After Radiotherapy for Breast Cancer – current Research Evidence and Practical Implications|| |
A meta-analysis conducted by the EBCTCG, published in 2011, which involved 10,801 women, participating in 17 randomized trials, revealed that RT for early-stage breast cancer can reduce the rates of recurrence and death from breast cancer. However, long-term follow ups in some trials have shown that RT can also increase the risk of morbidity and mortality from CHD, probably due to incidental irradiation of the heart. Unquestionably, the RT regimens for breast cancer have been changed, since the patients participating in the earlier trials were irradiated, and also, the RT doses to which the heart has been exposed are now lower. Nevertheless, in the majority of women, the mean RT doses, used for breast cancer, which are delivered to the heart are usually 1–2 Gy for the right breast disease and they are higher and more variable (the mean dose of 10 Gy) for the left breast disease. To explore the risk of CHD after RT, in relation to every individual patient's radiation dose to the heart and to each of the CV risk factors which were present during the RT, a population-based study was carried out, involving 2168 women with breast cancer exposed to the radiation dose to the heart in the range of 0.03–27.72 Gy (the mean dose of 4.9 Gy). According to this study results, the risk of major coronary events (confirmed by cardiology tests or autopsy records) was linearly increasing with the mean radiation dose to the heart. The magnitude of the CV risk was 7.4% per Gy, with no apparent threshold, below which there was no risk. Moreover, the risk started to increase within the first 5 years after the exposure and persisted for at least 20 years. In addition, the percentage increase in this risk per Gy was similar for women with and without CV risk factors at the time of RT. It should be highlighted that the absolute increases in CV risk, for a given radiation dose to the heart, were larger for women with pre-existing CV risk factors. Therefore, practical implications from this study should be to consider the estimated cardiac dose of radiation and CV risk factors, together with the specific doses of antitumor RT in the process of decision making and in the management of patients with breast cancer.
| > Differences in Cardiovascular Diseases among Patients Receiving Radiotherapy for Cancer of the Left Versus Right Breast|| |
In breast cancer, certain adverse consequences of RT on CVD can be addressed by comparing the cardiac conditions, among the women who received RT for cancer of the left versus right breast., Such a comparison between the women with left-sided tumors (who were usually treated with larger RT doses than the women with right-sided tumors) has revealed that the cardiac radiation doses in patients with left-sided tumors were higher than in those with right-sided tumors. Consequently, it has been reported that the RT might contribute to the increased mortality from CVD (occurring over 10 years after RT) among the patients with left-sided versus right-sided breast cancer. In contrast, among the breast cancer patients, who were not treated with RT, the subsequent risk of CVD was independent of the tumor laterality. Another study examining the incidence of CHD, following breast irradiation, has revealed a higher prevalence of exercise stress test abnormalities in patients with left-sided comparing to the ones with right-sided tumor location. In addition, among women with left-sided cancers, the CHD territorial distribution differed from the one that has typically been present in female patients. In particular, in this trial, a preponderance of the left anterior descending artery (LAD) disease has been revealed. It should be highlighted that the anterior part of the heart and the LAD territory represent the areas of the heart which are most often located within the tangential radiation fields used for breast cancer treatment. These results support the RT impact on the development of CHD, among females treated for breast cancer. In practical terms, a vigilant attitude and regular monitoring of the CV status in this patient population are crucial for the oncology treatment team in collaboration with the cardiology specialists.
| > Prevention of Cardiac Complications of Radiotherapy in Patients With Breast Cancer|| |
It should be emphasized that every attempt should be made to make the cardiac exposure to radiation as low as possible. At present, cardiac doses delivered by the modern RT techniques for breast cancer treatment are lower than those delivered in the past, and thus, the CV risk has also been reduced. Nevertheless, RT-induced cardiac complications still exist and have various significance depending on the particular clinical scenario and CV risk factors of each patient.
To assist clinicians in providing safe, comprehensive care to breast cancer patients, the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) provides updated summary reviews, including dose, volume, outcome data, and expert opinion with regard to limiting the toxicity risk for particular organs, including the heart., According to the QUANTEC data, it is recommended that no more than 5% of the whole heart exceeds 20 Gy for the left-sided breast cancers and 0% of the heart exceeds 20 Gy for the right-sided breast cancers. Similarly, no more than 30% of the whole heart exceeds 10 Gy for the left-sided breast cancers and no more than 10% of the heart exceeds 10 Gy for the right-sided breast cancers. In addition, the mean heart dose should not exceed 4 Gy. Moreover, the normal tissue complication probability (NTCP) model-based estimates predict that a V 25 Gy below 10% (in 2 Gy per fraction) is associated with <1% probability of cardiac mortality 15 years after RT.
It is important to keep in mind that the dose-volume constraints and NTCP parameters should be used mostly for guidance, and the best clinical judgment of a cardio-oncology treatment team should be applied for each patient case.
One of the key issues regarding intensity-modulated RT (IMRT) and three-dimensional (3D) conformal radiation therapy (3DCRT) for breast cancer is the accurate definition of target volumes. Conventional RT techniques have been based on physical examination (palpation) of breast tissue and anatomical landmarks of the chest wall. In contrast, current IMRT and 3DCRT require a volume-based target to create conformal dose distribution. At present, RT techniques usually include 3D treatment planning with dose-volume histogram (DVH) for accurate heart volume and dose calculation. In particular, IMRT requires standardized benchmarks for the assessment of DVHs for coverage of the targeted CT breast volumes and exclusion of normal structure volumes (e.g., heart). Since it is necessary to precisely define the location of boundaries in the breast tissue and lymph nodes, a consensus committee within the Radiation Therapy Oncology Group (RTOG) has developed guidelines (the RTOG breast atlas) for the definition of clinical target volumes and normal structures on CT for RT planning.
It should be highlighted that long-term follow-up of the Standardisation of Breast RT (START) trials confirmed that the appropriately dosed hypofractionated RT is safe and effective for patients with early breast cancer. In particular, the results of START revealed that although follow-up was still short for CV events, there was no major difference between the schedules for the number of cases of CVD in patients with the left-sided primary tumors. Moreover, some research suggests that hypofractionated breast RT might be safer for the heart than that of conventional regimens.
One of the state-of-the-art RT treatment trials, addressing cardiac safety issues, is the current Phase III trial of accelerated whole breast (WB) irradiation (WBI) with hypofractionation plus concurrent boost versus standard WB irradiation plus sequential boost for early-stage breast cancer (NRG 1005), involving 2312 women. The primary objectives of the NRG 1005 trial are to determine whether an accelerated course of hypofractionated WBI will prove to be noninferior in local control to a regimen of standard WBI (with a sequential boost following lumpectomy) for early-stage breast cancer patients. Importantly, the secondary goal of this study is to determine whether the risk of late cardiac toxicity in patients with left-sided breast cancer treated with hypofractionation will be noninferior to conventional fractionated RT. In addition, the NRG 1005 study will determine whether CT-based conformal methods, IMRT, and 3DCRT for WBI are feasible in a multi-institutional setting and whether dose-volume analyses can be established to assess treatment adequacy and the likelihood of toxicity. In the NRG 1005 trial, the treatment plans use forward planning methods or segmental techniques such as “field-in-field,” to meet dose-volume constraints and to improve the uniformity of the dose distribution. Although many of the presented initial findings are reassuring, the heart needs to be protected, irrespective of the dose fractionation regimen used.
| > Strategies to Reduce Cardiac Toxicity in Patients With Breast Cancer Treated by Radiotherapy|| |
In patients with breast cancer, the irradiated heart volume should be minimized (as outlined in the preceding text), without compromising the target coverage. This is very challenging, and the main techniques employed to minimize radiation exposure include cardiac shielding (with lead blocks), reduced fraction size (below 2 Gy/day), reduced total dose of radiation (below 30 Gy/day), using alteration in RT field or targeted radiation, as well as IMRT and 3DCRT. It should be pointed out that the use of a four-field IMRT technique can offer better sparing than the partial shielding technique, since the maximum heart depth is increased. It has been proposed that the maximum heart distance (e.g., the maximal distance between anterior cardiac contour and posterior tangential field edges) is a reliable predictor of the mean heart dose in the left-tangential breast or chest wall irradiation. Furthermore, a recent Phase III randomized trial of accelerated partial breast (PB) irradiation (APBI) with multi-catheter brachytherapy versus WBI including over 1000 women, has revealed that at 5-year follow-up, the cumulative incidence of local recurrence, disease-free survival, and overall survival was not significantly different from APBI compared with WBI. Importantly, patients in the APBI arm had reduced cardiac exposure to RT and a shorter treatment schedule. This study has implications for clinical practice, and the possible candidates for APBI would be women over 50 years of age, with invasive ductal carcinoma or ductal carcinoma in situ, small lesions (diameter <3 cm), negative surgical margins, negative sentinel lymph node, and no preoperative CHT. Convergently, the intensity-modulated partial organ RT (IMPORT LOW) is a multi-center, randomized, quality assurance trial that examines whether PB RT in women with low risk for early stage breast cancer is effective, but less damaging than WB RT. The aims of the IMPORT LOW study are to collect and analyze RT treatment plans from various trial centers and to ensure the compliance with the trial protocol. According to the IMPORT LOW protocol, the tumor bed should be localized with surgical clips and CT, and the dose distribution across the target volume should be modified with 3D dose compensation to ensure a dose homogeneity within the International Commission on Radiation Units and Measurements guidelines (from −5% to +7%). The interim analysis of the IMPORT LOW plans has demonstrated that all tumor bed localization methods produced similar PB field lengths and all participating centers were able to achieve dose homogeneity. These reports are encouraging in terms of possible implications into clinical practice.
To further decrease cardiac toxicity among patients with breast cancer treated by RT, it is important to focus on the risk factors for RIHD, in an attempt to modify some of them, whenever possible. The main risk factors for RIHD include RT dose above 30–35 Gy, dose per fraction above 2 Gy, relative field weighting (anterior/posterior positioning), technique (reduced with CT plan), type of radiation source (cobalt), large volume of irradiated heart, presence of tumor next to the heart, younger age at exposure, longer time since exposure, use of cytotoxic CHT (e.g., anthracyclines), endocrine therapy or trastuzumab, and the presence of traditional CV risk factors., In particular, some cardiometabolic risk factors such as diabetes mellitus, arterial hypertension, dyslipidemia, and obesity can be, to some degree, modified with pharmacotherapy and nonpharmacological approaches (e.g., proper nutrition and regular physical activity). It is estimated that RIHD occurs in 10–30% of the patients who receive chest RT, within 5–10 years after the treatment.,, Usually, cardiac structural and functional changes after RT can be detected early, by using ECHO, cardiac computed tomography (CCT), cardiac magnetic resonance (CMR), and radionuclide cardiac tests. To improve the safety of patients with breast cancer, the European Association of Cardiovascular Imaging of the European Society of Cardiology and the American Society of Echocardiography expert group have recommended that:
- Before starting a chest RT, patients should undergo screening for RIHD risk factors, a thorough clinical examination, and a baseline ECHO evaluation
- Patients receiving chest RT for breast cancer should undergo cardiac screening 5 years post-treatment (if they have any cardiac abnormality or are at a high CV risk) or 10 years post-treatment (if they are at a low CV risk)
- CV screening should be repeated for every 5–10 years, depending on the presence of cardiac abnormalities and the level of CV risk
- All patients who had chest RT for cancer in the past should receive a cardiac examination, including ECHO.,
ECHO is the first line of imaging assessment, and in some patients, additional examinations including stress ECHO, CCT, and CMR may be needed (e.g., myocardial fibrosis can be more precisely assessed by using CMR and coronary artery calcification can be more accurately evaluated by using CCT). It should be emphasized that noninvasive imaging for the detection of CVD such as CT coronary angiography is helpful in the stratification of patients with an intermediate CV risk into a low- or high-risk category. This, in turn, facilitates an effective management of patients with the highest CV risk. In addition, prior to the consideration of open heart surgery (e.g., CABG), obtaining a chest CT is useful for the assessment of possible mediastinal fibrosis. Moreover, a further registry of RIHD might help determine the prevalence of RIHD and long-term patient outcomes. In this way, a combination of screening, as a preventive measure, with regular monitoring should decrease the rate of developing RIHD in breast cancer patients, and must ensure introduction of an early cardiology treatment, when required., According to the European Society for Medical Oncology Clinical Practice Guidelines, in addition to a detailed physical examination, medical interview, routine blood work (e.g., CBC, renal and liver panel), and ECG, the baseline work-up for such patients should include:
- Lipid profile, exercise stress test, ECHO, or coronary angiography in case of CHD
- ECHO and chest X-ray in case of pericarditis
- ECHO and radioisotopic angiography in case of cardiomyopathy
- 24-h Holter monitoring in case of arrhythmias
- ECHO and cardiac catheterization in case of valvular diseases.,
In summary, RT-induced cardiac risk is lifelong, and thus, it requires a long-term follow-up. Many of the RIHD complications can be evaluated noninvasively (by using combined rest and stress ECHO), allowing the clinician to assess LV systolic and diastolic function, valvular function, pericardial integrity, and regional cardiac wall abnormalities.
In fact, screening and monitoring of CV status, among patients with cancer, is similar to the standard tests and procedures that are used by cardiologists for patients with CV risk factors or CVD. A careful consideration of each patient's specific clinical situation and quality of life is always necessary.
| > Further Research Directions Relevant to Radiotherapy and Cardiovascular Risk among Patients With Cancer|| |
There are some unanswered questions concerning specific cardiac structures and their sensitivity to the RT damage, as well as a possible threshold dose of radiation to the heart, below which there is no risk of damage. Furthermore, some relevant issues that merit exploration include the extent to which CV risk can be altered by various factors such as irradiation of other organs (e.g., kidneys), pre-existing CVD or cardiometabolic comorbidities (e.g., diabetes mellitus, dyslipidemia), lifestyle factors (e.g., tobacco smoking, alcohol abuse, physical inactivity, and poor nutrition), and adverse effects or interactions of certain chemotherapeutics, often used in combination with RT during cancer treatment. In particular, it is expected that the CardioRisk project will shed some light on these topics to help with the future implementation of strategies that might reduce the CV risk in patients receiving RT. Furthermore, a large scale (over 1 million women) multinational study of cause-specific mortality after the left-sided versus right-sided breast cancer irradiation (the Collaborative Group on Observational Studies of Breast Cancer Survivors [COBS]) will investigate the specific patterns of risk from RIHD among breast cancer survivors. In the near future, for a growing population of patients with cancer, some additional valuable information relevant to their CV morbidity and to some possible modifying effects of pre-existing CVD and traditional CV risk factors (e.g., diabetes mellitus, arterial hypertension, and dyslipidemia) will be available from both COBS and radiation-associated cardiac event (RACE) datasets., It should be pointed out that the retrospective RT dose estimates, which are less accurate than the analyses from the prospective trials (including the individual 3D treatment plans) should be interpreted with caution. However, the RACE database can still provide a wide dose-response relationship for RIHD (for doses in the range from 1 to 20 Gy), as well as useful information on the combined cardiotoxicity of RT and some commonly used chemotherapeutics, including anthracyclines, taxanes, and trastuzumab.
| > Conclusion|| |
The purpose of this review is to summarize the cardiotoxic effects associated with RT in patients with breast cancer and to outline the main management strategies to assess, monitor, reduce, or possibly prevent RT-induced cardiotoxicity.
This article emphasizes that in the oncology patients, RT-induced cardiotoxicity should be minimized by using modern RT procedures, as well as considering the estimated cardiac doses of radiation, together with the antitumor RT doses, and the patient CV risk factors in the process of therapeutic decision making. This overview also highlights that the regular, long-term follow-up of such patients, by closely cooperating and vigilant teams of oncology and cardiology specialists, is essential for the improvement of the patient outcomes. Such efforts should provide a basis for future clinical practice guidelines to decrease the negative impact of RIHD on patient survival.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Schultz PN, Beck ML, Stava C, Vassilopoulou-Sellin R. Health profiles in 5836 long-term cancer survivors. Int J Cancer 2003;104:488-95.
Darby SC, Cutter DJ, Boerma M, Constine LS, Fajardo LF, Kodama K, et al.
Radiation-related heart disease: Current knowledge and future prospects. Int J Radiat Oncol Biol Phys 2010;76:656-65.
Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: Prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol 2005;6:557-65.
Veinot JP, Edwards WD. Pathology of radiation-induced heart disease: A surgical and autopsy study of 27 cases. Hum Pathol 1996;27:766-73.
Basavaraju SR, Easterly CE. Pathophysiological effects of radiation on atherosclerosis development and progression, and the incidence of cardiovascular complications. Med Phys 2002;29:2391-403.
Paris F, Fuks Z, Kang A, Capodieci P, Juan G, Ehleiter D, et al.
Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 2001;293:293-7.
Orzan F, Brusca A, Conte MR, Presbitero P, Figliomeni MC. Severe coronary artery disease after radiation therapy of the chest and mediastinum: Clinical presentation and treatment. Br Heart J 1993;69:496-500.
Gyenes G, Fornander T, Carlens P, Glas U, Rutqvist LE. Detection of radiation-induced myocardial damage by technetium-99m sestamibi scintigraphy. Eur J Nucl Med 1997;24:286-92.
Jaworski C, Mariani JA, Wheeler G, Kaye DM. Cardiac complications of thoracic irradiation. J Am Coll Cardiol 2013;61:2319-28.
Fajardo LF. The pathology of ionizing radiation as defined by morphologic patterns. Keynote lecture, 5th
Nordic Conference on Radiation Oncology, Bergen, Norway. Acta Oncol 2005;44:13-22.
Stewart FA, Seemann I, Hoving S, Russell NS. Understanding radiation-induced cardiovascular damage and strategies for intervention. Clin Oncol (R Coll Radiol) 2013;25:617-24.
Brown ML, Schaff HV, Sundt TM. Conduit choice for coronary artery bypass grafting after mediastinal radiation. J Thorac Cardiovasc Surg 2008;136:1167-71.
Clare GC, Troughton RW. Management of constrictive pericarditis in the 21st
century. Curr Treat Options Cardiovasc Med 2007;9:436-42.
Heidenreich PA, Hancock SL, Lee BK, Mariscal CS, Schnittger I. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol 2003;42:743-9.
Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. JAMA 2003;290:2831-7.
Mertens AC, Liu Q, Neglia JP, Wasilewski K, Leisenring W, Armstrong GT, et al.
Cause-specific late mortality among 5-year survivors of childhood cancer: The childhood cancer survivor study. J Natl Cancer Inst 2008;100:1368-79.
Martinou M, Gaya A. Cardiac complications after radical radiotherapy. Semin Oncol 2013;40:178-85.
Adams MJ, Lipsitz SR, Colan SD, Tarbell NJ, Treves ST, Diller L, et al.
Cardiovascular status in long-term survivors of Hodgkin's disease treated with chest radiotherapy. J Clin Oncol 2004;22:3139-48.
Cheng SW, Ting AC, Lam LK, Wei WI. Carotid stenosis after radiotherapy for nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg 2000;126:517-21.
Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Altekruse SF, et al
. SEER Cancer Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD. Availlable from: http://seer.cancer.gov/csr/1975_2013/
. [Last accessed on 2016 Apr 02].
Cuzick J, Stewart H, Peto R, Baum M, Fisher B, Host H, et al.
Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer. Cancer Treat Rep 1987;71:15-29.
Early Breast Cancer Trialists' Collaborative Group. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and on 15-year survival: An overview of the randomised trials. Lancet 2005;366:2087-106.
Taylor CW, Nisbet A, McGale P, Darby SC. Cardiac exposures in breast cancer radiotherapy: 1950s-1990s. Int J Radiat Oncol Biol Phys 2007;69:1484-95.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Darby S, McGale P, Correa C, Taylor C, Arriagada R, et al.
Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011;378:1707-16.
Cuzick J, Stewart H, Rutqvist L, Houghton J, Edwards R, Redmond C, et al.
Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 1994;12:447-53.
Schubert LK, Gondi V, Sengbusch E, Westerly DC, Soisson ET, Paliwal BR, et al.
Dosimetric comparison of left-sided whole breast irradiation with 3DCRT, forward-planned IMRT, inverse-planned IMRT, helical tomotherapy, and topotherapy. Radiother Oncol 2011;100:241-6.
Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Brønnum D, et al.
Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 2013;368:987-98.
Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: Incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 2009;53:2231-47.
Bouillon K, Haddy N, Delaloge S, Garbay JR, Garsi JP, Brindel P, et al.
Long-term cardiovascular mortality after radiotherapy for breast cancer. J Am Coll Cardiol 2011;57:445-52.
Correa CR, Litt HI, Hwang WT, Ferrari VA, Solin LJ, Harris EE. Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer. J Clin Oncol 2007;25:3031-7.
Taylor CW, Povall JM, McGale P, Nisbet A, Dodwell D, Smith JT, et al.
Cardiac dose from tangential breast cancer radiotherapy in the year 2006. Int J Radiat Oncol Biol Phys 2008;72:501-7.
Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, et al.
Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109-22.
Gagliardi G, Constine LS, Moiseenko V, Correa C, Pierce LJ, Allen AM, et al.
Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys 2010;76 3 Suppl:S77-85.
Li XA, Tai A, Arthur DW, Buchholz TA, Macdonald S, Marks LB, et al.
Variability of target and normal structure delineation for breast cancer radiotherapy: An RTOG multi-institutional and multiobserver study. Int J Radiat Oncol Biol Phys 2009;73:944-51.
Haviland JS, Owen JR, Dewar JA, Agrawal RK, Barrett J, Barrett-Lee PJ, et al.
The UK standardisation of breast radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol 2013;14:1086-94.
Appelt AL, Vogelius IR, Bentzen SM. Modern hypofractionation schedules for tangential whole breast irradiation decrease the fraction size-corrected dose to the heart. Clin Oncol (R Coll Radiol) 2013;25:147-52.
A Phase III Trial of Accelerated Whole Breast Irradiation with Hypofractionation Plus Concurrent Boost Versus Standard Whole Breast Irradiation Plus Sequential Boost For Early-Stage Breast Cancer (NRG ONCOLOGY RTOG 1005). Available from: https://www.ctsu.org
. [Last accessed on 2016 Mar 16].
Bovelli D, Plataniotis G, Roila F; ESMO Guidelines Working Group. Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO Clinical Practice Guidelines. Ann Oncol 2010;21 Suppl 5:v277-82.
Strnad V, Ott OJ, Hildebrandt G, Kauer-Dorner D, Knauerhase H, Major T, et al.
5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ
carcinoma of the female breast: A randomised, phase 3, non-inferiority trial. Lancet 2016;387:229-38.
Ciurlionis L, Tsang Y, Titley J, Coles CE, Yarnold J, Bliss J, Behalf of the Import Trial Management Group. Interim Analysis of Treatment Plans in the Import Low Trial. Liverpool: NCRI National Cancer Conference; 2010.
Groarke JD, Nguyen PL, Nohria A, Ferrari R, Cheng S, Moslehi J. Cardiovascular complications of radiation therapy for thoracic malignancies: The role for non-invasive imaging for detection of cardiovascular disease. Eur Heart J 2014;35:612-23.
Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: A report from the European association of cardiovascular imaging and the American Society of echocardiography. Eur Heart J Cardiovasc Imaging 2013;14:721-40.
Cardiorisk. The Mechanism of Cardiovascular Risks after Low Radiation Doses. Available from: http://www.cardiorisk.eu/
. [Last accessed on 2016 Mar 16].
RACE Radiation Associated Cardiac Events. Available from: http://www.race.ki.se/
. [Last accessed on 2016 Mar 16].
|This article has been cited by|
||Risk Factors of Fluoropyrimidine Induced Cardiotoxicity among Cancer Patients: A Systematic Review and Meta-analysis
| ||Chao Li, Surachat Ngorsuraches, Chiahung Chou, Li Chen, Jingjing Qian |
| ||Critical Reviews in Oncology/Hematology. 2021; 162: 103346 |
|[Pubmed] | [DOI]|
||Cardiac computed tomography in cardio-oncology: an update on recent clinical applications
| ||Stefania Rosmini, Ankita Aggarwal, Daniel H Chen, John Conibear, Ceri L Davies, Amit Kumar Dey, Paula Edwards, Avirup Guha, Arjun K Ghosh |
| ||European Heart Journal - Cardiovascular Imaging. 2021; 22(4): 397 |
|[Pubmed] | [DOI]|
||Breast Radiotherapy-Related Cardiotoxicity. When, How, Why. Risk Prevention and Control Strategies
| ||Ana Díaz-Gavela, Lourdes Figueiras-Graillet, Ángel Luis, Juliana Salas Segura, Raquel Ciérvide, Elia del Cerro Peñalver, Felipe Couñago, Meritxell Arenas, Teresa López-Fernández |
| ||Cancers. 2021; 13(7): 1712 |
|[Pubmed] | [DOI]|
||High Density Lipoprotein and Its Precursor Protein Apolipoprotein A1 as Potential Therapeutics to Prevent Anthracycline Associated Cardiotoxicity
| ||George E. G. Kluck, Kristina K. Durham, Jeong-Ah Yoo, Bernardo L. Trigatti |
| ||Frontiers in Cardiovascular Medicine. 2020; 7 |
|[Pubmed] | [DOI]|
||Radiation metabolomics in the quest of cardiotoxicity biomarkers: the review
| ||Michalina Gramatyka, Maria Sokól |
| ||International Journal of Radiation Biology. 2020; 96(3): 349 |
|[Pubmed] | [DOI]|
||Protective effect of N-acetyl cysteine against radiotherapy-induced cardiac damage
| ||Songul Barlaz Us, Ozden Vezir, Metin Yildirim, Gülsen Bayrak, Serap Yalin, Ebru Balli, Ali Erdinç Yalin, Ülkü Çömelekoglu |
| ||International Journal of Radiation Biology. 2020; 96(5): 661 |
|[Pubmed] | [DOI]|
||Clinical Evaluation and Management of Cancer Survivors with Radiation Fibrosis Syndrome
| ||Tanya DiFrancesco, Ashish Khanna, Michael D. Stubblefield |
| ||Seminars in Oncology Nursing. 2020; 36(1): 150982 |
|[Pubmed] | [DOI]|
||Is 5 mm breath-hold window (BHW) sufficient to treat carcinoma left breast patients post-conservative surgery: a comparative study using forward intensity-modulated radiotherapy (FIMRT) and volumetric modulated arc therapy (VMAT)
| ||Karthikeyan Kalyanasundaram, Subramani Vellaiyan |
| ||Journal of Radiotherapy in Practice. 2020; : 1 |
|[Pubmed] | [DOI]|
||Characterization of the adenosinergic system in a zebrafish embryo radiotherapy model
| ||Fernanda Fernandes Cruz, Talita Carneiro Brandão Pereira, Stefani Altenhofen, Kesiane Mayra da Costa, Maurício Reis Bogo, Carla Denise Bonan, Fernanda Bueno Morrone |
| ||Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology. 2019; 224: 108572 |
|[Pubmed] | [DOI]|
|| The N-terminal polypeptide derived from vMIP-II exerts its anti-tumor activity in human breast cancer by regulating lncRNA SPRY4-IT1
| ||Haihua Wu, Yueyue Wang, Tiantian Chen, Yu Li, Haifeng Wang, Lingyu Zhang, Sulian Chen, Wenrui Wang, Qingling Yang, Changjie Chen |
| ||Bioscience Reports. 2018; 38(5) |
|[Pubmed] | [DOI]|