|Year : 2015 | Volume
| Issue : 1 | Page : 8-13
Radiation induced cardiotoxicity in left sided breast cancer - Where do we stand?
Pamela Alice Kingsley, Preety Negi
Department of Radiation Oncology, Christian Medical College and Hospital, Ludhiana, Punjab, India
|Date of Web Publication||14-Jan-2015|
Dr. Pamela Alice Kingsley
Department of Radiation Oncology, Christian Medical College and Hospital, Ludhiana - 141 008, Punjab
Source of Support: None, Conflict of Interest: None
Breast cancer is the commonest cancer in women, with around a million new cases diagnosed each year worldwide. Adjuvant radiotherapy (RT) is an important component of therapy for many women with early-stage breast cancer. With improving survival rates following breast cancer, patients are increasingly likely to die of other causes. As a result, long-term adverse effects of treatment are of major concern. To determine which treatment is optimal, clinician need to be aware of long-term risks and benefits of adjuvant therapies. An awareness of the potential cardiotoxicity of RT led to the application of improved RT techniques that minimize the irradiation to the heart. Although new techniques, including intensity-modulated RT combined with free breathing gating and helical tomotherapy may further reduce radiation-induced cardiac toxicities, the most important factors in limiting cardiac radiation are associated with the techniques used and the skill of the radiation oncologist.
Keywords: Breast cancer, cardiotoxicity, radiation
|How to cite this article:|
Kingsley PA, Negi P. Radiation induced cardiotoxicity in left sided breast cancer - Where do we stand?. CHRISMED J Health Res 2015;2:8-13
|How to cite this URL:|
Kingsley PA, Negi P. Radiation induced cardiotoxicity in left sided breast cancer - Where do we stand?. CHRISMED J Health Res [serial online] 2015 [cited 2020 Jan 29];2:8-13. Available from: http://www.cjhr.org/text.asp?2015/2/1/8/149338
| Introduction|| |
Cardiovascular diseases and cancer are the two leading causes of morbidity and mortality worldwide.  Over the last ½ century, radiation therapy has evolved to become one of the cornerstones of treatment of various types of cancers. It is estimated that >50% of patients with cancer are treated with radiotherapy (RT). Along with the development of novel chemotherapeutic agents, radiation therapy has revolutionized the prognosis of patients with various cancers. 
Breast cancer is the commonest cancer in women, with around a million new cases diagnosed each year worldwide. One in every eight American women will suffer from breast cancer during their lifetime.  In India, breast cancer is the most common cancer with an estimated 145,000 new diagnosis and the second most common cause of cancer-related death with approximately, 70,000 breast cancer deaths.  Adjuvant RT is an important component of therapy for many women with early-stage breast cancer. The addition of RT to the care of women treated with breast-conserving surgery produces outcome equivalent to those seen in women treated with mastectomy and allows the patient to retain her breast.  RT after mastectomy also decreases the risk of local recurrence and may improve overall survival.  Five year survival is ~80% in many countries, and there are now millions of breast cancer survivors. Various trials have also shown that RT can reduce 15-year overall mortality following breast conservation surgery and following mastectomy in node positive disease,  but much uncertainty still remains regarding the long term overall effect from modern breast cancer RT.
With improving survival rates following breast cancer, patients are increasingly likely to die of other causes. As a result, long-term adverse effects of treatment are of major concern.  Cardiovascular disease is particularly important as it represents the main cause of death among women in developed countries. Therapies that might increase the risk of cardiovascular disease can, therefore, cause more harm than good. To determine which treatment is optimal, clinician need to be aware of long-term risks and benefits of adjuvant therapies. 
An increasing body of evidence has suggested that the so-called older RT techniques can increase the rate of cardiovascular deaths, often largely negating the reduction in cancer-related deaths afforded by RT. These excess cardiovascular deaths appear mainly due to the incidental irradiation of large volumes of the heart to relatively high doses, such as was common with the techniques and beam qualities of previous radiation eras. Very large studies are combining tumor registry data with preexisting regional and national hospital discharge, diagnosis and death records and the Oxford meta-analysis of randomized trials found increased risk of coronary heart disease for irradiated patients compared with nonirradiated ones, or for patients treated with left breast or chest wall compared to those treated to the right side. 
Cardiac irradiation can result in significant pathological damage to the heart as manifested by diffuse myocardial interstitial fibrosis, microcirculatory damage leading to ischemia and fibrosis, fibrous thickening of the pericardium, valvular fibrosis and accelerated atherosclerosis. These pathological changes can produce multiple clinical complications including coronary artery disease, pericarditis, cardiomyopathy, valvular heart disease and conduction disturbances. 
Risk factors for radiation associated heart disease include: Dose >30-35 Gy, dose/fraction more than 2 Gy, large volume of irradiated heart, younger age at exposure, longer time since exposure, use of cytotoxic chemotherapy, endocrine therapy or trastuzumab, presence of other risk factors like diabetes, hypertension, dyslipidemias, obesity and smoking, etc. 
In a meta-analysis of randomized trials that included almost 8000 women, Cuzick et al., found 62% increase in cardiac deaths in women, who received radiation.  Similarly the Early breast Cancer Trialists' Collaborative Group (EBCTCG), meta-analysis of approximately, 20,000 women who were enrolled in 40 randomized trials of RT found a 30% increase in vascular mortality, although the analysis also documented a statistically significant reduction in breast cancer mortality. 
In the British Cancer Research Campaign trial, the relative risk (RR) for cardiac death after 5 years associated with radiation was 1.65 (95% confidence interval [CI] = 1.05-2.59). The RR for patients with left sided tumors was substantially higher (2.26) than for patients with right sided tumors (1.20). Also, the RR associated with orthovoltage radiation appeared to be higher (2.26) than with megavoltage techniques (1.27). 
In 1990, Rutqvist and Johansson conducted a study on the mortality by laterality of the primary tumor among 55,000 breast cancer patients from the Swedish Cancer Registry which confirmed the previous reports suggesting that RT for breast cancer can cause myocardial infarction. Under the assumption, that only half of these patients received RT; the RR for cardiac death can be estimated as 1.2. Similar estimates for different periods of follow-up were 1.1 (0-5 years), 1.3 (5-10 years), 1.4 (10-17 years). 
In an overview of randomized trials, long-term irradiated breast cancer survivors with left sided tumors had a 34% increased risk of death from cardiovascular causes compared to right sided tumors. 
Data from the Surveillance, Epidemiology and End Results-Medicare database, were used for women who were diagnosed with nonmetastatic breast cancer from 1986 to 1993. All the patients included in this study had known disease laterality, underwent breast surgery and received adjuvant RT. This study comprised of 8363 left sided breast cancer and 7,907 right sided breast cancer. Mean follow-up was 9.5 years (range 0-15 years). With up to 15 years follow-up there was no significant difference in cardiac morbidity after radiation for left versus right sided breast cancer. 
A prospective cohort study of about 300,000 women in US surveillance, epidemiology, and end results (SEER) cancer registries to evaluate the long-term mortality from heart disease and lung cancer after RT for early breast cancer revealed that the proportion of women with left-sided and right-sided breast cancer who received RT across many categories of stage, tumor location, age and race were virtually identical, suggesting that at least in this population, breast cancer laterality, has in the past played little part in determining who should be given RT. The study also showed that breast cancer patients who were not treated with RT the subsequent risk of heart disease was independent of tumor laterality, while for irradiated women the heart disease mortality ratio left-side versus right sided increased with increasing time since diagnosis (i.e. with increasing time since radiation). The increase is specific to heart disease, as for mortality from all other known causes the mortality ratio, left-side versus right side is close to unity in both irradiated and unirradiated women. This suggests that in this population, an increasing trend in the mortality ratio left-sided versus right sided for heart disease is a causal effect of RT. It also suggests that in other populations of women irradiated for breast cancer, subsequent patterns of heart disease can, when used with conjunction with information on breast cancer laterality and detailed dosimetry, provide insight into the dose-response relationship for radiation induced heart disease that is as credible as randomized evidence. 
In a recent study by Bouillon et al., on the long-term cardiovascular mortality after RT for breast cancer which included a total of 4,456 women who survived at least 5 years after treatment of breast cancer at Institute Gustave Roussy between 1954 and 1984 were followed up for mortality until the end of 2003, for over 28 years on average. A total of 421 deaths due to cardiovascular diseases were observed, of which 236 were due to cardiac disease. Women who had received RT had 1.76 fold (95% CI = 1.34-2.31) higher risk of dying of cardiac disease than those who have not received RT. Among women who have received RT, those who have been treated for left sided breast cancer had a 1.56 fold (95% CI = 1.27-1.90) higher risk of dying of cardiac disease than those who have been treated with right sided breast cancer. The RR increased with time since the breast cancer diagnosis (P = 0.05). This study confirmed that RT as delivered until the mid-1980s, increased the long term RR of dying from cardiovascular diseases. 
In 2005, Giordano et al. published data on the risk of cardiac death after adjuvant RT for breast cancer from the 12-registry 1973 to 2000 dataset from the National Cancer Institute's SEER program. Women (n = 27,283) treated with adjuvant radiation for breast cancer diagnosed in 1973-1989 were included in the study. Ischemic heart disease mortality was calculated at 15 years and compared for women diagnosed during 1973-1979, 1980-1984 and 1985-1989. Cox proportional hazards model were used to calculate the hazard of death from ischemic heart disease for women diagnosed 1973-1988 and censored at 12 years. For women diagnosed in 1973-1979, there was statistically significant difference in 15 year mortality from ischemic heart disease between patients with left sided (13.1%, 95% CI = 11.6-14.6) and those with right sided (10.2%, 95% CI = 8.9-11.5) breast cancer (P =0.02). No such difference was found for women diagnosed in 1980-1984 (9.4%, [95% CI = 8.1-10.6] vs. 8.7% [95% CI = 7.4-10.0]) respectively, (P = 0.64) or 1985-1989 (5.8% [95% CI = 4.8-6.8] vs. 5.2%[95% CI = 4.4-5.9]), respectively, (P = 0.98) in the Cox model, the hazard ratio (HR) for ischemic heart disease mortality for women with left sided versus women with right sided breast disease was 1.50 (95% CI = 1.19-1.87) in 1979. With each succeeding year after 1979, the hazard of death from ischemic heart disease for women with left sided versus those with right sided disease declined by 6% (HR = 0.94, 95% CI = 0.91-0.98). This study concluded that the risk of death from ischemic heart disease associated with radiation therapy for breast cancer has statistically significantly decreased over time. These encouraging data suggest that advances in radiation techniques have been translated into substantial benefits for women with breast cancer. Whether the risk of ischemic heart disease mortality resulting from RT has been entirely eliminated cannot be determined from this study. These reductions could be due to the fact that more patients in recent times have been treated to the intact breast without nodal irradiation, which eliminates cardiac radiation entirely in most patients and for those still exposed reduces the irradiated volume. 
Another nationwide cohort study of 90,000 Swedish women to assess the mortality from cardiovascular disease more than 10 years after RT for breast cancer from 1970 to 1996 concluded that the mortality ratio of left versus right of 1.10 for cardiovascular disease for more than 10 years after diagnosis of breast cancer is compatible with a substantial hazard among some of those actually irradiated. For example if about 30% of women surviving 10 years after breast cancer have been irradiated then cardiovascular mortality ratio of 1.10 in all women and 1.00 in unirradiated women would suggest a ratio of 1.33 in irradiated women. This could be produced by a 60% increase in late cardiovascular mortality, after irradiation for a left sided the tumor and 20% increase after irradiation for a right sided the tumor. The CI for the observed ratio of 1.10 is, however wide, so the true cardiovascular hazard from RT in the 1970s and 80s remains uncertain. 
In a study by Tukenova et al. (2010) the adjusted RR of death as a result of cardiac disease was significantly higher among patients treated with RT (RR = 7.4%; 95% CI = 1.0-56.5) and RR increased with increasing average radiation dose received by the heart and with cumulative exposure to anthracyclines. 
In the past, the heart was thought to be relatively radio resistant to the effects of radiation and damaged only by doses of ≥30 Gy. More recent data from several independent sources have provided substantial evidence that the mean heart dose of ≤ 20 Gy and even ≤ 5 Gy can increase the risk. These sources include information pertaining to atomic bomb survivors' and patients treated for childhood cancers, peptic ulcer disease and breast cancer. 
Data from the EBCTCG included women who were randomized within trials to RT or no RT. Retrospective estimation of mean heart doses, by three dimensional reconstructions of RT techniques specified within the trial protocols yields an increased RR of cardiac death of 3.1% per Gy. 
The treatment of breast cancer illustrates the urgent need to find out more about the long-term risk of heart disease from doses of ionizing radiation in the range of 0.5-5 Gy. One of the first suggestions that there might be an appreciable cardiac risk from doses of this magnitude came from the study of long-term survivors of the atomic bombings of Hiroshima and Nagasaki. In this population, risk of death from heart disease increased by 17% per Sv (90% CI = 8-20%) following single whole body doses in the range of 0-4 Sv, mostly from gamma radiation for which 1 Sv = 1 Gy. 
With tangential set-up substantial volume of heart and lung can be spared from the high radiation doses. Yet some of the patients are still at risk for an excess radiation induced cardiac mortality.  In general, there is great variation in the curvature of the chest wall and the separation of heart and lung from the breast target. And particularly in the treatment of women with large breasts, there is in many cases an unavoidable trade-off between tumor coverage and normal tissue sparing.  Conventional adjuvant breast or chest wall RT usually involves tangential beams, which deliver a radiation dose of around 2 Gy to the heart and around 8 Gy to the left anterior descending (LAD) coronary artery for left sided breast cancer. 
Mean doses for 50 patients treated in the United Kingdom with left tangential irradiation in 2006 ranged from 1.4 to 4.4 Gy (standard deviation 0.7) for the heart and from 2.4 to 21.2 Gy (standard deviation 4.5) for LAD coronary artery. In view of this variability individual patient cardiac dose assessment is needed to identify patients who would receive high cardiac doses from standard left-tangential irradiation for whom complex planning technique such as intensity modulated radiotherapy (IMRT) might be desirable. For right-tangential irradiation, the heart receives a lower dose. The average mean heart dose was 1.5 Gy for right sided breast cancer patients. The standard deviation was 0.2, indicating little variability in heart dose. 
The current gold standard of cardiac dose assessment is three-dimensional computed tomography (CT) planning. The organs at risk are contoured manually, and the cardiac doses are measured using the pencil beam or collapsed cone algorithms to generate dose volume histogram. The maximum heart distance (MHD) is the maximum distance between the anterior cardiac contour and the posterior tangential field edges. It can be easily and cheaply measured on the beams' eye view on a virtual simulator or a conventional simulation film. In this study of 50 patients treated with left-tangential irradiation, the MHD was a good predictor of the mean heart dose and biologically effective dose (BED) and gave an approximate indication of the dose and BED of the LAD coronary artery. In contrast, the assessment of midplane CT slice did not give an accurate indication of the heart dose. This relationship between MHD and cardiac dose can be used as a guide to identify patients who might benefit from more complex treatment plans. 
Recent studies documented drops in the mean dose to the heart from 13.3 to 2.3 and in the mean dose to the LAD coronary artery from 31.8 to 7.6 Gy over the last three decades.  Contemporary RT techniques can involve substantially lower cardiac exposure than those used previously. The situation has been achieved partly by omitting irradiation of the IMC in most patients. When an ipsilateral IMC field is used, however, an estimate dating from 2000 suggests that the mean cardiac dose could still be around 4-8 Gy for tumors of the left breast (with part of heart receiving more than 20 Gy in some patients) and 2-4 Gy for tumors of the right breast.  Unfortunately, it is eminently biologically plausible that these current doses of radiation are high enough to have long term consequences. In addition portions of heart and LAD coronary artery continue to receive large doses, with part of the heart receiving >20 Gy and part of the LAD receiving >30 Gy which is one of the most important sites of origin of fatal ischemic heart disease in many breast cancer patients. 
Although it is encouraging that adjuvant radiation does not appear to increase the risk of ischemic heart disease mortality with women treated in the late 1980s', the increased risk seen in women treated in the 1970s' adds to the evidence that radiation is potentially cardiotoxic. Therefore, every effort should be taken to avoid irradiating the cardiac structures. For example, CT based treatment planning permits precise imaging of the relationship of the heart to the RT fields. One study estimated that, as a result of the use of modern tangential breast fields and treatment planning, fewer than 5% of patients had heart volumes included in the radiation field that would place them at the risk of future cardiac damage. Yet imaging studies have demonstrated perfusion defects that appear within 2 years of adjuvant radiation in approximately 40% of patients, although without any clear clinical sequelae. 
Modern techniques of radiation therapy, such as IMRT and tomotherapy enable radiation oncologists to deliver doses with far more accuracy than was previously possible. The critical dose and volume relationships for individual cardiac structures and individual cardiovascular endpoints are not known with any accuracy. For example, it is not known, whether it might be advantageous to deliver a high dose to a small volume of the heart or a smaller dose to the larger volume of the heart. There is general view that the avoidance of cardiac doses of >30 Gy will eliminate any significant risks of late effects, but there is also evidence for increased risk from lower doses.
In addition, only limited data are available, as yet, on the potential interactions of radiation, both with drug treatments (such as anthracyclines and tyrosine kinase inhibitors) and with conventional cardiovascular risk factors (such as smoking and hypertension). These data will be essential to enable the accurate prediction of risks on an individual basis. It is also not known whether interventions after exposure-for example with antiplatelet drugs, angiotensin converting enzyme inhibitors or statins may lower cardiovascular risks. 
The estimation of the cardiac risk of today's breast RT requires the development of reliable dose-response relationships, which, in turn require detailed cardiac dosimetry of past regimens given to women for whom we have long term follow-up data. 
The endpoint of cardiac mortality might be more objective and readily assessed than cardiac morbidity. Nonetheless, cardiac morbidity is likely a more sensitive endpoint and one that manifests earlier than does mortality. 
An awareness of the potential cardio toxicity of RT led to the application of improved RT techniques that minimize the irradiation to the heart. These contemporary techniques appear to have substantially decreased the incidence of delayed complications, although whether or not there still is some residual risk remains uncertain. Although new techniques, including intensity-modulated RT  combined with free breathing gating  and helical tomotherapy,  may further reduce radiation-induced cardiac toxicities,  the most important factors in limiting cardiac radiation are associated with the techniques used and the skill of the radiation oncologist.
Further information on these topics is needed to enable estimation of the cardiac risks, which is likely to arise from the RT regimens in current use and those being considered for future use. Such knowledge would facilitate RT treatment planning and enable a reduction in cardiac risk while maintaining the known benefit in terms of breast cancer mortality. 
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