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A Dose-response Relationship for the Incidence of Radiation-related Heart Disease
... In addition, patients with BC are at risk for developing CVD due to the cardiotoxic effects of various treatment agents, which are anthracycline-based regimens, trastuzumab, and radiotherapy. [67][68][69][70][71][72][73][74][75][76][77] Anthracycline-based chemotherapy, which is the main drug class of choice in patients with BC, is known to be responsible for irreversible cardiotoxicity, especially in patients with coexisting cardiac risk factors. [67][68][69][70] Pinder et al 69 showed that for patients with BC older than 65 years who treated with adjuvant anthracycline chemotherapy; there were significant predictors of congestive heart failure, such as age, hypertension, DM, and CAD. ...
... 71 Radiotherapy increased the risk of developing ischemic heart disease, pericarditis, and valvular heart disease. 75 Cardiotoxic effects of radiotherapy differ with mean radiation doses, 76,77 locations of the therapies (left-sided vs right-sided BC), [76][77][78] and preexisting cardiac risk factors. 75,76 In a case-control study conducted with 2168 women who received radiotherapy for BC, it was found that radiotherapy exposure to heart increased the rate of coronary events by 7.4% per gray (Gy; 95% confidence interval [CI]: 2.9-14.5; ...
... 71 Radiotherapy increased the risk of developing ischemic heart disease, pericarditis, and valvular heart disease. 75 Cardiotoxic effects of radiotherapy differ with mean radiation doses, 76,77 locations of the therapies (left-sided vs right-sided BC), [76][77][78] and preexisting cardiac risk factors. 75,76 In a case-control study conducted with 2168 women who received radiotherapy for BC, it was found that radiotherapy exposure to heart increased the rate of coronary events by 7.4% per gray (Gy; 95% confidence interval [CI]: 2.9-14.5; ...
Mammography is a screening test with extensive international application and financial infrastructure promoting accessibility and affordability. Designed specifically to detect microcalcifications, mammography is powered to detect calcifications in vessel walls. Breast arterial calcifications (BAC) are one of the most common incidental findings documented by mammography. This review considers the literature regarding BAC in relation to cardiovascular disease (CVD) and its risk factors. The aim is to assess the possibility of using BAC as an early surrogate imaging biomarker of CVD.
... Breast cancer patients may have a higher CVD risk compared to the general population. Although cancer treatments such as anthracycline-based regimens, trastuzumab, and radiotherapy reduce the risk of cancer recurrence and death, they have been associated with an increased risk of CVD [9][10][11][12][13][14][15][16]. Anthracycline-based chemotherapy and trastuzumab increase the risk of heart failure by fivefold compared to regimens without these components [17,18]. ...
... Furthermore, studies have found increased risk of CVD events up to and beyond 20 years after diagnosis [8,9,55]. Age is a well-known CVD risk factor [56] and cardiac toxicity induced by radiotherapy manifest itself many years following treatment [15,57]. As the current study has a relative short follow-up time (median of 5-6 years), this may indicate that the risk of death from CVD in breast cancer patients may become larger over time. ...
Objectives
This study evaluates the risk of cardiovascular disease (CVD) following breast cancer, accounting for baseline CVD risk. Methods
Within the EPIC-NL (Dutch part of the European Prospective Investigation into Nutrition and Cancer) cohort, 1103 women were diagnosed with breast cancer. For every breast cancer patient, 3–4 women without breast cancer (n = 4328) were selected matched for age, year, and time since cohort enrollment. Based on CVD risk factors at cohort enrollment, 10-year risk of CVD was calculated and categorized: low (< 10%), intermediate (10–20%), high (> 20%). Cox proportional hazard models assessed the risk of CVD events (hospitalization or mortality) and CVD mortality of women with versus without breast cancer, adjusted for baseline CVD risk. ResultsAfter median follow-up of 5 and 6 years, 92 (8.3%) and 325 (7.5%) CVD events occurred in women with and without breast cancer, respectively. In the low CVD risk group, women with breast cancer had 1.44 (95% CI 1.00–2.06) times higher risk of CVD events than women without breast cancer. In the intermediate and high CVD risk categories, risk of CVD events was similar in women with and without breast cancer. Overall, women with breast cancer had 1.77 (95% CI 1.10–2.86) times higher risk of CVD mortality than women without breast cancer. Conclusions
Among women with low CVD risk, women with breast cancer have a higher risk of CVD event than women without breast cancer. Overall, women with breast cancer have a higher risk of CVD mortality than women without breast cancer.
... In an attempt to correlate cardiac dose with long-term morbidity, the Radiation-Associated Cardiovascular Events (RACE) collaboration retrospectively reviewed population-based disease registries and related the mean cardiac dose to the risk of developing heart disease (17). The risk of heart disease was greater with left-sided versus right-sided breast cancer, and the risk correlated with increasing heart doses. ...
... As previously discussed, the RACE collaboration reported a dose-response relationship between the risk of heart disease and the mean heart dose (17). Compared with women who had estimated heart doses <5 Gy, the relative risks of heart disease in women with estimated doses 5 to 14 Gy and >15 Gy were 15% and 108%, respectively. ...
Purpose:
To quantify cardiac radiation therapy (RT) exposure using sensitive measures of cardiac dysfunction; and to correlate dysfunction with heart doses, in the setting of adjuvant RT for left-sided breast cancer.
Methods and materials:
On a randomized trial, 32 women with node-positive left-sided breast cancer underwent pre-RT stress single photon emission computed tomography (SPECT-CT) myocardial perfusion scans. Patients received RT to the breast/chest wall and regional lymph nodes to doses of 50 to 52.2 Gy. Repeat SPECT-CT scans were performed 1 year after RT. Perfusion defects (PD), summed stress defects scores (SSS), and ejection fractions (EF) were evaluated. Doses to the heart and coronary arteries were quantified.
Results:
The mean difference in pre- and post-RT PD was -0.38% ± 3.20% (P=.68), with no clinically significant defects. To assess for subclinical effects, PD were also examined using a 1.5-SD below the normal mean threshold, with a mean difference of 2.53% ± 12.57% (P=.38). The mean differences in SSS and EF before and after RT were 0.78% ± 2.50% (P=.08) and 1.75% ± 7.29% (P=.39), respectively. The average heart Dmean and D95 were 2.82 Gy (range, 1.11-6.06 Gy) and 0.90 Gy (range, 0.13-2.17 Gy), respectively. The average Dmean and D95 to the left anterior descending artery were 7.22 Gy (range, 2.58-18.05 Gy) and 3.22 Gy (range, 1.23-6.86 Gy), respectively. No correlations were found between cardiac doses and changes in PD, SSS, and EF.
Conclusions:
Using sensitive measures of cardiac function, no clinically significant defects were found after RT, with the average heart Dmean <5 Gy. Although a dose response may exist for measures of cardiac dysfunction at higher doses, no correlation was found in the present study for low doses delivered to cardiac structures and perfusion, SSS, or EF.
... 5 Previous studies reported associations between some breast cancer treatments and the development of CVD, including anthracycline-based chemotherapy, 6 7 trastuzumab, 8 and radiotherapy treatments. 9 10 The highest risks of treatment-induced cardiotoxicity are seen in patients with preexisting CVD risk factors such as hypertension and high age. 11 12 In the last decade, many efforts have been made to reduce the risk of CVD induced by breast cancer treatments. ...
Objectives
To investigate trends in cardiovascular disease (CVD) risk following breast cancer using national registry data.
Methods
A nationwide cohort study was conducted, comprising 163 881 women with in situ (7.6%) or invasive (92.4%) breast cancer and women of the general population, ranging from 3 661 141 in 1996 to 4 566 573 in 2010. CVD mortality rate in women with and without breast cancer and hospitalisation rate after breast cancer were calculated for the years 1996–2010. Age-adjusted CVD and breast cancer mortality within 5 years after breast cancer admission (1997–2010) were compared with 1996 calculated with a Cox proportional hazard analysis.
Results
The absolute 10-year CVD mortality risk following breast cancer decreased from 56 per 1000 women in 1996 to 41 in 2005 (relative reduction=27.8%). In the general population, this decreased from 73 per 1000 women in 1996 to 55 in 2005 (–23.9%). The absolute risk of CVD hospitalisation within 1 year following breast cancer increased from 54 per 1000 women in 1996 to 67 in 2009 (+23.6%), which was largely explained by an increase in hospitalisation for hypertension, pulmonary embolism, rheumatoid heart/valve disease and heart failure. The 5-year CVD mortality risk was 42% lower (HR 0.58, 95% CI=0.48 to 0.70) for women admitted for breast cancer in 2010 compared with 1996.
Conclusions
CVD mortality risk decreased in women with breast cancer and in women of the general population, with women with breast cancer having a lower risk of CVD mortality. By contrast, there was an increase in hospitalisation for CVD in women with breast cancer.
... The association between left-sided breast cancer and radiotherapy treatment with a higher risk of CVD mortality was found among women diagnosed in the early 1980's [23,24,26]. Radiotherapy treatment was more cardiotoxic in these years as it usually involved higher doses with large irradiation fields irradiating parts of the heart [37,38]. This may also explain the increased risk of CVD mortality among breast cancer patients diagnosed in an earlier calendar period [18,25]. ...
Purpose:
Breast cancer incidence and survival is high, which results in high prevalence of breast cancer survivors. The risk of (death from) cardiovascular disease (CVD) is higher in patients exposed to cardiotoxic treatments, in particular if they have pre-existing CVD risk factors. This study systematically summarized the risk of death from CVD following breast cancer.
Methods:
Databases of Medline, Embase, and the Cochrane Library were systematically searched using the following terms and synonyms: breast cancer, cardiovascular disease, and cause of death. Articles reporting on both risk and risk factors of CVD mortality following breast cancer were eligible for inclusion. The methodological quality of each article was assessed using the Newcastle Ottawa quality assessment scale for cohort studies.
Results:
Fourteen articles were included assessing the risk of CVD mortality among 1,217,910 women with breast cancer. The methodological quality was high for the majority of the studies. Studies were heterogeneous in design, study population, length of follow-up, CVD outcomes, and risk factors. 1.6-10.4% of all women with breast cancer died of CVD. Women with breast cancer had a higher risk of CVD mortality than women from the general population. The risk of CVD mortality was higher among women with breast cancer with older age at diagnosis, left-sided tumor, diagnosis in an earlier calendar period, and black ethnic origin.
Conclusions:
CVD is an important cause of death following breast cancer. Identification of patients at high risk of CVD is important to optimize CVD prevention and tailor breast cancer treatment.
... The follow-up time of our study population was relatively short, which explains (part of) the low absolute risk of CVD mortality. Previous research has shown, that the risk of CVD mortality increases up to and beyond 20 years after diagnosis 4, 26, 27 , as age is a well-known CVD risk factor 28 and cardiac toxicity induced by radiotherapy manifest itself many years following treatment 29,30 . Furthermore, misclassification of cause of death due to CVD could have occurred, especially in cases of sudden death from CVD outside a hospital, for example at home, were it is difficult to state the proper cause of death by doctors or authorized medical practitioners that are not familiar with this particular women. ...
Breast cancer incidence and survival is high in Southeast Asia. As such, many women diagnosed with breast cancer are at risk of dying of other causes. Given the increased risk of cardiotoxicity induced by breast cancer treatments, it is important to identify patients at high risk of cardiovascular disease (CVD) mortality. The aim of this study was to investigate if this risk varies by age and ethnicity. Patient details were obtained from 5,868 Chinese, Malay, and Indian women diagnosed with in situ or non-metastasized invasive breast cancer at the National University Hospital of Singapore and KK Women’s and Children’s Hospital in Singapore. Death causes were obtained from the National Registry of Births and Deaths. Flexible parametric survival models estimated CVD mortality rates and hazard ratios. During a median follow-up of six years, 1,010 deaths occurred of which 6.8% were due to CVD. CVD mortality rates of older women peaked within the first year following diagnosis and increased over time since diagnosis. Indian had more than double the risk of CVD mortality than Chinese, independent of age at diagnosis and stage. Taking ethnicity and age into account may promote CVD risk stratification and management in (Southeast Asian) women with breast cancer.
... The follow-up time of our study population was relatively short, which explains (part of) the low absolute risk of CVD mortality. Previous research has shown, that the risk of CVD mortality increases up to and beyond 20 years after diagnosis 4, 26, 27 , as age is a well-known CVD risk factor 28 and cardiac toxicity induced by radiotherapy manifest itself many years following treatment 29,30 . Furthermore, misclassification of cause of death due to CVD could have occurred, especially in cases of sudden death from CVD outside a hospital, for example at home, were it is difficult to state the proper cause of death by doctors or authorized medical practitioners that are not familiar with this particular women. ...
Background: Over the past decades, breast cancer survival has improved substantially and many patients die of other, non-breast cancer related causes. In South East Asia, where large ethnic differences exist in stage at presentation and overall survival, causes of death of breast cancer patients have been understudied.
Aim: To examine cause-specific mortality among breast cancer patients in multi-ethnic Singapore and investigate effects of ethnicity, and age and tumor stage at diagnosis.
Methods: Data of women diagnosed with breast cancer between 1990 and 2011 at the National University Hospital in Singapore were retrieved from the hospital-based breast cancer registry. Cause of death was categorized as breast cancer (ICD8 174; ICD9 174; ICD10 C50), cardio- and cerebrovascular disease (ICD8 390 to 459; ICD9 390 to 459; ICD10 I00 to I99), other malignancies (ICD8 140 to 239; ICD9 140 to 239; ICD10 C00 to D48 except codes for death resulting from breast cancer), and death from other causes (all ICD codes except those already listed). Patients with unknown cause of death (n=6) were classified as death from other cause. Chi square statistics were used to compare cause of death distributions.
Results: Of 4108 patients, median age at diagnosis was 51 years (range 21- 98 years). The majority of women were Chinese (n=3223, 78%), followed by Malay (n=517, 12%), Indian (n=257, 6%) and other ethnicities (n=111, 3%). After a median follow-up of 7 years, 1125 (27%) patients died: 910 (81%) patients died of breast cancer, 70 (6%) of cardio- and cerebrovascular disease, 71 (6%) of other malignancies, and 83 (7%) of other causes. Compared with other ethnicities, Malay women most frequently died as a result of breast cancer (n=178, 90%). The highest percentage CVD deaths was observed among Indians (n=7, 11%). Breast cancer accounted for 92% of deaths in women younger than 50 years at diagnosis and for 60% in women older than 65. The proportion of deaths as a result of CVD, other cancer or other causes increased with age. Patients with higher tumor stages at diagnosis were more likely to die of breast cancer (96% of deaths of patients with TNM4 were breast cancer related).
Conclusion: The present study showed that breast cancer is the most important cause of death in breast cancer patients among all ethnic groups, and ages and stages in South East Asia. The highest risk of death due to breast cancer in Malay women might be explained by their presentation at advanced stages and young age at diagnosis. Breast cancer is less likely to be the cause of death in women of Chinese ethnicity, older age at diagnosis and early tumor stage. In these groups more attention for competing causes of death, in particular CVD, should be a priority for the future.
Citation Format: Ho P, Rijnberg N, Gernaat SAM, Emaus MJ, Grobbee RDE, Lee SC, Hartman M, Verkooijen HM. Competing causes of death among women with breast cancer in South East Asia: Effects of ethnicity, and age at diagnosis and stage at diagnosis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-46.
... Radiation Therapy Oncology Group protocol 0413 recommended that the volume of the heart receiving more than 5% of the prescribed dose (V 2.5Gy in our prescription) should be less than 40%. Darby et al (16) reported that the risk of heart disease was 27% higher in left-sided (heart D mean Z 6.6 Gy) than in right-sided (heart D mean Z 2.9 Gy) breast cancer, concluding that there is a 4% increased risk of heart disease per 1 Gy increase in mean heart dose. ...
To test tangential and not-tangential hybrid intensity modulated radiation therapy (IMRT) for whole-breast irradiation.
Seventy-eight (36 right-, 42 left-) breast patients were randomly selected. Hybrid IMRT was performed by direct aperture optimization. A semiautomated method for planning hybrid IMRT was implemented using Pinnacle scripts. A plan optimization volume (POV), defined as the portion of the planning target volume covered by the open beams, was used as the target objective during inverse planning. Treatment goals were to prescribe a minimum dose of 47.5 Gy to greater than 90% of the POV and to minimize the POV and/or normal tissue receiving a dose greater than 107%. When treatment goals were not achieved by using a 4-field technique (2 conventional open plus 2 IMRT tangents), a 6-field technique was applied, adding 2 non tangential (anterior-oblique) IMRT beams.
Using scripts, manual procedures were minimized (choice of optimal beam angle, setting monitor units for open tangentials, and POV definition). Treatment goals were achieved by using the 4-field technique in 61 of 78 (78%) patients. The 6-field technique was applied in the remaining 17 of 78 (22%) patients, allowing for significantly better achievement of goals, at the expense of an increase of low-dose (∼5 Gy) distribution in the contralateral tissue, heart, and lungs but with no significant increase of higher doses (∼20 Gy) in heart and lungs. The mean monitor unit contribution to IMRT beams was significantly greater (18.7% vs 9.9%) in the group of patients who required 6-field procedure.
Because hybrid IMRT can be performed semiautomatically, it can be planned for a large number of patients with little impact on human or departmental resources, promoting it as the standard practice for whole-breast irradiation.
Background:
Hypofractionation is now becoming the standard of care in breast irradiation. The aim of this study was to assess the toxicities and outcomes in patients with breast cancer treated with hypofractionated radiotherapy (HFRT).
Methods:
Patients with localized breast cancer who received adjuvant HFRT between 2013 and 2015 with a minimum follow-up of 6 months following radiation were included in this prospective study. Late toxicities were assessed using CTCAE v 4 and included chest/breast pain, limb pain, limb edema, skin pigmentation, skin fibrosis, and shoulder movement restriction. Outcomes assessed included locoregional control, disease-free survival, and overall survival. Statistical analysis was done using Microsoft Excel and SPSS v22.
Results:
A total of 81 patients fulfilled the inclusion criteria, of which 19 patients had died during follow-up. Regional nodal irradiation was done in 63 (77.8%) patients using the same hypofractionated schedule of 40 Gy in 15 fractions. Late toxicities were assessed for 62 patients. The median follow-up following the course of hypofractionated radiation was 45 months (range 14 - 65 months). Late toxicities were assessed for 62 patients. Grade 1/2 chest/breast pain, limb pain, limb edema, skin pigmentation, skin fibrosis, and shoulder movement restriction were seen in 11%, 12%, 7%, 6%, 8%, and 11% of cases, respectively. Distant recurrences were seen in 8% of cases, and there were no locoregional recurrences. Five-year overall survival was 76.5%.
Conclusion:
HFRT to whole breast or chest wall and the regional nodal areas was well-tolerated with acceptable rates of late toxicities on follow-up.
Résumé
Les femmes sont particulièrement exposées aux risques cardiaques d’une radiothérapie thoracique du fait du traitement du cancer du sein, en particulier du sein gauche et lors de l’irradiation de la chaîne mammaire interne. Le risque de survenue d’événements cardiaques est d’autant plus élevé que les patientes ont été irradiées jeunes, avant les années 1990, présentent des facteurs de risques cardiovasculaires, ont reçu des doses cumulées et fractionnées élevées et des chimiothérapies cardiotoxiques adjuvantes. Les lésions cardiaques postradiques peuvent atteindre toutes les tuniques (péricarde, myocarde, endocarde, valves) ainsi que les coronaires et l’aorte. Ces atteintes sont tardives et souvent combinées avec un pronostic péjoratif. Les recommandations de prise en charge, le suivi des patientes irradiées, les examens diagnostics et les traitements de ces lésions se sont améliorés grâce à la collaboration des sociétés savantes de cardiologie et d’oncologie. Un suivi cardiologique avec une échographie cardiaque tous les 5 ans, complété par un test fonctionnel pourrait être recommandé pour les patientes à risque ayant reçu une irradiation thoracique. Enfin, le pronostic néoplasique des patientes traitées pour cancer du sein s’est largement amélioré et il est capital de prévenir ces lésions postradiques tardives ; pour cela les progrès de la radiothérapie actuelle, couplée à l’imagerie permettent de réduire les doses cardiaques, mais les patientes doivent être suivies pour juger du bénéfice cardiovasculaire au long terme.
The radiotherapy of thoracic cancers exposes the heart to late radiation-induced complications. The physiopathological and clinical consequences of heart irradiation have been mostly studied in patients with Hodgkin lymphoma and breast cancer. The main cause of cardiac morbidity is radiation-induced coronaropathy with a relative risk estimated between 2 and 3 in earlier studies. Preexisting factors of cardiovascular risk, including chemotherapy, potentalize the cardiotoxicity of radiotherapy. Conformational radiotherapy, adapting the ballistics and the energy to the delineated volumes while carefully evaluating the dose–volume distribution in the organs at risk, allowed a drastic reduction in cardiac mortality. This toxicity no longer seems to be significant if the cardiac volume has received less than 30Gy. Nevertheless, the prolonged life expectancy of cancer patients and the expanding use of new cardiotoxic anticancer drugs underline the persistent need to further reduce the dose delivered to the heart. Indeed, 1Gy added to the mean heart dose would increase the cardiotoxic risk by 4% (IC 95%: 2–6%, P=0.0002). A strengthened collaboration between the radiation oncologist and the cardiologist aims at detecting and treating long-term complications after thoracic radiotherapy.
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