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Radiation oncologists' perspectives on reducing radiation-induced heart disease in early breast cancer
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Current Problems in Cancer journal homepage: www.elsevier.com/locate/cpcancer
Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer Hoda Mahdavi∗ Department of Radiation Oncology, Iran University of Medical Sciences, Tehran, Iran
a b s t r a c t Radiotherapy (RT) as an adjuvant treatment for breast cancer (BC), has caused a reduction of recurrences and BC-related deaths. But it has also induced cardiovascular mortality. Oxidative stress is the principle mediator of RT-induced heart disease, similar to many conventional cardiovascular risk factors. The aggregate effect of cardiovascular conditions, RT of heart substructures, implied techniques, and population cardiac mortality rates is not well understood. Due to uncertainties in this field, this article aims to briefly review the recommended strategies for risk assessment, plan optimization, and screening for prevention of RT-induced heart disease in BC patients. © 2019 Elsevier Inc. All rights reserved.
a r t i c l e
i n f o
Keywords: Radiotherapy; Radiation-induced heart disease; Breast cancer
Introduction During recent decades breast cancer (BC) survival rate has increased owing to improvements in early detection, treatment, and longevity of the population.1 Meanwhile, concerns for
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Financial disclosure: There are no competing financial interests. Conflict of interest: None. ∗ Correspondence to: Hoda Mahdavi, Department of Radiation oncology, Firoozgar General Hospital, Beh-Afarin St., Karimkhan-e-Zand Ave., Vali-e-Asr Sq., Tehran, Iran. E-mail address: [email protected] ✩✩
https://doi.org/10.1016/j.currproblcancer.2019.100509 0147-0272/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: H. Mahdavi, Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2019.100509
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survivorship and long-term effects of treatments including radiotherapy (RT) have risen. RT reduces local failure and prolongs survival of BC when it is used as an adjuvant to either lumpectomy or high-risk postmastectomy.2 Trends for broader RT coverage of regional lymph nodes such as the internal mammary nodes (IMN), and RT implementation in place of axillary lymph node dissection to minimize the burden of surgery have emerged. These approaches have led to an expansion of considerations for adjuvant RT. Nevertheless, the heart may incidentally receive irradiation that can potentially cause clinically significant manifestations of cardiac disease. The exact incidence is of RT-induced heart disease is unclear.3 However, given the increasing survivorship and indications for RT, the magnitude of this problem may not be negligible. An early meta-analysis of postmastectomy studies before 1975 showed an excess of cardiac deaths in 10 years, in the adjuvant RT group compared to surgery alone. This finding was seemingly offset by a reduced number of deaths due to BC treatment (64.2 excess cardiac deaths vs 49.5 less BC deaths).4 more recent review of trials since 1995 has validated that RT reduces the absolute risk of BC-related deaths compared to surgery alone. However, an excess cardiac mortality rate of 27% at 15 years was identified when RT was used adjuvant to surgery. Moreover, the difference in long-term mortality was not apparent in a subset of patients who gained relatively small local control benefit from RT.2 Later, a meta-analysis on over a million participants with pooled data gathered since 1966 discovered that RT to the breast has so far caused excess cardiac deaths with a ratio of 1.25 per thousand people a year.5 These negative observation of RT-related deaths have been linked to old 2-dimensional RT techniques with suboptimal total RT dose and fractionation, that would not allow for cardiac sparing.6 , 7 In this regard, several studies with contemporary RT techniques did not find a significant excess risk of ischemic heart disease in patients who received radiation.8 Later on, findings of a pivotal study by Darby et al showed a linear dose response relationship for relative risk of major cardiac events.9 In addition a residual risk for improved techniques may still be substantial for certain subsets of patients. Hence, this article aims to briefly review the risks of RT-induced heart disease and related uncertainties that may cause practical barriers.
Pathophysiology of RT-induced heart disease RT activates multiple pathways that are responsible for oxidative stress, inflammatory response, microvascular dysfunction, myocyte injury, and fibrosis.10 A spectrum of complications depending on the affected heart substructure has been described. The host of pathologies is related to coronary arteries, ventricular perfusion, pericardium, valves, conduction system, and the autonomous system.9 , 10 In general, the endothelial tissue is the principle target that within RT fields accelerated atherosclerosis and early vascular stenosis occurs. The occluded vessels are responsible for chronic myocardial ischemia.11 , 12 Since most of the cardiac risk is from ischemic heart disease,13 much attention is driven to perfusion alterations surrounding the left anterior (LAD) descending artery; a continuation of the left coronary artery and a cardinal route for blood supply for a large area of myocardial tissue. The majority of the consequent myocardial dysfunction is subclinical and is with uncertain clinical significance.3 However, patients may eventually develop symptomatic heart failure as early as 5-10 years postexposure that can be lifethreatening. Noticeably, the persistence of cardiac mortality risk could remain up to the third decade after treatment.5
Cardiovascular risk factors Cardiovascular disease (CVD) and BC are leading causes of morbidity in the female population. The 2 share risk factors such as age, dietary fat, tobacco and alcohol consumption, stationary lifestyle, obesity, and hormone replacement therapy.10 Relative to estimates in the general population, worse cardiovascular risk prevalence in early BC has been detected. This has been Please cite this article as: H. Mahdavi, Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2019.100509
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Table 1 Summary of risk factors for radiation-induced heart diseases in early breast cancer. Time and age factors younger age (<50 years), age >60 years, longer interval since exposure Pre-existing cardiovascular diseases Arrhythmia, myopathy, or chronic ischemic heart disease, chronic obstructive pulmonary disease, left ventricle ejection fraction ≤50%-55%, prior myocardial infarction, or moderate valvular heart disease Pre-existing cardiovascular risk factors Dyslipidemia, current smoking, hypertension, diabetes of any type, high body mass index (≥30) Anatomical factors Left side breast cancer, presence, and extent of tumor next to the heart, maximum heart distance >1 cm from the posterior tangential edge, number of slices on CT scans in which the heart contacts chest wall Medical treatment factors Adjuvant chemotherapy (anthracyclins, taxanes, antimetabolites, alkylating agents), HER2/neu directed therapies, endocrine therapies Radiation planning factors Low energy radiation: orthovoltage or 60 Co, field placement near the heart (anterior fields or internal mammary nodes coverage), suboptimal cardiac protection, large volume of irradiated heart, dose >30-35 Gy, higher dose per fraction >2 Gy
linked to a multihit process of direct effects of cardiotoxic therapies and indirect effects of modifiable lifestyle factors.14 For example, it has been observed that current smoking induced high absolute risks for secondary lung cancer (4%) and cardiac mortality (1%) in BC patients who received RT.15 In this regard, the overall synergy with RT in some instances outweighs the survival benefit of RT. The effect of some risk factors such as age is complex. An increased likelihood of mortality from myocardial infarction after 10-15 of treatment of left-sided was demonstrated in a Canadian population-based study conducted in the years 1982-1987.16 This result with limitations of a short follow-up interval may mirror the higher incidence and mortality rates of CVD by ageing. Besides, 2 separate analyses of database during 1970-1992 revealed an increased cardiac risk for left-sided BC patients younger than 50-60 years old. The relative risks of cardiac mortality did not reflect the baseline increases of risk by ageing.17 , 18 These findings are sensibly in accord with the ongoing nature of RT-related heart disease. Cardiac RT dose also depends on laterality. In right-BC patients the heart may receive dose from radiation scatter that is usually negligible. Instead, in the left-BC patients, the heart can be exposed to near-total RT dose, especially when the IMN is included; as a systematic review demonstrated that the average mean dose of heart (MHD) doubled when the IMN was included in left-breast plans.13 A meta-analysis showed that RT increases relative risks of developing coronary heart disease and related cardiac death by ratio of 1.29 and 1.22, respectively in the left BC as compared to the right BC.5 Seemingly, the risk difference between patients with left-sided and right-sided BC declined over time with contemporary techniques.6 A list of commonly described predisposing risks3 , 8 , 9 , 12 , 16 , 19-21 are summarized in Table 1.
Prevention of RT-induced heart disease Dosimetric clinical endpoints The radiation oncologist needs to define clinical or subclinical endpoints for an optimal cardiac sparing plan. This is achieved by point-dose (volumetric or dosimetric constraints), global (eg, MHD), or parametric model-based data such as Normal Tissue Complication Probability (NTCP) estimations. Recommendations are based on limited data so there might be high errors in their clinical estimation. Quantitative Analyses of Normal Tissue Effects in the Clinic recommends preserving MHD below 26 Gy, and V30 (volume receiving at least 30 Gy) of the heart below 46%. The Quantitative Analyses of Normal Tissue Effects in the Clinic’s conservative NTCP model suggests that heart V25 Gy below 10% is associated with less than 1% probability of Please cite this article as: H. Mahdavi, Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2019.100509
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cardiac mortality in 15 years. The drawback of the indices is point doses were extracted from a study on definitive chemoradiation for esophageal cancer. The parameters reduced the risk of pericardial effusion from 73% to 13%. In present, as the RT fields do not direct the mediastinum, pericarditis is a relatively uncommon self-limiting complication. Furthermore, with a notion of dosimetric data are most applicable in the disease setting which they were derived, these indicators are no longer appropriate. In addition the volumes receiving higher near typical prescription doses for BC are not included in the NTCP model. Notably, the beneficial survival effects of RT for BC could be offset by heart complications when an NTCP value is 5% or more. Estimates suggest that when heart V30-40 is kept within 30%-35%, there is still a 5% excess risk of cardiac death at 15 years.22 The heart is a typical example of a serial-parallel organ and is consisted of serial myocardium and parallel vessels.23 Several researches that are supported by mathematical analysis suggest a dominantly serial architecture for the heart.24 In many instances cardiomyocytes have been viewed relatively resistant to RT at doses below 30 Gy. Theoretically, small regions of dose above this tolerance limit drive the main risk. However, it is not yet known on a physiological basis that whether a relatively high radiation dose to a small volume or the lower average dose to the whole heart is responsible for cardiovascular effects. In a typical left breast or chest-wall plan with tangential photon beams, the apex, anterior heart, and the LAD are within a region that receives high dose.11 In general, it is reasonable to consider these substructures and the left ventricle (LV) where the highest risk of cardiac morbidity from RT arises, as Organs At Risk (OAR).12 , 25 The relative seriality model has usually been used to calculate the risk of excess late cardiac mortality. This model that assumes a homogenous dose distribution within the heart anticipates an extra mortality of up to 50% at 15 years when the heart myocardium receives 52 Gy.26 This is only slightly above typically prescribed doses for BC. Because of concerns of the related ischemic events, many investigators have calculated dose constraints for LAD. Piroth et al12 suggested Dmean LAD < 10 Gy, V30 LAD < 2%, V40 < 1% in both conventional and hypofractionated regimes in left BC RT based on publications extracted from literature. They also suggested Dmean LV < 3Gy, V5 LV < 17%, V23 LV < 5%. However, there is a lack of precise long-term clinical dose-response data to guide planning objectives. The MHD is among the most common parameters apprehended by radiation oncologists.21 Dose received by cardiac substructures are likely to correlate strongly with whole-heart dose. Nonetheless, MHD was not consistently representative of dose to the LAD in several studies. The population-based case-control model of BC patients treated in 1958-2001 of Darby et al showed a gradual increase of 7.4% per Gy MHD relative risk attributed to major coronary events within 5-20 years.9 One of their findings was that MHD may be a better predictor of the rate of major coronary events than the mean dose to LAD. Although the method for calculating cardiac dose was outdated,25 their model was validated in a survival analysis of a cohort treated in 20052008. It is now strongly recommended that a priority for plan optimisation should be keeping doses to the whole-heart as low as reasonably achievable.19 , 27 Current evidence shows that MHD in order of 1.6-2.5 Gy is a dose range that could probably be safe.12
Radiation therapy techniques In typical tangential photon plans, conformal blocking by field-in-field techniques can effectively reduce dosimetric hot areas of the heart particularly when the tumor is located in the upper portion of the breast. Planning CT does not clearly show heart structures and along with the heart movements in cardiac and respiratory cycles, defining vascular and myocardial volumes can be challenging.25 Guides for cardiac contouring for CT planning have been developed to adjust for the uncertainties regarding complex and obscure anatomy of heart substructures. Atlases do not usually account for variations in coronary divisions. However, registered to the planning CT, specific imaging modalities such as CT-based coronary angiography with electrocardiographic gaiting has enabled to overcome the mentioned shortcomings and provide more Please cite this article as: H. Mahdavi, Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2019.100509
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accurate image for contouring. In terms of gaiting images, not only limitations related to their availability and feasibility applying on a large number of patients exists, but also, dose delivery is not synchronized with cardiac cycle in conventional RT machines. Therefore, an appropriate planning risk volume should be added to the outlined structures to account for heart motion.28 There are 3 approaches used alone or in combination when there is a propensity for heart sparing. First, changing anatomical measures, second, using advanced technologies, and third, using partial breast irradiation. These are further discussed as follows. First, displacing the heart from the clinical target volume is achieved with breathing control methods or prone positioning of the patient. These are the most common techniques that are used in the United States of America.21 Breath-hold and respiratory gating successfully decreased MHD and ventricular dosimetric parameters. Their clinical benefit has not been studied in randomized trials, but a model estimate reported a reduction of cardiac mortality by 4.7% compared to free-breathing with a median cardiac mortality NTCP of 0.1%.25 However, their implementation depends on tolerance and anatomical factors of patients, require sufficient timing and expertise, and facilities that are certainly not universally available. Prone positioning is effective for cardiac sparing in over 50% of patients. However dosimetric values for cardiac sparing were not consistent in breasts with small volumes.25 The second is using advanced technologies for the RT plan and delivery. Intensity-modulated radiotherapy (IMRT) plans have theoretical advantage of dose conformity and homogeneity. Significant reductions of low- and high-dose cardiac measures, the MHD, and NTCP modeling of heart complications as well as lower dose to coronary arteries have been reported with IMRT. Large breasted patients may particularly benefit more.25 Dose constrains set in inverse IMRT, in particular, drive the cardiac dose; so depending on its strictness the amount of cardiac exposure can be variable. As in a systematic review by Taylor et al of reported MHDs from 2003 to 2013 showed that standard or rotational IMRT had surprisingly the highest average MHD among all applied techniques with albeit a wide range of reported values.13 Classic IMRT can be combined with tangential fields and the hybrid plans optimized in terms of cardiac sparing. An alternative technique is using multiple partial volumetric modulated Arc therapy (VMAT) arcs to restrain exposure to choices of OARs.29 Limited nonrandomized data support advantages of proton beam therapy for BC after breast conserving or mastectomy. Due to its lower exit dose compared to photons, it can effectively spare any OAR beyond its dose fall-off. Proton beam therapy poses the lowest reported average MHD for left-sided BC when IMNs were not treated (0.5 Gy; range, 0.1-0.8 Gy relative to 3.8 Gy; range, <0.1-12.4 Gy, for average MHD for left-tangential RT with no breathing control). It also appeared as a technique that had the best cardiac sparing results when IMNs were treated.13 However, it is most costly and less accessible than photons and thereby it is not a subject of advocacy. It still is a valuable option to receipt very low MHD to minimize cardiac risk. The third is to change the traditional targets of the whole breast to partial breast irradiation. This is not standard, has limited indications, depends on anatomical indices, and concerns about local recurrence rates have not been resolved.25 Finally, the planning system should correct for inhomogeneity of the lungs to prevent underestimation of the dose to the heart.22
Screening Cardiac mortality may be less concerning in BC than before as management of heart ischemia has improved and also population cardiac mortality rates have decreased.8 , 15 In the general population, nearly 80% of CVD can be prevented through lifestyle modification and control of high blood pressure, diabetes, and dyslipidemia.10 The health economic impact of controlling many of the modifiable risk factors and their effect on the deceleration of radiation damage in BC patients is not well known.3 , 22 Patients are usually managed the same as nonirradiated patients; however, prognosis, success rates, and complications, for heart interventions are usually worse in irradiated patients.11 The American Society of Clinical Oncology has no screening recommendations on prevention of risk for cardiac dysfunction for patients who receive Doxorubicin with doses lower than Please cite this article as: H. Mahdavi, Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2019.100509
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250 mg/m2 or trastuzumab alone. However, those who carry additional risks (eg, older age (60 ≥ years), sequential anthracycline and trastuzumab, multiple cardiovascular risk factors, compromised cardiac function, or low dose RT (<30 Gy) in combination with anthracyclines), require screening. Screening is also recommended for higher dose RT (>30 Gy) when the heart is in the treatment field. In these patients, modifiable cardiovascular risks should be assessed and controlled, a baseline echocardiogram should be performed, and RT fields should be tailored with advanced RT techniques.19 A practice guidelines by the European Society for Medical Oncology recommends screening all patients who are receiving anthracyclines or trastuzumab by Troponin (Tn).20 Tn type I (TnI) that is widely studied in patients with cancer can detect cardiac dysfunction in its earliest phase before any detectable left ventricular ejection fraction (LVEF) change. If positive, regular echocardiogram is indicated. Also, acute rise in TnI levels due to RT and its ability to predict late-effects has been described.30 Despite these findings, currently, follow-up protocols for irradiated patients who had not received anthracyclines are diverse and based on practitioners’ experience and patients’ needs.20 It is recommended by The European Association of Cardiovascular Imaging and the American Society of Echocardiography that cancers that require chest RT with at least 1 risk factor benefit from intensive risk control, and baseline and regular echocardiography. The risk items that are relevant to breast treatment are anterior or left chest irradiation, inadequate or absent RT shielding, age under 50, high-dose-per-fraction, and pre-existing cardiovascular risks or diseases.11
Conclusion For the OAR choice of heart, interaction between most cardiovascular risks and the heart dose-volume effect and their long-term outcome is poorly understood. It is more judicious to use individualized risk modification for appropriate patients regarding their comorbidities and overall prognosis. Certain subsets of BC patients, including young patients with cardiovascular or treatment-related risks, or unfavourable anatomy, may benefit from risk assessment and risk modification, cardiac-sparing RT planning techniques, and long-term follow-up. In selected patients, the irradiated heart volume should be minimized to a highest possible degree with no significant compromise of target coverage.
References 1. Miller KD, Nogueira L, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2019. CA: Cancer J Clin. 2019;69:363–385. 2. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366:2087–2106. 3. 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;35:612–623. 4. Cuzick J, Stewart H, Rutqvist L, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol. 1994;12:447–453. 5. Cheng YJ, Nie XY, Ji CC, et al. Long-term cardiovascular risk after radiotherapy in women with breast cancer. J Am Heart Assoc. 2017;6. 6. Giordano SH, Kuo Y-F, Freeman JL, Buchholz TA, Hortobagyi GN, Goodwin JS. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst. 2005;97:419–424. 7. Patt DA, Goodwin JS, Kuo Y-F, et al. Cardiac morbidity of adjuvant radiotherapy for breast cancer. J Clin Oncol. 2005;23:7475–7482. 8. Harris EE, Correa C, Hwang WT, et al. Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. J Clin Oncol. 20 06;24:410 0–4106. 9. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368:987–998. 10. Mehta LS, Watson KE, Barac A, et al. Cardiovascular disease and breast cancer: where these entities intersect: a scientific statement from the American Heart Association. Circulation. 2018;137:e30–e66. 11. Donnellan E, Phelan D, McCarthy CP, Collier P, Desai M, Griffin B. Radiation-induced heart disease: a practical guide to diagnosis and management. Cleve Clin J Med. 2016;83:914–922. 12. Piroth MD, Baumann R, Budach W, et al. Heart toxicity from breast cancer radiotherapy: current findings, assessment, and prevention. Strahlenther Onkol. 2019;195:1–12. Please cite this article as: H. Mahdavi, Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2019.100509
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13. Taylor CW, Wang Z, Macaulay E, Jagsi R, Duane F, Darby SC. Exposure of the heart in breast cancer radiation therapy: a systematic review of heart doses published during 2003 to 2013. Int J Radiat Oncol Biol Phys. 2015;93:845–853. 14. Jones LW, Haykowsky MJ, Swartz JJ, Douglas PS, Mackey JR. Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol. 2007;50:1435–1441. 15. Taylor C, Correa C, Duane FK, et al. Estimating the risks of breast cancer radiotherapy: evidence from modern radiation doses to the lungs and heart and from previous randomized trials. J Clin Oncol. 2017;35:1641–1649. 16. Paszat LF, Mackillop WJ, Groome PA, Schulze K, Holowaty E. Mortality from myocardial infarction following postlumpectomy radiotherapy for breast cancer: a population-based study in Ontario, Canada. Int J Radiat Oncol Biol Phys. 1999;43:755–762. 17. Hooning MJ, Aleman BM, van Rosmalen AJ, Kuenen MA, Klijn JG, van Leeuwen FE. Cause-specific mortality in long-term survivors of breast cancer: A 25-year follow-up study. Int J Radiat Oncol Biol Phys. 2006;64:1081–1091. 18. Paszat LF, Mackillop WJ, Groome PA, Boyd C, Schulze K, Holowaty E. Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. J Clin Oncol. 1998;16:2625–2631. 19. Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: american society of clinical oncology clinical practice guideline. J Clin Oncol. 2017;35:893–911. 20. Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2012;23(Suppl 7):vii155–166. 21. Desai N, Currey A, Kelly T, Bergom C. Nationwide trends in heart-sparing techniques utilized in radiation therapy for breast cancer. Adv Radiat Oncol. 2019;4:246–252. 22. Gagliardi G, Constine LS, Moiseenko V, et al. Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys. 2010;76:S77–S85. ˚ 23. Källman P, Agren A, Brahme A. Tumour and normal tissue responses to fractionated non-uniform dose delivery. Int J Radiat Biol. 1992;62:249–262. 24. Sardaro A, Petruzzelli MF, D’Errico MP, Grimaldi L, Pili G, Portaluri M. Radiation-induced cardiac damage in early left breast cancer patients: risk factors, biological mechanisms, radiobiology, and dosimetric constraints. Radiother Oncol. 2012;103:133–142. 25. Shah C, Badiyan S, Berry S, et al. Cardiac dose sparing and avoidance techniques in breast cancer radiotherapy. Radiother Oncol. 2014;112:9–16. 26. Gagliardi G, Lax I, Ottolenghi A, Rutqvist LE. Long-term cardiac mortality after radiotherapy of breast cancer–application of the relative seriality model. Br J Radiol. 1996;69:839–846. 27. van den Bogaard VA, Ta BD, van der Schaaf A, et al. Validation and modification of a prediction model for acute cardiac events in patients with breast cancer treated with radiotherapy based on three-dimensional dose distributions to cardiac substructures. J Clin Oncol. 2017;35:1171–1178. 28. Duane F, Aznar MC, Bartlett F, et al. A cardiac contouring atlas for radiotherapy. Radiother Oncol. 2017;122:416–422. 29. Jeulink M, Dahele M, Meijnen P, Slotman BJ, Verbakel WFAR. Is there a preferred IMRT technique for left-breast irradiation? J Appl Clin Med Phys. 2015;16:5266. 30. Zaher E, Fahmy E, Mahmoud K, El Kerm Y, Auf M. Assessment of the onset of radiation-induced cardiac damage after radiotherapy of breast cancer patients. Alexandria J Med. 2018;54:655–660.
Please cite this article as: H. Mahdavi, Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2019.100509
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Contents lists available at ScienceDirect
Current Problems in Cancer journal homepage: www.elsevier.com/locate/cpcancer
Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer Hoda Mahdavi∗ Department of Radiation Oncology, Iran University of Medical Sciences, Tehran, Iran
a b s t r a c t Radiotherapy (RT) as an adjuvant treatment for breast cancer (BC), has caused a reduction of recurrences and BC-related deaths. But it has also induced cardiovascular mortality. Oxidative stress is the principle mediator of RT-induced heart disease, similar to many conventional cardiovascular risk factors. The aggregate effect of cardiovascular conditions, RT of heart substructures, implied techniques, and population cardiac mortality rates is not well understood. Due to uncertainties in this field, this article aims to briefly review the recommended strategies for risk assessment, plan optimization, and screening for prevention of RT-induced heart disease in BC patients. © 2019 Elsevier Inc. All rights reserved.
a r t i c l e
i n f o
Keywords: Radiotherapy; Radiation-induced heart disease; Breast cancer
Introduction During recent decades breast cancer (BC) survival rate has increased owing to improvements in early detection, treatment, and longevity of the population.1 Meanwhile, concerns for
✩
Financial disclosure: There are no competing financial interests. Conflict of interest: None. ∗ Correspondence to: Hoda Mahdavi, Department of Radiation oncology, Firoozgar General Hospital, Beh-Afarin St., Karimkhan-e-Zand Ave., Vali-e-Asr Sq., Tehran, Iran. E-mail address: [email protected] ✩✩
https://doi.org/10.1016/j.currproblcancer.2019.100509 0147-0272/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: H. Mahdavi, Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2019.100509
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survivorship and long-term effects of treatments including radiotherapy (RT) have risen. RT reduces local failure and prolongs survival of BC when it is used as an adjuvant to either lumpectomy or high-risk postmastectomy.2 Trends for broader RT coverage of regional lymph nodes such as the internal mammary nodes (IMN), and RT implementation in place of axillary lymph node dissection to minimize the burden of surgery have emerged. These approaches have led to an expansion of considerations for adjuvant RT. Nevertheless, the heart may incidentally receive irradiation that can potentially cause clinically significant manifestations of cardiac disease. The exact incidence is of RT-induced heart disease is unclear.3 However, given the increasing survivorship and indications for RT, the magnitude of this problem may not be negligible. An early meta-analysis of postmastectomy studies before 1975 showed an excess of cardiac deaths in 10 years, in the adjuvant RT group compared to surgery alone. This finding was seemingly offset by a reduced number of deaths due to BC treatment (64.2 excess cardiac deaths vs 49.5 less BC deaths).4 more recent review of trials since 1995 has validated that RT reduces the absolute risk of BC-related deaths compared to surgery alone. However, an excess cardiac mortality rate of 27% at 15 years was identified when RT was used adjuvant to surgery. Moreover, the difference in long-term mortality was not apparent in a subset of patients who gained relatively small local control benefit from RT.2 Later, a meta-analysis on over a million participants with pooled data gathered since 1966 discovered that RT to the breast has so far caused excess cardiac deaths with a ratio of 1.25 per thousand people a year.5 These negative observation of RT-related deaths have been linked to old 2-dimensional RT techniques with suboptimal total RT dose and fractionation, that would not allow for cardiac sparing.6 , 7 In this regard, several studies with contemporary RT techniques did not find a significant excess risk of ischemic heart disease in patients who received radiation.8 Later on, findings of a pivotal study by Darby et al showed a linear dose response relationship for relative risk of major cardiac events.9 In addition a residual risk for improved techniques may still be substantial for certain subsets of patients. Hence, this article aims to briefly review the risks of RT-induced heart disease and related uncertainties that may cause practical barriers.
Pathophysiology of RT-induced heart disease RT activates multiple pathways that are responsible for oxidative stress, inflammatory response, microvascular dysfunction, myocyte injury, and fibrosis.10 A spectrum of complications depending on the affected heart substructure has been described. The host of pathologies is related to coronary arteries, ventricular perfusion, pericardium, valves, conduction system, and the autonomous system.9 , 10 In general, the endothelial tissue is the principle target that within RT fields accelerated atherosclerosis and early vascular stenosis occurs. The occluded vessels are responsible for chronic myocardial ischemia.11 , 12 Since most of the cardiac risk is from ischemic heart disease,13 much attention is driven to perfusion alterations surrounding the left anterior (LAD) descending artery; a continuation of the left coronary artery and a cardinal route for blood supply for a large area of myocardial tissue. The majority of the consequent myocardial dysfunction is subclinical and is with uncertain clinical significance.3 However, patients may eventually develop symptomatic heart failure as early as 5-10 years postexposure that can be lifethreatening. Noticeably, the persistence of cardiac mortality risk could remain up to the third decade after treatment.5
Cardiovascular risk factors Cardiovascular disease (CVD) and BC are leading causes of morbidity in the female population. The 2 share risk factors such as age, dietary fat, tobacco and alcohol consumption, stationary lifestyle, obesity, and hormone replacement therapy.10 Relative to estimates in the general population, worse cardiovascular risk prevalence in early BC has been detected. This has been Please cite this article as: H. Mahdavi, Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2019.100509
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Table 1 Summary of risk factors for radiation-induced heart diseases in early breast cancer. Time and age factors younger age (<50 years), age >60 years, longer interval since exposure Pre-existing cardiovascular diseases Arrhythmia, myopathy, or chronic ischemic heart disease, chronic obstructive pulmonary disease, left ventricle ejection fraction ≤50%-55%, prior myocardial infarction, or moderate valvular heart disease Pre-existing cardiovascular risk factors Dyslipidemia, current smoking, hypertension, diabetes of any type, high body mass index (≥30) Anatomical factors Left side breast cancer, presence, and extent of tumor next to the heart, maximum heart distance >1 cm from the posterior tangential edge, number of slices on CT scans in which the heart contacts chest wall Medical treatment factors Adjuvant chemotherapy (anthracyclins, taxanes, antimetabolites, alkylating agents), HER2/neu directed therapies, endocrine therapies Radiation planning factors Low energy radiation: orthovoltage or 60 Co, field placement near the heart (anterior fields or internal mammary nodes coverage), suboptimal cardiac protection, large volume of irradiated heart, dose >30-35 Gy, higher dose per fraction >2 Gy
linked to a multihit process of direct effects of cardiotoxic therapies and indirect effects of modifiable lifestyle factors.14 For example, it has been observed that current smoking induced high absolute risks for secondary lung cancer (4%) and cardiac mortality (1%) in BC patients who received RT.15 In this regard, the overall synergy with RT in some instances outweighs the survival benefit of RT. The effect of some risk factors such as age is complex. An increased likelihood of mortality from myocardial infarction after 10-15 of treatment of left-sided was demonstrated in a Canadian population-based study conducted in the years 1982-1987.16 This result with limitations of a short follow-up interval may mirror the higher incidence and mortality rates of CVD by ageing. Besides, 2 separate analyses of database during 1970-1992 revealed an increased cardiac risk for left-sided BC patients younger than 50-60 years old. The relative risks of cardiac mortality did not reflect the baseline increases of risk by ageing.17 , 18 These findings are sensibly in accord with the ongoing nature of RT-related heart disease. Cardiac RT dose also depends on laterality. In right-BC patients the heart may receive dose from radiation scatter that is usually negligible. Instead, in the left-BC patients, the heart can be exposed to near-total RT dose, especially when the IMN is included; as a systematic review demonstrated that the average mean dose of heart (MHD) doubled when the IMN was included in left-breast plans.13 A meta-analysis showed that RT increases relative risks of developing coronary heart disease and related cardiac death by ratio of 1.29 and 1.22, respectively in the left BC as compared to the right BC.5 Seemingly, the risk difference between patients with left-sided and right-sided BC declined over time with contemporary techniques.6 A list of commonly described predisposing risks3 , 8 , 9 , 12 , 16 , 19-21 are summarized in Table 1.
Prevention of RT-induced heart disease Dosimetric clinical endpoints The radiation oncologist needs to define clinical or subclinical endpoints for an optimal cardiac sparing plan. This is achieved by point-dose (volumetric or dosimetric constraints), global (eg, MHD), or parametric model-based data such as Normal Tissue Complication Probability (NTCP) estimations. Recommendations are based on limited data so there might be high errors in their clinical estimation. Quantitative Analyses of Normal Tissue Effects in the Clinic recommends preserving MHD below 26 Gy, and V30 (volume receiving at least 30 Gy) of the heart below 46%. The Quantitative Analyses of Normal Tissue Effects in the Clinic’s conservative NTCP model suggests that heart V25 Gy below 10% is associated with less than 1% probability of Please cite this article as: H. Mahdavi, Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2019.100509
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cardiac mortality in 15 years. The drawback of the indices is point doses were extracted from a study on definitive chemoradiation for esophageal cancer. The parameters reduced the risk of pericardial effusion from 73% to 13%. In present, as the RT fields do not direct the mediastinum, pericarditis is a relatively uncommon self-limiting complication. Furthermore, with a notion of dosimetric data are most applicable in the disease setting which they were derived, these indicators are no longer appropriate. In addition the volumes receiving higher near typical prescription doses for BC are not included in the NTCP model. Notably, the beneficial survival effects of RT for BC could be offset by heart complications when an NTCP value is 5% or more. Estimates suggest that when heart V30-40 is kept within 30%-35%, there is still a 5% excess risk of cardiac death at 15 years.22 The heart is a typical example of a serial-parallel organ and is consisted of serial myocardium and parallel vessels.23 Several researches that are supported by mathematical analysis suggest a dominantly serial architecture for the heart.24 In many instances cardiomyocytes have been viewed relatively resistant to RT at doses below 30 Gy. Theoretically, small regions of dose above this tolerance limit drive the main risk. However, it is not yet known on a physiological basis that whether a relatively high radiation dose to a small volume or the lower average dose to the whole heart is responsible for cardiovascular effects. In a typical left breast or chest-wall plan with tangential photon beams, the apex, anterior heart, and the LAD are within a region that receives high dose.11 In general, it is reasonable to consider these substructures and the left ventricle (LV) where the highest risk of cardiac morbidity from RT arises, as Organs At Risk (OAR).12 , 25 The relative seriality model has usually been used to calculate the risk of excess late cardiac mortality. This model that assumes a homogenous dose distribution within the heart anticipates an extra mortality of up to 50% at 15 years when the heart myocardium receives 52 Gy.26 This is only slightly above typically prescribed doses for BC. Because of concerns of the related ischemic events, many investigators have calculated dose constraints for LAD. Piroth et al12 suggested Dmean LAD < 10 Gy, V30 LAD < 2%, V40 < 1% in both conventional and hypofractionated regimes in left BC RT based on publications extracted from literature. They also suggested Dmean LV < 3Gy, V5 LV < 17%, V23 LV < 5%. However, there is a lack of precise long-term clinical dose-response data to guide planning objectives. The MHD is among the most common parameters apprehended by radiation oncologists.21 Dose received by cardiac substructures are likely to correlate strongly with whole-heart dose. Nonetheless, MHD was not consistently representative of dose to the LAD in several studies. The population-based case-control model of BC patients treated in 1958-2001 of Darby et al showed a gradual increase of 7.4% per Gy MHD relative risk attributed to major coronary events within 5-20 years.9 One of their findings was that MHD may be a better predictor of the rate of major coronary events than the mean dose to LAD. Although the method for calculating cardiac dose was outdated,25 their model was validated in a survival analysis of a cohort treated in 20052008. It is now strongly recommended that a priority for plan optimisation should be keeping doses to the whole-heart as low as reasonably achievable.19 , 27 Current evidence shows that MHD in order of 1.6-2.5 Gy is a dose range that could probably be safe.12
Radiation therapy techniques In typical tangential photon plans, conformal blocking by field-in-field techniques can effectively reduce dosimetric hot areas of the heart particularly when the tumor is located in the upper portion of the breast. Planning CT does not clearly show heart structures and along with the heart movements in cardiac and respiratory cycles, defining vascular and myocardial volumes can be challenging.25 Guides for cardiac contouring for CT planning have been developed to adjust for the uncertainties regarding complex and obscure anatomy of heart substructures. Atlases do not usually account for variations in coronary divisions. However, registered to the planning CT, specific imaging modalities such as CT-based coronary angiography with electrocardiographic gaiting has enabled to overcome the mentioned shortcomings and provide more Please cite this article as: H. Mahdavi, Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2019.100509
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accurate image for contouring. In terms of gaiting images, not only limitations related to their availability and feasibility applying on a large number of patients exists, but also, dose delivery is not synchronized with cardiac cycle in conventional RT machines. Therefore, an appropriate planning risk volume should be added to the outlined structures to account for heart motion.28 There are 3 approaches used alone or in combination when there is a propensity for heart sparing. First, changing anatomical measures, second, using advanced technologies, and third, using partial breast irradiation. These are further discussed as follows. First, displacing the heart from the clinical target volume is achieved with breathing control methods or prone positioning of the patient. These are the most common techniques that are used in the United States of America.21 Breath-hold and respiratory gating successfully decreased MHD and ventricular dosimetric parameters. Their clinical benefit has not been studied in randomized trials, but a model estimate reported a reduction of cardiac mortality by 4.7% compared to free-breathing with a median cardiac mortality NTCP of 0.1%.25 However, their implementation depends on tolerance and anatomical factors of patients, require sufficient timing and expertise, and facilities that are certainly not universally available. Prone positioning is effective for cardiac sparing in over 50% of patients. However dosimetric values for cardiac sparing were not consistent in breasts with small volumes.25 The second is using advanced technologies for the RT plan and delivery. Intensity-modulated radiotherapy (IMRT) plans have theoretical advantage of dose conformity and homogeneity. Significant reductions of low- and high-dose cardiac measures, the MHD, and NTCP modeling of heart complications as well as lower dose to coronary arteries have been reported with IMRT. Large breasted patients may particularly benefit more.25 Dose constrains set in inverse IMRT, in particular, drive the cardiac dose; so depending on its strictness the amount of cardiac exposure can be variable. As in a systematic review by Taylor et al of reported MHDs from 2003 to 2013 showed that standard or rotational IMRT had surprisingly the highest average MHD among all applied techniques with albeit a wide range of reported values.13 Classic IMRT can be combined with tangential fields and the hybrid plans optimized in terms of cardiac sparing. An alternative technique is using multiple partial volumetric modulated Arc therapy (VMAT) arcs to restrain exposure to choices of OARs.29 Limited nonrandomized data support advantages of proton beam therapy for BC after breast conserving or mastectomy. Due to its lower exit dose compared to photons, it can effectively spare any OAR beyond its dose fall-off. Proton beam therapy poses the lowest reported average MHD for left-sided BC when IMNs were not treated (0.5 Gy; range, 0.1-0.8 Gy relative to 3.8 Gy; range, <0.1-12.4 Gy, for average MHD for left-tangential RT with no breathing control). It also appeared as a technique that had the best cardiac sparing results when IMNs were treated.13 However, it is most costly and less accessible than photons and thereby it is not a subject of advocacy. It still is a valuable option to receipt very low MHD to minimize cardiac risk. The third is to change the traditional targets of the whole breast to partial breast irradiation. This is not standard, has limited indications, depends on anatomical indices, and concerns about local recurrence rates have not been resolved.25 Finally, the planning system should correct for inhomogeneity of the lungs to prevent underestimation of the dose to the heart.22
Screening Cardiac mortality may be less concerning in BC than before as management of heart ischemia has improved and also population cardiac mortality rates have decreased.8 , 15 In the general population, nearly 80% of CVD can be prevented through lifestyle modification and control of high blood pressure, diabetes, and dyslipidemia.10 The health economic impact of controlling many of the modifiable risk factors and their effect on the deceleration of radiation damage in BC patients is not well known.3 , 22 Patients are usually managed the same as nonirradiated patients; however, prognosis, success rates, and complications, for heart interventions are usually worse in irradiated patients.11 The American Society of Clinical Oncology has no screening recommendations on prevention of risk for cardiac dysfunction for patients who receive Doxorubicin with doses lower than Please cite this article as: H. Mahdavi, Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2019.100509
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250 mg/m2 or trastuzumab alone. However, those who carry additional risks (eg, older age (60 ≥ years), sequential anthracycline and trastuzumab, multiple cardiovascular risk factors, compromised cardiac function, or low dose RT (<30 Gy) in combination with anthracyclines), require screening. Screening is also recommended for higher dose RT (>30 Gy) when the heart is in the treatment field. In these patients, modifiable cardiovascular risks should be assessed and controlled, a baseline echocardiogram should be performed, and RT fields should be tailored with advanced RT techniques.19 A practice guidelines by the European Society for Medical Oncology recommends screening all patients who are receiving anthracyclines or trastuzumab by Troponin (Tn).20 Tn type I (TnI) that is widely studied in patients with cancer can detect cardiac dysfunction in its earliest phase before any detectable left ventricular ejection fraction (LVEF) change. If positive, regular echocardiogram is indicated. Also, acute rise in TnI levels due to RT and its ability to predict late-effects has been described.30 Despite these findings, currently, follow-up protocols for irradiated patients who had not received anthracyclines are diverse and based on practitioners’ experience and patients’ needs.20 It is recommended by The European Association of Cardiovascular Imaging and the American Society of Echocardiography that cancers that require chest RT with at least 1 risk factor benefit from intensive risk control, and baseline and regular echocardiography. The risk items that are relevant to breast treatment are anterior or left chest irradiation, inadequate or absent RT shielding, age under 50, high-dose-per-fraction, and pre-existing cardiovascular risks or diseases.11
Conclusion For the OAR choice of heart, interaction between most cardiovascular risks and the heart dose-volume effect and their long-term outcome is poorly understood. It is more judicious to use individualized risk modification for appropriate patients regarding their comorbidities and overall prognosis. Certain subsets of BC patients, including young patients with cardiovascular or treatment-related risks, or unfavourable anatomy, may benefit from risk assessment and risk modification, cardiac-sparing RT planning techniques, and long-term follow-up. In selected patients, the irradiated heart volume should be minimized to a highest possible degree with no significant compromise of target coverage.
References 1. Miller KD, Nogueira L, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2019. CA: Cancer J Clin. 2019;69:363–385. 2. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366:2087–2106. 3. 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;35:612–623. 4. Cuzick J, Stewart H, Rutqvist L, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol. 1994;12:447–453. 5. Cheng YJ, Nie XY, Ji CC, et al. Long-term cardiovascular risk after radiotherapy in women with breast cancer. J Am Heart Assoc. 2017;6. 6. Giordano SH, Kuo Y-F, Freeman JL, Buchholz TA, Hortobagyi GN, Goodwin JS. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst. 2005;97:419–424. 7. Patt DA, Goodwin JS, Kuo Y-F, et al. Cardiac morbidity of adjuvant radiotherapy for breast cancer. J Clin Oncol. 2005;23:7475–7482. 8. Harris EE, Correa C, Hwang WT, et al. Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. J Clin Oncol. 20 06;24:410 0–4106. 9. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368:987–998. 10. Mehta LS, Watson KE, Barac A, et al. Cardiovascular disease and breast cancer: where these entities intersect: a scientific statement from the American Heart Association. Circulation. 2018;137:e30–e66. 11. Donnellan E, Phelan D, McCarthy CP, Collier P, Desai M, Griffin B. Radiation-induced heart disease: a practical guide to diagnosis and management. Cleve Clin J Med. 2016;83:914–922. 12. Piroth MD, Baumann R, Budach W, et al. Heart toxicity from breast cancer radiotherapy: current findings, assessment, and prevention. Strahlenther Onkol. 2019;195:1–12. Please cite this article as: H. Mahdavi, Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2019.100509
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13. Taylor CW, Wang Z, Macaulay E, Jagsi R, Duane F, Darby SC. Exposure of the heart in breast cancer radiation therapy: a systematic review of heart doses published during 2003 to 2013. Int J Radiat Oncol Biol Phys. 2015;93:845–853. 14. Jones LW, Haykowsky MJ, Swartz JJ, Douglas PS, Mackey JR. Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol. 2007;50:1435–1441. 15. Taylor C, Correa C, Duane FK, et al. Estimating the risks of breast cancer radiotherapy: evidence from modern radiation doses to the lungs and heart and from previous randomized trials. J Clin Oncol. 2017;35:1641–1649. 16. Paszat LF, Mackillop WJ, Groome PA, Schulze K, Holowaty E. Mortality from myocardial infarction following postlumpectomy radiotherapy for breast cancer: a population-based study in Ontario, Canada. Int J Radiat Oncol Biol Phys. 1999;43:755–762. 17. Hooning MJ, Aleman BM, van Rosmalen AJ, Kuenen MA, Klijn JG, van Leeuwen FE. Cause-specific mortality in long-term survivors of breast cancer: A 25-year follow-up study. Int J Radiat Oncol Biol Phys. 2006;64:1081–1091. 18. Paszat LF, Mackillop WJ, Groome PA, Boyd C, Schulze K, Holowaty E. Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. J Clin Oncol. 1998;16:2625–2631. 19. Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: american society of clinical oncology clinical practice guideline. J Clin Oncol. 2017;35:893–911. 20. Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2012;23(Suppl 7):vii155–166. 21. Desai N, Currey A, Kelly T, Bergom C. Nationwide trends in heart-sparing techniques utilized in radiation therapy for breast cancer. Adv Radiat Oncol. 2019;4:246–252. 22. Gagliardi G, Constine LS, Moiseenko V, et al. Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys. 2010;76:S77–S85. ˚ 23. Källman P, Agren A, Brahme A. Tumour and normal tissue responses to fractionated non-uniform dose delivery. Int J Radiat Biol. 1992;62:249–262. 24. Sardaro A, Petruzzelli MF, D’Errico MP, Grimaldi L, Pili G, Portaluri M. Radiation-induced cardiac damage in early left breast cancer patients: risk factors, biological mechanisms, radiobiology, and dosimetric constraints. Radiother Oncol. 2012;103:133–142. 25. Shah C, Badiyan S, Berry S, et al. Cardiac dose sparing and avoidance techniques in breast cancer radiotherapy. Radiother Oncol. 2014;112:9–16. 26. Gagliardi G, Lax I, Ottolenghi A, Rutqvist LE. Long-term cardiac mortality after radiotherapy of breast cancer–application of the relative seriality model. Br J Radiol. 1996;69:839–846. 27. van den Bogaard VA, Ta BD, van der Schaaf A, et al. Validation and modification of a prediction model for acute cardiac events in patients with breast cancer treated with radiotherapy based on three-dimensional dose distributions to cardiac substructures. J Clin Oncol. 2017;35:1171–1178. 28. Duane F, Aznar MC, Bartlett F, et al. A cardiac contouring atlas for radiotherapy. Radiother Oncol. 2017;122:416–422. 29. Jeulink M, Dahele M, Meijnen P, Slotman BJ, Verbakel WFAR. Is there a preferred IMRT technique for left-breast irradiation? J Appl Clin Med Phys. 2015;16:5266. 30. Zaher E, Fahmy E, Mahmoud K, El Kerm Y, Auf M. Assessment of the onset of radiation-induced cardiac damage after radiotherapy of breast cancer patients. Alexandria J Med. 2018;54:655–660.
Please cite this article as: H. Mahdavi, Radiation oncologists’ perspectives on reducing radiation-induced heart disease in early breast cancer, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2019.100509