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Originally published as JCO Early Release 10.1200/JCO.2005.07.011 on September 26 2005 © 2005 American Society of Clinical Oncology.
Radiation-Induced Heart Disease: Vigilance Is Still RequiredDepartment of Radiation Oncology, Duke University Medical Center, Durham, NC Radiation therapy (RT) plays an important role in the multimodality management of patients with breast cancer. Trials conducted in the 1970s established that survival is equivalent after either breast conservation (local excision and RT) or mastectomy. Studies performed in the 1980s showed that the addition of RT to lumpectomy significantly reduces the risk of local recurrence and, in a meta-analysis, enhanced survival as well.1 Finally, trials conducted in the 1980s also demonstrated that RT after mastectomy dramatically decreases locoregional recurrence and significantly improves overall survival in patients with involved axillary nodes or large primary tumors.2 This silver cloud unfortunately has a black lining. In the late 1980s, data emerged that older radiotherapy (RT) techniques used in the treatment of breast cancer, particularly after mastectomy, resulted in increased rates of both cardiac morbidity and mortality. In a meta-analysis involving 19,582 women with breast cancer enrolled onto 40 randomized trials begun before 1990, the Early Breast Cancer Trialists Collaborative Group found that RT reduced the annual mortality from breast cancer by 13% but increased the annual mortality rate from other causes by 21% and that this increase was due primarily to an excess number of deaths from vascular causes (death rate ratio, 1.3 [SE 0.09]).3 In a similar meta-analysis, Cuzick et al4 reviewed individual patient-level data from 7,941 women enrolled onto 10 randomized trials of mastectomy, with or without RT, initiated before 1975 and found that the standardized mortality ratio was significantly higher for patients treated with RT compared with controls (1.11 v 0.69; P < .001). Critical factors in the genesis of radiation-induced heart disease are the volume of heart exposed and the radiation dose deposited in that volume. Older methods of delivering postmastectomy RT resulted in relatively large volumes of heart being incidentally exposed to moderate to high doses of radiation. The main culprit was thought to be the use of anterior photons to treat the ipsilateral internal mammary nodes, often as part of a larger L-shaped so-called hockey-stick field that also covered the supraclavicular and sometimes the axillary nodes. Once the adverse effects of RT on the heart were recognized, techniques evolved to irradiate the chest wall and regional nodes while reducing exposure of the heart. The hockey-stick method was abandoned by most radiation oncologists in favor of methods that included the internal mammary nodes (IMNs) within the same tangential RT fields used to irradiate the chest wall (so-called deep or partially wide tangents) or treated the IMNs mostly or entirely with superficially penetrating electrons, rather than deeply penetrating photons. Given the controversy about the necessity of treating the IMNs and the possible increased cardiac risk that came from electively doing so, other radiation oncologists elected to abandon IMN treatment altogether. The safety of irradiating the chest wall was also improved by the development of treatment planning based on computed tomography that enabled better visualization of the heart, leading to the selection of RT fields that minimized cardiac exposure. These heart-sparing RT methods for irradiating the chest wall (with or without the regional nodes), were also applied to the treatment of patients with an intact breast, which rapidly gained in popularity following the publication of the randomized trials comparing mastectomy with breast conservation. For patients with an intact breast, but uninvolved axillary lymph nodes, tangential fields that minimized cardiac exposure were used to treat only the breast itself. Have these modern methods of delivering adjuvant RT following mastectomy or lumpectomy eliminated the risk of cardiac injury? In this issue of the Journal of Clinical Oncology, Patt et al5 from the M.D. Anderson Cancer Center (Houston, TX) attempt to answer this question. Using data from the Surveillance, Epidemiology, and End Results (SEER) –Medicare database, they identified more than 16,000 women diagnosed with nonmetastatic breast cancer from 1986 to 1993 who received adjuvant RT following breast surgery. They then compared the rate of hospitalization for ischemic heart disease, valvular heart disease, congestive heart failure, and conduction abnormalities in patients with left- and right-sided breast cancer. With a mean follow-up of 9.5 years, there were no significant differences in the rate of hospitalization for any of the cardiac conditions examined in patients with left- compared to right-sided tumors. The same group of investigators also used the SEER-Medicare database to examine cardiac mortality after adjuvant RT for breast cancer. Giordano et al6 identified more than 27,000 patients diagnosed with early-stage breast cancer from 1973 to 1989 who received adjuvant RT. The 15-year rate of mortality from ischemic heart disease in patients with left- and right-sided tumors was compared for patients diagnosed in three different time periods: 1973 to 1979, 1980 to 1984, and 1985 to 1989. All patients were censored at 12 years of follow-up to ensure equal follow-up. Although ischemic heart disease mortality was higher for patients with left-sided tumors who were diagnosed in the earliest time period, no significant differences were seen for patients diagnosed in either of the two later time periods. The studies by Patt et al5 and the similar study by Giordano et al6 have a number of significant strengths. First, the sample size in both of these of these studies is large. The study by Giordano et al included 27,283 patients, and the study by Patt et al included 16,270 patients. These large sample sizes reduce the probability of type II error. Second, the mean follow-up in both studies was relatively long: 9.5 and 9.3 years for Patt et al and Giordano et al, respectively. Because radiation-induced heart disease is a late effect of radiotherapy, studies with extended follow-up are most useful. Finally, both studies address clinically meaningful end points. Giordano et al6 examined overall survival, perhaps the most clinically meaningful end point. The main drawback of this end point is that the latency between the onset of radiation-induced heart disease and secondary mortality may be many years. To overcome this obstacle, Patt et al examined the surrogate end point of cardiac morbidity. As the authors correctly point out, cardiac morbidity may be a more sensitive and earlier predictor of cardiac damage than mortality. Do the results of these studies provide definitive evidence that current techniques for irradiating patients with breast cancer do not endanger the heart? We think not. Although their analysis is methodologically sound, there are several limitations, most of which are acknowledged by the authors. First, the median follow-up of 9.5 years, while relatively long, may not be adequate to detect the long-term consequences of cardiac irradiation. Studies of the long-term survivors of breast cancer and Hodgkin’s disease have demonstrated that the risk for radiation-associated heart disease increases for at least 20 years after RT.7-9 The current report’s finding of no difference in cardiac morbidity in the first 10 years after RT is reassuring, but clinically meaningful differences may emerge with longer follow-up. Second, the SEER-Medicare data set does not contain information regarding RT technique. RT technique and patient anatomy are the primary factors that determine the volume and dose of incidental cardiac irradiation. With different techniques, the amount of heart in the RT fields may vary considerably. The study by Patt et al,5 therefore, does not ensure that all current RT methods are safe. Third, the underlying assumption on which the study is based, that patients with right-sided tumors did not receive any incidental cardiac irradiation and could therefore serve as the control group, may not be entirely true. Approximately 25% of the patients with both left- and right-sided tumors in the study had involvement of the regional lymph nodes and would therefore have been candidates for IMN treatment. If a significant fraction of patients with both right- and left-sided tumors had anterior IMN fields, long-term cardiac toxicity may have occurred in both groups. Fourth, these studies do not directly address the potentially synergistic cardiotoxic effects of systemic therapies and RT. Anthracyclines, currently a mainstay breast chemotherapy, and newer agents such as trastuzumab, are potentially cardiotoxic. The use of these agents likely increases the potential cardiac risks associated with radiation. Although neither the Patt et al5 nor the Giordano et al6 study observed differences in cardiac morbidity and mortality among patients with regional-stage disease receiving left-sided RT compared with right-sided RT (most of whom presumably received adjuvant chemotherapy), the percentage of patients in either study who received anthracyclines is unknown, due to the limitations of the SEER-Medicare database. Epidemiologic studies are useful in describing the scope of the problem of radiation-induced heart disease from the perspective of the larger population. However, they lack detailed individual dose and volume information needed to establish a pathophysiologic link between RT exposure and cardiac injury. We believe that this link is the key to identifying the subsets of patients who may be at increased risk for radiation-induced heart disease. To understand the pathophysiology of radiation-induced heart disease, we and others have examined the surrogate end points of radiologic changes in myocardial perfusion, wall motion, or ejection fraction (EF) after RT. In 1998, we began enrolling patients with left-sided breast cancer onto a prospective study to determine the potential cardiotoxic effects of RT using modern techniques. Patients had modern treatment planning based on computed tomography and pre-RT and serial post-RT single-photon emission computed tomography–gated cardiac myocardial perfusion scans to assess for changes in heart function. New perfusion defects occurred in 50% to 63% of women 6 to 24 months after RT.10,11 The incidence of perfusion defects was strongly correlated with the volume of left ventricle (LV) in the RT field, occurring in 25% of patients with 1% to 5% of the LV within the tangent fields, and in 55% of patients with more than 5% of the LV within the field. These perfusion defects generally persist at least 3 to 5 years after RT.12 The clinical significance of these perfusion defects is unknown. However, they appear to be associated with abnormalities in wall motion, declines in EF, and episodes of chest pain (likely pericarditis).13,14 The data from our study and others are summarized in the Table 1. Changes in EF have been apparent only in patients with relatively large fractions of the LV affected by perfusion defects.13,20
Thus, these data suggest that RT-induced cardiac injury may still occur with modern techniques. Furthermore, these cardiac abnormalities can be seen in patients with extremely small fractions (eg, 5%) of their LV included within the RT fields. Five percent of the LV corresponds to approximately 2% to 3% of the heart; a small fraction that is often difficult to discern on traditional dose volume histograms, which would generally be considered "safe" by most radiation oncologists. On the basis of these results, we frequently use a heart block to markedly reduce, and sometimes eliminate, incidental cardiac irradiation in our patients. In patients in whom such a block may result in inadequate coverage of tissues at high risk of harboring microscopic disease, compromises are made, or alternative techniques such as electron-patches or respiratory gating are considered. Although modern RT techniques have reduced radiation exposure to the heart, they may not have eliminated cardiotoxicity. It appears that contemporary RT methods may still cause cardiovascular disease. Changes in myocardial perfusion, wall motion, and EF have been demonstrated in patients undergoing treatment with modern techniques. Whether these radiographic changes will ultimately have clinical significance is unclear. The reports by Patt et al5 and Giordano et al6 provide some reassurance that the magnitude of the problem for the entire population of patients undergoing RT for breast cancer may not be large. However, they do not preclude the possibility that certain subsets of patients may be at high risk of radiation-induced heart disease. At present, we believe that radiation oncologists should use contemporary RT planning and delivery methods that minimize cardiac exposure, such as heart blocks21 and partially wide tangents.22 Treatment needs to be delivered accurately, given that small errors in patient setup may increase a patient’s risk of developing a perfusion defect.21 We and others currently are investigating techniques to further reduce cardiac exposure, such as intensity-modulated radiation therapy, respiratory gating, mixed electron/photon beams and tomotherapy.23-29 With treatment innovation, it is our goal to eliminate incidental irradiation of the heart and to make radiation-induced heart disease a historical footnote. Authors' Disclosures of Potential Conflicts of Interest The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Acknowledgment Supported in part by Grant No. DAMD17-02-1-0374 from the Department of Defense. REFERENCES
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2. Whelan TJ, Julian J, Wright J, et al: Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 18:1220-1229, 2000 3. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomised trials—Early Breast Cancer Trialists' Collaborative Group. Lancet 355:1757-1770, 2000[CrossRef][Medline] 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 12:447-453, 1994[Abstract]
5. Patt D, Goodwin J, Kuo Y-F, et al: Cardiac morbidity of adjuvant radiotherapy for breast cancer. J Clin Oncol 23:7475-7482, 2005
6. Giordano SH, Kuo YF, Freeman JL, et al: Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97:419-424, 2005
7. Hancock SL, Donaldson SS, Hoppe RT: Cardiac disease following treatment of Hodgkin's disease in children and adolescents. J Clin Oncol 11:1208-1215, 1993 8. Jones JM, Ribeiro GG: Mortality patterns over 34 years of breast cancer patients in a clinical trial of post-operative radiotherapy. Clin Radiol 40:204-208, 1989[CrossRef][Medline] 9. Rutqvist LE, Lax I, Fornander T, et al: Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer. Int J Radiat Oncol Biol Phys 22:887-896, 1992[Medline] 10. Hardenberg PH, Munley MT, Hu C, et al: Doxorubicin-based chemotherapy and radiation increase cardiac perfusion changes in patients treated for left-sided breast cancer. Int J Radiat Oncol Biol Phys 51:S158, 2001[CrossRef] 11. Hardenbergh PH, Munley MT, Bentel GC, et al: Cardiac perfusion changes in patients treated for breast cancer with radiation therapy and doxorubicin: Preliminary results. Int J Radiat Oncol Biol Phys 49:1023-1028, 2001[CrossRef][Medline] 12. Yu X, Zhou S, Kahn D, et al: Persistence of radiation (RT)-induced cardiac perfusion defects 3-5 years post RT. J Clin Oncol 23:33S, 2004 (suppl; abstr 625) 13. Marks LB, Yu X, Prosnitz RG, et al: The incidence and functional consequences of RT-associated cardiac perfusion defects. Int J Radiat Oncol Biol Phys 63:214-233, 2005[CrossRef][Medline] 14. Yu X, Prosnitz RR, Zhou S, et al: Symptomatic cardiac events following radiation therapy for left-sided breast cancer: Possible association with radiation therapy-induced changes in regional perfusion. Clin Breast Cancer 4:193-197, 2003[Medline] 15. Gyenes G, Fornander T, Carlens P, et al: Morbidity of ischemic heart disease in early breast cancer 15-20 years after adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 28:1235-1241, 1994[Medline] 16. Hojris I, Sand NP, Andersen J, et al: Myocardial perfusion imaging in breast cancer patients treated with or without post-mastectomy radiotherapy. Radiother Oncol 55:163-172, 2000[CrossRef][Medline] 17. Cowen D, Gonzague-Casabianca L, Brenot-Rossi I, et al: Thallium-201 perfusion scintigraphy in the evaluation of late myocardial damage in left-side breast cancer treated with adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 41:809-815, 1998[CrossRef][Medline] 18. Seddon B, Cook A, Gothard L, et al: Detection of defects in myocardial perfusion imaging in patients with early breast cancer treated with radiotherapy. Radiother Oncol 64:53-63, 2002[CrossRef][Medline] 19. Gyenes G, Fornander T, Carlens P, et al: Myocardial damage in breast cancer patients treated with adjuvant radiotherapy: A prospective study. Int J Radiat Oncol Biol Phys 36:899-905, 1996[CrossRef][Medline] 20. Marks LB, Prosnitz RG, Hardenbergh PH, et al: Functional consequences of radiation (RT)-induced perfusion changes in patients with left-sided breast cancer. Int J Radiat Oncol Biol Phys 54:3-4, 2002 21. Quaranta BP, Prosnitz RG, Steffey B: Customized blocking of tangential radiation (RT) breast fields: Excluding the heart vs. covering the breast—Striking a balance. Breast Cancer Res Treat 76:S118, 2002 22. Marks LB, Bentel GC, Hardenbergh PH, et al: A practical and easy method to locate the first three internal mammary lymph node-bearing areas. Int J Radiat Oncol Biol Phys 50:421-425, 2001[CrossRef][Medline] 23. Chen MH, Cash EP, Danias PG, et al: Respiratory maneuvers decrease irradiated cardiac volume in patients with left-sided breast cancer. J Cardiovasc Magn Reson 4:265-271, 2002[CrossRef][Medline] 24. Cho BC, Mijnheer BJ, Bartelink H: Determining optimal two-beam axial orientations for heart sparing in left-sided breast cancer patients. Med Phys 31:111-121, 2004[CrossRef][Medline] 25. Cho BC, Schwarz M, Mijnheer BJ, et al: Simplified intensity-modulated radiotherapy using pre-defined segments to reduce cardiac complications in left-sided breast cancer. Radiother Oncol 70:231-241, 2004[CrossRef][Medline] 26. Das SK, Bell M, Marks LB, et al: A preliminary study of the role of modulated electron beams in intensity modulated radiotherapy, using automated beam orientation and modality selection. Int J Radiat Oncol Biol Phys 59:602-617, 2004[CrossRef][Medline] 27. Deigert F, Gunn W, Lindemann F, et al: A blended beam technique to decrease toxic effects of post mastectomy irradiation by combining and sequentially mixing electrons and photons. Med Dosim 20:183-190, 1995[CrossRef][Medline] 28. Landau D, Adams EJ, Webb S, et al: Cardiac avoidance in breast radiotherapy: A comparison of simple shielding techniques with intensity-modulated radiotherapy. Radiother Oncol 60:247-255, 2001[CrossRef][Medline] 29. Remouchamps VM, Vicini FA, Sharpe MB, et al: Significant reductions in heart and lung doses using deep inspiration breath hold with active breathing control and intensity-modulated radiation therapy for patients treated with locoregional breast irradiation. Int J Radiat Oncol Biol Phys 55:392-406, 2003[CrossRef][Medline] Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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