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Originally published as JCO Early Release 10.1200/JCO.2006.07.7909 on August 14 2006 © 2006 American Society of Clinical Oncology.
Which Breast Cancer Patients Should Really Worry About Radiation-Induced Heart Disease—And How Much?
Department of Radiation Oncology, Harvard Medical School; and Beth Israel Deaconess Medical Center, Boston, MA The most difficult portion of my discussion with breast cancer patients about the potential adverse effects of radiation therapy (RT) is estimating their long-term chance of developing radiation-induced heart disease (RIHD). Very large studies combining tumor registry data with pre-existing regional or national hospital discharge diagnosis and death records1-4 and the Oxford meta-analyses of randomized trials5,6 found increased risks of coronary heart disease (CHD) for irradiated patients compared with nonirradiated ones, or for patients treated to the left breast or chest wall compared to those treated to the right side. However, most patients in these studies were treated with obsolete techniques that exposed much larger volumes of the heart to radiation than is done today,7 often with daily doses (fraction sizes) of 2.5 Gy or higher.8 Patients whose treatment was administered after 1975 to 1980 followed for median times of approximately 9 to 10 years had little or no increased risk of RIHD in these and additional registry9,10 and large clinical series (700 to 3,000 patients).11-14 For example, Giordano et al4 found that the 15-year risk of cardiac mortality for 8,652 patients treated from 1973 to 1979 was substantially higher when left-sided irradiation was administered than when right-sided irradiation was used (13.1% v 10.2%; P = .02). This absolute 15-year rate decreased substantially for 6,495 patients treated from 1980 to 1984 (9.4% v 8.7%, respectively; P = not significant), and there was further greater reduction for 12,136 patients treated from 1985 to 1989 (5.8% and 5.2%, respectively). Certainly, more patients in recent times have been treated to the intact breast without nodal irradiation, which eliminates cardiac irradiation entirely in most patients and, for those still exposed, reduces the irradiated volume.15 Improvements in treatment of CHD also no doubt played a major role in these absolute reductions in both laterality groups, a matter I will return to later. These data have shortcomings. Coding of whether patients actually received RT or had a cardiac event may be inaccurate, particularly in registry studies or when death certificates are the main source of information. For example, Vallis et al14 found that 16% of myocardial infarctions coded in Ontario (Canada) hospital registries were not verifiable according to standard criteria when individual medical records were reviewed. Further, RIHD can take at least 15 to 20 years to develop,16 and few of these more recently treated patients have been followed that long. Nonetheless, I am reasonably certain that patients treated today on average will have a very low risk of RIHD. My problem comes when trying to move beyond the average. For any one patient, the risk of RIHD seems likely to be a function of three variables: the cardiac "dose-volume histogram," the use of potentially cardiotoxic systemic therapy, and the presence and treatment of independent risk factors for CHD (such as hypertension, diabetes, cholesterol and lipid disorders, and smoking). Unfortunately, I do not have an equation at hand with which to make this calculation reliably. Only very recently has the widespread availability of computed tomography (CT) -based treatment planning made it possible to measure accurately how much of the heart is included in or near the RT fields for individual patients. Prosnitz and Marks17 recently reviewed studies of radionuclide cardiac imaging which correlate (imperfectly) the development of perfusion abnormalities with increasing irradiated cardiac volume. However, it is simply too early to know whether this is a reliable surrogate marker for the long-term risk of RIHD. (Indeed, some of these defects disappear with time.18) It is also not certain that this is the optimal parameter. Perhaps the critical target is really the coronary arteries, as suggested by a study of Hodgkin's disease patients treated at Stanford University (Stanford, CA) in which increased left ventricular blocking by itself did not reduce the risk of myocardial infarction.19 Tracing the coronary arteries requires administering intravenous contrast,20 something not usually done in day-to-day clinical RT planning or in these perfusion imaging correlation studies. There is surprisingly little short- or long-term data on cardiac toxicity rates for patients treated with both anthracyclines and RT.21-25 Perhaps the most important information so far comes from Bonneterre et al,25 who studied cardiac function in surviving node-positive patients included in the French Adjuvant Study Group Trial 05, conducted from 1990 to 1993. Patients received six cycles of fluorouracil, cyclophosphamide, and epirubicin, the latter administered at either 50 or 100 mg/m2/cycle (FEC50 or FEC100). Almost all patients had RT that included the internal mammary nodes (IMNs). With a median follow-up time of 102 months, the risk of left ventricular dysfunction in patients with right-sided cancers receiving FEC50 was 7% (two of 30), compared with none of 34 patients irradiated to the left side. For patients receiving FEC100, the respective rates were much higher in both groups, and also different between right and left: 21% (seven of 33) and 35% (17 of 49). (Of note, the two cases of congestive heart failure in this population were both in this last group; each patient also had pre-existing risk factors of older age, hypertension, and/or diabetes.) Participation was quite good for studies of this kind (150 of 278 eligible patients), though one must always of course be concerned whether the participants were truly representative of the entire population. In addition, the follow-up still is short for observing cardiac events. The use of RT did not influence the risk of early cardiac events in patients treated with trastuzumab in the North Central Cancer Treatment Group N9831 trial,26 although the median follow-up of only 1.5 years is clearly far too short to be definitive. (Of note, deliberate IMN irradiation was forbidden in this study.) The registry studies and the Oxford meta-analysis have inconsistent findings as to whether increasing patient age is a risk factor for RIHD.2,3,5,6 However, age is likely a poor surrogate for detailed knowledge of whether patients have specific risk factors for CHD.27 Such cardiac risk factors strongly affect the observed risk of RIHD in patients treated with mantle-field irradiation for Hodgkin's disease,19,28,29 but such information has not generally been collected either prospectively or retrospectively in breast cancer studies. The article by Harris et al30 from the University of Pennsylvania Cancer Center (Philadelphia, PA) in this issue of the Journal of Clinical Oncology is thus very important; it brings together long-term data on a relatively large number of fairly homogeneously treated patients with information on coexisting risk factors for CHD and determination of events gathered by review of individual medical records. Only 13% of patients had deliberate attempts made to irradiate the IMNs, which also makes the findings more relevant to the majority of patients treated today. They found a statistically significant interaction between hypertension and left-breast irradiation in the development of coronary artery disease and a similar, but nonsignificant, trend for myocardial infarction (see their Table 5). There was no interaction between RT and the risks of congestive heart failure or cardiac death. Other cardiac risk factors, such as smoking, did not affect the incidence of CHD. I know of only one other similarly ambitious study.31,32 This combined series from the Netherlands Cancer Institute in Amsterdam and the Daniel den Hoed Cancer Center in Rotterdam included 4,368 patients who survived at least 10 years after diagnosis who were treated between 1970 and 1987, of whom 86% received RT. Information on cardiac risk factors and events was gathered mainly from the patients' general practitioners. With a median follow-up of 18 years, only smoking interacted with RT to create a more-than-additive effect for the development of a myocardial infarction on multivariate analysis, with a hazard ratio of 3.0 (95% CI, 2.0 to 4.5). However, this risk-factor analysis was not performed separately for each of the different RT techniques employed, which included ones no longer used. (This experience has been published only in abstract form to date, and this issue may be clarified in their full report.) There is still much uncertainty in my mind about which cardiac risk factors are important in the development of RIHD. Partly this is a result of the discrepancy between the Penn and Amsterdam/Rotterdam studies as to which cardiac risk factors were important (hypertension in the former, smoking in the latter). The overall Penn result showed a nonsignificant trend towards an increased crude risk of cardiac mortality in patients with left-sided cancer (3.5%) compared with right-sided patients (2%), which (despite their slightly longer median follow-up) is also at variance with the several clinical studies noted above, including those in which the IMNs were targeted in most or all patients.12,13 Left-breast irradiation also did not increase the risk of CHD in the Amsterdam/Rotterdam study for the 671 patients treated to the breast alone from 1980 to 1987,32 whose median follow-up time was 16 years (M. de Hooning, personal communication, June 2006). Patients with pre-existing CHD were excluded from the Penn study, so we do not know whether this in itself is a risk factor for RIHD. Finally, neither the Penn nor Dutch study included significant numbers of patients treated with anthracyclines. Thus, although I can reassure most patients (after RT planning) that none or little of the heart will be treated, for the rest it is impossible to confidently estimate their personal risk of RIHD. This risk is likely to be low for patients treated to the breast alone, especially if they receive no or limited cumulative anthracycline doses. But what about other patients, particularly those with positive nodes or extensive lymphovascular invasion, whom I do not consider appropriate for partial-breast irradiation,33 or patients requiring regional nodal irradiation, for whom treatment in the lateral decubitus34 or prone35 positions (which usually eliminate cardiac irradiation) is not feasible? What if reducing the irradiated cardiac volume by cardiac blocking or field-border manipulation shields potential sites of disease? (At least one small study from Duke University [Durham, NC] suggests that this might increase the risk of in-breast recurrence for some patients.36) Should we include or exclude the IMNs, a very controversial topic on which radiation oncologists are deeply divided?37 Should we routinely use expensive and time-consuming techniques, such as respiratory gating or breath-hold techniques38 or intensity-modulated RT39,40 to limit irradiation of the heart? (And, if so, will insurers pay extra to prevent rare complications that may not happen for 15 years or more?) It will likely be years before sufficient data are available to achieve consensus on these matters. For now, I use 1.8-Gy daily fractions for all patients with left-sided cancers, hoping (without proof) that the smaller fraction size will reduce the risks of cardiac disease, and alternative RT positioning and newer treatment techniques in selected patients. I strongly encourage patients to vigorously treat their hypertension and hyperlipidemia—and, for God's sake, stop smoking! Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on August 14, 2006 REFERENCES 1. Rutqvist LE, Johansson H: Mortality by laterality of the primary tumor among 55,000 breast cancer patients from the Swedish Cancer Registry. Br J Cancer 61:866-868, 1990[Medline] 2. Paszat LF, Mackillop WJ, Groome PA, et al: Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the Surveillance, Epidemiology, and End-Results cancer registries. J Clin Oncol 16:2625-2631, 1998[Abstract] 3. Paszat LF, Mackillop WJ, Groome PA, et al: Mortality from myocardial infarction following postlumpectomy radiotherapy for breast cancer: A population-based study in Ontario, Canada. Int J Radiat Oncol Biol Phys 43:755-761, 1999[CrossRef][Medline] 4. 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 5. Early Breast Cancer Trialists' Collaborative Group: Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomised trials. Lancet 355:1757-1770, 2000[CrossRef][Medline] 6. Early Breast Cancer Trialists' Collaborative Group: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005[Medline] 7. Harris JR, Hellman S: Put the "hockey stick" on ice. Int J Radiat Oncol Biol Phys 15:497-499, 1988[CrossRef][Medline] 8. Ragaz J, Olivotto IA, Spinelli JJ, et al: Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst 97:116-126, 2005 9. Patt DA, Goodwin JS, Kuo Y-F, et al: Cardiac morbidity of adjuvant radiotherapy for breast cancer. J Clin Oncol 23:7475-7482, 2005 10. Darby SC, McGale P, Taylor CW, et al: Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: Prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol 6:557-565, 2005[CrossRef][Medline] 11. Rutqvist LE, Liedberg A, Hammar N, et al: Myocardial infarction among women with early-stage breast cancer treated with conservative surgery and breast irradiation. Int J Radiat Oncol Biol Phys 40:359-363, 1998[CrossRef][Medline] 12. Nixon AJ, Manola J, Gelman R, et al: No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques. J Clin Oncol 16:1374-1379, 1998 13. Højris I, Overgaard M, Christensen JJ, et al: Morbidity and mortality of ischemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: Analysis of DBCG 82b and 82c randomized trials. Lancet 354:1425-1430, 1999[CrossRef][Medline] 14. Vallis KA, Pintilie M, Chong N, et al: Assessment of coronary heart disease morbidity and mortality after radiation therapy for early breast cancer. J Clin Oncol 20:1036-1042, 2002 15. Danoff BF, Galvin JM, Cheg E, et al: The clinical application of CT scanning in the treatment of primary breast cancer, in Ames FC, Blumenschein GR, Montague ED (eds): Current Controversies in Breast Cancer. Austin, TX, University of Texas Press, 1984, pp 391-397 16. Shapiro CL, Recht A: Side effects of adjuvant therapy for breast cancer. N Engl J Med 344:1997-2008, 2001 17. Prosnitz RG, Marks LB: Radiation-induced heart disease: Vigilance is still required. J Clin Oncol 23:7391-7394, 2005 18. Yu X, Zhou S, Prosnitz RG, et al: Persistence of radiation (RT)-induced cardiac dysfunction 3-5 years post RT. Int J Radiat Oncol Biol Phys 60:S390-S391, 2004 (suppl 1; abstr 2093) 19. Hancock SL, Tucker MA, Hoppe RT: Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA 270:1949-1955, 1993 20. Krueger EA, Schipper MJ, Koelling T, et al: Cardiac chamber and coronary artery doses associated with postmastectomy radiotherapy techniques to the chest wall and regional nodes. Int J Radiat Oncol Biol Phys 60:1195-1203, 2004[CrossRef][Medline] 21. Valagussa P, Zambetti M, Biasi S, et al: Cardiac effects following adjuvant chemotherapy and breast irradiation in operable breast cancer. Ann Oncol 5:209-216, 1994 22. Shapiro CL, Harrigan-Hardenbergh P, Gelman R, et al: Cardiac effects of adjuvant doxorubicin and radiation therapy in node positive breast cancer patients. J Clin Oncol 16:3493-3501, 1998[Abstract] 23. Zambetti M, Moliterni A, Materazzo C, et al: Long-term cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation. J Clin Oncol 19:37-43, 2001 24. Meinardi MT, van Veldhuisen DJ, Gietema JA, et al: Prospective evaluation of early cardiac damage induced by epirubicin-containing adjuvant chemotherapy and locoregional radiotherapy in breast cancer patients. J Clin Oncol 19:2746-2753, 2001 25. Bonneterre J, Roche H, Kerbrat P, et al: Long-term cardiac follow-up in relapse-free patients after six courses of fluorouracil, epirubicin, and cyclophosphamide, with either 50 or 100 mg of epirubicin, as adjuvant therapy for node-positive breast cancer: French Adjuvant Study Group. J Clin Oncol 22:3070-3079, 2004 26. Halyard MY, Pisansky TM, Solin LJ, et al: Adjuvant radiotherapy (RT) and trastuzumab in stage I-IIA breast cancer: Toxicity data from North Central Cancer Treatment Group Phase III trial N9831. J Clin Oncol 24:8s, 2006 (suppl; abstr 523)[CrossRef] 27. Thom T, Haase N, Rosamond W, et al: Heart disease and stroke statistics–2006 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 113:e85-e151, 2006 28. Glanzmann C, Huguenin P, Lütolf UM, et al: Cardiac lesions after mediastinal irradiation for Hodgkin's disease. Radiother Oncol 30:43-54, 1994[CrossRef][Medline] 29. Reinders JG, Heijmen BJM, Olofsen-van Acht MJJ, et al: Ischemic heart disease after mantlefield irradiation for Hodgkin's disease in long-term follow-up. Radiother Oncol 51:35-42, 1999[CrossRef][Medline] 30. Harris EER, Correa C, Hwang W-T, et al: Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. J Clin Oncol 24:4100-4106, 2006 31. Hooning MJ, Botma A, Aleman BMP, et al: Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. EJC 2:76, 2005 (suppl 3; abstr 271) 32. Hooning MJ, Botma A, Aleman BMP, et al: Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. Breast Cancer Res Treat 94:S177, 2005 (suppl 1; abstr 4035)[CrossRef] 33. Recht A: Lessons of studies of breast-conserving therapy with and without whole-breast irradiation for patient selection for partial-breast irradiation. Semin Radiat Oncol 15:123-132, 2005[CrossRef][Medline] 34. Campana F, Kirova YM, Rosenwald JC, et al: Breast radiotherapy in the lateral decubitus position: A technique to prevent lung and heart irradiation. Int J Radiat Oncol Biol Phys 61:1348-1354, 2005[CrossRef][Medline] 35. Griem KL, Fetherston P, Kuznetsova M, et al: Three-dimensional photon dosimetry: A comparison of treatment of the intact breast in the supine and prone position. Int J Radiat Oncol Biol Phys 57:891-899, 2003[CrossRef][Medline] 36. Raj KA, Hardenbergh P, Hollis D, et al: Local recurrence under the heart block in patients with left-sided breast cancer. Int J Radiat Oncol Biol Phys 60:S403, 2004 (suppl 1) 37. Taghian A, Jagsi R, Makris A, et al: Results of a survey regarding irradiation of internal mammary chain in patients with breast cancer: Practice is culture driven rather than evidence based. Int J Radiat Oncol Biol Phys 60:706-714, 2004[CrossRef][Medline] 38. Remouchamps VM, Letts N, Vicini FA, et al: Initial clinical experience with moderate deep-inspiration breath hold using an active breathing control device in the treatment of patients with left-sided breast cancer using external beam radiation therapy. Int J Radiat Oncol Biol Phys 56:704-715, 2003[CrossRef][Medline] 39. Vicini FA, Sharpe M, Kestin L, et al: Optimizing breast cancer treatment efficacy with intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 54:1336-1344, 2002[CrossRef][Medline] 40. Krueger EA, Fraass BA, McShan DL, et al: Potential gains for irradiation of chest wall and regional nodes with intensity modulated radiotherapy. Int J Radiat Oncol Biol Phys 56:1023-1037, 2003[CrossRef][Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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