Correspondence to: Jack Cuzick, PhD, Cancer Research-UK, Centre for Epidemiology, Mathematics & Statistics, Wolfson Institute of Preventive Medicine, Charterhouse Square, London, EC1M 6BQ, United Kingdom (e-mail: jack.cuzick{at}cancer.org.uk).
The role of radiotherapy in the treatment of breast cancer has a long and controversial history. One of the first clinical trials ever performed, beginning in 1949, studied this question (1,2), and it remains the subject of new trials that are still being initiated today. Early trials clearly demonstrated that radiotherapy reduced local relapse, with a relative risk reduction that is now known to be about 70%. However, the reduction in relapse rates did not translate to a reduction in mortality. Many theories were suggested to explain this disparity, including a detrimental effect of radiotherapy on immune function (3). These mortality concerns were crystallized in the first individual patient data overview of cancer trials (4), which showed that radiotherapy had little effect on mortality in the first 10 years of follow-up but was potentially detrimental in the longer term. A report of Rutqvist et al. (5) and further evaluation of cause-specific mortality from the first overview (6) clearly demonstrated that there was a late excess of cardiac deaths that was masking a potential reduction in deaths from breast cancer. Further confirmation of these findings was provided by a larger subsequent overview that included many more recent trials (7).
The point of these overviews was not to dismiss radiotherapy as a treatment for breast cancer but to make clear that changes in its administration were needed if its benefit in terms of reduced late breast cancer deaths was not to be nullified by increased cardiac mortality. Radiotherapists have heeded this call, and important modifications to the fields used and individual patient planning have greatly reduced the cardiac dose. It is a matter of some satisfaction that these early overviews have changed practice and that we are now beginning to see the benefits of these improved protocols. Excess cardiac deaths do not appear to be occurring in the more recent trials, and breast cancer deaths are indeed reduced (8,9).
The study by Giordano et al. in this issue of the Journal (10), which is based on a much larger population drawn from routine practice, supports this conclusion. Unlike population-based studies, clinical trials can directly evaluate cardiac mortality from radiotherapy by comparing outcomes in women who were randomly assigned to it with outcomes in women who were not. By contrast, the ability to compare like with like is much more difficult to achieve outside of clinical trials, and several recent studies have highlighted the danger of trying to identify treatment effects from observational studies (11). Giordano et al. were fully aware of this problem and employed a clever method for avoiding it. They compared cardiac mortality in women receiving radiotherapy according to the laterality of the tumor. Because left-sided tumors received a much higher cardiac dose but laterally did not affect selection for radiotherapy, almost all of the benefits of randomization were maintained. The detrimental effects of radiotherapy may have been somewhat underestimated by this method, because some studies have shown excess cardiac deaths even in right-sided tumors, and the absolute rates of cardiac deaths reported by Giordano et al. are decreasing with time in both left- and right-sided tumors. However, the trend toward converging cardiac mortality rates in more recent times strongly indicates that the excess risk is being attenuated.
The authors were also careful to ensure that follow-up times were similar for all women by censoring follow-up after 1215 years (depending on the analysis). This strategy was essential to ensure comparability, because excess cardiac events are a late event. However, this restriction to "early" follow-up also highlights an important limitation of the present study: Most of the excess cardiac deaths in the clinical trials occurred after 10 or more years of follow-up, and the effects persisted for at least 20 years. Thus, the cohorts under study are just becoming informative for this time period. It would also have been helpful to see the rates separately for the period beginning after 8 years of follow-up, over which the differences are likely to be larger.
Other useful information would have been verification that the age distribution of treated women had not changed with time and determination of whether cardiac mortality differences were age specific. Expected numbers of cardiac deaths based on population rates (or rates in women with stage-matched breast cancer not treated with radiotherapy) after, e.g., 8 years of follow-up (to allow for selection biases in early follow-up) would also provide useful information for interpreting these trends in late effects, even though some bias may persist.
The authors correctly point out that further follow-up is essential to provide definitive evidence on whether excess cardiac mortality has disappeared completely. Radiotherapy is now used for very-good-prognosis invasive tumors and even for in situ breast cancers, for which life expectancy is almost equal to that of the general population and will exceed 20 years in many cases. A major advancement in the use of this modality appears to be emerging, but it is still too early to declare an absolute victory. We owe it to women with breast cancer to remain vigilant and continue follow-up of this and related cohorts for at least another decade.
REFERENCES
(1) Paterson R, Russell MH. Breast cancer: evaluation of post-operative radiotherapy. J Fac Radiol 1959;10:174180.
(2) Palmer MK, Ribeiro CG. Thirty-four year follow-up of patients with breast cancer in a clinical trial of postoperative breast cancer. Br Med J 1985;291:108891.[ISI][Medline]
(3) Stjernsward J. Decreased survival related to irradiation postoperatively in early operable breast cancer. Lancet 1977;ii:12856.
(4) Cuzick J, Stewart H, Peto R, Baum M, Fisher B, Host H, et al. Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer. Cancer Treat Rep 1987;71:1529.[ISI][Medline]
(5) Rutqvist LE, Lax I, Fornander T, Johansson H. Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer. Int J Radiat Oncol Biol Phys 1992;22:88796.[ISI][Medline]
(6) Cuzick J, Stewart H, Rutqvist L, Houghton J, Edwards R, Redmond C, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 1994;12:44753.[Abstract]
(7) EBCTCG. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000;355;175770.[CrossRef][ISI][Medline]
(8) Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997;337:94955.
(9) Hojris I, Overgaard M, Christensen JJ, Overgaard J. Morbidity and mortality of ischaemic heart disease in high-risk breast-cancer patients after adjuvant postmastectomy systemic treatment with or without radiotherapy: analysis of DBCG 82b and 82c randomised trials. Radiotherapy Committee of the Danish Breast Cancer Cooperative Group. Lancet 1999;354:142530.[CrossRef][ISI][Medline]
(10) 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;97:41924.
(11) Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:52334.
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