© The Author 2007. Published by Oxford University Press.
EDITORIALS |
Local Recurrence or Cardiovascular Disease: Pay Now or Later
Affiliation of authors: Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX
Correspondence to: Sharon H. Giordano, MD, MPH, Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe, Box 1354, Houston, TX 77030-4009 (e-mail: sgiordan{at}mdanderson.org).
Radiation therapy is an essential component of the local management of breast cancer. The overview from the Early Breast Cancer Trialists’ Collaborative Group (1) indicates that adjuvant radiation therapy after breast-conserving surgery results in statistically significant reductions in the 5-year risk of local recurrence (26% versus 7%), the 15-year breast cancer mortality risk (5.4% reduction), and overall mortality (5.3% reduction). The benefits of radiation therapy are similar for those patients treated after mastectomy, with reductions in local recurrence, breast cancer mortality, and overall mortality. Although the overview clearly shows the benefit of radiation, it also has confirmed the toxicities. Patients who were treated with radiation had increased risk of contralateral breast cancer, lung cancer, and mortality from cardiac disease (rate ratio = 1.27, P<.001). The increase in non–breast cancer mortality among irradiated patients, particularly the increase in deaths from heart disease, diminished the benefit of radiation on overall survival endpoints.
Individual randomized trials and epidemiologic studies have also demonstrated the cardiac toxicity of adjuvant breast radiotherapy (2–8). In a meta-analysis of eight randomized trials, Cuzick et al. (6) found a 62% increase in cardiac deaths among women who were treated with radiation therapy. However, all the individual studies in the meta-analysis were initiated before 1975 and used radiotherapy techniques that would now be considered suboptimal. Our own study (7), based on the Surveillance, Epidemiology, and End Results database, indicated that the risk of cardiac death due to radiotherapy has declined since the 1970s, but not enough time has elapsed to get firm estimates of the risk for women treated in the 1990s or 2000s, because cardiac toxicity is a late consequence of therapy that does not emerge until at least a decade after completing radiotherapy.
The report by Hooning et al. (9) in this issue of the Journal provides important new information on the cardiac toxicity of radiation therapy. The study focused on a cohort of 4414 women who were at least 10-year survivors of breast cancer and were identified through the Late Effects Breast Cancer Cohort in The Netherlands. The follow-up in this study was remarkably complete, with information available for 96% of all 10-year survivors. In addition, the median follow-up of almost 18 years was impressively long. Given the late emergence of radiation toxicity, the length of follow-up is critically important. The study has some other unique features: it evaluates morbidity as well as mortality, compares toxicity by radiation fields, and evaluates the impact of other cardiac risk factors.
Several interesting findings emerge from these analyses. First, this study is consistent with a growing body of literature showing that the risk of myocardial infarction due to radiation therapy has declined over time and provides additional good news for our patients (7,10). Thus, although patients who were diagnosed between 1970 and 1979 with radiation to the left chest wall or to right or left internal mammary fields had an increased risk of myocardial infarction, overall, the patients who were diagnosed between 1980 and 1986 did not. Although these analyses are reassuring, they do not directly address the shorter follow-up for the more recent cohort, and differences could continue to emerge with longer follow-up.
Most previous studies, with the exception of that by Patt et al. (11) have only examined endpoints related to ischemic heart disease. Hooning et al. also evaluated risk of congestive heart failure and valvular dysfunction. Patients who were treated with internal mammary and chest wall or breast radiation appeared to be at increased risk of developing congestive heart failure, regardless of the year of diagnosis. The authors also reported that patients who were treated with radiotherapy to the internal mammary chain had a higher risk of valvular dysfunction than patients not treated with radiation therapy. This risk was elevated for both right- and left-sided tumors, which could explain why higher rates of valvular disease were not seen in the study by Patt et al., which compared risk in left- versus right-sided tumors, without considering untreated control subjects. Of concern, the increased risk of valvular dysfunction was seen for both the earlier and later time periods. Valvular dysfunction has not been previously reported as a long-term complication for adjuvant breast radiotherapy, although it has been seen in survivors of Hodgkin lymphoma treated with chest radiation (12).
This study also reported the surprising finding that chemotherapy use (cyclophosphamide, methotrexate, and fluorouracil [CMF]) was associated with an increased risk of congestive heart failure among breast cancer survivors. Although anthracycline-based chemotherapy is known to cause congestive heart failure, heart failure is not an expected outcome for patients who were treated with CMF chemotherapy. This finding is especially odd given that the increase in risk was limited to those patients treated in the 1980s, when only six cycles of CMF were routinely given, and not seen among patients who were treated in the 1970s, when 12 cycles of chemotherapy was the standard. This association could represent a long-term toxicity of which we were previously unaware, or, as noted by the authors, could possibly be related to induction of menopause. More plausibly, it could be either a spurious finding or related to residual confounding because all patients who received chemotherapy were also treated with radiation.
The unexpected association between CMF chemotherapy and heart failure highlights one of the important limitations of this study: its observational design. When evaluating the results, it is important to keep in mind that this study was not randomized, and thus, selection biases and confounding could have influenced the results. As the authors duly note, both control groups are somewhat problematic. The population-based control may have different socioeconomic status or cardiac risk factors than the breast cancer patients, and the patients who received radiation may be systematically different from those who did not. The investigators have responded to these inherent limitations by using multiple control groups and adjusting for known cardiac risk factors. This study design does have some advantages over randomized trials or studies that compare toxicities in patients with left- versus right-sided breast cancers. Follow-up and patient numbers are often insufficient from randomized trials, and comparing risk by tumor laterality can mask toxicities that may occur with equal frequency in patients with left- versus right-sided breast cancers.
Long-term toxicities, such as those reported in this study, are increasingly being recognized as important consequences of therapy. Unfortunately, little research has been conducted in this area, and although clinical trials have effectively captured the short-term effects of cancer therapies, we still have a limited understanding of the potential long-term effects. Other breast cancer–related therapies besides radiation, such as chemotherapy with anthracyclines and targeted therapy with trastuzumab, have the potential to cause long-term cardiac toxicity. In the case of anthracycline-related cardiac toxicity, the short-term toxicities in adults are known, and the substantial long-term toxicity in children is also clear. However, we still have not quantified the magnitude of long-term toxicity in adults, even for these agents that have been in use for more than 30 years. Studies with prospective, extended monitoring will be essential to capture the true long-term as well as short-term toxicity profiles of cancer therapeutics, particularly with the increasing use of effective but cardiotoxic agents, like trastuzumab. Some long-term toxicities such as left ventricular dysfunction may be delayed or prevented when diagnosed in an early or asymptomatic phase whereas others, such as valvular dysfunction may be challenging to prevent. Ultimately, we will need to be able to identify patients who are at high risk or with early signs of cardiac disease and to develop effective interventions to prevent the development of late toxicities and minimize their effects on quality of life.
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J Natl Cancer Inst 2007 99: 365-375.
J Natl Cancer Inst 2007 99: 337.
J Natl Cancer Inst 2007 99: 337.
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