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Originally published as JCO Early Release 10.1200/JCO.2007.11.9537 on July 30 2007 © 2007 American Society of Clinical Oncology.
The Heart of the Matter
Medical Oncology Branch, National Cancer Institute, Bethesda, MD; and Washington Cancer Institute, Washington Hospital Center, Washington, DC Although anthracyclines have served as the mainstay of effective cytotoxic therapy for breast cancer during the last 30 years, the time has come to evaluate whether the benefits outweigh the significant risks of cardiac toxicity. In this issue of the Journal of Clinical Oncology, Pinder et al1 report an increased incidence of congestive heart failure (CHF) in older women who had more than 10 years follow-up and were treated with adjuvant anthracyclines for breast cancer. Women who received anthracyclines had higher rates of CHF, even though they were younger and had fewer comorbidities compared with women who received nonanthracycline regimens or no chemotherapy. For women aged 66 to 70 years at 10 years follow-up, a diagnosis of CHF was made in 38.4%, 32.5%, and 29% for anthracycline-treated, nonanthracycline-treated, and no-chemotherapy groups, respectively. Age, African American race, hypertension, diabetes, and coronary artery disease were significant predictors of CHF. Although follow-up was shorter and with fewer patients, trastuzumab treatment was a significant predictor of CHF. These results further emphasize the magnitude of long-term risk for cardiovascular disease in older patients treated with anthracyclines, which has been previously reported by others.2 The observation of ethnicity as an independent risk factor for CHF highlights the importance of population studies, because these patients are under-represented in clinical trials. In this study, African American women had a relative 49% higher risk of developing CHF compared with white women, but they also had more advanced disease at diagnosis and were more likely to receive anthracycline-containing chemotherapy. Identification of at-risk populations will help to tailor therapies aimed specifically to reduce anthracycline-related cardiac toxicities. However, like all population-based studies, this study has inherent limitations and weaknesses. The database used in this study was compiled for reimbursement purposes on the basis of nonrandomly selected populations. The Surveillance, Epidemiology, and End Results (SEER)-Medicare captures only services covered by Medicare and does not include information on health maintenance organization enrollees, who account for a significant percentage of the Medicare population. In addition, records of certain conditions are inaccurate because of inadequate coding.3-5 Therefore, when one interprets population studies, limitations of the data and potential bias of data sampling should be taken into consideration. Some of the specific concerns are as follows, and most of them are pointed out by the authors. First, because no information was available to determine the severity and diagnostic criteria for CHF or to discriminate between systolic and diastolic dysfunction, the potential for misdiagnosis of patients with mild or nonclassic symptoms was substantial. Second, critical information, such as cumulative anthracycline dose, other toxicities, and hormonal treatment, was not captured in the database. It should be noted that, on the basis of a study in which left ventricular ejection fraction was obtained carefully and frequently, cardiotoxicity occurred at doxorubicin cumulative doses of 300 mg/m2 and lower. This is much lower than a previously recommended threshold dose of 500 mg/m2.6 Third, the link between radiation and CHF may have been underestimated because of the lack of specific information on the techniques used and the dose of radiation to the heart. A recent report found that radiation to the internal mammary chain or a higher mean dose of radiation to the heart was associated with increased risk of CHF. This association was not apparent if radiation alone administered to the left or right side was independently considered.7 These limitations may have contributed to the surprising observation that anthracyclines did not significantly increase the risk of CHF in women ages 71 to 80 years. This finding directly contradicts the results from other studies suggesting that anthracycline-associated cardiac toxicity increases with increased age.8 In addition, by excluding other cardiac diseases and focusing on only CHF, this study may have missed an even broader scope of cardiovascular toxicity induced by anthracyclines, especially in this older population. Other factors that may have potential for causing long-term cardiac toxicity should also be considered. The rates of CHF reported in this study were high compared with CHF prevalence in the general population. It may have been useful to have a control group without breast cancer from the Medicare database. Increased long-term risk for CHF has been reported in patients who have received cyclophosphamide, methotrexate, and fluorouracil (CMF).2,7 Also, preliminary information from one trial with an aromatase inhibitor, letrozole, reported an increase in ischemia and CHF in the letrozole-treated group, although this was not statistically significant.9 Evidence of cardiac toxicity from other treatment modalities of breast cancer may emerge from longer follow-up. Despite its limitations, this study provides valuable information to the current debate on the role of adjuvant anthracyclines. The fate of anthracyclines as adjuvant treatment for breast cancer depends on our answers to the following questions: First, can we minimize, or even eliminate, cardiotoxicity from anthracyclines? Second, which subgroup of patients will benefit from anthracycline treatment? Third, can we replace anthracyclines with less cardiotoxic agents? Several approaches have been attempted to decrease cardiotoxicity of anthracyclines over the years. Dexrazoxane clearly reduced cardiotoxicity of anthracyclines in adult breast cancer patients, but was associated with a reduction in response rate in one study.10 In the pediatric population, dexrazoxane reduced cardiotoxicity but increased second malignancy.11,12 Longer infusions, use of anthracycline analogs, and use of liposomal doxorubicin are associated with less cardiotoxicity, as recently reviewed.13
Significant progress has been made to identify the molecular determinants of anthracycline sensitivity. It has been observed that HER-2–positive tumors are more sensitive to anthracyclines.14-16 As previously reviewed, studies have shown that amplification of the HER-2 oncogene is often accompanied by alterations of closely associated genes, including topoisomerase II In summary, we continue to gain insights from basic and clinical research in improving efficacy and reducing toxicity of cancer treatment. With increasing life span of cancer patients as a result of improved treatment, aging-related cardiac diseases will undoubtedly increase in this population. Risks and benefits of all cancer treatments, including adjuvant anthracyclines, should be carefully weighed. More importantly, our vigilance in long-term cardiac surveillance is crucial to the health of long-term survivors of cancer. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: Sandra M. Swain, Sanofi-Aventis, Genentech AUTHOR CONTRIBUTIONS Manuscript writing: Chia C. Portera, Sandra M. Swain NOTES published online ahead of print at www.jco.org on July 30, 2007. REFERENCES
1. Pinder MC, Zhigang D, Goodwin JS, et al: Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol 25:3808-3815, 2007 2. Doyle JJ, Neugut AI, Jacobson JS, et al: Chemotherapy and cardiotoxicity in older breast cancer patients: A population-based study. J Clin Oncol 23:8597-8605, 2005 3. McCarthy EP, Iezzoni LI, Davis RB, et al: Does clinical evidence support ICD-9-CM diagnosis coding of complications? Med Care 38:868-876, 2000[CrossRef][Medline] 4. Warren JL, Harlan LC, Fahey A, et al: Utility of the SEER-Medicare data to identify chemotherapy use. Med Care 40:IV-55-61, 2002 5. Bach PB, Guadagnoli E, Schrag D, et al: Patient demographic and socioeconomic characteristics in the SEER-Medicare database applications and limitations. Med Care 40:IV-19-25, 2002 6. Swain SM, Whaley FS, Ewer MS: Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials. Cancer 97:2869-2879, 2003[CrossRef][Medline] 7. Hooning MJ, Botma A, Aleman BM, et al: Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst 99:365-375, 2007 8. Jensen BV, Skovsgaard T, Nielsen SL: Functional monitoring of anthracycline cardiotoxicity: A prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol 13:699-709, 2002 9. Coates AS, Keshaviah A, Thurlimann B, et al: Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: Update of study BIG 1-98. J Clin Oncol 25:486-492, 2007 10. Swain SM, Whaley FS, Gerber MC, et al: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15:1318-1332, 1997 11. Lipshultz SE, Rifai N, Dalton VM, et al: The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 351:145-153, 2004 12. Tebbi CK, London WB, Friedman D, et al: Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol 25:493-500, 2007 13. Wouters KA, Kremer LC, Miller TL, et al: Protecting against anthracycline-induced myocardial damage: A review of the most promising strategies. Br J Haematol 131:561-578, 2005[CrossRef][Medline] 14. Pegram MD, Finn RS, Arzoo K, et al: The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene 15:537-547, 1997[CrossRef][Medline] 15. Thor AD, Berry DA, Budman DR, et al: ErbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 90:1346-1360, 1998 16. Paik S, Bryant J, Park C, et al: ErbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 90:1361-1370, 1998 17. Järvinen TA, Liu ET: Simultaneous amplification of HER-2 (ERBB2) and topoisomerase IIalpha (TOP2A) genes: Molecular basis for combination chemotherapy in cancer. Curr Cancer Drug Targets 6:579-602, 2006[CrossRef][Medline] 18. Knoop AS, Knudsen H, Balslev E, et al: Retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group. J Clin Oncol 23:7483-7490, 2005 19. Tanner M, Isola J, Wiklund T, et al: Topoisomerase IIalpha gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group trial 9401. J Clin Oncol 24:2428-2436, 2006 20. Slamon DJ: Phase III trail comparing AC-T with AC-TH and with TCH in the adjuvant treatment of HER2 positive early breast cancer patients: Second interim efficacy analysis. Presented at the 29th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 14-17, 2006 21. Jones SE, Savin MA, Holmes FA, et al: Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 24:5381-5387, 2006 Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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(TOP2A) on chromosome 17q12-21.
