Anthracycline-­Induced Cardiotoxicity: Risk Assessment and Management

OncologyONCOLOGY Vol 23 No 3
Volume 23
Issue 3

In the current issue of ONCOLOGY, Hershman and Shao provide a comprehensive review of anthracycline-induced cardiotoxicity (AIC). Risk factors for AIC include age (≤ 18 or ≥ 65 years) at time of treatment, increasing cumulative dose or dose intensity of anthracyclines, mediastinal radiation therapy (RT), and female gender.[1-4]

This article is a review of: Anthracycline  Cardiotoxicity After Breast Cancer Treatment

In the current issue of ONCOLOGY, Hershman and Shao provide a comprehensive review of anthracycline-induced cardiotoxicity (AIC). Risk factors for AIC include age (≤ 18 or ≥ 65 years) at time of treatment, increasing cumulative dose or dose intensity of anthracyclines, mediastinal radiation therapy (RT), and female gender.[1-4] The Surveillance, Epidemiology and End Results (SEER)-Medicare database showed that women 66 to 70 years of age who received nonanthracycline chemotherapy did not experience significant incremental cardiotoxicity compared to age-matched controls, but among the women who received anthracyclines, an excess rate of congestive heart failure (CHF) emerged.[5] For women 71 to 80 years of age, adjuvant chemotherapy type was not associated with CHF.

Classification of Anthracycline-Induced Toxicity

As described by Hershman and Shao, AIC can be categorized as three distinct types: acute, early, and late. Acute AIC, occurring during the anthracycline infusion or within 1 week of therapy, is rare and reversible. It may present as transient arrhythmia, a pericarditis-myocarditis syndrome, or acute failure of the left ventricle.[6-8] Delayed AIC typically presents as a cardiomyopathy and has been reported in approximately 5% of patients.[9,10] It is classified as early subacute cardiotoxicity occurring < 1 year or late cardiotoxicity occurring > 1 year after the cessation of chemotherapy.[11] Late cardiotoxicity may not be apparent until years to decades after the administration of anthracyclines.[11,12] Patients typically have reduced left-ventricular mass, mass index, and ventricular compliance, with increasing susceptibility to cardiac stressors.[13] The majority of patients who develop early subacute cardiotoxicity will manifest late cardiotoxicity.[11,14]

While numerous studies have reported late AIC in patients exposed to the drug during childhood, the incidence in the adult population has been difficult to determine, as follow-up time and cardiac monitoring are inadequate in most clinical trials. Our group reported long-term AIC in 32 of 85 patients treated with sequential dose-dense and dose-intense doxorubicin, paclitaxel, and cyclophosphamide (ATC).[15] At a median follow-up of 7 years, the median absolute change in left-ventricular ejection fraction (LVEF), measured by multigated acquisition (MUGA) from baseline was 5.5%, and from the end of chemotherapy was −2.0%. Four patients (12%) had an LVEF < 50%; two of the four patients had an LVEF < 50% at the end of chemotherapy. We concluded from this study that late asymptomatic decline in cardiac function is uncommon, and does not appear to significantly contribute to the morbidity or mortality of the regimen.

Monitoring of Cardiac Function

As Hershman and Shao note, echocardiogram (ECHO) and MUGA scans are standard methods used to monitor AIC. The authors refer to the limited applicability of MUGA scan for frequent monitoring as a result of cumulative radiation exposure; however, when a precisely reproducible measurement is required for patient management decisions or clinical trial monitoring, MUGA may be the method of choice.[16]

Serial MUGA assessments of LVEF vary between 2% and 4%, whereas serial ECHO assessments of LVEF vary between 13% and 17%. Several studies have reported a decrease in LVEF > 10 points from baseline or a fall below the institutional lower limit of normal as indicative of AIC.[17-20] However, such a drop is a late event and would not be detectable until significant cardiac damage has occurred.[21] Therefore, alternative methods of cardiac monitoring are being evaluated.

As described by Hershman and Shao, magnetic resonance imaging (MRI) is an alternative method used for assessment of myocardial function, perfusion, and tissue characterization. However, long-term data to support its use in this setting are lacking, especially with the limited availability of this technology.[22] Another modality under investigation is tissue doppler imaging (TDI), which allows the measurement of diastolic and systolic velocities of the ventricular walls and mitral annulus, and appears to be more reliable and less affected by loading conditions than conventional Doppler.[23] In a study by Tassan-Mangina et al, TDI confirmed the occurrence of early diastolic and late systolic impairment of left-ventricular function following moderate-dose anthracycline therapy.[23]

Hershman and Shao refer to troponin T and B-type natriuretic peptide (BNP) as potential biomarkers for earlier detection of cardiotoxicity. BNP levels were monitored for a small number of patients with acute leukemia treated with a daunorubicin-containing regimen; those who had abnormal BNP levels during subsequent stem-cell transplant developed heart failure, whereas those who had normal BNP levels did not.[24] Troponin levels were measured in 211 patients with breast cancer receiving high-dose therapy; abnormal levels predicted the development of future LVEF depression in a 12-month follow-up.[25]

Cardiac Risk Assessment and Management Recommendations

Although anthracyclines have served as the mainstay of effective cytotoxic therapy for breast cancer during the past 30 years, AIC remains a concern. Therefore, better methods for prevention, monitoring, and management of AIC are needed. When making treatment recommendations for breast cancer patients-especially those with early-stage disease-the presence of cardiac risk factors and strong cardiac family history need to be considered. Treatable cardiac risk factors such as hypetension, hyperlipidemia, and diabetes should be closely monitored and managed in an attempt to prevent additional cardiac injury.

In addition, long-term follow-up is needed to identify patients with subclinical late cardiac dysfunction, who may be at a higher risk for subsequent cardiac events. Patients with preexisting cardiac disease and poorly controlled risk factors may consider treatment with alternative non-anthracycline regimens with reported lower risk of cardiotoxicity.

As mentioned by Hershman and Shao, non-anthracycline-containing regimens have been evaluated for treatment of patients with early-stage breast cancer.[26,27] These non-anthracycline regimens appear to be comparable in efficacy and less cardiotoxic than the anthracycline regimens. While relatively short follow-up has been reported for these regimens, at very least they provide an alternative for breast cancer patients with a history of cardiac disease or cardiac risk factors. These nonanthracycline regimens should be discussed with patients as an alternative treatment, with acknowledgment of the relatively short duration of follow-up.

Finally, the potential for delayed cardiotoxicity should continue to be evaluated in adjuvant and neoadjuvant clinical trials, particularly in light of the recent advances with dose-dense therapy as well as with adjuvant trastuzumab (Herceptin).

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.


1. 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.
2. Green DM, Grigoriev YA, Nan B, et al: Congestive heart failure after treatment for Wilms’ tumor: A report from the National Wilms’ Tumor Study Group. J Clin Oncol 19:1926-1934, 2001.
3. Lipshultz SE, Lipsitz SR, Mone SM, et al: Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 332:1738-1743, 1995.
4. Fumoleau P, Roche H, Kerbrat P, et al: Long-term cardiac toxicity after adjuvant epirubicin-based chemotherapy in early breast cancer: French Adjuvant Study Group results. Ann Oncol 17:85–92, 2006.
5. Pinder MC, Duan Z, 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.
6. Steinberg JS, Cohen AJ, Wasserman AG, et al: Acute arrhythmogenicity of doxorubicin administration. Cancer 60:1213-1218, 1987.
7. Lenaz L, Page JA: Cardiotoxicity of adriamycin and related anthracyclines. Cancer Treat Rev 3:111-120, 1976.
8. Ferrans VJ: Overview of cardiac pathology in relation to anthracycline cardiotoxicity. Cancer Treat Rep 62:955-961, 1978.
9. Botti C, Vici P, Lopez M, et al: Prognostic value of lymph node metastasis after neoadjuvant chemotherapy for large sized operable cancer of the breast. J Am Coll Surg 181:202-208, 1995.
10. Bonadonna G, Valagussa P: Contribution of prognostic factors of adjuvant chemotherapy in breast cancer. Recent Results Cancer Res 96:34-45, 1984.
11. Grenier MA, Lipshultz SE: Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol 25(suppl 10):72–85, 1998.
12. Haq MM, Legha SS, Choksi J: Doxorubicin-induced congestive heart failure in adults. Cancer 56:1361-1365, 1985.
13. Steinherz L, Steinherz P, Tan C, et al: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266:1672–1677, 1991.
14. Abu-Khalaf M, Juneja V, Chung G, et al: Long term assessment of cardiac function after dose-dense and –intense sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) as adjuvant therapy for high risk breast cancer. Breast Cancer Res Treat 104:341-349, 2006.
15. Barry E, Alvarez JA, Scully RE, et al: Anthracycline-induced cardiotoxicity: Course, pathophysiology, prevention and management. Expert Opin Pharmacother 8:1039-1058, 2007.
16. Van Royen N, Jaffe CC, Krumholz HM, et al: Comparison and reproducibility of visual echocardiographic and quantitative radionucleotide left ventricular ejection fractions. Am J Cardiol 77:845-850, 1996.
17. Harris L, Batist G, Belt R, et al: Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer 94:25-36, 2002.
18. O’Brien ME, Wigler N, Inbar M, et al: Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 15:440-449, 2004.
19. Batist G, Ramakrishnan G, Rao CS, et al: Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol 19:1444-1454, 2001.
20. Chan S, Davidson N, Juozaityte E, et al: Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer. Ann Oncol 15:1527-1534, 2004.
21. Zuppinger C, Timolati F, Suter TM: Pathophysiology and diagnosis of cancer drug induced cardiomyopathy. Cardiovasc Toxicol 7:61-66, 2007.
22. Jurcut R, Wildiers H, Ganame J, et al: Detection and monitoring of cardiotoxicity-what does modern cardiology offer? Support Care Cancer 16:437-445, 2008.
23. Tassan-Mangina S, Codorean D, Metivier M, et al: Tissue Doppler imaging and conventional echocardiography after anthracycline treatment in adults: Early and late alterations of left ventricular function during a prospective study. Eur J Echocardiogr 7:141-146, 2006.
24. Okumura H, Iuchi K, Yoshida T, et al: Brain natriuretic peptide is a predictor of anthracycline-induced cardiotoxicity. Acta Haematol 104:158-163, 2000.
25. Cardinale D, Sandri M, Martinoni A, et al: Myocardial injury revealed by plasma troponin I in breast cancer treated with high-dose chemotherapy. Ann Oncol 13:710-715, 2002.
26. 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.
27. Robert NJ, Eiermann W, Pienkowski T, et al: BCIRG 006: Docetaxel and trastuzumab-based regimens improved DFS and OS over AC-T in node positive and high risk node negative HER2 positive early breast cancer patients: Quality of life at 36 months follow-up (abstract 19647). J Clin Oncol 25(18S):719s, 2007.

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