Correspondence
Doxorubicin-Induced Cardiomyopathy
N Engl J Med 1999; 340:653-655February 25, 1999
- Article
To the Editor:
In their review of doxorubicin-induced cardiomyopathy (Sept. 24 issue),1 Singal and Iliskovic advise frequent monitoring of the ejection fraction during therapy with doxorubicin and cite the recommendations of the Cardiology Committee of the Children's Cancer Study Group2 regarding modification of the dose on the basis of such monitoring. Our review of the data on which those recommendations were based found no support for the reliability and sensitivity of monitoring of the ejection fraction in this setting.3 Frequent ejection-fraction monitoring and corresponding reductions in the dose of doxorubicin did not lessen early cardiotoxicity.3,4 No data demonstrated that overall morbidity and mortality were improved by the reduction of the cumulative dose of doxorubicin in asymptomatic patients who had a decrease in the ejection fraction.3 On the basis of available data, we feel that monitoring of the ejection fraction does not provide sufficient information for the management of cardiomyopathy. Overstating the value of changes in the ejection fraction in this setting may potentially harm patients if the efficacy of their anticancer therapy is reduced by the withholding of doxorubicin and may slow the search for validated techniques for monitoring cardiotoxicity.
Increases in blood troponin levels and myocardial uptake of radiolabeled antimyosin antibody are sensitive and specific indicators of myocardial-cell injury. Troponin levels and uptake of antimyosin antibody are elevated in patients with acute doxorubicin-induced cardiotoxicity, even in the absence of a reduced ejection fraction, and they correlate significantly with histologic scores for doxorubicin-induced cardiotoxic effects and with echocardiographic abnormalities in these patients nine months later.5
We strongly support both the prevention of doxorubicin-induced cardiotoxicity and strategies to reduce progressive cardiotoxic effects in long-term survivors of cancer. In contrast to Singal and Iliskovic, we have not found continuous infusion to be protective against late cardiac abnormalities in children. Moreover, data on dexrazoxane from clinical trials are extensive and important.6 Finally, afterload-reduction therapy may favorably alter the intermediate course of asymptomatic doxorubicin-induced cardiotoxic effects in long-term survivors of cancer.
6 ReferencesSteven E. Lipshultz, M.D.
Michelle A. Grenier, M.D.
University of Rochester Medical Center, Rochester, NY 14642Steven D. Colan, M.D.
Children's Hospital, Boston, MA 021151
Singal PK ,Iliskovic N . Doxorubicin-induced cardiomyopathy. N Engl J Med 1998;339:900-905
Full Text | Web of Science | Medline2
Steinherz LJ ,Graham T ,Hurwitz R , et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Childrens Cancer Study Group. Pediatrics 1992;89:942-949
Web of Science | Medline3
Lipshultz SE ,Sanders SP ,Goorin AM ,Krischer JP ,Sallan SE ,Colan SD . Monitoring for anthracycline cardiotoxicity. Pediatrics 1994;93:433-437
Web of Science | Medline4
Krischer JP ,Epstein S ,Cuthbertson DD ,Goorin AM ,Epstein ML ,Lipshultz SE . Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J Clin Oncol 1997;15:1544-1552
Web of Science | Medline5
Lipshultz SE ,Rifai N ,Sallan SE , et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 1997;96:2641-2648
Web of Science | Medline6
Lipshultz SE . Dexrazoxane for protection against cardiotoxic effects of anthracyclines in children. J Clin Oncol 1996;14:328-331
Web of Science | Medline
To the Editor:
I do not understand the rationale for repeating echocardiographic studies 3, 6, and 12 months after the completion of doxorubicin therapy and every 2 years thereafter, nor that for performing radionuclide angiography after 12 months and then every 5 years. The authors themselves suggest that once the heart has been damaged by doxorubicin, the options for treatment are few. Why, then, seek evidence of damage in a costly manner at frequent intervals in large numbers of asymptomatic patients if the early detection of anomalies by laboratory examiners will not lead to meaningful intervention?
A. David Ginsburg, M.D.
Kingston Regional Cancer Centre, Kingston, ON K7L 5P9, CanadaTo the Editor:
Singal and Iliskovic suggest that cardiotoxic effects caused by doxorubicin are fatal or refractory to treatment in most cases. The studies cited in support of this idea are retrospective. In the older studies, because cardiotoxicity was a newly described phenomenon, prospective evaluation was not done. In a more recent study,1 my colleagues and I found that congestive heart failure begins at a lower cumulative dose than previously reported,2 approximately 300 mg per square meter of body-surface area, and is either reversible or manageable in most cases. In that study, there were 24 cases of congestive heart failure, 2 in patients receiving dexrazoxane and 22 in those receiving placebo. Two of the 24 patients died of congestive heart failure and another 2 of congestive heart failure and progressive disease.
The use of a cardioprotective agent, dexrazoxane, has conferred cardioprotection in all trials in which it was used with a regimen containing doxorubicin. I would dispute the statement of Singal and Iliskovic that such a strategy met with limited success. Two large, placebo-controlled, randomized trials have been completed in which more than 1000 patients with breast cancer were treated. These studies demonstrated that dexrazoxane had a significant cardioprotective effect, as measured by noninvasive testing and the incidence of clinical congestive heart failure. The hazard ratio with placebo as compared with dexrazoxane for a cardiac event, which was defined in the protocol as a change in the ejection fraction or the presence of congestive heart failure, was 2.63 (95 percent confidence interval, 1.61 to 4.27; P<0.001) in one study and 2.00 (95 percent confidence interval, 1.01 to 3.96; P=0.04) in the other study.
The clinical use of dexrazoxane is not limited by severe myelosuppression. In the two randomized studies just described, the frequency of grade 3 or grade 4 nadir granulocyte counts did not differ significantly between the patients treated with placebo and those treated with dexrazoxane (P=0.36).
In summary, congestive heart failure is more common at lower cumulative doses of doxorubicin than the early studies reported. Dexrazoxane is an option for cardioprotection in patients with breast cancer who have received 300 mg per square meter of doxorubicin.
2 ReferencesSandra M. Swain, M.D.
Comprehensive Breast Center, Greater Washington Area, Washington, DC 20015-20341
Swain SM ,Whaley FS ,Gerber MC , et al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 1997;15:1318-1332
Web of Science | Medline2
Von Hoff DD ,Layard WW ,Basa P , et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91:710-717
Web of Science | Medline
To the Editor:
With respect to doxorubicin-induced cardiomyopathy, the incidence of 4 percent cited by Singal and Iliskovic is much lower than the 15 to 20 percent suggested by more recent, prospective trials.1 Treatment regimens combining doxorubicin with taxanes2 or trastuzumab3 represent efforts to enhance antitumor effects, rather than to minimize the amount of doxorubicin used. These recent therapeutic developments emphasize the continued need for a cardioprotective strategy when new, effective combinations are used.
With respect to the prevention of cardiotoxicity, dexrazoxane was dismissed as a problematic drug because of its myelosuppressive effects. In several clinical trials, myelosuppression was not a factor that affected the ability to deliver adequate doses of chemotherapy safely for the treatment of breast cancer.1 Therefore, concern about myelosuppression is hardly a reason for limiting the use of dexrazoxane, particularly given the favorable experience with this drug before the availability of cytokines.4
More serious is the issue of interference with antitumor effects. Most data do not suggest that dexrazoxane alters the activity of doxorubicin.1 Although research on other cardioprotective agents, such as probucol, may be warranted, readers should not be left with the notion that the role of such agents has been defined, nor that they should now replace a drug with reproducible efficacy against doxorubicin-induced cardiotoxicity in seven species, including humans.5
5 ReferencesFranco M. Muggia, M.D.
James L. Speyer, M.D.
New York University Medical Center, New York, NY 100161
Swain SM . Adult multicenter trials using dexrazoxane to protect against cardiac toxicity. Semin Oncol 1998;25:Suppl 10:43-47
Web of Science | Medline2
Gianni L ,Munzone E ,Capri G , et al. Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 1995;13:2688-2699
Web of Science | Medline3
Slamon D ,Leyland-Jones B ,Shak S , et al. Addition of Herceptin (humanized anti-Her2 antibody) to first line chemotherapy for Her2 overexpressing metastatic breast cancer (Her2+/MBC) markedly increases anticancer activity: a randomized, multinational controlled phase III trial. Proc Am Soc Clin Oncol 1998;17:98a-98a abstract.4
Zinecard. Kalamazoo, Mich.: Pharmacia & Upjohn (package insert).
5
Ferrans VJ, Sanchez JA, Herman EH. Pathologic anatomy of animal models of the cardiotoxicity of anthracyclines. In: Muggia FM, Green MD, Speyer JL, eds. Cancer treatment and the heart. Baltimore: Johns Hopkins University Press, 1992:89-113.
Author/Editor Response
Dr. Singal and colleagues reply:
To the Editor: Although the assessment of the left ventricular ejection fraction by means of tests such as radionuclide angiography is common in practice,1 we agree with Lipshultz et al. that the sensitivity and specificity of these tests are disappointing. The Cardiology Committee of the Children's Cancer Group recommends a combination of echocardiography and radionuclide studies, as we did in our review.2 Monitoring with magnetic resonance imaging, as well as the study of troponin levels and uptake of antimyosin antibody, has high sensitivity but low specificity.
Lipshultz et al. comment that continuous infusion has no benefit, but do not cite studies to support their experience. Differences have been observed in studies that have compared infusion with bolus doses, as cited in our review.3 Could it be that children have a different response in this regard?
We agree with Ginsburg's point about the costs of serial echocardiography, but the approach is helpful in detecting changes in systolic and diastolic functions, especially in children, in whom echocardiographic images are clear and more easily measurable than in adults. Although most changes in echocardiographic fractional shortening are gradual and dose-related and are followed by recovery, there is a late and unexpected decrease in fractional shortening after viral illness that only serial monitoring would identify.4 As pointed out by Lipshultz et al., early detection may allow management with afterload-reduction therapy, which may at least “favorably alter the intermediate course of asymptomatic doxorubicin-induced cardiotoxic effects in long-term survivors of cancer.” Furthermore, early detection should remain one of the goals in order to provide important clinical information and options to patients.
Although we agree that dexrazoxane is effective and enables us to give more doxorubicin to patients with cancer, in one study in which patients with breast cancer received a combination of 5-fluorouracil, doxorubicin, and cyclophosphamide, patients receiving dexrazoxane had lower response rates and a shorter time to disease progression than controls, although there were no differences in survival.5 These findings suggest that dexrazoxane may interfere with the antitumor effect of doxorubicin. Among the patients taking dexrazoxane, some discontinued the study early, suggesting that the drug may also increase doxorubicin-induced toxic effects.5 Furthermore, the safety and effectiveness of dexrazoxane in children has not been established. For most patients with other kinds of cancer, the combination of 5-fluorouracil, doxorubicin, and cyclophosphamide is not recommended. Therefore, we think that the combination of doxorubicin and dexrazoxane is effective, but its application is limited.
We agree that the rationale for combination chemotherapy is to increase or enhance the antitumor effect while dispersing toxic effects to various organ systems. However, combining trastuzumab with doxorubicin may not be particularly appropriate, since trastuzumab has now been reported to cause cardiomyopathy.6
6 ReferencesPawan K. Singal, D.Sc.
Charles L.M. Olweny, M.D.
Timao Li, M.Sc.
St. Boniface General Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada1
Shan K ,Lincoff AM ,Young JB . Anthracycline-induced cardiotoxicity. Ann Intern Med 1996;125:47-58
Web of Science | Medline2
Steinherz LJ ,Graham T ,Hurwitz R , et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Childrens Cancer Study Group. Pediatrics 1992;89:942-949
Web of Science | Medline3
Singal PK ,Iliskovic N . Doxorubicin-induced cardiomyopathy. N Engl J Med 1998;339:900-905
Full Text | Web of Science | Medline4
Ali MK ,Ewer MS ,Gibbs HR ,Swafford J ,Graff KL . Late doxorubicin-associated cardiotoxicity in children: the possible role of intercurrent viral infection. Cancer 1994;74:182-188
CrossRef | Web of Science | Medline5
Zinecard: cardioprotective agent. Mississauga, Ont.: Pharmacia, January 31, 1995 (product monograph).
6
Slamon D ,Leyland-Jones B ,Shak S , et al. Addition of Herceptin (humanized anti-Her2 antibody) to first line chemotherapy for Her2 overexpressing metastatic breast cancer (Her2+/MBC) markedly increases anticancer activity: a randomized, multinational controlled phase III trial. Proc Am Soc Clin Oncol 1998;17:98a-98a abstract.
- Citing Articles (2)
Citing Articles
1
F. Zaja, V. Tomadini, A. Zaccaria, M. Lenoci, M. Battista, A. L. Molinari, A. Fabbri, R. Battista, M. G. Cabras, A. Gallamini, R. Fanin. (2006) CHOP-rituximab with pegylated liposomal doxorubicin for the treatment of elderly patients with diffuse large B-cell lymphoma. Leukemia & Lymphoma 47:10, 2174-2180
CrossRef2
Michael J Mihm, Fushun Yu, David M Weinstein, Peter J Reiser, John Anthony Bauer. (2002) Intracellular distribution of peroxynitrite during doxorubicin cardiomyopathy: evidence for selective impairment of myofibrillar creatine kinase. British Journal of Pharmacology 135:3, 581-588
CrossRef
