Correspondence

Doxorubicin-Induced Cardiotoxicity

N Engl J Med 1995; 333:1359-1360November 16, 1995

Article

To the Editor:

The study by Lipshultz et al. (June 29 issue)1 has confirmed the results of an earlier study of 150 survivors of cancer who were treated at the Children's Hospital of Philadelphia.2 Our study, published in 1993, analyzed abnormalities in either maximal cardiac output, indexed according to body-surface area, or the ejection fraction, as measured by resting or exercise gated nuclear angiography, in patients who had received anthracyclines and who had not been treated for at least one year. We omitted patients who received spinal radiation, since such treatment may also damage the heart.3 We found that after adjusting for the dose of anthracycline and the age at treatment, girls had a risk of cardiac-function abnormalities that was 3.2 times the risk in boys (95 percent confidence interval, 1.6 to 6.6). We postulated that differences in the relative composition of muscle and fat between boys and girls might account for such a difference in risk. To explore this further, we also performed a subanalysis of children 12 years of age or older at the time of treatment, since the differences in body composition between sexes are accentuated after puberty. We found that the risk of a cardiac abnormality in girls increased to 5.1 times the risk in boys (95 percent confidence interval, 1.5 to 17.9).

Many important questions remain to be answered about sex and anthracyclines. Can the mechanism of the finding be better understood? What clinical importance should we place on these cardiac abnormalities? How should the treatment and follow-up of female patients differ from those of male patients? Finally, what are the implications for adult patients who are receiving anthracyclines? There are no clear answers at present.

Jeffrey H. Silber, M.D., Ph.D.
Children's Hospital of Philadelphia, Philadelphia, PA 19104

Gerald Barber, M.D.
New York University Medical Center, New York, NY 10016

3 References

1. 1

   Lipshultz SE, Lipsitz SR, Mone SM, et al. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 1995;332:1738-1743
   Full Text | Web of Science | Medline

2. 2

   Silber JH, Jakacki RI, Larsen RL, Goldwein JW, Barber G. Increased risk of cardiac dysfunction after anthracyclines in girls. Med Pediatr Oncol 1993;21:477-479
   CrossRef | Medline

3. 3

   Jakacki RI, Goldwein JW, Larsen RL, Barber G, Silber JH. Cardiac dysfunction following spinal irradiation during childhood. J Clin Oncol 1993;11:1033-1038
   Web of Science | Medline

To the Editor:

In the study by Lipshultz et al. analyzing the late cardiac effects of doxorubicin treatment in a cohort of long-term survivors of acute lymphoblastic leukemia and osteogenic sarcoma in childhood, female sex and a higher rate of drug administration were identified as independent risk factors for late toxicity. An imbalance in the ratio of men to women (1:3) in whom anthracycline-induced congestive heart failure developed has been previously reported.1

This difference between male and female patients in doxorubicin-induced cardiotoxicity may be determined at least partially by differences in drug clearance. Dobbs et al. have studied the variability of doxorubicin pharmacokinetics in 27 adults with normal liver function.2 The 6 men had a significantly higher doxorubicin clearance than the 21 women (59 vs. 27 liters per hour per square meter of body-surface area, P<0.001). In addition, the ratio of the area under the curves for doxorubicinol and doxorubicin was higher in men than in women. Therefore, the greater systemic exposure (including cardiac tissues) to the active drug in female patients may be responsible for the decrease in myocardial contractility. A similar sex-based difference was reported for the pharmacokinetics of epirubicin.3

L. Paz-Ares, M.D.
University of Glasgow, Glasgow G61 1BD, United Kingdom

N. Dobbs, B.Sc.
Guy's Hospital, London SE1 9RT, United Kingdom

C. Twelves, M.D
University of Glasgow, Glasgow G61 1BD, United Kingdom

3 References

1. 1

   Hrushesky WJ, Fader DJ, Berestka JS, Sommer M, Hayes J, Cope FO. Diminishment of respiratory sinus arrhythmia foreshadows doxorubicin-induced cardiomyopathy. Circulation 1991;84:697-707
   Web of Science | Medline

2. 2

   Dobbs NA, Twelves CJ, Gillies H, James CA, Harper PG, Rubens RD. Gender effects the doxorubicin pharmacokinetics in patients with normal liver biochemistry. Cancer Chemother Pharmacol (in press).
   

3. 3

   Wade JR, Kelman AW, Kerr DJ, Robert J, Whiting B. Variability in the pharmacokinetics of epirubicin: a population analysis. Cancer Chemother Pharmacol 1992;29:391-395
   CrossRef | Web of Science | Medline

Citing Articles (5)

Citing Articles

1. 1

   Joydeep Das, Jyotirmoy Ghosh, Prasenjit Manna, Parames C. Sil. (2011) Taurine suppresses doxorubicin-triggered oxidative stress and cardiac apoptosis in rat via up-regulation of PI3-K/Akt and inhibition of p53, p38-JNK. Biochemical Pharmacology 81:7, 891-909
   CrossRef

2. 2

   Joy M. Fulbright. (2011) Review of Cardiotoxicity in Pediatric Cancer Patients: During and after Therapy. Cardiology Research and Practice 2011, 1-9
   CrossRef

3. 3

   Yu Du, Hongxiang Lou. (2008) Catechin and proanthocyanidin B4 from grape seeds prevent doxorubicin-induced toxicity in cardiomyocytes. European Journal of Pharmacology 591:1-3, 96-101
   CrossRef

4. 4

   András Csaba Nagy, Zsuzsanna Cserép, Edina Tolnay, Tamás Nagykálnai, Tamás Forster. (2008) Early Diagnosis of Chemotherapy-induced Cardiomyopathy: a Prospective Tissue Doppler Imaging Study. Pathology & Oncology Research 14:1, 69-77
   CrossRef

5. 5

   Michael S. Ewer, Francis J. Martin, I. Craig Henderson, Charles L. Shapiro, Robert S. Benjamin, Alberto A. Gabizon. (2004) Cardiac safety of liposomal anthracyclines. Seminars in Oncology 31, 161-181
   CrossRef