Increased risk of anthracycline-related cardiomyopathy is associated with the following:[10,11,12,13,14,15,16,17,18,19,20,21,22]
- Female gender.
- Cumulative doses greater than 200 mg/m2 to 300 mg/m2.
- Younger age at time of exposure.
- Increased time from exposure.
Among these factors, cumulative dose appears to be the most significant in regard to risk of CHF, which develops in less than 5% of survivors after anthracycline exposure of less than 300 mg/m2, approaches 15% at doses between 300 and 500 mg/m2, and exceeds 30% for doses greater than 600 mg/m2.[5,12,23,24,25]
Schedule of administration of doxorubicin may influence risk of cardiomyopathy. One study looked at the effect of continuous (48 hour) versus bolus (1 hour) infusions of doxorubicin in 121 children who received a cumulative dose of 360 mg/m2 for treatment of acute lymphoblastic leukemia (ALL) and found no difference in the degree or spectrum of cardiotoxicity in the two groups. Because the follow-up time in this study was relatively short, it is not yet clear whether the frequency of progressive cardiomyopathy will differ between the two groups over time. Another study compared cardiac dysfunction in 113 children who received doxorubicin either by single-dose infusion or by a consecutive divided daily-dose schedule. The divided-dose patients received one-third of the total cycle dose over 20 minutes for 3 consecutive days. Patients treated according to a single-dose schedule received the cycle dose as a 20-minute infusion. There was no significant difference in the incidence of cardiac dysfunction between the divided-dose and single-dose infusion groups. Earlier studies in adults have shown decreased cardiotoxicity with prolonged infusion; thus, further evaluation of this question is warranted.
Prevention or amelioration of doxorubicin-induced cardiomyopathy is clearly important because the continued use of doxorubicin is required in cancer therapy. Dexrazoxane is a bisdioxopiperazine compound that readily enters cells and is subsequently hydrolyzed to form a chelating agent. Evidence supports its capacity to mitigate cardiac toxicity in patients treated with doxorubicin.[27,28,29,30,31] Studies suggest that dexrazoxane is safe and does not interfere with chemotherapeutic efficacy. There is a single-study experience suggesting that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity; other studies, however, do not show increased risk of malignancies.[31,32,33,34] However, at this time, this should not preclude treatment with dexrazoxane.[35,36]