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]
Emerging evidence suggests that genetic factors, such as polymorphisms that impact drug metabolism and distribution, may explain the heterogeneity in susceptibility to anthracycline cardiac injury.[22,26] Pharmacogenetic studies of this type, if consistently replicated across diverse study populations, may ultimately facilitate identification of newly diagnosed individuals at high risk of cardiac toxicity for whom anthracyclines should be avoided, and long-term survivors who may benefit from heightened surveillance after treatment with anthracyclines. Further study of genetic risk profiling of anthracycline injury is needed to integrate such pharmacogenetic data into clinical practice.
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 cardiac toxic effects in the two groups. Because the follow-up time in this study was relatively short, whether the frequency of progressive cardiomyopathy differs between the two groups over time is not yet clear. 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. The incidence of cardiac dysfunction in the divided-dose and single-dose infusion groups did not differ significantly. Earlier studies in adults have shown decreased cardiac toxic effects with prolonged infusion; thus, further evaluation of this question is warranted.