Abstract
Background: As more patients survive cancer chemotherapy, problems associated with the late complications of therapy have become increasingly apparent; late doxorubicin cardio-myopathy being one of the most pressing. The relationship between initial dose, schedule employed, and etiology are still not well defined. This study attempts to clarify some of these issues. Methods: Patients receiving large total doses of doxorubicin by schedules designed to minimize peak drug levels were monitored in regard to their cardiac status for up to 31 years following completion of doxorubicin therapy. A computer program predicting the amount of doxorubicin retained by the heart vs. schedules employed was devised with the predictions of the computer program being compared to the clinical findings. Results: 1365 patients receiving doses of doxorubicin greater than 610 mgm./M2 were monitored for up to 31 years following completion of such therapy. No patient developed unequivocal clinical and pathologic evidence of a doxorubicin related cardiomyopathy. Knowing that human cardio-myocytes contain enzymes capable of neutralizing doxorubicin, a computer program predicted that by increasing their efficiency, the schedules employed substantially l decreased the relative amount of drug retained by the heart, findings compatible with both animal experiments and clinical results. Conclusions: administration of doxorubicin by schedules in which peak plasma levels of drug were minimized resulted in marked decreases in both acute and long-term cardiac toxicity; believed to be due to potentiation of myocardial enzymes capable of inactivating the drug.
Highlights
Between 1976 in 1996 our group has treated over 6500 patients with doxorubicin, 1365 receiving over 610 mgm./M2, 1014 over 800 mgm./M2, 777 over 900 mgm./M2, and 448 over 1000 mgm./M2
Minimal extra-cellular edema was noted. These findings were reviewed by several expert pathologists, and a typical statement was “if this was Adriamycin cardiomyopathy it is unlike any pictures that I have ever seen of Adriamycin cardiomyopathy” [6] [8]
After doxorubicin was introduced, it was noted that cardiomyopathy occurred in a significant percentage of individuals receiving more than 550 mgm./M2, and that two modifications of scheduling, one in which an equivalent amount of drug was given weekly instead of once every 21 days, and another in which the drug is given by continuous infusion, permitted the administration of higher total doses [3] [4] [8]
Summary
Between 1976 in 1996 our group has treated over 6500 patients with doxorubicin, 1365 receiving over 610 mgm./M2, 1014 over 800 mgm./M2, 777 over 900 mgm./M2 , and 448 over 1000 mgm./M2. Methods: Patients receiving large total doses of doxorubicin by schedules designed to minimize peak drug levels were monitored in regard to their cardiac status for up to 31 years following completion of doxorubicin therapy. Results: 1365 patients receiving doses of doxorubicin greater than 610 mgm./M2 were monitored for up to 31 years following completion of such therapy. Knowing that human cardio-myocytes contain enzymes capable of neutralizing doxorubicin, a computer program predicted that by increasing their efficiency, the schedules employed substantially l decreased the relative amount of drug retained by the heart, findings compatible with both animal experiments and clinical results. Conclusions: administration of doxorubicin by schedules in which peak plasma levels of drug were minimized resulted in marked decreases in both acute and long-term cardiac toxicity; believed to be due to potentiation of myocardial enzymes capable of inactivating the drug
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