The Relation between the Initial Type of Schedule Used to Administer Doxorubicin and Long-Term Doxorubicin Cardiotoxicity

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./M 2 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.

Three Protocols Designed to Individualize and Maximize Anti-Cancer Drug Therapy

“…This is due to the finding that the simultaneous use of G-Csf with a standard schedule of 5-fluorouracil and topotecan resulted in a marked increase in the toxicity of each drug [37]- [39]. As the data in this paper demonstrates, and as other publications show, this is not true for doxorubicin [40]- [44], an anthracycline, ifosphamide [40] [41], an alkylating agent, and vinorelbine [45], a vinca alkaloid. With these 3 agents, the simultaneous administration of Gm-Csf decreased the level of toxicity for a specific dose thereby allowing the total dose per course to be substantially increased.…”

“…Essentially all patients in the doxorubicin studies received further therapy with doxorubicin. Despite the very large amount of doxorubicin received by many of these patients, none developed any evidence of either early or late doxorubicin related cardiac disease [44]. Another factor to consider in these studies is the fact these many of these cytokines have anti-tumor effects as isolated agents and may have a synergistic effect when used in combination with standard chemotherapeutic agents.…”

A Hypothesis Concerning the Effect of Schedule on the Pattern of 5-Fluorouracil Toxicity

“…While hematological toxicity is dose limiting in the majority of agents in common use, the degree of toxicity to other organ systems can also be dose limiting and be substantially affected by the schedule used. The degree of toxicity to the heart associated with the administration of one of the anthracyclines [17] [18], the degree of toxicity to the gut from the administration of 5-fluorouracil [1]- [5] [11]- [14], and the degree of neurotoxicity from the taxanes [19] are significantly decreased when the drug is given by slow intravenous infusion while the degree of stomatitis from these agents is increased by repeated low dose injections or by continuous, slow infusion.…”

“…In some cases, such as with doxorubicin, the total dose required to in hematological toxicity is relatively independent of schedule [17] [18], in others, 5-fluorouracil for example, it is dependent upon the schedule used [11] [14].…”

“…Both uptake and disposition of the drug are known to be active processes with dihydropyrimidine dehydrogenase being a major factor, especially in the liver; several other enzyme complexes are also known to be important and present in different strengths in many tissues [24]- [28]. This is unlike doxorubicin cellular metabolism, in which passive diffusion, an essentially linear process, is believed to be responsible for most cellular ingress processes, and many cells lack any means of disposing of intra-cellular drug [18] [29]- [31]. Thus compared to programs studying the effect of schedule changes upon doxorubicin toxicity, the programs analyzing cellular metabolism of 5-fluorouracil are complex.…”