Infusional therapy with alkylating agents.
In 1990, Donehower editorialized in the Journal of the National Cancer Institute, entitled "Evaluating Cancer Chemotherapy by Infusion" (92). In the same issue, Goldberg reported a phase III study comparing etoposide and cDDP administered by either bolus or infusion to patients with non-small cell lung cancer (93). There was no advantage to the infusional schedule; in fact, it produced greater myelotoxicity. In the editorial, Donehower commented that the daily etoposide dose was not substantially pharmacokinetically different from a daily bolus schedule (because of the drug's relatively long half-life), and the greater myelotoxicity of infusional cDDP might have been predicted by preclinical studies. He suggested that studies of cancer drugs given by infusion should only be undertaken in the context of strong accompanying pharmacologic and preclinical experimental rationale, and that phase III studies of this concept should only be undertaken after a strong justification is developed. The concept that infusions of AA are generally less toxic than bolus dosing formed much of the rationale for infusional AA administered with BMT. The detailed studies of Teicher (1) and Frei (89), cited above, provided strong preclinical data suggesting that improvement in the therapeutic index could be achieved for most AA when infusional schedules were used. Additionally, the high toxic risk accompanying high-dose combination AA therapy with hematopoietic cell support mandated detailed PK studies. Data produced by these efforts (5, 12) now add additional basis for systemic exploration of AA infusions. Armed with the basic data suggested by Donehower, a more scientifically based study of AA infusion can take place in the future. Compelling rationales now support such studies. The availability of means to avoid fatal hematologic toxicity for virtually all patients suggests that the next era of exploration of AA infusions will be fruitful, and accompanied by a deeper understanding of the relationship between visceral organ toxicities and PK/PD changes produced by AA administered over prolonged periods.
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