PROTRACTED DRUG INFUSIONS IN CANCER-TREATMENT - AN APPRAISAL OF 5-FLUOROURACIL, DOXORUBICIN, AND PLATINUMS

The feasibility to deliver chemotherapeutic agents by protracted i.v. infusion has greatly increased in the recent past. Indwelling ports, l onger lasting central venous catheters requiring less than daily maint enance 'flushing, surgical expertise in placement, use in analgesia an d nutrition, and 'smart' pump technology have all contributed to their increasing popularity. Justification for use of infusions in cancer c hemotherapy has been slow in appearing with few studies proceeding to the comparative stage. This review will focus on three drugs in common use in cancer treatment, with the purpose of appraising the role of s uch infusions in cancer therapeutics and of deriving some lessons that might be applicable to other drugs or to drug development in general. For fluorouracil and doxorubicin the rationale and clinical findings favoring further development of infusion regimens is particularly stro ng. In the case of platinum compounds, some toxicologic advantages hav e emerged, but other measures designed to protect against the toxiciti es of cisplatin compete with infusion regimens in this regard. The the rapeutic potential for this form of drug delivery, therefore, appears still confined to a subset of patients. Stronger rationales for the us e of protracted infusions may be forthcoming from pharmacodynamic find ings as in the case of etoposide, combined modality therapy with radia tion for FU and cisplatin, biochemical modulation for FU, and reversal of multidrug resistance and its modulation for doxorubicin. While awa iting research into these areas of clinical and pre-clinical investiga tions, the role of infusion appears most evident in the cardiotoxicity protection of anthracyclines, and in further efficacy exploration (th rough dose or modulation) of FU. Both mechanistic and pharmacologic co nsiderations could also provide additional stimulus for development of new formulations such as long circulating liposomes, and drugs more s uitable for oral administration.