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, longer lasting central venous catheters requiring less than daily maintenance 'flushing', surgical expertise in placement, use in analgesia and nutrition, and 'smart' pump technology have all contributed to their increasing popularity. Justification for use of infusions in cancer chemotherapy 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 such 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 strong. In the case of platinum compounds, some toxicologic advantages have emerged, but other measures designed to protect against the toxicities of cisplatin compete with infusion regimens in this regard. The therapeutic potential for this form of drug delivery, therefore, appears still confined to a subset of patients. Stronger rationales for the use of protracted infusions may be forthcoming from pharmacodynamic findings as in the case of etoposide, combined modality therapy with radiation for FU and cisplatin, biochemical modulation for FU, and reversal of multidrug resistance and its modulation for doxorubicin. While awaiting research into these areas of clinical and pre-clinical investigations, the role of infusion appears most evident in the cardiotoxicity protection of anthracyclines, and in further efficacy exploration (through dose or modulation) of FU. Both mechanistic and pharmacologic considerations could also provide additional stimulus for development of new formulations such as long circulating liposomes, and drugs more suitable for oral administration.
DelaFlor-Weiss
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Division of Medical Oncology, Norris Cancer Center, University of Southern California, Los Angeles.
Uziely
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B
Muggia
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FM
D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous / Q000009:adverse effects; D009369:Neoplasms / Q000188:drug therapy*
D004317:Doxorubicin; D002945:Cisplatin; D005472:Fluorouracil