Cost-Effectiveness of Bone Marrow Transplantation for Chronic Myeloid Leukemia
Is there a Better Way to Give Gemcitabine?
Abstract & Commentary
Gemcitabine is a deoxycytidine analogue similar in structure to cytarabine, but with two fluorine atoms attached to the 2’ carbon in the sugar moiety rather than the single hydroxyl group present at that site in cytarabine. Like cytarabine, the drug is metabolically activated by phosphorylation and the active metabolite is difluorodeoxycytidylate (difluoroCTP). DifluoroCTP is incorporated into elongating DNA chains where it is resistant to repair mechanisms and inhibits ribonucleotide reductase thereby decreasing the pool of reduced nucleotides for DNA synthesis. The active metabolite is inactivated by cytidine deaminase, similar to cytarabine. Despite its similarities to cytarabine, gemcitabine appears to have a broader spectrum of antitumor effects. Gemcitabine is active in pancreatic cancer, nonsmall cell lung cancer, breast cancer, ovarian cancer, head and neck cancer, and Hodgkin’s disease. The basis of its broad spectrum activity is not completely clear.
Gemcitabine is usually administered in weekly 30-minute intravenous bolus infusions of 1000 mg/m2 three weeks out of four. However, pharmacology studies suggest that peripheral blood levels of 20 mmol/l maximize the rate of difluoroCTP accumulation in malignant cells and this maximally effective peripheral blood concentration is achieved at infusion rates as low as 10 mg/m2/min. The common method of gemcitabine administration results in much higher serum levels of difluoroCTP, but the excess blood levels may increase toxicity without improving efficacy. Thus, Touroutoglou and colleagues from the M.D. Anderson Cancer Center wondered if the standard method of gemcitabine administration was maximally effective. They reasoned that sufficient intracellular levels of difluoroCTP might be able to be maintained for longer time periods if the infusion rate of gemcitabine was controlled to hold the serum concentration at the level where intracellular uptake was maximal.
A phase I study was performed involving 31 patients receiving 103 courses of gemcitabine. The drug was administered at a constant rate of 10 mg/m2/min; doses were escalated from 1200 mg/m2 over 120 minutes to 2800 mg/m2 over 280 minutes. Weekly administration was scheduled but doses could be held based on toxicity. The first cycle maximum tolerated dose (MTD) was 2250 mg/m2; however, due to cumulative myelotoxicity in subsequent cycles, the recommended starting dose for phase II studies was reduced to 1500 mg/m2 over 150 minutes. Ten percent of patients had an objective response and one-third had stable disease. However, the ability of the altered schedule to improve response rates will need to be ascertained by additional clinical trials. (Touroutoglou N, et al. Ann Oncol 1998;9:1003-1008.)
Commentary
An objective assessment of the contribution of rationally designed schedules of administration of antineoplastic drugs to the practice of medical oncology would be that the results of rational hypotheses have been disappointing. Nevertheless, some of the failures of rational administration schedules have been related to the inadequate understanding we have of how drugs actually work. For example, it has been only a recent insight that the DNA damage done by many antineoplastic agents kills cells not by interfering with DNA replication but by the initiation of a DNA damage-response pathway in cells that leads to Fas-mediated suicide. It remains tempting to think that maximizing the duration of exposure of the tumor cell to maximally effective concentrations of the drug may lead to better antitumor effects.
In this spirit, Touroutoglou et al noted that the 30-minute administration of 1000 mg/m2 of gemcitabine produced serum levels of the drug that were beyond the levels found to be necessary for maximal cell uptake. They wondered whether administering the same total dose over 100 minutes would not result in preservation of effective intracellular concentrations of the active drug metabolite for longer time periods. This study does not include pharmacologic monitoring to assess whether their hypothesis was true. However, they did find that the maximum tolerated dose of gemcitabine is higher when it is administered at a maximum rate of 10 mg/m2/min.
Gemcitabine is an interesting new tool for medical oncologists and its apparent efficacy in solid tumors that are often refractory to chemotherapy is encouraging. Preclinical models suggest that gemcitabine might potentiate the antitumor effects of platinum compounds by inhibiting the repair of DNA-platinum adducts. Other interactions with DNA-damaging agents are also possible, if gemcitabine can broadly inhibit DNA repair mechanisms. Understanding the intracellular pharmacology of gemcitabine may permit the maintenance of the repair inhibition for longer periods of time. Thus, continued carefully designed, hypothesis-driven studies to maximize the therapeutic ratio of gemcitabine and work other drugs into gemcitabine-based combinations would seem to be a potentially fruitful endeavor.
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