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Originally published as JCO Early Release 10.1200/JCO.2003.05.081 on July 28 2003 © 2003 American Society for Clinical Oncology
It’s What’s Inside That CountsUniversity of Michigan, Ann Arbor, MI ALTHOUGH RESEARCH that improves the effectiveness of an approved chemotherapeutic agent does not grab headlines like the introduction of new molecularly targeted therapies, such research can yield important benefits for patients. This kind of investigation is required because the dose and schedule for many of the most widely used chemotherapeutic agents is largely empirical. When drugs are introduced into the clinic in a standard phase I trial design, dosing is, in part, based on the plasma pharmacokinetics of the parent drug, to achieve high dose-intensity with acceptable toxicity. While this strategy is reasonable for drugs that are active in their parent form, a different approach may be required for drugs that require activation within the tumor cell. For example, nucleoside analogs such as cytarabine and gemcitabine require intracellular activation to their triphosphate metabolites, and it has been shown that the retention of these derivatives in leukemia or blood mononuclear cells is far longer than that of the parent nucleoside in plasma.1–3 Although this approach is rarely used, it has been proposed that dosing of these drugs should be based on the intracellular pharmacokinetics of the active metabolite. In this issue of the Journal of Clinical Oncology, Tempero et al4 report on the results of a randomized phase II trial of two dosing schedules for gemcitabine in patients with pancreatic cancer, one based on the standard 30-minute infusion of a high dose of gemcitabine (2,200 mg/m2), and the other, a fixed dose rate infusion (1,500 mg/m2 given at 10 mg/m2/min), based on maximizing the intracellular pharmacokinetics of gemcitabine activation. They provide convincing evidence that the fixed dose rate infusion does, as predicted, produce significantly higher peak levels of gemcitabine triphosphate in circulating mononuclear cells, which correlates with the increased hematological toxicity observed in that treatment arm. In addition, the study provides encouraging, though not definitive, results suggesting that this more rational form of administration may increase clinical benefit. The fixed dose rate infusion is based on clinical studies demonstrating that conversion of gemcitabine to its triphosphate was saturable in peripheral blood mononuclear cells in patients.3,5 In these studies, gemcitabine was administered at different doses during a standard 30-minute infusion. Measurement of plasma gemcitabine and intracellular gemcitabine triphosphate demonstrated that the rate of accumulation and peak value for gemcitabine triphosphate were highest when the plasma gemcitabine was approximately 20 to 30 µM, which was typically achieved at a dose rate of approximately 10 mg/m2/min. These results were confirmed in in vitro studies,6 and are likely due to the saturation of the initial activating enzyme for gemcitabine, deoxycytidine kinase.7 However, this longer infusion schedule has not been used extensively in the clinic, due to convenience and the appearance of lower dose-intensity (lower total dose delivered) in the fixed dose rate, compared with the standard 30-minute infusion, as well as the limitations of determining superiority from a randomized phase II trial. In the present study, analysis of gemcitabine triphosphate in peripheral blood mononuclear cells during therapy demonstrated that the peak median concentration- of gemcitabine triphosphate inside the cell was twice as high in the fixed dose rate arm compared with the standard dose arm. The authors note that this advantage was not apparent early in the infusion, as the median maximum concentration was lower at 30 minutes for the fixed dose rate compared with the standard arm. The authors did not discuss whether the area under the curve (AUC) was increased by the fixed dose rate infusion, and it will be important in future studies to determine whether clinical response correlates with AUC or peak level of active gemcitabine. In any case, the fixed dose rate accomplished exactly what it was designed to—increase the peak amount of active gemcitabine within cells. The longer infusion of gemcitabine at the fixed dose rate also increased hematologic toxicity, though it was tolerable. These data are consistent with early clinical trials of gemcitabine, in which the maximum-tolerated dose increased as the duration of gemcitabine infusion decreased.10,11 The confirmation that higher peak intracellular levels of the active metabolite are achieved by continuous infusion strongly supports the use of mechanistic studies to motivate clinical trial design. Although the fixed dose rate schedule clearly produces higher levels of activated gemcitabine in circulating mononuclear blood cells, it is important to ask whether this schedule increases levels in solid tumors. In view of the rapid half-life for gemcitabine in plasma (approximately 10 to 15 minutes),3,8 it is not clear that saturating levels of drug will be present long enough at the site of the tumor to significantly inhibit activation. This is a difficult issue to resolve since measuring in vivo drug metabolism is much more complex for solid tumors than mononuclear cells. Some insight into the activation of gemcitabine in solid tumors was provided by a small study that we performed in patients with head and neck cancer who had accessible tumor tissue for biopsy.9 At doses ranging from 50 mg/m2 to 300 mg/m2 administered over 30 minutes, tumors biopsied at 2 hours postinfusion had µM levels of gemcitabine triphosphate, which, based on in vitro studies, would be anticipated to produce potent radiosensitization.9 This demonstrates that substantial concentrations of gemcitabine were present in tumor after low intravenous doses, despite the rapid deamination of parent drug, suggesting that much higher, even saturable, concentrations may occur after the much higher doses used in the current study. In contrast to the apparent success of the Tempero et al4 trial in supporting the pharmacological concept, the results concerning tumor response are somewhat more difficult to interpret. It seems that overall median, 1-year, and 2-year survival, which were secondary end points of the study, are increased when gemcitabine is delivered by fixed dose rate infusion. However, the analysis is complicated by the initial inclusion of eight patients with locally advanced, nonmetastatic disease. Patients with locally advanced, nonmetastatic disease clearly represent a different patient population from those with metastatic disease. The median survival for patients with nonmetastatic disease treated with gemcitabine alone has been reported to be approximately of 7 months, rather than the 5 months typically reported for patients with metastatic disease.12 However, radiation combined with chemotherapy produces median survival times closer to a year,13 suggesting that chemotherapy alone may be an inferior therapy for patients with locally advanced nonmetastatic disease. Thus, it was appropriate that it was decided early in the study to accrue only patients with metastatic disease, and to perform analyses without patients with locally advanced disease. Although the overall trend toward better survival in the fixed dose rate arm remained, none of the differences between treatment arms for metastatic patients remained statistically significant. How can we understand this result? Perhaps the most likely reason is that there was insufficient power to demonstrate a real, though modest, improvement. It is possible that the greater toxicity of the continuous infusion arm was better tolerated by patients without metastatic disease, who presumably had better performance status. Given the possible improvement in survival produced by the fixed dose rate infusion of gemcitabine, it is puzzling there was no difference in the primary end point: the time-to-treatment failure for all patients between the two arms (1.8 months v 2.1 months for standard versus fixed dose rate). How can a lack of difference in time to treatment failure produce improved survival in one of the arms? Perhaps, as the authors suggest, time to failure is simply not yet a well-understood intermediate end point of success. All end points, other than overall survival, have some ambiguity. However, a potential confounding issue is the use of second-line chemotherapy, which was twice as common in the patients undergoing fixed dose rate infusion gemcitabine. Although second-line chemotherapy is not often effective in pancreatic cancer, it remains possible that some clinical impact of such treatment may explain some of the improved survival seen in the fixed dose rate arm. Taking all of the findings together, this study by Tempero et al4 suggests that the administration of gemcitabine at a fixed dose rate, based on a pharmacologic rationale, does increase intracellular levels of activated drug and may improve the outcome of patients with pancreatic cancer. However, the absence of a difference between arms regarding the primary end point of time-to-failure and the lack of a statistically significant improvement in survival in metastatic patients means that the treatment results of this study can best be viewed as hypothesis-generating, rather than definitive. The continuous fixed dose rate strategy is now being tested in randomized trials in Cancer and Leukemia Group B (89904) and in Eastern Cooperative Group (E6201), the latter in a phase III trial, with the standard dose schedule of gemcitabine as the control arm. A third arm of E6201 is the gemcitabine-oxaliplatin combination, which combines fixed dose rate gemcitabine with oxaliplatin. While we continue our search for new and better drugs, the trial reported on by Tempero et al provides strong motivation to use sound scientific rationale to optimize the traditional therapeutics that still form the mainstay of cancer treatment. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES
1. Rustum YM, Preisler HD: Correlation between leukemic cell retention of 1-ß-D-arabinofuranosylcytosine 5'-triphosphate and response to therapy. Cancer Res 39:42–49, 1979 2. Plunkett W, Iacoboni S, Estey E, et al: Pharmacologically directed ara-C therapy for refractory leukemia. Semin Oncol 12:20–30, 1985[Medline] 3. Abbruzzese JL, Grunewald R, Weeks EA, et al: A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491–498, 1991[Abstract]
4. Tempero M, Plunkett W, Ruiz van Haperen V, et al: Randomized phase II comparison of dose intense gemcitabine: Thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 21:3402–3408, 2003 5. Grunewald R, Abruzzese JL, Tarassoff P, et al: Saturation of 2', 2'-difluorodeoxycytidine 5'-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine. Cancer Chemother Pharmacol 27:258–262, 1991[CrossRef][Medline]
6. Grunewald R, Kantarjian H, Keating MJ, et al: Pharmacologically directed design of the dose rate and schedule of 2', 2'-difluorodeoxycytidine (gemcitabine) administration in leukemia. Cancer Res 50:6823–6826, 1990 7. Hughes TL, Hahn TM, Reynolds KK, et al: Kinetic analysis of human deoxycytidine kinase with the true phosphate donor uridine triphosphate. Biochemistry 36:7540–7547, 1997[CrossRef][Medline] 8. Storniolo AM, Allerheiligen SRB, Pearce HL. Preclinical, pharmacologic, and phase I studies of gemcitabine. Semin Oncol 24:72–77, 1997
9. Eisbruch A, Shewach DS, Bradford CR, et al: Radiation concurrent with gemcitabine for locally advanced head and neck cancer: A phase I trial and intracellular drug incorporation study. J Clin Oncol 19:792–799, 2001 10. Poplin EA, Corbett T, Flaherty L, et al: Difluorodeoxycytidine (dFdC)-gemcitabine: A phase I study. Invest New Drugs 10:165–170, 1992[CrossRef][Medline] 11. Lund B, Kristjansen PEG, and Hansen HH: Clinical and preclinical activity of 2', 2'-difluorodeoxycytidine (gemcitabine). Cancer Treat Rev 19:45–55, 1993[Medline] 12. Storniolo AM, Enas NH, Brown CA, et al: An investigational new drug treatment program for patients with gemcitabine: Results for over 3000 patients with pancreatic carcinoma. Cancer 85:1261–1268, 1999[CrossRef][Medline]
13. McGinn CJ, Zalupski MA, Shureiqi I, et al: Phase I trial of radiation dose escalation with concurrent weekly full dose gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 19:4202–4208, 2001
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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