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Journal of Clinical Oncology, Vol 25, No 36 (December 20), 2007: pp. 5691-5694 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.6879
Questions About Gemcitabine Dose Rate: Answered or Unanswered?Departments of Experimental Therapeutics and Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX Even before 2',2'-difluorodeoxycytidine (dFdC) was given the name gemcitabine, laboratory studies were investigating the biochemical feature of its phosphorylation to demonstrate that the rate of accumulation of its triphosphate (dFdCTP, gemcitabine triphosphate) was saturated by 10 to 20 µmol/L of exogenous gemcitabine. The first investigation that established the saturability for gemcitabine triphosphate accumulation was done in a cell line.1 This was extended to primary cells in vitro2 and in peripheral-blood mononuclear cells (PBMCs) during therapy.3 In the clinic, when gemcitabine was administered at different doses during a standard 30-minute infusion, the rate of intracellular accumulation of gemcitabine triphosphate was highest when plasma gemcitabine was about 20 µmol/L. Pharmacokinetic studies during therapy further established that such gemcitabine levels (20 µmol/L) were achieved in plasma with a dose rate of 10 mg/m2/min, hence coining the term fixed dose rate (FDR) of gemcitabine.3-5 At this dose rate, a continuous increase in gemcitabine triphosphate concentration was observed for up to 18 hours.6 For the FDR delivery, generally 1,000 or 1,500 mg/m2 is infused during 100 or 150 minutes, respectively. In contrast, a phase I dose escalation trial established that the maximum tolerated dose of gemcitabine was 2,200 mg/m2/wk for 3 weeks when administered as a 30-minute infusion. This half-hour administration has been the most used schedule and has been termed the standard (STD) dose schedule of gemcitabine.7 Saturation kinetics that led to a defined dose rate have been observed for cytarabine, a prototype of nucleoside analogs. The reason that phosphorylated moieties of cytarabine (cytarabine triphosphate) and gemcitabine (gemcitabine diphosphate, gemcitabine triphosphate) are the active and cytotoxic metabolites of these nucleoside analogs further underscored the importance of the dose rate of infusion during clinical trials.8 Although several clinical trials have been performed with gemcitabine, either with STD doses or with FDR schedules, only a few were designed to ask two specific questions: First, is there a greater accumulation of gemcitabine triphosphate with a FDR of gemcitabine; and, second, does this result in a better clinical outcome (Table 1).
Is There a Pharmacokinetic Advantage of FDR Gemcitabine? The first head-to-head comparison of two schedules was done by Tempero et al9 by administering gemcitabine either as 2,200 mg/m2 during 30 minutes (STD) or as 1,500 mg/m2 during 150 minutes (FDR) to patients with pancreatic cancer.9 Measurement of gemcitabine triphosphate in PBMCs during therapy demonstrated that the peak median concentration was twice as high in the FDR arm compared with the STD arm, even though the total dose was higher in the STD infusion schedule. Similar results were obtained for patients with non–small-cell lung cancer who received gemcitabine either 750 mg/m2 infused during 75 minutes or 1,000 mg/m2 administered during 30 minutes. Even with a two-fold higher gemcitabine level in the plasma of patients who received the STD schedule, the area under the concentration-time curve (AUC) of gemcitabine triphosphate was higher with FDR delivery.17 Comparison of plasma and intracellular pharmacokinetics was done by Liebes et al11 with an infusion of the same dose of gemcitabine 1,000 mg/m2 in patients with pancreatic carcinoma who received the drug either by a 30-minute infusion or by a 100-minute infusion. Hence, the results were consistent in all these studies; however, all studies were done in two different cohorts of patients. To make direct comparisons, Patel et al14 infused the same dose of gemcitabine to the same patients either on the STD schedule (week 1) or using the FDR delivery (week 2). Few patients were available for cellular pharmacokinetic investigations, and the data demonstrated increased gemcitabine triphosphate levels with the FDR schedule. All patients received the STD dose on week 1 and the FDR dose on week 2, but the reverse schedule (ie, FDR first, followed by STD) was not investigated. Overall, there were indications of pharmacokinetic benefit with FDR delivery of gemcitabine in these investigations, but they all lacked either consistency with dose in the two schedules, investigations in the same patients, or the number of patients necessary for statistical evaluation. These deficiencies were fulfilled in the work reported by Grimison et al.21 in this issue of the Journal of Clinical Oncology. These authors performed a randomized crossover study in 33 patients who received gemcitabine 1,000 mg/m2 either by a 30-minute infusion or by a 100-minute administration. On the second week, the same patients were crossed over to the alternate schedule. The objective was to compare plasma pharmacology of gemcitabine and cellular pharmacokinetics of gemcitabine triphosphate, in which each patient served as his or her own control. Unfortunately, even though data were available, the authors did not perform paired analyses for each patient but, rather, expressed and compared data as the mean and standard deviation for each group. With a reasonable number of patients in this optimally designed clinical trial, the answers to the gemcitabine dose rate questions were expected to be achieved. However, an unexpected result was noticed that confounded the conclusion. The authors observed that, irrespective of the dose rate, there was an autoinduction of gemcitabine triphosphate accumulation (not gemcitabine, as mentioned in the title) during the second week. In short, the data demonstrated that there was a schedule-dependent increase in gemcitabine triphosphate during the second week of infusion, and it raised the question of whether there was a dose rate–dependent augmentation of the analog triphosphate with a 100-minute infusion of gemcitabine. From this report,21 if the gemcitabine triphosphate AUC for all patients at week 1 is compared with that of all patients at week 2, an approximate 1.5-fold increase in the AUC was observed on week 2 (Figure 1B in the accompanying report). In two separate cohorts, when the week 1, 30-minute infusion is compared with the week 2 30-minute infusion, the AUC again increased by 1.5-fold. This was also true when the week 1, 100-minute infusion was compared with the week 2, 100-minute infusion. Hence, it appears that, with all different comparisons, the week 2 AUC increased by approximately 1.5-fold. If this expected increase is computed for arm 1, then the AUC value of approximately 90 µmol/106 cells·h obtained on week 1 with a 30-minute infusion would increase to 135 µmol/106 cells·h on week 2. However, the observed AUC was close to 200 µmol/106 cells·h, which suggests that the additional augmentation resulted from the dose rate (100 mg/m2) rather than from a first- or second-infusion effect (Fig 1C, columns 1 and 2).21 On the contrary, the 100-minute infusion on week 1 compared with the 30-minute infusion on week 2 was not significantly different (Fig 1C, columns 3 and 4). 21 Together, these mathematical and pharmacokinetic data lead us to conclude that 100-minute infusions result in higher AUCs, which surpass the increase on week 2 compared with week 1. The true comparison, however, would be achieved by administering the 30-minute and 100-minute doses with a longer interval between the two infusions. Is There a Clinical Advantage of FDR Gemcitabine? The optimal benefit of any schedule or dose is when a clinical advantage is observed. At best, the data are sketchy with respect to clinical gain with the FDR schedule. The first randomized trial in 92 patients with pancreatic cancer demonstrated an increased median survival time (5 months with a STD dose v 8 months with the FDR schedule) and, compared with the STD arm, 1- and 2-year survival rates were three- or eight-fold greater with the FDR arm, respectively.9 However, no differences in the response rate and survival data were observed in non–small-cell lung cancer or in hepatocellular carcinoma12,13,20. Patients with the former disease who received a combination of either carboplatin (resulting in a slightly higher response rate17) or cisplatin (reducing brain metastases15) with FDR gemcitabine experienced different response rates but, again, without a survival benefit.15 Other investigations in the same disease did not show any clinical benefit with FDR gemcitabine in combination with either carboplatin,18 cisplatin,16 or paclitaxel.19 The inconsistency regarding clinical results may result from patient population differences: small numbers, heterogeneous disease, and heavily pretreated patients with extremely low response rate. Hopefully, the statistically powered (n = 833) phase III trial of gemcitabine in patients with advanced pancreatic cancer (E6201) may provide a clear indication for clinical response and a survival advantage, although the interim analyses do not show a clinical benefit.10 In general, gemcitabine was well tolerated in both arms12,17,19; however, in some studies, increased incidences of hematologic and/or other adverse effects were reported with the FDR arm.9,13,16,20 Is the FDR Schedule Better Than STD Dose for Target Tissue? The accompanying study in the current issue of JCO compares two dose rates administered to the same patients at the same doses. This is a step forward from what has been reported before for pharmacokinetic comparisons of FDR versus STD schedules. Nonetheless, all studies, including the current, have a caveat that the cellular pharmacokinetic data are obtained from a surrogate tissue (circulating PBMCs) rather than from the target solid tumor tissue. Because the gemcitabine drug level in or near solid tumor tissue is not known, and because levels of gemcitabine-activating and -inactivating enzymes such as cytidine deaminase, deoxycytidine kinase and nucleotidases are not known, it would be merely an assumption that FDR infusion would result in greater AUCs and/or peak levels of gemcitabine triphosphate even in solid tumor cells. Such studies are technically challenging and have not been performed, except for a single trial in which micromolar levels of gemcitabine triphosphate were reported in head and neck tumor tissue during a clinical trial.22 An appropriate model system for such studies could be a comparison of gemcitabine triphosphate pharmacokinetics in lymphocytes with that in ovarian cancer tumor tissue obtained from the peritoneal cavity, which is relatively easily accessible. Why Does Gemcitabine Triphosphate Increase During the Second Week? Gemcitabine pretreatment has been demonstrated to modulate activity of deoxycytidine kinase and result in an increase in subsequent phosphorylation of other nucleoside analogs that use this enzyme for conversion to monophosphate, which is generally a rate-limiting step in the phosphorylation of nucleoside analogs and of gemcitabine itself.1 This biochemical modulation is linked to inactivation of ribonucleotide reductase activity followed by a decrease in deoxynucleoside triphosphate (especially deoxycytidine triphosphate) pool, which is a feedback inhibitor of the kinase. Gemcitabine-mediated augmentation of phosphorylation of nucleoside analog triphosphate accumulation has been demonstrated for several analogs that use cell lines as a model system.1 Consistent with this, inhibition of ribonucleotide reductase also enhanced gemcitabine activity.23-25 However, in these studies, the interval between the two drugs is only a few hours or a day. It is unknown whether the biochemical modulation effect will last for 1 week, as observed in current report.21 A testable hypothesis would be that gemcitabine-mediated alkylation of ribonucleotide reductase results in a mechanism-based inactivation26,27 and that the recovery of protein takes longer than 1 week, thus leading to modulation for the second dose of gemcitabine on week 2. Among the clinically used ribonucleotide reductase inhibitors, gemcitabine's action on the enzyme is unique, as it irreversibly inactivates the protein. Other agents, such as hydrea and triphosphates of fludarabine, cladribine, and clofarabine, inhibit the enzyme, but this is reversed after elimination of the drug or its metabolites from the cells. In conclusion, the FDR schedule of gemcitabine results in increased gemcitabine triphosphate in PBMCs. Whether this is true in target tumor tissue has not been evaluated vigorously. Finally, clinical data are mixed regarding therapeutic benefit with respect to response rate and survival advantage. Author's Disclosure of Potential Conflicts of Interest The author(s) indicated no potential conflicts of interest.
REFERENCES
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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 23. Zhou B, Mi S, Mo X, et al: Time and sequence dependence of hydroxyurea in combination with gemcitabine in human KB cells. Anticancer Res 22:1369-1377, 2002[Medline] 24. Yen Y, Chow W, Leong L, et al: Phase I pharmacodynamic study of time and sequence dependency of hydroxyurea in combination with gemcitabine: A California cancer consortium trial. Cancer Chemother Pharmacol 50:353-359, 2002[CrossRef][Medline] 25. Yen Y, Margolin K, Doroshow J, et al: A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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