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Originally published as JCO Early Release 10.1200/JCO.2003.09.140 on July 28 2003 © 2003 American Society for Clinical Oncology Randomized Phase II Comparison of Dose-Intense Gemcitabine: Thirty-Minute Infusion and Fixed Dose Rate Infusion in Patients With Pancreatic Adenocarcinoma
From the University of California San Francisco, San Francisco, CA; University of Texas M.D. Anderson Cancer Center, Houston, TX; Sarah Cannon Cancer Center, Nashville, TN; New York University Medical Center, New York, NY; and the Hague, the Netherlands. Address reprint requests to Margaret Tempero, MD, Deputy Director, University of California San Francisco Comprehensive Cancer Center, 1600 Divisadero St, B726, UC Box 1770, San Francisco, CA 94115; e-mail: mtempero{at}medicine.ucsf.edu.
Purpose: To conduct a randomized phase II trial of dose-intense gemcitabine using a standard 30-minute infusion or the fixed dose rate (FDR) infusion (10 mg/m2/min) in patients with pancreatic adenocarcinoma. Patients and Methods: In this prospective trial, patients with locally advanced and metastatic pancreatic adenocarcinoma were treated with 2,200 mg/m2 gemcitabine over 30 minutes (standard arm) or 1,500 mg/m2 gemcitabine over 150 minutes (FDR arm) on days 1, 8, and 15 of every 4-week cycle. The primary end point of this trial was time to treatment failure. Secondary end points included time to progression, median survival, safety, and pharmacokinetic studies of gemcitabine. Results: Ninety-two patients were enrolled onto this study; 91% of the patients had metastatic disease. Time to treatment failure was comparable in both treatment groups; however, the median survival for all patients was 5.0 months in the standard arm and 8.0 months in the FDR arm (P = .013). For patients with metastases, the median survival was 4.9 months in the standard arm and 7.3 months in FDR arm (P = .094). The 1- and 2-year survival rates for all patients were 9% (standard arm) versus 28.8% (FDR; P = .014) and 2.2% (standard arm) versus 18.3% (FDR; P = .007), respectively. Patients in the FDR infusion arm experienced consistently more hematologic toxicity. Pharmacokinetic analyses demonstrated a two-fold increase in intracellular gemcitabine triphosphate concentration in the FDR arm (P = .046). Conclusion: Pharmacokinetic and clinical data in this trial supports the continued evaluation of the FDR infusion strategy with gemcitabine.
GEMCITABINE (2', 2'-DIFLUORODEOXYCYTIDINE) is a potent cytotoxic agent with a broad spectrum of activity in pancreatic, bladder, lung, ovarian, and breast cancer.1 The chemical structure of this nucleoside analog antimetabolite differs from deoxycytidine by the addition of two fluorines in the geminal configuration at the 2' position in the carbohydrate moiety. Gemcitabine is a prodrug that is initially phosphorylated by deoxycytidine kinase to gemcitabine monophosphate, and subsequent phosphorylation steps yield gemcitabine diphosphate and gemcitabine triphosphate.2 Gemcitabine diphosphate inhibits ribonucleotide reductase,3 decreasing the cellular pool of deoxycytidine triphosphate that competes with gemcitabine triphosphate for incorporation into DNA. Incorporation of gemcitabine triphosphate into DNA inhibits replication with subsequent induction of apoptosis.4,5 Gemcitabine is cleared through metabolic elimination by cytidine deaminase and cytidylate deaminase, respectively.6,7 The velocity of the latter reaction is stimulated by deoxycytidine triphosphate. Thus, its action in reducing deoxycytidine triphosphate pools may at once increase the cellular half-life of gemcitabine triphosphate, while enhancing the likelihood of the analog being incorporated into DNA.8 As with other therapeutic nucleosides, phosphorylation of gemcitabine to the monophosphate by deoxycytidine kinase is the rate-limiting step in the accumulation of the active diphosphate and triphosphate metabolites.9 The saturation in the rate of triphosphate accumulation in cells has been explained by investigations of the kinetic mechanism of the purified enzyme,10 deoxycitidine kinase. In addition, Grunewald et al9 and Abbruzzese et al11 demonstrated in vivo in early phase I studies that the ability of mononuclear cells to accumulate gemcitabine triphosphate during therapy was saturable, and that the optimal plasma concentration of gemcitabine that maximized the rate of formation of gemcitabine triphosphate was approximately 20 µmol/L. In these studies, this target gemcitabine concentration in plasma was achieved, and the rate of gemcitabine triphosphate accumulation by mononuclear cells and leukemia cells was optimized using dose rates approximating 10 mg/m2/min. Conversely, preclinical data, using primary human tumor cultures growing in soft agar and human tumor cell lines (including pancreatic carcinoma cell lines), have suggested a possible dose-response relationship.12,13 Thus, these data suggest that exposure to high concentrations of gemcitabine, independent of infusion duration, might correlate with improved cytoxicity and enhanced clinical effectiveness. In light of these issues, we designed a study using a randomized phase II design exploring gemcitabine treatment of patients with pancreatic adenocarcinoma, using two different approaches to dose intensification. One group of patients in this study was randomly assigned to weekly doses of high-dose gemcitabine administered using a standard 30-minute infusion. The basis for the dose and schedule selected were established in a phase I dose escalation trial conducted by Fossella et al14 in patients with advanced non–small-cell lung cancer. The other dose-intense regimen also employed weekly dosing, but used a fixed dose rate (FDR) of 10 mg/m2/min. The starting dose for this arm, administered over 150 minutes, was based on phase I trials conducted by Brand et al15 and Touroutoglou et al.16 The primary end point of this trial was time to treatment failure (TTF). Time to treatment failure was defined as the time at which therapy stopped for any reason, such as progressive disease (PD), declining clinical status, or treatment toxicity. Secondary end points studied included time to progression (a parameter assessed only in patients with measurable primary tumors or metastatic disease), median survival, objective response in patients with measurable disease, and characterization of the toxicity profile of each regimen. In patients treated at the M.D. Anderson Cancer Center (Houston, TX), the pharmacokinetic behavior of gemcitabine in peripheral blood mononuclear cells was also analyzed.
Patient Selection Patients with histologically or cytologically confirmed locally advanced or metastatic adenocarcinoma of the pancreas were initially enrolled onto this study. Shortly after the study was activated, it was amended with a clarification to exclude patients without metastases. Measurable disease was not required, but measurable tumor lesions, if present, were defined as bidimensionally measurable metastases with a minimum size of 2 x 2 cm. The primary lesion in the pancreas was not considered measurable. Other eligibility criteria were age  18 years, ECOG performance status (PS) of  2, life expectancy 12 weeks, and adequate bone marrow reserve (WBC count 3.5 x 109/L, platelets 100 x 109/L, hematocrit 30%, and hemoglobin 10 g/L). Major exclusion criteria were CNS metastases, second primary malignancies, inadequate liver function (bilirubin 1.5 mg/dL; and ALT and AST levels greater than 3 times the normal levels [UNL] in patients with no liver metastases and greater than 5 times the UNL in patients with known liver metastases), or other serious comorbid disease. The study was approved by the institutional review boards of the participating centers. Written informed consent was obtained from all patients before entering the study.
Study Design Patients received full supportive care. The use of growth factors was permitted for prolonged myelosuppression (AGC < 0.5 x 109/L for at least 5 days, neutropenic fever of any duration, or neutropenia with a documented infection).
Baseline Efficacy and Safety Evaluation During treatment, patients were observed with a limited physical examination, weight measurement, analgesic use questionnaire (based on a graded scale for category of analgesic required), assessment of PS (using an ECOG scale), urinalysis, disease-related symptoms, and toxicity rating according to WHO scale before each treatment cycle. Following every two cycles, radiologic imaging was performed to document disease status. Tumor measurements were assessed using images generated by CT or MRI. All patients who entered the study (signed the consent form) were assessable for safety, TTF, and survival, and those patients with measurable or assessable disease who had been enrolled (randomly assigned) were assessable for response and time to tumor progression. Based on intent-to-treat analysis, patients who discontinued treatment owing to toxicity before receiving three doses of gemcitabine were also considered assessable for other measures of efficacy (analgesic use, PS, and weight change). To adjust each weekly dose of gemcitabine, a complete hemogram and differential was obtained on each day of treatment. Blood chemistry measurements were repeated at the start of each cycle. Patients were discontinued from the study when the treatment was associated with unacceptable toxicities or evidence of PD, or at the patient or investigator’s request. WHO criteria17 were used for assessment of response in patients with defined measurable disease, using previously published definitions of complete response, partial remission, stable disease, and PD.
Pharmacokinetic Analysis
Statistical Analysis The planned inclusion of 40 patients per treatment arm allowed at least a 90% chance of correctly selecting between a dose of 2,200 mg/m2 given over 30 minutes and a dose of 1,500 mg/m2 given at a rate of 10 mg/m2/min, the regimen with the longest median TTF when it is superior to the least preferable regimen by a difference of at least 8 weeks in median TTF. The underlying assumption with this procedure was that the difference in probability of treatment failure past median TTF between the most and the least preferable regimen was at least equal to 15%. The survival curves were calculated according to the Kaplan-Meier method. Statistical differences between the two treatment arms were calculated using the log-rank test. Pharmacokinetic data were analyzed using a two-tailed t test.
Patient Characteristics Ninety-two patients (49 in the standard arm, 43 in the FDR arm) were enrolled in the study from 15 centers. All patients were assessable for safety. The median age of patients was 62 years (range, 31 to 89 years), and 59 of the patients (64%) were men. Patient characteristics at study entry are presented in Table 1  . An ambiguity in the eligibility criteria permitted early enrollment of 8 patients with locally advanced but not metastatic disease. The majority of patients (91%) had metastatic disease, with liver metastases documented in 77 patients. Ten patients had been previously treated with fluorouracil (FU) and radiation for management of primary tumors. All other patients were chemotherapy-naïve.
Time-to-Event Results and Tumor Response In the standard arm, median TTF for all patients was 1.8 months (95% confidence interval [CI], 1.7 to 2.1 months) versus 2.1 months (95% CI, 1.8 to 3.6 months) for the FDR arm. For patients with metastatic disease, the median TTF was 1.8 months (95% CI, 1.7 to 2.2 months) and 2.0 months (95% CI, 1.6 to 3.6 months), respectively, for the standard and FDR arms. The TTF curves are shown in Figures 1A and 1B. This difference did not reach statistical significance (P = .09).
The median time to PD was analyzed only in those patients meeting our criteria for measurable disease. The median time to PD was 1.9 months (95% confidence interval [CI], 1.8 to 5.3 months) for the standard arm and 3.4 months (95% CI, 1.6 to 3.6 months) for the FDR arm. This difference was not statistically significant (P = .68).
The median survival time for all patients was 5.0 months (95% CI, 3.4 to 7.3 months) for the standard arm and 8.0 months (95% CI, 6.1 to 10.9 months) for the FDR arm (P = .013). In the metastatic patient population, the median survival time was 4.9 months (95% CI, 3.4 to 7.2 months) for the standard arm and 7.3 months (95% CI, 4.8 to 10 months) for the FDR arm (P = .094). The survival curves for these patient populations are given in Figures 2A
Only 39 patients (22 in the standard arm and 17 in the FDR arm) had measurable metastatic disease and were therefore assessable for response. The other patients were not assessable for this end point because of lack of extra pancreatic metastases (8 patients), lack of measurable metastases based on our criteria (34 patients), failure to complete at least one full cycle of therapy (6 patients), and lack of appropriate follow-up (4 patients). Of the patients meeting criteria for measurable disease, two (9.1%) in the standard arm had partial responses. One partial response (5.9%) was observed in the FDR arm. Investigators reported additional responses (two complete and two partial) in the FDR arm among patients who did not meet criteria for measurable disease. Since response was not a primary end point, independent confirmation of response was not performed. CA19-9 results will be analyzed separately and presented in a future publication.
Other Measures of Efficacy
Toxic Effects
Other nonhematologic toxic effects typical of gemcitabine delivered at approved lower doses were observed. These included cutaneous reactions, fever, diarrhea, and nausea or vomiting. However the incidence was comparable between the two treatment arms.
Dose Omissions and Reductions
Pharmacokinetic Analysis
The ultimate goal of this trial was to identify the appropriate dose intensification regimen for further development, especially in combination with other agents. The primary end point of these studies was TTF with secondary end points of time to progression, median survival, objective response, safety, and gemcitabine pharmacokinetics. Benchmarks for clinical outcome with gemcitabine treatment in patients with pancreatic adenocarcinoma are perhaps best drawn from the pivotal trial conducted by Burris et al,21 as well as from the data file for more than 3,000 patients with pancreatic cancer treated on the investigational new drug treatment program while gemcitabine was undergoing review by the Food and Drug Administration.22
In the trial conducted by Burris et al,21 patients were randomly assigned to receive either gemcitabine 1,000 mg/m2 over 30 minutes weekly x7, followed by one week of rest, then weekly for 3 weeks of every 4 weeks thereafter, or FU 600 mg/m2 by bolus IV injection once weekly. This trial included 63 patients in each arm. Eligibility criteria included a baseline Karnofsky PS of less than 80, and baseline analgesic consumption of The report on the investigational new drug treatment program by Storniolo et al22 included patients with stage III (493 patients) and stage IV (1,989 patients) disease. The median time to disease progression was available for approximately 2,000 of these patients and was estimated at 2.7 months. The median survival for 2,380 patients for whom survival data were available was 4.8 months. The breakdown for stage II/III patients and stage IV patients revealed median survival times of 6.3 months and 4.3 months, respectively. In comparison with these collective data, the outcomes of patients on our dose-intense schedule using a 30-minute infusion (standard arm) were similar. Although the time to PD was somewhat shorter at 1.9 months, the median survival for all patients was 5.0 months (95% CI, 3.4 to 7.3 months), and for patients with metastatic disease, 4.9 months (95% CI, 3.4 to 7.2 months). In contrast, using the FDR infusion, the time to PD was 3.4 months (95% CI, 1.6 to 3.6 months), and overall median survival was 8.0 months (95% CI, 6.1 to 10.9 months) for all patients, and 7.3 months (95% CI, 4.8 to 10.0 months) for patients with metastatic disease. In addition, the 1-, 2-, and 3-year survival rates of 28.8%, 18.3%, and 12%, respectively, in the FDR arm are extremely encouraging. For patients with metastatic disease, the 1-, 2-, and 3-year survival rates were 19.9%, 13.2%, and 8%, respectively. It is somewhat surprising that the survival advantage seen in the FDR arm was not accompanied by a similar improvement in the primary end point, TTF. We also did not observe a significant improvement in the median time to PD. There are several explanations for this. TTF, an end point that may result from poor tolerance to therapy, clinical deterioration, or true objective progression, has not been commonly used in pancreatic cancer clinical trials and may not be a good predictor for survival benefit. Our assessment of time to PD was applied only to the subset of patients with measurable disease by our more strict criteria. Thus, the sample size may have been too small to demonstrate a meaningful difference. The encouraging 1-, 2-, and 3-year survival rates seen in this study may have resulted from a more durable treatment effect, which would also not relate well to the primary end point. Another factor that can influence survival is second-line therapy. Fifty percent of the patients in the FDR arm and 25% of the patients in the standard arm received subsequent chemotherapy. Information on the type of chemotherapy was not collected as part of this trial. While it is possible that subsequent chemotherapy influenced survival, it is also possible that more patients receiving FDR infusion were able to proceed to second-line treatment based on a better PS and/or better organ function. Other clinical indicators may favor the FDR arm. Improvements in analgesic requirements occurred in 27.3% of the patients in the FDR arm and 15.6% of the patients in the standard infusion arm. In the FDR arm, 25.7% of the patients also experienced improvement in PS, compared with only 9.1% of the patients in the standard infusion arm. No apparent differences in weight gain were observed. A moderate rate of grade 3 and 4 myelosuppression occurred with both treatment schedules. The FDR infusion schedule seemed more toxic, with 48.8% of patients experiencing grade 3 and 4 neutropenia and 37.2% experiencing grade 3 and 4 thrombocytopenia. However, despite this level of myelosuppression, an appreciably higher incidence of dose reductions or omissions was not observed. Overall, other grade 3 and 4 laboratory and nonlaboratory toxicities were uncommon except for grade 3 and 4 nausea and vomiting, occurring in 14.3% in the standard infusion arm and 18.6% in the FDR arm. The pharmacokinetic studies for these two gemcitabine regimens are particularly interesting. Although there is considerable interpatient variability with both infusion rates, the peak accumulation of gemcitabine triphosphate occurred early during the sampling period and rapidly reached a plateau in the standard arm. The median concentrations of gemcitabine triphosphate in this group were 103 µmol/L and 197 µmol/L at 30 and 150 minutes, respectively. For the FDR infusion schedule, the formation of gemcitabine triphosphate remained linear and did not reach a peak during the sampling period of 150 minutes. The concentrations were 66 µmol/L and 398 µmol/L at 30 and 150 minutes, respectively. Overall, using peripheral blood mononuclear cells as a surrogate, the aggregate data support a two-fold increase in gemcitabine triphosphate using the FDR infusion. It is important to note that our results with dose-intense gemcitabine over a 30-minute infusion differ from a recently reported trial by Ulrich-Pur et al23 in which a similar dose and schedule of gemcitabine was given to a cohort of 43 patients with metastatic adenocarcinoma of the pancreas. These patients were also treated with gemcitabine 2,200 mg/m2 given as a 30-minute IV infusion, though treatment was administered every 2 weeks on a 4-week cycle. The time to progression was reported as 5.3 months with a median survival of 8.8 months, and a probability of surviving beyond 12 months at 26.3%. One important difference between this trial and our study was the fact that gemcitabine was given on biweekly basis. As a result, this regimen resulted in a much lower incidence of high-grade toxicity, and only 5% of the patients had delayed courses of therapy, with none requiring a dose reduction. Patients in the standard infusion arm in our study experienced a much higher incidence of grade 3 and 4 hematologic toxicity, and 12% of 450 planned doses of gemcitabine were reduced, while 6.7% were omitted. Thus, one explanation for the difference between these two studies would be that maintenance of intended dose without need for dose reduction may be important in improving outcome with gemcitabine on a standard 30-minute infusion schedule. In summary, TTF, time to progression, and objective response were comparable in both arms of this study. However, a modest overall improvement in survival, with an unusually high 1-, 2-, and 3-year survivorship, favors further exploration of the FDR administration technique. Evidence of clinical benefit based on analgesic requirement and changes in PS, while not significantly better, also favors the FDR approach. Hematologic toxicity was the major adverse event observed. This seemed to be more prevalent with the FDR infusion; however, the number of dose modifications and the number of dose omissions were comparable in both arms. Pharmacokinetic studies demonstrate an advantage in accumulation of gemcitabine triphosphate in the FDR infusion arm. As previously noted, the purpose of this trial was to assess the efficacy of two dose-intense schedules of gemcitabine using a standard infusion time and an infusion rate based on pharmacokinetic principles (FDR), to select a dose and infusion rate for further development in combination with potentially synergistic drugs. This study does not definitively favor one regimen over the other. However, both the pharmacologic and clinical data support the continued evaluation of the FDR infusion strategy for gemcitabine, either alone or in combination with other agents.
The authors indicated no potential conflicts of interest.
The authors gratefully acknowledge the outstanding technical assistance of Min Du and the dedicated care and careful data collection of all our nurses and data managers.
Financial support for this study was provided by Eli Lilly and Co, Indianapolis, IN. Presented in part at the Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15–18, 1999.
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21. Burris HA III, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15:2403–2413, 1997 22. 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] 23. Ulrich-Pur H, Kornek GV, Raderer M, et al: A phase II trial of biweekly high dose gemcitabine for patients with metastatic pancreatic adenocarcinoma. Cancer 88:2505–2511, 2000[CrossRef][Medline] Submitted September 30, 2002; accepted May 2, 2003. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
