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© 2003 American Society for Clinical Oncology Intravesical Gemcitabine Therapy for Superficial Transitional Cell Carcinoma of the Bladder: A Phase I and Pharmacokinetic Study
From Department of Urology and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins Hospital, Baltimore, MD; Division of Hematology/Oncology and Department of Pharmacology, University of Pittsburgh School of Medicine, and Program of Molecular Therapeutics/Drug Discovery, University of Pittsburgh Cancer Institute, Pittsburgh, PA; Department of Urology, Sheba Medical Center, Tel Hashomer, and Department of Urology, Bnai Zion Medical Center, Haifa, Israel. Address reprint requests to Merrill J. Egorin, MD, University of Pittsburgh Cancer Institute, Room G 27-E, Hillman Research Pavilion, 5117 Centre Ave, Pittsburgh, PA 15213-1863; email: egorinmj{at}msx.upmc.edu.
Purpose: To determine maximum-tolerated dose, toxicities, and pharmacokinetics associated with weekly intravesical gemcitabine therapy in patients with superficial bladder cancer. Patients and Methods: Fifteen patients with recurrent superficial transitional cell bladder carcinoma who experienced prior intravesical therapy failure were studied. Two to 4 weeks after complete transurethral resection, gemcitabine was administered intravesically, once weekly for 6 consecutive weeks. Dwell time was 2 hours. Pharmacokinetics of gemcitabine and its metabolite, 2'2'-difluorodeoxyuridine (dFdU), were studied in plasma and urine. Cystoscopy was repeated 6 weeks after therapy.
Results: Three-patient cohorts were enrolled sequentially at doses of 500, 1,000, and 1,500 mg in 100 mL 0.9% NaCl. Two patients received 2,000 mg in 100 mL. An additional four patients received 2,000 mg in 50 mL. No grade 4 toxicity or clinically relevant myelosuppression was noted. Nine of 13 evaluable patients were recurrence-free at 12 weeks. Low concentrations of gemcitabine ( Conclusion: Intravesical gemcitabine, at doses up to 2 g/wk, is well tolerated, is associated with minimal systemic absorption, and has promising efficacy in treatment of superficial bladder cancer.
CARCINOMA OF the bladder is a common neoplasm, with an estimated incidence of 56,500 new cases in the United States in 2002.1 Most of these tumors are transitional cell carcinomas. Approximately 70% to 80% of patients with bladder cancer present with superficial tumors, which include tumors limited to the mucosa, submucosa, and lamina propria.2 Transurethral resection of the bladder tumor (TURBT) is the initial treatment for such patients. Unfortunately, tumors recur in 40% to 80% of patients following TURBT, and 20% to 30% of such patients develop muscle-invasive disease that requires more aggressive therapy.2,3 The risk of recurrence following TURBT depends on factors such as pathological grade and depth of invasion, size of the lesion, and multiplicity.4 Patients at high risk for recurrence require additional therapy after TURBT. Intravesical instillation of bacille Calmette-Guérin (BCG) is the most commonly used therapy.2 Although randomized studies have documented a 30% to 40% decrease in the risk of recurrence with BCG therapy, intravesical therapy with BCG is not innocuous and is associated with toxicities ranging from dysuria and frequency of urination to systemic tuberculosis.5 Unfortunately, there are no effective treatment options for patients with persistent disease following BCG therapy. A number of cytotoxic drugs, including mitomycin C,6 thiotepa,7,8 doxorubicin,9 epirubicin,10 and valrubicin11 have been evaluated as intravesical therapy. Unfortunately, none of these agents is as effective as BCG.12 Intravesical therapy with chemotherapeutic agents may also be limited by toxicity related to systemic absorption of the drugs.13 Hence, there remains a need to develop novel chemotherapeutic options with effective antitumor activity and pharmacokinetic profiles that are suitable for regional therapy. Gemcitabine (2',2'-difluorodeoxycytidine) is a pyrimidine analog that exhibits antitumor activity against a variety of solid tumors.14–17 In the United States, gemcitabine is approved for treatment of non–small-cell lung cancer and pancreatic cancer. Recent studies have shown gemcitabine to produce robust response rates in patients with metastatic bladder cancer.18 The combination of gemcitabine and a platinum compound is an effective first-line therapy option for patients with metastatic bladder cancer.19 In addition, gemcitabine possesses pharmacokinetic properties that are ideal for regional therapy.20,21 On intravenous administration, gemcitabine is rapidly deaminated by cytidine deaminase, resulting in the inactive metabolite 2',2'-difluorodeoxyuridine (dFdU).22 Hence, gemcitabine has a high total body clearance. In that the relative advantage of a drug for regional therapy is directly proportional to its total body clearance and inversely proportional to the rate of absorption into the systemic circulation, gemcitabine is well suited for regional therapy. Furthermore, animal studies have documented that gemcitabine can be administered safely by the intravesical route.20 On the basis of the high relative advantage for regional therapy with gemcitabine and the proven efficacy of systemically administered gemcitabine against bladder cancer, we conducted a phase I trial to define the optimal dose and pharmacokinetics of intravesical gemcitabine in patients with superficial bladder cancer who had experienced failure of prior intravesical therapy.
Eligibility Patients eligible for this multicenter, nonrandomized, dose-escalation study had histologically confirmed diagnosis of stages Tis, Ta, or T1 transitional cell bladder carcinoma, with persistent or recurrent disease despite prior intravesical therapy. Other eligibility criteria included age  18 years; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; adequate bone marrow function as defined by WBC 3,000/µL, absolute neutrophil count (ANC) 1,500/µL, platelets 100,000/µL; normal renal (serum creatinine  1.5 mg/dL) and hepatic function (serum total bilirubin 1.5 mg/dL, serum ALT and serum aspartate aminotransferase levels two times the upper limit of normal); and the ability to provide signed informed consent before protocol therapy. Patients with at least one of the following criteria were excluded from study: evidence of locally invasive or metastatic bladder cancer (stage T2), presence of upper urinary tract cancer, immunotherapy or radiotherapy within 4 weeks of initiation of the study, and unresolved bacterial infection requiring active treatment with antibiotics. Patients of reproductive age were required to use appropriate contraception before and during participation in the study. The study protocol was reviewed and approved by the institutional review board at each participating institution
Treatment Plan and Response Assessment
Pharmacokinetic Sample Acquisition and Handling In vitro studies were also performed to document the stability of gemcitabine in urine. Gemcitabine was added to three control urine samples to produce a final concentration of 5 µg/mL, and the resulting urinary solutions were incubated at 37°C in a shaking water bath. At 5, 15, 30, 45, 60, 90, and 120 minutes, duplicate aliquots of urine were removed, frozen, and stored at -20°C until analysis.
High-Pressure Liquid Chromatography Determination of Gemcitabine
Pharmacokinetic Evaluations
Clinical and Response Characteristics Between July 1999 and February 2001, 15 patients were enrolled at two institutions (Table 1  ). Three patients/dose were enrolled at dose levels of 500, 1,000, and 1,500 mg. Six patients were enrolled at the 2,000-mg dose. Two of these patients received gemcitabine in a volume of 100 mL. Concerns regarding tolerable volumes that could be instilled led to the remaining four patients receiving 2,000 mg in 50 mL. One patient treated with 1,500 mg received a second cycle of intravesical gemcitabine.
Six of 15 patients had received prior therapy with BCG alone, whereas seven had received prior intravesical chemotherapy in addition to BCG (Table 1  ). Two patients received prior intravesical therapy with mitomycin C only. Intravesical gemcitabine was well tolerated by all patients. The most common grade 1 to 2 toxicities experienced were dysuria, hematuria, urinary retention, urinary frequency, fatigue, hyperglycemia, rhinitis, leukopenia, and headache (Table 2). A majority of the toxicities were grade 1 in severity. Two patients experienced grade 3 toxicities, which included urinary retention in one patient treated at the 1,000-mg dose level and frequency of urination in a patient treated at the 2,000-mg dose level. The only patient who was given a second course of intravesical gemcitabine experienced grade 3 epididymitis during the second course. Two patients received only two doses of intravesical gemcitabine. One patient treated with 2,000 mg in 50 mL discontinued therapy because of depression. Another patient treated with 2,000 mg in 100 mL discontinued therapy because of toxicity (grade 3 urinary frequency and grade 2 urinary incontinence).
Repeat cystoscopy was performed in all patients at 6 weeks after completion of intravesical therapy. No evidence of recurrent disease was noted in nine patients. This included one patient in whom a tumor located in a diverticulum could not be resected because of technical reasons. Four patients were noted to have recurrence of superficial tumor, whereas two were not evaluable for response (they did not complete the planned course of therapy). Among the nine patients without recurrence of tumor, eight were treated with gemcitabine doses 1,000 mg.
Pharmacokinetic Studies
Gemcitabine was only observed in plasma of the four patients treated with 2,000 mg of gemcitabine instilled in a 50-mL volume. Peak concentrations never exceeded 1 µg/mL (Fig 1
dFdU was not detected in plasma of any patient treated with 500 or 1,000 mg of gemcitabine. In contrast, dFdU was detected in plasma of all patients treated with 1,500 or 2,000 mg of gemcitabine (Fig 2 , Table 3). Plasma concentrations of dFdU increased progressively during the first 60 to 90 minutes of dwell time, after which they remained relatively constant (Fig 2). There was no obvious decrease in plasma dFdU concentrations during the 60 minutes after voiding of the instilled gemcitabine. The time course of dFdU accumulation in patient plasma was similar across the cohorts of patients treated with 1,500 mg of gemcitabine in 100 mL, 2,000 mg of gemcitabine in 100 mL, and 2,000 mg of gemcitabine in 50 mL. There was substantial interpatient variability in the dFdU Css produced in plasma of patients treated at each dose (Table 3). There was overlap in the plasma dFdU Css associated with each of the three groups of patients (Table 3). The dFdU Css in plasma corresponded to gemcitabine absorption rates from the bladder of 0.08 to 0.092 mg/min. On the basis of these rates and the 120-minute dwell time, predicted amounts of gemcitabine absorbed from the bladder ranged from 10 to 110 mg, corresponding to 0.52% to 5.52% of the total gemcitabine dose instilled.
Because some patients had problems retaining the entire gemcitabine dose for the full 120-minute dwell time and others had substantial postvoid residual volumes in their bladders, the percentage of administered dose recovered in voided urine could not be calculated in all patients. In the 11 patients for whom this calculation could be made, recovery of administered dose ranged from 61% to essentially 100%, with the lowest recoveries being calculated for patients subsequently shown to have substantial postvoid residual volumes (Fig 3 ).
Our study demonstrates the safety of administration of intravesical gemcitabine for patients with recurrent superficial transitional cell carcinoma of the bladder. Only two of 15 patients treated with intravesical gemcitabine experienced grade 3 toxicity. At the highest dose level of gemcitabine (2,000 mg), one of six patients experienced grade 3 frequency of urination. This patient received 2,000 mg of gemcitabine in 100 mL. Hence, up to 2,000 mg of gemcitabine can be administered intravesically to patients with superficial bladder cancer. Among the nine patients who did not have recurrence of disease at repeat cystoscopy, eight had received gemcitabine doses 1,000 mg, whereas all three patients treated with 500 mg of gemcitabine experienced recurrence of disease. Although efficacy was not a primary end point of our study, the absence of recurrence of disease in nine of 15 patients at repeat cystoscopy is promising and worthy of evaluation in phase II clinical trials. Our trial was designed with an extensive pharmacokinetic component in recognition of the importance of such data in interpretation of studies of regional drug delivery. The pharmacokinetic results obtained indicate a number of issues relevant to the clinical application of intravesically administered gemcitabine. At the same time, the results also raise a number of questions to be pursued. The dose-escalation scheme employed in this study involved not only escalating doses of gemcitabine over a fourfold range but also involved instillation of gemcitabine concentrations between 5 and 40 mg/mL. Our data indicate that these doses and concentrations are associated with little absorption of gemcitabine from the bladder into the systemic circulation. Gemcitabine was only detected in the plasma of those patients treated with 40 mg/mL instillations of gemcitabine, that is, 2,000 mg in 50 mL, and those plasma concentrations observed were low and transient. The fact that plasma concentrations of gemcitabine decreased during the time that gemcitabine was residing in the bladder indicates that the initial influx of gemcitabine into the bladder might be associated with the process of drug administration, rather than presence of the drug in the bladder. The failure to observe gemcitabine in the plasma of many patients given the drug intravesically may not be surprising when one considers the high total body clearance of gemcitabine, which reflects the large amount of cytidine deaminase present in red cells and other tissues. The low dFdU concentrations present in plasma after intravesical gemcitabine delivery further reinforce the concept that only a small portion of intravesically administered gemcitabine is absorbed into the systemic circulation. Although the amount of gemcitabine absorbed seems to be small, there was still substantial interpatient variability in absorption, with no obvious clinical characteristics associated with those patients having the highest or lowest rates of gemcitabine absorption. The concept of only a small percentage of a dose of gemcitabine administered into the bladder being absorbed is also supported by the urinary recovery data presented in this article. In many patients, there was essentially quantitative recovery of the entire dose administered. In some patients, the percentage of administered dose recovered in voided urine was less than expected on the basis of the plasma dFdU concentrations measured, which probably reflects the imprecision inherent in urinary collections from patients with varying degrees of postvoid residuals and, in some cases, the inability to retain the entire instilled dose for the complete 120-minute dwell time. The urinary data presented also imply that bladder mucosa lacks cytidine deaminase because no dFdU was measured in the urine of any patient studied. The approach used to calculate the rate of gemcitabine absorption, although innovative, clearly involves a number of approximations, and therefore, the precision with which the rate of absorption or absolute amount of gemcitabine absorbed is calculated is less than ideal. Nevertheless, the theory behind how rates of absorption were calculated is sound, and there can be reasonable confidence in the estimates of absorption calculated. An additional benefit that can be derived from the data and methodology in this study would be a limited sampling strategy for application in phase II and phase III studies of intravesical gemcitabine. The fact that plasma dFdU concentrations come to steady state before completion of the 2-hour dwell time and remain stable for at least 1 hour after voiding means that a blood sample obtained around the time of void could be used to predict, with reasonable confidence, the rate of absorption and amount of gemcitabine absorbed in individual patients. These data could be used in at least two ways. The most obvious, and possibly most clinically relevant, would be to explore pharmacokinetic and pharmacodynamic relationships between amount of drug absorbed and the occurrence of toxicity or response in individual patients. Less obvious, but possibly of equal importance, would be the ability to document intrapatient variation in gemcitabine absorption with sequential intravesical instillations of that agent. It is of potential importance to document whether repeated intravesical administration of gemcitabine is associated with either a systematic increase or a decrease in its absorption. Although it is obvious that the data from this study provide information relevant to a number of questions involved in the therapeutic evaluation of intravesical gemcitabine for superficial carcinoma of the bladder, a number of questions remain unanswered or are raised by the results of this study. It is unclear whether the bladder mucosa produces 2',2'-difluorodeoxycytidine triphosphate (dFd)CTP, the cytotoxic metabolite of gemcitabine. Furthermore, it is unclear whether, if such metabolism occurs, there is a differential between rates of production of dFdCTP in normal tissue and malignant tissue. Furthermore, as mentioned, it remains unclear whether there are any predictors for patients likely to have greater or lesser rates of gemcitabine absorption than the general population, and whether in any set of patients there is a systematic change in gemcitabine absorption with repeated instillations. The first of these questions can conceivably be addressed through examination of cells obtained at the time of voiding of the instilled gemcitabine dose. The latter question should be easily addressed through implementation of the limited sampling strategy described earlier. Taken as a whole, the clinical and pharmacokinetic data presented in this article provide a strong impetus for further evaluation of intravesically administered gemcitabine as a treatment for superficial carcinoma of the bladder. The recommended dose for phase II and possible phase III trials would be 2,000 mg instilled in 50 mL. This reflects the practical limitations of gemcitabine solubility, as well as the volume that patients will tolerate instilled in anticipation of a 2-hour dwell time. The safety of intravesical administration is documented clearly in the clinical results presented and is further substantiated by the evidence of how little gemcitabine is actually absorbed into the systemic circulation. Although this study used a weekly administration schedule, there is no evidence that this is the optimal schedule. In another phase I study reported recently,24 gemcitabine was administered intravesically twice weekly in 100 mL of buffered solution for a total of six treatments, and the treatment cycle was repeated after a 1-week break. Dose escalation proceeded from 500 mg to 2,000 mg. Among the 18 high-risk patients who completed therapy, there were no grade 3 or 4 toxicities, and there were complete responses in seven patients. Should the twice-weekly schedule of administration be selected for further clinical evaluation, the documented utility of a blood sample obtained at the time of voiding should still allow subsequent phase II and III trials to define desired pharmacokinetic-pharmacodynamic relationships and the effect of administering gemcitabine in a buffered solution.
We thank Ezekiel Woods for excellent secretarial assistance in preparing this manuscript and Dr David Clinthorne for consistent encouragement and support in performance of this study.
Supported, in part, by a grant from Eli Lilly and Company.
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14. Hensley ML, Maki R, Venkatraman E, et al: Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: Results of a phase II trial. J Clin Oncol 20:2824–2831, 2002
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20. Cozzi PJ, Bajorin DF, Tong W: Toxicology and pharmacokinetics of intravesical gemcitabine: A preclinical study in dogs. Clin Cancer Res 5:2629–2637, 1999 21. Pestieau SR, Anthony Stewart O, Chang D, et al: Pharmacokinetics of intraperitoneal gemcitabine in a rat model. Tumori 84:706–711, 1998[Medline] 22. Abbruzzese JL, Grunewald R, Weeks EA: A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491–498, 1991[Abstract]
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24. Dalbagni G, Russo P, Sheinfeld J, et al: Phase I trial of intravesical gemcitabine in Bacillus Calmette-Guerin-refractory transitional-cell carcinoma of the bladder. J Clin Oncol 20:3193–3198, 2002 Submitted September 5, 2002; accepted October 31, 2002.
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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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ABSTRACT
INTRODUCTION
