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© 2002 American Society for Clinical Oncology Phase I Trial of Intravesical Gemcitabine in Bacillus Calmette-Guérin–Refractory Transitional-Cell Carcinoma of the BladderByFrom the Department of Urology; the Division of Epidemiology and Biostatistics; Pharmacology and Analytical Laboratory; and the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Guido Dalbagni, MD, Department of Urology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: dalbagng{at}mskcc.org
PURPOSE: The aim of this phase I study was to determine the safety and toxicity profile of gemcitabine administered as an intravesical agent in patients with transitional-cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS: Patients with superficial bladder cancer refractory to intravesical bacillus Calmette-Guérin (BCG) therapy and refusing a cystectomy were considered eligible for the trial. Gemcitabine was given in the bladder for 1 hour twice weekly in 100 mL sodium chloride for a total of six treatments. After a 1-week break, a second course of six treatments over 3 weeks was given, followed by response assessment. Four dose levels were explored: 500 mg, 1,000 mg, 1,500 mg, and 2,000 mg. RESULTS: Eighteen patients completed therapy: three at 500 mg, six at 1,000 mg, three at 1,500 mg, and six at 2,000 mg. No grade 3 or 4 toxicity was observed at 500 mg. At 1,000 mg, three patients developed hematuria and one had a skin reaction resembling grade 3 hand-foot syndrome. Three patients at 1,500 mg had no grade 3 or 4 toxicity. Of six patients at 2,000 mg, one had grade 3 thrombocytopenia and neutropenia without infection. Seven patients had a complete response (negative cytology and posttreatment biopsy), and four patients had a mixed response (negative bladder biopsy but positive cytology). CONCLUSION: Gemcitabine has substantial activity as an intravesical agent in BCG-refractory TCC and warrants further investigation. Therapy given twice weekly was associated with minimal bladder irritation and tolerable myelosuppression. The recommended phase II dose for twice-weekly therapy is 2,000 mg.
BLADDER CANCER IS the fifth most common cancer in the United States, with an estimated 54,300 new cases predicted for 2001.1 Seventy percent of bladder tumors are superficial at presentation and are managed conservatively by endoscopic resection. Sixty percent to 70% of superficial tumors recur,2 and 20% to 30% of recurrent tumors will progress to a higher stage or grade.3 Progression is defined as the development of muscle invasion or metastasis, and occurs in 20% to 30% of patients who present with superficial disease. The National Bladder Cancer Collaborative Group A identified tumor grade, lamina propria invasion (T1), and associated carcinoma-in-situ (CIS) as indicators of progression.4 The high progression rate (up to 45% with grade 3 tumors) and unpredictability of the progression pattern have led to the widespread use of intravesical therapy. Intravesical instillation of biologic and chemotherapeutic agents promotes direct contact with the bladder mucosa and tumor. A distinct advantage of this approach is that high doses of agents can be used with minimal systemic side effects because of the lack of absorption.5-7 Bacillus Calmette-Guérin (BCG) is the most effective agent in the treatment of CIS8 and decreases the rate of progression.9-15 However, only two thirds of patients respond to BCG, and one third of the responders will have recurrent disease.16 Recurrence after BCG treatment is associated with a poor prognosis.17 With long-term follow-up, a significant proportion of patients will progress.18 Historically, intravesical therapy using older chemotherapeutic agents has not been particularly effective for high-grade, superficial disease. First-line intravesical instillation of chemotherapy can decrease the recurrence rate19 but has not been demonstrated to decrease progression. In a review of 2,011 patients enrolled onto 10 different studies of older chemotherapy agents, progression occurred in 7.5% of patients receiving intravesical therapy versus 6.9% of those treated by transurethral resection alone.6 Recently, a resurgence of interest in intravesical chemotherapy has occurred because of the efficacy of valrubicin as second-line chemotherapy in patients failing BCG. However, the new agent resulted in a complete response (defined as a negative biopsy and cytology at 6 months) of only 21%.20 Given that the only other accepted standard treatment for BCG-refractory urothelial cancer is radical cystectomy, identification of active agents in this disease is clearly warranted. Gemcitabine (2',2'-difluoro-2' deoxycytidine; Gemzar, Eli Lilly and Co, Indianapolis, IN) is a novel deoxycytidine analog with a broad spectrum of antitumor activity. It was first approved in the United States for the treatment of pancreatic cancer,21,22 but has since been found to be effective in many other tumor types. Gemcitabine has a molecular weight of 299.66, and after intracellular activation, the active metabolite is incorporated into DNA, resulting in inhibition of further DNA synthesis. Gemcitabine may also inhibit ribonucleotide reductase and cytidine deaminase as part of its cytotoxic activity.21 Gemcitabine has been shown to be highly effective (overall response rates ranging from 22.5% to 28%) and well tolerated as both first- and second-line, single-agent therapy for the treatment of metastatic transitional-cell carcinoma (TCC).23-25 Gemcitabine was well tolerated in these studies, with a low incidence of systemic side effects. Recently, a randomized, multicenter, phase III study demonstrated that unresectable and metastatic patients treated with gemcitabine plus cisplatin had a similar survival to patients treated with methotrexate, vinblastine, doxorubicin, and cisplatin, but with a better safety profile and tolerability.26 On the basis of its excellent clinical activity, patient tolerability, and chemical characteristics, gemcitabine represents a logical candidate for intravesical therapy. We previously reported a preclinical study in beagle dogs demonstrating that gemcitabine given as an intravesical agent as frequently as three times weekly was well tolerated by the bladder mucosa.27 Herein, we report the results of a phase I trial of intravesical gemcitabine in patients with BCG-refractory TCC. The objectives of the study were to determine (1) the safety of intravesical gemcitabine, (2) the toxicity profile of gemcitabine by an intravesical route, and (3) a phase II dose level for efficacy trials. The patient population included only patients with TCC refractory to BCG for whom a cystectomy was recommended as standard management, but refused by patients.
Inclusion Criteria All patients on this trial had superficial TCC refractory to BCG therapy for which a cystectomy was recommended but refused. Clinical stages of disease included refractory CIS, multiple unresected T1 carcinoma, and uncontrollable Ta carcinoma. Additional eligibility criteria included pathologic confirmation by the Department of Pathology at Memorial Sloan-Kettering Cancer Center (MSKCC), a Karnofsky performance status  70%, adequate marrow function defined as granulocytes more than 1,500 cells/mm3 and platelets more than 150,000 cells/mm3, age 18 years, adequate hepatic function defined as total bilirubin less than 1.5 times normal and AST less than 2 times normal, and informed consent. Exclusion criteria included prior radiation to the pelvis and intractable urinary tract infection. The institutional review board at MSKCC approved the protocol, and an investigational new drug application was filed and approved by the United States Food and Drug Administration.
Intravesical Instillation
Study Design Patients demonstrating a complete response by cystoscopy, cytology, and bladder biopsy underwent close surveillance. The surveillance schedule included serial cystoscopies every 3 months to evaluate for recurrence. If disease recurred, an additional two courses (6 weeks of intravesical treatment) could be considered by the treating physician, followed by re-evaluation. Standard management consisting of a radical cystectomy was recommended in patients who did not achieve an initial complete response or in whom a relapse was observed. This phase I trial started at approximately 20% of the maximum-tolerated dose (MTD) in the animal study previously performed at MSKCC.27 Doses of 100 mg and 350 mg in beagles (equivalent to a human dose of 1,000 mg/m2) three times a week for 4 weeks were well tolerated, with no clinical side effects. A total dose of 500 mg (300 mg/m2 in the 1.7-m2 individual) twice a week for 3 weeks was chosen as the starting dose in this human phase I trial. The total intravesical dose levels were as follows: level 1, 500 mg; level 2, 1,000 mg; level 3, 1,500 mg; and level 4, 2,000 mg. Pretreatment studies included an ECG and chest radiograph. Physical examination and assessment of toxicity were performed before each administration of chemotherapy. A complete blood count was obtained and the results checked before each intravesical instillation. A biochemistry panel examining electrolytes and liver enzymes was performed at the completion of each 3-week course of intravesical gemcitabine. Serum levels of gemcitabine were obtained 1 hour after the first, third, seventh, and ninth instillations. An evaluation under anesthesia with bladder biopsies was performed at the end of the intravesical therapy (approximately 1 week after the last dose of gemcitabine) to assess for response.
Statistical Analysis The probability that dose escalation (PrDE) would occur at any stage during MTD determination was calculated as a function of the underlying DLT rate (p) at the dose level. This probability was calculated as the sum of the binomial probabilities of the following three outcomes that would permit escalation to occur: (1) no DLT observed in the first three patients; (2) one DLT is observed in the first three patients, followed by no DLT observed in three additional patients at the same dose level; and (3) one DLT observed in the first three patients, followed by one DLT observed in three additional patients at the same dose level. The probability of dose escalation was then expressed by the following formula: PrDE = q3 + 3pq5 + 9p2q4, where q = 1 - p. The true risk of excessive toxicity was expected to be in the range of 10% to 50%. The following values show the corresponding probabilities of PrDE: true risk of toxicity, .10, .20, .30, .40, and .50; and probability of escalation, .96, .87, .69, .50, and .31. If zero of three patients entered at a dose level experience DLT, subsequent patients were entered at the next dose level. If one of three patients entered at a dose level experienced DLT, an additional three patients were entered at that dose level. If two or fewer of six patients develop DLT, subsequent patients were entered at the next dose level. If at any dose level three or more of six patients experienced DLT, the dose level below that one would be defined as the MTD.
Intravesical treatment was discontinued if the patient developed neutropenic fever (absolute granulocyte count less than 1,000 cells/mm3 at the time of a documented temperature of
Patient Characteristics Eighteen patients were entered onto the study (Table 1). There were 14 males and four females, for a male/female ratio of 4:1. The median age was 74 years, with a range of 37 to 86 years. Twelve patients had refractory CIS, and six patients had recurrent T1 carcinoma with or without CIS. Patients were pretreated with one to four courses of BCG. Five patients received prior intravesical chemotherapy including mitomycin, thiotepa, Adriamycin, and valrubicin.
Toxicity Intravesical gemcitabine was generally well tolerated. Three patients were enrolled at the first dose level (500 mg), and one patient experienced grade 1 nausea. No urothelial toxicity was observed. Six patients were enrolled at the second dose level (1,000 mg). Four patients developed a grade 2 urinary frequency defined by more than 2 times normal frequency of urination, and one patient experienced a grade 3 frequency defined as more than hourly urination with urgency. Three patients developed intermittent gross hematuria without clots. The systemic manifestations included grade 1 nausea and fatigue in two patients, and a skin reaction resembling a grade 3 hand-foot syndrome. Three patients who were enrolled at level 3 (1,500 mg) experienced minimal urinary symptoms and no systemic symptoms. Six patients were enrolled at level 4 (2,000 mg), and only minimal urinary symptoms were observed. Systemic toxicity included one patient who developed grade 3 thrombocytopenia and neutropenia, but without infectious complications. There were no grade 4 systemic toxicities. We did not reach a DLT, and 2,000 mg was the highest soluble dose in 100 mL of sodium chloride (Table 2).
Pharmacokinetics Serum was obtained to detect systemic levels of gemcitabine after the first, third, seventh, and ninth instillations at all four dose levels. The levels of gemcitabine were undetectable at the first three dose levels (500, 1,000, and 1,500 mg). However, gemcitabine was detected in two patients at the fourth dose level (2,000 mg), including the patient who experienced grade 3 thrombocytopenia and neutropenia.
Response
This first reported phase I study has demonstrated an excellent tolerability to intravesical gemcitabine given twice a week. Treatment was well tolerated at doses up to 2,000 mg per instillation (20 mg/mL). The presence of activity in a heavily pretreated patient population is promising and warrants further investigation. On the basis of the results of this phase I study, we recommend a dose of 2,000 mg twice a week (20 mg/mL) for 3 weeks, followed by a second course after a week of rest. Several factors need to be taken into account during intravesical chemotherapeutic trials. These considerations include the dose and concentration of the drug, the dwell time, and the frequency of instillation. Recent data support a linear correlation between the drug concentration and the bladder tissue uptake.28 Improvement in therapeutic efficacy can be achieved by restricting fluid intake and emptying the bladder before intravesical instillation. This approach will maintain the constant concentration of drug by preventing excessive dilution.29 The PrDE of this phase I study took into consideration both the dose and concentration of gemcitabine. The bladder was completely emptied by straight catheterization before the instillation of gemcitabine, and the patient was instructed to avoid excessive fluid intake starting the day before treatment to decrease urine output. The dwell time, which in most intravesical chemotherapeutic trials has ranged from 30 minutes to 2 hours,30 has been a source of controversy. A longer dwell time is associated with a greater cytotoxic effect, but also increases systemic absorption and decreases drug concentration because of urine production. In this study, gemcitabine was retained for 1 hour, because preclinical toxicity and pharmacokinetics data were derived from a 1-hour dwell time.27 Furthermore, some patients in this population experienced significant frequency that would have rendered a 2-hour dwell time impractical. Gemcitabine is a potent cytotoxic agent that showed maximal activity in vivo when given every third day.21 However, systemic administration of gemcitabine on a twice-weekly schedule is not possible because of severe thrombocytopenia.25 Intravesical administration of gemcitabine given on a twice-weekly schedule is well tolerated, and provides a unique opportunity to explore this new schedule in a phase II trial. We detected serum gemcitabine in two of six patients treated with 2,000 mg. This is not unusual because gemcitabine has a low molecular weight. Intravesical absorption of low-molecular-weight chemotherapeutic agents such as thiotepa have been reported,31 resulting in episodes of myelosuppression.32 Furthermore, we noticed the presence of significant systemic absorption in dogs with peak serum levels at 30 to 60 minutes after instillation.27 Another factor that might have increased the absorption of gemcitabine is the alkalinization of the urine. The pKa of gemcitabine is 3.6, and its reconstitution results in a solution with a pH of 2.7 to 3.2. We adjusted the gemcitabine solution to pH 5.5 to 7.0 to prevent excessive bladder irritation from instillation of a solution with a low pH. This would have increased the nonionic form of the drug, facilitating its diffusion.33 Although the MTD has not been reached, 2,000 mg in 100 mL (20 mg/mL) has been selected for a phase II trial, as a higher concentration is not soluble at the adjusted pH. Radical cystectomy remains the recommended treatment for patients with BCG-refractory TCC. However, many patients are reluctant to undergo a major surgical intervention and are willing to explore alternatives. The only Food and Drug Administration–approved treatment for patients with BCG-refractory CIS who refuse cystectomy is valrubicin, a semisynthetic analog of doxorubicin. A multi-institutional trial has shown a 21% response rate to weekly instillation of valrubicin, with a disease-free probability of 13% after a year.20 There is a need for more effective agents, and on the basis of excellent tolerability and activity in heavily pretreated patients, intravesical gemcitabine should be further explored in a phase II study.
Supported in part by Eli Lilly and Co, Indianapolis, IN.
1. Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 51: 15-36, 2001 2. Reuter V: The lower urinary tract, in Sternberg S (ed): Diagnostic Surgical Pathology. New York, Raven Press, 1994, pp 1767-1805 3. Soloway MS: Overview of treatment of superficial bladder cancer. Urology 26: 18-26, 1985[Medline] 4. Heney NM, Ahmed S, Flanagan MJ, et al: Superficial bladder cancer: Progression and recurrence. J Urol 130: 1083-1086, 1983[Medline] 5. Herr HW, Laudone VP, Whitmore WF Jr: An overview of intravesical therapy for superficial bladder tumors. J Urol 138: 1363-1368, 1987[Medline] 6. Lamm DL, Riggs DR, Traynelis CL, et al: Apparent failure of current intravesical chemotherapy prophylaxis to influence the long-term course of superficial transitional cell carcinoma of the bladder. J Urol 153: 1444-1450, 1995[CrossRef][Medline] 7. Witjes JA, Mulders PF, Debruyne FM: Intravesical therapy in superficial bladder cancer. Urology 43: 2-6, 1994[Medline] 8. Dalbagni G, Herr HW: Current use and questions concerning intravesical bladder cancer group for superficial bladder cancer. Urol Clin North Am 27: 137-146, 2000[CrossRef][Medline] 9. Lamm DL, Blumenstein BA, Crawford ED, et al: A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional cell carcinoma of the bladder. N Engl J Med 325: 1205-1209, 1991[Abstract] 10. Rintala E, Jauhiainen K, Alfthan O, et al: Intravesical chemotherapy (mitomycin C) versus immunotherapy (bacillus Calmette-Guerin) in superficial bladder cancer. Eur Urol 20: 19-25, 1991[Medline] 11. Vegt PD, Witjes JA, Witjes WP, et al: A randomized study of intravesical mitomycin C, bacillus Calmette-Guerin Tice and bacillus Calmette-Guerin RIVM treatment in pTa-pT1 papillary carcinoma and carcinoma in situ of the bladder. J Urol 153: 929-933, 1995[CrossRef][Medline] 12. Krege S, Giani G, Meyer R, et al: A randomized multicenter trial of adjuvant therapy in superficial bladder cancer: Transurethral resection only versus transurethral resection plus mitomycin C versus transurethral resection plus bacillus Calmette-Guerin—Participating clinics. J Urol 156: 962-966, 1996[CrossRef][Medline] 13. Lundholm C, Norlen BJ, Ekman P, et al: A randomized prospective study comparing long-term intravesical instillations of mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. J Urol 156: 372-376, 1996[CrossRef][Medline] 14. Malmstrom PU, Wijkstrom H, Lundholm C, et al: 5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma: Swedish-Norwegian Bladder Cancer Study Group. J Urol 161: 1124-1127, 1999[CrossRef][Medline] 15. Melekos MD, Zarakovitis I, Dandinis K, et al: BCG versus epirubicin in the prophylaxis of multiple superficial bladder tumours: Results of a prospective randomized study using modified treatment schemes. Int Urol Nephrol 28: 499-509, 1996[Medline] 16. Hudson MA, Herr HW: Carcinoma in situ of the bladder. J Urol 153: 564-572, 1995[CrossRef][Medline] 17. Herr HW, Badalament RA, Amato DA, et al: Superficial bladder cancer treated with bacillus Calmette-Guerin: A multivariate analysis of factors affecting tumor progression. J Urol 141: 22-29, 1989[Medline] 18. Cookson MS, Herr HW, Zhang ZF, et al: The treated natural history of high risk superficial bladder cancer: 15-year outcome. J Urol 158: 62-67, 1997[CrossRef][Medline] 19. Tolley DA, Parmar MK, Grigor KM, et al: The effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: A further report with 7 years of follow up. J Urol 155: 1233-1238, 1996[CrossRef][Medline] 20. Steinberg G, Bahnson R, Brosman S, et al: Efficacy and safety of val-rubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder: The Valrubicin Study Group. J Urol 163: 761-767, 2000[CrossRef][Medline]
21. Hertel LW, Boder GB, Kroin JS, et al: Evaluation of the antitumor activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine). Cancer Res 50: 4417-4422, 1990
22. 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
23. Moore MJ, Tannock IF, Ernst DS, et al: Gemcitabine: A promising new agent in the treatment of advanced urothelial cancer. J Clin Oncol 15: 3441-3445, 1997
24. Stadler WM, Kuzel T, Roth B, et al: Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol 15: 3394-3398, 1997 25. Lorusso V, Pollera CF, Antimi M, et al: A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum: Italian Co-operative Group on Bladder Cancer. Eur J Cancer 34: 1208-1212, 1998[CrossRef][Medline]
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27. Cozzi PJ, Bajorin DF, Tong W, et al: Toxicology and pharmacokinetics of intravesical gemcitabine: A preclinical study in dogs. Clin Cancer Res 5: 2629-2637, 1999 28. Gao X, Au JL, Badalament RA, et al: Bladder tissue uptake of mitomycin C during intravesical therapy is linear with drug concentration in urine. Clin Cancer Res 4: 139-143, 1998[Abstract]
29. Au JL, Badalament RA, Wientjes MG, et al: Methods to improve efficacy of intravesical mitomycin C: Results of a randomized phase III trial. J Natl Cancer Inst 93: 597-604, 2001 30. Duque JL, Loughlin KR: An overview of the treatment of superficial bladder cancer: Intravesical chemotherapy. Urol Clin North Am 27: 125-135, 2000[CrossRef][Medline] 31. Jones H, Swinney J: Thiotepa in the treatment of tumours of the bladder. Lancet 2: 615-618, 1961[Medline]
32. Hollister D Jr, Coleman M: Hematologic effects of intravesicular thiotepa therapy for bladder carcinoma. JAMA 244: 2065-2067, 1980 33. Benet LZ, Kroetz DL, Sheiner LB: Pharmacokinetics: The dynamics of drug absorption, distribution and elimination, in Hanehman JG, Limbird LE (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics ed 9 . New York, McGraw-Hill, 1996, p 4 Submitted February 13, 2002; accepted April 30, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
