Affiliations of authors: J. L.-S. Au, R. A. Badalament, M. G. Wientjes, D. C. Young, J. A. Warner, D. L. Pollifrone, Ohio State University, Columbus; P. L. Venema, Leyenburg Teaching Hospital, The Hague, The Netherlands; J. D. Harbrecht, Riverside Methodist Hospital, Columbus, OH; J. L. Chin University of Western Ontario, London, Canada; S. P. Lerner, B. J. Miles, Baylor College of Medicine, Houston, TX.
Correspondence to: Jessie L.-S. Au, Pharm.D., Ph.D., Ohio State University, 496 W. 12th Ave., Columbus, OH 43210 (e-mail: au.1{at}osu.edu).
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ABSTRACT |
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INTRODUCTION |
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These findings suggested several approaches to enhance the mitomycin C concentration in urine and thereby to enhance the drug concentration in tumor cells: 1) increasing the dose from the conventional 20 mg to 40 mg, 2) reducing the dosing volume from the conventional 40 mL to 20 mL, 3) minimizing the volume of residual urine at the time of treatment, 4) reducing urine production before and during treatment by voluntary dehydration, and 5) alkalinizing the urine by use of oral sodium bicarbonate. We used computer simulation to show the pharmacokinetics and pharmacodynamics of such modified intravesical mitomycin C therapy (9). On the basis of the simulation results, we hypothesized that enhancing drug delivery to tumor cells would enhance the recurrence-free fraction from 20% to 40% (9).
This study tested this hypothesis in an international, multicenter, prospective phase III trial in patients with superficial bladder cancer who are at high risk for recurrence. The primary objective of the trial was to compare the efficacy of an optimized regimen designed to enhance drug delivery with that of a standard regimen commonly used in the community. The secondary objective was to determine the toxicity of the optimized regimen and to establish factors that may be used to predict response to intravesical mitomycin C therapy.
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SUBJECTS AND METHODS |
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The study population consisted of patients with histologically proven transitional cell carcinoma of the bladder who were considered at high risk for tumor recurrence because of the presence of at least one of the following: 1) two or more episodes of histologically proven Ta, Tis, or T1 transitional cell carcinoma (10); 2) multifocal bladder tumors (defined as three or more papillary tumors present simultaneously or Tis involving at least 25% of the bladder surface area and/or in two or more biopsy sites); and 3) primary or solitary tumors that were more than 5 cm in size, were grade III (11), or exhibited DNA aneuploidy. All patients were registered for randomization within 34 days (mean and median values of 20 days) of transurethral bladder tumor resection, had adequate bone marrow reserve (white blood cell count >4000/mm3 and platelet count >100 000/mm3), had adequate renal function (serum creatinine level 2.0 mg/dL or 177 µM), and had a Karnofsky performance score of 50100. Exclusion criteria included prior treatment with mitomycin C within 56 weeks of registration, prior muscle-invasive (T2T4) transitional cell carcinoma of the bladder, concurrent malignancy within 5 years of registration (except for basal cell carcinoma), and pregnancy.
Study Protocol
Fourteen academic and research centers participated in the trial. The study protocol was approved by the institutional review board of the individual study sites. Written informed consent, which detailed the treatments of the two arms, was obtained from all patients. Because this trial was sponsored by the National Cancer Institute (Bethesda, MD), we also obtained the mandated approval from the Office of Protection Against Research Risk of the National Institutes of Health (Bethesda, MD). Appropriate clearance from the State Department (Washington, DC) was also obtained for the non-U.S. sites.
Patient randomization and data collection were performed in a central office located at The Ohio State University Comprehensive Cancer Center (Columbus). Patients were randomly allocated to one of the two treatment arms by use of stratified blocked randomization across 16 (2 x 2 x 2 x 2) strata resulting from four prognostic criteria: 1) presence versus absence of Tis tumor, 2) grade III versus grades I and II tumors, 3) multifocal versus unifocal tumors, and 4) recurrent versus primary tumors. Information on tumor pathology provided by the treatment site was used for stratification. Within a given stratum, treatment allocation was balanced in 10 patient blocks. Stratification based on prognostic factors was performed to ensure treatment group equability and to obviate the need for post hoc covariate adjustment.
The starting date of patient accrual at the 14 study sites ranged from October 1992 to March 1998. The accrual ended on March 23, 1999. A total of 230 patients were enrolled and randomly assigned to either the standard-treatment arm (111 patients) or the optimized-treatment arm (119 patients). Eight of the enrolled patients (three from the standard arm and five from the optimized arm) were found subsequently not to meet the eligibility criteria. Of the remaining 222 patients (108 in the standard arm and 114 in the optimized arm), two (one in each arm) had protocol violations; 12 did not complete six treatments because of refusal (one in the standard arm and two in the optimized arm), because of toxicity (two in each arm), or because of other reasons (two in the standard arm and three in the optimized arm); two (one in each arm) refused follow-up; and five (two in the standard arm and three in the optimized arm) had incomplete data. The remaining 201 patients (99 in the standard arm and 102 in the optimized arm) were evaluable (Fig. 1). The median follow-up time was 11.7 months as of March 31, 2000.
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Patients allocated to the standard arm were not instructed to refrain from drinking fluids and did not receive oral sodium bicarbonate. In these patients, bladders were emptied via the Foley catheter, but no additional measures were undertaken to minimize the residual urine volume. These patients received a lower dose of mitomycin C (20 mg in 20 mL of sterile water) that was retained in the bladder for the same 2-hour duration.
Our previous pharmacokinetic study (5) of the mitomycin treatment used in the standard arm has shown that there is minimal systemic absorption of the drug, with plasma concentrations well below the threshold concentration associated with hematologic toxicity. Hence, complete blood cell counts were not mandatory in the standard-treatment arm and were done at the discretion of the treating physician. Because the systemic pharmacokinetics of mitomycin C administered by the optimized-treatment regimen had not been studied previously, the protocol called for mandatory complete blood cell counts in the first 20 patients in the optimized arm 1 week after the first dose was administered (i.e., before administration of the second dose) and, in the absence of toxicity in these 20 patients, termination of this mandate in subsequent patients. As shown in the "Results" section, hematologic toxicity was indeed absent. Hence, mandatory blood cell counts were discontinued, and monitoring of hematologic toxicity in subsequent patients was done at the discretion of the treating physician. Samples of urine, serum, and tumors were obtained for companion pharmacologic studies, whose results will be reported elsewhere.
Patient Follow-up
Patients were followed with cystoscopic and cytologic examination quarterly for the first 2 years, biannually for years 35 at the discretion of the treating physician, and annually thereafter. Investigators were encouraged to perform a biopsy on suspicious areas for tumor recurrence. Tumors were determined to have recurred when the patient had a positive post-treatment biopsy or a positive cytology. The time to recurrence was defined as the length of time from randomization to the first pathologic or cytologic evidence of tumor recurrence.
Patient Evaluability
Patients were considered to be evaluable when they completed the six weekly treatments, provided complete treatment and follow-up data, and had no protocol violations.
Statistical Analysis
As stated above, our computer simulation results (9) predicted that the changes adopted in the optimized-treatment arm, compared with the standard-treatment arm, will enhance the recurrence-free fraction from 20% to 40%. By using these predicted values and by assuming exponential failure-time distribution, a median time to recurrence of 13 months in the standard regimen, and a 20% nonevaluable rate, we calculated that a sample size of 290 patients, or 116 recurrences, would be required for a two-sided of 0.05 and a power of 0.80. The sample size of 290 was calculated on the basis of a 2-year accrual period with final analysis in year 3, and the recurrence number of 116 was calculated on the basis of a ratio of 1.7 for the median time to recurrence in the optimized arm to that in the standard arm. Because of a slower-than-expected accrual rate and the resulting longer-than-anticipated follow-up period, the 116 recurrences were attained with a reduced sample size of 230 patients.
Two interim analyses with O'Brien and Fleming (12)-adjusted levels of statistical significance were conducted after accrual of 100 and 200 patients. Neither interim analysis reached the necessary level of statistical significance for early termination. Hence, patient accrual continued until 116 recurrences were observed.
Analysis of the primary endpoint of the time to recurrence was performed by use of KaplanMeier survival analysis with log-rank tests. Overall and stratified log-rank tests were used. The proportion of patients free of recurrence at 5 years was also analyzed. Analyses were performed both on an intent-to-treat basis and on the evaluable group. Comparisons of continuous data were performed by Student's t test, and discrete data were analyzed by use of Fisher's exact tests or chi-square tests. All tests used a two-sided .05 level of significance.
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RESULTS |
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The patient populations in the two treatment arms were comparable with respect to demographics (Table 1), disease characteristics used for randomization stratification (Table 2
), and history of intravesical therapy (Tables 1 and 3
). The only demographic variable that approached statistical significance was age (P = .07); the average age of the patients in the optimized arm was approximately 3 years older than that of the patients in the standard arm.
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For patients in the standard arm, the protocol did not call for mandatory monitoring of hematologic toxicity. However, at their physicians' discretion, 19 patients in the standard arm were evaluated for hematologic toxicity. Only one patient, who had a history of demyelinating radiculopathy and was receiving weekly immunoglobulin treatments, showed an alteration of white blood cell count (a transient reduction from a pretreatment level of 8100/mm3 to a level of 3700/mm3 5 days after the first treatment, followed by a return to 4500, 4100, and 4900/mm3 during the subsequent three treatments). No hematologic toxicity was observed for the remaining patients.
For patients in the optimized arm, the protocol called for the monitoring of hematologic toxicity 1 week after the first dose of mitomycin C in the first 20 patients to determine whether this previously untested regimen would be associated with unexpected toxicity. We chose this time point because we had found previously that systemic drug absorption is maximal after the first dose, with nearly undetectable absorption after the subsequent doses and hematologic toxicity takes several days to become apparent (5). No hematologic toxicity was observed in the first 20 patients treated in the optimized arm. Hence, a mandatory complete blood cell count was discontinued. In the additional 31 patients who were monitored at the discretion of the treating physicians, no hematologic toxicity was observed.
There were minimal differences in nonhematologic toxicity in the two treatment arms (Table 4). Dysuria was the only toxic effect that was statistically significantly higher in the optimized arm than in the standard arm, but it did not result in a higher frequency of treatment termination in the optimized arm. (Treatment was terminated in one patient each in both arms because of dysuria.) Grade 1 dysuria (mild pain on urination) and grade 2 dysuria (painful urination controlled by pyridium) were problematic but manageable. Grade 3 dysuria (painful urination not controlled by pyridium) occurred in four patients in the optimized arm but in no patients in the standard arm. Twelve patients who complained of dysuria or cystitis (two in the standard arm and 10 in the optimized arm) were treated prophylactically with antibiotics for possible urinary-tract infection. The two patients in the standard arm turned out to have negative urine cultures. Of the 10 patients in the optimized arm, one had a positive urine culture, two had a positive urinalysis by urinalysis strip that was not verified by urine cultures, five had negative cultures, and two were not tested. Among the two arms, the optimized arm showed a trend of a higher incidence of cystitis and a lower incidence of urinary frequency, although the differences did not reach statistical significance. Patients in both arms showed a similar ability to tolerate the treatment regimen.
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KaplanMeier analyses of recurrence in both the intent-to-treat group and the evaluable group indicated that, in both groups, patients in the optimized arm had a statistically significantly longer time to recurrence and a higher recurrence-free fraction at all time points than patients in the standard arm (Fig. 2). Improvements were found across all stratification risk groups (tumor stage, grade, focality, and recurrence by stratified log-rank test), and improvements or trends toward improvement were found in all tested subgroups (Tables 5 and 6
). There was no sex-related difference in treatment outcome, as determined by KaplanMeier analysis with log-rank test.
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DISCUSSION |
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The standard arm in the present investigation used an induction intravesical mitomycin C therapy that is nearly identical to the induction therapy used in the Southwest Oncology Group (SWOG) protocol 8795. The SWOG study was a randomized prospective comparison with bacille Calmette-Guérin (BCG) (15). Both protocols used 20 mg of mitomycin C at a concentration of 1 mg/mL of water, and neither controlled residual urine volume, urine production rate, or urine pH. A minor difference was that the maximal time to treatment after transurethral bladder tumor resection was 14 days in the SWOG protocol but 28 days in this study. The extension was for logistical reasons, including waiting for laboratory results, obtaining consent from patients, and waiting for the availability of appointments. The SWOG protocol also used a monthly maintenance therapy with mitomycin C. This study did not include a maintenance therapy because the benefit of maintenance therapy has not been established. The median time to recurrence was 22 months in the SWOG study and 12 months in the standard arm of this study. This difference may be due to the different patient populations in the two studies. This study included patients who had had prior mitomycin C and BCG therapy, whereas the SWOG trial excluded these patients. We speculate that this difference resulted in a worse prognosis for the patients in our study.
An unexpected finding in this study was the ineffectiveness of intravesical mitomycin C therapy in African-American patients. The small number of African-American patients and the unplanned nature of the analysis limit the confidence that can be placed in this finding. Nevertheless, we speculate that a genetic basis for the differential response may exist. Mitomycin C undergoes metabolic activation by quinone reductases. The two major reductive enzymes are DT-diaphorase and cytochrome p450 reductase, and laboratory studies (1625) have indicated a correlation between the antitumor activity of mitomycin C and the activity of these enzymes. Whether there is genetic variation in enzyme activity or a relationship between enzyme activity and treatment outcome is not known and requires further investigation.
Intravesical BCG is often used as the first-line therapy for superficial bladder cancer, in part because of its relatively low cost. Seven randomized prospective clinical trials have compared the recurrence rates of bladder cancer after treatment with intravesical mitomycin C with those after treatment with intravesical BCG. Three studies (15,26,27) showed intravesical BCG to be superior, whereas four studies (2831) showed no difference. However, the mitomycin C regimens in these earlier trials were not designed to optimize the drug delivery to tumors. For example, in the SWOG protocol 8795, the mitomycin C regimen was similar to the less effective standard arm used in our study. Our results raise the possibility that mitomycin C, when used as described in the more effective optimized regimen, represents a viable alternative to BCG in the treatment of superficial bladder cancer. In addition, the relatively low toxicity of mitomycin C, as compared with BCG, represents an important advantage. Hence, a randomized prospective trial comparing the optimized mitomycin C regimen with BCG is warranted.
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APPENDIX |
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NOTES |
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Supported in part by Public Health Service grants R01CA58983, R01CA58988, and R01CA58989 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
Bristol-Myers Squibb (Princeton, NJ) provided mitomycin C for patients who were not eligible for reimbursement from their medical insurance carriers as well as partial support for the annual investigator meetings.
See "Appendix" for members of the International Mitomycin C Consortium.
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Manuscript received August 17, 2000; revised February 12, 2001; accepted February 15, 2001.
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