Methods to Improve Efficacy of Intravesical Mitomycin C: Results of a Randomized Phase III Trial

Jessie L.-S. Au, Robert A. Badalament, M. Guillaume Wientjes, Donn C. Young, Jill A. Warner, Pieter L. Venema, David L. Pollifrone, Jeffrey D. Harbrecht, Joseph L. Chin, Seth P. Lerner, Brian J. Miles, For the International Mitomycin C Consortium

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).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 
Background: Intravesical chemotherapy (i.e., placement of the drug directly in the bladder) with mitomycin C is beneficial for patients with superficial bladder cancer who are at high risk of recurrence, but standard therapy is empirically based and patient response rates have been variable, in part because of inadequate drug delivery. We carried out a prospective, two-arm, randomized, multi-institutional phase III trial to test whether enhancing the drug's concentration in urine would improve its efficacy. Methods: Patients with histologically proven transitional cell carcinoma and at high risk for recurrence were eligible for the trial. Patients in the optimized-treatment arm (n = 119) received a 40-mg dose of mitomycin C, pharmacokinetic manipulations to increase drug concentration by decreasing urine volume, and urine alkalinization to stabilize the drug. Patients in the standard-treatment arm (n = 111) received a 20-mg dose without pharmacokinetic manipulations or urine alkalinization. Both treatments were given weekly for 6 weeks. Primary endpoints were recurrence and time to recurrence. Treatment outcome was examined by use of Kaplan–Meier analysis with log-rank tests. Statistical tests were two-sided. Results: Patients in the two arms did not differ in demographics or history of intravesical therapy. Dysuria occurred more frequently in the optimized arm but did not lead to more frequent treatment termination. In an intent-to-treat analysis, patients in the optimized arm showed a longer median time to recurrence (29.1 months; 95% confidence interval [CI] = 14.0 to 44.2 months) and a greater recurrence-free fraction (41.0%; 95% CI = 30.9% to 51.1%) at 5 years than patients in the standard arm (11.8 months; 95% CI = 7.2 to 16.4 months) and 24.6% (95% CI = 14.9% to 34.3%) (P = .005, log-rank test for time to recurrence). Improvements were found in all risk groups defined by tumor stage, grade, focality, and recurrence. Conclusions: This study identified a pharmacologically optimized intravesical mitomycin C treatment with statistically significantly enhanced efficacy.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 
Intravesical chemotherapy, as adjuvant to surgical removal of superficial bladder cancer, has been shown to be beneficial in patients at high risk for recurrence (1). However, the selection of the drug and the administration regimen have largely been empiric. We completed a series of studies (28) to determine the basis of the incomplete and variable response of patients to intravesical mitomycin C and doxorubicin, evaluating drug sensitivity of bladder tumors in patients, plasma and urine pharmacokinetics in animals and patients, and spatial drug distribution in bladder tissues in animals and patients. On the basis of these studies, we concluded that the variable and incomplete response is partly due to the insensitivity of highly malignant tumors to the drug and partly due to inadequate drug delivery to tumor cells. The inadequate drug delivery, in turn, is a result of dilution, in part, of the drug solution by residual urine in the bladder, dilution by continuous urine production during the 2-hour treatment, and the inability of the drug to penetrate the deep-muscle layers in the bladder. In the case of mitomycin C, instability of the drug in acidic urine is an additional problem.

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.


    SUBJECTS AND METHODS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 
Selection of Patients

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 50–100. Exclusion criteria included prior treatment with mitomycin C within 56 weeks of registration, prior muscle-invasive (T2–T4) 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. 1Go). The median follow-up time was 11.7 months as of March 31, 2000.



View larger version (32K):
[in this window]
[in a new window]
 
Fig. 1. Trial flow diagram.

 
Patients in both arms received six weekly treatments with intravesical mitomycin C dissolved in 20 mL of sterile water. Among the 217 patients who received intravesical chemotherapy, 214 received mitomycin C from Bristol-Myers Squibb (Princeton, NJ) and three received mitomycin C from Kyowa Hakko Kogyo Co. (Tokyo, Japan). The major differences between the two arms were the higher dose and the manipulations used to maintain a high drug concentration in the urine in the optimized arm. Patients allocated to the optimized arm were instructed to refrain from drinking fluids for 8 hours before and during intravesical mitomycin C treatment. They were also given oral doses of 1.3 g of sodium bicarbonate the night before, the morning of, and 30 minutes before drug treatment. Just before treatment, a Foley catheter was inserted to empty the bladder. The postvoid residual urine volume was measured by use of a bladder ultrasound instrument (Diagnostic Ultrasound, Redmond, WA) and was reduced, if necessary, by repositioning the catheter and/or by changing the position of the patient. This procedure was repeated until the residual urine volume was less than 10 mL. Mitomycin C (40 mg in 20 mL of sterile water) was then instilled intravesically through the Foley catheter by gravity. Drug solution was retained in the bladder for 2 hours.

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 3–5 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 {alpha} 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 Kaplan–Meier 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.


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 
Patient Characteristics

The patient populations in the two treatment arms were comparable with respect to demographics (Table 1Go), disease characteristics used for randomization stratification (Table 2Go), and history of intravesical therapy (Tables 1 and 3GoGo). 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.


View this table:
[in this window]
[in a new window]
 
Table 1. Characteristics of registered patients
 

View this table:
[in this window]
[in a new window]
 
Table 2. Patient population balanced by stratification factors
 

View this table:
[in this window]
[in a new window]
 
Table 3. History of intravesical therapy in all intent-to-treat group patients*
 
Toxicity

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 4Go). 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.


View this table:
[in this window]
[in a new window]
 
Table 4. Nonhematologic toxicity in patients who received at least one dose of mitomycin C*
 
Tumor Recurrence

Kaplan–Meier 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. 2Go). 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 6GoGo). There was no sex-related difference in treatment outcome, as determined by Kaplan–Meier analysis with log-rank test.



View larger version (15K):
[in this window]
[in a new window]
 
Fig. 2. Treatment outcome in intent-to-treat (left) and evaluable (right) groups. Results of the Kaplan–Meier analysis are shown. Symbols indicate censored patients, and error bars show 95% confidence intervals (CIs). 1) In the intent-to-treat group of patients (n = 230), the median time to recurrence was 11.8 months in the standard-treatment arm (n = 111) and 29.1 in the optimized-treatment arm (n = 119). At 3 years after treatment, 28.4% (95% CI = 18.8% to 38%) of the patients in the standard-treatment arm and 44.5% (95% CI = 34.7% to 54.3%) of the patients in the optimized-treatment arm were recurrence free. At 5 years after treatment, the recurrence-free percentages were 24.6% (95% CI = 14.9% to 34.3%) and 41% (95% CI = 30.9% to 51.1%), respectively. 2) In the evaluable patients (n = 201), the median time to recurrence was 11.3 months in the standard-treatment arm (n = 99) and 29.1 in the optimized-treatment arm (n = 102). At 3 years after treatment, 27.1% (95% CI = 17.5% to 36.7%) of the patients in the standard-treatment arm and 44.4% (95% CI = 34.1% to 54.7%) of the patients in the optimized-treatment arm were recurrence free. At 5 years after treatment, the recurrence-free percentages were 23.5% (95% CI = 14% to 33%) and 42.6% (95% CI = 32.3% to 52.9%), respectively.

 

View this table:
[in this window]
[in a new window]
 
Table 5. Treatment efficacy of standard- and optimized-treatment arms in subgroups of the 230 patients in the intent-to-treat group*
 

View this table:
[in this window]
[in a new window]
 
Table 6. Treatment efficacy of standard- and optimized-treatment arms in subgroups of the 201 patients in the evaluable group*
 
An unexpected finding of this study was an association between race and treatment outcome. In an attempt to enhance the accrual of minorities, we included several major metropolitan areas in our study sites. Nevertheless, African-Americans accounted for only 3% of the patients accrued to the study. The risk factors for the six African-American patients (three in each treatment arm) were similar to those for all patients (grade: I/II [four of six patients] and III [two of six]; stage: Ta [four of six patients], T1 [one of six], and Tis [one of six]; focality: unifocal [one of six patients] and multifocal [five of six]; and occurrence: primary [two of six patients] and recurring [four of six]). However, in all of the African-American patients, the disease recurred in less than 1 year. The difference in the recurrence data between the African-American and Caucasian patients was highly statistically significant (Fig. 3Go), although the very small number of African-American patients in this unplanned analysis makes a conclusion tentative. In the protocol design, race had not been included as a stratification factor because there were no data to suggest differential responses to mitomycin C by different ethnic groups. However, the even distribution of the African-American patients in the two treatment arms indicates that the low response rate in these patients was not due to the difference in the treatment received.



View larger version (19K):
[in this window]
[in a new window]
 
Fig. 3. Kaplan–Meier curves of the risk of recurrence among evaluable African-American and Caucasian patients. The median time to recurrence was 5.2 months in the African-American patients (n = 6) and 16 months in the Caucasian patients (n = 188). The remaining seven evaluable patients were of other ethnic groups and were not included in the analysis. The percentage of patients who were recurrence free at 5 years was 0% in the African-American patients and 34% in the Caucasian patients (P<.001, log-rank test for time to recurrence). Symbols indicate censored patients, and error bars show 95% confidence intervals.

 

    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 
Intravesical mitomycin C therapy has been used for more than two decades as adjuvant treatment of superficial bladder cancer. The doses and treatment conditions have been based empirically. Multiple studies [e.g., (13,14)] evaluated different doses (range, 20–60 mg) and different instillation durations (range, 0.5–2 hours). Some of the studies indicate a higher response rate for treatments by use of a higher dose and/or a longer instillation, whereas other studies do not support this conclusion. The inconsistent results are partly due to the highly variable and incomplete patient response rate and partly due to the relatively small patient sample size of some of the studies, which precludes meaningful statistical evaluation. We have shown (28) that the variable patient response rate may be due to several physiologic variables (i.e., residual urine volume at the time of treatment, urine production rate, and urine pH), which reduce the drug concentration in urine and thereby lower drug delivery to tumor cells. This study was designed to test the hypothesis that drug delivery to tumor cells could be enhanced and the response rate could be improved by controlling the physiologic variables and by increasing the dose. Our results demonstrate that these changes reduced the recurrence rate and lengthened the median time to recurrence. These improvements in therapeutic efficacy were found for all stratification groups, and they were achieved without clinically significant enhancement in toxicity. On the basis of these results, we recommend that intravesical mitomycin C therapy be given under the conditions described for the optimized arm, i.e., a dose of 40 mg at a concentration of 2 mg/mL in water, complete bladder emptying just before dose administration, fluid restriction, and oral bicarbonate to alkalinize the urine.

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.


    APPENDIX
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 
Members of the International Mitomycin C Consortium are as follows: 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), Y. Fradet (Laval University, Quebec, Canada); C. Dinney (The University of Texas M. D. Anderson Cancer Center, Houston); R. N. Farah (Henry Ford Hospital, Detroit, MI); D. L. Lamm (West Virginia University, Morgantown, WV); E. A. Klein (Cleveland Clinic, OH); R. B. Bracken (University of Cincinnati, OH); G. P. Haas (Wayne State University, Detroit, MI, and State University of New York Upstate Medical University at Syracuse); S. I. Escaf (University of Oviedo, Spain); and M. I. Resnick (Case Western Reserve University, Cleveland, OH).


    NOTES
 
The data reported in this article have been licensed to Situs Corporation (San Diego, CA).

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.


    REFERENCES
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Appendix
 References
 

1 Smith JA, Labasky RF, Montie JE, Rowland RG, Cockett AT, Fracchia JA. Report on the management of non-muscle-invasive bladder cancer, stages Ta, T1 and Tis. Baltimore (MD): American Urological Association, Inc.; 1999. p. 9–49.

2 Wientjes MG, Dalton JT, Badalament RA, Dasani BM, Drago JR, Au JL. Method to study drug concentration–depth profiles in tissues: mitomycin C in dog bladder wall. Pharm Res 1991;8:168–73.[Medline]

3 Schmittgen TD, Wientjes MG, Badalament RA, Au JL. Pharmacodynamics of mitomycin C in cultured human bladder tumors. Cancer Res 1991;51:3849–56.[Abstract]

4 Wientjes MG, Dalton JT, Badalament RA, Drago JR, Au JL. Bladder wall penetration of intravesical mitomycin C in dogs. Cancer Res 1991;51:4347–54.[Abstract]

5 Dalton JT, Wientjes MG, Badalament RA, Drago JR, Au JL. Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients. Cancer Res 1991;51:5144–52.[Abstract]

6 Wientjes MG, Badalament RA, Wang RC, Hassan F, Au JL. Penetration of mitomycin C in human bladder. Cancer Res 1993;53:3314–20.[Abstract]

7 Chai M, Wientjes MG, Badalament RA, Burgers JK, Au JL. Pharmacokinetics of intravesical doxorubicin in superficial bladder cancer patients. J Urol 1994;152(2 Pt 1):374–8.[Medline]

8 Wientjes MG, Badalament RA, Au JL. Penetration of intravesical doxorubicin in human bladders. Cancer Chemother Pharmacol 1996;37:539–46.[Medline]

9 Wientjes MG, Badalament RA, Au JL. Use of pharmacologic data and computer simulations to design an efficacy trial of intravesical mitomycin C therapy for superficial bladder cancer. Cancer Chemother Pharmacol 1993;32:255–62.[Medline]

10 Beahrs OH, Myers MH, editors. In: Bladder. Manual for staging of cancer. Philadelphia (PA): Lippincott; 1983.

11 Koss LG. Tumors of the urinary bladder. In: Firminger HI, editor. Atlas of tumor pathology. 2nd series. Washington (DC): Armed Forces Institute of Pathology; 1975. p. 6–17.

12 O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35:549–56.[Medline]

13 De Bruijn EA, Sleeboom HP, van Helsdingen PJ, van Oosterom AT, Tjaden UR, Maes RA. Pharmacodynamics and pharmacokinetics of intravesical mitomycin C upon different dwelling times. Int J Cancer 1992;51:359–64.[Medline]

14 Fair WR, Fuks ZY, Scher HI. Cancer of the bladder. In: DeVita VT Jr, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 4th ed. Philadelphia (PA): Lippincott; 1993. p. 1052–72.

15 Lamm DL, Blumenstein BA, Crawford ED, Crissman JD, Lowe BA, Smith JA, et al. Randomized intergroup comparison of bacillus Calmette-Guerin immunotherapy and mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder. Urol Oncol 1995;1:119–26.

16 Tomasz M, Lipman R. Reductive mechanism and alkylating activity of mitomycin C induced by rat liver microsomes. Biochemistry 1981;20:5056–61.[Medline]

17 Siegel D, Beall H, Senekowitsch C, Kasai M, Arai H, Gibson NW, et al. Bioreductive activation of mitomycin C by DT-diaphorase. Biochemistry 1992;31:7879–85.[Medline]

18 Mikami K, Naito M, Tomida A, Yamada M, Sirakusa T, Tsuruo T. DT-diaphorase as a critical determinant of sensitivity to mitomycin C in human colon and gastric carcinoma cell lines. Cancer Res 1996;56:2823–6.[Abstract]

19 Singh SV, Scalamogna D, Xia H, O'Toole S, Roy D, Emerson EO, et al. Biochemical characterization of a mitomycin C-resistant human bladder cancer cell line. Int J Cancer 1996;65:852–7.[Medline]

20 Malkinson AM, Siegel D, Forrest GL, Gazdar AF, Oie HK, Chan DC, et al. Elevated DT-diaphorase activity and messenger RNA content in human non-small cell lung carcinoma: relationship to the response of lung tumor xenografts to mitomycin C. Cancer Res 1992;52:4752–7.[Abstract]

21 Spanswick VJ, Cummings J, Smyth JF. Current issues in the enzymology of mitomycin C metabolic activation. Gen Pharmacol 1998;31:539–44.[Medline]

22 Traver RD, Siegel D, Beall HD, Phillips RM, Gibson NW, Franklin WA, et al. Characterization of a polymorphism in NAD(P)H : quinone xidoreductase (DT-diaphorase). Br J Cancer 1997;75:69–75.[Medline]

23 Traver RD, Horikoshi T, Danenberg KD, Stadlbauer TH, Danenberg PV, Ross D, et al. NAD(P)H : quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity. Cancer Res 1992;52:797–802.[Abstract]

24 Hoban PR, Walton MI, Robson CN, Godden J, Stratford IJ, Workman P, et al. Decreased NADPH : cytochrome P-450 reductase activity and impaired drug activation in a mammalian cell line resistant to mitomycin under aerobic but not hypoxic conditions. Cancer Res 1990;50:4692–7.[Abstract]

25 Bligh HF, Bartoszek A, Robson CN, Hickson ID, Kasper CB, Beggs JD, et al. Activation of mitomycin C by NADPH : cytochrome P-450 reductase. Cancer Res 1990;50:7789–92.[Abstract]

26 Jauhiainen K, Rintala E, Alfthan O. Immunotherapy (BCG) versus chemotherapy (MMC) in intravesical treatment of superficial bladder cancer. In: deKernion JB, editor. International Society of Urology Reports. Immunotherapy of urological tumors. New York (NY): Churchill-Livingstone; 1990. p. 13–26.

27 Lundholm C, Norlen BJ, Ekman P, Jahnson S, Lagerkvist M, Lindeborg T, Olsson JL, 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 1996;156(2 Pt 1):372–6.[Medline]

28 DeBruyne FM, van der Meijden AP, Geboers AD, Franssen MP, van Leeuwen MJ, Steerenberg PA, et al. BCG (RIVM) versus mitomycin intravesical therapy in superficial bladder cancer. First results of randomized prospective trial. Urology 1988;31(3 Suppl):20–5.[Medline]

29 Ruebben H, Graf-Dubberstein C, Ostwald R, Staufferberg A, Jaeger N, Deutz FJ, et al. Prospective randomized study of adjuvant therapy after complete resection of superficial bladder cancer: mitomycin C vs BCG Connaught vs BCG TUR alone. In: deKernion JB, editor. International Society of Urology Reports. Immunotherapy of urological tumors. New York (NY): Churchill-Livingstone; 1990. p. 27.

30 Krege S, Giani G, Meyer R, Otto T, Rubben H. 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 1996;156:962–6.[Medline]

31 Witjes JA, van der Meijden AP, Sylvester LC, Debruyne FM, van Aubel A, Witjes WP. Long-term follow-up of an EORTC randomized prospective trial comparing intravesical bacille Calmette-Guerin–RIVM and mitomycin C in superficial bladder cancer. EORTC GU Group and the Dutch South East Cooperative Urological Group. European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group. Urology 1998;52:403–10.[Medline]

Manuscript received August 17, 2000; revised February 12, 2001; accepted February 15, 2001.


This article has been cited by other articles in HighWire Press-hosted journals:


             
Copyright © 2001 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement