Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial.

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.

Pharmacodynamics of mitomycin C in cultured human bladder tumors.

The effects of mitomycin C (MMC) concentration and exposure time on the inhibition of tumor cell labeling index (LI) were studied using surgical bladder tumor samples from 14 patients. The bladder tumors were cultured as 1-mm3 fragments on collagen gels. LI was determined by incorporation of [3H]thymidine and autoradiography. All tumors responded to MMC. However, the sensitivity varied significantly between tumors. At a 2-h exposure, the concentrations required for 50 and 90% inhibition (IC50 and IC90) ranged from 0.237 to 14.9 and 2.76 to 74.5 micrograms/ml, respectively. There was an inverse correlation between MMC activity and tumor LI; the IC values were higher for the more rapidly proliferating tumors. Exposure time had a pronounced effect on MMC activity. Shortening the exposure time from 2 to 0.5 h increased the IC50 3-fold, while prolonging the exposure time from 2 to 24 h decreased the IC50 6-fold. To determine the minimum concentration and exposure time necessary to reduce tumor LI by 90%, the data for 6 tumors were computer fitted to the pharmacodynamic relationship Cn x T = k. The analysis showed that, on average, a 2.5-h exposure of 3 micrograms/ml was needed for 50% inhibition and a 7-h exposure of 8 micrograms/ml was needed for 90% inhibition. A comparison of the IC values of MMC determined in this study with the literature values determined using monolayer and spheroid cultures of established human bladder tumor cell lines showed that the drug activity in cultured tumor fragments ranged from 7- to 5300-fold lower than that in established cell lines. In summary, our data demonstrate a heterogeneity in the response of bladder tumors from individual patients to MMC, a decreased sensitivity to MMC with increasing tumor proliferation, and that drug concentration and exposure time are critical determinants of MMC activity.

Bladder wall penetration of intravesical mitomycin C in dogs.

We examined the kinetics of penetration of mitomycin C (MMC) in the dog bladder wall after intravesical instillation of 20 mg/40 ml, a dose used in patients. Bladder tissues were harvested and concentration-depth profiles were established by analysis of thin tissue slices cut parallel to the urothelial surface of the bladder. Tissue concentrations after a dwell time of 5-7 min were similar to those after 30-120 min. In tissues harvested 60 and 75 min after removal of the dose, MMC was not detected in 5 of 6 samples and was less than 1 micrograms/g at the mucosa in the remaining sample, suggesting a rapid "washout" of the drug. The rapid equilibrium between the drug in urine and bladder tissue indicates that the duration of exposure of the bladder wall tissue was approximately equal to the dwell time of intravesical therapy. Tissue concentrations declined log-linearly with respect to the depth of penetration. The concentration immediately underneath the urothelium (C0) showed considerable intra- and interanimal variability. Bladder distention appeared to increase C0 by several fold. C0 ranged from 2 to 275 micrograms/g wet tissue weight, with a median value of 24 micrograms/g, or 11 micrograms/g when two animals with distended bladders were excluded. MMC concentrations in 3 different sites of the same bladder varied up to 5-fold. Within the capillary-perfused mucosa and muscularis (between 50 and 2000 microns from the urothelial surface), concentrations decreased by 50% for each 500-microns distance. The median concentration at 2000 microns was 1 microgram/g (n = 24). At 2000-3000 microns, tissue concentrations in most (18 of 24) specimens either declined to an asymptotic value or were lower than the detection limit of 0.1 microgram/g. Concentrations in the bladder contents were 200-500 micrograms/ml, the average tissue concentration from 50 to 3000 microns was 10 micrograms/g, and plasma concentrations were less than 0.1 microgram/ml. This supports the therapeutic advantage of intravesical therapy of high local drug concentrations while minimizing systemic exposure. A comparison of the urine concentration and C0 indicated a 30-fold decline in concentration across the urothelium. This suggests the importance of the urothelium as a barrier to MMC absorption. A separate study in our laboratories showed that 16 micrograms/ml of MMC was needed to produce a 90% inhibition of the labeling index of explants of human bladder cancers located in the urothelium (Ta tumor, TNM classification), 25 micrograms/ml in the lamina propria (T1 tumors), and 43 micrograms/ml in the muscle layer (T2 tumors).(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients.

Intravesical mitomycin C (MMC) therapy is used to treat superficial bladder cancer. This study was to establish the intra- and intersubject variabilities in the systemic (plasma) and target site (bladder) exposure to the drug and to identify the factors which contribute to these variabilities. The pharmacokinetics of MMC were studied in 10 patients. Treatment consisted of transurethral tumor resection followed by six weekly intravesical treatments with MMC (20 mg in 40 ml of water). The dosing solution was maintained in the bladder for 2 h. Pharmacokinetic studies were performed at the time of the first, fourth, and sixth or first, second, and fourth treatments with MMC for a total of 28 treatments. Concentration-time profiles of the plasma and bladder contents (i.e., urine), urine volumes, and urine pH were determined during and for up to 4 h after intravesical administration. Maximal plasma MMC concentrations averaged 43 ng/ml (range, 2.1-180.5 ng/ml) in treatment 1. In comparison, the MMC plasma concentration for myelosuppression reported in the literature is 400 ng/ml. Maximal plasma concentrations in treatments 2, 4, and 6 were at least 4-fold lower than those in treatment 1 and in most cases were below the detection limit of 0.5 ng/ml. This indicates that the absorption of MMC during the later treatments was less than in the first treatment given shortly after surgery. Urinary MMC concentrations during instillation declined from 519.4 +/- 34.8 micrograms/ml (mean +/- SD) in the dosing solution to 64.6 +/- 39.4 micrograms/ml 2 h after instillation. Thus, the superficial bladder tissue was exposed to drug concentrations 300- to greater than 34,000-fold higher than the plasma-perfused systemic tissues. Intravesical exposure to MMC, as determined by the area under the urine concentration-time curve, showed large intra- and intersubject variabilities (range, 2,185-40,411 micrograms-min/ml). Pharmacokinetic analysis showed that the bladder exposure to MMC inversely correlated with the residual urine volume at the time of drug administration (P less than 0.001), the urine production rate (P = 0.05), and the rate of drug removal by degradation and absorption during therapy (P less than 0.01). At the end of the 2-h treatment, recovery of MMC from the bladder instillate ranged from 1 to 100% and correlated with the urine pH at the time of removal (P less than 0.001). At pH between 5 and 5.5, less than 30% of the dose was recovered.(ABSTRACT TRUNCATED AT 400 WORDS)

Penetration of mitomycin C in human bladder.

The penetration of mitomycin C (MMC) in bladder tissue was studied in patients who received intravesical chemotherapy at the time of radical cystectomy. An intravesical dose of MMC (20 mg/40 ml) was instilled and maintained in the bladder for 60 to 120 min at which time the solution was drained. Within 10 to 60 min after draining the drug solution, the bladder vasculature was ligated, and the bladder was removed. Tissues were sectioned serially in layers parallel to the urothelium and analyzed for MMC concentration. Of the 24 patients evaluated, 17 patients had a low final MMC concentration in urine (< 66 micrograms/ml) or had the MMC solution drained more than 30 min before ligation of the blood vessels. Among these 17 patients, the concentration in the urothelium was measurable in only 4 patients, while the concentrations in deeper tissues were not measurable. In the remaining 7 patients where the urine concentration was > 120 micrograms/ml and where the vasculature was ligated within 30 min after the MMC solution was drained, the bladder wall contained significant MMC concentrations. The drug penetration was studied in the latter 7 patients, using sections of bladder wall that were grossly normal and non-tumor bearing. Concentrations in the bladder wall declined semilogarithmically with tissue depth from the urothelium to the deep muscle and reached a plateau at about 2000 microns depth. The median MMC concentrations were 5.6 micrograms/g in the urothelium and lamina propria interface, 2.7 micrograms/g in the lamina propria, and 0.9 microgram/g in the muscularis. The distance over which the MMC concentration decreased by one-half was about 500 microns. The concentration ratio between the urine and urothelium/lamina propria interface was about 35-fold. The mean plasma concentrations were 0.003, 0.1, and 0.4% of the mean concentration in urine, urothelium, and the averaged bladder tissue concentrations, respectively. Paired superficial tumor and normal tissues were obtained from 5 bladders. In 4 of 5 cases, the concentration in tumors was higher than in normal tissues, while the reverse was seen in the remaining tumor. In one sessile bladder tumor a complete concentration-depth profile could be obtained. While the concentrations in the tumor tissue were 2-3-fold higher than that in the adjacent normal tissue, the rate of concentration declined with respect to tissue depth and hence the distance over which the MMC concentration decreased by one-half was similar in both tumors.(ABSTRACT TRUNCATED AT 400 WORDS)

A prospective randomized trial of maintenance versus nonmaintenance intravesical bacillus Calmette-Guérin therapy of superficial bladder cancer.

Between August 1981 and July 1984, 93 patients with polychronotopic superficial papillary carcinoma (Ta and/or T1), flat carcinoma in situ (Tis), or concomitant superficial papillary and in situ bladder carcinoma were entered into a prospective randomized trial of maintenance v nonmaintenance intravesical bacillus Calmette-Guérin (BCG) therapy. Forty-six patients who received BCG weekly for 6 weeks were compared with 47 patients receiving the six-weekly doses of BCG plus monthly BCG for 2 years. Both groups were evaluated every 3 months by cytology, cystoscopy, and biopsy. A significant reduction in the number of recurrent tumors per patient-month was demonstrated for both groups (P less than .0001); however, the difference in reduction of tumors between the two groups was not significant. Additionally, patients receiving maintenance and nonmaintenance therapy had similar tumor recurrence and progression rates. These results indicate that monthly maintenance BCG does not prevent, delay, or reduce tumor recurrence or progression observed with the 6-week regimen. Maintenance BCG was associated with increased local toxicity, primarily dysuria, frequency, and urgency. Dosage reduction was required in 22 of 47 patients (46.8%). When the data were subjected to multivariate analysis, the presence or absence of tumor following induction BCG and PPD skin test results were found to be significant variables. Controlling for either the presence or absence of tumor following induction BCG, tumor recurrence and progression rates were not significantly different for the two treatment groups. However, the absence of tumor after induction BCG was associated with a longer disease-free duration (P = .00001) and time to progression (P = .095). Patients with a reactive tuberculin skin test before and after induction BCG had significantly less tumor recurrences than patients with different PPD skin tests results (P = .02). Tumor progression was not related to tuberculin skin testing.

Bacillus Calmette-Guérin therapy alters the progression of superficial bladder cancer.

The effectiveness of BCG in preventing disease progression in patients with superficial bladder cancer is evaluated. Long-term follow-up of high-risk patients treated in a previously reported randomized control trial of intravesical plus percutaneous BCG shows that progression occurred in 41/43 (95%) of control and 23/43 (53%) of BCG-treated patients. Muscle invasive and/or metastatic disease occurred with equal frequency in the two groups, but was significantly delayed by BCG treatment (P = .012). Cystectomies were required in 18/43 (42%) control and 11/43 (26%) BCG-treated patients. Median time to cystectomy was 8 months for control v 24 months for BCG-treated patients. Based on initial treatment, survival was improved by BCG therapy (P = .032) (median follow-up 6 years). These results suggest that in high-risk patients intravesical BCG can delay disease progression, prolong the period of bladder preservation, and increase overall survival.

Bladder tissue uptake of mitomycin C during intravesical therapy is linear with drug concentration in urine.

The design of an ongoing Phase III study of intravesical mitomycin C therapy to treat bladder cancer is partly based on the assumption that drug penetration into bladder tissue is linearly related to drug concentration. The present study was designed to (a) test this assumption and (b) to compare drug concentrations in tumor and adjacent normal tissues in human bladders. We previously reported the uptake kinetics of a 20-mg dose in dog and human bladders (M. G. Wientjes et al., Cancer Res., 51: 4347-4354, 1991, and Cancer Res., 53: 3314-3320, 1993). The present study used a 40 mg/20 ml dose. Serial blood and urine samples were taken from dogs during the 120-min instillation. Bladder tissues were harvested from dogs and patients at the end of instillation. A comparison of the results of the present and previous studies indicates identical tissue penetration kinetic parameters in dogs for the two doses, i.e., a approximately 30-fold concentration drop across the urothelium and a half-width of approximately 500 microns. In addition, the average tissue concentration in dog and human bladders attained with the 40-mg dose (8.77 micrograms/g in dogs and 7.55 micrograms/g in humans) was about twice that achieved with the 20-mg dose (4.33 micrograms/g in dogs and 3.91 micrograms/g in humans). In dogs, the plasma concentration of MMC reached a steady state within 10 min; the mean maximal plasma concentration was 8.5 ng/ml. This plasma concentration is indistinguishable from the concentration derived from the 20-mg dose and indicates a minimal systemic exposure even at the higher dose. The average MMC concentration in tumor-bearing tissues was about 40% higher than the concentration in adjacent normal tissues (P = 0.01). In conclusion, the linear relationship between drug uptake in bladder tissues and drug concentration in urine supports the assumption used in the design of the ongoing Phase III clinical trial.

Pharmacodynamics of doxorubicin in human bladder tumors.

Intravesical doxorubicin treatment delivers high drug concentrations to the bladder wall, yet the treatment produces only a variable and incomplete response in superficial bladder cancer and insignificant activity in muscle-invading disease. This study evaluated the pharmacological basis for the clinical observations and potential prognostic indicators of tumor sensitivity to doxorubicin. The pharmacodynamics of doxorubicin were studied using histocultures of surgical specimens of seven superficial (Ta and T1) and nine invasive (T2-T4) tumors. After a 2-h exposure, drug treatment caused a concentration-dependent inhibition of proliferation, as measured by bromodeoxyuridine incorporation into DNA. Extensive cell death was observed at high concentrations (>10 micrometer) in sensitive tumors. The IC50 values ranged from 0.14 to 5.2 micrometer for superficial tumors and from 1.4 to >100 micrometer for invasive tumors. A comparison of the IC50 and IC90 values with the drug concentrations previously determined in human bladder walls showed that IC50 was achieved in all Ta tumors, 67-100% of T1 tumors, and one of the nine invasive tumors, whereas IC90 was achieved in all Ta tumors but none of the other tumors. To determine the biological basis of variable doxorubicin sensitivity among different tumors, we examined the relationship of chemosensitivity with tumor pathology and with expression of multidrug resistance p-glycoprotein (Pgp) and p53 protein. The invasive, high-grade, highly proliferative, p53- and Pgp-positive tumors were more resistant than the superficial, lower-grade, p53- and Pgp-negative tumors. All tumors were negative for bcl-2. The rank order of these factors was p53 expression > tumor stage > grade > bromodeoxyuridine labeling index > Pgp. Statistical analysis using the Akaike Information Criterion indicates that the two-parameter combination of p53 expression with stage further improved the predictive value. The present study shows that: (a) there was a >700-fold difference in doxorubicin sensitivity among superficial and invasive tumors; (b) the variable and incomplete response of superficial bladder cancer to intravesical doxorubicin therapy is likely due to the 35-fold variability in tumor chemosensitivity and, to a lesser degree, the 4-fold variability in tissue pharmacokinetics; (c) the lack of response of invasive cancer to intravesical doxorubicin therapy is likely the result of the inadequate drug concentrations presented to the deep muscle layers and the low chemosensitivity of the more aggressive tumors; and (d) the combination of p53 expression and high stage was the most significant predictor of doxorubicin sensitivity, whereas Pgp expression was the least important.

Paraganglioma of urethra.

Paraganglioma of the urethra is a rare tumor; only 4 cases have been reported previously. We report a fifth case of urethral paraganglioma and review the literature.

Transrectal ultrasonography. Early experience with use as prostate cancer detection tool.

Two hundred forty asymptomatic males, aged fifty-five to seventy years, underwent transrectal ultrasound of the prostate as part of a screening examination in conjunction with The National Prostate Cancer Detection Project (NPCDP). Nineteen prostate adenocarcinomas were detected, eight of which were nonpalpable. Fifteen of these patients had pathologic Stage B, 2 had microscopic Stage C (seminal vesicle involvement), and 2 had Stage D2 (bone) disease. While the activity and treatment of the eight nonpalpable lesions remain in question, the diagnosis certainly was made only with this type of examination. The use of transrectal ultrasound as a screening tool must continue to be prospectively evaluated in a multicenter trial.

Radical prostatectomy 1972-1987 single institutional experience: comparison of standard radical prostatectomy and nerve-sparing technique.

During the period of time from 1972 to 1987 a total of 104 radical prostatectomies were performed at the Ohio State University. From 1972 to 1985, standard radical retropubic prostatectomy was done in 60 patients and from 1986 to June 30, 1987, radical retropubic nerve-sparing prostatectomy was carried out in 44 patients. Transrectal ultrasound evaluation was available only for three quarters of the patients in the latter group. In the early part of the series, standard prostatectomy revealed 51 percent of the patients to have organ-confined disease and in the latter series 75 percent had organ-confined disease. In the earlier study only a retrospective analysis of the pathology reports was available, and in the latter study prospective evaluation was available with regard to pre- and postoperative staging, erectile function, blood loss and replacement, PSA data, and clinical and pathologic staging. It appears the radical nerve-sparing prostatectomy has several advantages including decreased blood loss, increased reservation of erectile function in 70 percent of the patients who were potent preoperatively, and a more accurate assessment of clinical stage prior to surgery through the use of transrectal ultrasonography.

Conservative management of epidermoid cyst of testis.

Epidermoid cysts are rare benign tumors of the testicle whose management is controversial. Only 186 cases have been reported, and most were treated with radical orchiectomy. We report 2 cases managed with local excision, and we review the world literature.

Localized staging of prostate carcinoma: comparison of transrectal ultrasound and magnetic resonance imaging.

To evaluate the usefulness of two new imaging modalities in the clinical staging of prostate cancer the following study was done. Twelve patients with biopsy-proved carcinoma of the prostate were evaluated preoperatively with magnetic resonance imaging (MRI) of the pelvis and transrectal ultrasound of the prostate. The main parameters evaluated were the ability of these two modalities to accurately predict capsular penetration and seminal vesicle involvement in these 12 patients: 10 went on to pelvic lymph node dissections, and 8 had radical retropubic prostatectomies. Thus the preoperative studies could be compared to the pathologic results. Based on our results we believe transrectal ultrasonography is more accurate in the assessment of seminal vesicle involvement and comparable to MRI in determining capsular penetration. Because of the lower cost of ultrasound we believe it to be both an economical and accurate way to preoperatively stage prostate carcinoma.

Testicular torsion and its effects on contralateral testicle.

Twenty-six male adult Noble (Nb) rats underwent unilateral left testicular torsion of 720 degrees. The testicles of the 6 control animals were immediately detorsed. The experimental animals were divided into 4 groups according to the surgical approach (abdominal vs. scrotal) and location where the torsed testicle was placed (abdomen vs. scrotum). After six hours all torsed testicles in the experimental groups were detorsed. One month later all animals were sacrificed, and the contralateral testicles were examined for spermatogenesis and mean seminiferous tubular diameter. All groups displayed decreased spermatogenesis with smaller mean seminiferous tubular diameter as compared with the control group.

Relative value of prostate-specific antigen and prostatic acid phosphatase in diagnosis and management of adenocarcinoma of prostate. Ohio State University experience.

Serum concentrations of prostate-specific antigen (PSA), prostate-specific acid phosphatase (PAP), and transrectal prostatic ultrasound were utilized in the evaluation of 193 men with various urologic disorders. Of the 193 patients, 48 had prostate cancer, and the other 145 included 5 with genitourinary neoplasms, 69 with benign prostatic hypertrophy, and 71 with other non-neoplastic genitourinary disease. PSA levels were elevated in 35 patients with prostate cancer and in 25 of the 145 without prostate cancer. PAP levels were elevated in 15 with prostate cancer and in 2 of the 145 without prostate cancer. The data indicate that PSA is a more sensitive but less specific tumor marker than PAP in the detection of prostate cancer. PSA appears to be more sensitive than PAP in monitoring the response to treatment. The use of PSA and PAP jointly to detect and to monitor prostate cancer did not appear to enhance the clinical utility over that of PSA alone.

Radical prostatectomy: OSU and affiliated hospitals' experience 1985-1989.

A total of 528 patients have been treated with radical prostatectomy and node dissection during the last five years. Correlation of clinical and pathologic staging will be presented. Over 85 percent of these patients had Gleason scores of 6 or less. Patients who had nerve-sparing surgery had a potency rate of over 60 percent post surgery.

Computed tomography of primary transitional cell carcinoma of upper urinary tracts.

Preoperative computed tomography (CT) was utilized to evaluate 20 patients with primary transitional cell carcinoma of the upper urinary tracts. Of the 20 patients, 18 (90%) had CT visualization of the tumor as either a discrete mass or local ureteral and/or renal pelvic wall thickening; 2 (10%) had false-negative examinations. Seven of the 20 patients (35%) had CT evidence of tumor extension demonstrated by frank tumor invasion beyond the urothelium or by perirenal pelvic and/or periureteral fat streaks. Of the 4 patients with fat streaks, 2 (50%) had superficial tumors (T(A)T2), 1 had a T1 (25%) tumor, and 1 had a T3 (25%) tumor. All 3 patients with CT findings of direct extension of tumor through the wall of the ureter or renal pelvis had T3 tumors. Among the 13 with localized noninvasive tumor on CT, 5 (38%) had superficial tumors (TA, TIS, T1), 5 (38%) had T2 tumors, and 3 (21%) had T3 tumors. Of the 5 patients with enlarged regional lymph nodes (greater than or equal to 1.5 cm) on CT, 2 had tumor confirmed histologically, 2 had subsequent negative CT-guided biopsies, and 1 had a negative lymphadenectomy. Distant metastasis was discovered in 1 patient. The data suggest that when CT demonstrates direct tumor extension through the renal pelvic or ureteral wall, it is a sensitive indicator of high-stage disease. However, in the absence of this finding, CT is of limited value in staging patients with primary transitional cell carcinoma of the pyeloureteral system.

Surgical treatment of brain metastases from renal cell carcinoma.

Between January 1976 and December 1986, 22 patients with renal cell carcinoma underwent surgical resection of brain metastases at Memorial Sloan-Kettering Cancer Center. Ten of the patients had metastases limited to the brain and 12 also had extracranial metastases. Twenty patients received external radiotherapy. Five had craniotomy after failing radiation therapy and 15 had adjuvant radiotherapy. Two patients died within thirty days following craniotomy; the median survival of the remaining 20 patients was 20.9 +/- 6.8 months calculated according to a Weibull survival model. Variables examined in relation to survival included absence or presence of extracranial metastases at time of craniotomy, time interval between nephrectomy and diagnosis of cerebral metastases, neurologic status prior to craniotomy, location of the brain tumor, and patient age. None of the variables was significant at the 10 percent level by the Weibull analysis. However, three favorable prognostic factors, namely metachronous brain metastasis more than one year after nephrectomy, minimal or no neurologic deficit at time of craniotomy, and infratentorial lesions show a trend toward improved survival with p less than 0.20. The data suggest that surgical resection of a single and occasionally multiple brain metastases is warranted in selected patients with renal cell carcinoma.

Use of pharmacologic data and computer simulations to design an efficacy trial of intravesical mitomycin C therapy for superficial bladder cancer.

Treatment of superficial bladder cancers by intravesical mitomycin C (MMC) chemotherapy gives a varying and incomplete response. Our recent pharmacokinetics and pharmacodynamics studies have shown that treatment effectiveness is limited by drug degradation in acidic urine and by drug dilution due to residual urine volume and urine production. A model was developed to predict drug exposure in tumors in the bladder wall and to correlate drug exposure with antitumor effect. The model is based on the known pharmacokinetic data in patients treated with intravesical chemotherapy, drug-penetration data in the bladder wall of patients undergoing radical cystectomy, and pharmacodynamic data on patients' bladder-tumor chemosensitivity. Computer simulations based on the model were generated. The simulations predicted that changes in treatment parameters would affect the therapeutic outcome in the following rank order: dose > residual volume > urine production > dosing volume > urine pH > dwell time. Tissue exposure could be enhanced by increased dose, complete bladder emptying, reduced fluid intake, use of the minimal dosing volume, and alkalinization of the urine to a neutral pH. Increasing the dwell time from 2 to 4 h gave an insignificant improvement and posed a compliance problem. The selected optimized regimen of a 40-mg dose, no residual volume, 0.62-ml/min urine production, a 20-ml dosing volume, and alkaline urine pH yielded a calculated 8.5-fold increase in tissue exposure over that achieved by the standard regimen, which consisted of a 20-mg dose, 32-ml residual volume, 1.5-ml/min urine production, a 20-ml dosing volume, and acidic urine pH. On the basis of previously established pharmacodynamic data, we hypothesize that the increase in tissue exposure in the optimized treatment would result in a 20% improvement over the standard therapy along with an increase in the recurrence-free rate from 56% to 76% of patients. A phase III efficacy trial comparing the optimized and standard regimens is proposed.