Robert L. Stephen

Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial

BACKGROUND The rationale for combining anticancer drugs has not been applied consistently to use of intravesical agents for treatment of superficial bladder cancer, for which immunotherapeutic BCG and chemotherapeutic mitomycin seem to be a potentially effective combination. We aimed to do a prospective, randomised comparison of BCG alone with that of sequential BCG and electromotive mitomycin in patients with stage pT1 bladder cancer. METHODS After transurethral resection and multiple biopsies, 212 patients with stage pT1 bladder cancer were randomly assigned to: 81 mg BCG infused over 120 min once a week for 6 weeks (n=105); or to 81 mg BCG infused over 120 min once a week for 2 weeks, followed by 40 mg electromotive mitomycin (intravesical electric current 20 mA for 30 min) once a week as one cycle for three cycles (n=107). Complete responders underwent maintenance treatment: those assigned BCG alone had one infusion of 81 mg BCG once a month for 10 months, and those assigned BCG and mitomycin had 40 mg electromotive mitomycin once a month for 2 months, followed by 81 mg BCG once a month as one cycle for three cycles. The primary endpoint was disease-free interval; secondary endpoints were time to progression; overall survival; and disease-specific survival. Analyses were done by intention to treat. This trial has been submitted for registration at the US National Cancer Institute website . FINDINGS Median follow-up was 88 months (IQR 63-110). Patients assigned sequential BCG and electromotive mitomycin had higher disease-free interval than did those assigned BCG alone (69 months [95% CI 55-86] vs 21 months [15-54]; difference between groups 48 months [42-54], log-rank p=0.0012). Patients assigned sequential BCG and electromotive mitomycin also had lower recurrence (41.9% [32.7-51.5] vs 57.9% [48.7-67.5]; difference between groups 16.0% [2.7-29.3], log-rank p=0.0012); progression (9.3% [3.8-14.8] vs 21.9% [17.9-25.9]; difference between groups 12.6% [3.0-22.2], log-rank p=0.004); overall mortality (21.5% [13.5-29.5] vs 32.4% [23.4-41.4], difference between groups 10.9% [0.6-21.2], log-rank p=0.045); and disease-specific mortality (5.6% [1.2-10.0] vs 16.2% [6.1-23.3], difference between groups 10.6% [2.5-18.7], log-rank p=0.01). Side-effects were mainly localised to the bladder. INTERPRETATION BCG-induced inflammation might increase the permeability of the bladder mucosa such that mitomycin can reach the target tissue more easily and exert its anticancer effect.

Intravesical Capsaicin Versus Resiniferatoxin In Patients With Detrusor Hyperreflexia: A Prospective Randomized Study

PURPOSE Capsaicin and resiniferatoxin (Sigma Chemical Co., St. Louis, Missouri) administered intravesically are attractive options for treating detrusor hyperreflexia. Because the 2 agents differ in chemical structure and relative potency, possible differences in their clinical and urodynamic effects were investigated in this prospective comparative study. MATERIALS AND METHODS A group of 24 spinal cord injured patients with refractory detrusor hyperreflexia were randomly assigned to receive a single dose of 2 mM. capsaicin in 30 ml. ethanol plus 70 ml. 0.9% sodium chloride or 100 nM. resiniferatoxin in 100 ml. 0.9% sodium chloride. Dwell time was 40 minutes with urodynamic monitoring. Urodynamics were performed at baseline before treatment, and after followups of 30 and 60 days. The frequency of daily catheterizations, incontinence episodes and side effects was recorded. RESULTS There was no significant urodynamic or clinical improvement in the capsaicin arm at 30 and 60 days of followup. In the resiniferatoxin arm the mean uninhibited detrusor contraction threshold plus or minus standard deviation increased from 176 +/- 54 to 250 +/- 107 ml. at 30 days (p <0.05) and to 275 +/- 98 ml. at 60 days (p <0.01). Mean maximum bladder capacity increased from 196 +/- 75 to 365 +/- 113 ml. at 30 days (p <0.001) and to 357 +/- 101 ml. at 60 days (p <0.001). Daily catheterizations and incontinent episodes were significantly decreased at 30 and 60 days of followup. Autonomic dysreflexia, limb spasms, suprapubic discomfort and hematuria developed in most patients who received capsaicin but in none who received resiniferatoxin. CONCLUSIONS Intravesical administration of resiniferatoxin is superior to that of capsaicin in terms of urodynamic results and clinical benefits in spinal cord injured patients and it does not cause the inflammatory side effects associated with capsaicin.

Electromotive drug administration of lidocaine to anesthetize the bladder before intravesical capsaicin.

PURPOSE The discomfort caused by intravesical capsaicin during instillation may restrict its use in some patients. We studied the effectiveness of using electromotive drug administration (EMDA) of lidocaine to anesthetize the bladder before capsaicin. MATERIALS AND METHODS EMDA of lidocaine and epinephrine was performed in 8 patients with detrusor hyperreflexia using catheters, electrodes and an electrical current generator (20 mA., 15 minutes) followed immediately by intravesical capsaicin (2 mmol./l.) for 30 minutes under urodynamic monitoring. The patients scored suprapubic pain at 5 minutes and at the end of the capsaicin instillations on a scale of 0 to 10. Of the 8 patients 5 had had previous capsaicin treatments and the scores were compared to previous scores when intravesical lidocaine without EMDA had been used as local anesthesia before capsaicin. RESULTS The pain scores during capsaicin instillations after EMDA of lidocaine were much lower than those during capsaicin instillations after lidocaine alone. EMDA virtually eliminated the hyperreflexic contractions of the bladder occurring during capsaicin instillations, thus reducing the risk of urethral leakage, and prevented autonomic dysreflexia that had previously occurred in 1 patient. CONCLUSIONS EMDA of lidocaine is an effective means of reducing pain during subsequent intravesical capsaicin, which makes the use of capsaicin in the treatment of detrusor hyperreflexia more acceptable.

ELECTROMOTIVE ADMINISTRATION OF INTRAVESICAL BETHANECHOL AND THE CLINICAL IMPACT ON ACONTRACTILE DETRUSOR MANAGEMENT:: INTRODUCTION OF A NEW TEST

PURPOSE It is often difficult to determine the functional status of the detrusor muscle in patients with detrusor areflexia. We performed a clinical study to establish a test defining residual detrusor capacity in such patients. MATERIALS AND METHODS In phase 1, 5 controls with detrusor areflexia were tested with an intravesical instillation of 20 mg. bethanechol in 150 cc of sodium chloride 0.3% with and without 20 mA. of pulsed current applied via an electrode catheter through the saline. Cystometry simultaneously recorded intravesical pressure changes. In phase 2, 45 patients with detrusor areflexia were tested with electromotive administration of intravesical bethanechol. In phase 3, 25 mg. bethanechol given orally once daily were prescribed for 15 patients and voiding control was assessed after 6 weeks of therapy. RESULTS Neither bethanechol without current nor current through saline only led to increased intravesical pressure. However, we noted a mean pressure increase of 34 cm. water during the electromotive administration of bethanechol in 24 of 26 patients with areflexia and neurological disease compared to only 3 cm. water in 3 of 11 with a history of chronic bladder dilatation. Oral bethanechol restored spontaneous voiding in 9 of 11 patients who had had a positive response to the electromotive administration of bethanechol, whereas all 4 without a pressure increase during the electromotive administration of bethanechol did not void spontaneously. CONCLUSIONS Electromotive administration of intravesical bethanechol identifies patients with an atonic bladder and adequate residual detrusor muscle function who are candidates for restorative measures, such as oral bethanechol and intravesical electrostimulation. Those who do not respond to the electromotive administration of bethanechol do not benefit from oral bethanechol and are candidates for catheterization.

INTRAVESICAL ELECTROMOTIVE ADMINISTRATION OF OXYBUTYNIN IN PATIENTS WITH DETRUSOR HYPERREFLEXIA UNRESPONSIVE TO STANDARD ANTICHOLINERGIC REGIMENS

PURPOSE About 15% to 20% of patients with detrusor hyperreflexia do not benefit from oral oxybutynin regimens, frequently because of unpleasant side effects. Several reports indicate that intravesical oxybutynin is effective in many of these patients but there are some who still fail to respond. MATERIALS AND METHODS A select group of 10 adults with detrusor hyperreflexia unresponsive to standard oral and intravesical oxybutynin regimens were treated at weekly intervals with 5 mg. oxybutynin orally, or 5 mg. oxybutynin in 100 ml. intravesically for 60 minutes of passive diffusion and for 30 minutes with 5 mA. electrical current. Each treatment (plus oral placebo and 2 intravesical controls) was associated with an 8-hour, full urodynamic monitoring session, and periodic blood and bladder content sampling. RESULTS There was no significant objective improvement with oral or intravesical passive diffusion oxybutynin. Conversely there was significant improvement in 5 of 6 objective urodynamic measurements with intravesical electromotive oxybutynin. Plasma profiles were a single peak and decay following oral oxybutynin and 2 distinct peaks with intravesical passive diffusion and electromotive oxybutynin. Area under the curve for intravesical passive diffusion were 709 ng. per 8 hours versus oral 1,485 (p <0.05) versus intravesical electromotive 2,781 (p <0.001). Bladder content samples confirmed oxybutynin absorption. Oral oxybutynin caused anticholinergic side effects in 7 of 10 patients. There were no side effects with intravesical passive diffusion or electromotive administrations. CONCLUSIONS Accelerated intravesical administration results in greater bioavailability and increased objective benefits without side effects in previously unresponsive patients compared with oral and intravesical passive diffusion oxybutynin administration.

INTRAVESICAL OXYBUTYNIN: MODE OF ACTION ASSESSED BY PASSIVE DIFFUSION AND ELECTROMOTIVE ADMINISTRATION WITH PHARMACOKINETICS OF OXYBUTYNIN AND N-DESETHYL OXYBUTYNIN

PURPOSE A proportion of patients with detrusor hyperreflexia who are unresponsive to oral oxybutynin often benefit from intravesical oxybutynin instillation. To our knowledge the precise mode of action of this method is obscure. MATERIALS AND METHODS In 12 patients with detrusor hyperreflexia who were previously unresponsive to oral and intravesical passive diffusion of 5 mg. oxybutynin we administered 5 mg. oxybutynin orally as well as increased doses of 15 mg. oxybutynin intravesically with passive diffusion and with 15 mA. associated electric current. Each administration mode per patient was associated with an 8-hour urodynamic monitoring session during which oxybutynin and N-desethyl oxybutynin plasma levels, and intravesical oxybutynin uptake were measured. RESULTS A dose of 5 mg. oxybutynin orally induced no urodynamic improvement with an area under the plasma concentration time curve of combined N-desethyl oxybutynin plus oxybutynin of 16,297 ng./8 hours and an area under the curve ratio of N-desethyl oxybutynin-to-oxybutynin of 11:1. Passive diffusion oxybutynin resulted in 12 mg. oxybutynin intravesical uptake and significant improvement in 3 of 8 urodynamic measurements, although the area under the curve of combined N-desethyl oxybutynin plus oxybutynin was only 2,123 ng./8 hours and the N-desethyl oxybutynin-to-oxybutynin ratio was 1.1:1.0. Electromotive administration of oxybutynin resulted in almost complete intravesical uptake of the 15 mg. dose, significant improvement in all 8 urodynamic measurements and an increased oxybutynin level versus oral and passive diffusion, although the area under the curve of combined N-desethyl oxybutynin plus oxybutynin was 4,574 ng./8 hours and the N-desethyl oxybutynin-to-oxybutynin ratio was inverted at 1.0:1.4. The oral dose of 5 mg. oxybutynin caused anticholinergic side effects in 8 of the 12 patients. Neither intravesical passive diffusion nor electromotive administration caused side effects with an uptake of 12 and 15 mg., respectively. CONCLUSIONS A large proportion of intravesical oxybutynin is sequestered, probably in the urothelium. Intravesical oxybutynin administration confers therapeutic benefits via localized direct action within the bladder wall.

Sequential Bacillus Calmette Guèrin and electromotive mitomycin-C versus Bacillus Calmette Guèrin alone for high-risk superficial bladder cancer: A prospective controlled study

4539 Background: Intravesical bacillus Calmette-Guèrin (BCG) and mitomycin C (MMC) are a theoretically attractive combination for the treatment of high risk superficial bladder cancer. We conducted a prospective, controlled study comparing BCG with sequential BCG + electromotive delivery MMC in patients with T1 bladder cancer. METHODS Following transurethral resection and multiple biopsies we randomized 175 patients with T1 bladder cancer into 2 groups. Group I received BCG 81 mg; 6 weekly instillations. Group II received sequential BCG and electromotive (intravesical electric current; 20 mA for 30 min.) MMC at weekly intervals thus: (BCG, BCG, MMC) x 3, totaling 6 BCG and 3 MMC instillations. Non responders received repeat courses at 3 months. All complete responders underwent maintenance regimens of monthly instillations. Group I: 10 BCG treatments. Group II: (MMC, MMC, BCG) x 3, treatments. RESULTS Group I vs Group II: median (IQR or 95% CI). Follow up (months): 64 (38-82) vs 71 (49-87); p = 0.054 Recurrence: 47% (36-58) vs 28% (19-39); p = 0.013 Months to Recurrence: 11 (6-19) vs 20 (16-33); p = 0.001 Progression: 20% (12-30) vs 14% (7-22); p = 0.312 Months to Progression: 17 (10-21) vs 46 (21-58); p = 0.002 % 5-years mortality by any cause: 11.6 (5.7-20.3) vs 4.5 (1.2-11.1); p = 0.099 % 5-years mortality by bladder cancer: 9.3 (4.1-17.5) vs 1.1 (0.02-6.1); p = 0.017 Side effects were numerous but mainly localized to the bladder. There were no treatment related deaths nor episodes of serious illness nor bladder contractures. CONCLUSIONS Intravesical sequential BCG/electromotive MMC is superior to BCG alone in the treatment of high risk bladder cancer. [Table: see text].

Long term follow up of resiniferatoxin intravesical administration in the treatment of detrusor hyperreflexia in spinal cord injured patients

MATERIAL & METHODS: Eleven patients were included in this prospective study. After a basal evaluation with urodynamics and the frequency of daily incontinent episodes, patients received intravesical administrations of RTX 0.6 mM in 50 ml of normal saline. RTX instillations were repeated when there was recurrence of urinary symptoms and/or urodynamic worsening. Uninhibited detrusor contractions (UDC) threshold and maximum pressure, and maximum bladder capacity were measured at baseline and during follow up. The frequency of daily incontinent episodes was recorded by means of a voiding diary. Local or systemic side effects were also noted.

Intravesical Electromotive Drug Administration for the Treatment of Non-Infectious Chronic Cystitis

Seventeen patients with non-infectious chronic cystitis (NICC) (9 with interstitial cystitis, 6 patients with radiation cystitis, 1 with chemocystitis and 1 with lupoid cystitis) were treated with electromotive administration of intravesical lidocaine and dexamethasone followed by hydrodistension of the bladder. Complete resolution of symptoms for an average of 7.5 months was observed in 11 patients (65%), partial improvement in 4 (23.5%). In this series no complications occurred. Electromotive drug administration (EMDA) and cystodistension were well tolerated by all patients. The treatment was performed on an outpatient basis, thus reducing therapeutic costs. The results presented demonstrate that the combination of EMDA and bladder hydrodistension is an effective first-line treatment for NICC patients.