The initial results in muscle-invading bladder cancer of RTOG 95-06: phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on the initial response.

PURPOSE: To assess the safety, tolerance, and efficacy of transurethral surgery plus concomitant cisplatin, 5-fluorouracil (5-FU), and radiation therapy in conjunction with selective bladder preservation in patients with muscle-invading bladder cancer. Patients and Methods. Thirty-four eligible patients with clinical stage T2-T4a, Nx M0 bladder cancer without hydronephrosis were entered into a protocol aimed at selective bladder preservation. Treatment began with as complete a transurethral resection as possible followed by induction chemoradiation. This consisted of cisplatin 15 mg/m(2) i.v. and 5-fluorouracil (5-FU) 400 mg/m(2) i.v. in the mornings on d 1, 2, 3, 15, 16, and 17. On d 1, 3, 15, and 17, radiation was given immediately following the chemotherapy using twice-a-day 3 Gy per fraction cores to the pelvis for a total radiation dose of 24 Gy. Response was evaluated by cystoscopy, cytology, and rebiopsy four weeks later. Patients with a complete response received consolidation therapy with the same drugs and doses on d 1, 2, 3, 15, 16, and 17 combined with twice-daily radiation therapy to the bladder and bladder tumor volume of 2.5 Gy per fraction for a total consolidation dose of 20 Gy and a total induction plus consolidation dose to the bladder and bladder tumor of 44 Gy. Patients who did not achieve a complete response were advised to undergo prompt cystectomy, as were those with a subsequent invasive recurrence. The median follow up is 29 months. RESULTS: Of the 34 eligible patients, 26 had a visibly complete transurethral resection. One patient did not complete induction treatment due to acute hematologic toxicity. After induction treatment, 22 (67%) of the 33 patients had no tumor detectable on urine cytology or rebiopsy. Of the 11 patients who still had detectable tumor, six underwent radical cystectomy and five underwent consolidation chemoradiation (one because of refusal to have the recommended cystectomy and four because the treating institutions erroneously assigned them to receive consolidation chemoradiation rather than cystectomy). No patient has required a cystectomy for radiation toxicity. Six patients have died of bladder cancer. The actuarial overall survival at three years is 83%. The probability of surviving with an intact bladder is 66% at three years. A total of seven patients (21%) developed grade 3 or grade 4 hematologic toxicity in conjunction with this treatment. CONCLUSION: This aggressive protocol comprising local surgery plus concurrent 5-FU, cisplatin, and high-dose hypofractionated radiation has been associated with moderately severe hematologic toxicity. Longer follow-up will be necessary to assess efficacy. Both the 67% complete response rate to induction therapy and the 66% three-year survival with an intact bladder are encouraging.

Removal of UroLume endoprosthesis: experience of the North American Study Group for detrusor-sphincter dyssynergia application.

PURPOSE: We present the experience of the North American UroLume Multicenter Study Group with removal of the UroLume endoprosthesis. MATERIALS AND METHODS: A total of 160 neurologically impaired patients were enrolled in the North American UroLume Multicenter Study Group for detrusor external sphincter dyssynergia application. Analysis was performed in 2 groups of patients in which the device was removed during insertion and after implantation, respectively. RESULTS: Device retrieval was required during insertion in 21 patients (13%) mainly due to misplacement or migration in 17. Extraction was done with minimal complications and in all but 2 cases subsequent UroLume implantation was successful. Of 158 men with the device in place 31 (19.6%) required removal. In 34 procedures 44 devices were removed, mainly due to migration. Time from implantation to removal ranged from 4 days to 66 months (mean 22 months). The UroLume was removed en bloc in 20 cases and in parts or wire by wire in 19. The majority of patients had no or minimal complications after extraction. Only 2 patients had serious temporary complications, including bleeding and urethral injury, with no lasting consequences. No malignancy developed as a result of UroLume insertion. CONCLUSIONS: While there is a potential for urethral injury and bleeding, UroLume endoprosthesis removal is largely a simple procedure with minimal complications and consequences.

Long-term followup of the North American multicenter UroLume trial for the treatment of external detrusor-sphincter dyssynergia.

PURPOSE: We determine the long-term efficacy and safety of the UroLume stent as minimally invasive treatment for external detrusor-sphincter dyssynergia in spinal cord injured men. MATERIALS AND METHODS: A total of 160 spinal cord injured men with a mean age plus or minus standard deviation of 36.3 +/- 12.1 years (range 16 to 74) were prospectively treated with an endoprosthesis at 15 centers as part of the North American UroLume trial for external detrusor-sphincter dyssynergia. Urodynamic parameters, including voiding pressure, residual urine volume and bladder capacity, were compared before treatment and at 1, 2, 3, 4 and 5 years after treatment. RESULTS: Mean voiding pressure was 75.1 +/- 28.2 cm. water before treatment in the 160 patients, and 37.4 +/- 23.9 at year 1 in 97, 39.5 +/- 22.2 at year 2 in 84, 42.6 +/- 27.3 at year 3 in 61, 46.3 +/- 33.2 at year 4 in 57 and 44.2 +/- 28.9 cm. at year 5 in 41 after stent insertion (p <0.001). Residual urine volume decreased after stent placement and was maintained throughout the 5-year followup (p <0.001). Mean cystometric capacity remained constant from 269 +/- 155 before insertion to 337 +/- 182 ml. 5 years later (p = 0.17). Hydronephrosis and autonomic dysreflexia improved or stabilized in most patients with functioning stents. Stent explant was necessary in 24 patients (15%), of whom 4 (16.7%) had another stent implanted. CONCLUSIONS: The UroLume stent demonstrates long-term safety and efficacy for the treatment of external detrusor-sphincter dyssynergia. The outcome was similar in men with and without previous sphincterotomy.

Periurethral implantation of glutaraldehyde cross-linked collagen (Contigen) in women with type I or III stress incontinence: quantitative outcome measures.

OBJECTIVE: To evaluate the effectiveness of periurethral collagen (Contigen) implantation as a treatment for stress incontinence, using quantitative measures of urine loss and the patients' subjective response. PATIENTS AND METHODS: Twelve women, age range 46-87 years, had video urodynamic testing--confirming Type I or III stress urinary incontinence and were eligible for periurethral collagen implant. Eleven had had at least one anti-incontinence operation. One woman was withdrawn from the study because of a severe subcutaneous skin reaction 21 days after the skin-test and one patient declined follow-up. Ten patients had up to two implants each, introduced 3-5 months apart under local anaesthetic (5 mL collagen per implant). All patients underwent 10 h pad tests (with 2-hourly pad changes) at baseline and 8 weeks after collagen implant. The following quantitative measures of incontinence severity and voiding function were studied: urine loss during the 10 h test, number of wet pads, weight of urine in the wettest pad, maximum voided volume, residual volume on ultrasound, maximum flow rate and urinary flow curve pattern. Blind to the quantitative results, patients were asked to categorize their outcome as cured, improved and failed. RESULTS: There was a significant decrease in urine loss (P = 0.007), number of wet pads (P = 0.05) and weight of the wettest pad (g) (P = 0.03) from baseline to 8 weeks after the second collagen implant. There was no significant difference at any point in maximum voided volume, maximum urinary flow rate and residual volume after voiding measured on ultrasound. Objectively, two women appeared cured (< 5 g urine loss on 10 h pad test); subjectively, both reported themselves as improved (not cured); one subject stated she was cured and on pad test had 11 g urine loss; two women stated there was no change yet urine loss decreased markedly by > 60% from 434 g to 123 g and 533 g to 199 g. The remaining six stated they were improved although, objectively, their urine loss after the collagen implant remained high (mean 132 g, range 87-185). CONCLUSION: These results show a significant reduction in urine loss at 8 weeks after the second collagen implant and an objective cure rate of 18%. There was little relationship between the objective measure of success and the self-report. Of interest is the fact that no obstructive changes occurred in the voided amount, the flow curve and the residual volume after voiding.

Diagnosis of prostatic carcinoma: the yield of serum prostate specific antigen, digital rectal examination and transrectal ultrasonography.

Three tests are commonly used to diagnose prostate carcinoma to date: serum prostate specific antigen (PSA), digital rectal examination and transrectal ultrasonography. We evaluated these 3 tests in 1,001, 6-sector prostate needle biopsies to rule out prostate carcinoma. Of the biopsies 253 (25.3%) revealed prostate cancer. As a single test, PSA was superior to digital rectal examination or transrectal ultrasonography in predicting cancer in this patient population using difference of proportions tests. Receiver operating characteristic analysis also showed PSA to be the superior test. The combinations of PSA plus transrectal ultrasonography and PSA plus digital rectal examination were superior to digital rectal examination plus transrectal ultrasonography. We found cancer in 35 of 188 patients (18.6%) with intermediate PSA levels of 4.1 to 10.0 ng./ml. and normal or asymmetric nonindurated rectal examinations. Only 5 of 79 patients (6.3%) with a normal digital rectal examination and PSA level of less than 4.0 ng./ml. demonstrated carcinoma on biopsy. Of the 5 patients 4 had annual increases in PSA of 40% or greater. While hypoechoic sectors were more than twice as likely as isoechoic sectors of the prostate to contain malignancy on biopsy, nearly 37.6% of the cancers were found in isoechoic sectors. A strategy of performing biopsy of only hypoechoic sectors would have misdiagnosed 24.6% of the patients with prostate cancer. We conclude that serum PSA is the most accurate of the 3 diagnostic tests evaluated. We also recommend a systematic sextant biopsy technique.

Multicenter trial in North America of UroLume urinary sphincter prosthesis.

We investigated the effectiveness and associated complications of treatment with an endoluminal urethral sphincter prosthesis in 153 spinal cord injury men (mean age 36 years, range 16 to 74 years) with urodynamically diagnosed detrusor-external sphincter dyssynergia. These patients were prospectively treated with a urethral sphincter stent at 15 centers in North America. Followup ranged from 2 to 33 months. Voiding pressures averaged 76 +/- 28, 42 +/- 21, 44 +/- 38, 35 +/- 18 and 32 +/- 20 cm. water, respectively, before prosthesis insertion in 153 patients and at 3 months in 123, 6 months in 114, 12 months in 98 and 24 months in 22. A significant decrease in voiding pressure was noted in the 22 patients at 24 months compared with matched preoperative data (80 +/- 25 cm. water, p = 0.03). The residual urine decreased from 181 +/- 154 ml. before insertion to 82 +/- 93 ml. at 24 months (p = 0.01). Maximum cystometric capacity remained constant, with a mean of 195 +/- 158 ml. before insertion to 248 +/- 122 ml. at 24 months (p = 0.17). No significant differences were apparent after 24 months of followup in any of the urodynamic parameters between 44 patients with and 109 without previous external sphincterotomy. Hemorrhage requiring blood transfusion, obstructive hyperplastic epithelial overgrowth and soft tissue erosion did not occur. No deleterious effects were observed on renal or erectile function. Of the patients 43 (28.1%) required 2 prostheses to bridge the external sphincter completely. Stent removal was required in 10 patients. Seven explantations were required for prosthesis migration, 1 for pain and urethral edema, 1 for inability to maintain a condom catheter, and 1 for nonepithelialization and secondary bladder neck obstruction. A total of 13 patients (8.5%) required a subsequent operation for bladder neck obstruction. Therefore, the sphincter prosthesis is an attractive modality for the treatment of external sphincter dyssynergia in patients with and without previous external sphincterotomy because of its ease of deployment and minimal associated morbidity.

Screening for prostatic carcinoma with prostate specific antigen.

Prostate specific antigen (PSA), neutral serine protease secreted exclusively by prostatic epithelial cells, has a number of applications in the management of men with prostatic carcinoma. While it is widely recognized that elevated PSA correlates with the presence of carcinoma, little data exist regarding the use of PSA as the initial test in the early detection of prostatic cancer. We measured serum PSA levels in men older than 50 years and performed digital rectal examination and ultrasound guided prostate biopsy of those who had a PSA level of greater than 4.0 ng./ml. A total of 1,249 men entered the protocol, of whom 187 (15.0%) had PSA levels above 4.0 ng./ml. Digital rectal examination and ultrasound guided biopsy were performed at our facility in 105 patients (56.2%). A total of 32 carcinomas (30.5%) was detected, including 23 in men with PSA between 4.1 and 10.0 ng./ml. and 9 in men with a PSA of greater than 10.0 ng./ml. Of the 32 carcinomas 12 (37.5%) occurred in men with normal prostates or glands demonstrating only asymmetry on digital rectal examination, and 3 men had carcinoma despite normal digital rectal examination and no hypoechoic peripheral zone lesion detected on ultrasound. Of the 32 patients 30 had clinically localized carcinoma but 7 of the 16 undergoing radical prostatectomy had pathological upstaging. We conclude that PSA represents an important adjunct to digital rectal examination for the early detection of prostatic carcinoma. The efficacy of this or any other early detection test to decrease prostate cancer mortality necessitates the results of prospectively randomized clinical trials.

Lower urinary tract dysfunction in multiple sclerosis.

Previous investigators have shown that in multiple sclerosis failure to empty the bladder was secondary to detrusor-distal sphincter dyssynergia or areflexia. However, our urodynamic evaluation of 46 female and 43 male patients with multiple sclerosis revealed that 63 percent of patients failed to empty their bladders because of a hypocontractile detrusor, and only 6 percent had areflexia. Detrusor-distal sphincter dyssynergia (6%) and bladder neck obstruction (6%) were present in only 12 percent of patients. Hyperreflexia was common (78%) and was associated with hypocontractility in 63 percent of patients. Urgency incontinence was significantly more common in females and voiding difficulty significantly more common in males. Sensation was also reduced in 74 percent of female and 77 percent of male patients. In conclusion, failure to empty the bladder in multiple sclerosis is most commonly associated with hypocontractility, and the combination of hyperreflexia and hypocontractility produces the symptoms of urgency and incomplete emptying.

Nuclear magnetic resonance spectroscopy and sensitizer-adduct measurements of photodynamic therapy-induced ischemia in solid tumors.

Dunning R3327-AT prostate carcinomas growing in Fischer X Copenhagen rats were treated with interstitial photodynamic therapy (PDT--15 mg/kg Photofrin II 4 hours before illumination with 630-nm light via four parallelly implanted optical fibers) at different light intensities. Forty to 60 minutes after treatment, 31P-nuclear magnetic resonance spectra of tumors in anesthetized animals were obtained at 2.35 Tesla using surface coil localization. Areas under resonance peaks were normalized to the area under the peak of a phosphorus standard positioned at a fixed distance on the opposite side of the surface coil. Tumor concentrations of phosphomonoesters and phosphodiesters showed no change after tumor light doses up to 3000 J. Phosphocreatine, alpha-adenosine triphosphate (ATP), beta-ATP, and gamma-ATP signals decreased and inorganic phosphate signals increased with increasing light doses. The intratumor pH did not change significantly at these short times after PDT. In other R3327-AT and R3327-H tumor-bearing animals, [3H]misonidazole was administered 30 minutes prior to PDT treatments of both tumors. Twenty-four hours later, the tumors were resected in toto, and levels of retained [3H]misonidazole were determined in lased tumor specimens by liquid scintillation procedures. The amount of [3H]misonidazole activity in tumor tissue (covalently bound after hypoxic reduction) increased with light doses up to 3000 J. Sensitizer-adduct formation was found to correlate with the ratio of the concentration of inorganic phosphate to that of beta-ATP, both of which are presumed measures of tumor oxygenation status. These measurements have high-lighted the heterogenous nature of the oxygenation status of these experimental tumors. The precision of each assay for estimating tumor oxygenation is discussed.