José A. Martínez-Piñeiro

Predicting Nonmuscle Invasive Bladder Cancer Recurrence and Progression in Patients Treated With Bacillus Calmette-Guerin: The CUETO Scoring Model

PURPOSE Bacillus Calmette-Guerin is the most effective therapy for nonmuscle invasive bladder cancer. Recently to calculate the risks of recurrence and progression based on data from 7 European Organisation for Research and Treatment of Cancer trials a scoring system was reported. However, in that series only 171 patients were treated with bacillus Calmette-Guerin. We developed a risk stratification model to provide accurate estimates of recurrence and progression probability after bacillus Calmette-Guerin. MATERIALS AND METHODS Data were analyzed on 1,062 patients treated with bacillus Calmette-Guerin and included in 4 Spanish Urological Club for Oncological Treatment trials. Stepwise multivariate Cox models were used to determine the effect of prognostic factors. In each patient the weight of all factors was summed to a total score. Patients were then divided into groups, and cumulative recurrence and progression rates were calculated. RESULTS A scoring system was calculated with a score of 0 to 16 for recurrence and 0 to 14 for progression. Patients were categorized into 4 groups by score, and recurrence and progression probabilities were calculated in each group. For recurrence the variables were gender, age, grade, tumor status, multiplicity and associated Tis. For progression the variables were age, grade, tumor status, T category, multiplicity and associated Tis. For recurrence calculated risks using Spanish Urological Club for Oncological Treatment tables were lower than those obtained with Sylvester tables. For progression probabilities were lower in our model only in patients with high risk tumors. CONCLUSIONS We propose a scoring model to stratify the risk of recurrence and progression in patients treated with bacillus Calmette-Guerin.

Endourological treatment of upper tract urothelial carcinomas: analysis of a series of 59 tumors.

PURPOSE We analyzed a series of 59 reno-ureteral units with upper tract urothelial carcinoma treated endourologically at our institution. MATERIALS AND METHODS Between January 1980 and January 1995, 54 of 185 patients with a clinically diagnosed upper tract tumor were considered candidates for endourological treatment. Of the patients 14 had either bilateral disease or a solitary kidney. The primary approach was ureteroscopy in 39 reno-ureteral units and percutaneous nephroscopy in 20. Superficial stage pTa, T1 or Tis disease was noted in 48 cases, infiltrating stage pT2 cancer in 4 and inverted papilloma in 4, while the tumor was impossible to classify in 3. A total of 32 patients received adjuvant supplemental therapy. RESULTS Ureteroscopy failed in 11 cases (28.2%), with salvage by nephroureterectomy in 6 and percutaneous nephroscopy in 5. Primary nephroscopy failed in 3 cases (15%) that were salvaged by open surgery. Two patients died of unrelated causes postoperatively and 14 (26%) had intraoperative or late complications that were treated conservatively in 12. After a mean followup of 30.6 months (range 2 to 119), 2 patients died of progressive upper tract tumor, 2 died of concurrent bladder cancer and 2 died of a second cancer. Of 42 upper tracts treated solely by endourological means 10 (23.8%) had recurrences, which were treated endourologically in 6. Bacillus Calmette-Guerin and mitomycin C seemed to be effective at preventing recurrences, with recurrence rates of 12.5 and 14.2%, respectively, compared to 60% for thiotepa, and 40% for oral combination 5-fluorouracil and uracil. CONCLUSIONS Endourological treatment of low grade, small, noninvasive tumors of the upper urinary tract is a feasible and safe alternative even in patients with a normal contralateral kidney.

Original Articles: Bladder Cancer: Neoadjuvant Cisplatin Chemotherapy Before Radical Cystectomy in Invasive Transitional Cell Carcinoma of the Bladder: A Prospective Randomized Phase III Study

ABSTRACTFrom November 1984 to April 1989, 122 patients with clinical T2-4a Nx-2 M0 transitional cell carcinoma of the bladder were entered in a prospective randomized trial to compare survival between a control group of 60 patients treated only with radical cystectomy (arm A) and a group of 62 patients treated with 3 cycles of 100 mg./m2. neoadjuvant cisplatin before radical cystectomy (arm B). Secondary objectives of the trial were comparison of the disease-free interval and time to death, significance of response of the primary tumor to cisplatin, pattern of relapse and toxicity. As of April 1993 after a median followup of 78.2 months (range 48 to 101) no difference in survival between the control patients and those who received neoadjuvant cisplatin has been observed. The overall direct survival is 37.3% for arm A and 35.5% for arm B. The survival rate of the 109 patients who complied with the protocol is 38.2% for 55 patients of the control group and 40.7% for 54 patients of the cisplatin group. Survi...

The EORTC Tables Overestimate the Risk of Recurrence and Progression in Patients with Non–Muscle-Invasive Bladder Cancer Treated with Bacillus Calmette-Guérin: External Validation of the EORTC Risk Tables

BACKGROUND European Organization for Research and Treatment of Cancer (EORTC) risk tables only included 171 patients treated with bacillus Calmette-Guérin (BCG) for non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE To evaluate the external validity of the EORTC tables in patients with NMIBC treated with BCG over 5-6 mo. DESIGN, SETTING, AND PARTICIPANTS Data on 1062 patients treated with BCG were analyzed. MEASUREMENTS Discrimination was assessed using the concordance index (c-index) and the prognostic separation index (PSEP). For calibration, probabilities of recurrence and progression obtained with the EORTC risk tables in our series were compared with those reported by the EORTC. RESULTS AND LIMITATIONS With respect to the discriminative ability of the EORTC model, c-index was similar to those reported in the EORTC series for recurrence. However, c-indices for progression in our series were lower than c-indices reported by Sylvester et al. [1]. Although PSEP in our series was lower than in the EORTC series for recurrence at 1 yr, similar results were found at 5 yr. Regarding progression, PSEP in our series was lower than in the EORTC series. Whilst a successful stratification of recurrence and progression probability at 1 and 5 yr was achieved using the EORTC tables in our series, model calibration showed lower risks of recurrence than those reported by Sylvester et al. [1] in all groups. For progression, lower risks were found in higher-risk groups. There are some limitations in the present study. A different distribution of patients was found, with higher proportions of primary grade 3 T1 tumors and tumors in situ than in the EORTC series. An additional limitation is that prior recurrence of the EORTC table was not included in our parameters. Consequently, two separate analyses were performed for recurrence. CONCLUSIONS The EORTC model successfully stratified recurrence and progression risks in our cohort. However, the discriminative ability of the EORTC tables decreased in our patients for progression. Moreover, these tables overestimated risks of recurrence and progression after BCG therapy.

Improving the safety of BCG immunotherapy by dose reduction

The preliminary results of a randomized, multicentre, prospective trial conducted by the Spanish Oncology Group (CUETO) are presented. The primary aim of the trial was to determine whether or not lowering the dose of bacillus Calmette-Guérin (BCG) could reduce toxicity without compromising efficacy. From February 1991 to June 1992, 500 patients with superficial bladder cancer (TaG2-3, T1G1-3) entered the trial. Of these patients, 252 were included in group A (BCG, 81 mg) and 248 in group B (BCG, 27 mg). There were no significant differences in clinical and pathological characteristics between the two groups. Following treatment, significant differences arose between groups A and B in local severe toxicity (22.6 vs. 4.2%, respectively; p < 0.01). Systemic toxicity was more common in group A than in group B (p < 0.01): pulmonary effects (2.3 vs. 0.4%), fever (26.9 vs. 12.9%) and malaise (16.2 vs. 8.4%), all p < 0.01. Regarding efficacy, 204 patients in group A and 210 in group B were evaluated after a mean follow-up of 18.6 months. No significant differences in recurrence rate (18.1 vs. 19.5%) or progression rate (2.4 vs. 4.8%) were found. However, in patients with superficial bladder cancer with high risk of recurrence and progression (carcinoma in situ and G3), caution must be exercised in selecting the dose.

Long-term follow-up of a randomized prospective trial comparing a standard 81mg dose of intravesical bacille calmette-guérin with a reduced dose of 27mg in superficial bladder cancer.1: BJU Int 2002;89:671–680.

Abstract Objectives: To determine the efficacy of a three-fold reduced dose (RD, 27 mg) of intravesical bacille Calmette-Guerin (BCG) against the standard dose (81 mg) in patients with superficial bladder cancer, assessing recurrence, progression, and differences in toxicity. Patients and Methods: Five hundred patients with superficial bladder cancer (Ta, T 1 , Tis) were enrolled and randomly assigned to be treated after transurethral resection of all visible lesions with intravesical BCG Connaught strain (weekly × six and thereafter fortnightly × six) either with the standard or RD instillation. Results: All but one of the 500 patients were evaluable for efficacy and toxicity (252 in the standard arm and 247 in the RD arm). The median follow-up was 69 months (maximum 104); 71 (28%) patients in the standard arm and 76 (31%) in the RD arm developed recurrences; the median time to recurrence has not yet been attained, but at 5 years the mean (sd) percentage of recurrence-free patients was 70.5 (3.12) and 70.4 (3.1) for the standard and RD arms, respectively. In patients presenting with multifocal tumours, the standard dose was more effective against recurrences than the RD ( P = 0.0151). In those with G3 and high-risk tumours overall, the superiority of the standard dose was marginal ( P = 0.060 and P = 0.082). Twenty-nine (11.5%) tumours in the standard arm and 33 (13.3%) in the RD arm progressed to invasive disease; the median time to progression has not yet been attained, but the percentage of progression-free patients at 5 years was 88.8 (2.23) and 86.9 (2.31) for the standard and RD arms, respectively. The standard dose was more effective than the RD against progression only in patients with multifocal disease ( P = 0.048). Twelve (4.8%) cystectomies were performed in the standard and 15 (6.1%) in the RD arm. Currently, 106 (21.2%) patients have died, but only 38 (7.6%) from bladder cancer, i.e., 20 (7.9%) in the standard and 18 (7.5%) in RD arm. Overall the disease-specific death rate was lower for those patients who completed the scheduled treatment. The cause-specific survival at 5 years did not differ between the arms ( P = 0.76) but there was a trend toward better cause-specific survival for patients with multifocal tumours in the standard arm. Toxicity differed between the arms, significantly more patients having no toxicity in the RD arm, and fewer having delayed instillations or withdrawing. However, severe systemic toxicity occurred even in patients treated with the RD, in a similar proportion to those receiving the standard dose. Conclusion: Overall, the RD gave similar results for recurrence and progression but with significantly less toxicity. However, patients with multifocal tumours fared better with the standard dose and there was a trend towards better recurrence rates in patients with high-risk tumours. We recommend continuing to use the standard dose for high-risk tumours, whereas we consider the RD safe and effective for intermediate-risk lesions and for maintenance schedules.

Maintenance Therapy with 3-monthly Bacillus Calmette-Guérin for 3 Years is Not Superior to Standard Induction Therapy in High-risk Non–muscle-invasive Urothelial Bladder Carcinoma: Final Results of Randomised CUETO Study 98013

BACKGROUND Bacillus Calmette-Guérin (BCG) maintenance therapy for 3 yr following BCG induction can reduce the progression of urothelial bladder carcinoma versus BCG induction alone, but is associated with high toxicity. OBJECTIVE To investigate whether a modified 3-yr BCG maintenance regimen following induction therapy is more effective than standard BCG induction therapy alone and exhibits a low toxicity profile. DESIGN, SETTING, AND PARTICIPANTS Patients from the outpatient clinics of the participating centres with high-risk non-muscle-invasive bladder carcinoma (NMIBC) were randomised between October 1999 and April 2007. INTERVENTION Participants received BCG induction once-weekly for 6 wk (no maintenance arm) or BCG induction followed by one BCG instillation every 3 mo for 3 yr (maintenance arm). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary endpoints were disease-free interval (DFI) and time to progression (TTP). Secondary endpoints included survival duration and toxicity. Differences between treatment arms were tested using Students t test and χ(2) and log-rank tests. RESULTS AND LIMITATIONS A total of 397 patients were randomised, 195 to the no-maintenance and 202 to the maintenance arm. A median time to recurrence was not reached in either treatment arm. DFI was similar between the arms (hazard ration [HR] 0.83; 95% CI 0.61-1.13; p=0.2) with disease relapse at 5 yr of 33.5% and 38.5%, respectively. TTP was also similar between the treatment arms (HR 0.79; 95% CI 0.50-1.26; p=0.3), with a progression rate at 5 yr of 16% and 19.5%, respectively. There were no significant differences between the treatment groups for overall survival and cancer-specific survival at 5 yr. Twenty and five patients in the maintenance and no-maintenance arms, respectively, stopped treatment because of toxicity. The most common local side effects were frequency (65% of patients), dysuria (63%), and haematuria (43%); the most frequent systemic side effects were general malaise (7.2%) and fever (34%). CONCLUSIONS In NMIBC patients treated with maintenance therapy comprising a single BCG instillation every 3 mo for 3 yr following standard induction BCG, we did not observe a decrease in recurrence and progression rates versus induction therapy alone. PATIENT SUMMARY Patients who undergo surgery to remove bladder cancer are usually treated with bacillus Calmette-Guérin (BCG) for 6 wk if there is a high risk of disease recurrence. Extending BCG therapy by 3 yr can further minimise disease recurrence and progression, but is associated with more side effects. We report that a modified 3-yr BCG treatment regimen showed low toxicity, but seemed to be no more effective than 6-wk treatment. TRIAL REGISTRATION CUETO 98013.

Preliminary Results of a Comparative Study with Intracavernous Sodium Nitroprusside and Prostaglandin E1 in Patients with Erectile Dysfunction

We compared the effect of intracavernous administration of sodium nitroprusside, a nitric oxide donor and, therefore, stimulator of the cyclic guanosine monophosphate pathway, with the activity of prostaglandin E1, which is a stimulator of the cyclic adenosine monophosphate pathway. To date 105 patients with erectile dysfunction have entered the study. As part of the diagnostic evaluation every patient received an intracavernous injection of 20 micrograms prostaglandin E1 and a second injection of sodium nitroprusside at different concentrations (100 micrograms in 10 patients, 300 micrograms in 60 and 400 micrograms in 35). Sodium nitroprusside at a dose of 100 micrograms was not effective for inducing erections. Prostaglandin E1 induced better responses overall than sodium nitroprusside at 300 and 400 micrograms (p < 0.001). The overall duration of erections was also significantly longer with prostaglandin E1 (mean 88.5 minutes) than with 300 micrograms sodium nitroprusside (mean 50.8 minutes, p < 0.001) but did not reach statistical significance compared to 400 micrograms sodium nitroprusside (mean 42.2 minutes). Side effects were minimal with both drugs. Although sodium nitroprusside has several benefits over prostaglandin E1 for intracavernous use (such as lower cost, absence of local pain and shorter action, allowing detumescence after orgasm and decreasing the risk of priapism), prostaglandin E1 still remains the agent of choice for intracavernous use.

Prospective Comparative Study with Intracavernous Sodium Nitroprusside and Prostaglandin E1 in Patients with Erectile Dysfunction

Purpose: To compare the effectiveness of intracavernous administration of sodium nitroprusside and prostaglandin E1 to induce penile erection in men with erectile dysfunction. Material and Methods: 100 patients with erectile dysfunction entered the study prospectively. As part of the diagnostic workup, each patient received an intracavernous injection of 20 µg prostaglandin E1 and a second injection of 600 µg sodium nitroprusside 1–7 days later. A tourniquet was placed at the base of the penis before each injection. The data recorded included time required to initiate tumescence, local and systemic side effects, objective and subjective quality of erections, duration of tumescence and patient satisfaction by means of a personal questionnaire. Results: Prostaglandin E1 induced better overall responses than sodium nitroprusside, the difference being almost significant (p = 0.055). The overall duration of erections was also significantly longer with prostaglandin E1 (mean 81.3 min) than with sodium nitroprusside (mean 65.4 min; p < 0.04). 67% of the patients considered the erections induced with prostaglandin E1 to be of better quality than those with sodium nitroprusside, and only 11% stated that sodium nitroprusside was superior. Side effects were minimal with both drugs, the most frequent side effect being systemic hypotension, which was induced by sodium nitroprusside in 7% of the patients. Conclusions: The moderate risk of systemic hypotension and the lower potency of sodium nitroprusside to induce erections compared to prostaglandin E1 rules out sodium nitroprusside as a routine alternative intracavernous drug in men with erectile dysfunction at the doses employed. Sodium nitroprusside, however, could be used in patients who have intolerance or penile pain with intracavernous prostaglandin E1.

Surgical repair of anterior hypospadias with fish-mouth meatus and intact prepuce based on anatomical characteristics.

Purpose: A variant form of anterior hypospadias, called a megameatus and intact prepuce (MIP), is thought to be less amenable to conventional distal hypospadias repair. The feasibility of using the standard technique with a parameatal-based foreskin flap is described herein. Materials and Methods: Nine children with the MIP variant underwent repair. A foreskin flap for urethroplasty was harvested from either the ventral (Mathiew) or unilateral site. The glans was split along with the cleft glanular groove to create the glans wings. The flap was laid on the urethral plate to form a neourethra, and glanulomeatoplasty was completed by approximation of the glans wings. Sleeve reapproximation of the penile foreskin was performed for uncircumcised skin closure. Results: The functional and cosmetic results of the procedure were excellent in 8 cases including 1 with temporary postoperative edema of redundant foreskin. The last case underwent excision of the ventral excess foreskin for cosmetic reasons. Conclusions: Although the etiology of the MIP variant remains obscure, the urethral plate distal to the meatus is uniformly pliable and healthy in this variant. Furthermore, the ventral portion just proximal to the meatus is well developed and not atretic so that the parameatal ventral foreskin is safely harvested for onlay urethroplasty.