J. Palou

MULTIVARIATE ANALYSIS OF THE PROGNOSTIC FACTORS OF PRIMARY SUPERFICIAL BLADDER CANCER

PURPOSE We evaluate the prognostic factors of recurrence, progression and disease specific mortality in patients with primary superficial Ta and T1 transitional cell carcinoma of the bladder. MATERIALS AND METHODS We studied a cohort of 1,529 patients with primary superficial transitional cell carcinoma of the bladder treated with transurethral resection and random bladder biopsies. Mean followup was 4.2 years. Statistical analysis was performed using the Kaplan-Meier method and multivariate analysis was done with the Cox proportional hazards model with stepwise forward selection. All p values were 2-sided, with odds ratios and 95% confidence intervals. RESULTS Multiple tumors (odds ratio 2), tumor greater than 3 cm. (1.65) and carcinoma in situ (1.6) increased, whereas intravesical bacillus Calmette-Guerin (BCG) instillations (0.39) decreased the risk of recurrence. Grade 3 disease (odds ratio 19.9), multiple tumors (1.9), tumor greater than 3 cm. (1.7) and carcinoma in situ (2.1) increased, whereas BCG (0.3) decreased the risk of progression. Grade 3 disease (odds ratio 14) and carcinoma in situ (odds ratio 3) increased the risk of disease specific mortality. CONCLUSIONS Neither tumor stage nor dysplasia influenced tumor evolution. Multiple tumors, tumor greater than 3 cm. and intravesical BCG instillations were risk factors of recurrence and progression. Carcinoma in situ influenced recurrence, progression and disease specific mortality. Finally, the main predictor of progression and mortality was grade 3 disease.

European Guidelines for the Diagnosis and Management of Upper Urinary Tract Urothelial Cell Carcinomas: 2011 Update

CONTEXT The European Association of Urology (EAU) Guideline Group for urothelial cell carcinoma of the upper urinary tract (UUT-UCC) has prepared new guidelines to aid clinicians in assessing the current evidence-based management of UUT-UCC and to incorporate present recommendations into daily clinical practice. OBJECTIVE This paper provides a brief overview of the EAU guidelines on UUT-UCC as an aid to clinicians in their daily practice. EVIDENCE ACQUISITION The recommendations provided in the current guidelines are based on a thorough review of available UUT-UCC guidelines and papers identified using a systematic search of Medline. Data on urothelial malignancies and UUT-UCCs in the literature were searched using Medline with the following keywords: urinary tract cancer, urothelial carcinomas, upper urinary tract, carcinoma, transitional cell, renal pelvis, ureter, bladder cancer, chemotherapy, nephroureterectomy, adjuvant treatment, neoadjuvant treatment, recurrence, risk factors, and survival. A panel of experts weighted the references. EVIDENCE SYNTHESIS There is a lack of data in the current literature to provide strong recommendations due to the rarity of the disease. A number of recent multicentre studies are now available, whereas earlier publications were based only on limited populations. However, most of these studies have been retrospective analyses. The TNM classification 2009 is recommended. Recommendations are given for diagnosis as well as for radical and conservative treatment; prognostic factors are also discussed. Recommendations are provided for patient follow-up after different therapeutic options. CONCLUSIONS These guidelines contain information for the diagnosis and treatment of individual patients according to a current standardised approach. When determining the optimal treatment regimen, physicians must take into account each individual patients specific clinical characteristics with regard to renal function including medical comorbidities; tumour location, grade and stage; and molecular marker status.

PRIMARY SUPERFICIAL BLADDER CANCER RISK GROUPS ACCORDING TO PROGRESSION, MORTALITY AND RECURRENCE

PURPOSE We identified risk groups in primary superficial bladder cancer according to progression, mortality and recurrence rates. MATERIALS AND METHODS The prognostic factors of progression, mortality and recurrence were identified by multivariate analysis in a cohort of 1,529 patients with primary superficial bladder cancer. Risk groups were designed by combining the relative risk of these prognostic factors. We performed survival analysis of progression, tumor mortality and recurrence by risk group using the Kaplan-Meier method. Relative risk in each group was calculated by Cox regression. We present timetables of progression, mortality and recurrence by risk group. RESULTS Risk groups were classified as low-grade 1 stage Ta disease and a single grade 1 stage T1 tumor, intermediate-multiple grade 1 stage T1 tumors, grade 2 stage Ta disease and a single grade 2 stage T1 tumor, and high-multiple grade 2 stage T1 tumors, grade 3 stages Ta and T1 disease, and any stage disease associated with carcinoma in situ. Survival analysis of progression, mortality and recurrence revealed a statistically significant difference among the 3 risk groups. The rates of recurrence, progression and mortality were 37%, 0% and 0% in the low, 45%, 1.8% and 0.73% in the intermediate, and 54%, 15% and 9.5% in the high risk group, respectively. The relative risks of recurrence, progression and mortality in the low versus the intermediate and high risk groups were 1.37, 2.84 and 1, and 1.87, 24.76 and 14.69, respectively. CONCLUSIONS Risk group classification based on prognostic factors defines progression, mortality and recurrence rates in primary superficial bladder cancer. It may be useful for designing treatment and followup strategies.

Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer

PURPOSE Radical cystectomy and pelvic lymphadenectomy (PLND) remains the standard treatment for localized and regionally advanced invasive bladder cancers. We have constructed an international bladder cancer database from centers of excellence in the management of bladder cancer consisting of patients treated with radical cystectomy and PLND. The goal of this study was the development of a prognostic outcomes nomogram to predict the 5-year disease recurrence risk after radical cystectomy. PATIENTS AND METHODS Institutional radical cystectomy databases containing detailed information on bladder cancer patients were obtained from 12 centers of excellence worldwide. Data were collected on more than 9,000 postoperative patients and combined into a relational database formatted with patient characteristics, pathologic details of the pre- and postcystectomy specimens, and recurrence and survival status. Patients with available information for all selected study criteria were included in the formation of the final prognostic nomogram designed to predict 5-year progression-free probability. RESULTS The final nomogram included information on patient age, sex, time from diagnosis to surgery, pathologic tumor stage and grade, tumor histologic subtype, and regional lymph node status. The predictive accuracy of the constructed international nomogram (concordance index, 0.75) was significantly better than standard American Joint Committee on Cancer TNM (concordance index, 0.68; P < .001) or standard pathologic subgroupings (concordance index, 0.62; P < .001). CONCLUSION We have developed an international bladder cancer nomogram predicting recurrence risk after radical cystectomy for bladder cancer. The nomogram outperformed prognostic models that use standard pathologic subgroupings and should improve our ability to provide accurate risk assessments to patients after the surgical management of bladder cancer.

The ARESC study: an international survey on the antimicrobial resistance of pathogens involved in uncomplicated urinary tract infections

The ARESC (Antimicrobial Resistance Epidemiological Survey on Cystitis) study is an international survey to investigate the prevalence and susceptibility of pathogens causing cystitis. Female patients (n=4264) aged 18-65 years with symptoms of uncomplicated cystitis were consecutively enrolled in nine European countries as well as Brazil during 2003-2006. Pathogens were identified and their susceptibility to nine antimicrobials was determined. Escherichia coli accounted for 76.7% of isolates. Among E. coli, 10.3% of the isolates were resistant to at last three different classes of antimicrobial agents. Resistance was most common to ampicillin (48.3%), trimethoprim/sulfamethoxazole (29.4%) and nalidixic acid (18.6%). Fosfomycin, mecillinam and nitrofurantoin were the most active drugs (98.1%, 95.8% and 95.2% susceptible strains, respectively) followed by ciprofloxacin, amoxicillin/clavulanic acid and cefuroxime (91.7%, 82.5% and 82.4%, respectively). Resistance to ciprofloxacin was >10% in Brazil, Spain, Italy and Russia. Overall, Proteus mirabilis were more susceptible to beta-lactams and less susceptible to non-beta-lactams than E. coli, whereas Klebsiella pneumoniae strains, which are intrinsically resistant to ampicillin, were less susceptible to mecillinam (88.8%), fosfomycin (87.9%), cefuroxime (78.6%) and nitrofurantoin (17.7%). Resistance was rare in Staphylococcus saprophyticus, with the exception of ampicillin (36.4%) and trimethoprim/sulfamethoxazole (10.2%). In Italy, Spain, Brazil and Russia, the countries most affected by antimicrobial resistance, extended-spectrum beta-lactamase (ESBL) enzymes (mainly CTX-M type) were detected in 48 strains (39 E. coli, 6 K. pneumoniae and 3 P. mirabilis). Despite wide intercountry variability in bacterial susceptibility rates to the other antimicrobials tested, fosfomycin and mecillinam have preserved their in vitro activity in all countries investigated against the most common uropathogens.

Urine Markers for Detection and Surveillance of Non-Muscle-Invasive Bladder Cancer

CONTEXT Bladder cancer diagnosis and surveillance includes cystoscopy and cytology. The limitation of urinary cytology is its low sensitivity for low-grade recurrences. As of now, six urine markers are commercially available to complement cystoscopy in the detection of bladder cancer. Several promising tests are under investigation. OBJECTIVE In this nonsystematic review, we summarize the existing data on commercially available and promising investigational urine markers for the detection of bladder cancer. EVIDENCE ACQUISITION A PubMed search was carried out. We reviewed the recent literature on urine-based markers for bladder cancer. Articles were considered between 1997 and 2011. Older studies were included selectively if historically relevant. EVIDENCE SYNTHESIS Although different studies have shown the superiority of urine markers regarding sensitivity for bladder cancer detection as compared with cytology, none of these tests is ideal and can be recommended unrestrictedly. CONCLUSIONS Urine markers have been studied extensively to help diagnose bladder cancer and thereby decrease the need for cystoscopy. However, no marker is available at present that can sufficiently warrant this. Several urinary markers have higher but still insufficient sensitivity compared with cytology. Urinary cytology or markers cannot safely replace cystoscopy in this setting. To identify an optimal marker that can delay cystoscopy in the diagnosis of bladder cancer, large prospective and standardized studies are needed.

CONTROL GROUP AND MAINTENANCE TREATMENT WITH BACILLUS CALMETTE-GUERIN FOR CARCINOMA IN SITU AND/OR HIGH GRADE BLADDER TUMORS

PURPOSE Intravesical instillations of bacillus Calmette-Guerin have demonstrated satisfactory results in the treatment of vesical carcinoma in situ and high grade superficial bladder tumors. We designed a protocol to evaluate the decrease in tumor recurrence with maintenance therapy. MATERIALS AND METHODS Between June 1989 and May 1995 an initial course of 6 intravesical instillations of Connaught strain bacillus Calmette-Guerin was administered in patients with carcinoma in situ and/or high grade superficial bladder tumors. Six months later 131 disease-free patients were randomly assigned to a control group or a maintenance therapy group that received 6 instillations every 6 months (6 x 6) for a 2-year period. RESULTS Of the 126 evaluable patients at a mean followup of 79 months there were no significant differences in recurrence nor progression. A total of 16 patients (26.2%) in the control and 10 (15.1%) in the maintenance group had superficial relapse at a mean of 24 and 20 months, respectively (p = 0.07). Eight patients underwent radical cystectomy due to bladder contraction in 1, high grade superficial recurrence in 4 and disease progression in 3. Of the 65 patients on maintenance therapy 22 (33.85%) completed the planned 2-year treatment. CONCLUSIONS Six-month maintenance therapy in patients treated initially for carcinoma in situ and/or high grade superficial bladder tumors who are disease-free at 6 months did not significantly decrease recurrence or progression.

Upper Tract Transitional Cell Carcinoma Following Cystectomy for Bladder Cancer

Purpose: We assessed the incidence of upper urinary tract tumors (UUTTs) after cystectomy for invasive or superficial transitional cell carcinoma (TCC) of the bladder. The risk factors, patients’ characteristics and evolution of those who developed UUTTs are analyzed. Materials and Methods: From August 1980 to February 1994, 568 radical cystectomies were performed for TCC of the bladder: in 469 instances (82.5%) due to invasive tumor (T2–T4), and in 99 cases (17.5%) for superficial tumor (Ta, T1, Tis). All patients were followed for at least 5 years or until death. A retrospective study of patients who developed UUTTs has been performed. A revision of bladder tumor and UUTT characteristics, and the intervals between both is also evaluated. Results: 26 patients (4.5%) developed UUTTs: 11 of the 99 patients cystectomized for superficial TCCs (11.1%); 6 of the 392 patients with primary invasive TCC (1.5%), and 9 of the 77 (11.6%) patients with invasive tumors and a prior history of superficial TCC. The interval to the development of UUTT was higher after cystectomy for superficial tumor. TCCs of the bladder that subsequently developed UUTTs were high grade in 84%, multifocal in 80%, or had carcinoma in situ in 65%, tumor in the prostatic urethra in 52%, and involvement of the distal ureter in 57%. Twenty–two UUTTs (84%) were located in the calyces or the renal pelvis, 3 were bilateral (11.5%), 14 multiple (58%) and 4 superficial (16%). With a median follow–up time of 18 (range 3–103) months, 14 patients (53.8%) died of tumor, 2 were alive with disease, 2 were lost for follow–up, and 8 (30%) were alive and free of disease. Conclusions: We found that patients cystectomized for superficial or invasive TCC with a prior history of superficial TCC have a higher incidence of UUTTs. These cases require follow–up with annual urography or loopography.

Intravesical bacillus calmette-gue??rin for the treatment of superficial bladder cancer in renal transplant patients

Background. Intravesical instillations with bacillus Calmette-Guérin (BCG) is considered the treatment of choice in the prophylaxis of high-grade superficial bladder carcinoma and in the treatment of carcinoma in situ (CIS) of the bladder. Methods. There is no previous experience with BCG treatment in patients with renal transplantation. Theoretically, immunosuppression is a contraindication because of the risk of severe morbidity and sepsis. We present our experience with endovesical BCG in three renal transplant patients, under immunosuppressive treatment, with high-grade superficial bladder cancer and CIS. Results. Two patients are free of disease at 17 and 60 months. One patient developed disease recurrence and underwent a radical cystectomy. There was neither change in renal function nor any clinical evidence of tuberculous infection. Conclusions. Intravesical BCG in superficial bladder cancer and/or CIS is a valid option, with no added morbidity to renal transplant patients.

Transurethral Resection of the Intramural Ureter as the First Step of Nephroureterectomy

Nephroureterectomy is the standard surgical approach for upper urinary tract carcinoma. In 1952 a modified technique was described based on a prior endoscopic disconnection of the intramural ureter as an initial step for subsequent nephroureterectomy via a single lumbar incision. Since October 1989 we performed 31 nephroureterectomies with this technique in 26 men and 5 women (average age 64.5 years). Of the patients 9 had prior bladder carcinoma. The predominant pathological diagnosis of the nephroureterectomy specimens was high grade infiltrating tumor. There were no intraoperative complications except for 1 case of intra-abdominal extravasation detected in the immediate postoperative period and treated conservatively. With an average followup of 20 months, tumor has not recurred at either the resected trigonal area or the retroperitoneum. We believe that our experience assesses the feasibility of this technique to improve and simplify nephroureterectomy, thus, decreasing the morbidity rate and operating time while maintaining the same oncological radicality.