Upper Urinary Tract Carcinoma In Situ: Current Knowledge, Future Direction.

PURPOSE: Carcinoma in situ of the urinary tract is a high grade form of nonmuscle invasive urothelial cancer. Our understanding of this entity in the upper tract is poor, and case management remains challenging due to knowledge gaps regarding the definition, diagnosis, treatment options and followup of the disease. We reviewed the available literature for similarities and differences between bladder and upper tract carcinoma in situ, and herein summarize the best available data. MATERIALS AND METHODS: We reviewed PubMed® and MEDLINE™ databases from January 1976 through September 2014. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement was used to screen publications. All authors participated in the development of a consensus definition of disease. RESULTS: A total of 61 publications were found suitable for this review. All studies were retrospective. Compared to bladder carcinoma in situ, upper tract carcinoma in situ appears to have lower progression rates and improved survival. All available studies demonstrate topical therapy to be effective in treating upper tract carcinoma in situ, with decreased recurrence rates compared to bladder carcinoma in situ. Highlighted areas of current knowledge gaps include variable definitions of disease, methods of drug delivery and ideal treatment course. Improving methods for detection may allow easier diagnosis and more effective treatment. CONCLUSIONS: Based on the available data, organ preserving therapy with topical agents is an alternative to radical surgery in select patients with upper tract carcinoma in situ, although this method has not been evaluated in prospective trials. A paradigm shift regarding detection and treatment is needed to improve care and allow better renal preservation. A consensus definition of the disease is offered, and several areas of major knowledge gaps and opportunities for future research are identified.

Increasing age is not associated with toxicity leading to discontinuation of treatment in patients with urothelial non-muscle-invasive bladder cancer randomised to receive 3 years of maintenance bacille Calmette-Guérin: results from European Organisation for Research and Treatment of Cancer Genito-Urinary Group study 30911.

OBJECTIVE: To determine the relationship of age to side-effects leading to discontinuation of treatment in patients with stage Ta-T1 non-muscle-invasive bladder cancer (NMIBC) treated with maintenance bacille Calmette-Guérin (BCG). PATIENTS AND METHODS: We evaluated toxicity for 487 eligible patients with intermediate- or high-risk Ta-T1 (without carcinoma in situ) NMIBC randomised to receive 3 years of maintenance BCG therapy (247 BCG alone and 240 BCG + isoniazid) in European Organisation for Research and Treatment of Cancer Genito-Urinary Group trial 30911. The percentage of patients who stopped for toxicity and the number of treatment cycles that they received were compared in four age groups, ≤60, 61-70, 71-75 and >75 years, using the Mantel-Haenszel chi-square test for trend. RESULTS: The percentage of patients stopping BCG for toxicity was 17.9% in patients aged ≤60 years, 21.9% in patients aged 61-70 years, 22.9% in patients aged 71-75 years, and 16.4% in patients aged >75 years (P = 0.90). For both systemic and local side-effects, there was likewise no significant difference. CONCLUSION: In patients with intermediate- and high-risk Ta-T1 NMIBC treated with BCG, no differences in toxicity as a reason for stopping treatment were detected based on patient age.

Can gemcitabine instillation ablate solitary low-risk non-muscle-invasive bladder cancer? Results of a phase II marker lesion study.

PURPOSE: The purpose of this phase II study was to evaluate whether low-risk non-muscle-invasive bladder cancer can be ablated with intravesical gemcitabine in a marker lesion study. PATIENTS AND METHODS: The study had a Simon II-stage design. Thirteen patients were to be recruited for stage I. In the event of ≥4 responses, another 30 patients were to be recruited. Patients were given gemcitabine 2,000 mg intravesically once per week for 6 weeks and the response was assessed with endoscopic, histological, and urine cytological findings. RESULTS: Fourteen patients evaluated for efficacy completed the study; complete responses were achieved by 2 patients (14.3%), both of these patients had lesions of <1 cm. Eleven patients (78.6%) were non-responders and 1 patient (7.1%) had progressive disease. Since the response rate in stage I was below the minimal pre-defined limit, the study was stopped. CONCLUSIONS: This study shows that intravesical gemcitabine does not merit further study in this patient population. A tumor size of >1 cm may be a critical factor in accounting for the low response rate.

New strategies in the treatment of Ta-T1 transitional cell carcinoma (TCC) of the bladder.

In recent years, there have been many advances in the treatment of superficial bladder cancer. Standard intravesical chemotherapeutic agents can now be delivered more effectively thanks to new technological advances in drug delivery. Local microwave hyperthermia and electromotive drug administration are of particular interest. Research has also shown that different combinations of drugs and sequential drug delivery of two or more different drugs for differing periods of time also increase the effectiveness of possible treatments of superficial bladder cancer. Furthermore, new chemotherapeutic drugs for intravesical use are being investigated in various clinical trials, with gemcitabine showing particularly promising results. Also in the pipeline are new approaches to treatment such as gene therapy, but these will need to be developed much more before they become part of routine practice.

EORTC Nomograms and Risk Groups for Predicting Recurrence, Progression, and Disease-specific and Overall Survival in Non-Muscle-invasive Stage Ta-T1 Urothelial Bladder Cancer Patients Treated with 1-3 Years of Maintenance Bacillus Calmette-Guérin.

BACKGROUND: There are no prognostic factor publications on stage Ta-T1 non-muscle-invasive bladder cancer (NMIBC) treated with 1-3 yr of maintenance bacillus Calmette-Guérin (BCG). OBJECTIVE: To determine prognostic factors in NMIBC patients treated with 1-3 yr of BCG after transurethral resection of the bladder (TURB), to derive nomograms and risk groups, and to identify high-risk patients who should be considered for early cystectomy. DESIGN, SETTING, AND PARTICIPANTS: Data for 1812 patients were merged from two European Organization for Research and Treatment of Cancer randomized phase 3 trials in intermediate- and high-risk NMIBC. INTERVENTION: Patients received 1-3 yr of maintenance BCG after TURB and induction BCG. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prognostic factors for risk of early recurrence and times to late recurrence, progression, and death were identified in a training data set using multivariable models and applied to a validation data set. RESULTS AND LIMITATIONS: With a median follow-up of 7.4 yr, 762 patients recurred; 173 progressed; and 520 died, 83 due to bladder cancer (BCa). Statistically significant prognostic factors identified by multivariable analyses were prior recurrence rate and number of tumors for recurrence, and tumor stage and grade for progression and death due to BCa. T1G3 patients do poorly, with 1- and 5-yr disease-progression rates of 11.4% and 19.8%, respectively, and 1- and 5-yr disease-specific death rates of 4.8% and 11.3%. Limitations include lack of repeat transurethral resection in high-risk patients and exclusion of patients with carcinoma in situ. CONCLUSIONS: NMIBC patients treated with 1-3 yr of maintenance BCG have a heterogeneous prognosis. Patients at high risk of recurrence and/or progression do poorly on currently recommended maintenance schedules. Alternative treatments are urgently required. PATIENT SUMMARY: Non-muscle-invasive bladder cancer patients at high risk of recurrence and/or progression do poorly on currently recommended bacillus Calmette-Guérin maintenance schedules, and alternative treatments are urgently required. TRIAL REGISTRATION: Study 30911 was registered with the US National Cancer Institute clinical trials database (protocol ID: EORTC 30911). Study 30962 was registered at ClinicalTrials.gov, number NCT00002990; http://clinicaltrials.gov/ct2/show/record/NCT00002990.

World Urologic Oncology Federation Bladder Cancer Prevention Program: a global initiative.

Bladder cancer is an international public health problem, and the incidence and mortality are closely tied to cigarette smoking. Urologists are, mostly, not involved in smoking cessation with their patients. The World Urologic Oncology Federation has launched a global initiative to incorporate smoking cessation into urological practice. We believe that urologists can readily be influenced to engage their patients, primary care physicians, and communities in bladder cancer prevention. The World Urologic Oncology Federation, a federation of 17 regional/national societies of urologic oncology around the world, is well positioned to lead this global effort. The results would be an extremely cost-effective program, which has the potential to substantially improve the health of the world's population.

The effect of age on the efficacy of maintenance bacillus Calmette-Guérin relative to maintenance epirubicin in patients with stage Ta T1 urothelial bladder cancer: results from EORTC genito-urinary group study 30911.

BACKGROUND: Although maintenance bacillus Calmette-Guérin (BCG) is the recommended treatment in high-risk non-muscle-invasive bladder cancer (NMIBC), its efficacy in older patients is controversial. OBJECTIVE: To determine the effect of age on prognosis and treatment outcome in patients with stage Ta T1 NMIBC treated with maintenance BCG. DESIGN, SETTING, AND PARTICIPANTS: A total of 957 patients with intermediate- or high-risk Ta T1 (without carcinoma in situ) NMIBC were randomized in European Organization for Research and Treatment of Cancer (EORTC) trial 30911 comparing six weekly instillations of epirubicin, BCG, and BCG plus isoniazid followed by three weekly maintenance instillations over 3 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox multivariate proportional hazards regression models were used to assess the relative importance of age for recurrence, progression, overall survival, and NMIBC-specific survival with adjustment for EORTC risk scores. RESULTS AND LIMITATIONS: Overall, 822 eligible patients were included: 546 patients in the BCG with or without INH arms and 276 in the epirubicin arm. In patients treated with BCG with or without INH, 34.1% were >70 yr of age and 3.7% were >80 yr. With a median follow-up of 9.2 yr, patients >70 yr had a shorter time to progression (p=0.028), overall survival (p<0.001), and NMIBC-specific survival (p=0.049) after adjustment for EORTC risk scores in the multivariate analysis. The time to recurrence was similar compared with the younger patients. BCG was more effective than epirubicin for all four end points considered, and there was no evidence that BCG was any less effective compared with epirubicin in patients >70 yr. CONCLUSIONS: In intermediate- and high-risk Ta T1 urothelial bladder cancer patients treated with BCG, patients >70 yr of age have a worse long-term prognosis; however, BCG is more effective than epirubicin independent of patient age. PATIENT SUMMARY: Intravesical bacillus Calmette-Guérin for non-muscle-invasive bladder cancer is less effective in patients >70 yr of age, but it is still more effective than epirubicin. TRIAL REGISTRATION: This study was registered with the US National Cancer Institute clinical trials database (protocol ID: EORTC 30911; http://www.cancer.gov/clinicaltrials/search/view?cdrid=77075&version=HealthProfessional&protocolsearchid=12442243#StudyIdInfo_CDR0000077075).

ICUD-EAU International Consultation on Bladder Cancer 2012: Non-muscle-invasive urothelial carcinoma of the bladder.

CONTEXT: Our aim was to present a summary of the Second International Consultation on Bladder Cancer recommendations on the diagnosis and treatment options for non-muscle-invasive urothelial cancer of the bladder (NMIBC) using an evidence-based approach. OBJECTIVE: To critically review the recent data on the management of NMIBC to arrive at a general consensus. EVIDENCE ACQUISITION: A detailed Medline analysis was performed for original articles addressing the treatment of NMIBC with regard to diagnosis, surgery, intravesical chemotherapy, and follow-up. Proceedings from the last 5 yr of major conferences were also searched. EVIDENCE SYNTHESIS: The major findings are presented in an evidence-based fashion. We analyzed large retrospective and prospective studies. CONCLUSIONS: Urothelial cancer of the bladder staged Ta, T1, and carcinoma in situ (CIS), also indicated as NMIBC, poses greatly varying but uniformly demanding challenges to urologic care. On the one hand, the high recurrence rate and low progression rate with Ta low-grade demand risk-adapted treatment and surveillance to provide thorough care while minimizing treatment-related burden. On the other hand, the propensity of Ta high-grade, T1, and CIS to progress demands intense care and timely consideration of radical cystectomy.

Treatment options available for bacillus Calmette-Guérin failure in non-muscle-invasive bladder cancer.

CONTEXT: Intravesical bacillus Calmette-Guérin (BCG) is a standard conservative treatment for patients with high-risk non-muscle-invasive bladder cancer (NMIBC). Many patients will experience recurrence or progression following BCG and are termed BCG failures. OBJECTIVE: To summarise the current treatment options available for patients with high-risk NMIBC who experience BCG failure. EVIDENCE ACQUISITION: We searched the Medline, Embase, and Cochrane Trials databases for studies of BCG failure using predetermined relevant Medical Subject Heading terms and free text terms. EVIDENCE SYNTHESIS: Radical cystectomy (RC) should be strongly recommended when a patient has been deemed to fail BCG, if the patient is fit and fully informed of the risks, benefits, and quality-of-life issues. RC achieves long-term survival in excess of 90% with ongoing improvements in morbidity. While other salvage intravesical therapies have to be considered oncologically inferior to RC, several options are now available if bladder preservation is the objective. The options can be categorised as immunotherapy, chemotherapy, device-assisted therapy, and sequential combinations of these newer modalities with conventional therapy. Some agents have shown specific promise in BCG-failure patients (eg, gemcitabine, thermochemotherapy, taxane chemotherapy), and some modalities have been shown to be effective only in non-BCG-failure cohorts (eg, electromotive mitomycin). CONCLUSIONS: The definition, prediction, and treatment of BCG failure remain unclear secondary to inconsistent studies and the heterogeneous entity of patients with NMIBC. RC should be the default position upon failing BCG, but if bladder preservation is sought, then several promising intravesical salvage options are available. It will be necessary to individually tailor the management of such patients based on tumour risk and medical profiles. Currently data are still inadequate to formulate definitive recommendations, and larger studies of salvage intravesical agents are urgently required.

Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin, and bacillus Calmette-Guérin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder.

BACKGROUND: Intravesical chemotherapy and bacillus Calmette-Guérin (BCG) reduce the recurrence rate in patients with stage Ta T1 urothelial bladder cancer; however, the benefit of BCG relative to chemotherapy for long-term end points is controversial, especially in intermediate-risk patients. OBJECTIVE: The aim of the study was to compare the long-term efficacy of BCG and epirubicin. DESIGN, SETTING, AND PARTICIPANTS: From January 1992 to February 1997, 957 patients with intermediate- or high-risk stage Ta T1 urothelial bladder cancer were randomized after transurethral resection to one of three treatment groups in the European Organization for Research and Treatment of Cancer Genito-Urinary Group phase 3 trial 30911. INTERVENTION: Patients received six weekly instillations of epirubicin, BCG, or BCG plus isoniazid (INH) followed by three weekly maintenance instillations at months 3, 6, 12, 18, 24, 30, and 36. MEASUREMENTS: End points were time to recurrence, progression, distant metastases, overall survival, and disease-specific survival. RESULTS AND LIMITATIONS: With 837 eligible patients and a median follow-up of 9.2 yr, time to first recurrence (p<0.001), distant metastases (p=0.046), overall survival (p=0.023), and disease-specific survival (p=0.026) were significantly longer in the two BCG arms combined as compared with epirubicin; however, there was no difference for progression. Three hundred twenty-three patients with stage T1 or grade 3 tumors were high risk, and the remaining 497 patients were intermediate risk. The observed treatment benefit was at least as large, if not larger, in the intermediate-risk patients compared with the high-risk patients. CONCLUSIONS: In patients with intermediate- and high-risk stage Ta and T1 urothelial bladder cancer, intravesical BCG with or without INH is superior to intravesical epirubicin not only for time to first recurrence but also for time to distant metastases, overall survival, and disease-specific survival. The benefit of BCG is not limited to just high-risk patients; intermediate-risk patients also benefit from BCG. TRIAL REGISTRATION: This study was registered with the US National Cancer Institute clinical trials database [protocol ID: EORTC-30911]. http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=77075&version=HealthProfessional&protocolsearchid=6540260.

Complications following radical cystectomy for bladder cancer in the elderly.

CONTEXT: The incidence of bladder cancer increases with advancing age. Considering the increasing life expectancy and the increasing proportion of elderly people in the general population, radical cystectomy will be considered for a growing number of elderly patients who suffer from muscle-invasive or recurrent bladder cancer. OBJECTIVE: This article reviews contemporary complication and mortality rates after radical cystectomy in elderly patients and the relationship between age and short-term outcome after this procedure. EVIDENCE ACQUISITION: A literature review was performed using the PubMed database with combinations of the following keywords cystectomy, elderly, complications, and comorbidity. English-language articles published in the year 2000 or later were reviewed. Papers were included in this review if the authors investigated any relationship between age and complication rates with radical cystectomy for bladder cancer or if they reported complication rates stratified by age groups. EVIDENCE SYNTHESIS: Perioperative morbidity and mortality are increased and continence rates after orthotopic urinary diversion are impaired in elderly patients undergoing radical cystectomy. Complications are frequent in this population, particularly when an extended postoperative period (90 d instead of 30 d) is considered. CONCLUSIONS: Although age alone does not preclude radical cystectomy for muscle-invasive or recurrent bladder cancer or for certain types of urinary diversion, careful surveillance is required, even after the first 30 d after surgery. Excellent perioperative management may contribute to the prevention of morbidity and mortality of radical cystectomy, supplementary to the skills of the surgeon, and is probably a reason for the better perioperative results obtained in high-volume centers.

Retroperitoneal lymph node dissection (RPLD) in conjunction with nephroureterectomy in the treatment of infiltrative transitional cell carcinoma (TCC) of the upper urinary tract: impact on survival.

OBJECTIVES: To evaluate the prognostic impact of retroperitoneal lymph node dissection (RPLD) performed during nephroureterectomy on time to recurrence and survival in patients with infiltrative transitional cell carcinoma (TCC) of the upper urinary tract. METHODS: The charts of 82 patients with T2-T4 TCC of the upper tract were retrospectively reviewed. The median patient age was 67.7 yr. Seventy-nine patients underwent nephroureterectomy and three had partial nephrectomy. Forty patients (48.8%) had RPLD with removal of more than five nodes after nephroureterectomy (group 1), whereas 42 (51.2%) had nephroureterectomy only (group 2). Median follow-up was 64.7 mo. The prognostic role of RPLD, T (2 vs. 3-4), G (2 vs. 3), N (0 vs. 1-2 vs. x), age (<65 vs. >65 yr) and sex on time to recurrence and survival were evaluated. RESULTS: Median time to recurrence and overall survival were 51.2 and 52.5 mo, respectively, in group 1 and 18.5 and 21.2 mo in group 2. Univariate analysis demonstrated that RPLD and T and N status were significantly related both to time to recurrence (p=0.009, 0.008, and 0.009, respectively) and survival (p=0.000006, 0.003, and 0.003). When analyzed using the Cox proportional hazard model, RPLD and T category were the only two factors demonstrating independent significance on overall survival (p=0.004 and 0.008). CONCLUSIONS: The results indicate a possible curative role of RPLD in the treatment of patients with infiltrative TCC of the upper urinary tract. Further randomized trials are needed to confirm these results.

The use of local anesthesia with N-DO injector (Physion) for transurethral resection (TUR) of bladder tumors and bladder mapping: preliminary results and cost-effectiveness analysis.

OBJECTIVE: We evaluated feasibility of TUR of Ta-T1 TCC of the bladder or bladder mapping under local anesthesia using a Physion endoinjector to see if correct tumor staging was possible, to check patient tolerability, and to analyze cost-effectiveness. METHODS: Thirty patients with bladder tumors and 10 patients with hematuria and/or doubtful cytologies were treated in a day hospital setting. TUR or biopsies were performed after injecting lidocaine into the outer area of the lesion in the bladder at 2-3 sites under the mucosa. A single injection per biopsy site was necessary for bladder mapping. We evaluated tolerability using the VAS questionnaire. Cost analysis considered length of hospital stay, number of anesthesiological procedures, and complications. RESULTS: The stage and grade after TUR were 19 TaG1-2, 10 T1G2, and 1 papillary hyperplasia. After bladder mapping, 5 patients had CIS and 5 had inflammation. Sixty percent of patients had no or mild pain, 30% moderate pain requiring light sedation or analgesia, and 10% severe pain requiring spinal or general anesthesia. The mean hospital stay was 9h. Four of 40 patients complained of macroscopic hematuria; one was readmitted to the ward. This procedure saved 1097.07 euros per case and 36 anesthesiological procedures were avoided. CONCLUSIONS: This is a simple, safe, cost-effective technique, allowing TUR of bladder tumors and bladder mapping in 60% of patients and, with light sedation or analgesia, in 90% of patients, with a low complication rate. Tumor staging was correct in 90% of cases. The mean hospital stay was 9h.