Transurethral Resection of Non–muscle-invasive Bladder Cancer

Transurethral resection of the bladder (TURB) is the initial and critical step in the management of bladder tumours. The aim of the procedure is to establish the histologic diagnosis, determine the tumour stage and grade, and achieve complete removal of papillary non–muscle-invasive tumours. Although TURB is a frequently performed procedure, its results are limited by the high recurrence rate and by the risk of tumour understaging. The major prerequisite for optimal outcomes is a systematically and meticulously performed procedure by a well-trained urologist. Smaller tumours can be resected en bloc; tumours >1 cm should be resected separately in fractions. Deep resection, including the detrusor muscle, is essential for correct staging. The biopsy should be taken from all areas suggestive of carcinoma in situ (CIS), and biopsies from normal-looking mucosa are recommended only in patients with positive cytology or non-papillary tumours. TURB should be performed with modern equipment, including new telescopes and video systems. Moreover, urologists should be aware of promising innovations, including new imaging techniques, and their possible benefits.Re-TUR can improve recurrence-free survival (RFS) and tumour staging. It is recommended in any patient with a T1 or high-grade tumour at initial resection and when the pathologist has reported that the specimen contained no muscle. It should also be considered in cases where the urologist is not sure that the initial resection was complete, especially in extensive and multiple tumours.     

The Role of Bacillus Calmette-Guérin in the Treatment of Non–Muscle-Invasive Bladder Cancer

Context

Bacillus Calmette-Guérin (BCG) remains the most effective intravesical treatment for non–muscle-invasive bladder cancer (NMIBC), but the clinical development of BCG has been accompanied by controversy. Recent publications have called into question a number of aspects related to its use.

Objective

To review the current clinical role of BCG in NMIBC, focusing on efficacy and tolerability as primary objectives and on strategies to predict response and decrease toxicity as secondary objectives.

Evidence acquisition

We performed a systematic literature search of published articles in PubMed, Embase, and the Cochrane Central Register of Controlled Trials databases for the period from 1976 to November 2008. The following “free text” combination was used in the first instance: “BCG and intravesical and bladder cancer.” Further free text searches were performed by separately adding the following keywords to the combination “BCG and intravesical”: survival, progression, recurrence, maintenance, dosing, toxicity, tolerability, side effects, prognostic factors.

Evidence synthesis

BCG is the most effective intravesical agent for preventing NMIBC recurrence, but its role in disease progression remains controversial. In intermediate-risk NMIBC, the superiority of BCG over chemotherapy is well established for disease recurrence but not for progression and needs to be balanced against higher toxicity. With regard to high-risk NMIBC, there is sufficient evidence to show that BCG is the most effective treatment of carcinoma in situ for ablation, disease-free interval, and progression, but the impact of BCG on the natural history of T1G3 tumors relies on a low level of evidence. Maintenance remains crucial for efficacy. The dose can be safely and effectively reduced to decrease its toxicity, which is slightly greater than chemotherapy.

Conclusions

BCG should still be viewed as the most effective intravesical agent, but its role in the progression of papillary tumors needs to be clarified. BCG remains an alternative to intravesical chemotherapy in intermediate-risk NMIBC, and it is recommended as the standard of care for high-risk NMIBC.     

Intravesical Instillation Treatment of Non–muscle-invasive Bladder Cancer

Bacillus Calmette-Guérin (BCG) is a proven and valuable adjunct to transurethral resection (TUR) for decreasing recurrence and progression of non–muscle-invasive bladder cancer (NMIBC). The European Association of Urology (EAU) and American Urological Association (AUA) have similar recommendations for induction and maintenance treatment in patients based on clinical and pathologic risk factors. To most effectively treat this disease, clinicians must be aware of the risk factors for treatment failure, strategies to deal with failures and BCG intolerance, and the appropriate threshold to proceed with radical cystectomy (RC). Combination, alternative, and multimodal intravesical treatments for patients with BCG failure have arisen in recent years, and the outcomes data are reviewed here.     

Early Single Instillation Chemotherapy Is Very Beneficial and Should Be the Standard Approach in Non–Muscle-Invasive Bladder Cancer

ContextIt has been demonstrated that an early single instillation of chemotherapy significantly reduces the recurrence rate of patients with non–muscle-invasive bladder cancer (NMIBC); however, the clinical relevance of recurrence reduction has recently been questioned.ObjectiveIn this paper we review the current evidence on the statistical and clinical relevance of an early single instillation of chemotherapy in patients with NMIBC.Evidence acquisitionThis paper was based on a presentation given at the “Early single instillation” session at the 6th Meeting of the European Society of Oncological Urology (ESOU). This presentation was based mainly on review articles dealing with the administration of an early single chemotherapy agent as well as the early or delayed administration of a full chemotherapy scheme in patients with NMIBC.Evidence synthesisAn early single immediate administration, alone or associated with a full chemotherapy scheme, is effective in reducing recurrences in patients at intermediate and high risk for recurrence. Benefits include (1) decreases in requirements for transurethral resection of the bladder (TURB) and in potential complications; (2) a reduction in adjuvant intravesical chemotherapy for all initial patients as well as for patients who need adjuvant therapies after recurrence (in these cases, full intravesical chemotherapy scheme or bacillus Calmette-Guérin (BCG) plus maintenance will be spared); (3) cost savings, as all or the vast majority of recurrent patients need overnight procedures and adjuvant therapies in exchange for nothing or only one more chemotherapy instillation, if BCG was required; and (4) lower anxiety for patients who are likely to develop recurrence.ConclusionsAn early single instillation of chemotherapy reduces TURB requirements, adjuvant therapies, costs, and anxiety, with a minimal increase in toxicity and with slight intensity, if some precautions are taken. It should be considered the standard approach for patients with NMIBC.     

Maintenance Bacillus Calmette-Guérin: The Standard of Care for the Prophylaxis and Management of Intermediate- and High-Risk Non–Muscle-Invasive Bladder Cancer

ContextAlthough bacillus Calmette-Guérin (BCG) is currently regarded as the most effective treatment available for the management of non–muscle-invasive bladder cancer (NMIBC), maintenance BCG is underutilised and debate still remains as to whether the routine use of maintenance therapy is required for optimal outcomes.ObjectiveTo review evidence supporting the need for maintenance BCG and provide practical strategies for improving both patient and physician compliance with maintenance regimens.Evidence acquisitionData from immunologic studies, animal studies, randomised clinical trials, and meta-analyses were reviewed during a satellite symposium at the 25th Annual European Association of Urology (EAU) Congress, held in Barcelona, Spain, in April 2010.Evidence synthesisThree well-designed, long-term clinical trials and various meta-analyses have shown maintenance BCG to be significantly superior to intravesical chemotherapy and induction therapy alone in reducing recurrence, progression, and mortality in patients with intermediate- and high-risk NMIBC. Despite these findings, BCG therapy is underutilised. Experts have questioned whether this is solely due to BCG-associated adverse events or whether other patient- and physician-related factors, such as lack of patient knowledge and physician attitudes, may affect utilisation and adherence to BCG therapy.ConclusionsRecent evidence has addressed controversies surrounding the use of maintenance BCG. Maintenance BCG should now be considered the “gold standard” therapy for the prophylaxis and management of intermediate- and high-risk NMIBC. Although BCG-associated adverse events are generally considered to be the primary reason for poor adherence, these adverse events can be prevented and successfully managed in most patients. Furthermore, other patient- and physician-related factors need to be addressed to help promote adherence to maintenance BCG and optimise outcomes in patients with NMIBC.     

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.     

Immediate Post–Transurethral Resection of Bladder Tumor Intravesical Chemotherapy Prevents Non–Muscle-invasive Bladder Cancer Recurrences: An Updated Meta-analysis on 2548 Patients and Quality-of-Evidence Review

Context

Non–muscle-invasive bladder cancer (NMIBC) commonly recurs, requiring invasive and costly transurethral resection of bladder tumor (TURBT). A meta-analysis of seven trials published in 2004 demonstrated that intravesical chemotherapy (IVC) following TURBT reduces recurrences. Despite European Association of Urology endorsement, adoption of this practice has been modest.

Objective

To investigate whether immediate postoperative IVC prolongs the recurrence-free interval (RFI) and early recurrences (ERs) in light of new trial data and to explore the quality of evidence supporting its use.

Evidence acquisition

A systematic literature review of random controlled trials (RCTs) published before March 2013 was performed using the Medline, Embase, and Cochrane databases. Trials examining NMIBC recurrence for adults receiving IVC immediately following TURBT were included. RFI was estimated by hazard ratio (HR), and ER was estimated by absolute risk reduction (ARR) of recurrences within 1 yr of TURBT. Both outcomes were synthesized using random-effects models. Risk of bias was assessed using the Cochrane Collaboration risk-of-bias tool, and quality of evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation system.

Evidence synthesis

Thirteen studies with 2548 patients were included. IVC prolonged RFI by 38% (HR: 0.62; 95% confidence interval [CI], 0.50–0.77; p < 0.001; I²: 69%), and ERs were 12% less likely in the intervention population (ARR: 0.12; 95% CI, −0.18 to −0.06; p < 0.001, I²: 0%). The number needed to treat to prevent one ER was 9 (95% CI, 6–17 patients). There was high risk of bias present in 12 of 13 publications. Quality of evidence for RFI was very low and low for ERs.

Conclusions

Our updated meta-analysis supports that IVC prolongs RFI and reduces ERs of NMIBC when administered immediately after TURBT. However, contemporary methodology suggests low evidence quality for examined outcomes. Thus RCTs with careful randomization and blinding are still warranted to clarify the usefulness of immediate postoperative IVC in this population.     

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.     

EAU Guidelines on Non–Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2013

Context

The first European Association of Urology (EAU) guidelines on bladder cancer were published in 2002 [1]. Since then, the guidelines have been continuously updated.

Objective

To present the 2013 EAU guidelines on non–muscle-invasive bladder cancer (NMIBC).

Evidence acquisition

Literature published between 2010 and 2012 on the diagnosis and treatment of NMIBC was systematically reviewed. Previous guidelines were updated, and the levels of evidence and grades of recommendation were assigned.

Evidence synthesis

Tumours staged as Ta, T1, or carcinoma in situ (CIS) are grouped as NMIBC. Diagnosis depends on cystoscopy and histologic evaluation of the tissue obtained by transurethral resection (TUR) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TUR is essential for the patient's prognosis. Where the initial resection is incomplete, where there is no muscle in the specimen, or where a high-grade or T1 tumour is detected, a second TUR should be performed within 2–6 wk. The risks of both recurrence and progression may be estimated for individual patients using the EORTC scoring system and risk tables. The stratification of patients into low-, intermediate-, and high-risk groups is pivotal to recommending adjuvant treatment. For patients with a low-risk tumour, one immediate instillation of chemotherapy is recommended. Patients with an intermediate-risk tumour should receive one immediate instillation of chemotherapy followed by 1 yr of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or by further instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1–3 yr is indicated. In patients at highest risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is recommended in BCG-refractory tumours. The long version of the guidelines is available from the EAU Web site: http://www.uroweb.org/guidelines/.

Conclusions

These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice.

Patient summary

The EAU Panel on Non-muscle Invasive Bladder Cancer released an updated version of their guidelines. Current clinical studies support patient selection into different risk groups; low, intermediate and high risk. These risk groups indicate the likelihood of the development of a new (recurrent) cancer after initial treatment (endoscopic resection) or progression to more aggressive (muscle-invasive) bladder cancer and are most important for the decision to provide chemo- or immunotherapy (bladder installations). Surgical removal of the bladder (radical cystectomy) should only be considered in patients who have failed chemo- or immunotherapy, or who are in the highest risk group for progression.     

Maintenance Bacillus Calmette-Guérin Treatment of Non–muscle-invasive Bladder Cancer: A Critical Evaluation of the Evidence

Context

Despite the effectiveness of bacillus Calmette-Guérin (BCG) therapy in non–muscle-invasive bladder cancer (NIMBC) to delay recurrence and disease progression, the evidence supporting maintenance treatment and its optimal duration is unkown.

Objective

The purposes of this paper are to critically review the evidence supporting the use of maintenance BCG after an initial series of induction instillations and to illustrate the factors contributing to current dilemmas in establishing the optimal duration of BCG treatment.

Evidence acquisition

The following terms were used in Medline database searches for original articles published before February 1, 2013: bladder cancer, urothelial cancer, bacillus Calmette-Guérin, maintenance, and induction. All randomized controlled trials and meta-analyses, including those based on indirect comparisons, were evaluated.

Evidence synthesis

Seven randomized studies compared induction BCG plus maintenance to induction alone, with or without retreatment with BCG on recurrence. All but one of these studies were underpowered and the largest study used a broad, composite end point: worsening-free survival. Seven meta-analyses have been conducted, three of which included data from observational cohort studies. They demonstrated the benefit of maintenance BCG to reduce disease recurrence and delay progression compared to various control groups; however, the analyses were based on suboptimal data. Although there is new evidence that 1 yr of maintenance BCG is sufficient treatment in intermediate-risk patients, the optimal duration of BCG maintenance remains unknown. A new randomized trial is proposed, which includes induction BCG with retreatment on recurrence as a control arm, to study this question.

Conclusions

The optimal duration of BCG treatment in patients with NMIBC remains unknown and should be the subject of further studies. We recommend that in addition to 3 yr of maintenance BCG, guideline panels also include 1 yr of therapy and induction BCG with retreatment on recurrence as a possible treatment options for patients with NMIBC, albeit with a lower level of evidence and grade of recommendation.