Comparative Outcomes of Primary,Recurrent, and Progressive High-risk Non–muscle-invasive Bladder Cancer

Background

The treatment of high-risk non–muscle-invasive bladder cancer (BCa) is problematic given the variable natural history of the disease. Few reports have compared outcomes for primary high-risk tumours with those that develop following previous BCas (relapses). The latter represent a self-selected cohort, having failed previous treatments.

Objective

To compare outcomes in patients with primary, progressive, and recurrent high-risk non–muscle-invasive BCa.

Design, setting, and participants

We identified all patients with primary and relapsing high-risk BCa tumours at our institution since 1994. Relapses were divided into progressive (previous low- or intermediate-risk disease) and recurrent (previous high-risk disease) cancers.

Outcome measurements and statistical analysis

Relationships with outcome analysed using multivariable Cox regression and log-rank analysis.

Results and limitations

We identified 699 primary, 110 progressive, and 494 recurrent high-risk BCa tumours in 809 patients (average follow-up: 59 mo [interquartile range: 6–190]). Muscle invasion occurred most commonly in recurrent (23%) tumours, when compared to progressive (20%) and primary (14.6%) cohorts (log rank p < 0.001). Disease-specific mortality (DSM) occurred more frequently in patients with recurrent (25.5%) and progressive (24.6%) tumours compared to primary disease (19.2%; log rank p = 0.006). Other-cause mortality was similar in all groups (log rank p = 0.57), and overall mortality was highest in the progressive cohort (62%) compared with the recurrent (58%) and primary groups (54%; log rank p < 0.001). In multivariable analysis, progression and DSM were predicted by tumour grouping (hazard ratio [HR]: >1.15; p < 0.026), stage (HR: >1.30; p < 0.001), and patient age and sex (HR: >1.03; p < 0.037). Carcinoma in situ was only predictive of outcome in primary tumors. Limitations include retrospective design and limited details regarding bacillus Camille-Guérin use.

Conclusions

Patients with relapsing, high-risk, BCa tumors have higher progression, DSM, and overall mortality rates than those with primary cancers. The use of bladder-sparing strategies in these patients should approached cautiously. Carcinoma in situ has little predicative role in relapsing, high-risk, BCa tumors.     

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.     

Impact of Smoking and Smoking Cessation on Oncologic Outcomes in Primary Non–muscle-invasive Bladder Cancer

Background

Cigarette smoking is the best-established risk factor for urothelial carcinoma (UC) development, but the impact on oncologic outcomes remains poorly understood.

Objective

To analyse the effects of smoking status, cumulative exposure, and time from smoking cessation on the prognosis of patients with primary non–muscle-invasive bladder cancer (NMIBC).

Design, setting, and participants

We collected smoking data from 2043 patients with primary NMIBC. Smoking variables included smoking status, average number of cigarettes smoked per day (CPD), duration in years, and time since smoking cessation. Lifetime cumulative smoking exposure was categorised as light short term (≤19 CPD, ≤19.9 yr), light long term (≤19 CPD, ≥20 yr), heavy short term (≥20 CPD, ≤19.9 yr) and heavy long term (≥20 CPD, ≥20 yr). The median follow-up in this retrospective study was 49 mo.

Interventions

Transurethral resection of the bladder with or without intravesical instillation therapy.

Outcome measurements and statistical analysis

Univariable and multivariable logistic regression and competing risk regression analyses assessed the effects of smoking on outcomes.

Results and limitations

There was no difference in clinicopathologic factors among never (24%), former (47%), and current smokers (29%). Smoking status was associated with the cumulative incidence of disease progression in multivariable analysis (p = 0.003); current smokers had the highest cumulative incidences. Among current and former smokers, cumulative smoking exposure was associated with disease recurrence (p < 0.001), progression (p < 0.001), and overall survival (p < 0.001) in multivariable analyses that adjusted for the effects of standard clinicopathologic factors and smoking status; heavy long-term smokers had the worst outcomes, followed by light long-term, heavy short-term, and light short-term smokers. Smoking cessation >10 yr reduced the risk of disease recurrence (hazard ratio [HR]: 0.66; 95% confidence interval [CI], 0.52–0.84; p < 0.001) and progression (HR: 0.42; 95% CI, 0.22–0.83; p = 0.036) in multivariable analyses. The study is limited by its retrospective nature.

Conclusions

Smoking status and a higher cumulative smoking exposure are associated with worse prognosis in patients with NMIBC. Smoking cessation >10 yr abrogates this detrimental effect. These findings underscore the need for integrated smoking cessation and prevention programmes in the management of NMIBC patients.     

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.     

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.     

Photodynamic Diagnosis in Non–Muscle-Invasive Bladder Cancer

ContextAlthough crucial to optimal management, transurethral resection of the bladder (TURB) techniques and results are highly heterogeneous in Europe, due in part to site-specific variations in the detection of cancer foci.Optimizing detection is of tantamount importance. Techniques were designed that took advantage of the ubiquitous observation that cancer cells exhibit abnormal heme metabolism resulting in increased intracellular concentrations of protoporphyrin IX (PPIX) after topical or systemic application of heme precursors. In the bladder, the excitation of PPIX by blue light (380–450 nm) induced a faint red (640-nm) fluorescence of cancer cells that gave rise to the concept of photodynamic diagnosis (PDD) in non–muscle-invasive bladder cancer (NMIBC).Evidence acquisitionThis paper is based on a presentation at the 2010 meeting of the European Society of Oncological Urology. A structured comprehensive literature review was performed. The latest version of the European Association of Urology (EAU) guidelines on NMIBC was also accessed.Evidence synthesisCurrent diagnosis of NMIBC is based on white light (WL) cystoscopy. The current literature on NMIBC suggests that there is significant room for improvement in that setting. One solution was to augment the signal-to-noise ratio of suspicious lesions versus normal mucosa by highlighting cancer cells either indirectly, through the alteration in their stromal support such as in narrow-band imaging, or directly, as in Hexvix-based PDD. Hexvix is now available in most European countries and use is steadily increasing.Recent evidence at the molecular level has confirmed clinicians’ suspicions that NMIBC is a very heterogeneous condition. Sylvester et al identified six independent risk factors (number of tumors, tumor size, prior recurrence rate, T category, carcinoma in situ [CIS], and grade), the combination of which was predictive of progression to muscle-invasive state and of recurrence. As recommended by the EAU guidelines, these factors are used to stratify patients into risk groups that drive treatment and follow-up modalities.In the setting of low-risk NMIBC, three objectives can be addressed by Hexvix PDD—detection, quality control of resection, confirmation of the absence of CIS—with the ultimate objective of reducing the recurrence rate and related costs. Hexvix PDD increases the rate of detection of NMIBC by 20%. It is a valuable tool in controlling the quality of resection at the end of TURB and was recently shown to reduce the recurrence rate at 9 mo by 21%, which is anticipated to offset the supplementary costs for equipment and Hexvix within the first year of follow-up.Regarding high-risk NMIBC, Hexvix PDD facilitates the detection of CIS and might improve treatment results by reallocating the case to a higher level of risk, requesting more intensive treatment (eg, bacillus Calmette-Guérin), and by improving the quality of resection. Mixed results were observed in control resection, where Hexvix PDD can be used to detect additional lesions such as associated CIS when the first TURB was conducted under WL.Five endoscopic criteria (smooth of slightly raised appearance, intensity [mild or intense], homogeneous or irregular fluorescence, well-delineated or indistinct limits, detachment of the fluorescent mucosa by the loop) were prospectively recorded to assess their respective value in detecting CIS among the wide array of flat PDD-positive lesions. We showed that a slightly raised appearance and detachment of fluorescence by gentle stroking with the loop were associated with the diagnostic of CIS. This new semiology could refine the level of suspicion of PDD-positive flat lesions to reduce the number of false-positive results.ConclusionsIn low-risk NMIBC, Hexvix PDD helps to avoid overlooking small preexisting papillary lesions and to optimize resection. It was recently shown to reduce 9-mo recurrence rates by 20%, which is anticipated to be sufficient to offset the supplementary costs in equipment and drugs. In high-risk NMIBC, Hexvix PDD can be of value in restaging TURB to detect additional lesions such as associated CIS when the first TURB was conducted under WL. Finally, the high rate of false-positive results for flat PDD-positive lesions can be controlled by implementing simple semiotic analysis and focusing on CIS-associated characters such as slightly raised appearance and detachment of fluorescence by gentle stroking with the loop (pink veil sign).     

Photodynamic Diagnosis of Non–muscle-invasive Bladder Cancer with Hexaminolevulinate Cystoscopy: A Meta-analysis of Detection and Recurrence Based on Raw Data

Background

Studies on hexaminolevulinate (HAL) cystoscopy report improved detection of bladder tumours. However, recent meta-analyses report conflicting effects on recurrence.

Objective

To assess available clinical data for blue light (BL) HAL cystoscopy on the detection of Ta/T1 and carcinoma in situ (CIS) tumours, and on tumour recurrence.

Design, setting, and participants

This meta-analysis reviewed raw data from prospective studies on 1345 patients with known or suspected non–muscle-invasive bladder cancer (NMIBC).

Intervention

A single application of HAL cystoscopy was used as an adjunct to white light (WL) cystoscopy.

Outcome measurements and statistical analysis

We studied the detection of NMIBC (intention to treat [ITT]: n = 831; six studies) and recurrence (per protocol: n = 634; three studies) up to 1 yr. DerSimonian and Laird's random-effects model was used to obtain pooled relative risks (RRs) and associated 95% confidence intervals (CIs) for outcomes for detection.

Results and limitations

BL cystoscopy detected significantly more Ta tumours (14.7%; p < 0.001; odds ratio [OR]: 4.898; 95% CI, 1.937–12.390) and CIS lesions (40.8%; p < 0.001; OR: 12.372; 95% CI, 6.343–24.133) than WL. There were 24.9% patients with at least one additional Ta/T1 tumour seen with BL (p < 0.001), significant also in patients with primary (20.7%; p < 0.001) and recurrent cancer (27.7%; p < 0.001), and in patients at high risk (27.0%; p < 0.001) and intermediate risk (35.7%; p = 0.004). In 26.7% of patients, CIS was detected only by BL (p < 0.001) and was also significant in patients with primary (28.0%; p < 0.001) and recurrent cancer (25.0%; p < 0.001). Recurrence rates up to 12 mo were significantly lower overall with BL, 34.5% versus 45.4% (p = 0.006; RR: 0.761 [0.627–0.924]), and lower in patients with T1 or CIS (p = 0.052; RR: 0.696 [0.482–1.003]), Ta (p = 0.040; RR: 0.804 [0.653–0.991]), and in high-risk (p = 0.050) and low-risk (p = 0.029) subgroups. Some subgroups had too few patients to allow statistically meaningful analysis. Heterogeneity was minimised by the statistical analysis method used.

Conclusions

This meta-analysis confirms that HAL BL cystoscopy significantly improves the detection of bladder tumours leading to a reduction of recurrence at 9–12 mo. The benefit is independent of the level of risk and is evident in patients with Ta, T1, CIS, primary, and recurrent cancer.     

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.