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

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1 EUROPEAN UROLOGY 63 (2013) available at journal homepage: Platinum Priority Urothelial Cancer Editorial by J. Alfred Witjes on pp of this issue Comparative Outcomes of Primary, Recurrent, and Progressive High-risk Non muscle-invasive Bladder Cancer Francis Thomas a,y, Aidan P. Noon a,y, Naomi Rubin a, John R. Goepel b, James W.F. Catto a, * a The Academic Urology Unit and Institute for Cancer Studies, University of Sheffield, Sheffield, UK; b Department of Pathology, Royal Hallamshire Hospital, Sheffield, UK Article info Article history: Accepted August 28, 2012 Published online ahead of print on September 5, 2012 Keywords: Bladder cancer High-risk CIS Outcome Prognosis Abstract 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 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 bladdersparing strategies in these patients should approached cautiously. Carcinoma in situ has little predicative role in relapsing, high-risk, BCa tumors. Crown Copyright # 2012 Published by Elsevier B.V. on behalf of European Association of Urology. All rights reserved. y These authors contributed equally to this work. * Corresponding author. Institute for Cancer Studies, G Floor, The Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK. Tel. +44 (0) ; Fax: +44 (0) addresses: j.catto@sheffield.ac.uk, jimcatto@yahoo.co.uk (J.W.F. Catto) /$ see back matter Crown Copyright # 2012 Published by Elsevier B.V. on behalf of European Association of Urology. All rights reserved.

2 146 EUROPEAN UROLOGY 63 (2013) Introduction Bladder cancer (BCa) is the fifth most common tumour in the Western world and one of the most expensive to manage [1,2]. The histologic subtype of the majority of tumours is urothelial cell carcinoma (UCC). Non muscle-invasive (NMI) UCC accounts for the majority of cancers and may be subdivided into tumours with low, intermediate, or high risk of progression to invasion or metastases [3,4]. High-risk NMI BCas (hereafter referred to as high risk) represent around one-third of the disease burden and include those with either poor cellular differentiation (grade 3), lamina propria invasion (pt1), or carcinoma in situ (CIS). The incidence of progression to muscle invasion varies considerably for highrisk tumours (eg, 25 75% [3]), making the clinical care of affected patients difficult [5]. Progression marks a dramatic increase in the risk of metastasis and disease-specific mortality (DSM) [6]. Consequently, the clinical care of patients with high-risk disease is directed at preventing or the early detection of muscle invasion. To date, various authors have reported the long-term outcome of high-risk tumours [7,8]. However, many reports are limited in size, contain heterogeneous populations, or have short follow-up. Furthermore, few authors have distinguished the outcomes for primary versus relapsing high-risk tumours [9,10]. The latter represent a selected cohort of cancers that have recurred despite treatment and so may have a worse outcome than de novo disease. With this is mind, we undertook a retrospective analysis to compare the outcomes for primary and relapsing high-risk BCas. We stratified relapsing disease according to the risk of previous BCas and aimed to define the comparative outcome for such tumours within a large series managed at a single institution. We hypothesised that relapsing tumours are more aggressive than primary cancers and so may require different therapeutic strategies. Furthermore, relapsing tumours may differ in behaviour between those arising in patients with previous low/intermediate- and high-risk BCas. 2. Materials and Methods 2.1. Patients and tumours The Royal Hallamshire Hospital (RHH) provides the sole urologic service for the city of Sheffield, UK (approximately people). Patients from this community attend and remain under the care of this hospital for treatment and surveillance of urologic diseases. As detailed previously, we created a database of all patients with BCa treated at our institution between 1 January 1994 to 31 December 2009 [11]. To do this, we matched hospital billing (date and type of visit), pathologic, pharmacy (intravesical chemotherapy), and death certification records from the Trent Cancer Registry for all patients with histologically proven BCa. Two people separately merged data streams, created parallel databases, and compared/resolved data discrepancies by case review in committee Tumour classification and selection criteria Histologic staging and grading of UCC was performed by dedicated uropathologists using the TNM and 1973 World Health Organisation classifications. We identified all tumours with high-risk features, which we defined as those with any one of poor differentiation (grade 3), lamina propria invasion (T1), or the presence of any CIS. We stratified these into (1) primary tumours (first BCa is high risk), (2) progressive tumours in patients with previous non high-risk BCas, and (3) recurrent high-risk tumours in patients with one or more previous high-risk tumours. To ensure we were studying NMI cancers, we excluded patients who developed muscle invasion within 6 mo of a new diagnosis (ie, patients with first primary tumour). We also excluded patients with <6 mo follow-up and those referred for a second opinion or treatment from another hospital (this group comprised tumours first identified in radical cystectomy specimens) Treatment of tumours All patients underwent cystoscopic surveillance after the initial resection according to evidence-based regimens [12]. High-risk tumours were managed by local resection, intravesical bacillus Calmette-Guérin (BCG), and rigid cystoscopic surveillance for their first check and during BCG use. During the period evaluated, the benefits from early reresection for high-risk tumours became apparent. Re-resection was introduced as standard practice in Patients were offered either induction or maintenance BCG as first-line treatment, according to clinician preference. Radical cystectomy was performed for muscleinvasive disease, for BCG-refractory cancers at the surgeon s discretion, or for patients with severe urinary symptoms Statistical analysis The primary outcomes were progression-free survival and DSM. Secondary outcomes were NMI tumour recurrence (defined as low/intermediate and high risk [any grade 3, any pt1, any CIS]), other-cause mortality (OCM) (ie, death not from BCa), and overall survival. Progression was defined as a new tumour with pathologically proven muscle invasion or radiologically proven metastases. Cause of death was identified from death certificates. DSM was defined when BCa was the main attributable cause of death (part 1a or 1b of the UK death certificate) or suggested from case notes (eg, pathologic or radiologic evidence of metastases or tumour progression, palliative treatment prior to death). OCM was defined in patients where the death certificate attributed a non-bca cause of death and this was supported by pathologic or case note review. Patients with an equivocal cause of death without postmortem proof (eg, renal failure with a prior history of UCC) were excluded from analysis. Associations between clinicopathologic features and subsequent bladder behaviour were examined using univariable and stepwise multivariable Cox proportional hazards regression models (SPSS v.14.0; IBM Corp., Armonk, NY, USA). Outcomes with respect to time were plotted using the Kaplan-Meier method and compared using a log-rank test. All statistical tests were two tailed and significance defined as p < Results 3.1. Patient and tumour characteristics We identified 951 primary, 110 progressive, and 494 recurrent high-risk tumours (total: 1555) in 1061 patients (Fig. 1). Of patients with primary tumours, we excluded 72 who had muscle invasion within 6 mo of diagnosis, 117 with insufficient follow-up, 54 from other hospitals, and 9 with non-ucc histology, leaving a total of 699 primary tumours in 699 patients (mean follow-up: 59 mo [interquartile range (IQR): 6 190]). We identified 110 patients with progressive high-risk tumour (mean follow-up: 59.2 mo [IQR: 7 179]) and 318 patients with 494 recurrent high-risk tumours

3 [(Fig._1)TD$FIG] EUROPEAN UROLOGY 63 (2013) and no re-resection in 678 (52%). When combined, 1193 (91.6%) samples had either detrusor muscle present in the tumour specimen or the patient underwent re-resection within 6 mo without finding muscle invasion, or both, to confirm a diagnosis of NMI disease. Comparisons among the three groups (primary, progressive, and recurrent high-risk BCas) revealed statistical differences among the tumours but not the patients (Table 1). For example, progressive tumours were less often of high grade (52% vs 72% primary and 86% recurrent; p < ), and primary tumours were more advanced than the other cancers (68% pt1 vs 60% progressive and 45% recurrent; p < 0.001). Primary tumours were also larger (assessed by transurethral resection specimen weight) and had more histologic variants of UCC than the other cancers. Recurrent high-risk tumours had the highest incidence of CIS (53% vs 31% primary and 30% progressive; p < 0.001) Comparative outcomes of primary, progressive, and recurrent high-risk tumour behaviour Fig. 1 The grouping and exclusion strategy for tumours within this study. MIBC = muscle-invasive bladder cancer; RHH = Royal Hallamshire Hospital; UCC = urothelial cell carcinoma. (range: 1 8 per patient; mean follow up: 59.4 mo [IQR: 6 188]). By the design of our selection, all progressive and recurrent tumours were suitable for inclusion (ie, all had UCC because the previous tumours were UCC), all patients were under the care of our unit (previous tumours had been resected at RHH), all had sufficient follow-up (follow-up was used to identify cases), and none had muscle invasion (as excluded from selection). Analysis of these 1303 tumours in 809 patients revealed no detrusor muscle in 239 (18.3%) [(Fig._2)TD$FIG] There were significant differences in the outcomes of the patients within the three cohorts (Tables 2 and 3, Figs. 2 and 3). For example, patients with progressive tumours had the highest rate of low/intermediate-risk recurrence (n = 43 [39.1%]; 95% confidence interval [CI], %) than patients in the primary cohort (n = 147 [21.0%]; 95% CI, %) and in the recurrent cohort (n = 76 [15.4%]; 95% CI, %) (log-rank test; p < 0.001). Patients with progressive tumours also had the lowest rate of high-risk NMI recurrence (n = 31[28.2%]; 95% CI, %) versus the primary cohort (n = 273[39.1%]; 95% CI, %) and the recurrent cohort (n = 238 [48.2%]; 95% CI, %) (log-rank test; p < 0.004). Progression to muscle invasion occurred most commonly in patients with recurrent (23%) high-risk tumours compared to the primary (14.6%) and progressive (20%) cohorts (log-rank test; p < 0.001). Progression affected DSM, which increased from the primary (19.2%) to the progressive (24.6%) and recurrent (25.5%) cohorts (log-rank test; p = 0.006). OCM did not differ among the groups (primary: n = 231 [33.1%; 95% CI, %] vs Fig. 2 The natural history of primary, progressive, and recurrent high-risk non muscle-invasive bladder tumours. MIBC = muscle-invasive bladder cancer; DSM = disease-specific mortality.

4 148 EUROPEAN UROLOGY 63 (2013) Table 1 Composition of the patients and tumours in the primary, progressive, and recurrent high-risk bladder cancer cohorts Primary Progression Recurrent x2 p n % n % n % Total Gender Male Female Age, yr, median (range) 73.7 (42 96) 73.1 (49 84) 73.2 (40 97) TUR weight 3 g <0.001 >3 g Grade < Stage ptis <0.001 pta pt NK Growth Solid <0.001 Papillary Mixed NK Histology Variant UCC Vascular invasion Yes Flat urothelium Normal <0.001 CIS Absent Muscle in TUR Yes <0.001 TUR = transurethral resection; NK = not known; UCC = urothelial cell carcinoma; CIS = carcinoma in situ. Significant differences between the cohorts are highlighted in bold. progressive: n = 40 [36.4%, 95% CI, %] vs recurrent: n = 153 [31.0%, 95% CI, %]) (log-rank test; p =0.57). There were differences, however, in overall survival (overall mortality occurred in 376 primary patients [53.8%; 95% CI, %], 68 progressive patients [61.8%; 95% CI, %], and 284 recurrent patients [57.5%; 95% CI, %]; log-rank test; p < 0.001). An analysis of clinicopathologic factors revealed common and unique associations with progression and DSM (Tables 2 and 3). In all cohorts we found older patients and females had worse outcomes (HR: >1.4; p < 0.02). The same was similar for tumours with high-grade differentiation (but this was not related to DSM in patients with recurrent high-risk tumours who had had one or more previous high-risk tumours). In contrast, CIS in the background urothelium was only related to progression and DSM in the primary tumour cohort (HR: >1.3; p < 0.05). In addition, subsequent NMI recurrence within the bladder, regardless of tumour risk, was more highly associated with DSM in the primary tumour cohort than for the other cohorts. In all patients, progression to invasion was strongly associated with DSM (HR: ; p < 0.001). Our cohort included high-risk tumours with different stages. Substage analysis revealed greater differences between the primary and relapsing tumours in those with lamina propria invasion (pt1) when compared to those without invasion (pta and ptis) (Fig. 3) Tumour group as a predictor of outcome Multivariable analysis using all clinicopathologic features (Table 4) revealed that the tumour grouping predicted both progression and DSM (HR: >1.15; p < 0.026). Other predictive factors included patient age and sex (HR: >1.03; p < 0.037) and tumour stage (HR: >1.30; p < 0.001). Low/ intermediate-risk recurrence was associated with reduced risk of progression and DSM (HR: < 0.68; p < 0.04). In all tumours, the strongest predictor of DSM was progression to muscle invasion (HR: 4.36; p < 0.001). Tumour size predicted progression but not DSM. When compared, tumour grouping was less predictive than tumour stage, grade, and patient sex. 4. Discussion We report a large series of high-risk tumours treated at a single institution using evidence-based protocols. We compared outcomes for primary tumours to those in which there had been previous NMI disease. We found that

5 Table 2 Associations with clinicopathologic features and progression to muscle invasion Primary, N = 699 Progressive, N = 110 Recurrent, N = 494 Progression HR 95% CI p value Progression HR 95% CI p value Progression HR 95% CI p value No. % * Lower Upper No. % ** Lower Upper No. % *** Lower Upper Total events Sex Male Female Age, yr > TUR specimen weight, g < > Tumour grade Tumour stage ptis pta pt Tumour growth Solid Papillary Both Histology Variant UCC Vascular invasion Yes No Background urothelium Normal Cis Absent Muscle in TUR samples Yes No Low/intermediate-risk reccurrence Yes No High-risk recurrence Yes No CI = confidence interval; HR = hazard ratio; TUR = transurethral resection; UCC = urothelial cell carcinoma; Cis = carcinoma in situ. * The percentage refers to the number of events as a percentage of the total in the primary cohort. ** The percentage refers to the number of events as a percentage of the total in the progressive cohort. *** The percentage refers to the number of events as a percentage of the total in the recurrent cohort. EUROPEAN UROLOGY 63 (2013)

6 Table 3 Associations with clinicopathologic features and disease-specific mortality Primary, N = 699 Progressive, N = 110 Recurrent, N = DSM HR 95% CI p value DSM HR 95% CI p value DSM HR 95% CI p value No. % * Lower Upper No. % ** Lower Upper No. % *** Lower Upper Total events Sex M F Age, yr > TUR specimen weight, g < > Tumour grade % Tumour stage ptis pta pt Tumour growth Solid Papillary Both Histology Variant UCC Vascular invasion Yes No Background urothelium Normal Cis Absent Muscle in TUR samples Yes No Low/intermediate-risk reccurrence Yes No High-risk recurrence Yes No Progression Yes No EUROPEAN UROLOGY 63 (2013) DSM = disease-specific mortality; CI = confidence interval; HR = hazard ratio; TUR = transurethral resection; UCC = urothelial cell carcinoma; Cis = carcinoma in situ. * The percentage refers to the number of events as a percentage of the total in the primary cohort. ** The percentage refers to the number of events as a percentage of the total in the progressive cohort. *** The percentage refers to the number of events as a percentage of the total in the recurrent cohort.

7 [(Fig._3)TD$FIG] EUROPEAN UROLOGY 63 (2013) Fig. 3 Progression-free, disease-specific, and other-cause specific survival stratified by tumour grouping in (a) all patients, (b) those with no invasion (pta and ptis), and (c) those with lamina propria invasion (pt1). Data were plotted using the Kaplan-Meier method. DSM = disease-specific mortality; OCM = other-cause mortality. relapsing tumours, regardless of previous disease risk, had worse clinical outcomes than primary cancers; consequently, we should accept our initial hypothesis that relapsing tumours are more aggressive than primary cancers and so may require different therapeutic strategies. Our findings support previous observations regarding the ominous nature of high-risk NMI bladder tumours [7,8,11] and cautious use of bladder-sparing strategies in patients with relapsing disease. There are several important observations that can be made from this work. First, it is important to know the outcomes for relapsing high-risk tumours. As stated, these outcomes were worse than those of patients with primary high-risk tumours. The outcomes are equally poor for patients with previous low/intermediate- and high-risk tumours. Given the different molecular pathways for lowand high-grade disease [4], we initially hypothesised that new high-risk tumours within patients with previous low/ intermediate-risk disease represents the development of a new cancer clone [13]. Consequently, we expected these tumours to behave similarly to primary high-risk tumours. Surprisingly, the data suggested this is not the case. Potential explanations are that these tumours arise on the background of low/intermediate-grade urothelial carcinogenesis and, therefore, have accelerated molecular progression when compared to de novo high-grade disease; that there is a delay in diagnosis as patients defer presentation until their next cystoscopy [14]; or that a proportion of patients had BCG for recurrent, intermediaterisk disease. The second interesting observation concerns CIS in the background urothelium. It is recognised that CIS within the bladder is a predictor of progression to invasion and DSM in patients with primary high-risk tumours. This has been shown in patients in randomised controlled trials, large single-centre cohorts [3,5], and in our primary tumour group [11]. However, in relapsing high-risk tumours, we found that CIS was not predictive of outcome. Reasons for this appeared to differ between the relapsed cohorts. In recurrent high-risk tumours, we found CIS was present in most of the bladders (53 of 70 [75%]) in which flat urothelium was sampled. This ubiquitous presence of CIS

8 Table 4 Intergroup analysis of clinicopathologic associations with progression to muscle invasion and disease-specific mortality Univariable analysis Multivariable analysis Univariable analysis Multivariable analysis 152 Progression HR 95% CI p value HR 95% CI p value DSM HR 95% CI p value HR 95% CI p value No. % Lower Upper Lower Upper No. % Lower Upper Lower Upper Cohort Primary Progressive Recurrent Sex Male < Female Age, yr < <0.001 > TUR specimen weight, g < > Tumour grade < Tumour stage ptis <0.001 pta pt Tumour growth Solid Papillary Both Histology variants Variants UCC Vascular invasion Yes No Background urothelium Normal Cis Absent Muscle in TUR samples Yes No Low/intermediate risk reccurrence Yes < No High-risk recurrence Yes No Progression Yes < <0.001 No EUROPEAN UROLOGY 63 (2013) CI = confidence interval; HR = hazard ratio; TUR = transurethral resection; UCC = urothelial cell carcinoma; Cis = carcinoma in situ.

9 EUROPEAN UROLOGY 63 (2013) prevented any discriminative role and probably reflects a detection bias (ie, more sampling of these bladders identified more bladders with CIS). The reasons for the lack of a predictive role for CIS in the progressive cohort are less obvious given that its presence was similar to that in the primary cancer group. The main differences between these two cohorts is the higher rate of progression/dsm and the higher proportion of grade 2 lesions (52% vs 72% primary) in the progressive cohort. Thus, perhaps the biologic outcomes of these tumours is driven less by highgrade tumour clones (as found in the CIS lesions) and more by the grade 2 (intermediate-risk) disease. Support for this assumption is that this cohort had both the highest rate of low/intermediate-nmi recurrences and the highest overall mortality. The alternate explanation is that the higher rate of progression within this cohort prevented a modest predictive contribution from the presence of CIS. Our finding that, in all three high-risk groups, female patients had a poorer prognosis than their male equivalents is in keeping with the study by van Rhijn et al. [15], who found female sex to be an independent risk factor for progression in BCG-treated pt1 disease. The authors speculated that these differences may be due to the thinner female bladder wall, differences in immunologic response, or perhaps delay in diagnosis. Our findings complement the few previous reports that compare the outcomes of primary and relapsing high-risk tumours. For example, Alkhateeb et al. reported the outcomes of 95 primary and 96 nonprimary high-risk tumours [9]. This group limited their analysis to tumours invading the lamina propria (pt1), as they felt these represent a distinctly high-risk cohort. In keeping with our findings, higher progression rates for nonprimary tumours were seen when compared to primary cancers (71.9% vs 51.5%, respectively). This difference was apparent on multivariate analysis, but did not translate into a significant difference in disease-specific survival. However, the mortality curves appear similar to ours (ie, worse outcomes for nonprimary tumours) and so the low sample size may have prevented significance being reached. Fernandez-Gomez et al. reported the outcomes of 1062 patients treated with BCG within randomised controlled trials [10]. This cohort included primary (66.5%) and relapsing (33.5%) high- and intermediate-risk cancers. In multivariate analysis, relapsing tumours had significantly higher recurrence rates (HR: 1.9; 95% CI, ) and progression (HR: 1.6; 95% CI, ) when compared to primary cancers. Saint et al. reviewed predictive outcomes for BCG response in bladder cancer [16]. Intotal, seven reports describing 624 patients were found in which the presence of previous tumours was of prognostic significance. In each, the effect of previous disease was to increase progression rates when compared to primary cancers. 5. Conclusions We have shown that relapsing high-risk tumours have higher progression and DSM rates than primary tumours. The worse outcomes also include patients whose previous tumours have been of low/intermediate risk. Consequently, the use of bladder-sparing strategies in these patients should be approached cautiously. Finally, the presence of CIS in the flat urothelium has little role in predicting progression and mortality in patients with relapsing highrisk tumours. Author contributions: James W.F. Catto had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Catto. Acquisition of data: Thomas, Rubin, Goepel. Analysis and interpretation of data: Thomas, Noon, Catto. Drafting of the manuscript: Thomas, Catto. Critical revision of the manuscript for important intellectual content: Catto, Noon. Statistical analysis: Thomas, Catto. Obtaining funding: Catto. Administrative, technical, or material support: None. Supervision: Catto. Other (specify): None. Financial disclosures: James W.F. Catto certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: James W.F. Catto was supported by a GlaxoSmithKline Clinician Scientist fellowship and project grants from Yorkshire Cancer Research, Sheffield Hospitals Charitable Trust, Astellas Educational Foundation, and the European Union (European Community s Seventh Framework Programme. Grant Numbers: FP7/ , HEALTH-F ). Funding/Support and role of the sponsor: None. Acknowledgement statement: The authors wish to thank Drs. Anderson, Chapple, Hastie, Hall, Hamdy, Haynes, Inman, Oakley, Reid, Rosario, and Smith for allowing us to study their patients and the staff and patients of the Royal Hallamshire Hospital. References [1] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61: [2] Sievert KD, Amend B, Nagele U, et al. Economic aspects of bladder cancer: what are the benefits and costs? World J Urol 2009;27: [3] Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006;49:466 77, discussion [4] Catto JW, Alcaraz A, Bjartell AS, et al. MicroRNA in prostate, bladder, and kidney cancer: a systematic review. 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