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

EUROPEAN UROLOGY 63 (2013) 145 154 available at www.sciencedirect.com journal homepage: www.europeanurology.com Platinum Priority Urothelial Cancer Editorial by J. Alfred Witjes on pp. 155 157 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 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 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)114 226 1229; Fax: +44 (0)114 271 2268. E-mail addresses: j.catto@sheffield.ac.uk, jimcatto@yahoo.co.uk (J.W.F. Catto). 0302-2838/$ see back matter Crown Copyright # 2012 Published by Elsevier B.V. on behalf of European Association of Urology. All rights reserved. http://dx.doi.org/10.1016/j.eururo.2012.08.064

146 EUROPEAN UROLOGY 63 (2013) 145 154 1. 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 800 000 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. 2.2. 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). 2.3. 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 2000. 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. 2.4. 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 < 0.05. 3. 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

[(Fig._1)TD$FIG] EUROPEAN UROLOGY 63 (2013) 145 154 147 and no re-resection in 678 (52%). When combined, 1193 (91.6%) samples had either detrusor muscle present in the tumour specimen or the patient underwent re-resection within 6 mo without finding muscle invasion, or both, to confirm a diagnosis of NMI disease. Comparisons among the three groups (primary, progressive, and recurrent high-risk BCas) revealed statistical differences among the tumours but not the patients (Table 1). For example, progressive tumours were less often of high grade (52% vs 72% primary and 86% recurrent; p < 0.0001), and primary tumours were more advanced than the other cancers (68% pt1 vs 60% progressive and 45% recurrent; p < 0.001). Primary tumours were also larger (assessed by transurethral resection specimen weight) and had more histologic variants of UCC than the other cancers. Recurrent high-risk tumours had the highest incidence of CIS (53% vs 31% primary and 30% progressive; p < 0.001). 3.2. Comparative outcomes of primary, progressive, and recurrent high-risk tumour behaviour Fig. 1 The grouping and exclusion strategy for tumours within this study. MIBC = muscle-invasive bladder cancer; RHH = Royal Hallamshire Hospital; UCC = urothelial cell carcinoma. (range: 1 8 per patient; mean follow up: 59.4 mo [IQR: 6 188]). By the design of our selection, all progressive and recurrent tumours were suitable for inclusion (ie, all had UCC because the previous tumours were UCC), all patients were under the care of our unit (previous tumours had been resected at RHH), all had sufficient follow-up (follow-up was used to identify cases), and none had muscle invasion (as excluded from selection). Analysis of these 1303 tumours in 809 patients revealed no detrusor muscle in 239 (18.3%) [(Fig._2)TD$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], 30.5 48.4%) than patients in the primary cohort (n = 147 [21.0%]; 95% CI, 18.2 24.2%) and in the recurrent cohort (n = 76 [15.4%]; 95% CI, 12.5 18.8%) (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, 20.6 37.2%) versus the primary cohort (n = 273[39.1%]; 95% CI, 35.5 42.7%) and the recurrent cohort (n = 238 [48.2%]; 95% CI, 43.8 52.3%) (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, 30.0 36.6%] 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.

148 EUROPEAN UROLOGY 63 (2013) 145 154 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 699 110 494 Gender Male 547 78 87 79 384 78 0.946 Female 152 22 23 21 110 22 Age, yr, median (range) 73.7 (42 96) 73.1 (49 84) 73.2 (40 97) 0.664 TUR weight 3 g 464 66 78 74 367 81 <0.001 >3 g 235 34 28 26 85 19 Grade 1 18 3 7 6 4 1 <0.001 2 181 26 46 42 66 13 3 500 72 57 52 424 86 Stage ptis 157 23 32 29 130 26 <0.001 pta 62 9 12 11 139 28 pt1 475 68 66 60 221 45 NK 5 1 0 0 4 1 Growth Solid 35 5 1 1 24 5 <0.001 Papillary 382 55 86 78 222 45 Mixed 199 29 14 13 86 17 NK 83 12 9 8 162 33 Histology Variant 77 11 3 3 12 2 0.078 UCC 622 89 107 97 482 98 Vascular invasion Yes 25 4 6 6 21 4 0.563 Flat urothelium Normal 156 22 28 25 85 17 <0.001 CIS 217 31 33 30 260 53 Absent 326 47 49 45 149 30 Muscle in TUR Yes 468 67 70 64 277 56 <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, 28.0 45.7%] vs recurrent: n = 153 [31.0%, 95% CI, 27.1 35.2%]) (log-rank test; p =0.57). There were differences, however, in overall survival (overall mortality occurred in 376 primary patients [53.8%; 95% CI, 50.1 57.5%], 68 progressive patients [61.8%; 95% CI, 52.5 70.4%], and 284 recurrent patients [57.5%; 95% CI, 53.1 61.8%]; 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: 4.4 6.9; 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). 3.3. 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

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 102 15 12.00 17.40 22 20 13.60 28.40 112 23 19.20 26.60 Sex Male 74 14 1.42 0.92 2.19 0.114 14 16 2.70 1.13 6.48 0.026 79 21 1.58 1.05 2.37 0.028 Female 28 18 8 35 33 30 Age, yr 72.73 36 11 2.01 1.33 3.03 0.001 5 10 3.41 1.25 9.30 0.017 42 18 1.83 1.24 2.69 0.020 >72.73 66 17 17 27 70 27 TUR specimen weight, g <3 73 16 0.97 0.94 1.00 0.079 16 21 0.93 0.79 1.09 0.035 96 26 0.98 0.94 1.02 0.210 >3 29 12 6 21 15 18 Tumour grade 1 2 11 1.59 1.04 2.44 0.032 1 14 2.50 1.09 5.74 0.030 0 0 2.12 1.10 4.09 0.025 2 20 11 5 11 9 14 3 80 16 16 28 103 24 Tumour stage ptis 15 10 1.27 0.99 1.62 0.063 2 6 1.87 1.01 3.47 0.047 30 23 1.11 0.91 1.36 0.306 pta 11 18 3 25 30 22 pt1 76 16 17 26 52 24 Tumour growth Solid 7 20 1.03 0.83 1.29 0.796 0 0 0.90 0.49 1.66 0.733 5 21 1.00 0.85 1.18 0.993 Papillary 42 11 12 14 51 23 Both 38 19 6 43 18 21 Histology Variant 95 14 1.67 0.78 3.61 0.189 0 0 0.05 0.00 2370 0.581 0 0 0.05 0.00 9.22 0.257 UCC 7 21 22 21 112 23 Vascular invasion Yes 4 16 1.00 1.00 1.00 0.679 13 22 1.00 1.00 1.00 0.943 3 14 1.00 1.00 1.00 0.439 No 64 15 0 0 67 22 Background urothelium Normal 13 8 2.70 1.46 5.04 0.002 6 21 1.00 1.00 1.00 0.743 18 21 0.71 0.41 1.23 0.200 Cis 43 20 7 21 52 20 Absent 46 14 9 18 42 28 Muscle in TUR samples Yes 66 14 1.00 1.00 1.00 0.584 13 19 1.00 1.00 1.00 0.770 55 20 1.00 1.00 1.00 0.435 No 21 14 4 25 19 25 Low/intermediate-risk reccurrence Yes 19 13 0.73 0.45 1.18 0.197 6 14 0.42 0.17 1.09 0.075 11 15 0.44 0.24 0.82 0.010 No 82 15 16 24 98 24 High-risk recurrence Yes 54 20 1.71 1.16 2.52 0.007 7 23 1.11 0.45 2.71 0.827 49 25 1.01 0.69 1.47 0.979 No 48 11 15 19 60 21 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) 145 154 149

Table 3 Associations with clinicopathologic features and disease-specific mortality Primary, N = 699 Progressive, N = 110 Recurrent, N = 494 150 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 134 19 27 25 126 26 Sex M 95 17 1.55 1.06 2.24 0.022 17 20 2.78 1.27 6.10 0.011 80 21 2.15 1.49 3.09 0.001 F 39 26 10 44 46 42 Age, yr 72.73 35 11 3.48 2.35 5.15 0.001 8 17 2.97 1.28 6.90 0.011 37 16 3.16 2.14 4.66 0.001 >72.73 99 26 19 31 89 35 TUR specimen weight, g <3 90 20 1.01 0.84 1.23 0.905 20 26 1.04 0.61 1.76 0.889 100 28 1.10 0.86 1.41 0.430 >3 44 19 6 22 22 26 Tumour grade 1 2 11 1.47 1.03 2.11 0.034 0 0 3.07 1.37 6.84 0.006 0% 0 1.34 0.82 2.19 0.249 2 30 17 7 15 16 24 3 102 20 20 35 110 26 Tumour stage ptis 16 10 1.45 1.14 1.85 0.003 5 16 1.43 0.89 2.30 0.135 32 25 1.17 0.96 1.44 0.123 pta 11 18 3 25 25 18 pt1 107 23 19 29 68 31 Tumour growth Solid 6 17 1.08 0.89 1.32 0.443 0 0 0.88 0.51 1.53 0.649 7 29 1.11 0.95 1.30 0.182 Papillary 56 15 20 23 58 26 Both 52 26 4 29 23 27 Histology Variant 9 27 1.56 0.79 3.07 0.196 2 67 2.40 0.57 10.15 0.235 2 17 0.71 0.18 2.88 0.632 UCC 125 19 25 23 124 26 Vascular invasion Yes 4 16 1.00 1.00 1.00 0.407 1 17 1.00 1.00 1.00 0.629 1 5 1.00 1.00 1.00 0.330 No 87 20 16 27 77 25 Background urothelium Normal 24 15 1.28 1.011 1.632 0.050 4 15 1.00 1.00 1.01 0.100 19 22 1.00 1.00 1.01 0.120 Cis 52 24 5 15 58 23 Absent 57 17 18 37 49 34 Muscle in TUR samples Yes 87 24 1.00 1.00 1.00 0.870 15 21 1.00 1.00 1.00 0.437 74 27 1.00 1.00 1.00 0.093 No 30 20 6 38 19 25 Low/intermediate-risk reccurrence Yes 20 14 0.48 0.30 0.76 0.002 10 23 0.72 0.33 1.58 0.411 21 28 0.76 0.47 1.21 0.250 No 114 21 17 26 104 26 High-risk recurrence Yes 71 26 1.65 1.17 2.31 0.004 9 29 1.12 0.50 2.49 0.787 55 28 0.93 0.65 1.32 0.666 No 63 15 18 23 70 25 Progression Yes 64 63 6.24 4.44 8.77 0.001 13 59 6.90 3.09 15.40 0.001 66 59 4.38 3.08 6.22 0.001 No 70 12 14 16 60 16 EUROPEAN UROLOGY 63 (2013) 145 154 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.

[(Fig._3)TD$FIG] EUROPEAN UROLOGY 63 (2013) 145 154 151 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

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 102 15 1.33 1.16 1.52 0.001 1.33 1.16 1.53 0.001 134 19 1.22 1.08 1.37 0.002 1.15 1.02 1.31 0.026 Progressive 22 20 27 25 Recurrent 112 23 126 26 Sex Male 167 16 1.58 1.19 2.09 0.001 1.37 1.03 1.83 0.030 192 19 1.89 1.48 2.42 <0.001 1.34 1.04 1.72 0.025 Female 69 24 95 33 Age, yr 72.73 83 14 1.99 1.52 2.60 0.001 1.03 1.01 1.04 0.001 80 13 3.26 2.51 4.24 <0.001 1.07 1.05 1.08 <0.001 >72.73 153 22 207 30 TUR specimen weight, g <3 185 20 0.97 0.94 0.99 0.006 0.97 0.95 0.99 0.013 210 24 0.97 0.85 1.12 0.702 >3 50 14 72 21 Tumour grade 1 3 10 1.92 1.39 2.65 0.001 1.74 1.24 2.43 0.001 2 7 1.64 1.25 2.15 <0.001 1.26 0.95 1.66 0.109 2 34 12 53 18 3 199 20 232 24 Tumour stage ptis 47 15 1.16 1.00 1.34 0.052 1.32 1.13 1.55 0.001 53 17 1.23 1.07 1.42 0.003 1.30 1.12 1.51 <0.001 pta 44 21 39 18 pt1 145 19 194 26 Tumour growth Solid 12 20 0.94 0.83 1.07 0.344 13 22 1.03 0.92 1.16 0.604 Papillary 105 15 134 19 Both 62 21 79 26 Histology variants Variants 7 14 0.81 0.38 1.73 0.591 13 27 1.29 0.74 2.25 0.369 UCC 229 18 274 22 Vascular invasion Yes 7 14 1.00 1.00 1.00 0.805 6 12 1.00 1.00 1.00 0.912 No 144 18 180 23 Background urothelium Normal 36 13 1.00 1.00 1.00 0.921 48 18 1.00 1.00 1.00 0.524 Cis 102 20 115 23 Absent 98 19 124 24 Muscle in TUR samples Yes 134 16 1.00 1.00 1.00 0.097 176 22 1.00 1.00 1.00 0.401 No 44 18 55 23 Low/intermediate risk reccurrence Yes 36 14 0.57 0.40 0.80 0.001 0.69 0.48 0.99 0.041 51 19 0.60 0.44 0.81 <0.001 0.68 0.50 0.93 0.016 No 196 19 235 23 High-risk recurrence Yes 110 22 1.30 1.01 1.68 0.046 1.27 0.98 1.64 0.075 135 27 1.26 1.00 1.59 0.051 No 123 16 151 19 Progression Yes 143 61 5.48 4.34 6.92 <0.001 4.36 3.43 5.54 <0.001 No 144 14 EUROPEAN UROLOGY 63 (2013) 145 154 CI = confidence interval; HR = hazard ratio; TUR = transurethral resection; UCC = urothelial cell carcinoma; Cis = carcinoma in situ.

EUROPEAN UROLOGY 63 (2013) 145 154 153 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, 1.5 2.4) and progression (HR: 1.6; 95% CI, 1.1 2.3) 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: FP7/2007-2013, HEALTH-F2-2007-201438). 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;61:69 90. [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: 295 300. [3] Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. 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