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2010 THE AUTHORS. JOURNAL COMPILATION Urological Oncology

2010 BJU INTERNATIONAL

LONG-TERM FOLLOW-UP OF BLADDER CANCER AFTER BCG KAKIASHVILI ET AL.

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Long-term follow-up of T1 high-grade bladder cancer after intravesical bacille Calmette-Guérin treatment

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David M. Kakiashvilia, Bas W.G. van Rhijn†a, Greg Trottier, Michael A.S. Jewett, Neil E. Fleshner, Antonio Finelli, Julian Azuero, Chris H. Bangma†, Rati Vajpeyi, Sultan Alkhateeb, Sally Hanna, Alex Kostynsky, Cynthia Kuk*, Theodorus H. Van Der Kwast‡§ and Alexandre R. Zlotta* Departments of Surgical Oncology (Division of Urology), Princess Margaret Hospital, *Mount Sinai Hospital, University of Toronto and ‡Department of Surgical Pathology, University Health Network, Toronto, Ontario, Canada, Departments of †Urology and §Pathology, Erasmus MC, Rotterdam, the Netherlands Accepted for publication 1 April 2010 a

These authors contributed equally to this work.

Study Type – Therapy (cohort) Level of Evidence 2b OBJECTIVE To report the long-term results of bacille Calmette-Guérin (BCG) intravesical therapy in relation to disease progression and recurrence in primary T1 high-grade (HG) bladder cancer (BC) confirmed by central pathological review. PATIENTS AND METHODS In all, 136 patients from two university centres (Rotterdam, n = 49; Toronto, n = 87) were diagnosed with primary T1HG BC. One experienced uro-pathologist reviewed all slides, ensuring all cases were indeed HG and that muscle was present in all specimens. Patients were treated with BCG induction (six instillations) after transurethral resection (TUR) of the tumour and followed with cystoscopy and urinary cytology. Predictors for recurrence, progression and survival were assessed with multivariable Cox regression models. RESULTS

What’s known on the subject? and What does the study add? High-grade non muscle invasive bladder cancer is a very aggressive disease, potentially lethal if not managed adequately, because of the ability of these tumours to invade surrounding tissues and become metastatic. Treatment with intravesical BCG has been shown to delay progression to muscle invasive or/and metastatic disease, preserve the bladder, and decrease the risk of death from bladder cancer. However, most studies have analyzed patients with short follow-up, and long-term data about the real efficacy of BCG to prevent tumour recurrence, progression and impact mortality are lacking. This study has analyzed a large series of patients with high-grade non muscle invasive bladder cancer treated with intravesical BCG in two University Institutions (Toronto and Rotterdam), with a central pathology review by a very experienced uro-pathologist. It provides further insight into the long-term risks of progression of patients harbouring high-grade T1 bladder cancer treated with BCG, demonstrating that about 30% of patients are at risk of progression and that late progressions even more than 3 years after the initial resection and BCG treatment are rare but not exceptional. for recurrence (P = 0.52), progression (P = 0.35) and disease-specific survival (DSS) (P = 0.69) between the two centres. Among the cohort, 47 patients (35%) recurred and 42 (30.9%) progressed with a median time to progression of 2.1 years; 16 (38%) of these progressions occurred ≥3 years after the initial BCG course; 22 (16%) patients who progressed died from BC. Overall, 96 (71%) patients had no evidence of disease at the last follow-up. Carcinoma in situ was the only independent predictor for recurrence in multivariate analysis (P = 0.011). No independent predictors were found for progression.

Mean (range) follow-up was 6.5 (0.3–21.6) years. There were no significant differences

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CONCLUSIONS Conservative treatment with BCG is a valid option in primary T1HG BC. Nevertheless, the aggressive nature of T1HG BC is evident in the fact that 30% progressed, with a high proportion of these progression events occurring ≥3 years after BCG. Caution should be exercised when relying on the long-term effects of BCG, and close follow-up of these patients should not be neglected. KEYWORDS Bacille Calmette-Guérin (BCG), bladder cancer, high grade, disease progression, recurrence, T1

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2 0 1 0 B J U I N T E R N A T I O N A L | 1 0 7 , 5 4 0 – 5 4 6 | doi:10.1111/j.1464-410X.2010.09572.x

LONG-TERM FOLLOW-UP OF BLADDER CANCER AFTER BCG

INTRODUCTION Optimal management of high-grade (HG) non-muscle-invasive bladder cancer (NMIBC) with lamina propria involvement (American Joint Committee on Cancer stage T1) is challenging. Defined as a highly malignant tumour, T1HG bladder cancer (BC) has variable and somewhat unpredictable biological potential [1,2]. This form of BC with or without associated carcinoma in situ (CIS), although classified among NMIBC, can progress to muscle invasion in a significant percentage of patients and thereby carries a notable lethal risk [3,4]. Intravesical BCG is an accepted treatment option in combination with transurethral resection (TUR) for this tumour. Approximately 30% of patients remain recurrence-free after BCG, an additional 30% will recur without disease progression, and 30% progress to muscle invasion [4]. Prognostic factors [5–7] and molecular markers [8] that are predictive for progression have been studied for T1HG BC, but none are currently implemented in daily clinical practice. BCG failure cannot be predicted accurately on an individual basis, such that the window of curability for patients progressing who were treated conservatively appears narrow. Based on this rationale, some authors have advocated for more aggressive treatments, such as radical cystectomy [9,10]. The ability of BCG to reduce disease progression and improve disease-specific survival (DSS) remains controversial [1,11,12]. Few studies have reported follow-up data beyond 5 years and, likewise, a meta-analysis of available studies has shown the potential of BCG to prevent tumour progression with a short follow-up of only 2.5 years [13]. Other limitations of previous series include low patient numbers and mixed patient cohorts, including grades 1–3 and/or Ta disease [13]. Nearly all previous studies used the World Health Organization (WHO) 1973 classification and therefore the long-term ability of BCG to prevent tumour progression in primary T1HG BC remains questionable. In the present study, we report the longterm efficacy of intravesical BCG combined with TUR in a large cohort of patients with primary T1HG BC treated at two university institutions from different continents. We limited our study to primary T1HG BC to minimize inconsistencies in previous

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treatment regimens. The present study is unique in that a very experienced uropathologist (T.v.d.K.) reviewed all samples to ensure that all cases were truly T1 and HG according to the WHO 2004 classification system, as most samples were originally graded by the WHO 1973 classification system.

PATIENTS AND METHODS From 1984 to 2006, 136 consecutive patients from two academic hospitals, the University Health Network (UHN), Toronto, Canada (n = 87) and Erasmus MC, Rotterdam, the Netherlands (n = 49), were diagnosed with primary T1 BC with or without CIS and managed conservatively with BCG as a first intent. The term ‘primary’ for T1 BC is used to emphasize that patients had no previous history of BC. Clinical and histopathological data were collected by retrospective chart review after approval by the ethical committees of both hospitals. All patients underwent macroscopically complete (control) TUR with the intention of removing all visible tumour. A central pathology review by a single experienced pathologist (T.d.v.K.) was undertaken to identify only cases of T1HG and also to classify them according to the WHO 1973 grading system. Only patients who had muscularis propria present in pathological specimens were included in the study. A second-look TUR was not routinely performed. TUR was followed by a BCG induction course using the classical 6-weekly intravesical instillation regimen. Much of the retrospective data for these patients came before the benefits of maintenance BCG regimens were recognized so that many patients only received induction treatment. Patients who failed induction BCG were considered either for a second induction course of BCG or for radical cystectomy. Failure was defined as a ≥ T1HG recurrence at 3 months. The duration and overall number of BCG instillations were recorded for each patient. Follow-up included cystoscopy accompanied by cytology every 3–4 months in the first 2 years and every 6 months thereafter. Upper urinary tract imaging with CT intravenous pyelogram (IVP), conventional IVP or retrograde pyelography was performed every 2 years, or sooner if clinically indicated. Recurrence-free survival, progression-free survival and DSS were the main endpoints of the study. Recurrence was defined as non-

muscle-invasive (NMI) recurrence (3)

P-value, two-sided Fisher’s exact test for categorical and ANOVA for continuous variables. *Data on multiplicity are available for 60 of the 87 patients treated in UHN.

1.0

Hospital

0.8

ErasmusMC UHN ErasmusMC-censored UHN-censored

0.6 0.4 0.2 0.0

TABLE 2 Type and number of intravesical instillations. The number of patients who had either intravesical BCG only or BCG + chemotherapy treatment in the two cohorts. The bottom row shows the number of patients who had 6, 12, 18 or >18 instillations

0 b

between the two cohorts (P = 0.82). However, during follow-up the patients from Erasmus MC received more alternative intravesical treatments in addition to BCG (P < 0.001).

RECURRENCE Overall, BC never recurred in 47 (35%) patients after TUR and BCG. Another 47 (35%) patients experienced NMI recurrence (≤pT1) only. Median (±SD) times to recurrence in the Rotterdam and Toronto cohorts were 1.2 (±3.7) and 1.3 (±3.2) years, respectively (nonsignificant difference). Six (12.8%) patients with NMI recurrence underwent radical cystectomy as per the patient’s decision and remained disease-free. Thus, 88/136 (65%) patients were treated conservatively for recurrence and remained with an intact urinary bladder and no evidence of disease at last follow-up. In terms of recurrence-free survival, there was no significant difference between the two institutions (34 [39%] patients at UHN and 13 [26.5%] patients at Erasmus MC; P = 0.52; Fig. 1a). An upper tract recurrence was detected in one (1.2%) patient in the Toronto group and in three (6%) patients in the Erasmus MC cohort (P = 0.10) during follow-up.

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Erasmus MC (n = 49) 36 13 15, 12, 7, 15

P-value 18)

5 10 15 Duration of follow-up, years

0.4 0.2 0.0 0

15 20 5 10 Duration of follow-up, years

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23/42 (55%) patients with progression had or developed metastases (i.e. 12/25 in the cystectomy group and 11/17 in the non-cystectomy group). The median (range) time to progression for the 42 patients with disease progression was 2.14 (0.3–11.9) years. Of note, 16 patients (38%) progressed ≥3 years after their initial


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Progression-free survival

FIG. 2. Kaplan–Meier analysis comparing T1 grade 2 tumours with T1 grade 3 tumours for progressionfree survival (P = 0.18). 1.0

Grade review (WHO 1973)

0.8

G2 G3 G2-cencored G3-censored

0.6

TABLE 3 History of NMIBC treated with TUR + BCG, or radical cystectomy according to the literature Study TUR + BCG [11] [14] [15] [16] [17] [18] [19] [20] [21] [22] [12] [23] [4] [24] [25] [26] [27] Present study TUR + cystectomy [28] [29] [30] [31] [32] [33] [26] [34]

0.4 0.2 0.0 0

5 10 15 20 Duration of follow up, years

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BCG regimen. Patients who progressed in the Erasmus MC group had a significantly longer follow-up (mean ± SD, 8.7 ± 4.3 years; median [range], 8.6 [1.0–21.6] years) than the UHNToronto cohort (5.3 ± 3.6 years; 4.1 [0.3–14.9] years; P < 0.001). As a consequence, the median time (±SD) to progression for patients who progressed was longer in the Erasmus MC group than in the UHN group (3.5 ± 3.4 vs 1.3 ± 1.5 years, respectively, P < 0.05). They also had longer median (±SD) time to death from disease: 6.9 ± 3.7 vs 3.3 ± 1.7 years, respectively. On the other hand, Kaplan–Meier analyses showed no significant difference between the two cohorts in terms of progression-free survival (P = 0.35; Fig. 1b) and DSS (P = 0.69; Fig. 1c). Moreover, there was no difference in progression-free survival between patients with and without maintenance BCG. In all, 22 (16.2%) patients died from BC and 21 of these had nodal or distant metastatic disease. One N0 M0 patient died from postoperative complications at the time of cystectomy. Overall, 96/136 (71%) patients had no evidence of disease at last follow-up, including two patients with pN1 disease at the time of cystectomy. PROGNOSTIC FACTORS In univariate analysis, tumour multiplicity (P = 0.04) and CIS (P = 0.02) were significant predictors for recurrence, while age (P = 0.5), tumour size (P = 0.6), sex (P = 0.12), CIS and WHO 1973 grade review (P = 0.7) were not. In multivariate analysis, only CIS was a statistically significant predictor of recurrence (P = 0.011). Age (P = 0.79), tumour size (P = 0.33) and tumour multiplicity (P = 0.94)

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Year

Patients (n)

Duration of follow-up

Progression (%)

1992 1992 1995 1999 1996 1998 1998 1999 2000 2002 2002 2002 2003 2003 2004 2004 2007 2009

16 30 26 51 50 35 78 25 44 50 81 75 92 57 36 92 132 136

59 months 39 months 54 months 85 months 52 months 45 months 56 months 63 months 43 months 65 months 76 months 41 months 64 months 53 months 24/33/46 months 6.9 years 68 months 6.5 years

19 7 27 18 12 12 8 4 16 22 15 49 33 23 25 33 41 31

1988 1991 1994 1995 2001 2003 2004 2008

32 74 166 182 208 77 29 54

5 years 60 months 120 months 120 months 10 years 45 months 6.9 years 5.1 years

were not predictive for disease progression, whereas female sex (P = 0.10), CIS (P = 0.13) and WHO 1973 Grade review (P = 0.21) showed only a positive trend towards statistical significance. Figure 2 shows the Kaplan–Meier analysis for progression after subdividing the patient cohort based on WHO 1973 grade review. None of the above factors (age [P = 0.2], female sex [P = 0.83], tumour multiplicity [P = 0.96], tumour size [P = 0.089], CIS [P = 0.17] and WHO 1973 grade [P = 0.18]) were found to be significant for predictors for DSS, although tumour size approached significance.

DISCUSSION The present series of primary T1HG BC treated with BCG in two academic centres is one of the largest reported with long-term followup. The studies in Table 3 used the old WHO grading system and generally had a shorter follow-up. A major advantage of our study

DSS (%)

92 86 94

89 86 94 59 77 88 86 80 89 84 67 71 66 77 76 76 69 92

was a pathology review by a single, very experienced uro-pathologist, thereby reducing inter-observer variability. We are the first to report such results using the current WHO 2004 grading system. Numerous publications have discussed and reported the outcomes of conservative intravesical treatment with BCG as a management option over immediate cystectomy in T1HG (T1G3) tumours (Table 3) [4,6,35–38]. While a majority of patients with T1HG BC are controlled by TUR and BCG alone, when BCG fails and the disease progresses, over 30% will eventually succumb to the disease [38,39]. For instance, in a study in which 62 patients with T1HG disease failed BCG treatment and were treated with cystectomy, the 5-year DSS was only 38% [39]. The results of the present study are similar to these studies, supporting conservative treatment with BCG and TUR as a management option for primary T1HG BC since there was no evidence of disease in 96

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(71%) patients at the last follow-up (mean follow-up of 6.5 years). The DSS in our series was 84% at last follow-up, in line with other reports [4,6,18,35]. Nevertheless, 42 patients (30.9%) experienced disease progression in our cohort. Of these patients, 23 already had metastases at the time of progression to invasion of muscle or went on to develop them, suggesting a narrow window of curability when progression occurs. Schrier et al. [38] showed that BC progressing from NMIBC to muscle invasion has a worse outcome when treated than those diagnosed with primary disease invading bladder muscle [38]. Moreover, more than one-third of all progressions occurred ≥3 years after BCG treatment, emphasizing the long-term lethal potential of this disease entity despite BCG and also the importance of lifelong follow-up for these patients. One of the most useful tools for predicting outcome in NMIBC could be the European Organisation for Research and Treatment of Cancer (EORTC) risk calculator based on 2596 patients, although only 194 patients had T1G3 BC and few patients received BCG [7]. The presence of CIS with T1G3 was the most important poor prognostic factor, with 1- and 5-year progression probabilities of 29 and 74%, respectively, vs 10 and 29% without CIS. In our study, CIS was a significant independent predictor of recurrence and not progression. This difference could be explained by the fact that all patients in our series were treated with BCG and all tumours were primary T1HG rather than all combinations of NMIBC. This is also a point of value in the present study, in that our cohort of patients is homogeneous with respect to grade/stage and confirmed by a single, very experienced uro-pathologist. The Spanish Club Urológico Español de Tratamiento Oncológico (CUETO) group also evaluated risk factors for recurrence and progression after BCG [5]. As in the present study, the Spanish investigators found CIS to be an independent risk factor for recurrence but not for progression. Apart from possible differences in pathological examinations, explanations for this observation could be that the patient population in the CUETO study included more high-risk patients than the EORTC study, which included all risk groups, and/or that BCG treatment given in the CUETO study was a more effective treatment for CIS [5,7]. Nevertheless, immediate cystectomy for T1G3 BC with associated CIS has been advocated because CIS was related to a lower DSS in a

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deferred cystectomy group in another study [20]. Histological grade was also shown to be an important predictor of progression in NMIBC based on the EORTC risk calculator and data from Spain [5,7]. The new WHO 2004 grading system differentiates NMIBC patients into two groups, low- and high-grade. We addressed the issue of the WHO 2004 vs 1973 systems in this cohort of primary T1HG BC after systematic review of all slides for both grading systems by one pathologist. Grade was not a significant predictor for any endpoints in the study, thereby establishing validity for the new grading system in T1 disease. Whether an immediate cystectomy can salvage patients with high-risk features who are destined to progress despite BCG remains a dilemma. Disease-specific death rates of 20% have been reported even with up-front cystectomy [9,10]. The long-term ability of BCG to prevent progression remains controversial, even in cases where a complete response is achieved. Cookson et al. [40] reported that, after 15 years of follow-up, 53% of patients with high-risk NMIBC progressed to cancer invading bladder muscle, 36% eventually required cystectomy and 34% died from the disease. Only 27% of those who were alive retained their bladder. In the series in the present study, 38% of progressions occurred ≥3 years after BCG. Of those who underwent cystectomy, close to 50% already had, or developed, metastases. Progression is clearly a major concern in this population. The present study has several limitations. It is a retrospective multi-centre non-randomized case series including two historical cohorts of patients for over two decades carrying potential cohort biases. There is a possibility of selection bias, as only patients who were diagnosed with muscle in the specimen were included. There is lack of a control comparison group so that determining the utility of BCG is limited. Heterogeneity in treatment regimens is evident, with patients from Rotterdam having more alternative intravesical treatments in conjunction with BCG. This is a consequence of slightly different regional approaches to treatment of this condition. Nevertheless, all patients were treated with at least induction BCG, and the number of BCG instillations between the two centres was equivalent. Furthermore, the use of

alternative intravesical therapies did not appear to diminish the outcomes in the present study since there were no differences in any of the survival endpoints between the UHN and Rotterdam cohorts. Not all patients in the series in the present study received BCG maintenance and this could be considered a limitation as well. Many suggest optimal efficacy of an induction course should be followed by maintenance BCG [13,41–43], although the true benefits of maintenance have been challenged and are not clear in T1HG disease [44]. Furthermore, we found no significant difference in PFS between patients with and without maintenance BCG, although the number of patients was small. Another potential limitation is the lack of uniform second-look TUR in our series. This recommendation appeared in the 2008 European Association of Urology guidelines after our cohort accrual period ended in 2006 [3]. In theory, the lack of a uniform secondlook TUR policy might have had an impact on our results [45,46], but the uniformity of the patient population and surgical management, along with the presence of muscle in all specimens, support the validity of our data. We encourage future studies on BCG outcomes using cohorts with systematic second-look TUR. In conclusion, the present report on primary T1HG BC with long-term follow-up and central pathology review supports conservative management with BCG as an option since a majority of our patients did not progress in the long term. Whether patients had G3 or G2 T1 BC did not affect their prognosis, suggesting that the WHO 2004 HG designation appropriately combined the G3 and G2 entities. Despite the low progression rate in the present study, T1HG BC can be a lethal entity, as 30% of patients, progressed, with 55% of these patients eventually dying from their disease. One can argue that this mortality percentage is unacceptable and that up-front cystectomy should remain high on the list of treatment options when first diagnosed. Without prospectively comparing survival of initial cystectomy to conservative intravesical BCG, this question cannot be answered. Another important outcome was that more than one-third of progressions occurred ≥3 years after initial TUR and BCG, thereby questioning the long-term utility of BCG in preventing progression. In the future, biomarkers are desperately needed to help define those T1HG BC patients who are at higher risk of progression and mortality.


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ACKNOWLEDGMENTS

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The authors would like to thank Roni Sambas, Rob Bristow and Gina Lockwood for help and advice. CONFLICTS OF INTEREST

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In the present study there was no financial support that might be considered as constituting an apparent conflict of interest. 10 REFERENCES 1

2

3

4

5

6

7

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Brake M, Loertzer H, Horsch R, Keller H. Recurrence and progression of stage T1, grade 3 transitional cell carcinoma of the bladder following intravesical immunotherapy with bacillus CalmetteGuerin. J Urol 2000; 163: 1697–701 Soloway MS, Sofer M, Vaidya A. Contemporary management of stage T1 transitional cell carcinoma of the bladder. J Urol 2002; 167: 1573–83 Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Bohle A, Palou-Redorta J. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2008; 54: 303–14 Shahin O, Thalmann GN, Rentsch C, Mazzucchelli L, Studer UE. A retrospective analysis of 153 patients treated with or without intravesical bacillus Calmette-Guerin for primary stage T1 grade 3 bladder cancer: recurrence, progression and survival. J Urol 2003; 169: 96–100; discussion Fernandez-Gomez J, Solsona E, Unda M et al. Prognostic factors in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin: multivariate analysis of data from four randomized CUETO trials. Eur Urol 2008; 53: 992–1001 Patard JJ, Rodriguez A, Leray E, RiouxLeclercq N, Guille F, Lobel B. Intravesical Bacillus Calmette-Guerin treatment improves patient survival in T1G3 bladder tumours. Eur Urol 2002; 41: 635–41; discussion 42 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: 466–5; discussion 75–7

11

12

13

14

15

16

17

18

Zlotta AR, Noel JC, Fayt I et al. Correlation and prognostic significance of p53, p21WAF1/CIP1 and Ki-67 expression in patients with superficial bladder tumors treated with bacillus CalmetteGuerin intravesical therapy. J Urol 1999; 161: 792–8 Hautmann RE, Simon J. Ileal neobladder and local recurrence of bladder cancer: patterns of failure and impact on function in men. J Urol 1999; 162: 1963– 6 Stein JP, Lieskovsky G, Cote R et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001; 19: 666–75 Cookson MS, Sarosdy MF. Management of stage T1 superficial bladder cancer with intravesical bacillus Calmette-Guerin therapy. J Urol 1992; 148: 797–801 Pansadoro V, Emiliozzi P, de Paula F, Scarpone P, Pansadoro A, Sternberg CN. Long-term follow-up of G3T1 transitional cell carcinoma of the bladder treated with intravesical bacille CalmetteGuerin: 18-year experience. Urology 2002; 59: 227–31 Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a metaanalysis of the published results of randomized clinical trials. J Urol 2002; 168: 1964–70 Eure GR, Cundiff MR, Schellhammer PF. Bacillus Calmette-Guerin therapy for high risk stage T1 superficial bladder cancer. J Urol 1992; 147: 376–9 Pfister C, Landé P, Hervé JM, Barré P, Barbagelatta M, Camey M, Botto H. T1 G3 bladder tumors: the respective role of BCG and cystectomy. Prog Urol 1995; 5: 231–7 Hurle R, Losa A, Manzetti A, Lembo A. Intravesical bacilli Calmette-Guérin in Stage T1 grade 3 bladder cancer therapy: a 7-year follow-up. Urology 1999; 54: 258–63 Serretta V, Piazza S, Pavone C, Piazza B, Pavone-Macaluso M. Results of conservative treatment (transurethral resection plus adjuvant intravesical chemotherapy) in patients with primary T1, G3 transitional cell carcinoma of the bladder. Urology 1996; 47: 647– 51 Lebret T, Gaudez F, Herve JM, Barre P, Lugagne PM, Botto H. Low-dose BCG

19

20

21

22

23

24

25

26

27

28

instillations in the treatment of stage T1 grade 3 bladder tumours: recurrence, progression and success. Eur Urol 1998; 34: 67–72 Baniel J, Grauss D, Engelstein D, Sella A. Intravesical bacillus Calmette-Guérin treatment for Stage T1 grade 3 transitional cell carcinoma of the bladder. Urology 1998; 52: 785–9 Gohji K, Nomi M, Okamoto M, Takenaka A, Hara I, Okada H, Arakawa S, Fujii A, Kamidono S. Conservative therapy for stage T1b, grade 3 transitional cell carcinoma of the bladder. Urology 1999; 53: 308–13 Brake M, Loertzer H, Horsch R, Keller H. Recurrence and progression of stage T1, grade 3 transitional cell carcinoma of the bladder following intravesical immunotherapy with bacillus CalmetteGuerin. J Urol 2000; 163: 1697–701 Patard JJ, Rodriguez A, Leray E, RiouxLeclercq N, Guillé F, Lobel B. Intravesical Bacillus Calmette-Guerin treatment improves patient survival in T1G3 bladder tumours. Eur Urol 2002; 41: 635–41 Griffiths TR, Charlton M, Neal DE, Powell PH. Treatment of carcinoma in situ with intravesical bacillus CalmetteGuerin without maintenance. J Urol 2002; 167: 2408–12 Peyromaure M, Guerin F, AmsellemOuazana D, Saighi D, Debre B, Zerbib M. Intravesical bacillus Calmette-Guerin therapy for stage T1 grade 3 transitional cell carcinoma of the bladder; recurrence, progression and survival in a study of 57 patients. J Urol 2003; 169: 2110–2 Cheng CW, Chan SF, Chan LW, Chan CK, Ng CF, Cheung HY, Chan SY, Wong WS, Lai FM, Li ML. 15-year experience on intravesical therapy of T1G3 urinary bladder cancer: a conservative approach. Jpn J Clin Oncol 2004; 34: 202–5 Thalmann GN, Markwalder R, Shahin O, Burkhard FC, Hochreiter WW, Studer UE. Primary T1G3 bladder cancer: organ preserving approach or immediate cystectomy? J Urol 2004; 172: 70–5 Denzinger S, Fritsche HM, Otto W, Blana A, Wieland WF, Burger M. Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? Eur Urol 2008; 53: 146–52 Siref LE, Zincke H. Radical cystectomy for historical and pathologic T1, N0, M0 (stage A) transitional cell cancer. Need for

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K A K I A S H V I L I ET AL.

29

30

31

32

33

34

adjuvant systemic chemotherapy? Urology 1988; 31: 309–11 Pagano F, Bassi P, Galetti TP, Meneghini A, Milani C, Artibani W, Garbeglio A. Results of contemporary radical cystectomy for invasive bladder cancer: a clinicopathological study with an emphasis on the inadequacy of the tumor, nodes and metastases classification. J Urol 1991; 145: 45–50 Amling CL, Thrasher JB, Frazier HA, Dodge RK, Robertson JE, Paulson DF. Radical cystectomy for stages Ta, Tis and T1 transitional cell carcinoma of the bladder. J Urol 1994; 151: 31–5 Freeman JA, Esrig D, Stein JP, Simoneau AR, Skinner EC, Chen SC, Groshen S, Lieskovsky G, Boyd SD, Skinner DG. Radical cystectomy for high risk patients with superficial bladder cancer in the era of orthotopic urinary reconstruction. Cancer 1995; 76: 833–9 Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, Skinner E, Bochner B, Thangathurai D, Mikhail M, Raghavan D, Skinner DG. Radical cystectomy in the treatment of invasive bladder cancer: log-term results in 1,054 patients. J Clin Oncol 2001; 19: 666–75 Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R, Studer UE. Radical cystectomy for bladder cancer today – a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003; 21: 690–6 Denzinger S, Fritsche HM, Otto W, Blana A, Wieland WF, Burger M. Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? Eur Urol 2008; 53: 146–52

546

35 Emiliozzi P, Pansadoro A, Pansadoro V. The optimal management of T1G3 bladder cancer. BJU Int 2008; 102: 1265–73 36 Herr HW, Donat SM. A re-staging transurethral resection predicts early progression of superficial bladder cancer. BJU Int 2006; 97: 1194–8 37 Nieder AM, Brausi M, Lamm D et al. Management of stage T1 tumors of the bladder: International Consensus Panel. Urology 2005; 66: 108–25 38 Schrier BP, Hollander MP, van Rhijn BW, Kiemeney LA, Witjes JA. Prognosis of muscle-invasive bladder cancer: difference between primary and progressive tumours and implications for therapy. Eur Urol 2004; 45: 292–6 39 Huguet J, Crego M, Sabate S, Salvador J, Palou J, Villavicencio H. Cystectomy in patients with high risk superficial bladder tumors who fail intravesical BCG therapy: pre-cystectomy prostate involvement as a prognostic factor. Eur Urol 2005; 48: 53– 9; discussion 9 40 Cookson MS, Herr HW, Zhang ZF, Soloway S, Sogani PC, Fair WR. The treated natural history of high risk superficial bladder cancer: 15-year outcome. J Urol 1997; 158: 62–7 41 Bohle A, Bock PR. Intravesical bacille Calmette-Guerin versus mitomycin C in superficial bladder cancer: formal metaanalysis of comparative studies on tumor progression. Urology 2004; 63: 682–6; discussion 6–7 42 Lamm DL, Blumenstein BA, Crissman JD et al. Maintenance bacillus CalmetteGuerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000; 163: 1124–9

43 van der Meijden AP, Sylvester RJ, Oosterlinck W, Hoeltl W, Bono AV. Maintenance Bacillus Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial. Eur Urol 2003; 44: 429–34 44 Herr HW. Is maintenance Bacillus Calmette-Guerin really necessary? Eur Urol 2008; 54: 971–3 45 Divrik RT, Yildirim U, Zorlu F, Ozen H. The effect of repeat transurethral resection on recurrence and progression rates in patients with T1 tumors of the bladder who received intravesical mitomycin: a prospective, randomized clinical trial. J Urol 2006; 175: 1641– 4 46 Jakse G, Algaba F, Malmstrom PU, Oosterlinck W. A second-look TUR in T1 transitional cell carcinoma: why? Eur Urol 2004; 45: 539–46; discussion 46 Correspondence: Alexandre R Zlotta, C, Department of Surgery, Division of Urology, University of Toronto, Mount Sinai Hospital and University Health Network, 60 Murray Street, 6th Floor, Box 19, Toronto, Ontario, M5T 3L9, Canada. e-mail: [email protected] Abbreviations: BC, bladder cancer; CIS, carcinoma in situ; DSS, disease-specific survival; EORTC, European Organisation for Research and Treatment of Cancer; HG, high-grade; IVP, intravenous pyelogram; NMI, non-muscle-invasive; NMIBC, nonmuscle-invasive bladder cancer; TUR, transurethral resection; TUR, transurethral resection.


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