EUROPEAN UROLOGY SUPPLEMENTS 9 (2010)

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1 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) available at journal homepage: Maintenance Bacillus Calmette-Guérin: The Standard of Care for the Prophylaxis and Management of Intermediate- and High-Risk Non Muscle-Invasive Bladder Cancer Donald Lamm a, *, Raj Persad b, Marc Colombel c, Maurizio Brausi d a Department of Surgery, University of Arizona; BCG Oncology, Phoenix, Arizona, USA b Department of Urology/Surgery, Bristol Royal Infirmary & Bristol Urological Institute, Bristol, UK c Department of Urology, Claude Bernard University, Hôpital Edouard Herriot, Lyon, France d Department of Urology, AUSL Modena Estense and B Ramazzini Hospitals, Modena, Italy Article info Keywords: Bacillus Calmette-Guérin BCG Chemotherapy Immunotherapy Intravesical therapy Maintenance therapy NMIBC Non muscle-invasive bladder cancer Please visit europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Context: Although bacillus Calmette-Guérin (BCG) is currently regarded as the most effective treatment available for the management of non muscle-invasive bladder cancer (NMIBC), maintenance BCG is underutilised and debate still remains as to whether the routine use of maintenance therapy is required for optimal outcomes. Objective: To review evidence supporting the need for maintenance BCG and provide practical strategies for improving both patient and physician compliance with maintenance regimens. Evidence acquisition: Data from immunologic studies, animal studies, randomised clinical trials, and meta-analyses were reviewed during a satellite symposium at the 25th Annual European Association of Urology (EAU) Congress, held in Barcelona, Spain, in April Evidence synthesis: Three well-designed, long-term clinical trials and various meta-analyses have shown maintenance BCG to be significantly superior to intravesical chemotherapy and induction therapy alone in reducing recurrence, progression, and mortality in patients with intermediate- and high-risk NMIBC. Despite these findings, BCG therapy is underutilised. Experts have questioned whether this is solely due to BCG-associated adverse events or whether other patient- and physician-related factors, such as lack of patient knowledge and physician attitudes, may affect utilisation and adherence to BCG therapy. Conclusions: Recent evidence has addressed controversies surrounding the use of maintenance BCG. Maintenance BCG should now be considered the gold standard therapy for the prophylaxis and management of intermediate- and high-risk NMIBC. Although BCG-associated adverse events are generally considered to be the primary reason for poor adherence, these adverse events can be prevented and successfully managed in most patients. Furthermore, other patient- and physicianrelated factors need to be addressed to help promote adherence to maintenance BCG and optimise outcomes in patients with NMIBC. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. BCG Oncology, PC, North 40th St, Ste E, Phoenix, AZ 85032, USA. Tel ; Fax: address: dlamm@bcgoncology.com (D. Lamm) /$ see front matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 716 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) Introduction Bacillus Calmette-Guérin (BCG) is currently regarded as the most effective treatment available for the management of non muscle-invasive bladder cancer (NMIBC). Numerous randomised trials and subsequent meta-analyses have concluded that maintenance BCG therapy is superior to both chemotherapy and induction BCG alone for the prevention of recurrence and progression of NMIBC [1 9]. As a result, guidelines recommend BCG as the intravesical therapy of choice for high-risk disease [10 12]. Despite the high level of evidence in support of BCG, debate still remains as to whether the routine use of maintenance BCG is justified, particularly in intermediate-risk patients, and whether previous intravesical chemotherapy could bias outcomes in favour of BCG. In addition, although concerns surrounding BCG-associated adverse events have been expressed in the past, our extensive experience with the use of BCG in patients with bladder cancer has shown that these events can be successfully managed and potentially avoided in the majority of cases. To address these controversies and provide a deeper insight into the safety, efficacy, and optimal use of BCG, a distinguished faculty of experts in bladder cancer management reviewed the evidence surrounding maintenance BCG and provided practical strategies for improving both patient and physician compliance with maintenance regimens. This supplement provides a comprehensive summary of the data reviewed by these experts. It is the hope of the authors that the information provided in this supplement will confirm the need for maintenance BCG to optimise the care and management of patients with intermediate- and high-risk NMIBC. 2. Evidence acquisition This supplement is based on presentations given at the satellite symposium entitled, The Value of BCG Maintenance Therapy: What does the data tell us? held at the 25th Annual European Association of Urology (EAU) Congress in Barcelona, Spain, in April These presentations provided a comprehensive overview of data from immunologic studies, animal studies, randomised clinical trials, and meta-analyses that strongly support the role of BCG maintenance therapy as the standard of care for the prophylaxis and management of NMIBC. 3. Evidence synthesis 3.1. Why is maintenance bacillus Calmette-Guérin necessary? In most patients with NMIBC, the risk for tumour recurrence, progression, and death from bladder cancer is lifelong. BCG significantly reduces these risks by inducing both local and systemic immune responses that are associated with an elimination or reduction of non muscle-invasive bladder tumours [13]. Extensive research has demonstrated multiple beneficial immunologic effects of BCG, but T-cell-dependent antitumour effects appear to be most important [14 16]. Although the protective effects of BCG are long term, they are not infinite. In fact, without maintenance therapy, there is no evidence that BCG protects against bladder cancer beyond 10 yr. Furthermore, adequately powered randomised controlled trials using immunologically sound maintenance schedules and meta-analyses have demonstrated that maintenance BCG is superior to both induction BCG and chemotherapy for reducing recurrence, progression, and even death from bladder cancer. This section will review the extensive evidence supporting the need for BCG maintenance therapy Bacillus Calmette-Guérin immunology: protective immunity wanes Data from animal studies have shown that BCG eradication of bladder cancer requires an intact cellular immune system and stimulation of T cells [17]. In mice, for example, BCGinduced immunity can be transferred with T cells [18]. Memory T cells produce an accelerated and heightened immune response upon re-exposure to antigens such as BCG, and regulatory T cells can suppress the immune response in the event of excess stimulation. However, the immune stimulation induced by BCG wanes with time. Studies in humans have shown that BCG vaccination induces immunologic memory to mycobacterial antigens that is still present and measurable for at least 14 yr in the majority of vaccinees, but the magnitude of the response begins to decrease within 3 mo after vaccination [19]. In bladder cancer, BCG protection from tumour recurrence appears to decrease at mo [9], and is completely lost beyond 10 yr following the last instillation [20]. Results obtained from animal studies provide further confirmation that the protective immunity induced by BCG wanes with time. Reichert and Lamm demonstrated that mice that survived transitional cell carcinoma (MBT2) transplantation with the aid of BCG immunotherapy experienced no additional benefit from repeat BCG treatment given at 8 mo after initial BCG treatment, suggesting that effective BCG immune stimulation persists in the mouse for 8 mo and that maintenance is not needed. However, repeat BCG given mo after initial BCG treatment was found to significantly reduce the growth of bladder cancer (Fig. 1), suggesting that in the mouse, BCG immune protection wanes by mo [21]. These findings not only support the need for maintenance BCG, but also indicate that clinical trials with short-term follow-up can mistakenly conclude that maintenance is unnecessary if it is given while the BCG immune response remains strong The need for bacillus Calmette-Guérin maintenance: evidence from randomised clinical trials In 1987, two controlled, single-institution trials showed no significant benefit of maintenance BCG therapy. One of these trials used quarterly single BCG instillations and included only 42 patients followed for a maximum of 33 mo [22]. The other trial compared 6-wk induction BCG with monthly maintenance in 93 patients who were followed for

3 [(Fig._1)TD$FIG] EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) Fig. 1 Mean tumour growth rates in mice 8 mo and mo after bacillus Calmette-Guérin (BCG) treatment. At 8 mo, BCG did not significantly reduce bladder cancer growth in BCG-treated mice, but by mo, BCG significantly reduced tumour growth compared with all other groups ( p < 0.01). Reprinted with permission from the American Urological Association [21]. BCG = bacillus Calmette-Guérin. [(Fig._2)TD$FIG] Fig. 2 Southwest Oncology Group (SWOG) 8507 trial results: (A) recurrence-free survival, (B) worsening-free survival, and (C) survival (in months) by arm (maintenance vs no maintenance) for eligible patients with no evidence of disease at randomisation. With 10-yr follow-up, recurrence was reduced from 52% to 25% ( p < ), worsening-free survival increased from 52% to 60% ( p < 0.04), and overall survival increased from 52% to 58% ( p=0.08, not significant) with bacillus Calmette-Guérin maintenance versus no maintenance. Reprinted with permission from the American Urological Association [1].

4 718 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) yr[23]. Despite the fact that these studies should have been criticised for their lack of power, short follow-up, and lack of well-devised maintenance schedules, they had a major impact on clinical practice and dictated the use of BCG for more than a decade. It is now recognised that in order to demonstrate a statistically significant reduction in tumour recurrence, disease progression, metastasis, and mortality with BCG, clinical trials must 1) use an effective BCG maintenance regimen, 2) consist of an adequate sample size, and 3) have a sufficient duration of follow-up to allow the efficacy of induction BCG to wane. Three randomised clinical trials, all using a 3-wk maintenance schedule, have met these criteria and have demonstrated the unparalleled superiority of maintenance BCG: the Southwest Oncology Group (SWOG) 8507 trial [1], the European Organisation for Research and Treatment of Cancer (EORTC) trial [8], and the Japanese Cooperative Study [9]. In the SWOG 8507 trial, 550 transitional-cell carcinoma (TCC) patients with carcinoma in situ (CIS) or an increased risk of recurrence (defined as two or more episodes of tumour within the most recent year, or three or more tumours within 6 mo) were randomised to BCG induction alone or BCG induction plus 3-wk maintenance given at 3, 6, 12, 18, 24, 30, and 36 mo. A total of 384 subjects were [(Fig._3)TD$FIG] disease free at 3 mo and eligible for comparison. After a median follow-up of 90 mo, maintenance BCG significantly improved median recurrence-free survival (from 36 to 77 mo; p < ) and worsening-free survival (defined as no evidence of progression including pathologic stage T2 disease or greater, or the use of cystectomy, systemic chemotherapy, or radiation therapy; p < 0.04) compared to BCG induction alone (Fig. 2). Despite the increased use of cystectomy, radiation therapy, and systemic chemotherapy in the induction-only group, 5-yr survival increased from 78% to 83% with BCG maintenance ( p=0.08) [1]. In the EORTC trial, patients with intermediate- (n = 497) and high-risk (n = 323) NMIBC without CIS were randomised to receive six, weekly, intravesical instillations of epirubicin, BCG, or BCG plus isoniazid after transurethral resection of the bladder tumour (TURBT). All three groups also received 3-wk maintenance for 3 yr as used in the SWOG trial. After a median follow-up of 9.2 yr, time to first recurrence (hazard ratio [HR], 0.62; p < 0.001), time to distant metastases (HR, 0.55; p=0.046), and overall (HR, 0.76; p=0.023) and disease-specific survival (HR, 0.47; p=0.026) were all significantly prolonged in the two BCG arms combined compared with the epirubicin arm (Fig. 3). However, no difference in progression was noted between the treatment arms. The investigators concluded that both Fig. 3 European Organisation for Research and Treatment of Cancer (EORTC) trial results: (a) cumulative incidence of first recurrence, (b) distant metastases, (c) death due to bladder cancer, and (d) overall duration of survival for patients treated with bacillus Calmette-Guérin (BCG) versus epirubicin. Reprinted with permission from Elsevier [8]. O = observed number of events; N = number of patients.

5 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) intermediate- and high-risk patients benefit from BCG therapy [8]. The positive outcomes noted with 3-wk maintenance BCG in the SWOG 8507 and EORTC trials are further supported by recent results from the Japanese Cooperative Study [9]. In this study, 115 patients who had been diagnosed with multiple or recurrent NMIBC (stage Ta or T1) without CIS after a complete TURBT were randomised to epirubicin for 2 wk and every other week for 7 wk, induction BCG for 6 wk, or induction plus maintenance BCG given as three weekly instillations at 3, 6, 12, and 18 mo (half the duration of the SWOG wk maintenance schedule). At 2 yr, recurrence-free survival was 85% in the BCG induction plus maintenance group, 65% in the induction only group, and 28% in the epirubicin group. Recurrence-free survival was significantly prolonged in the combined BCG group compared with the epirubicin group ( p < ), and in the BCG maintenance versus nonmaintenance group ( p=0.019). Figure 4 presents the smoothed recurrence hazard curves for epirubicin, and induction and maintenance BCG. As can be seen in the figure, a high recurrence hazard continued for 2 yr post TURBT with epirubicin, whereas a reduction in recurrence was seen after 6 mo with induction BCG. Most notable is the suppression of recurrence with 3-wk maintenance that was maintained for up to 2 yr after TURBT [9]. Progression rates at the time of first recurrence were also significantly lower in the combined BCG group versus the epirubicin group ( p=0.0047) and in the maintenance BCG group versus the epirubicin group ( p=0.0021). Although no statistically significant difference was found between the BCG maintenance and nonmaintenance arms in terms of progression, no cases of progression were noted in the maintenance arm [9]. In summary, although early, inadequately powered clinical trials using suboptimal maintenance regimens initially refuted the value of maintenance BCG, three well-designed, long-term trials have now confirmed the unparalleled superiority of the 3-wk maintenance BCG [(Fig._4)TD$FIG] regimen in reducing recurrence, progression, and mortality in patients with NMIBC The need for bacillus Calmette-Guérin maintenance: evidence from meta-analyses In addition to the randomised clinical trials discussed above, numerous meta-analyses further confirm that maintenance BCG therapy reduces recurrence and disease progression in patients with NMIBC and is required to demonstrate the uniform superiority of BCG over chemotherapy [2 7]. The most compelling evidence supporting the need for BCG maintenance comes from a large EORTC meta-analysis of 24 trials involving 4863 patients. Five different BCG strains were used; in 20 of the 24 trials some form of BCG maintenance was used. In four trials, only a 6-wk induction course was applied. Based on a median follow-up of 2.5 yr and a maximum of 15 yr, 260 of 2658 patients (9.8%) on BCG progressed compared with 304 of 2205 (13.8%) in the control groups (TURBT alone, TURBT plus intravesical chemotherapy, or TURBT plus another immunotherapy). Overall, treatment with BCG was associated with a 27% reduction in the risk of tumour progression. Similar effects were reported in the patients with Ta,T1 papillary tumours and in those with CIS [2]. The results of this EORTC meta-analysis also demonstrate that maintenance BCG therapy is required for optimal efficacy. No reduction in progression was noted in the four trials in which maintenance BCG therapy was not administered. However, in the 20 trials in which some form of BCG maintenance was given, a reduction of 37% in the risk of progression was observed ( p= ). The Forest plot of progression according to the use of BCG maintenance is shown in Fig. 5 [2]. Another EORTCmeta-analysis of nine randomised trials, including 700 patients with CIS, compared BCG with mitomycin C (MMC), epirubicin, adriamycin, or sequential MMC/adriamycin. A complete response was noted in 203 of the 298 patients on BCG (68.1%) compared with 158 of the 307 patients on chemotherapy (51.5%), which Fig. 4 Japanese Cooperative Study results: smoothed recurrence hazard curves for epirubicin, bacillus Calmette-Guérin (BCG) without maintenance, and BCG with maintenance. Reprinted with permission from BJU International [9]. EPI = epirubicin.

6 720 [(Fig._5)TD$FIG] EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) Fig. 5 Forest plot of progression by bacillus Calmette-Guérin (BCG) maintenance. Reprinted with permission from the American Urological Association [2]. OR = odds ratio; CI = confidence interval; SD = standard deviation; maint = maintenance BCG therapy; O-E = observed number of progressions minus expected number of progressions; Var = variance. represents a 47% reduction in the odds of nonresponse on BCG (odds ratio [OR], 0.53; 95% confidence interval [CI], ; p=0.0002). Furthermore, BCG was found to be superior to MMC only in the trials where maintenance therapy was provided (OR, 0.57; 95% CI, ; p=0.04) (Fig. 6) [5]. In a meta-analysis of 11 clinical trials involving 2749 patients with Ta, T1 disease, BCG was also found to be superior to MMC in reducing tumour recurrences (OR, 0.56; 95% CI, ; p=0.005). Approximately 39% of patients treated with BCG experienced a tumour recurrence compared with 46% of patients treated with MMC. Furthermore, all six studies using BCG maintenance therapy found BCG to be significantly superior to MMC for reducing [(Fig._6)TD$FIG] recurrences (OR, 0.42; p=0.001), compared with only one of five studies not using maintenance BCG (Fig. 7) [3]. Another meta-analysis of nine clinical trials comparing BCG and MMC in 2410 patients followed for a median of 26 mo found no significant difference in progression between the MMC (9.44%) and BCG (7.67%) groups. However, in the five studies in which BCG maintenance was provided, a significant 34% reduction in tumour progression was noted (OR, 0.66; p=0.02) (Fig. 8) [4]. A meta-analysis conducted by investigators in China adds to the overwhelming evidence confirming the superiority of maintenance BCG. In this meta-analysis of 4767 patients from 25 clinical trials, BCG treatment was associated with a significant 39% reduction in the odds of Fig. 6 European Organisation for Research and Treatment of Cancer (EORTC) meta-analysis of carcinoma in situ trials: Forest plot of no evidence of disease in studies with mitomycin C according to bacillus Calmette-Guérin (BCG) maintenance. Reprinted with permission from the American Urological Association [5]. Pub = publication; OR = odds ratio; CI = confidence interval; SD = standard deviation; O-E = observed number minus expected number; Var = variance; Chemo = chemotherapy.

7 [(Fig._7)TD$FIG] EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) Fig. 7 Forest plot of tumour recurrence (all studies by maintenance) with odds ratio (OR) as effect size. Lines indicate 95% confidence interval (CI) and squares indicate OR estimates, whereas square size is proportional to sample size, and rhombi meta-analytically pooled OR estimates plus or minus 95% CI. Reprinted with permission from the American Urological Association [3]. BCG = bacillus Calmette-Guérin; Mainten = BCG maintenance regimen; Lower, Upper = lower and upper 95% CI of OR; P = p value (2 sided); Ntotal = total sample size; n/n = number of events per number of cases in treatment group; Fixed = fixed effect model; Random = random effect model; MMC = mitomycin C. recurrence compared with no BCG treatment (OR, 0.61; 95% CI, ; p < ), and maintenance BCG significantly reduced the odds of recurrence by 53% compared with no maintenance (OR, 0.47; 95% CI, ; p=0.004). In addition, papillary disease was found to be more responsive than CIS (OR, 0.50; 95% CI, ; p=0.0008). Therefore, the investigators concluded that adjuvant intravesical BCG with maintenance should be the treatment of choice for patients with papillary carcinoma [6]. In individual patient data (IPD) meta-analyses, data on each participant from every relevant trial are centrally collected, processed, and analysed. Results from a recent IPD meta-analysis of nine trials that included 2820 patients further highlight the importance of BCG maintenance [(Fig._8)TD$FIG] therapy. This meta-analysis found no overall difference in the time to first recurrence ( p=0.09) between BCG and MMC. However, in the trials using BCG maintenance, a 32% reduction in the risk of recurrence with BCG versus MMC was found ( p < ), while there was a 28% risk increase ( p=0.006) for BCG in the trials without maintenance (Fig. 9) [7]. It should be noted, however, that the four studies showing an overall recurrence benefit with MMC when no BCG maintenance was used involved study populations who were at relatively low risk for recurrence. Furthermore, two of the studies used what is potentially reported to be an immunosuppressive schedule of BCG: primarily two 6-wk courses. This schedule has been shown to be no more effective than induction therapy alone. The other two Fig. 8 Forest plot of tumour progression according to bacillus Calmette-Guérin (BCG) maintenance in trials comparing BCG versus mitomycin C (MMC). Lines indicate 95% confidence interval (CI), squares indicate odds ratio (OR) estimates, whereas square size is proportional to sample size, and rhombi represent meta-analytically pooled OR estimates plus or minus 95% CI. Reprinted with permission from Elsevier [4]. Lower, Upper = lower and upper 95% CI of OR; Ntotal = total sample size; n/n = number of events per number of cases in treatment group; Fixed = fixed effect model; Random = random effect model.

8 722 [(Fig._9)TD$FIG] EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) Fig. 9 Individual patient data meta-analysis results: time to first recurrence per treatment group in: (a) all patients, (b) no bacillus Calmette-Guérin (BCG) maintenance, and (c) BCG maintenance. Reprinted with permission from Elsevier [7]. MMC = mitomycin C; O = observed number of events; N = number of patients. studies used no maintenance BCG and compared it with an extended MMC schedule. Therefore, according to Lamm and colleagues, these data suggest that in lower-risk patients, MMC maintenance reduces recurrence by 11% (43.6% vs 31.8%) compared with suboptimal BCG immunotherapy [24]. Although no significant survival advantage with BCG was found in the IPD meta-analysis, bladder cancer deaths were lower in the BCG group (ie, 5.6% vs 9.3% in the MMC group), and cystectomy was done in only 8.6% of the BCG-treated patients versus 15% of the MMC-treated subjects [7]. It is again important to highlight that although no survival advantage was noted with BCG, only one study included in this IPD meta-analysis used the SWOG 3-wk maintenance regimen, which has been shown to reduce recurrence, progression, and death from bladder cancer [1,8]. Meta-analyses have the power to detect differences between treatment groups that are not always detectable in clinical trials. The various meta-analyses discussed in this section have confirmed the superiority of maintenance BCG in reducing tumour recurrences and progression in NMIBC compared with chemotherapy or induction therapy alone. A recent Cochrane review of >80 randomised trials and 11 meta-analyses concluded that the majority of the available evidence indicates that intravesical BCG therapy with maintenance should be the gold standard treatment regimen for patients with intermediate- and high-risk NMIBC. The Cochrane investigators further suggested that chemotherapy be regarded as an option for those failing, or who are unsuitable for, BCG therapy [25] Optimal bacillus Calmette-Guérin maintenance schedule At present there is no uniform consensus on the most appropriate BCG maintenance schedule. However, as discussed earlier, results from the SWOG 8507 and EORTC trials suggest that the SWOG regimen of three weekly instillations at 3 and 6 mo post induction and every 6 mo thereafter for up to 3 yr leads to the best outcomes in terms of reducing progression, recurrence, and mortality in NMIBC. In fact, this regimen has been recommended by the International Bladder Cancer Group (IBCG), the First International Consultation on Bladder Tumours (FICBT), and the American Urological Association (AUA) [10,11, 26,27]. The EAU acknowledges that, based on the extent of

9 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) intravesical immune response, three consecutive weekly instillations give a maximum response, and recommends that at least 1 yr of maintenance therapy be provided [11]. Although the optimal dose of BCG is unknown, most clinical studies and meta-analyses have utilised standard dosing, and this remains the global standard of care. Evidence suggests that one-third dose BCG provides similar results for recurrence and progression as standard-dose BCG [28,29]. However, these results also indicate that patients with multifocal tumours fared better with the standard dose ( p=0.048) and there was a trend towards lower recurrence rates in patients with high-risk tumours receiving the full BCG dose ( p=0.082) [28] Treatment goals The treatment goals for intermediate-risk disease differ slightly among the various clinical practice guidelines available for the management of NMIBC. The EAU, for example, indicates that the treatment goal in these patients is the prevention of disease recurrence and progression [11], while the AUA considers prevention or delay of recurrence as the primary treatment goal [10]. Despite the differences in therapeutic goals for intermediate-risk NMIBC, all guidelines agree that the primary goal in patients with high-risk disease is the prevention or delay of disease progression. However, one can argue that the prevention of recurrences is also a reasonable treatment goal for high-risk NMIBC. One-year recurrence rates in patients with high-risk disease range from 55 67% [30]. Frequent recurrences necessitate repeat TURBTs, and although repeat resections may improve outcomes in patients with NMIBC, they are also associated with increased costs, anaesthetic risks, and, most importantly, an increased risk of complications that can lead to bladder damage [31]. In fact, the complication rate associated with repeat TURBTs has been estimated to be as high as 20%, and includes such complications as bladder perforation, urethral strictures, prostatitis, pyelonephritis, epididymitis, cystitis, thrombosis, pulmonary embolisms, bleeding, and cardiac events. Bladder perforation, in particular, is more likely to occur when resecting at a previous resection site, and has been associated with the potential for tumour seeding and progression, as well as an increased incidence of urinary tract infections and septicaemia [32]. Therefore, reducing tumour recurrences may help preserve bladder physiology and reduce the potential for bladder damage that can result from repeated TURBTs. Furthermore, most events of disease progression are detected during the course of repeated tumour recurrences in the bladder. Hence, it has been postulated that achieving recurrence-free survival over a long period of time by using maintenance BCG will also reduce the risk of progression [9] Bacillus Calmette-Guérin maintenance is more effective than chemotherapy in intermediate-risk non muscle-invasive bladder cancer All current clinical practice guidelines agree that adjuvant therapy with either BCG or chemotherapy is necessary in intermediate-risk NMIBC. However, recent data from both the EORTC trial and the IPD meta-analysis by Malmström et al suggest that BCG with maintenance is superior to chemotherapy for intermediate-risk disease and should be the intravesical therapy of choice for this patient population [7,8]. The EORTC trial compared the long-term efficacy of six weekly intravesical instillations of epirubicin, BCG, and BCG plus isoniazid followed by three weekly maintenance instillations of epirubicin or BCG at months 3, 6, 12, 18, 24, 30, and 36 after TURBT in 837 patients with high (defined as stage T1 or G3 tumours) and intermediate-risk NMIBC (defined as neither stage T1 and/ or G3 tumours). The majority of patients included in this trial were classified as intermediate-risk (ie, approximately 60%). After a median follow-up of 9.2 yr, overall results showed that time to first recurrence ( p < 0.001), time to distant metastases ( p=0.046), and disease-specific survival ( p=0.026) and overall survival ( p=0.023) were all significantly prolonged in the two BCG arms combined compared with the epirubicin arm. When the investigators further examined the data according to whether patients were intermediate or high risk, the observed treatment benefit was found to be at least as large, if not larger, in the intermediaterisk group. For the majority of events analysed, treatmentcomparison hazard ratios (HRs) were more extreme in the intermediate-risk patients (Table 1) [8]. According to the investigators, the apparently larger effect of BCG in intermediate-risk patients may have been due to the fact that, at the time of study enrolment, secondlook TURBTs were not standard practice. Therefore, some high-risk patients may have had residual T2 disease for which intravesical therapy is not effective. Furthermore, the 1973 World Health Organisation (WHO) grading system was used to classify tumours in this study. Hence, it is possible that some of the G2 intermediate-risk tumours would have been reclassified as high risk if the 2004 WHO grading system had been utilised; this potentially could have reduced the observed disparity in results between intermediate- and high-risk patients. It has also been postulated that, as a nonspecific immunotherapy, BCG may be more effective in patients with a lower tumour burden. In fact, data from animal studies have consistently shown that the efficacy of BCG is limited by tumour burden. Although no significant effect of BCG on disease progression was found in this trial, the investigators noted that there were too few progressions (ie, 25) to make meaningful comparisons in this regard [8]. Furthermore, other experts have argued that metastases and death from bladder cancer (both of which were significantly reduced with BCG maintenance) are clear and universally accepted signs of disease progression. As such, these experts have argued that it is erroneous to state that the EORTC trial showed no significant effect of BCG maintenance on disease progression. As discussed earlier, the IPD meta-analysis by Malmström et al found a significant 32% reduction in the risk of recurrence with BCG versus MMC in the trials using BCG maintenance ( p < ). It should be noted that the majority of patients included in this IPD meta-analysis were

10 724 Table 1 European Organisation for Research and Treatment of Cancer (EORTC) results: comparison of epirubicin and bacillus Calmette-Guérin (BCG) in the intermediate- and high-risk groups and the total study population * Intermediate risk High risk Total Events/patients (%) HR (95% CI) p value Events/patients (%) HR (95% CI) p value Events/patients (%) HR (95% CI) p value Recurrence Epirubicin 100/170 (58.8) 1 46/104 (44.2) 1 147/279 (52.7) 1 BCG 131/327 (40.1) 0.59 ( ) < /219 (37.4) 0.69 ( ) /558 (38.2) 0.62 ( ) <0.001 Progression Epirubicin 12/170 (7.1) 1 12/104 (11.5) 1 24/279 (8.6) 1 BCG 13/327 (4.0) 0.56 ( ) /219 (13.2) 0.92 ( ) /558 (7.5) 0.84 ( ) 0.55 Distant metastases Epirubicin 15/170 (8.8) 1 9/104 (8.7) 1 24/279 (8.6) 1 BCG 12/327 (3.7) 0.42 ( ) /219 (7.3) 0.66 ( ) /558 (5.0) 0.55 ( ) Progression or distant metastases Epirubicin 23/170 (13.5) 1 16/104 (15.4) 1 39/279 (14.0) 1 BCG 17/327 (5.2) 0.39 ( ) /219 (15.5) 0.80 ( ) /558 (9.1) 0.63 ( ) Death: all causes Epirubicin 66/170 (38.8) 1 40/104 (38.5) 1 106/279 (38.0) 1 BCG 99/327 (30.3) 0.79 ( ) /219 (33.3) 0.68 ( ) /558 (30.8) 0.76 ( ) Death: bladder cancer Epirubicin 12/170 (7.1) 1 7/104 (6.7) 1 19/279 (6.8) 1 BCG 8/327 (2.4) 0.35 ( ) /219 (5.0) 0.60 ( ) /558 (3.4) 0.47 ( ) BCG = bacillus Calmette-Guérin; CI = confidence interval; HR = hazard ratio. * Reprinted with permission from Elsevier [8]. EUROPEAN UROLOGY SUPPLEMENTS 9 (2010)

11 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) intermediate risk (74%), further confirming the superiority of BCG maintenance therapy in this patient population. It is also important to highlight that although no significant difference in progression and death were noted between treatment groups, the low number of these events in this primarily intermediate-risk cohort precluded such an analysis [7]. Both this meta-analysis and the EORTC trial support the conclusions of a recent Cochrane review, which states that maintenance BCG should be the gold-standard intravesical therapy for patients with intermediate-risk NMIBC [25] Previous chemotherapeutic treatment does not bias results in favour of bacillus Calmette-Guérin Investigators have questioned the value of BCG therapy on the basis that the inclusion of patients previously treated with chemotherapy in clinical trials may have biased study results in favour of BCG [33,34]. However, results from the IPD meta-analysis by Malmström et al have finally put to rest this proposition. As can be seen in Fig. 10, BCG with maintenance was more effective than MMC in both patients previously treated and those not previously treated with chemotherapy [7] Heterogeneity of intermediate-risk non muscle-invasive bladder cancer: impact on the use of bacillus Calmette-Guérin NMIBC represents a heterogeneous group of tumours with varying oncologic outcomes. In recent years, low-, intermediate-, and high-risk categories have been defined, based on tumour stage and grade, that can be used to predict prognosis and to guide the treatment of patients with NMIBC. Traditionally, bladder carcinomas have been graded according to the WHO 1973 grading of urothelial papilloma: well-differentiated (G1), moderately differentiated (G2), or poorly differentiated (G3). However, this system has been criticised for the lack of clear definitions for the three grades and the high percentage of NMIBC cases classified as the intermediate-grade G2 (the default diagnosis). In an [(Fig._10)TD$FIG] attempt to address these criticisms, the WHO and the International Society of Urological Pathology (ISUP) published a new grading system in 2004 that differentiates between papillary urothelial neoplasms of low-malignant potential (PUNLMP) and low-grade and high-grade urothelial carcinomas [35,36]. Comparisons of the 1973 and 2004 classification systems are shown in Fig. 11 [37]. As can be seen in the figure, the intermediate grade (G2), which was the subject of controversy in the 1973 WHO classification, has been eliminated. Although the use of this new system is purported to result in a more uniform diagnosis of tumours, which will be better classified according to risk potential, all clinical practice guidelines recommend that tumours be graded using both the 1973 and 2004 WHO classifications until the 2004 system has been further validated. While the classifications of low-risk (ie, solitary, primary TaG1) and high-risk disease (ie, any T1, G3, or CIS) have been well-defined using the 1973 WHO grading system, the intermediate-risk category has traditionally comprised all patients excluded from either of these categories. As a result, intermediate-risk disease, which represents approximately 35% of all cases of NMIBC, consists of a heterogeneous group of patients ranging from those with solitary, but recurrent, TaG1 tumours to those with multiple, recurrent TaG2. Therefore, the intermediate-risk category can be subdivided into those with low-intermediate-risk disease and those with high-intermediate-risk disease. Given the heterogeneity of the intermediate-risk group, most guidelines have proposed that management involve either adjuvant chemotherapy or BCG following a complete TURBT. However, according to the EORTC risk tables, intermediate-risk patients are not only at high risk of recurrence, but also have a risk of progression of up to 17% at 5 yr (Table 2) [30]. Since maintenance BCG has been shown to be superior to chemotherapy for the prevention of both disease recurrence and progression, many patients with intermediate-risk disease will benefit from maintenance BCG therapy. Until further validation of the 2004 Fig. 10 Individual patient data meta-analysis results: time to first recurrence per treatment group in those treated with bacillus Calmette-Guérin (BCG) maintenance and (a) no prior chemotherapy or (b) prior chemotherapy. Reprinted with permission from Elsevier [7]. MMC = mitomycin C; O = observed number of events; N = number of patients.

12 726 [(Fig._1)TD$FIG] EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) Fig. 11 Comparison of the 1973 and 2004 World Health Organisation (WHO) grading systems. Some 1973 WHO grade 1 carcinomas are reassigned to the papillary urothelial neoplasm of low malignant potential (PUNLMP) category and others to the 2004 WHO low-grade carcinoma category. Similarly, 1973 WHO grade 2 carcinomas are reassigned, some to the low-grade carcinoma category, and others to the high-grade carcinoma category. All 1973 WHO grade 3 tumours are assigned to the 2004 WHO high-grade carcinoma category. Reprinted with permission from Elsevier [37]. TCC = transitional cell carcinoma. WHO grading system, the relative advantages of intravesical BCG in intermediate-risk disease need to be considered on a case-by-case basis, taking into account the patient s previous history, his or her overall condition, and the patient s individual risk for recurrence and progression based on tumour characteristics [8] Given the overwhelming evidence in support of maintenance bacillus Calmette-Guérin therapy, why is it still not being optimally used in the management of non muscle-invasive bladder cancer? Despite the highest level of evidence and guideline recommendations supporting the need for maintenance BCG therapy in intermediate- and high-risk NMIBC, intravesical BCG is still being underutilised. For example, the Surveillance, Epidemiology, and End Results (SEER) study, which examined data from 685 patients with primary NMIBC treated in US academic institutions, found that intravesical therapy was used in only 31% of these patients. In the subset of 350 high-risk patients, only 42% received intravesical therapy, suggesting that BCG therapy is significantly underused and that patients with high-risk NMIBC are severely undertreated [38]. Even in published clinical trials, BCG drop-out rates have been shown to range from 3% to 32% (Table 3) [28,29,39 48]. In the SWOG trial that used 3-wk maintenance BCG, only 16% of study participants completed all seven planned cycles, and less than half completed more than three cycles [1]. Although BCG-associated adverse events are common reasons for the Table 2 Probability of recurrence and progression in intermediate-risk non muscle-invasive bladder cancer [30] Probability of recurrence % 1 yr yr Probability of progression % 1yr <1 5 5 yr 1 17 poor compliance with BCG noted in these studies, other patient- and physician-related factors also appear to be responsible for the less-than-optimal use of maintenance BCG Bacillus Calmette-Guérin toxicity is not the only factor The success of BCG immunotherapy relies on the intravesical administration of live BCG and the generation of a localised immune response in the bladder. Since BCG is a live bacterium, it has the potential to produce local and systemic adverse events. Historically, poor technique and nonrecognition of a BCG-related systemic adverse event has led to serious morbidity and, in rare instances, mortality. In fact, early publications reporting deaths due to BCG sepsis and the high prevalence of other BCG-associated adverse events, such as cystitis, have strongly influenced patients fears and physicians attitudes towards the use of BCG. However, with increasing experience in applying BCG, the side-effects now appear to be less prominent, and few, if any, deaths due to BCG therapy have been reported in the recent literature. In fact, serious side-effects are encountered in < 5% of treated Table 3 Bacillus Calmette-Guérin (BCG) drop-out rates in published clinical studies of BCG therapy * Study Patients (n) Study withdrawal (%) Lamm 1995 [39] Krege 1996 [40] Witjes 1996 [41] Jimenez-Cruz 1997 [42] 61 4 Witjes 1998 [43] Ali-El Dein 1999 [44] 58 7 van der Meijden 2001 [45] Martinez-Pineiro 2002 [28] Martinez-Pineiro 2005 [29] de Reijke 2005 [46] Colombel 2006 [47] Di Stasi 2006 [48] * Reproduced with permission from Marc Colombel [56].

13 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) patients, and most adverse events can be effectively managed in virtually all cases [49]. Cystitis is the most common side-effect of BCG, occurring in approximately 80% of BCG-treated patients, and is the most frequently cited reason for postponement of BCG instillations. Haematuria frequently occurs with cystitis and appears to be related to the extent of the previous TURBT [50,51]. More severe local side-effects associated with BCG therapy include granulomatous prostatitis and epididymo-orchitis, which appear to be caused by BCG-contaminated urine. Although rare, a contracted bladder and ureteral obstructions may also occur. A contracted bladder appears to be associated with multiple TURBTs and maintenance instillations, while ureteral obstructions are likely due to resection and subsequent fibrosis around the ureteral orifice [40,52 54]. BCG-associated systemic side-effects are less frequent than local side-effects but are more likely to be severe. The most common systemic side-effects associated with BCG therapy are general malaise, fever, myalgia, and nausea. Low-grade fever has been shown to develop in about 30% of BCG-treated patients, while fever >39 8C has been reported in 5 20%. These side-effects generally resolve within 48 h, with or without the use of antipyretics [49]. Although rare, a systemic BCG reaction is a systemic granulomatous illness that may occur subsequent to BCG exposure. Because it is usually difficult to isolate BCG organisms from affected organs, it is often unclear to what extent such a reaction is caused by an infectious process versus an inflammatory hypersensitivity reaction, hence the term systemic BCG reaction [49]. BCG infection is rare and usually occurs immediately after instillation. It is generally associated with high-grade fever and may progress to multiple organ failure. BCG infection generally occurs in patients receiving BCG soon after TURBT and may be associated with intravenous absorption resulting from traumatic catheterisation. Allergic reactions to intravesical BCG are also rare, but may include skin rashes and arthralgia [49]. Although these BCG-associated adverse events are a common reason for nonadherence to maintenance BCG regimens, approximately 30 50% of patients stop BCG therapy without medical cause or for other reasons [55 57]. These findings suggest that there are also other patient- and physician-related factors that affect compliance with BCG maintenance therapy. Adherence to any long-term therapy is a complex behavioural process that is strongly influenced by the health care providers practice and the health care system, disease- and treatment-related factors, as well as patientrelated factors. Patient-related factors that have been shown to affect adherence include patients knowledge and belief about their illness and treatment; motivation to manage their illness; confidence in their ability to follow the treatment regimen; fear of possible side-effects; lack of communication with health care providers; lack of family or social support networks; and unrealistic expectations regarding the outcomes of treatment and the consequences of poor adherence [58]. Various physician- or health care provider-related factors can also negatively affect adherence to BCG maintenance therapy. One of the major factors affecting the use of maintenance BCG is the treating urologist s belief in the value of maintenance therapy. If the urologist fails to acknowledge Level 1 evidence from well-designed clinical trials, as well as current guideline recommendations supporting the need for BCG maintenance, then it is unlikely that the patient will even be scheduled for maintenance therapy. Furthermore, the assessment and management of BCG-associated adverse events is subjective, and strongly associated with the personal opinions of the treating physician towards BCG, as well as his or her knowledge regarding the prevention and management of these adverse events. Some urologists believe that BCG only works if side-effects are observed. However, large, randomised, controlled trials have found no difference in BCG efficacy between patients experiencing and not experiencing adverse events [59,60]. Therefore, BCG toxicity does not appear to be a prognostic factor for treatment efficacy. There is also a common misconception among physicians and other health care providers that BCG-associated adverse events will increase with maintenance therapy. Therefore, many physicians opt to use induction therapy alone or discontinue maintenance therapy early to protect their patients from severe adverse events. However, evidence has shown that BCG-associated side-effects are generally seen during induction and the first 6 mo of maintenance therapy [57,60]. During further maintenance, BCG-related adverse events do not significantly increase and instillations are generally well tolerated [60]. Furthermore, many physicians fail to realise that most BCG-associated side-effects can be prevented and/or managed successfully in the majority of patients. Therefore, in addition to the potential adverse events of BCG therapy, many patient- and physician- or health care provider-related factors can affect compliance with long-term maintenance therapy, and these need to be addressed to achieve adherence and optimal outcomes in patients with NMIBC Impact of noncompliance with bacillus Calmette-Guérin therapy Evidence has shown that early discontinuation of BCG therapy has a deleterious impact on patient outcomes. Andius et al, for example, performed a retrospective analysis of clinical records from a cohort of 236 patients with NMIBC (papillary stage Ta/T1) treated with BCG and found an increased risk of progression in patients who discontinued induction therapy (HR, 0.334; 95% CI, ; p=0.002) [61]. Another, more recent, retrospective analysis of 106 Japanese patients with NMIBC who had undergone an initial course of BCG therapy after TURBT also found discontinuation of BCG therapy to be an independent predictor for tumour recurrence (relative risk [RR], 2.06; p=0.018) [62]. A prospective study of 111 patients with NMIBC at high risk of recurrence and who were scheduled to receive BCG per the SWOG 3-wk, 3-yr maintenance schedule found that patients who received at least three maintenance BCG

14 728 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) cycles had a significantly reduced risk of recurrence compared with patients receiving only induction BCG (HR, 0.23; p=0.0064). Twelve months after the completion of maintenance, recurrence-free survival was 89% for patients who received at least three maintenance BCG cycles, 67% for those who received two maintenance cycles, and 41% for those who received only induction therapy or one maintenance cycle ( p=0.0003) [63]. Recently, Picard and colleagues retrospectively examined the impact of BCG discontinuation on recurrence and progression in 302 patients with NMIBC from two urology academic centres in France. The investigators found discontinuation of BCG therapy to be an independent predictor of disease recurrence. Kaplan-Meier survival curves showed that discontinuation of BCG induction therapy significantly increased the risk of both recurrence and progression. Early discontinuation of maintenance therapy was also associated with an increased risk of recurrence and a trend toward increased disease progression (Fig. 12) [56]. These findings confirm that noncompliance to BCG therapy leads to suboptimal outcomes in patients with NMIBC Improving physician compliance with maintenance bacillus Calmette-Guérin The first step in improving compliance with maintenance BCG is to ensure that physicians are both aware of and believe in the value of maintenance therapy. As discussed earlier, evidence from well-designed randomised clinical trials using effective maintenance schedules (ie, the SWOG 3-wk, 3-yr regimen) as well as various meta-analyses have confirmed that maintenance BCG is necessary to achieve optimal outcomes in patients with NMIBC. Physicians also need to be aware of and apply current evidence-based guidelines for the management of intermediate- and highrisk NMIBC. The key influencing clinical practice guidelines from the EAU, the FICBT, the National Comprehensive Cancer Network (NCCN), and the AUA all regard BCG as the [(Fig._12)TD$FIG] gold-standard treatment for high-risk patients. Given the superiority of BCG over chemotherapy in reducing tumour recurrences and disease progression, the EAU, FICBT, NCCN, and AUA guidelines all advocate a role for BCG in the management of intermediate-risk disease [10 12,27]. According to the NCCN, BCG is the preferred intravesical option for these patients [12]. Furthermore, all guidelines emphasise the importance of a maintenance schedule for optimal BCG efficacy and advocate a minimum of 1 yr of BCG maintenance therapy. Physicians should also recognise that BCG-related adverse events can be treated successfully in most patients (even those with serious side-effects), and that the keys to management of these adverse events are education, prevention, and awareness. Education on correct catheterisation techniques and the use of overall good clinical practice with regard to BCG administration will help prevent most BCG-associated adverse events (Table 4) [49]. Good clinical practice with respect to BCG administration requires that BCG only be instilled after a minimum of 2 wk following a TURBT. If gross haematuria is present, BCG should be delayed until this has resolved. If the patient has a urinary tract infection (UTI), then BCG treatment is deferred until resolution of the UTI with antibiotics. If the catheterisation is traumatic, then BCG instillations should be deferred for 1 wk. Furthermore, if a BCG systemic reaction is suspected, then early initiation of antitubercular and quinolone antibiotics is recommended. Recognition and early treatment of suspected BCG systemic reactions will help eliminate virtually all serious adverse events [49]. Variations in the reported frequency of BCG-associated adverse events appear to be caused by variations in the dose of BCG instillations. Although the optimal dose of BCG is unknown, most clinical studies have utilised standard dosing, and this remains the global standard of care. However, dose reductions may be a reasonable option for the prevention of BCG-associated adverse events, particularly for those patients known to be intolerant to Fig. 12 Kaplan-Meier analysis of (A) recurrence-free survival and (B) progression-free survival in patients who discontinued induction bacillus Calmette- Guérin (BCG), completed induction only, discontinued maintenance BCG, or completed induction and maintenance therapy. Reproduced with permission from Marc Colombel [56].