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, Raj Persad, Marc Colombel, Maurizio Brausi  European Urology Supplements  Volume 9, Issue 9, Pages 715-734 (December 2010) DOI: 10.1016/j.eursup.2010.08.005 Copyright © 2010 European Association of Urology Terms and Conditions

Fig. 1 Mean tumour growth rates in mice 8 mo and 10–15 mo after bacillus Calmette-Guérin (BCG) treatment. At 8 mo, BCG did not significantly reduce bladder cancer growth in BCG-treated mice, but by 10–15 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. European Urology Supplements 2010 9, 715-734DOI: (10.1016/j.eursup.2010.08.005) Copyright © 2010 European Association of Urology Terms and Conditions

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<0.0001), 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]. European Urology Supplements 2010 9, 715-734DOI: (10.1016/j.eursup.2010.08.005) Copyright © 2010 European Association of Urology Terms and Conditions

Fig. 3 European Organisation for Research and Treatment of Cancer (EORTC) 30911 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. European Urology Supplements 2010 9, 715-734DOI: (10.1016/j.eursup.2010.08.005) Copyright © 2010 European Association of Urology Terms and Conditions

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. European Urology Supplements 2010 9, 715-734DOI: (10.1016/j.eursup.2010.08.005) Copyright © 2010 European Association of Urology Terms and Conditions

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. European Urology Supplements 2010 9, 715-734DOI: (10.1016/j.eursup.2010.08.005) Copyright © 2010 European Association of Urology Terms and Conditions

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. European Urology Supplements 2010 9, 715-734DOI: (10.1016/j.eursup.2010.08.005) Copyright © 2010 European Association of Urology Terms and Conditions

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. European Urology Supplements 2010 9, 715-734DOI: (10.1016/j.eursup.2010.08.005) Copyright © 2010 European Association of Urology Terms and Conditions

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. European Urology Supplements 2010 9, 715-734DOI: (10.1016/j.eursup.2010.08.005) Copyright © 2010 European Association of Urology Terms and Conditions

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. European Urology Supplements 2010 9, 715-734DOI: (10.1016/j.eursup.2010.08.005) Copyright © 2010 European Association of Urology Terms and Conditions

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. European Urology Supplements 2010 9, 715-734DOI: (10.1016/j.eursup.2010.08.005) Copyright © 2010 European Association of Urology Terms and Conditions

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. European Urology Supplements 2010 9, 715-734DOI: (10.1016/j.eursup.2010.08.005) Copyright © 2010 European Association of Urology Terms and Conditions

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]. European Urology Supplements 2010 9, 715-734DOI: (10.1016/j.eursup.2010.08.005) Copyright © 2010 European Association of Urology Terms and Conditions