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All Bacillus Calmette-Gue´rin (BCG) Strains Are Equal, but Some BCG Strains Are More Equal Than Others Aidan P. Noon, Girish S. Kulkarni * University of Toronto, Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, Toronto, Canada

Thirty-seven years have elapsed since the first report by Morales et al. [1] on intravesical bacillus Calmette-Gue´rin (BCG) treatment for urothelial bladder carcinoma. One could be forgiven for expecting that clinical differences between BCG strains would be well elucidated by now; unfortunately, that is not the case. The reasons for assuming a lack of clinical equivalence between available BCG strains are becoming more obvious. They include (1) observed differences among BCG response rates in randomised trials comparing one particular BCG strain with other chemotherapeutic intravesical agents (this reason was cited as a rationale for a trial started in the early 1980s [2]), (2) perceived differences in BCG strains in their role as a vaccine for tuberculosis, and (3) differences among commercially available BCG strains in terms of their number of colonyforming units per standard dose [3]. To this list, we can add new, emerging data of sophisticated genetic differences elucidated among the BCG strains [4]. What are the reasons for the lack of comparative trials among different BCG strains? Due to BCG’s unique discovery and history of global distribution (reviewed by Gan et al. [4]), many early researchers simply used the strain of BCG available to them in their countries and focused their attentions on proving BCG efficacy (against other intravesical chemotherapeutic agents) and on how best to administer it. Another speculative explanation could be a lack of commercial interest from BCG manufacturers in initiating such trials. A lack of comparative effectiveness may have contributed to wide variation in intravesical BCG strain use around the world, with more than seven different strains used in the contemporary era. Some of the variation is related to

changes in governance, as illustrated in Switzerland in 1994, changes in availability due to global production shortages [5], and a lack of definitive level 1 evidence favouring any one particular strain. The Swiss situation arose when, in 1994, BCG Pasteur was withdrawn from the market, leaving Connaught and TICE as the only available options. Admirably, sensing an opportunity to evaluate the efficacy of the available BCG strains, a prospective randomised trial was established, the results of which are reported by Rentsch et al. [6] in this issue of European Urology. In this nonblinded prospective randomised controlled trial, 132 of the originally randomised 142 patients with high-risk, non–muscle-invasive bladder cancer (NMIBC) received either BCG Connaught (n = 71) or BCG TICE (n = 60) as six weekly instillations following transurethral resection of bladder tumour. The 5-year recurrence-free survival rate was 74% for BCG Connaught and 48% for BCG TICE, which was significantly different ( p = 0.01); however, no statistically significant difference was observed for progressionfree-survival and overall survival. This is the second time that BCG TICE has been compared with another BCG strain: Vegt et al. [7] in the Dutch Cooperative Trial also compared BCG TICE and BCG RIVM (Dutch) and mitomycin C (a summary of comparative trials of different BCG strains is shown in Table 1). The Dutch Cooperative Trial eventually concluded that there was no difference between the strains but hinted at the possible inferiority of BCG TICE [7]. Between 1988 and 1991, a multicentre UK study successfully recruited 99 patients for a randomised trial comparing the UK BCG strain (Glaxo) and the Pasteur strain [8]. In this trial, no statistical difference was observed at 3 mo between the two strains. It is unfortunate that the trial

DOI of original article: * Corresponding author. University of Toronto, Division of Urology, 3-130, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Tel. +1 416 924 2555; Fax: +1 416 946 6590. E-mail address: [email protected] (G.S. Kulkarni). 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Noon AP, Kulkarni GS. All Bacillus Calmette-Gue´rin (BCG) Strains Are Equal, but Some BCG Strains Are More Equal Than Others. Eur Urol (2014),

EURURO-5624; No. of Pages 3 2


Table 1 – Summarised trials comparing different strains of bacillus Calmette-Gue´rin as intravesical treatments for urothelial bladder carcinoma BCG strains

Patient group*

Mukherjee et al. [9], 1992

Evans (Glaxo) Pasteur

Multiple recurrent pTa/pT1 n = 21

Vegt et al. [7], 1995


pTa-pT1  CIS 1987–1990 Multicentre n = 437 pTa/T1 = 387 CIS = 50


Fellows et al. [8], 1994

Evans (Glaxo) Pasteur

Multiple recurrent pTa/pT1 Multicentre trial n = 94

Inamoto et al. [10], 2013

pTa/T1  CIS n = 38

Sengiku et al. [11], 2013

Tokyo (low dose 40 mg) Connaught regular dose Tokyo and Connaught

Rentsch et al. [6], in press

Connaught and TICE

BCG protocol studied Intradermal BCG 48 h before and after a completed 6  1 wk of intravesical BCG Intravesical BCG  1 per month if CR or repeat 6  1 wk of intravesical BCG if PR TURBT BCG once a week for 6 wk If superficial tumour recurred or CIS persisted at 3 mo or 6 mo, a second 6-wk course with BCG instillations was given after complete transurethral resection or biopsy BCG once a week for 6 wk N.B. one ‘‘marker’’ lesion preserved for subsequent evaluation at 3 mo Trial ran for 3 yr (1988– 1991) BCG once a week for 6 wk

pTa/T1 and pTis n = 129

BCG once per week for 6–8 wk Trial ran 2004–2012

CIS, any high-grade tumour, any low-grade tumour with >2 recurrences in 2 yr, n = 142

BCG once per week for 6 wk Trial ran 1998–2010



At 5 yr: CR: Pasteur = 4 (44%) Glaxo = 5 (42%)

Numbers too small for statistical comparison

At 5 yr: pTa/T1 DF: TICE = 42 (36%) RIVM = 72 (54%)

Assumed 65% of patients will have at least one recurrence Not enough recurrence events for results to be statistically reliable

At 3 mo: Fewer tumours Evans = 42 (82%) Pasteur = 39 (85%) p = 0.06

3 patients in Pasteur group excluded from analysis, no intention-to-treat analysis performed

Median follow-up: 16.5 mo CR: Tokyo = 13 (72%) Connaught = 15 (75%) 1-yr RFS, p = 0.69 At 5 yr: RFS: Tokyo = 62% Connaught = 56% p = 0.74 At 5 yr: RFS: Connaught = 74% TICE = 48% p = 0.01 PFS and OS: no significant difference

Trial stopped prematurely due to production of BCG issues

Multicentre closed in 2003 due to lack of accrual Single centre closed in 2010 because of clinically evident discrepancy in efficacy

BCG = bacillus Calmette-Gue´rin; CIS = carcinoma in situ; CR = complete response; DF = disease free; MMC = mitomycin C; OS = overall survival; PR = partial response; PFS = progression-free survival; RFS = recurrence-free survival. * Numbers in trial indicate cases randomised after exclusion.

by Rentsch et al. [6] managed to recruit only 142 of the 300 patients needed, based on their power calculations, over a 12-yr period (1998–2010). The reason for the trial’s failure to recruit is not discussed in the paper, but one can speculate that, as the trend towards maintenance therapy became established, clinicians or patients were less accepting of the trial design, which included only induction. If the lack of maintenance therapy was an issue for recruitment, it could have been possible to alter the trial design early on. The long recruitment period of the trial also raises questions about whether a cohort effect may exist, with present-day high-risk NMIBC patients being different from those recruited in the early part of the trial. Further evidence in support of this is shown in the trial’s definition of high-risk NMIBC, which included low-grade tumours with two recurrences within 2 yr, which would not be considered high risk today. None of the patients in this trial had a single postoperative instillation of mitomycin C, which is common practice today and is recommended by international guidelines. There was also no blinding of the clinicians to the treatment given to the patients, although this would have been desirable and not impossible, given a

comparison of two drugs with similar modes of application and apparent clinical equipoise. The lack of blinding becomes a possible trial design issue when the authors explain their reasons for prematurely terminating the trial. They state that it became clinically apparent that there were fewer recurrences with one strain of BCG; fortunately, this observation was validated statistically when an unplanned interim analysis was performed, but it raises the question of possible bias. This paper, just like its predecessors, places emphasis on reducing the number of recurrences, and it is possible that now clinicians want greater reassurance in preventing disease progression. As we are learning more about the genetic differences in high-risk NMIBC, it is not certain that the best BCG strain for preventing recurrence is also the best at preventing progression. For the ideal end point of progression to be evaluated, a trial with much longer follow-up would likely be needed but may not be possible in a cohort with a low event rate. Despite its shortcomings, the work by Rentsch and colleagues [6] represents the best-conducted efficacy trial we have comparing two BCG strains. Their paper presents

Please cite this article in press as: Noon AP, Kulkarni GS. All Bacillus Calmette-Gue´rin (BCG) Strains Are Equal, but Some BCG Strains Are More Equal Than Others. Eur Urol (2014),


evidence, but not conclusive proof, that the two evaluated BCG strains have a clinical difference in the same way that the basic science component of the paper explores a possible explanation for the lack of efficacy of the BCG TICE strain. The authors should be congratulated for their efforts in trying to answer an important clinical question. It is hoped that this paper will encourage further clinical and basic science studies.


[6] Rentsch CA, Birkha¨user FD, Biot C, et al. Bacillus Calmette-Gue´rin strain differences have an impact on clinical outcome in bladder cancer immunotherapy. Eur Urol. In press. 10.1016/j.eururo.2014.02.061 [7] Vegt PD, Witjes JA, Witjes WP, Doesburg WH, Debruyne FM, van der Meijden AP. A randomized study of intravesical mitomycin C, bacillus Calmette-Guerin Tice and bacillus Calmette-Guerin RIVM treatment in pTa-pT1 papillary carcinoma and carcinoma in situ of the bladder. J Urol 1995;153:929–33. [8] Fellows GJ, Parmar MK, Grigor KM, Hall RR, Heal MR, Wallace DM.

Conflicts of interest: The authors have nothing to disclose.

Marker tumour response to Evans and Pasteur bacille CalmetteGuerin in multiple recurrent pTa/pT1 bladder tumours: report from

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the Medical Research Council Subgroup on Superficial Bladder Cancer (Urological Cancer Working Party). Br J Urol 1994;73: 639–44. [9] Mukherjee A, Persad R, Smith PJ. Intravesical BCG treatment for superficial bladder cancer: long-term results using two different strains of BCG. Br J Urol 1992;69:147–50. [10] Inamoto T, Ubai T, Nishida T, Fujisue Y, Katsuoka Y, Azuma H. Comparable effect with minimal morbidity of low-dose Tokyo 172 strain compared with regular dose Connaught strain as an intrave-

Tokyo172 substrain for superficial bladder cancer: characterization

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and antitumor effect. J Urol 2005;173:1507–12.

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[4] Gan C, Mostafid H, Khan MS, Lewis DJ. BCG immunotherapy for bladder cancer–the effects of substrain differences. Nat Rev Urol 2013;10:580–8. [5] Noon AP, Catto JW. Bladder cancer in 2012: challenging current paradigms. Nat Rev Urol 2013;10:67–8.

Urol Ann 2013;5:7–12. [11] Sengiku A, Ito M, Miyazaki Y, Sawazaki H, Takahashi T, Ogura K. A prospective comparative study of intravesical bacillus CalmetteGuerin therapy with the Tokyo or Connaught strain for nonmuscle invasive bladder cancer. J Urol 2013;190:50–4.

Please cite this article in press as: Noon AP, Kulkarni GS. All Bacillus Calmette-Gue´rin (BCG) Strains Are Equal, but Some BCG Strains Are More Equal Than Others. Eur Urol (2014),

All bacillus Calmette-Guérin (BCG) strains are equal, but some BCG strains are more equal than others.

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