E U R O P E A N U R O L O G Y 6 0 ( 2 0 1 1 ) 3 7 – 3 8

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Platinum Priority – EditorialReferring to the article published on pp. 32–36 of this issue

Thirty-Five Years of Intravesical Bacillus Calmette-Guerin for

Bladder Cancer: Where Now?

James W.F. Catto *

Institute for Cancer Studies and Academic Urology Unit, G Floor, The Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, United Kingdom

It is 35 yr since Morales described the use of intravesical

bacillus Calmette-Guerin (BCG) for non–muscle invasive

bladder cancer (BC). In the intervening years we have learned

much about this treatment. Although BCG is one of the most

studied medicines in urology, many questions regarding its

use remain [1]. In this month’s European Urology, Herr

et al report their use of induction BCG for high-risk BC [2].

The authors demonstrate excellent outcomes in BCG

complete responders and suggest the need for a new trial

to reevaluate induction and maintenance BCG. Their findings

and suggestion highlight the gaps in our knowledge and point

to issues that need resolving with BCG in this context.

The current dilemmas with BCG are well illustrated

using a historical perspective. In 1991, Lamm et al reported

that BCG was more effective than intravesical doxorubicin

at reducing BC recurrence [3]. When compared, 20% more

patients were disease free, and the time to recurrence was

around 1 yr longer for BCG-treated patients. In 2000, the

Southwest Oncology Group (SWOG) reported a comparison

of induction and maintenance BCG [4]. In 348 randomised

patients, maintenance BCG reduced the 5-yr recurrence,

worsening disease (including cystectomy), and death rates

by a further 19%, 6%, and 5%, respectively, when compared

with induction BCG. These data were the largest trial

included in key meta-analyses (eg, Sylvester et al [5]),

whose findings are central to our current use of BCG and

require exploration. First, maintenance BCG reduced

progression and death by 4% and 2.1%, respectively, when

compared with induction BCG and other treatments.

Second, the natural history of high- and intermediate-risk

non–muscle-invasive BC appeared relatively indolent. By

2.5 yr (median follow-up), progression to invasive disease

had occurred in only 9.8–13.8% and death from BC in only

DOI of original article: 10.1016/j.eururo.2011.03.051* Tel. +44 0 114 226 1229; Fax: +44 0 114 271 2268.E-mail address: j.catto@sheffield.ac.uk.

0302-2838/$ – see back matter # 2011 European Association of Urology. Publis

5.6–7.7% of patients. Thus maintenance BCG appeared an

effective treatment for a relatively safe disease. These

findings defined a role for maintenance BCG in the first-line

management of high- and intermediate-risk BC [6].

However, there were weaknesses in the data reported by

these meta-analyses. First, patient follow-up was short

(median: 2.5 yr). Natural history reports clearly show that

progression and BC death rates are directly proportional to

the length of follow-up (reviewed in Kulkarni et al [7]). The

median time to BC mortality from these cancers is 3–5 yr and

was therefore not reached by tumours in the meta-analyses.

Second, few tumours were high risk (8% were grade 3). As

progression rates rise from 10–15% for grade 2 to 25–75% for

grade 3 tumours [8], the meta-analyses potentially under-

estimated the risk of muscle invasion in poorly differentiated

tumours. Third, the benefit of maintenance BCG, over

induction, probably relied on the power generated by a

single trial (the SWOG trial). Other randomised controlled

trials (RCTs) have failed to show a benefit for maintenance

BCG over induction treatment alone (reviewed in Gontero

et al [1]). To address aspects of these concerns, a newer meta-

analysis with longer follow up (median: 4.4 yr) and a higher

proportion of grade 3 tumours (16%) was reported in 2009

[9]. This analysis used individual patient data, which is the

most rigorous method of comparison, but did not include the

SWOG trial cases and so was consequently smaller (n = 2820

[9] versus n = 4863 patients [5]). Maintenance BCG was found

to reduce the frequency but not the timing of recurrence

when compared with induction BCG and intravesical

chemotherapy. When progressions to invasion and BC-

specific death were evaluated, no statistical differences with

either treatment were seen. Proponents for maintenance BCG

could correctly point to trends for improved progression-free

hed by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2011.04.024

E U R O P E A N U R O L O G Y 6 0 ( 2 0 1 1 ) 3 7 – 3 838

and BC-specific survival with maintenance BCG, and they

suggest that perhaps the low sample size precluded

statistical significance. However, if significance is not

reached with 800 cases, then one wonders if the difference

is of clinical benefit.

The perceived downsides of maintenance BCG are toxicity

and compliance. Around half of treated patients complain of

side effects, which are judged to be serious in up to 5% [1].

Toxicity has an impact on compliance such that, even in the

most enthusiastic hands, only a third of patients complete the

3-yr regimen [4]. Few studies have prospectively evaluated

quality of life on maintenance BCG. The poor compliance,

frequent side effects, and anxiety regarding tumour status

suggest life quality is compromised and support the need for

alternative treatments/schedules. With this in mind, Herr

et al report the long-term outcomes of complete responders

to induction BCG [2]. Induction BCG should avoid some of the

toxicity and compliance issues affecting a maintenance

regimen. Complete responders were defined as those free of

tumour at 6 mo, following reresection and 6 wk of induction

BCG, and they represented 79% of the initial patient cohort. As

detailed within the report, most of these tumours were high

grade, half were invading the lamina propria, and pTis was

present in the majority (62%). With a minimum 5-yr follow-

up, the authors observed recurrence of any tumour in half of

these patients (50% of which occurred within 2 yr) and

progression to muscle invasion in 11%. Radical cystectomy

was performed in 8% of cases, and BC-specific death occurred

in 4%. These data compare favourably with those from

maintenance BCG reports, as detailed within the report’s

discussion. For example, the most recent meta-analysis

reported progression to invasion and BC-related death in 12%

and 8% of patients, respectively [9]. So induction BCG appears

to offer a similar progression-free survival to maintenance

with (presumably) lower toxicity. However, this benefit is

balanced by a higher recurrence rate.

Where does this report now leave us? First, these data

reopen the debate regarding maintenance and induction

BCG. Herr et al have shown good outcomes with induction

BCG, and so we must recognise this is a viable treatment.

Second, we should wonder why this group has produced

outcomes not reliably replicated in multicentred studies.

Although authors and statisticians focus on BCG, this is only

part of the treatment for BC. Of equal or more importance is

the transurethral resection (TUR). It is likely that high-quality

TUR and careful patient selection contributed significantly to

these reported outcomes. TUR should clear all possible

tumour, adequately stage the disease (including detrusor

muscle from the correct region), and assess the urothelium

(including from the prostatic fossa). The differences reported

in residual tumour and upstaging rates demonstrate the wide

variation in TUR quality [10]. A poor quality TUR may not only

leave residual tumour but also fail to obtain sufficient

information to assess the bladder adequately. We should

imagine the difference in outcomes from an RCT comparing

high- and low-quality TUR. This current report suggests we

should also focus our attention on TUR quality. Finally, Herr

et al support the first-line use of BCG for high-risk disease. But

what was the outcome of all patients treated by BCG?

Specifically, did patients within the 21% of nonresponders

lose out by their 3-mo trial of BCG and check cystoscopy? We

know in muscle-invasive disease that a delay of 3 mo can

adversely affect outcome. So, despite numerous RCTs on

these cancers, we still do not know what the maximum

possible survival is for newly diagnosed high-risk disease.

Without this context it is hard to place BCG treatment data.

Retrospective series suggest immediate radical cystectomy

provides a survival benefit over delayed surgery in BCG

failures (reviewed in Kulkarni et al [7]). However, the benefit

is not uniform and so is likely to include selection bias.

In summary, these data suggest that complete respon-

ders to induction BCG have a good prognosis, if managed

carefully. Rather than the need for a new trial, I suggest we

accept these findings and include induction BCG as an

option when counselling patients. Further RCTs are needed,

but these should be aimed at placing BCG in context and

evaluating newer therapies/delivery strategies to reduce

progression and cancer-specific death.

Conflicts of interest: The author has nothing to disclose.

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