EUROPEAN UROLOGY 65 (2014) 69–76
available at www.sciencedirect.com
journal homepage: www.europeanurology.com
Platinum Priority – Bladder Cancer
Editorial by Joan Palou on pp. 77–78 of this issue
Side Effects of Bacillus Calmette-Guérin (BCG) in the Treatment of
Intermediate- and High-risk Ta, T1 Papillary Carcinoma of the
Bladder: Results of the EORTC Genito-Urinary Cancers Group
Randomised Phase 3 Study Comparing One-third Dose with Full
Dose and 1 Year with 3 Years of Maintenance BCG
Maurizio Brausi a, Jorg Oddens b,*, Richard Sylvester c, Aldo Bono d, Cees van de Beek e,
George van Andel f, Paolo Gontero g, Levent Turkeri h, Sandrine Marreaud c,
Sandra Collette c, Willem Oosterlinck i
a
Department of Urology, New Estense S. Agostino Hospital Ausl Modena, Modena, Italy; b Department of Urology, Jeroen Bosch Ziekenhuis, ’s-Hertogenbosch,
The Netherlands; c Headquarters, European Organisation for Research and Treatment of Cancer, Brussels, Belgium;
e
d
Department of Urology, Ospedale di
f
Circolo, Varese, Italy; Department of Urology, Academisch Ziekenhuis Maastricht, Maastricht, The Netherlands; Department of Urology, OLVG, Amsterdam,
The Netherlands;
g
Urology Clinic, Department of Surgical Sciences, University of Studies of Torino, Torino, Italy;
h
Department of Urology, Marmara
University School of Medicine, Istanbul, Turkey; i Department of Urology, Ghent University Hospital, Ghent, Belgium
Article info
Abstract
Article history:
Accepted July 15, 2013
Published online ahead of
print on July 24, 2013
Background: Although bacillus Calmette-Guérin (BCG) has proven highly effective in non–muscleinvasive bladder cancer (NMIBC), but it can cause severe local and systemic side effects.
Objectives: The objective was to determine whether reducing the dose or duration of BCG was
associated with fewer side effects. Efficacy comparisons of one-third dose versus full dose BCG given
for 1 yr versus 3 yr have previously been published.
Design, setting, and participants: After transurethral resection, patients with intermediate- and
high-risk NMIBC without carcinoma in situ were randomised to one-third dose or full dose BCG and
1 yr or 3 yr of maintenance.
Outcome measurements and statistical analysis: Local and systemic side effects were recorded at
every instillation and divided into three time periods: during induction, during the first year after
induction, and during the second and third years of maintenance.
Results and limitations: Of the 1316 patients who started BCG, 826 (62.8%) reported local side
effects, 403 (30.6%) reported systemic side effects, and 914 (69.5%) reported local or systemic side
effects. The percentage of patients with at least one side effect was similar in the four treatment arms
( p = 0.41), both overall and in the different time periods. The most frequent local and systemic side
effects were chemical cystitis in 460 (35.0%) patients and general malaise in 204 patients (15.5%);
103 patients (7.8%) stopped treatment because of side effects. No significant difference was seen
between treatment groups ( p = 0.74). In the 653 patients randomised to 3 yr of BCG, 35 (5.4%)
stopped during the first year, and 21 (3.2%) stopped in the second or third year.
Conclusions: No significant differences in side effects were detected according to dose or duration of
BCG treatment in the four arms. Side effects requiring stoppage of treatment were seen more
frequently in the first year, so not all patients are able to receive the 1–3 yr of treatment
recommended in current guidelines.
This study was registered at ClinicalTrials.gov with identifier NCT00002990 (http://clinicaltrials.
gov/ct2/show/record/NCT00002990).
Keywords:
Urothelial carcinoma
Non–muscle-invasive bladder
cancer
Maintenance BCG
Dose reduction
Side effects
Please visit www.eu-acme.org/
europeanurology to read and
answer questions on-line.
The EU-ACME credits will
then be attributed automatically.
# 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Department of Urology, Jeroen Bosch Ziekenhuis, PO Box 90153, 5200 ME,
‘s-Hertogenbosch, The Netherlands. Tel. +31 73 553 2407.
E-mail address: [email protected] (J. Oddens).
0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.eururo.2013.07.021
70
1.
EUROPEAN UROLOGY 65 (2014) 69–76
Introduction
After transurethral resection (TUR), intravesical immunotherapy with bacillus Calmette-Guérin (BCG) is considered
the most effective prophylactic treatment for patients with
intermediate- and high-risk urothelial non–muscleinvasive bladder cancer (NMIBC) [1,2]. BCG induction
instillations are classically given according to the empirical
6-wk schedule that Morales introduced >35 yr ago
[3]. Several randomised trials and meta-analyses published
thereafter suggested that maintenance BCG instillations
during 1–3 yr is superior to both chemotherapy and
induction BCG alone in reducing recurrences and even
progression to muscle-invasive disease [4–8]. As a result,
current clinical practice guidelines recommend BCG
with 1–3 yr of maintenance as the intravesical therapy
of choice for high-risk disease [1,2].
Although BCG has proved effective in Ta–T1 high-grade
tumours and carcinoma in situ (CIS), it can produce
moderate to severe local and systemic side effects. In the
report by Lamm et al. on maintenance BCG, only 16% of
patients were able to receive all instillations of the 3-yr
treatment, mainly because of side effects [5]. More recently,
in the report on European Organisation for Research and
Treatment of Cancer (EORTC) trial 30911 comparing
maintenance BCG with and without isoniazid (INH) versus
epirubicin, 19% of patients in the BCG group had to stop
treatment because of side effects, but 29% completed all
3 yr of treatment [9].
The occurrence of side effects is one of the main reasons
why urologists try to avoid the use of BCG, particularly in
intermediate-risk patients, for whom chemotherapeutic
agents are often prescribed. A reduction in side effects
might be achieved in several different ways, for example,
with the administration of the antituberculosis drug INH
[9–11] or the antibiotic ofloxacin [12] or by reducing the
BCG dose [13–15]. After EORTC trial 30911 showed that INH
did not reduce the side effects of BCG, EORTC study 30962
was designed with the primary objective of determining
whether one-third dose was inferior to full dose, whether
1 yr of maintenance was inferior to 3 yr of maintenance, and
whether one-third dose and 1 yr of maintenance were
associated with fewer side effects. As the efficacy results
have already been reported [16], this article focuses on
toxicity.
2.2.
Randomisation and study interventions
Within 14 d after TUR, patients were randomised to one of four
treatment groups:
1/3D-1yr: One-third dose of BCG with 1 yr of maintenance, where BCG
was given once per week for 6 wk followed by three weekly
instillations at months 3, 6, and 12 for a total of four cycles and 15
instillations
FD-1yr: Full dose of BCG with 1 yr of maintenance
1/3D-3yr: One-third dose of BCG with 3 yr of maintenance, where BCG
was given once per week for 6 wk followed by three weekly
instillations at months 3, 6, 12, 18, 24, 30, and 36 for a total of eight
cycles and 27 instillations
FD-3yr: FD of BCG with 3 yr of maintenance.
For this study, OncoTICE (Organon Teknika, Boxtel, The Netherlands),
containing 5 108 colony forming units, was used; one-third dose was
prepared either by dissolving one vial with 150 ml of saline and then
taking 50 ml or by dissolving the dose with 50 ml, taking 17 ml, and then
diluting this mixture to 50 ml.
Patients stopped protocol treatment at the second Ta/T1 recurrence
after randomisation and at progression to muscle-invasive disease,
appearance of CIS, carcinoma in the upper urinary tract or prostatic
urethra, or distant metastases. Further treatment was at the discretion of
the local investigator.
2.3.
End points
The primary end point, the duration of the disease-free interval, has
previously been reported [16]. Secondary end points included the
occurrence of side effects and their relationship to reduced dose or
shorter duration of maintenance. The time of appearance of the side
effects will be addressed in this article.
2.4.
Side effects
At each instillation, patient complaints and symptoms were recorded, as
were urine cultures. Information about the presence or absence of local
and systemic side effects and their impact on further treatment
instillations was collected and reported during each cycle of protocol
treatment according to a predefined format used in previous EORTC
studies.
Local side effects included bacterial or chemical cystitis, frequency,
haematuria, and other. Bacterial cystitis was defined as the occurrence of
culture-proven (not BCG-related) cystitis. Irritative bladder symptoms
with negative urine culture were classified as BCG-induced (chemical)
cystitis. Other local side effects included granulomatous prostatitis,
epididymitis, ureteral obstruction, and contracted bladder.
2.
Materials and methods
Systemic side effects included fever (>39 8C); influenza-like symptoms, including general malaise and chills; BCG-induced lung infection;
2.1.
Inclusion and exclusion criteria
liver toxicity; and BCG sepsis. Skin rash, arthralgia, and arthritis were
classified as possible allergic reactions.
Patients with biopsy-proven, completely resected, solitary pT1G3 or
The protocol provided recommendations for the treatment of BCG-
multiple pTa–T1 grade 1–3 (1973 World Health Organisation [WHO]
related complications (Table 1). Based on the severity of the adverse
classification) urothelial carcinoma (UC) of the bladder were included.
effects, the treating physician decided whether instillations were to be
Patients with solitary tumours except T1G3, >10 tumours, CIS, tumours
postponed or even definitively stopped.
stage T2, those >85 yr of age, WHO performance status 3 or 4, previous
In addition to an overall assessment of side effects, the treatment
treatment with BCG, and intravesical chemotherapy during the previous
period was divided into three time intervals to evaluate when the side
3 mo were excluded. An intravenous pyelography was performed to
effects appeared: (1) the induction period (first 6 weekly instillations);
rule out upper-tract tumours. Informed consent was obtained in
(2) the first year of therapy after induction (next 9 instillations); and
accordance with the Declaration of Helsinki or existing national and
(3) the second and third years of therapy (next 12 instillations, only in
local regulations.
the 3-yr maintenance arms). In an analysis of side effects that led to
71
EUROPEAN UROLOGY 65 (2014) 69–76
Table 1 – Treatment recommendations for bacillus Calmette-Guérin–related complications, as provided in the study protocol
Complication
Recommended treatment
Fever <38.5 8C, BCG cystitis, mild malaise
Fever >38.5 8C for 12–24 h
Allergic reactions (arthralgia, myalgia, rash)
Acute severe illness, local or systemic pneumonitis, hepatitis,
prostatitis, ureteral obstruction, renal abscess, persisting
high fever >39 8C
BCG sepsis
No treatment; hold BCG until symptoms resolve
Isoniazid 300 mg daily for 3 mo; may resume BCG when asymptomatic
Isoniazid 300 mg; further BCG indicated only if benefit exceeds risk
Isoniazide 300 mg, rifampin 600 mg, ethambutol 1200 mg daily for 6 mo; no further BCG
Isoniazid 300 mg, rifampin 600 mg, ethambutol 1200 mg, cycloserine 500 mg
twice daily orally; consider intravenous prednisolone 40 mg immediately
BCG = bacillus Calmette-Guérin.
246 (36.4%) patients randomised to receive BCG for 3 yr.
Globally, 650 of 1316 patients (49.4%) started but did not
complete their treatment, the main reason being treatment
inefficacy in 338 (25.7%) patients. Side effects as the reason
for stopping treatment occurred in 103 (7.8%) patients,
while in 221 (16.8%) patients, other reasons for stopping
were reported (Fig. 2).
In the 1316 patients who started BCG, 826 (62.8%)
reported local side effects, 403 (30.6%) reported systemic
side effects, and 914 (69.5%) reported local or systemic side
effects. The various local and systemic side effects are listed
by treatment in Table 3. The percentage of patients with
local side effects, systemic side effects, and local or systemic
side effects was similar in the four treatment groups
( p = 0.14, 0.40, and 0.41, respectively). Likewise, no
significant differences in the occurrence of side effects
between the 1/3D and FD groups and the 1yr and 3yr groups
were seen.
The most frequent side effects were local: chemical
cystitis in 460 (35.0%) patients, bacterial cystitis in 307
patients (23.3%), frequency of more than once per hour
in 310 patients (23.6%), and macroscopic haematuria in
298 patients (22.6%). Twenty-seven patients (2.1%)
complained of urinary incontinence. The most frequent
systemic side effects were general malaise in 204 patients
(15.5%) and fever in 106 patients (8.1%). Sepsis was
observed in four patients (0.3%). When divided according
to the time period of treatment (first six instillations, the
the decision to stop treatment, a distinction was made between the first
year of therapy and the second and third years of treatment (in the 3-yr
maintenance arms) to judge whether continuing with a 3-yr maintenance schedule leads to a higher percentage of patients with severe
toxicity. The percentage of patients experiencing side effects in the
treatment groups was compared using the Pearson x2 statistic; p values
were not adjusted for multiple testing.
3.
Results
After the quality control exclusion of 450 patients from
six institutions, 1355 patients were centrally randomised
by 51 institutions from 13 European countries between
March 1997 and April 2005. Seventy-five patients (5.5%)
were ineligible. Delay between TUR and randomisation
(>21 d) and type of tumour were the most common
reasons for ineligibility. Three hundred forty-one patients
were randomised to 1/3D-1yr BCG, 339 to FD-1yr BCG,
337 to 1/3D-3yr BCG, and 338 to FD-3yr BCG (Fig. 1).
Patient characteristics were generally well balanced
among the arms. Patient and disease characteristics along
with the efficacy results have already been published
[16].
The amount of treatment actually received is listed in
Table 2. Thirty-nine patients (2.9%) did not receive any
treatment, 11 of whom were ineligible. Four hundred
twenty (61.8%) patients randomised to receive BCG
maintenance for 1 yr completed the treatment versus
Table 2 – Amount of treatment received
Bacillus Calmette-Guérin treatment arm
No treatment
Started treatment
Amount of treatment
6 wk
3 mo
6 mo
12 mo
18 mo
24 mo
30 mo
36 mo
>36 mo
Completed treatment
1/3D-1yr group
(n = 341)
FD-1yr group
(n = 339)
1/3D-3yr group
(n = 337)
FD-3yr group
(n = 338)
No. (%)
No. (%)
No. (%)
No. (%)
7 (2.1)
334 (97.9)
10 (2.9)
329 (97.1)
14 (4.2)
323 (95.9)
8 (2.4)
330 (97.6)
48
35
44
198
8
0
1
0
0
207
36
37
43
210
2
0
1
0
0
213
33
33
46
29
16
18
24
115
9
124
37
37
37
37
18
23
19
119
3
122
(14.1)
(10.3)
(12.9)
(58.1)
(2.3)
(0.0)
(0.3)
(0.0)
(0.0)
(60.7)
(10.6)
(10.9)
(12.7)
(61.9)
(0.6)
(0.0)
(0.3)
(0.0)
(0.0)
(62.8)
(9.8)
(9.8)
(13.6)
(8.6)
(4.7)
(5.3)
(7.1)
(34.1)
(2.7)
(36.8)
(10.9)
(10.9)
(10.9)
(10.9)
(5.3)
(6.8)
(5.6)
(35.2)
(0.9)
(36.1)
[(Fig._1)TD$IG]
72
EUROPEAN UROLOGY 65 (2014) 69–76
Fig. 1 – Consolidated Standards of Reporting Trials diagram.
ITT = intention to treat.
[(Fig._2)TD$IG]
Fig. 2 – Reasons for stopping treatment.
73
EUROPEAN UROLOGY 65 (2014) 69–76
Table 3 – Local and systemic side effects in all treatment arms
At any time
Total
1 yr, no. (%)
One-third dose
3 yr, no. (%)
Full dose
334
Bacterial cystitis
Chemical cystitis
Other local side effects
Frequency (more than once per hour)
Macroscopic haematuria
Local side effects
71
94
76
63
73
195
(21.3)
(28.1)
(22.8)
(18.9)
(21.9)
(58.4)
69
109
70
76
78
205
(21.0)
(33.1)
(21.3)
(23.1)
(23.7)
(62.3)
90
127
80
87
77
217
(27.9)
(39.3)
(24.8)
(26.9)
(23.8)
(67.2)
77
130
82
84
70
209
(23.3)
(39.4)
(24.8)
(25.5)
(21.2)
(63.3)
307
460
308
310
298
826
(23.3)
(35.0)
(23.4)
(23.6)
(22.6)
(62.8)
17
2
1
7
42
48
92
(5.1)
(0.6)
(0.3)
(2.1)
(12.6)
(14.4)
(27.5)
29
1
1
7
51
52
100
(8.8)
(0.3)
(0.3)
(2.1)
(15.5)
(15.8)
(30.4)
27
0
0
9
49
62
100
(8.4)
(0.0)
(0.0)
(2.8)
(15.2)
(19.2)
(31.0)
33
2
2
9
62
61
111
(10.0)
(0.6)
(0.6)
(2.7)
(18.8)
(18.5)
(33.6)
106
5
4
32
204
223
403
(8.1)
(0.4)
(0.3)
(2.4)
(15.5)
(16.9)
(30.6)
Local or systemic side effects
221 (66.2)
323
Full dose
No. of patients
Fever
Lung infection
Sepsis
Skin rash
General malaise
Other systemic side effects
Systemic side effects
329
One-third dose
228 (69.3)
330
227 (70.3)
1316
238 (72.1)
914 (69.5)
Treatment comparisons:
Local side effects: four treatment groups: p = 0.14; one-third dose vs full dose (adjusted for duration of maintenance): p = 0.98; 1 yr vs 3 yr (adjusted for bacillus
Calmette-Guérin dose): p = 0.07.
Systemic side effects: four treatment groups: p = 0.40; one-third dose vs full dose (adjusted for duration of maintenance): p = 0.28; 1 yr vs 3 yr (adjusted for
bacillus Calmette-Guérin dose): p = 0.19.
Local or systemic side effects: four treatment groups: p = 0.41; one-third dose vs full dose (adjusted for duration of maintenance): p = 0.33; 1 yr vs 3 yr
(adjusted for bacillus Calmette-Guérin dose): p = 0.17.
first year of treatment after induction, and after 1 yr of
treatment [in treatment arms with 3 yr of maintenance]),
the distributions of side effects in the treatment groups
were similar (Table 4).
In 207 (15.7%) patients, instillations were delayed or
temporarily stopped because of side effects. Most treatment discontinuations resulting from side effects occurred
within the first year: 103 patients (7.8%) stopped for
toxicity, with 82 patients (6.2%) stopping during the
first year. Among the 653 patients randomised to 3 yr of
BCG, 35 (5.4%) stopped during the first year of treatment
because of side effects, and 21 (3.2%) stopped during the
second or third year (Tables 5 and 6).
4.
Discussion
Maintenance BCG has been advocated by many investigators as the therapy of choice for patients with Ta–T1 highgrade UC of the bladder or CIS. This is reflected in the
various guidelines on NMIBC that include BCG as first-line
adjuvant therapy after TUR in high-risk patients [1,2].
The most widely used maintenance schedule is based on
the Southwest Oncology Group regimen, starting with a
series of six weekly inductions followed by three weekly
instillations at 3 mo and 6 mo, and then every 6 mo for
3 yr [5]. Based on several meta-analyses, the European
Association of Urology guidelines recommend at least 1 yr
of BCG maintenance therapy [1], but the side effects of BCG
are well known. As a result, many urologists are reluctant to
administer BCG to their patients, particularly when the
disease is not high risk. It is therefore important to decrease
BCG toxicity while maintaining its efficacy.
Many strategies have been advocated to reduce the side
effects of BCG. In EORTC study 30911, with 3 yr of
maintenance BCG in intermediate- and high-risk patients,
the prophylactic administration of INH did not decrease
BCG’s side effects. On the contrary, transient liver function
disturbances were encountered more frequently when INH
was administered, so the use of prophylactic INH is not
recommended [9,15].
Another possible way to decrease BCG toxicity is by the
administration of antibiotics at the time of BCG instillation. Colombel et al. showed that two doses of ofloxacin
given shortly after BCG reduced side effects, but its effect
on long-term efficacy is unknown [12]. Recently, Johnson
et al. [17] showed that oxybutynin increased urinary
frequency and burning on urination compared with
placebo and concluded that it should not be used in the
routine prophylaxis against urinary symptoms during BCG
therapy.
The most studied option is to decrease the dose. The
EORTC Genito-Urinary Cancers Group showed in a phase 2
marker lesion study that one-quarter dose of BCG was
active [18]. Club Urológico Español de Tratamiento Oncológico (CUETO) compared one-third dose of BCG to standard
dose in intermediate- and high-risk patients. The reduced
dose of BCG was as effective as the full dose in intermediaterisk patients, but in high-risk patients, full dose provided
the best results [13]. In a second study, in high-risk patients
(T1G3 and/or CIS), CUETO showed that one-third dose BCG
was as effective as full dose against recurrence and
74
93 (51.1)
100 (54.9)
175 (59.7)
160 (55.2)
165 (56.3)
153 (53.5)
143 (43.3)
149 (46.1)
172 (52.3)
160 (47.9)
Local or systemic side effects
(3.3)
(0.5)
(0.0)
(0.5)
(10.4)
(11.0)
(18.1)
6
1
0
1
19
20
33
(1.6)
(0.0)
(0.0)
(2.2)
(6.6)
(11.5)
(18.1)
3
0
0
4
12
21
33
(6.1)
(0.0)
(0.3)
(1.4)
(10.9)
(11.6)
(22.5)
18
0
1
4
32
34
66
(3.1)
(0.0)
(0.0)
(1.7)
(7.2)
(12.4)
(20.7)
9
0
0
5
21
36
60
(5.8)
(0.0)
(0.3)
(1.4)
(11.6)
(9.2)
(21.2)
17
0
1
4
34
27
62
(1.7)
(0.3)
(0.3)
(1.0)
(8.0)
(10.8)
(17.8)
5
1
1
3
23
31
51
(3.9)
(0.3)
(0.3)
(1.5)
(7.6)
(8.5)
(16.1)
13
1
1
5
25
28
53
(5.3)
(0.0)
(0.0)
(0.6)
(8.7)
(6.8)
(16.1)
17
0
0
2
28
22
52
(4.6)
(0.3)
(0.0)
(1.2)
(7.9)
(10.6)
(19.1)
15
1
0
4
26
35
63
(3.6)
(0.3)
(0.0)
(1.2)
(8.4)
(7.2)
(17.1)
12
1
0
4
28
24
57
Fever
Lung infection
Sepsis
Skin rash
General malaise
Other systemic side effects
Systemic side effects
(11.0)
(30.8)
(17.0)
(19.2)
(9.9)
(46.2)
20
56
31
35
18
84
49
60
34
25
32
133
Bacterial cystitis
Chemical cystitis
Other local side effects
Frequency (more than once per hour)
Macroscopic haematuria
Local side effects
(14.7)
(18.0)
(10.2)
(7.5)
(9.6)
(39.8)
55
55
38
38
39
145
(16.7)
(16.7)
(11.6)
(11.6)
(11.9)
(44.1)
48
52
40
27
34
133
(14.9)
(16.1)
(12.4)
(8.4)
(10.5)
(41.2)
42
54
31
20
29
121
(12.7)
(16.4)
(9.4)
(6.1)
(8.8)
(36.7)
33
63
53
45
48
135
(11.5)
(22.0)
(18.5)
(15.7)
(16.8)
(47.2)
31
79
50
54
46
147
(10.6)
(27.0)
(17.1)
(18.4)
(15.7)
(50.2)
43
84
43
44
46
144
(14.8)
(29.0)
(14.8)
(15.2)
(15.9)
(49.7)
43
92
43
56
39
150
(14.7)
(31.4)
(14.7)
(19.1)
(13.3)
(51.2)
23
52
30
40
21
93
(12.6)
(28.6)
(16.5)
(22.0)
(11.5)
(51.1)
182
182
293
290
293
286
330
323
329
334
No. of patients
Full dose
One-third dose
Full dose
One-third dose
Full dose
One-third dose
Full dose
One-third dose
Full dose
One-third dose
3 yr, no. (%)
3 yr, no. (%)
1 yr, no. (%)
3 yr, no. (%)
1 yr, no. (%)
During induction
Table 4 – Local and systemic side effects in all treatment arms according to time of occurrence
During the first year of maintenance (after induction)
During years 2 and 3 of
maintenance
EUROPEAN UROLOGY 65 (2014) 69–76
progression but had significantly less toxicity. The number
of patients who stopped BCG for toxicity did not differ
significantly between the two arms [14]. A third report from
CUETO found that 1/6 dose was significantly less effective
than one-third dose for the treatment of intermediate-risk
NMIBC, suggesting that one-third dose is the minimum
effective dose of BCG in these patients [15]. In these three
reports, the maximum duration of maintenance BCG was
only 5 mo, whereas in the current study, the minimum
treatment duration was 1 yr.
The purpose of EORTC study 30962 was to see whether
by reducing the dose of BCG to one-third the toxicity could
be reduced while maintaining the same efficacy and to
evaluate whether 1 yr of maintenance was inferior to 3 yr
with respect to efficacy. The results of our study have
shown that no significant differences exist in toxicity
according to dose or duration of BCG treatment. Fifty (7.6%)
patients receiving one-third dose stopped treatment for
toxicity versus 53 (8.0%) patients who received full-dose
BCG. Forty-seven (7.1%) patients randomised to 1 yr of
maintenance stopped BCG because of side effects versus 56
(8.6%) patients randomised to 3 yr. The additional 2 yr
of maintenance are not associated with an appreciable
increase in toxicity.
These results on the discontinuation rate of BCG for
toxicity are better than those observed in our previous
study (30911), where 19.0% of patients had to stop BCG
therapy because of adverse events [19]. Likewise, for the
most frequent side effects other than bacterial cystitis,
the percentage of patients reporting side effects tended to
be lower in the current trial than in the previous study. The
reason for this cannot be explained but may be associated
with the greater experience of urologists and nurses in
administering BCG therapy today.
Our results confirm the observation from study 30911
that the majority of side effects occurred within the
first year [19]. This suggests that systemic side effects
depend mainly on the host and not on the number of
instillations.
The awareness of possible adverse events when administering BCG together with the proper use of antituberculosis drugs can improve local or systemic side effects. In
addition, a meticulous discussion with patients receiving
BCG on its efficacy and possible adverse events has been
proven to improve patient compliance [20].
Limitations of this study include the lack of a placebo
control arm, which is not ethical in this patient group,
and the absence of standardised criteria to define intravesical BCG toxicity as a reason for postponing or stopping
treatment. Although side effects were reported according to
a predefined format used in previous studies, the clinical
implications of the same adverse event could differ among
investigators from unacceptable to normal drug activity. In
the absence of validated international guidelines for the
definition and treatment of side effects, the description of
local and systemic side effects by expert urologists involved
using predefined case report forms across many prospective, randomised EORTC studies could be considered a
surrogate standard.
75
EUROPEAN UROLOGY 65 (2014) 69–76
Table 5 – Definitive stop of instillations because of side effects in patients who started treatment (per treatment group)
Bacillus Calmette-Guérin treatment arm
Systemic or local
side effects
Within first year
After the first year
Total
1/3D-1yr group
(n = 334)
FD-1yr group
(n = 329)
1/3D-3yr group
(n = 323)
FD-3yr group
(n = 330)
Total
(n = 1316)
No. (%)
No. (%)
No. (%)
No. (%)
No. (%)
24 (7.2)
0 (0.0)
24 (7.2)
23 (7.0)
0 (0.0)
23 (7.0)
17 (5.3)
9 (2.8)
26 (8.1)
18 (5.5)
12 (3.6)
30 (9.1)
82 (6.2)
21 (1.6)
103 (7.8)
Comparison of the percentage of patients stopping treatment because of side effects in the four treatment groups: p = 0.74.
Table 6 – Definitive stop of instillations because of side effects in patients who started treatment (per treatment type)
Bacillus Calmette-Guérin intervention
Systemic or
local side effects
One-third
dose, 1 yr + 3 yr
(n = 657)
Full dose,
1 yr + 3 yr
(n = 659)
1 yr, one-third
dose + full
dose (n = 663)
3 yr, one-third
dose + full
dose (n = 653)
No. (%)
No. (%)
No. (%)
No. (%)
41 (6.2)
9 (1.4)
50 (7.6)
41 (6.2)
12 (1.8)
53 (8.0)
47 (7.1)
0 (0.0)
47 (7.1)
35 (5.4)
21 (3.2)
56 (8.6)
Within the first year
After the first year
Total
5.
Conclusions
Funding/Support and role of the sponsor: This publication was supported
by grant numbers 5U10 CA11488-26 through 5U10 CA011488-40 from
No significant differences in toxicity were detected
according to dose (one-third dose vs full dose) or duration
(1 yr vs 3 yr) of BCG treatment in the four arms. Neither
reducing the dose nor shortening the duration of maintenance decreased the percentage of patients who stopped
treatment because of side effects. Side effects requiring
stoppage of treatment were seen more frequently in the
first year of therapy, preventing some patients from
receiving the 1–3 yr of treatment recommended in current
guidelines.
the National Cancer Institute (Bethesda, MD, USA) and by a donation
from the Kankerbestrijding/KWF from The Netherlands through the
EORTC Charitable Trust. Its content is solely the responsibility of the
authors and does not necessarily reflect the official views of the National
Cancer Institute. Organon Teknika, now a subsidiary of Merck & Co., Inc.,
provided free BCG-TICE (OncoTICE) in the countries where the product
was not marketed but no financial support for the study. MSD/Organon
Teknika also reviewed the draft manuscript.
References
[1] Babjuk M, Oosterlinck W, Sylvester R, et al., European Association of
Urology (EAU). EAU guidelines on non–muscle-invasive urothelial
Author contributions: Jorg Oddens had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Brausi, Oddens, Sylvester.
Acquisition of data: Oddens, Brausi, Bono, Van de Beek, Van Andel,
Gontero, Turkeri, Oosterlinck.
Analysis and interpretation of data: Oddens, Brausi, Sylvester, Collette.
Drafting of the manuscript: Brausi, Oddens.
Critical revision of the manuscript for important intellectual content:
Oddens, Brausi, Sylvester, Bono, Van de Beek, Van Andel, Gontero,
Turkeri, Collette, Oosterlinck.
Statistical analysis: Sylvester, Collette.
Obtaining funding: Sylvester, Marreaud.
Administrative, technical, or material support: None.
Supervision: Oddens.
Other (specify): None.
carcinoma of the bladder: the 2011 update. Eur Urol 2011;59:
997–1008.
[2] Brausi M, Witjes JA, Lamm D, et al. A review of current guidelines
and best practice recommendations for the management of non
muscle-invasive bladder cancer by the International Bladder Cancer
Group. J Urol 2011;186:2158–67.
[3] Morales A, Eidinger D, Bruce AW. Intracavitary bacillus CalmetteGuerin in the treatment of superficial bladder tumors. J Urol 1976;
116:180–3.
[4] Sylvester RJ, van der Meijden AP, Lamm DL. Intravesical bacillus
Calmette-Guerin reduces the risk of progression in patients with
superficial bladder cancer: a meta-analysis of the published results
of randomized clinical trials. J Urol 2002;168:1964–8.
[5] Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus
Calmette-Guerin 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.
Financial disclosures: Jorg Oddens certifies that all conflicts of interest,
[6] Malmstrom PU, Sylvester RJ, Crawford DE, et al. An individual patient
including specific financial interests and relationships and affiliations
data meta-analysis of the long-term outcome of randomised studies
relevant to the subject matter or materials discussed in the manuscript
comparing intravesical mitomycin C versus bacillus Calmette-Guerin
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
for non–muscle-invasive bladder cancer. Eur Urol 2009;56:247–56.
stock ownership or options, expert testimony, royalties, or patents filed,
[7] Böhle A, Bock PR. Intravesical bacillus Calmette-Guerin versus
received, or pending), are the following: None.
mitomycin C in superficial bladder cancer: formal meta-analysis
76
EUROPEAN UROLOGY 65 (2014) 69–76
of comparative studies on tumour progression. Urology 2004;
63:682–6.
[14] Martı́nez-Piñeiro JA, Martı́nez-Piñeiro L, Solsona E, et al., Club
Urológico Español de Tratamiento Oncológico (CUETO). Has a 3-fold
[8] Böhle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guerin
decreased dose of bacillus Calmette-Guerin the same efficacy against
versus mitomycin C for superficial bladder cancer: a formal meta-
recurrence and progression of T1G3 and Tis bladder tumors than the
analysis of comparative studies on recurrence and toxicity. J Urol
standard dose? Results of a prospective randomized trial. J Urol
2003;169:90–5.
2005;174:1242–7.
[9] Sylvester RJ, Brausi M, Kirkels WJ, et al., EORTC Genito-Urinary Tract
[15] Ojea A, Nogueira JL, Solsona E, et al., CUETO Group (Club Urológico
Cancer Group. Long-term efficacy results of EORTC genito-urinary
Español De Tratamiento Oncológico). A multicentre, randomized
group randomized phase 3 study 30911 comparing intravesical
prospective trial comparing three intravesical adjuvant therapies
instillations of epirubicin, bacillus Calmette-Guerin and bacillus
for intermediate-risk superficial bladder cancer: low-dose bacillus
Calmette-Guerin plus isoniazid in patients with intermediate and
Calmette-Guerin (27 mg) versus very low-dose bacillus Calmette-
high risk stage Ta–T1 urothelial carcinoma of the bladder. Eur Urol
2010;57:766–73.
Guerin (13.5 mg) vs mitomycin C. Eur Urol 2007;52:1398–406.
[16] Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU
[10] Van der Meijden AP, Brausi M, Zambon V, Kirkels W, de Balincourt C,
cancer group randomized study of maintenance bacillus Calmette-
Sylvester R, members of the EORTC Genito-Urinary Group. Intrave-
Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of
sical instillation of epirubicin, bacillus Calmette-Guerin and bacillus
the urinary bladder: one-third dose versus full dose and 1 year
Calmette-Guerin plus isoniazid for intermediate and high risk Ta, T1
versus 3 years maintenance. Eur Urol 2013;63:462–72.
papillary carcinoma of the bladder: a European Organization for
[17] Johnson MH, Nepple KG, Peck V, et al. Randomized controlled trial
Research and Treatment of Cancer Genito-Urinary Group random-
of oxybutynin extended release versus placebo for urinary symp-
ized phase III trial. J Urol 2001;166:476–81.
[11] Vegt PD, van der Meijden AP, Sylvester R, Brausi M, Höltl W, de
toms during intravesical bacillus Calmette-Guérin treatment. J Urol
2013;189:1268–74.
Balincourt C. Does isoniazid reduce side effects of intravesical
[18] Mack D, Höltl W, Bassi P, et al., European Organization for Research
bacillus Calmette-Guerin therapy in superficial bladder cancer?
and Treatment of Cancer Genitourinary Group. The ablative effect
Interim results of EORTC protocol 30911. J Urol 1997;157:1246–9.
of quarter dose bacillus Calmette-Guerin on a papillary marker
[12] Colombel M, Saint F, Chopin D, Malavaud B, Nicolas L, Rischmann P.
lesion of the bladder. J Urol 2001;165:401–3.
The effect of ofloxacin on bacillus Calmette-Guerin induced toxicity
[19] van der Meijden AP, Sylvester RJ, Oosterlinck W, Hoeltl W, Bono AV,
in patients with superficial bladder cancer: results of a randomized,
EORTC Genito-Urinary Tract Cancer Group. Maintenance bacillus
prospective, double-blind, placebo controlled multicenter study.
Calmette-Guerin for Ta T1 bladder tumors is not associated with
J Urol 2006;176:935–9.
increased toxicity: results from a European Organisation for Re-
[13] Martı́nez-Piñeiro JA, Flores N, Isorna S, et al., CUETO (Club Urológico
Español de Tratamiento Oncológico). Long-term follow-up of a
search and Treatment of Cancer Genito-Urinary Group phase III
trial. Eur Urol 2003;33:429–34.
randomized prospective trial comparing a standard 81 mg dose
[20] Witjes JA, Palou J, Soloway MS, et al. Clinical practice recommenda-
of intravesical bacillus Calmette-Guerin with a reduced dose of
tions for the prevention and management of intravesical therapy–
27 mg in superficial bladder cancer. BJU Int 2002;89:671–7.
associated adverse events. Eur Urol Suppl 2008;7:667–74.