5-Year Outcome of a Randomized Prospective Study Comparing

bacillus Calmette-Gue
rin with Epirubicin and Interferon-a2b

in Patients with T1 Bladder Cancer
Tammer Hemdan,* Robert Johansson, Staffan Jahnson, Pekka Hellstro€ m,
€ m and Members of the Urothelial
Ilker Tasdemir, Per-Uno Malmstro
Cancer Group of the Nordic Association of Urology
From the Departments of Urology and Surgical Sciences, University Hospital Uppsala, Uppsala (TH, PUM), Oncological
Center, Umeå University Hospital, Umeå (RJ), and Department of Urology, University Hospital Linköping, Linköping (SJ),
Sweden; Department of Urology, University Central Hospital, Oulu, Finland (PH), and Department of Urology,
Central Hospital of Rogaland, Stavanger, Norway (IT)

Purpose: In a multicenter, prospectively randomized study we evaluated the

Abbreviations
and Acronyms
BCG ¼ bacillus Calmette-Gu
erin
CIS ¼ carcinoma in situ
CSS ¼ cancer specific survival
IFN-a2b ¼ interferon-a2b
RFS ¼ recurrence-free survival
TF ¼ treatment failure
TURB ¼ transurethral resection of
bladder cancer
Accepted for publication November 6, 2013.
Study received ethics committee approval.
* Correspondence: Department of Urology,
Surgical Sciences, University Hospital Uppsala,
SE-75185 Uppsala, Sweden (e-mail: tammer.
hemdan@surgsci.uu.se).
For another article on a related
topic see page 1422.
5-year outcomes of bacillus Calmette-Gu
erin alone compared to a combination
of epirubicin and interferon-a2b in the treatment of patients with T1 bladder
cancer.
Materials and Methods: Transurethral resection was followed by a second
resection and bladder mapping. Stratification was for grade and carcinoma in
situ. Followup entailed regular cystoscopy and cytology during the first 5 years.
The end points assessed in this analysis were recurrence-free survival, time
to treatment failure and progression, cancer specific survival and prognostic
factors.
Results: The study recruited 250 eligible patients. The 5-year recurrence-free
survival rate was 38% in the combination arm and 59% in the bacillus Calmette-
Gu
erin arm (p ¼ 0.001). The corresponding rates for the other end points were
not significantly different, as free of progression 78% and 77%, treatment failure
75% and 75%, and cancer specific survival 90% and 92%, respectively. The type
of treatment, tumor size and tumor status at second resection were independent
variables associated with recurrence. Concomitant carcinoma in situ was not
predictive of failure of bacillus Calmette-Gu
erin therapy. An independent factor
for treatment failure was remaining T1 stage at second resection.
Conclusions: Bacillus Calmette-Gu
erin was more effective than the tested
combination therapy. The currently recommended management with second
resection and 3-week maintenance bacillus Calmette-Gu
erin entails a low risk
of cancer specific death. More aggressive treatment in patients with infiltrative
tumors at second resection might improve these results. In particular, concom-
itant carcinoma in situ was not a predictive factor for poor outcome after bacillus
Calmette-Gu
erin therapy.

Key Words: urinary bladder neoplasms; chemotherapy, adjuvant

THE introduction of guidelines for the high level evidence, preferably from
management of urological disease has meta-analyses of randomized pro-
received much attention. The basis spective clinical trials. In the field
for these recommendations should be of bladder cancer an abundance of

0022-5347/14/1915-1244/0 http://dx.doi.org/10.1016/j.juro.2013.11.005

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THE JOURNAL OF UROLOGY®
© 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Vol. 191, 1244-1249, May 2014
Printed in U.S.A.
 NORDIC T1 BLADDER CANCER STUDY FOLLOWUP
evidence is available but also lacking in important
areas. An example of this is concerning the
management of patients with T1 tumors. The
EAU (European Association of Urology) guidelines
recommend initial bladder sparing therapy with
instillations of BCG.1 In detail the treatment should
consist of complete transurethral resection of visible
tumors followed by an immediate postoperative
instillation with a chemotherapeutic agent (drug
optional) and a second resection after 4 to 6 weeks,
followed by intravesical induction and maintenance
BCG for at least 1 year. To our knowledge no high
level evidence data on the efficacy of this manage-
ment algorithm have been reported.
Among the difficulties with BCG therapy are
the side effects, which make maintenance therapy
difficult, even impossible, in a proportion of
patients. Thus, alternative schedules and drugs
have been tested. We have previously reported the
24-month outcome of a Nordic study comparing
epirubicin plus IFN-a2b to BCG,2 a study concept
based on a Finnbladder trial.3 In our Nordic trial
for prophylaxis of recurrence, BCG was more effec-
tive than the combination therapy. No significant
differences were found for adverse events. Discon-
tinuation due to side effects was rare (9% for BCG
and 2% for combination therapy). In this study we
analyze the end points of recurrence-free survival,
treatment failure, progression and cancer specific
survival after 5-year followup, and assess possible
prognostic factors.
MATERIALS AND METHODS
Study Design
Between 1999 and 2006 a total of 256 patients were
enrolled at 20 urological units in Sweden (206), Norway
(26) and Finland (24) in a prospective, randomized,
multicenter study conducted by the Nordic Urothelial
Cancer Group. Of the randomized patients 6 were
excluded because of violation of inclusion criteria. Of the
remaining eligible 250 patients 198 were men and 52 were
women. Overall 126 patients were randomly assigned to
the BCG arm and 124 were assigned to the combined,
experimental arm. The trial was prematurely stopped due
to slow recruitment. Stratification was based on histo-
logical grade and associated CIS. The other tumor char-
acteristics, size and multiplicity, were also well-balanced.
The study protocol was designed to meet the criteria of the
Helsinki Declaration, including written informed consent
signed by the patients. Ethics approval was granted by
the Medical Faculty Ethical Committee of Umeå Univer-
sity (Dnr 98-145).
The inclusion criteria were patients with recently
detected T1 G2-G3 bladder cancer. Good performance sta-
tus was one of the conditions, as the protocol recommended
cystectomy if T1 disease persisted or recurred and if pro-
gression was observed at the 6-month followup. Exclusion
1245
criteria were 1) recurrent bladder tumor of any stage;
2) muscle invasive bladder tumor at a second look resection;
3) involvement of the urethra, prostate (ducts or stroma) or
upper urinary tract; 4) hydronephrosis; 5) anticoagulation
with warfarin; 6) a history of radiotherapy or systemic
chemotherapy; 7) previous endovesical treatment with the
investigational drugs other than a single instillation of
chemotherapy, including epirubicin after TURB; 8) history
of tuberculosis; and 9) immune deficiency and other ma-
lignancy (except basal cell carcinoma of the skin).
Pretreatment examination studies included physical
examination, blood analysis, cytology, bladder volume,
urine culture (if necessary) and chest x-ray. Excretory
urography in the last 6 weeks was also required. All
patients underwent initial TURB of all visible tumors
followed by a second look resection, including bladder
mapping and biopsy of the prostatic urethra within 4 to
8 weeks. Randomization was done by computer through
a telephone service at the Oncology Centre at Umeå
University after the second look.
Patients received treatment with 1 ampoule (1-8  108
cfu, 2 ml in 100 ml saline) BCG (OncoTICE, Organon
Teknika, Boxtel, the Netherlands) or the combination
of 50 mg of the dry substance epirubicin (Farmorubicin,
Pharmacia GmbH, Erlangen, Germany) and 10 million
units (dissolved in 100 ml saline) IFN-a2b (Intron A,
Schering-Plough, Kenilworth, New Jersey). Both regi-
mens were given as induction treatment for 6 weeks fol-
lowed by 3-week maintenance therapy for 2 years (fig. 1).
Study Variables and Analysis
Followup entailed cystoscopy and cytology every third
month for the first 2 years and, if there was no recurrence,
every 6 months until 5 years from the start of the treat-
ment. The primary end point was RFS at 6 months. Sec-
ondary end points were side effects of the 2 treatments,
time to TF, progression, CSS and overall survival.
All recurrence had to be verified by histopathology
and progression was defined as muscle infiltrative tumor
or metastatic disease. TF applied to those patients who
experienced disease progression, underwent cystectomy
or were treated with radiotherapy.
Crossover to the other treatment arm was recommended
if a patient had remaining CIS or stage Ta recurrence.
Cystectomy was recommended for recurrence of T1 tumors
and for progression in stage (T2 or higher). Patients deemed
unsuitable for cystectomy or those with generalized disease
were treated according to the routines of the clinic.
Statistical Analysis
All investigations were prespecified with an intent to treat
approach. The event-free period was calculated according
to the Kaplan-Meier method. Comparison between the
groups was performed using the log rank test. Multivar-
iate analyses were performed with the Cox proportional
hazards regression model. All tests were 2-tailed and
p <0.05 was considered statistically significant.
RESULTS
At the time of this analysis the median observation
time for patients alive was 6.9 years (range 1 to 13).
1246 NORDIC T1 BLADDER CANCER STUDY FOLLOWUP

Figure 1. Treatment and assessment schedule. TUR-B, transurethral resection of bladder tumor, and if no tumor, TUR-B at primary
location. Sec look, TUR-B at primary tumor location plus mapping. R, randomization. Pex, multiple biopsies. Int, interferon-a2b.
Epi, epirubicin. Shaded boxes represent cystoscopy plus bladder washing/cytology.

However, all survival analyses were performed at
the end of 5 years of observation. The different out-
comes are depicted in the CONSORT (CONsolidated
Standards of Reporting Trials) diagram (fig. 2).
The 5-year recurrence-free survival rate was 38%
in the combination arm vs 59% in the BCG arm
(p ¼ 0.001). RFS is depicted in figure 3 and was also
analyzed according to the stratification criteria.
Patients with associated CIS in the combination
arm had a significantly worse outcome (p <0.001)
than the other subgroups, including those with CIS
in the BCG arm (fig. 4).
The outcomes for the other end points for com-
bination and BCG treated cases were free of pro-
gression 78% and 77%, TF 75% and 75%, and CSS
90% and 92%, respectively. None of these differ-
ences was significant.
Crossover after relapse was instituted in 10 and
30 of the patients treated with BCG and the
combination therapy, respectively. Second line BCG
resulted in a recurrence-free rate of 63% (9 of 33)
at 2 years while 30% (3 of 10) obtained this with
combination therapy (fig. 5). During the followup
33 patients underwent cystectomy and 15 were
given radiotherapy (table 1).
In a multivariate analysis the type of intra-
vesical therapy, tumor size and tumor status at
second resection were independent variables asso-
ciated with recurrence. When this analysis was
performed per treatment arm, tumor size was the
only independent factor in the BCG group while
this was the case for tumor status at second resec-
tion, age and concomitant CIS in the other group.
An independent factor for progression and TF was
T1 stage at second resection. In terms of CSS none
of the variables was independent. However, T1

Figure 2. Flow of patients during 5-year followup Figure 3. RFS according to randomization arm (p ¼ 0.001)
 NORDIC T1 BLADDER CANCER STUDY FOLLOWUP
Figure 4. RFS in subgroups according to CIS status. BCG, no CIS
vs epirubicin, no CIS: p ¼ 0.38. BCG, no CIS vs BCG, CIS:
p ¼ 0.41. BCG, no CIS vs epirubicin, CIS: p <0.001. Epirubicin,
no CIS vs BCG, CIS: p ¼ 0.13. Epirubicin, no CIS vs epirubicin,
CIS: p <0.001. BCG, CIS vs epirubicin, CIS: p <0.001.
stage at second resection was of borderline signifi-
cance (p ¼ 0.076, table 2).
DISCUSSION
Instillation therapy with BCG has been used for
more than 30 years. At present we know much
about the strengths and limitations of this therapy,
and these limitations have stimulated efforts to find
new drugs or combinations with better efficacy. An
-
Figure 5. RFS after crossover (stage at crossover Tad28, T1d2,
Tisd10) (p ¼ 0.007).
1247
Table 1. Secondary treatments up to 60 months
No. BCG No. Epirubicin/Interferon
Crossover 10 33
Cystectomy 16 17
Radiation 11 4
example is the Nordic CIS trial, in which a combi-
nation of mitomycin C and BCG was tested.4 Un-
fortunately the results with alternative therapies in
this and other trials have been disappointing.
Several attempts have been made to subcatego-
rize T1 tumors prognostically. When designing this
trial histological grade 3 and concomitant CIS were
generally regarded as indications of poor prognosis,
which was the reason for stratifying for these
factors.
It is currently common to include any T1,
regardless of grade, in the high risk, nonmuscle
invasive bladder cancer category. In our 24-month
analysis grade (2 or 3) was an independent factor
for recurrence. However, this was not seen at the
longer followup, nor was it an important factor
for the other end points. This finding is in agree-
ment with recent ICUD (International Consultation
on Urologic Disease)-EAU recommendations that
any invasive tumor should be designated high
grade.5 The presence of concomitant CIS with T1
tumors was shown to be a risk factor in several
studies6e9 and increased the risk of progression
sixfold according to EORTC (European Organisa-
tion for Research and Treatment of Cancer) risk
tables.10 Interestingly we now show that this was
not evident with the recommended modern man-
agement as opposed to nonBCG therapy. This
is more in accordance with the findings of the
CUETO group of a modest increased risk.11 The
difference in their studies was that no second
resection was performed and the BCG maintenance
period was shorter.
Another change in risk grouping should be
incorporation of tumor status at second resection.
The prognostic importance of stage at second
resection was shown in an analysis of a large case
series several years ago.12 We found that patients
with remaining T1 tumor at second resection had
a greater than twofold increased risk of recurrence
compared to those with less tumor burden, calling
into question whether bladder sparing is a viable
alternative for these patients. Thus, it now seems
evident that risk tables have to be updated with
information based on currently recommended
management of high risk tumors.
Despite the modern treatment and relatively
large size, our trial has some limitations. The
study never recruited the planned number of
patients, making subgroup analysis more uncertain.
1248 NORDIC T1 BLADDER CANCER STUDY FOLLOWUP

Table 2. Multivariate analysis of risk of recurrence, TF and cancer specific death at 60 months for all patients and according to
treatment arm

All Pts BCG Epirubicin

95% CI for Exp(B) 95% CI for Exp(B) 95% CI for Exp(B)

p Value HR Lower Upper p Value HR Lower Upper p Value HR Lower Upper

Risk of recurrence:
Treatment (BCG, epirubicin) 0.002 1.883 1.26 2.813
Second look Ta 0.001 2.267 1.453 3.539 0.036 2.152 1.051 4.408 0.001 3.381 1.846 6.195
Second look T1 0.001 3.476 2.128 5.678 0.051 2.129 0.996 4.551 0.001 8.175 4.074 16.404
Size (less than 3 cm, 0.008 1.689 1.145 2.493 0.01 2.191 1.205 3.983 0.424 1.235 0.736 2.07
greater than 3 cm)
Multiplicity (1, greater than 1) 0.115 1.365 0.927 2.009 0.493 1.24 0.67 2.297 0.383 1.267 0.744 2.157
Gender (M, F) 0.703 0.912 0.569 1.463 0.512 1.272 0.62 2.612 0.188 0.653 0.346 1.232
Age (younger than 67 yrs, 0.559 0.894 0.615 1.301 0.543 1.204 0.661 2.194 0.038 0.581 0.348 0.97
67 yrs or older)
TIS (no, yes) 0.238 1.278 0.851 1.921 0.545 0.805 0.398 1.626 0.003 2.176 1.297 3.652
Treatment failure:
Treatment (BCG, epirubicin) 0.936 0.977 0.557 1.713
Second look Ta 0.435 1.329 0.651 2.714 0.294 1.756 0.614 5.022 0.499 1.487 0.471 4.696
Second look T1 0.001 3.457 1.8 6.639 0.082 2.359 0.896 6.212 0.001 7.728 2.572 23.223
Size (less than 3 cm, 0.087 1.641 0.931 2.892 0.109 2.022 0.854 4.785 0.373 1.537 0.597 3.956
greater than 3 cm)
Multiplicity (1, greater than 1) 0.468 1.229 0.703 2.148 0.326 1.52 0.659 3.507 0.344 0.641 0.255 1.61
Gender (M, F) 0.266 0.661 0.319 1.372 0.138 0.332 0.077 1.425 0.185 0.48 0.162 1.42
Age (younger than 67 yrs, 0.663 1.129 0.654 1.949 0.922 1.042 0.461 2.354 0.062 2.39 0.956 5.976
67 yrs or older)
TIS (no, yes) 0.279 1.374 0.772 2.445 0.158 1.911 0.777 4.699 0.445 0.694 0.273 1.769
Ca specific death:
Treatment (BCG, epirubicin) 0.892 1.071 0.4 2.87
Second look Ta 0.168 2.329 0.701 7.743
Second look T1 0.076 3.035 0.891 10.343
Size (less than 3 cm, 0.515 1.394 0.513 3.785
greater than 3 cm)
Multiplicity (1, greater than 1) 0.588 0.758 0.279 2.061
Gender (M, F) 0.554 0.68 0.19 2.439
Age (younger than 67 yrs, 0.769 1.154 0.443 3.005
67 yrs or older)
TIS (no, yes) 0.478 1.444 0.524 3.981

In addition, the numbers of patients receiving a
single instillation of chemotherapy after TURB and
those excluded because of stage T2 or higher disease
at second resection were not registered. No central
pathological review has been performed on the total
material but review of the samples from the Swed-
ish patients (177) showed a concordance of more
than 90% with local pathology. Finally patients
unfit for major surgery were not included as sec-
ondary cystectomy was a recommendation.
We previously reported our results after cross-
over in a trial comparing mitomycin C and BCG.13
Crossover treatment in that study was successful
in 39% of patients with second line BCG compared
to 63% in the present trial. The former trial had
different inclusion criteria which made comparisons
difficult. The advantage with the crossover possi-
bility is that nonresponding patients will have an
alternate therapy sooner and this therapy can be
registered as opposed to outside protocol treatment.
The disadvantage is that this could be a confounder
when assessing end points other than primary
recurrence.
The 5-year CSS in this trial was more than 90%,
which is better than the 83% reported with imme-
diate cystectomy.14 However, randomized compari-
sons are needed to evaluate this end point.
Biomarkers with the ability to predict response
to BCG are important as nonresponders can be
recommended for immediate cystectomy. Several
potential candidates have been reported and these
will be further investigated in the specimens from
our trial.
CONCLUSIONS
The currently recommended bladder sparing man-
agement of patients with T1 bladder cancer entails
a low risk of cancer specific death during the first
5 years of followup. Importantly concomitant CIS
is not a predictive factor for poor outcome after
BCG therapy.
ACKNOWLEDGMENTS
Drs. Miloı̂s Duchek, Oddvar Mestad and Sverker
Hellsten provided assistance.
 NORDIC T1 BLADDER CANCER STUDY FOLLOWUP 1249

APPENDIX
The following hospitals and urologists also participated in this study: Sweden:
Eskilstuna/Katrineholm - Torsten Lindeborg, G€oteborg/Sahlgrenska - Sten
Finland:
Holm€ang, Stockholm/Huddinge - Hans Wijkstr€om, Link€oping - Staffan Jahnsson
Oulu - Pekka Hellstr€om
och Ole Damm, Lund - Wiking M ansson och Fredrik Liedberg, Malm€o - Rajne
Helsinki - Erkki Rintala
S€oderberg och Sverker Hellsten, Stockholm/Karolinska - Peter Wiklund
Kuopio - Kari Tuhkanen
och Abei Husseini, Stockholm/S€oS - Ulf Norming, Claes R Nyman och Rolf
L€ansi-Pohja - Juhani Ottelin
Zimmerman, Uppsala - Per-Uno Malmstr€om, V€aster as - Thorvald Granfors
Mikkeli - Tapani Liukkonen €
och Farhood Alamdari, Orebro - J€orgen Pedersen och Dag Sandblom,
Tampere - Jukka H€akkinen
Ume a - Radica Tamic, B€orje Ljungberg, Bengt Friedrich och Jan Jacobssen
Turku - Esa K€ahk€onen
Hyvink€a€a - Eero Kaasinen
Norway:
Stavanger - Oddvar Mestad

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