Gemcitabine Versus Bacille Calmette-Guerin

After Initial Bacille Calmette-Guerin Failure

in Non-Muscle-Invasive Bladder Cancer
A Multicenter Prospective Randomized Trial
Giuseppe Di Lorenzo, MD, PhD
1
; Sisto Perdona`, MD
2
; Rocco Damiano, MD
3
; Adriana Faiella, MD
1
;
Francesco Cantiello, MD
3
; Sandro Pignata, MD
4
; Paolo Ascierto, MD
5
; Ester Simeone, MD
5
;
Marco De Sio, MD, PhD
6
; and Riccardo Autorino, MD, PhD
6
BACKGROUND: The efficacy of intravesical gemcitabine was evaluated compared with repeated administration of
bacille Calmette-Guerin (BCG) after BCG failure in high-risk, non-muscle-invasive bladder cancer (BC). METHODS: In
this multicenter, prospective, randomized, phase 2 trial, eligible patients were those with high-risk non-muscle-inva-
sive BC, failing 1 course of BCG therapy. All patients were randomly allocated to Group A, receiving intravesical gem-
citabine (at a dose of 2000 mg/50 mL) twice weekly for 6 consecutive weeks and then weekly for 3 consecutive
weeks at 3, 6, and 12 months, or Group B, receiving intravesical BCG (Connaught strain, 81 mg/50 mL) over a 6-week
induction course and each week for 3 weeks at 3, 6, and 12 months. Outcome measures were recurrence rate, time to
first recurrence, and progression rate. Treatment-related complications were also evaluated. RESULTS: Eighty partici-
pants were enrolled, 40 for each group 52.5% in Group A developed disease recurrence versus 87.5% of those in
Group B (P .002). There was no statistically significant difference in mean time to the first recurrence (Group A, 3.9
months; Group B, 3.1 months; P .09). Kaplan-Meier analysis of 2-year recurrence-free survival showed significant dif-
ferences between Group A and B (19% and 3%, respectively, P < .008). Seven of 21 (33%) patients in Group A and 13
of 35 (37.5%) patients in Group B had disease progression and underwent radical cystectomy (P .12). Both intraves-
ical administrations were generally well tolerated. CONCLUSIONS: Gemcitabine might represent a second-line treat-
ment option after BCG failure in high-risk non-muscle-invasive BC patients. Cancer 2010;116:1893900. VC
2010
American Cancer Society.
KEYWORDS: bacille Calmette-Guerin, failure, gemcitabine, superficial bladder cancer.
The primary therapeutic goal in patients with high-risk non-muscle-invasive bladder cancer (BC) is the prevention or
delay of disease progression. Large meta-analyses have shown that bacille Calmette-Gue

rin (BCG) therapy is associated

with a reduction in the risk of tumor progression compared with chemotherapy.
1,2
BCG was also shown to be superior to
chemotherapy in reducing tumor recurrence.
3
Between 20% and 40% of patients apparently fail after BCG with recurring tumors, depending on the follow-up
time and their initial risk profile.
4
When BCG is used as therapy, it induces a 70% initial complete response rate, which
remains in 50%of patients after long follow-up.
5
DOI: 10.1002/cncr.24914, Received: April 15, 2009; Revised: June 22, 2009; Accepted: July 9, 2009, Published online February 16, 2010 in Wiley InterScience
(www.interscience.wiley.com)
Corresponding author: Riccardo Autorino, MD, PhD, FEBU, Clinica Urologica, Seconda Universita` degli Studi di Napoli, AOU Policlinico Piazza Miraglia 2, 80138
Napoli, Italy; Fax: (011) 39081446664; [email protected]
1
Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, Naples, Italy;
2
Urology Unit, National Tumor Institute, Pascale Founda-
tion, Naples, Italy;
3
Urology Unit, Magna Graecia University, Catanzaro, Italy;
4
Medical Oncology Unit, National Tumor Institute, Pascale Foundation, Naples, Italy;
5
Medical
Oncology and Innovative Therapy Unit, National Tumor Institute, Pascale Foundation, Naples, Italy;
6
Urology Clinic, Second University of Naples, Naples, Italy
The first 2 authors contributed equally to this article.
We thank Boldface Editors for linguistic revision.
Contributions to the study were as follows: conception and design, Autorino, Di Lorenzo, Perdona`; acquisition of data, Autorino, Cantiello, Di Lorenzo; analysis and
interpretation of data, Autorino, De Sio, Di Lorenzo, Perdona`, Pignata; drafting the manuscript, Autorino, Di Lorenzo; critical revision of the manuscript for important
intellectual content, Ascierto, Damiano, De Sio, Simeone; statistical analysis, Di Lorenzo, Faiella; supervision, Perdona`; patient enrollment, Autorino, Cantiello, Faiella,
Perdona`, Simeone.
Cancer April 15, 2010 1893
Original Article
The fate of patients failing intravesical therapy and
showing progression into muscle-invasive disease is sur-
prisingly bad. Examining patients showing progression af-
ter BCG treatment, Sylvester et al
1
reported a bladder
cancer-specific death rate of 64% at 2.5 years after pro-
gression from a superficial tumor. Similar figures were
more recently found by a Spanish group.
6
Thus, the window of opportunity is these patients
remains limited, and the management of BCG treatment
failures represents an important issue in non-muscle-inva-
sive BC, particularly in high-risk disease. According to the
European Association Of Urology,
7
3 months of BCG
therapy can be administered, as this has been associated
with a complete response in >50%of patients.
8
Changing
from BCG to chemotherapy can provide further remis-
sion in selected patients failing BCG therapy. However,
in most cases of high-risk BCG failure, immediate cystec-
tomy is strongly advocated.
7
As some of these patients cannot be submitted to
radical surgery because they are unfit for it and/or refuse
it, more conservative approaches with other cytotoxic
drugs may be considered in this setting.
9
Gemcitabine, a novel deoxycytidine analog with a
broad spectrum of antitumor activity, is considered
standard in systemic therapy for advanced bladder cancer.
10
Given its pharmacokinetic properties, gemcitabine has
been suggested as an ideal candidate for regional therapy
and has been studied for its potential in intravesical use.
11
Intravesical gemcitabine was first reported as a new
treatment option for BCG-refractory non-muscle-inva-
sive BC patients by Dalbagni et al.
12
More recently, the
same group reported a phase 2 study assessing the efficacy
of gemcitabine administered as an intravesical agent in
BCG-refractory patients refusing cystectomy. Thirty eligi-
ble patients were included in the study, and the median
follow-up for all was 19 months. Of these patients, 15
(50%) achieved a complete response. However, the 2-year
disease-free rate was only about 8% (2 of 30), suggesting
that durability remains a problem.
13
The aim of our study was to evaluate the efficacy of
intravesical gemcitabine compared with repeated adminis-
tration of BCG as second-line therapy in high-risk non-
muscle-invasive BCpatients refusing or not candidates for
radical cystectomy after initial BCGfailure.
MATERIALS AND METHODS
This is a multicenter, prospective, randomized, phase 2
trial carried out between June 2006 and May 2008. The
study was approved by the local research ethical commit-
tee of each participating center. Written informed consent
was obtained fromall patients.
Inclusion Criteria
Eligible patients were those with high-risk non-muscle-
invasive BC, based on the European Organization for
Research and Treatment of Cancer scoring system,
14
fail-
ing BCG therapy,
7
for whom radical cystectomy was indi-
cated but not conducted because of refusal or ineligibility
because of age or comorbidities and high anesthesiological
risk. Tumors were pathologically staged according to the
1997 TNM classification and graded following the 1998
World Health Organization/International Society of Uro-
logic Pathology scale. Exclusion criteria were concurrent
or previous muscle-invasive disease, concurrent or previ-
ous tumor in the upper urinary tract or prostatic urethra,
chronic urinary tract infection, cured or active tuberculo-
sis, any other malignancy except basal cell carcinoma of
skin, previous pelvic irradiation, creatinine higher than
twice the standard, glutamate oxaloacetic transaminase
and glutamate pyruvic transaminase higher than twice the
standard, pregnancy or lactation, and any other disease
with immunodeficiency.
Study Design
All patients started treatment after 4 to 6 weeks from the
last transurethral resection (TUR), performed after the
failure of the first treatment with BCG, as defined by
the European Association Of Urology.
7
Re-TUR had
been performed in all T1 high-grade cases. By using a
central computer-generated randomization list, patients
were randomly allocated to 1 of the 2 groups. An open-
label study design was used, that is, patients and investi-
gators were not masked as to the drugs they were
assigned.
Group A received intravesical gemcitabine, twice
weekly (Days 1 and 4) at a dose of 2000 mg/50 mL for 6
consecutive weeks (induction course), and then weekly for
3 consecutive weeks at 3, 6, and 12 months. Group B was
given intravesical BCG (Connaught strain, 81 mg/50
mL) over a 6-week induction course and then each week
for 3 weeks, at 3, 6, and 12 months.
The prestudy clinical evaluation comprised medical
history, general physical examination, electrocardiogram,
computed tomography (CT)-urography, chest x-ray, and
hematological evaluation (including white blood cell-pla-
telet count, electrolytes, and liver and kidney function).
Urine analyses with urine culture were also done weekly
during the treatment. Clinical, hematological, and
Original Article
1894 Cancer April 15, 2010
biochemical assessments were performed every third week
and were repeated at the end of treatment.
Cytological analysis of voided urine and cystoscopy
were performed at 3-month intervals. Intravenous urogra-
phy or CT-urography was performed annually.
Recurrence was determined by lesions that were
detected at cystoscopy and pathologically confirmed after
TUR. A positive cytology alone was not considered as a
recurrence. In case of positive cytology, a bladder map-
ping was performed, and only if there was pathological
confirmation of a tumor was a case counted as a recur-
rence. Time to first recurrence was defined as the time
from TUR to the date of the first recurrence.
Progression was defined as an increase in tumor
stage and grade. Time to progression was defined as the
time between TUR and first progression.
Toxicity was assessed on the first day of each cycle
with the use of the Common Toxicity Criteria version
3.0.
15
Grade 3 side effects resulted in patients exclusion
from the study. In the case of grade 2 toxicity, the treat-
ment was delayed for 1 week and repeated. If toxicity
relapsed at grade 2, the treatment was stopped. Side effects
were checked after each instillation and were recorded in
the database. No dose reduction was allowed.
Statistics
The study was designed to compare the effect of gemcita-
bine with a second cycle of BCG with respect to efficacy
and safety. The primary endpoint was the recurrence rate
(percentage of recurring patients) at 1-year follow-up.
Secondary endpoints were time to recurrence, progression
rate, time to progression, and toxicity. Considering that a
second course of BCG in this subset of patients might
show a recurrence rate of almost 80%,
16
to obtain a signif-
icant improvement of a second-line intravesical treatment
efficacy, we assumed a recurrence rate of 50% in gemcita-
bine-treated patients, with an absolute difference of 30%
at 1 year. To obtain this result, a final target of 40 patients
per group of treatment would allow the study to obtain
80% potency with 5% significance. Considering ineli-
gible cases, we set the number of patients to be recruited
as 46 in each group (n 92 total).
Quantitative data are described by the median
(range), and qualitative data are described as counts and
percentages. Duration of the disease-free interval was esti-
mated according to the Kaplan-Meier method, and com-
parison between treatment groups was estimated by
means of the log-rank test. Chi-square and Fisher exact
test were used to assess the significance of all correlations.
Statistical significance was achieved if P < .05. All
reported P values are 2-sided. All data were recorded, col-
lected, and analyzed using standard statistical software.
RESULTS
Of 92 initially screened patients with high-risk non-mus-
cle-invasive BC failing BCG therapy, 80 were eligible and
enrolled in this trial (Fig. 1). All patients were randomly
assigned to 2 groups of 40 (Groups A and B). The clinical
and pathological characteristics of the 2 groups are shown
in Table 1. Median follow-up was 15.2 months (range,
6-22) in Group A and 15.8 months (range, 7-21) in
Group B.
Disease Recurrence
In Group A, 52.5% (21 of 40) of patients developed dis-
ease recurrence versus 87.5% (35 of 40) in Group B (P
.002). The difference between the 2 groups in terms of
time to first recurrence (Group A: 3.9 months; 95% con-
fidence interval [CI], 3-7; Group B: 3.1 months; 95% CI,
2.2-6) was not statistically significant (hazard ratio [HR],
1.1; CI 95%, 0.8-1.2; P .09). Kaplan-Meier analysis of
2-year recurrence-free survival showed significant differ-
ences between Group A (19%; 95% CI, 5-39) and Group
B (3%; 95% CI, 0-21; HR, 0.15; 95% CI, 0.1-0.3; P <
.008; Fig. 2).
Figure 1. A diagram of the study is shown. BCG indicates
bacille Calmette-Guerin; CT, computed tomography.
Gemcitabine After BCG Failure in BC/Di Lorenzo et al
Cancer April 15, 2010 1895
Disease Progression
Seven of 21 (33%) patients in Group A and 13 of 35
(37.5%) patients in Group B had disease progression and
underwent radical cystectomy with ileostomy or uretero-
cutaneostomy. Moreover, 9 of 21 (43%) patients in
Group A and 14 of 35 (40%) patients in Group B were
submitted to radiation therapy plus systemic chemother-
apy. At the time of the last follow-up visit, all patients
were alive in Group A, and 1 had died because of meta-
static disease in Group B. No statistically significant dif-
ference was reported (P .12).
Toxicity
Both intravesical administrations of gemcitabine and
BCG were generally well tolerated (Table 2). Overall, few
severe (grade 3) adverse events occurred, with no statisti-
cally significant difference between the 2 groups. In 2
cases, we observed grade 3 dysuria, and in 1 case, grade 3
thrombocytopenia in Group A. One case of dysuria, 1 of
hematuria, and 1 of fever (>38

C) represented the grade

3 events in Group B. In all these 6 cases, treatment was
delayed, accounting for a 7.5%delay rate in both groups.
Table 1. Baseline Patient Characteristics
Characteristic
Group A
(Total540)
Group B
(Total540) P
Men/Women 27/13 22/18 NS
Mean age, ySD 69.38.4 71.47.9 NS
ASA score
NS
II 6 8
III-IV 34 32
Classification NS
Ta 10 8
T1 30 32
Grade (1998 WHO) NS
Low 11 13
High 29 27
Number of tumors NS
Single 10 8
2-7 25 26
8 5 6
Tumor diameter NS
<3 cm 15 17
>3 cm 25 23
Concomitant CIS 12 13 NS
Recurrence rate NS
Primary 3 5
1 per year 10 9
>1 per year 27 26
EORTC progression score NS
7-13 5 7
14-23 35 33
NS indicates not significant (Fisher exact test); ASA, American Society of
Anesthesiologists; WHO, World Health Organization; CIS, carcinoma in situ;
EORTC, European Organization for Research and Treatment of Cancer.
Figure 2. Kaplan-Meier estimation of 2-year recurrence-free
survival is shown (Group A, gemcitabine; Group B, bacille
Calmette-Guerin).
Table 2. Toxicity in the Treatment Groups
Toxicity
Group A
(n540)
Group B
(n540) P
Dysuria
Grade 2 4 7
Grade 3 2 1
Hematuria
Grade 2 2 4
Grade 3 0 1
Fever
Grade 2 1 2
Grade 3 0 1
Neutropenia-thrombocytopenia
Grade 2 1 0
Grade 3 1 0
Dermatitis
Grade 2 2 0
Grade 3 0 0
Nausea-vomiting
Grade 2 2 0
Grade 3 0 0
Total events
Grade 2 12 13 .12
Grade 3 3 3 .25
Original Article
1896 Cancer April 15, 2010
DISCUSSION
Intravesical BCG represents the standard adjuvant treat-
ment in patients with high-risk non-muscle-invasive BC,
according to the European Association Of Urology guide-
lines.
7
However, not all patients benefit from intravesical
BCG.
4
The fate of patients failing intravesical therapy and
showing progression into muscle-invasive disease is sur-
prisingly bad. Sylvester et al, looking at patients showing
progression after BCG treatment, reported that the blad-
der cancer-specific death rate was 64% at 2.5 years after
progression from a superficial tumor.
5
More recently,
Huguet et al
6
found that of 62 failures treated with cystec-
tomy, 17 patients appeared to have stage pT2 or higher.
The 5-year disease-specific survival of these progressive
patients was 38%, significantly lower than nonprogressive
patients (90%).
Current options for high-risk BCG failure are radi-
cal cystectomy or alternative intravesical therapy. Various
immunological and chemotherapeutic regimens have
been evaluated for this purpose, but their efficacy is still a
matter of debate. To date, radical cystectomy remains the
recommended treatment option in these patients.
9
The
advantage of cystectomy in non-muscle-invasive BC
patients failing BCGis obvious, with a tumor-specific sur-
vival between 80%and 90%at 5 years.
17
Conversely, the price for this potential survival
advantage is also obvious. Cystectomy is major surgery,
and not everyone is fit or willing to try it. Even in the best
hands, the mortality rate is 2% to 3%, and short-term or
long-term morbidity occurs in approximately
1
=
3
of
patients.
17
Thus, many patients are willing to explore
alternatives.
One phase 2 trial specifically addressed the efficacy
of bropirimine, an oral immunomodulator, in BCG-re-
sistant carcinoma in situ (CIS) of the bladder. Of 65
evaluable patients, 21 had a complete response, including
14 of 47 BCG-resistant patients. Median response dura-
tion was >12 months, and only 4 patients progressed to
invasive disease or metastasis. Although bropirimine was
considered an alternative to cystectomy for some CIS
patients after BCG, no further evaluation of the drug has
been reported so far.
18
The combination of interferon alpha (IFN-a) and
BCG for BCG failure has been the subject of a large, mul-
ticenter, phase 2 trial.
19
Patients previously having BCG
failure received IFN-a (50,000,000 U) plus reduced-dose
BCG, whereas patients naive to BCG received the same
IFN-a dose with standard-dose BCG. All patients who
were relapse-free received an additional 3 series of 3-week
reduced-dose BCG plus IFN-a treatments at 3, 9, and 15
months after completing induction. Of 1007 valuable
patients, 59% and 45% of patients naive to BCG and
those having BCG failure, respectively, remained disease-
free at a 24-month median follow-up. Stage T1, tumor
size >5 cm, prior BCGfailure more than once, and multi-
focality were all statistically significant risk factors for
recurrence. The authors concluded that although BCG
plus IFN-a can be effectively applied both to patients
naive to BCG and to those having BCG failure, certain
patient and tumor characteristics influence durable
response. Thus the combination of BCG and IFN-a
represents a promising second-line regimen after BCG
failure, but results should be confirmed.
Thermochemotherapy is also reported to be success-
ful in BCG failure.
20
In 41 patients failing BCG treat-
ment, the 1- and 2-year recurrence rates were 23% and
41%, which are at least as good as the results achieved
with BCG and IFN-a. Still, longer follow-up and more
results will have to indicate the value of thermochemo-
therapy in patients in whomBCGfails.
Waidelich et al
21
used photodynamic therapy
(PDT) in 24 high-risk BCG-failing patients, including
those with CIS. They found that 3 of 5 CIS patients and 4
of 19 patients with papillary tumors were recurrence-free
after a median of 36 months. Thus, PDT might be a sec-
ond-line treatment for patients with tumor recurrence af-
ter BCGfailure.
Only a few attempts were made to treat BCG failure
with conventional intravesical chemotherapy, and some
interesting new drugs have been recently studied. Valrubi-
cin, a semisynthetic analog of doxorubicin, is the only
drug approved by the US Food and Drug Administration
for patients with CIS failing intravesical BCG therapy.
This was based on a relatively small, multicenter, phase 2
trial with 90 patients, with only a 21% response rate and
8% disease-free 2-year survival.
22
However, valrubicin
currently remains underused.
Attempts have already been made to test the activity
of intravesical gemcitabine in high-risk non-muscle-inva-
sive BC patients (Table 3). In their first phase 1 study,
Dalbagni et al
12
treated patients refractory to BCG and
refusing cystectomy. Four dose levels of gemcitabine were
given intravesically for 1 hour twice a week. Patients
received 2 courses of 6 instillations. Only 1 patient (high-
est dose level of 2000 mg in 100 mL) experienced grade 3
toxicity. Eleven patients had negative biopsies after treat-
ment, of whom 7 also had negative cytology. In their
more recently reported phase 2 study, the same group
Gemcitabine After BCG Failure in BC/Di Lorenzo et al
Cancer April 15, 2010 1897
treated 30 BCG-refractory patients with biweekly 2000
mg gemcitabine diluted in 100 mL saline solution for 3
weeks, with each course separated by 1 week of rest.
13
Complete disappearance of all evidence of disease was
achieved in 50% of patients. However, almost 8% of
patients remained disease free at 1 year. This points out
that gemcitabine in our study was being used to treat a
higher-risk group of patients than in the Dalbagni study.
Bartoletti et al
23
administered intravesical gemcita-
bine as a prophylactic treatment in BCG-refractory
patients. Eighteen of 24 intermediate-risk and 7 of 16
high-risk patients remained recurrence-free. Notably,
these excellent results in terms of 1-year recurrence-free
survival were achieved using a 3-year maintenance sched-
ule identical to the 1 currently suggested for BCG. The
same group of investigators reported a small series of
selected BCG-resistant T1G3 patients, unsuitable for rad-
ical treatment, who were treated with gemcitabine and
compared with 10 pT1G3 patients previously treated
with further conservative endovesical BCG administra-
tion.
24
Of the 9 patients treated with gemcitabine, 3 were
recurrence free after 13, 17, and 21 months, and 7 kept an
intact bladder, with an overall survival rate of 100%.
Among 10 patients treated with BCG instillation, 1 was
recurrence free after 27 months, and 6 kept their bladders,
with a survival rate of 80%.
Finally, Gunelli et al
25
presented a phase 2 study
evaluating the activity of biweekly intravesical treatment
with gemcitabine. Patients with BCG-refractory Ta-1G3
non-muscle-invasive BC underwent TUR of the bladder
and then intravesical instillation with 2000 mg diluted in
50 mL saline solution on Days 1 and 3 for 6 consecutive
weeks. Thirty-eight (95%) of the 40 patients showed per-
sistent negative post-treatment cystoscopy and cytology 6
months after treatment. At a median follow-up of 28
months, recurrence was noted in 14 patients.
Pharmacokinetic data from several phase 1 studies
show clearly that systemic absorption of intravesical gem-
citabine at up to 40 mg/mL (2000 mg in 50 mL), when
kept in the bladder for up to 2 hours, is minimal and tran-
sient, and thus unlikely to produce clinically significant
adverse events.
26
Overall, no systemic toxicity exceeding
grade II was recorded in any of the phase 1 studies, except
for 1 case of grade 3 myelosuppression and thrombocyto-
penia, reported at 20 mg/mL by Dalbagni et al.
12
In that
study, 2 factors in the design may have promoted an
increased systemic absorption, resulting in significant
hematological toxicity: first, the drug was administered
twice a week; second, the low pH of the gemcitabine solu-
tion, which was adjusted to prevent bladder irritation,
resulted in an increased nonionic form of the drug more
likely to diffuse through the bladder mucosa.
27
Another Italian group reported the preliminary data
of a multicenter study on the use of gemcitabine to pre-
vent recurrence of multiply recurring non-muscle-invasive
BC after intravesical antiblastic agents and/or BCG.
16
Fifty-three of 61 (86.9%) patients completed the cycle.
Side effects appeared in 14 patients; 8 of these had to
Table 3. Gemcitabine in High-Risk NonMuscle-Invasive Bladder Cancer: Current Evidence
Author
No. of
Patients Study Type Schedule Activity Toxicity
Bassi 2005
28
9 Bicenter phase 1 3 dose levels weekly for 6 weeks 4 CR No systemic absorption
with only slightly bladder
irritative symptoms
Gacci 2006
24
9 Multicenter comparative
nonrandomized
2000 mg/50 mL weekly for 6 weeks,
then weekly for 3 weeks at
3, 6, 12, 18, and 24 months
3 recurrence free, 7 with
intact bladder, overall
survival 100%
No severe and only
2 minor adverse events
Morabito 2006
16
64 Multicenter phase 1-2 2000 mg/50 mL weekly for 8 weeks Not reported Side effects in 14 patients,
8 of them suspended
the treatment
Gunelli 2007
25
40 Multicenter phase 2 2000 mg/50 mL twice
weekly for 6 weeks
38 CR, 14 recurrences Low urinary and systemic
toxicity; no alteration
in biochemical profile
Dalbagni 2006
13
30 Single center phase 2 2000 mg/100 mL twice weekly
for 3 weeks and 1 week rest
15 CR, 27/30 patients
recurring in the
1st year
Generally well tolerated;
6 patients experienced
grade 3 dysuria
Bartoletti 2005
23
16 Multicenter phase 2 2000 mg/50 mL weekly for 6 weeks No recurrence in
7 patients
Good tolerability and good
patient compliance
BCG indicates bacille Calmette-Gue rin; CR, complete response.
Original Article
1898 Cancer April 15, 2010
suspend treatment. Severe side effects were systemic in 4
patients and local in 4 patients. In 6 patients, pelvic pain,
hematuria, strangury, and urinary tract infection were
observed, none requiring treatment interruption.
Nine patients with CIS refractory to intravesical
BCG were enrolled in a phase 1 study by Bassi et al.
28
Gemcitabine was given once weekly for 6 consecutive
weeks at different dose levels. Grade 1 neutropenia was
observed in only 1 patient. Grade 1 urinary frequency and
hematuria were observed in 1 and 3 patients, respectively.
No grades 2 to 4 toxicity or clinically relevant myelosup-
pression was observed. With regard to activity, 4 complete
responses were observed. Thus, gemcitabine was well tol-
erated, and no systemic absorption with a clinical or phar-
macological effect was detected. Only slightly irritative
bladder symptoms were observed.
To our knowledge, our study is the first prospective
randomized study to compare intravesical gemcitabine to
BCG in this selected subset of patients with very high-risk
non-muscle-invasive BC, failing first-line adjuvant intra-
vesical BCG, for whom radical cystectomy is indicated.
We found gemcitabine to be more effective than BCG in
reducing recurrence rates (52.5% vs 87.5%, P .002),
whereas no significant difference was found in terms of
time to first recurrence (3.9 months vs 3.1 months in
Group B, P .03). Note that we had a relatively low dis-
ease-free rate in the BCG group. This, together with the
high progression rate for the entire group (33% in Group
A, 37.5% in Group B, P .12), accounts for the very
high-risk profile of our study population.
Disease progression was no different between the
groups and was exceedingly high at 35%. Moreover,
43% of patients needed systemic chemotherapy and/or
radiation. The clinical significance of this dismal result
deserves comment about the very high-risk nature of such
conservative therapy. Indeed, in many ways, this study
might be relatively immature, because deaths from blad-
der cancer would appear to be imminent within the next 1
to 2 years.
Gemcitabine was administered with an extensive
schedule (twice weekly for 6 weeks). This compared favor-
ably with the 3-week schedule proposed by Dalbagni et
al
13
in their phase 2 study. Gontero and Frea
26
have al-
ready questioned whether a more intensive scheme might
be appropriate in selected high-risk cases. The major con-
cern was obviously related to the potential toxicity. Uri-
nary symptoms represented the main adverse events in
both study groups. They were mostly managed success-
fully with anticholinergic, antibiotic, and/or anti-inflam-
matory drugs. Treatment-specific side effects, such as
nausea, dermatitis, and thrombocytopenia, were unique
to the gemcitabine-treated group, whereas hematuria and
cystitis appeared more frequently in the BCG group.
Overall, similarly to the data of Dalbagni et al,
12,13
our data support the use of such an intensive schedule in
terms of toxicity profile, because intravesical administra-
tion of gemcitabine was generally well tolerated.
Moreover, we followed the maintenance schedule
suggested by Gacci et al.
24
Of course, it is clear that no
standard regimen exists in this setting, and the optimal
frequency and duration of maintenance instillations
remain unknown. Thus, further investigation addressing
this issue is needed.
It would have been interesting, also, to compare
gemcitabine versus 1 of the other treatment options cur-
rently available in this setting, namely, thermochemother-
apy, PDT, or the combination of IFN-a and BCG.
Unfortunately, none of these options was available at our
respective centers.
Moreover, albeit prospective and randomized, our
trial suffers from some limitations related to the study
design. Among them, the relatively small sample size, not
guaranteeing against possible clinical imbalance, the lim-
ited follow-up period, not allowing definitive oncological
conclusions, and the open-label design might account for
some initial bias.
Clinical trials of novel intravesical agents in the
BCG-failure setting should be supported to improve the
standard of care, because treatment options for these
patients are severely limited. To date, gemcitabine seems
to have fulfilled the requirements to be a promising new
candidate for standard intravesical therapy in high-risk
non-muscle-invasive BC patients. The Southwest Oncol-
ogy Group (http://www.clinicaltrials.gov) is recruiting
participants in a phase 2 study to assess the efficacy of
intravesical gemcitabine in patients with high-risk non-
muscle-invasive BCwho have failed BCGtherapy.
Conclusions
High-risk non-muscle-invasive BC patients in whom
BCG fails remain a challenge to the urologist. Even if rad-
ical cystectomy still remains the best treatment, some
patients refuse it or are unsuitable for it. Gemcitabine
used as second-line treatment after BCG failure in high-
risk non-muscle-invasive BC patients might represent a
safe and effective option. Further clinical research is war-
ranted, as larger phase 3 trials are necessary to corroborate
Gemcitabine After BCG Failure in BC/Di Lorenzo et al
Cancer April 15, 2010 1899
these findings and to define the best treatment protocol in
this setting.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
REFERENCES
1. Sylvester RJ, van der Meijden APM, Lamm DL. Intravesical
bacillus Calmette-Guerin reduces the risk of progression in
patients with superficial bladder cancer: a combined analysis
of the published results of randomized clinical trials. J Urol.
2002;168:1964-1970.
2. Bohle A, Bock PR. Intravesical bacille Calmette-Guerin ver-
sus mitomycin C in superficial bladder cancer: formal meta-
analysis of comparative studies on tumour progression.
Urology. 2004;63:682-686.
3. Bohle A, Jocham D, Bock PR. Intravesical bacillus Calm-
ette-Guerin versus mitomycin C for superficial bladder can-
cer: a formal meta-analysis of comparative studies on
recurrence and toxicity. J Urol. 2003;169:90-95.
4. Witjes JA. Management of BCG failures in superficial blad-
der cancer: a review. Eur Urol. 2006;49:790-797.
5. Sylvester RJ, van der Meijden APM, Witjes JA, Kurth KH.
Bacillus Calmette-Guerin versus chemotherapy in the intra-
vesical treatment of patients with carcinoma in situ of the
bladder: a meta-analysis of the published results of random-
ized clinical trials. J Urol. 2005;174:86-92.
6. Huguet J, Crego M, Sabate S, Salvador J, Palou J, Villavi-
cencio H. Cystectomy in patients with high risk superficial
bladder tumours who fail intravesical BCG therapy: pre-cys-
tectomy prostate involvement as a prognostic factor. Eur
Urol. 2005;48:53-59.
7. Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Bohle A,
Palou-Redorta J. EAU guidelines on non-muscle-invasive uro-
thelial carcinoma of the bladder. Eur Urol. 2008;54:303-314.
8. Herr HW, Dalbagni G. Defining bacillus Calmette-Guerin
refractory superficial bladder tumours. J Urol. 2003;169:
1706-1708.
9. Joudi FN, ODonnell MA. Second-line intravesical therapy
versus cystectomy for bacille Calmette-Guerin (BCG) fail-
ures. Curr Opin Urol. 2004;14:271-275.
10. El Karak F, Flechon A. Gemcitabine in bladder cancer.
Expert Opin Pharmacother. 2007;8:3251-3256.
11. Gontero P, Marini L, Frea B. Intravesical gemcitabine for
superficial bladder cancer: rationale for a new treatment
option. BJU Int. 2005;96:970-976.
12. Dalbagni G, Russo P, Sheinfeld J, et al. Phase I trial of
intravesical gemcitabine in bacillus Calmette-Guerin-refrac-
tory transitional-cell carcinoma of the bladder. J Clin Oncol.
2002;20:3193-3198.
13. Dalbagni G, Russo P, Bochner B, et al. Phase II trial of
intravesical gemcitabine in bacille Calmette-Guerin-refrac-
tory transitional cell carcinoma of the bladder. J Clin Oncol.
2006;24:2729-2734.
14. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al.
Predicting recurrence and progression in individual patients
with stage Ta T1 bladder cancer using EORTC risk tables:
a combined analysis of 2596 patients from 7 EORTC trials.
Eur Urol. 2006;49:466-475.
15. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: devel-
opment of a comprehensive grading system for the adverse
effects of cancer treatment. Semin Radiat Oncol. 2003;13:
176-181.
16. Morabito F, Rossi R, Graziano ME, et al. Multicenter study
on the use of gemcitabine to prevent recurrence of multiple-
recurring superficial bladder tumors following intravesical
antiblastic agents and/or BCG: evaluation of tolerance. Arch
Ital Urol Androl. 2006;78:1-4.
17. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in
the treatment of invasive bladder cancer: long-term results
in 1054 patients. J Clin Oncol. 2001;19:666-675.
18. Sarosdy MF, Manyak MJ, Sagalowsky AI, et al. Oral bropir-
imine immunotherapy of bladder carcinoma in situ after
prior intravesical bacille Calmette-Guerin. Urology. 1998;5:
226-231.
19. ODonnell MA, Lilli K, Leopold C. Interim results from a
national multicenter phase II trial of combination bacillus
Calmette-Guerin plus interferon alfa-2b for superficial blad-
der cancer. J Urol. 2004;172:888-893.
20. Van Der Heijden AG, Kiemeney LA, Gofrit ON, et al. Pre-
liminary European results of local microwave hyperthermia
and chemotherapy treatment in intermediate or high risk su-
perficial transitional cell carcinoma of the bladder. Eur Urol.
2004;46:65-72.
21. Waidelich R, Stepp H, Baumgartner R, Weninger E, Hof-
stetter A, Kriegmair M. Clinical experience with 5-aminole-
vulinic acid and photodynamic therapy for refractory
superficial bladder cancer. J Urol. 2001;165:1904-1907.
22. Steinberg G, Bahnson R, Brosman S, et al. Efficacy and
safety of valrubicin for the treatment of Bacillus Calmette-
Guerin refractory carcinoma in situ of the bladder. J Urol.
2000;163:761-767.
23. Bartoletti R, Cai T, Gacci M, et al. Intravesical gemcitabine
therapy for superficial transitional cell carcinoma: results of
a phase II prospective multicenter study. Urology. 2005;66:
726-731.
24. Gacci M, Bartoletti R, Cai T, et al. Intravesical gemcitabine
in BCG-refractory T1G3 transitional cell carcinoma of the
bladder: a pilot study. Urol Int. 2006;76:106-111.
25. Gunelli R, Bercovich E, Nanni O, et al. Activity of endoves-
ical gemcitabine in BCG-refractory bladder cancer patients:
a translational study. Br J Cancer. 2007;97:1499-1504.
26. Gontero P, Frea B. Actual experience and future develop-
ment of gemcitabine in superficial bladder cancer. Ann
Oncol. 2006;17(suppl 5):123-128.
27. Hendricksen K, Witjes JA. Intravesical gemcitabine: an
update of clinical results. Curr Opin Urol. 2006;16:361-366.
28. Bassi P, De Marco V, Tavolini IM, et al. Pharmacokinetic
study of intravesical gemcitabine in carcinoma in situ of the
bladder refractory to bacillus Calmette-Guerin therapy. Urol
Int. 2005;75:309-313.
Original Article
1900 Cancer April 15, 2010