EUROPEAN UROLOGY 62 (2012) 1088–1096

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Collaborative Review – Bladder Cancer

Treatment Options Available for Bacillus Calmette-Guérin

Failure in Non–muscle-invasive Bladder Cancer

David R. Yates a,*, Maurizio A. Brausi b, James W.F. Catto a, Guido Dalbagni c, Morgan Rouprêt d,
Shahrokh F. Shariat e, Richard J. Sylvester f, J. Alfred Witjes g, Alexandre R. Zlotta h,
Juan Palou-Redorta i
a
Academic Department of Urology, Royal Hallamshire Hospital, Sheffield, UK; b Department of Urology, Ausl Modena, Italy; Ospedale Sant’Agostino-Estense,
Modena, Italy; c Department of Urology, Memorial Sloan-Kettering Cancer Centre, New York, NY, USA; d The Academic Department of Urology of La Pitié-
Salpetriere, Assistance-Publique Hôpitaux de Paris, Faculté de Medecine Pierre et Marie Curie, University Paris VI, Paris, France; e Department of Urology and
Division of Medical Oncology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA; f EORTC Headquarters, Brussels, Belgium;
g
Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; h Division of Urology, Department of Surgical Oncology,
Princess Margaret Hospital and the University Health Network, Mt. Sinai Hospital, University of Toronto, Ontario, Canada; i Department of Urology, Fundació
Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain

Article info Abstract

Article history: Context: Intravesical bacillus Calmette-Guérin (BCG) is a standard conservative treat-
Accepted August 27, 2012 ment for patients with high-risk non–muscle-invasive bladder cancer (NMIBC). Many
Published online ahead of patients will experience recurrence or progression following BCG and are termed BCG
failures.
print on September 3, 2012 Objective: To summarise the current treatment options available for patients with high-
risk NMIBC who experience BCG failure.
Keywords: Evidence acquisition: We searched the Medline, Embase, and Cochrane Trials databases
for studies of BCG failure using predetermined relevant Medical Subject Heading terms
Bladder cancer
and free text terms.
Non-muscle invasive Evidence synthesis: Radical cystectomy (RC) should be strongly recommended when a
Urothelial carcinoma patient has been deemed to fail BCG, if the patient is fit and fully informed of the risks,
BCG benefits, and quality-of-life issues. RC achieves long-term survival in excess of 90% with
Bacille Calmette-Guérin ongoing improvements in morbidity. While other salvage intravesical therapies have to
be considered oncologically inferior to RC, several options are now available if bladder
Cystectomy preservation is the objective. The options can be categorised as immunotherapy,
Intravesical therapy chemotherapy, device-assisted therapy, and sequential combinations of these newer
modalities with conventional therapy. Some agents have shown specific promise in
BCG-failure patients (eg, gemcitabine, thermochemotherapy, taxane chemotherapy),
and some modalities have been shown to be effective only in non–BCG-failure cohorts
(eg, electromotive mitomycin).
Conclusions: The definition, prediction, and treatment of BCG failure remain unclear
secondary to inconsistent studies and the heterogeneous entity of patients with
NMIBC. RC should be the default position upon failing BCG, but if bladder preservation
is sought, then several promising intravesical salvage options are available. It will be
necessary to individually tailor the management of such patients based on tumour risk
and medical profiles. Currently data are still inadequate to formulate definitive
recommendations, and larger studies of salvage intravesical agents are urgently
required.
# 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Department of Urology, Royal Hallamshire Hospital, Glossop Road, Sheffield,
S10 2JF, UK. Tel. +44 114 271 3599; Fax: +44 114 271 1755.
E-mail address: d.yates@sheffield.ac.uk (D.R. Yates).
0302-2838/$ – see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.eururo.2012.08.055
 EUROPEAN UROLOGY 62 (2012) 1088–1096 1089

1. Introduction studies that frequently combine different classes of failure

have made it difficult to stratify BCG failure [6]. It is a
Adjuvant intravesical bacillus Calmette-Guérin (BCG) is a controversial yet highly important aspect of managing
first-line treatment used principally for high-risk (G3, CIS, patients with high-risk NMIBC.
T1) non–muscle-invasive bladder cancer (NMIBC) following There are currently three published concepts of how to
transurethral resection (TUR) [1,2]. However, 40–50% of categorise disease that reappears during or following
patients experience disease recurrence and/or progression intravesical BCG. The European Association of Urology
and are said to have failed BCG [3]. Both NMIBC and BCG states that BCG is considered to have failed whenever
failure are heterogeneous entities, and studies to date have (1) muscle-invasive tumour is detected during follow-up;
not correlated the primary indication for BCG failure. When (2) high-grade NMIBC is present at both 3 and 6 mo; or (3)
considering the varying patient profiles, it is difficult to any worsening of disease occurs under BCG treatment such
choose the best treatment option upon failing BCG. To date, as higher number of recurrences, higher T stage or higher
the vast majority of published studies of BCG failure are in grade, or appearance of CIS, despite an initial response [1].
patients with high-risk NMIBC. The purpose of this review is The International Bladder Cancer Group tried to empha-
to highlight the available evidence and current manage- sise the importance of distinguishing recurrence from
ment options available, including radical cystectomy (RC), treatment failure and proposed two definitions in its clinical
intravesical bladder-preserving strategies, and entry into practice recommendations: ‘‘Recurrence refers to reappear-
active clinical trials. ance of disease (any grade, T category, or CIS) after
completion of therapy,’’ whereas treatment failure is defined
2. Evidence acquisition as ‘‘any recurrence or progression that occurs during
intravesical therapy.’’ [7]. The same group acknowledged
A literature search was conducted using the Medline, the usefulness of defining BCG failure and reiterated what
Embase, and Cochrane Central Register of Controlled Trials we currently recognise as the four subcategories of
databases with specific keyword combinations: urothelial BCG failure [8,9]: (1) BCG intolerance (recurrent disease
cancer, bladder cancer, transitional cell carcinoma, bacillus in setting of patient intolerant of BCG and/or side-effects),
Calmette-Guérin, BCG, BCG failure, BCG refractory, intravesical (2) BCG resistance (recurrence or persistence of lesser stage
treatment, non–muscle-invasive bladder cancer, and high- or grade after an initial course that then resolves with
grade superficial bladder cancer. Identified articles were further BCG), (3) BCG relapsing (recurrence after initial
examined by a single author (D.R.Y.), and the most relevant resolution with BCG further defined by time of recurrence),
articles were selected according to their level of evidence. and (4) early (<12 mo), intermediate (12–24 mo), late (>24
The initial list of selected papers was further enhanced by mo); and BCG-refractory disease (nonimproving or worsen-
individual suggestions from each co-author, all recognised ing disease despite BCG).
as international experts in the field. The current definitions of BCG failure take into account
the timing of failure but do not reflect the type of BCG
3. Evidence synthesis schedule administered or the primary indication for BCG.
The concept of refractory low-grade disease is completely
3.1. Role of bacillus Calmette-Guérin different from that of high-grade papillary NMIBC or CIS.
The implications of disease recurrence if intravesical BCG is
The primary indication for the use of BCG is as an adjuvant given for high-grade NMIBC differ for patients who receive
treatment for patients with intermediate- and high-risk it for low/intermediate-risk NMIBC. In addition, there are
NMIBC following TUR [1,2]. The rationale for BCG use is published differing outcomes for patients who receive just
multifold and includes treating coexisting carcinoma in situ induction BCG compared with a maintenance schedule. To
(CIS), preventing or delaying recurrence, reducing progres- resolve such debatable issues and formulate a more
sion, and avoiding RC. The risk from BCG is that patients universal, clinically acceptable definition, it will be neces-
develop toxicity and side-effects, or they do not respond sary to perform new, more in-depth analyses combining
and progress to muscle-invasive bladder cancer (MIBC) and large single institutional databases containing patients who
have an adverse survival outcome [4,5]. Furthermore, we have failed BCG.
currently still do not know the best regimen, how to predict
response accurately, who would benefit from primary or 3.3. Predicting bacillus Calmette-Guérin failure
early RC, and its true effect on progression. Due to the
varying natural history of NMIBC, it is plausible that we At present there are no variables capable of accurately
should be tailoring BCG protocols to the individual patient’s predicting, on an individual patient basis, response to BCG.
medical, tumour, and risk profiles. Clinical response observed can act as a guide as to whether
conservative or radical treatment is most appropriate [10]. It
3.2. Definition of bacillus Calmette-Guérin failure is the combination of clinical, pathologic, molecular, and
immunologic markers that will allow us to more accurately
BCG failure is a heterogeneous term that encompasses a predict the risk of BCG failure prior to commencing treatment
number of differing clinical scenarios. A lack of standard so as to recommend primary cystectomy in a more timely
definitions, inconsistent methods of reporting results, and fashion [11]. The clinicopathologic variables thought to
1090 EUROPEAN UROLOGY 62 (2012) 1088–1096

increase the risk of failure include female sex [12], older age elderly population, one can expect a complication rate of
[13], multifocality [12], recurrent tumours [12], associated 24–60% and a 90-d mortality rate of 10% [30]. Even when RC
CIS (particularly in the prostatic urethra) [14], lymphovas- is performed in a clinical setting of presumed non–muscle-
cular invasion [15], detectable disease at 3-mo check-up invasive disease, the formal pathologic and survival out-
cystoscopy [16], depth (and multifocality) of lamina propria comes are still undesirable. Upstaging (to pT2 or higher),
invasion [17], timing of failure (eg, early vs late) [18], and two the presence of positive lymph nodes, disease recurrence,
or more prior courses of BCG [19]. and death from urothelial cancer (UC) still occur in 20–30%,
10–20%, 20–30%, and 10–20%, respectively [22,35].
3.4. Treatment options for bacillus Calmette-Guérin failure
3.4.2. Bladder preservation strategies for bacillus Calmette-Guérin
Once a patient is deemed to have failed BCG, the options failure
available, broadly speaking, are RC or further intravesical It is not an uncommon scenario for an onco-urologic surgeon
bladder-preserving strategies, with the former being the to be faced with a patient who, having been deemed to fail
default position if the patient is medically fit and willing. BCG treatment for high-risk NMIBC, is not willing or is unfit
for RC. It is key to inform patients that treatments other than
3.4.1. Cystectomy for bacillus Calmette-Guérin failure cystectomy must be considered oncologically inferior at the
Most guidelines recommend that patients failing BCG present time. Several bladder preservation strategies are now
should be offered RC [1,2]. With an overall BCG failure rate available that can be categorised as immunotherapy, chemo-
of 30–50% and the significant potential for progression therapy, device-assisted therapy, and combination therapy. In
specific to high-risk NMIBC, some clinicians argue that this section, we discuss these different treatment modalities
immediate RC (IRC) is the preferred first-line treatment in relation to whether they have been well tested in BCG-
option in high-risk patients [20]. There is accumulating failure patients, evaluated in small initial studies, or are
evidence that IRC improves disease-specific survival considered promising strategies not yet tested in BCG-failure
[21,22], life expectancy [23], and quality of life–years patients (Table 1).
[24] and decreases cost [24]. RC becomes even more
imperative if a patient has persistent or progressive disease 3.4.2.1. Strategies tested in bacillus Calmette-Guérin–failure patients
despite intravesical BCG, as this portends a poor prognosis
[25]. If cystectomy is performed before progression to 3.4.2.1.1. Interferon-a/bacillus Calmette-Guérin. Interferon-a
muscle-invasive disease, then cancer-specific survival (CSS) (INF-a) is a naturally occurring cell-signalling cytokine
is >90%, whereas survival drops to 70% for muscle-invasive that is produced by the immune system in response to
disease [26]. Patients progressing to invasive disease after insults such as tumour cell growth. It has been utilised in
BCG have a poorer prognosis compared with stage-matched conjunction with BCG in patients with high-risk NMIBC who
primary muscle-invasive disease (3-yr CSS: 37% vs 67%) either have failed or were naı̈ve for BCG. A national
[4,5]. Retrospective studies have shown that early RC gives a multicentre randomised phase 2 trial, involving 1007
5-yr CSS of 80% [27] and a 10-yr CSS of 76–78% [28]. For patients, compared the effect of INF-a (50 million U) plus
deferred RC, the outcomes are inferior, with 5- and 10-yr reduced-dose BCG in BCG-failure patients to a cohort of
CSS rates of 69% [27] and 51–61% [28], respectively. BCG-naı̈ve patients who received the same INF-a dose but
This default position of RC after BCG failure is with a standard-dose BCG protocol. Fifty-nine percent of the
confounded by the several factors relative to individual BCG-naı̈ve cohort remained disease free, with a 24-mo
patients, namely, advanced age, competing morbidity, and median follow-up compared with 45% of the previous BCG
expressed wish for bladder preservation. Classification of failure group [36]. Further analysis of the trial results by the
patients as unfit should be as objective as possible so as not same group reported that if BCG failure occurred >1 yr after
to unnecessarily discount some patients purely based on BCG treatment, then combination INF-a/BCG is a reasonable
chronologic age. Contemporary RC with smaller incisions, salvage option compared with BCG failure occurring <1 yr
improved anatomic knowledge, equipment advances, lower after starting BCG or after two or more BCG failures, when
transfusion rates, and excellent perioperative management cystectomy should be offered in preference to INF-a/BCG
has led to improvements in morbidity and mortality [18]. In summary, these phase 2 results are promising, but
following RC [29]. The use of RC to manage high-risk or because they concern only one trial, albeit large, the results
invasive bladder cancer in the elderly is acknowledged to should be confirmed in further studies.
be too low (4–11%) for such an ageing population [30].
There are conflicting reports on whether RC in the elderly 3.4.2.1.2. Gemcitabine. Gemcitabine is a standard first-line
(eg, >80 yr) induces a higher rate of complications [31,32]. systemic chemotherapeutic agent used in the neoadjuvant,
Because comorbidity is much more influential on complica- adjuvant, and palliative treatment of UC. It is a nucleoside
tions than age alone, investigators have attempted to devise analogue that causes defective DNA replication, leading to
risk-prediction models including clinical variables (eg, age, apoptosis of tumour cells. To date, phase 1 and 2 studies have
stage, Charlson comorbidity index, and albumin) [33]. been published [37,38]. In a phase 2 study of 30 patients with
Recent series seem to indicate that when carefully selecting NMIBC who were deemed BCG failures, With a median follow-
patients, no differences are noted between age groups with up of 19 mo (range: 0–35), Dalbagni et al. [38] reported a
respect to recurrence-free survival [34]. Realistically, in an complete response (CR) rate of 50% and a 1-yr recurrence-free
 EUROPEAN UROLOGY 62 (2012) 1088–1096 1091

Table 1 – Studies of bladder-preserving intravesical treatments in patients with bacillus Calmette-Guérin failure

First author Treatment modality n Failures Follow-up NED, RFS, Rec, Prog, RC, Comments
(study phase) % % % % %

Dalbagni [37] IV gemcitabine 30 26 19 mo 50 21 40 3.5 37 Phase 2 trial

(range: 0–35)
Dalbagni [38] IV gemcitabine 18 16 12 wk 39 – – – –Phase 1 trial
Bartoletti [39] IV gemcitabine 116 40 13.6 mo – – 32.5 – –Recurrence in 32.5% of BCG failures vs
21% BCG-naı̈ve group;
43.7% of high-risk failures developed
recurrence vs 25% of intermediate-risk
failures; phase 2 study
Mohanty [40] IV gemcitabine 35 35 18 mo 60 – 31.4 8.75 – –
Di Lorenzo [41] IV gemcitabine 80 80 15.5 mo – 19 52.5 33 33 Recurrence and 2-yr DFS better for GC
(range: 6–22) vs BCG ( p = 0.002 and p < 0.008,
respectively); phase 3 RCT
Addeo [42] IV gemcitabine 54 46 36 mo – – 28 11 – Recurrence free: 72% GC vs 61% MMC;
DFS in favour of GC ( p = 0.0021);
phase 3 RCT
McKiernan [49] IV docetaxel 18 18 12 wk 28 – 72 5.5 – Phase 1 study
Laudano [50] IV docetaxel 18 18 48.3 mo 22 44–61 61 5.5 33 Long-term follow-up of McKiernan [49];
median DFS, 13.3 mo
Barlow [51] IV docetaxel 33 33 29 mo 61 32–45 39 – – 5-yr DSS: 83%; 5-yr OS: 71%
Bassi [54] IV paclitaxel 16 16 1 wk 60 – 40 – – Phase 1 study
McKiernan [55] IV paclitaxel 18 18 6 wk 56 – 44 0 22 Phase 1 study
Joudi [36] BCG plus interferon-a 1007 467 24 mo 45 – – – Of BCG-failure group, 45% disease
free vs 59% BCG naı̈ve ( p < 0.0001);
phase 2 trial
Witjes [45] Thermochemotherapy 51 34 27 mo 51 – 49 – 10.2 Synergo working party study
Nativ [46] Thermochemotherapy 111 111 16 mo – – 56–85 3 – 2-yr recurrence rate 61% if no
(range: 2–74) maintenance vs 39% for maintenance
( p = 0.01)
Halachmi [47] Thermochemotherapy 56 19 20 mo 67 49.3 33.3 7.9 12 KM-estimated probability of
(range: 2–49) recurrence 50.7% at 2 yr for BCG-failure
cohort vs 42.9
Waidelich [57] Photodynamic therapy 24 24 36 mo 29 – 70.8 16.6 12.5 –
(range: 12–51)
Berger [58] Photodynamic therapy 31 10 23.7 mo – 40 60 – – –
(range: 1–73)
Breyer [56] MMC plus gemcitabine 10 9 26 mo 60 – 40 10 0 Only 10 patients

NED = no evidence of disease; RFS = recurrence-free survival; Rec = recurrence; Prog = progression; RC = radical cystectomy; BCG = bacillus Calmette-Guérin;
IV = intravesical; DFS = disease-free survival; GC = gemcitabine and cisplatin; RCT = randomised controlled trial; MMC = mitomycin C; DSS = disease-specific
survival; OS = overall survival; KM = Kaplan-Meier.

survival (RFS) rate of 21%. Patients each received two GC versus BCG, Di Lorenzo et al. [41] reported on 80 high-
courses of intravesical gemcitabine and cisplatin (GC) risk NMIBC patients that failed one course of BCG therapy.
twice weekly at a dose of 2000 mg/100 ml for 3 consecutive These patients were subsequently randomised between
wk. Thirty-seven percent (37%) required a subsequent gemcitabine (2000 mg in 50 ml) versus BCG Connaught
cystectomy. Bartoletti et al. [39] reported the results of a strain (81 mg). The authors reported that gemcitabine
phase 2 prospective multicentre study of intravesical GC reduces incidence of recurrence (87.5% vs 52.5%; p = 0.002)
following transurethral resection. A total of 116 patients and improves 2-yr recurrence-free survival (19% vs 3%;
with intermediate (24 BCG-refractory) and high-risk (16 p = 0.008). There was no effect on progression or time to
BCG-refractory) bladder cancer were treated with one cycle first recurrence. Addeo et al. [42] reported the superiority
(once a week for 6 wk) of GC 2000 mg. It was well tolerated, of GC (6-wk course) compared with mitomycin C (MMC)
with 81% reporting no side-effects. In the BCG-refractory (4-wk course) in 120 randomised patients with median
intermediate-risk group, after 12-mo follow-up, recur- 36-mo follow-up. Of the 109 patients that completed the
rence developed in only 25% (6 of 24) compared with 56% treatment regimen, 91 had previously failed BCG. Seventy-
(9 of 16) in the corresponding high-risk cohort. Mohanty et al. two percent (72%) of patients in the GC arm remained
[40] evaluated 35 BCG-failure patients who were given recurrence free compared with 61% in the MMC arm, and
intravesical GC 2 wk after TUR for 6 wk and followed for a the GC arm had a significant improvement in disease-free
mean of 18 mo. Twenty-one (60%) patients showed no survival ( p = 0.0021), with a lower incidence of chemical
recurrence and three (8.75%) progressed, with an average cystitis ( p = 0.012). In conclusion, intravesical gemcitabine
time to recurrence and progression of 12 mo and 16 mo, is a definite alternative for BCG-failure patients to consider,
respectively. In a multicentre prospective randomised phase but the long-term ability of this chemotherapy to prevent
2 trial (with median 15.2-mo follow-up) of maintenance progression is unproven.
1092 EUROPEAN UROLOGY 62 (2012) 1088–1096

3.4.2.1.3. Thermochemotherapy. Bladder-wall hyperthermia Ten patients (56%) were disease free at the completion of
used in combination with intravesical MMC is referred to the trial (12 wk), but the durability was only 22% at a median
as thermochemotherapy (TC) and is otherwise known as the 48.3 mo [50]. The same group has now updated its single-
Synergo system. Inducing temperatures of approximately institution experience in 33 patients with BCG-refractory
42 8C in the bladder wall (using a thermocoupled catheter NMIBC, with a median follow-up of 29 mo. All patients
and microwave equipment) significantly improves the received a 6-wk induction course. Twenty (61%) had CR, of
absorption of sequentially administered intravesical MMC which 10 were given maintenance docetaxel therapy for
compared with conventional MMC alone. In early studies, 9 mo. The 1- and 2-yr RFS rates were 45% and 32%,
both prophylactic (40 mg MMC) and ablative (80 mg MMC) respectively [51].
protocols were evaluated. The recurrence-free rates for Monthly maintenance therapy extend the longevity of
prophylactic and ablative TC, with intermediate-term follow- response to induction treatment in a selected group of BCG-
up, were approximately 60% and 80%, respectively [43,44]. refractory NMIBC patients. Most recently, investigators
The European Synergo working party has recently have recognised that potential exists to maximise thera-
reported the results in patients with CIS. Fifty-one patients, peutic benefit of such chemotherapy agents by altering the
including 34 who had previously failed BCG, underwent formulation to promote drug delivery and concentration.
weekly outpatient TC for 6–8 wk, followed by four to six One such method is to bind standard chemotherapy agents
sessions every 6–8 wk. The initial CR rate was 92%, which to mucoadhesive nanoparticulates. In an in vivo preclinical
was maintained in approximately 50% of patients after 2 yr evaluation, Mugabe et al. [52] have shown that mucoadhe-
[45]. Nativ et al. [46] evaluated a larger cohort of 111 sive nanoparticulate docetaxel is superior to standard
patients who had BCG-refractory high-risk bladder cancer docetaxel for intravesical treatment of NMIBC due to an
with a similar protocol to the one described above. The increased inhibitory effect on UC cell proliferation.
estimated disease-free survival was 85% and 56% after 1 yr Paclitaxel (Taxol), which was first described in 1967 and
and 2 yr, respectively. Lack of a maintenance regimen led to is an extract of the rare Pacific yew tree, is another taxane-
an increased recurrence rate at 2 yr (61% vs 39%), and the type chemotherapy agent that has benefited from binding
overall progression rate was 3%. to albumin (gelatin nanoparticles) to increase its neoplastic
Halachmi et al. [47] analysed 56 patients with high- activity. Lu et al. [53] demonstrated (in dogs) that gelatin
grade T1 UC, of which 33.9% (n = 19) had failed BCG. Overall nanoparticle-bound paclitaxel minimises the problem of
recurrence was 33% with median time to recurrence of drug dilution by physiologic urine production and maintains
9 mo. Kaplan–Meier estimated recurrence at 2 yr and 4 yr higher drug levels in tumours. Bassi et al. [54] have reported a
was 42.9% and 51%, respectively. For those who failed prior phase 1 study of a paclitaxel-hyaluronic acid bioconjugate
BCG, there was a 50.7% estimated recurrence rate at 2 yr. (ONCOFID-P-B) given to 16 BCG-refractory CIS patients. Nine
Progression occurred in just 7.9% with a quoted bladder patients (60%) showed a CR with 11 adverse events reported
preservation rate of 88%. With a median follow-up of 18 mo by seven patients. No dose-limiting toxicity was observed.
(range: 2–49), 33 (59%) of the treated patients were disease In a second study, McKiernan et al. [55] reported the use
free with an intact bladder. When looking at estimated 4-yr of intravesical nanoparticle albumin-bound paclitaxel
disease-specific survival (DSS), there was no difference for (Abraxane) in a phase 1 study. They showed that it had
the BCG-failure cohort (46% vs 44%; p = 0.54). better solubility and lower toxicity and allowed signifi-
In a recent systematic review of TC, it was reported that cantly higher concentrations to be given compared with
TC offered a 59% relative reduction in NMIBC recurrence docetaxel. Of the 18 patients, systemic absorption occurred
compared with MMC alone, with a bladder preservation in 1 patient. Grade 1 toxicity occurred in 56%, with dysuria
rate of 87.6%, allowing the authors to speculate that TC being the most common symptom. Five patients (28%) had
could become the standard of care in a BCG-failure setting no evidence of disease at posttreatment evaluation. Phase 2
[48]. A new UK bladder cancer trial (HYMN, ClinicalTrials. studies are ongoing (Table 2).
gov identifier NCT01094964) aims to further define the role In summary, all taxanes should be further explored as
of TC. It is a randomised phase 3 trial of hyperthermia plus intravesical therapy, potentially with nanoparticle technol-
MMC versus a second course of BCG in patients with NMIBC ogy, for BCG-refractory patients.
with disease recurrence following BCG. TC has shown
consistent and promising results in BCG-failure patients, 3.4.2.1.5. Mitomycin C and gemcitabine. In a small study of
but more studies are needed to define its ultimate role. 10 BCG-refractory patients, with a median follow-up of
26.5 mo, Breyer et al. [56] reported their experience with
3.4.2.1.4. Taxane chemotherapy agents. Docetaxel (Taxotere) is a the combination of intravesical MMC (40 mg) and gemci-
semisynthetic microtubule depolymerisation inhibitor that tabine (1000 mg) given as a 6-wk induction course followed
belongs to the taxane group of chemotherapy agents. by a maintenance regimen once a month for 12 mo.
McKiernan et al. [49] first reported a phase 1 trial of Encouragingly, six patients (60%) were recurrence free at
intravesical docetaxel in 18 patients with NMIBC refractory time of data analysis.
to ‘‘standard intravesical therapy,’’ not specifically ‘‘BCG
failure.’’ Docetaxel was administered as six weekly instilla- 3.4.2.1.6. Photodynamic therapy. Excitation of photosensitised
tions using a dose-escalation model. Forty-four percent bladder tumour cells with a specific wavelength of
reported mild grade 1 or 2 toxicity, mainly dysuria. intravesical light can cause tumour cell destruction and is
 EUROPEAN UROLOGY 62 (2012) 1088–1096 1093

Table 2 – Current international trials investigating treatment options for bacillus Calmette-Guérin failure

Study title Phase Investigator Study ID

Phase 3 randomised study of intravesical MMC and bladder hyperthermia versus intravesical 3 Cancer Research UK HYMN;
BCG or standard therapy as second-line therapy in patients with recurrent NMIBC after NCT01094964
induction or maintenance BCG
Efficacy and safety evaluation of EN3348 (MCC) as compared to MMC in the intravesical 3 Endo Pharmaceuticals NCT01200992
treatment of subjects with BCG-recurrent/refractory NMIBC
Phase 1 and 2 trial of Abraxane for treatment of refractory BCa 1+2 Abraxis Oncology NCT00583349
RAD0001 and intravesical gemcitabine in BCG-refractory primary or secondary carcinoma 1+2 Novartis Pharmaceuticals NCT01259063
in situ of the bladder
Phase 2b trial of intravesical DTA-H19/PEI in patients with intermediate-risk superficial BCa 2b BioCancell Therapeutics NCT00595088
Sunitinib malate in treating patients with recurrent transitional cell BCa (trial ongoing but 2 Pfizer NCT01118351
not recruiting at present)
Study of Mycobacterium w in BCG-refractory superficial transitional cell BCa (trial recently 1 Cadila Pharmaceuticals NCT00694798
completed)
Efficacy study of recombinant adenovirus for patients with resistant superficial BCa 2+3 Cold Genesys Inc. NCT01438112
(approved but not yet active)
Oral lenalidomide and intravesical BCG for therapy of BCa 2 University of South Florida NCT01373294
Phase 2 study of selective bladder-preserving radiotherapy and concurrent cisplatin in 2 National Cancer Institute NCT00981656
patients with stage I BCa
Phase 1b intravesical administration of SCH721015 1b MD Anderson Cancer Center NCT01162785
Cis-urocanic acid in patients with primary or recurrent NMIBC 1 BioCis Pharma NCT01458847

MMC = mitomycin C; BCG = bacillus Calmette-Guérin; NMIBC = non–muscle-invasive bladder cancer; BCa = bladder cancer.

referred to as photodynamic therapy (PDT). Orally adminis- patients who received EMDA compared with passive
tered 5-aminolevulinic acid (5-ALA) has been given to diffusion [60]. In summary, EMDA MMC is equal to BCG
patients with rapidly recurring, multifocal BCG-refractory in terms of recurrence rate in BCG-naı̈ve high-risk NMIBC
high-risk NMIBC. With a median follow-up of 36 mo, 7 of and is significantly superior to passive standard MMC.
24 patients (29%) were recurrence free, 4 patients (17%)
progressed, and 3 (12.5%) underwent cystectomy [57]. The 3.4.2.2.2. Sequential therapy. Sequential BCG and EMDA MMC,
authors noted a high incidence of haemodynamic instability compared with BCG alone, appears to generate a superior
in patients with preexisting cardiovascular comorbidity. A response, as it is postulated the BCG-induced inflammation
similar high recurrence rate was reported by Berger et al. may increase the permeability of the bladder urothelium to
[58]. In a small BCG-failure cohort (10 patients) and after an MMC delivered via EMDA [61,62]. Di Stasi et al. [61]
average follow-up of 23.7 mo, 60% (6 of 10) recurred. These evaluated 212 patients who were randomised to the two
studies involved small numbers of patients, with less than arms, but there were no patients with previous BCG failure.
encouraging results, so PDT is not a realistic option for After a median follow-up of 88 mo, those who received
BCG-failure patients currently. sequential BCG and EMDA MMC had a higher disease-free
interval (69 mo vs 21; p = 0.0012), lower recurrence (42% vs
3.4.2.2. Potential strategies for bacillus Calmette-Guérin–failure pa- 58%; p = 0.0012), lower progression (9.3% vs 22%; p = 0.004),
tients. Several treatment regimens have been investigated lower disease-specific mortality (5.6% vs 16.2%; p = 0.01),
recently in NMIBC, and though they have not been and lower overall mortality (21.5% vs 32.4%; p = 0.045) than
specifically evaluated in patients who have failed prior those assigned BCG alone.
BCG, they represent potential options and need to be tested
in these patients. 3.4.2.2.3. Radiochemotherapy. No evidence shows that radio-
therapy (RT) is better than conservative therapy for pT1G3
3.4.2.2.1. Electromotive drug administration. It is possible to bladder cancer [63], and currently no data are available for
enhance transmembrane transport of intravesical chemo- the use of radiochemotherapy in patients with high-risk
therapy agents by applying a current gradient between the NMIBC who have failed prior intravesical BCG. Weiss et al.
drug and the bladder wall, and this technique, termed [64] evaluated 84 patients with high-risk T1 disease, who
electromotive drug administration (EMDA), has been proven were treated with platinum-based RT after TUR. Tumour
superior to passive MMC transport [59,60]. A randomised progression at 5 yr and 10 yr was 13% and 29%, respectively.
prospective study of EMDA MMC versus passive MMC DSS rates were 80% and 71% at 5 yr and 10 yr, respectively,
versus standard BCG was conducted in 108 BCG-naı̈ve with a >80% bladder preservation rate.
patients with high-risk NMIBC. The CR for EMDA MMC,
passive MMC, and BCG was 53%, 28%, 56% ( p = 0.036), 3.5. Future agents, concepts, and potential trials
respectively, at 3 mo and 58%, 31%, 64% ( p = 0.012),
respectively, at 6 mo. Median time to recurrence was 35, The future approach to improving the management of high-
19.5, and 26 mo ( p = 0.013). Peak plasma concentrations of risk NMIBC needs to be multifaceted and to reflect the
MMC were 5.5 times higher (43 ng/ml vs 8 ng/ml) in individual nature of each tumour and patient. We need to
1094 EUROPEAN UROLOGY 62 (2012) 1088–1096

elucidate the factors (clinical, pathologic, molecular) that Financial disclosures: David R. Yates certifies that all conflicts of interest,
will allow clinicians to identify the ‘‘at risk’’ patient who including specific financial interests and relationships and affiliations
would benefit from immediate cystectomy and avoid BCG relevant to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
totally. For patients who are unwilling or unfit to undergo
stock ownership or options, expert testimony, royalties, or patents filed,
radical surgery, we need tolerable second-line intravesical
received, or pending), are the following: None.
therapies with long-term efficacy. Because there are
very few US Food and Drug Administration–approved Funding/Support and role of the sponsor: None.
intravesical agents available, enrolment in a clinical trial
may be a favourable option for many patients who fail to
respond to BCG and are looking for an alternative to References
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