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Topic issue on new treatments in bladder cancer

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Topic issue on new treatments in bladder cancer.

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World J Urol (2009) 27:285–287
DOI 10.1007/s00345-009-0390-4
EDITORIAL
Topic issue on new treatments in bladder cancer
J. A. Witjes 
Received: 30 January 2009 / Accepted: 2 February 2009 / Published online: 20 February 2009
©  The Author(s) 2009. This article is published with open access at Springerlink.com
This topic issue of the world journal of urology deals with
new treatments in non muscle invasive bladder cancer
(NMIBC). NMIBC is a frequent, important and costly dis-
ease. After several decades in which no or only few new
developments were noted, NMIBC is currently a disease
where several studies with new drugs and drug applications
are tested.
In the Wrst manuscript, Ploeg and coworkers look at the
present and future burden of urinary bladder cancer (UBC)
worldwide. UBC occurrence is about three to four times
higher in developed countries. This is caused by diVerences
in exposure to carcinogens like smoking, but also by diVer-
ences in registration. For example, NMIBC is not always
included in the registration. Still, in both the USA and
Western Europe, the lifetime probability to develop UBC
(pTa included) is more than 4 and 1.2% in males and
females, respectively. This obviously translates in a high
number of patients alive with bladder cancer at a speciWc
point in time. With the “duration” of the disease estimated
to be 7.5 years, and 357,000 new cases worldwide each
year, the prevalence can be estimated at almost 2.7 million.
In developed countries the incidence is decreasing, predom-
inantly due to decreasing smoking habits and better indus-
trial circumstances, in spite of aging of the population. In
the developing countries incidence will increase due to
more smoking and industrialization. In all, bladder cancer
is a signiWcant and increasing health problem.
Obviously, this increasing problem is a costly problem.
Sievert and coworkers looked at the economic side of bladder
cancer diagnosis and treatment. UBC is one of the most
costly cancers, and has the highest lifetime treatment costs
per patient of all cancers. The high recurrence rate of
NMIBC and the subsequent need for follow up are impor-
tant issue in the economic and human burden of this dis-
ease. New possibilities to reduce costs are urinary markers,
outpatient transurethral resection (TUR), better intravesical
therapy and the use of photodynamic diagnosis (PDD).
Many new developments initially induce more costs. Uri-
nary markers, although improving sensitivity, still cannot
replace cystoscopy. PDD, clearly improves diagnosis and
treatment as described elsewhere in this topic issue, and
also lowers long term costs as shown with models in sev-
eral countries. Finally, the training of urologic surgeons
must be improved as initial therapy has a profound impact
on the patient and total BC costs. A renewed interest and
investment in BC research would be essential to ensure
future advancements.
In the third manuscript, Goh and Lerner discuss current
and new technology in bladder cancer diagnosis. The cur-
rent standard, white light cystoscopy has signiWcant limita-
tions. Even under optimal conditions many lesions are
overlooked. In high risk tumors re-resection reveals 40–
60% residual tumor, and in case of CIS also up to 50% is
missed. A signiWcant improvement has been achieved with
Xuorescence cystoscopy. Both 5-ALA and hexyl 5-ALA
(HAL) have been studied extensively, and improve diag-
nostic accuracy with approximately 20–25%. This results in
a more complete TUR, better treatment and lower recur-
rence rates. Limitations are amongst others a small increase
in the false positive rate, and photobleeching, something
that is not a problem with Hypericin. Hypericin, however,
has low solubility, and is still under investigation. Optical
coherence tomography (OCT) has a high resolution and it
permits micro-architectural detection to a depth of 1–2 mm.
J. A. Witjes (&)
Department of Urology (659), 
Radboud University Nijmegen Medical Centre, 
PO Box 9101, 6500 HB Nijmegen, The Netherlands
e-mail: f.witjes@uro.umcn.nl123
286 World J Urol (2009) 27:285–287This might enhance diagnosis and staging, but this also has
to be studied in larger studies. Narrow-band imaging (NBI)
is another new imaging technique, which utilizes a
restricted optical spectrum which better detects (small)
blood vessels. An obvious limitation is that hyper-vascular-
ity is not cancer speciWc. Virtual cystoscopy, Wnally, uses
reconstructed imaging data to display the urinary tract. An
advantage is that it is not invasive, disadvantages are the
limited detection of smaller lesions and CIS, there is no
morphologic information and it does not allow simulta-
neous intervention. In all, newer techniques will certainly
improve the (endoscopic) diagnosis of bladder cancer in the
coming years.
Not only seeing a bladder tumor is of importance, but
also the initial operation should be optimal. Unfortunately,
a TUR is not always appreciated as a real operation, and
textbook information on TUR techniques is sparse. Wilby
and coworkers have looked at the technique of TUR and
also at new TUR techniques. Current golden standard TUR
techniques, Wrst described in 1931, are associated with
unacceptably high early recurrence rates, probably due to
incomplete resection in a substantial number of these cases.
Early second resection has shown to Wnd residual tumors in
25–40% and has been shown to reduce recurrence rates,
and increase response to intravesical therapy. It should be
considered in high risk NMIBC in case of bladder conser-
vation. Some techniques from TURP might also be used in
the bladder. Bipolar resection gives less tissue damage and
less obturator nerve reaction. Laser resection could facili-
tate day case management in some patients. As mentioned
above, Xuorescence cystoscopy also signiWcantly improves
the quality of TUR. Finally, the traditional ‘incise and scat-
ter’ resection technique goes against all oncological surgi-
cal principles. En-bloc resection of tumors could be far
better and is currently subject of further development and
evaluation. In all, the golden standard TUR needs to evolve
since residual tumor and recurrence rates of post TUR are
unacceptably high.
However, even with better diagnosis and TUR technique
adjuvant therapy remains necessary. Currently used drugs,
such as MMC and BCG, are on the market for several
decades. New drugs are needed and studied, but there is an
increasing need to study eYcacy before testing new drugs
in humans. Arentsen and coworkers give an overview of
preclinical testing of new intravesical therapeutic agents.
The ideal bladder tumor model should grow intravesically
in an immunocompetent and large enough animal and
should be a urothelial cell carcinoma (UCC) in diVerent
stages. Finally it should be easy to develop and to repro-
duce. Rat models, therefore, are preferred over murine
models, as are intravesical models over subcutaneous mod-
els. Indeed intravesical rat UCC models exist, which can
even be monitored with cystoscopy. Remaining challenges
are tumor cell implantation methods, follow up monitoring
and the short period the tumors are non invasive and suit-
able for intravesical treatment testing.
One of the new treatments that have been tested in ani-
mals is intravesical apaziquone. Hendricksen and cowork-
ers report their 2-year follow-up of a phase II marker lesion
study with apaziquone. In 46 patients, all but one non mus-
cle invasive tumors were resected, and apaziquone was
given weekly for 6 weeks. Short term side eVects were
mild, long term side eVects absent. The initial 3 months his-
tologically conWrmed complete response rate was 31/46
(67.4%). The intention-to-treat analysis showed that 49.5%
of the complete responders remained free of recurrence at
24 months follow up. The overall recurrence-free survival
was 39% (18/46) at 24 months follow up. In conclusion, the
initial high complete response rate and subsequent recur-
rence free survival in patients with this risk proWle indicates
that apaziquone is a potent drug, and further studies are
ongoing.
Not only new drugs are under investigation, but also new
treatment modalities are being studied. Di Stasi and Riedl
report on their experience with electromotive drug adminis-
tration (EMDA). The principles are described. The concept
is that EMDA increases local eYcacy of drugs by enhanc-
ing the transmembranous transport into tissue. The combi-
nation of EMDA and MMC in vitro indeed showed a four-
to sevenfold increase in bladder wall MMC concentration
over passive diVusion (PD). In human studies, these higher
MMC concentrations were shown to result in lower recur-
rence rates than PD in randomized studies. A subsequent
study in CIS patients showed that EMDA/MMC was at
least as eVective as BCG. Both treatments were superior to
PD with MMC with regard to response and recurrence
rates, not with regard to progression. Toxicity of EMDA/
MMC was between that of BCG and PD/MMC. Although
combinations of BCG and MMC have been studied, results
are inconclusive. However, in a randomized study with 212
patients and 88 months median follow up, the combination
of BCG and EMDA/MMC showed superior outcome com-
pared to BCG alone for all endpoints, including progression
and disease speciWc survival.
A new concept is pre-TUR EMDA/MMC. In a random-
ized trial with 167 patients, pre-TUR EMDA/MMC was
signiWcantly better than TUR follow by one immediate
instillation with MMC or TUR alone. In all, in spite of
modestly increased costs, the use of EMDA appears a sig-
niWcant improvement in these initial studies in the treat-
ment of several risk categories of patients with NMIBC,
and should be studied further.
DiYcult patients to treat are those refractory to BCG.
Guidelines advise cystectomy for these patients, but not all
are willing of Wt enough to undergo major surgery. There-
fore, especially in these patients, new approaches are needed.123
World J Urol (2009) 27:285–287 287Barlow and coworkers have updated their experience
with intravesical docetaxel in BCG refractory patients.
They report on 33 patients treated in and after a phase I
trial. Side eVects appear to be extremely mild. A total of 20
patients achieved a complete response, 10 of which
received maintenance docetaxel. The 1- and 2-year recur-
rence free rates were 45 and 32% respectively, with a ten-
dency to better results in the highest used dose (75 mg/
100 mL) and maintenance treatment. This makes docetaxel
a promising and safe alternative in these patients, worth
further study.
Witjes and coworkers report on intravesical thermo-che-
motherapy (TCT) in (predominantly) BCG refractory CIS
patients. TCT has proven its value as adjuvant therapy in
intermediate and high risk patients. Also as second line
treatment TCT has shown promising eVects. In this retro-
spective analysis, 51 patients with CIS are reported of
which 34 were treated before with BCG. TCT was done
with MMC and a temperature range between 41 and 44°C.
The schedule was a six weekly induction course followed
by maintenance therapy up to 1 year. Side eVects were mild
and predominantly transient bladder complaints. A total of
49 patients were evaluable, and 45 had a biopsy and cytol-
ogy proven complete response (92%). In two additional
patients CIS disappeared, but they had persistent papillary
lesions. After a mean follow up of 27 months, 22 of the 45
complete responders (49%) experienced recurrent tumor, of
which 4 had tumor progression to invasive bladder cancer.
In all, TCT seems an eVective and safe treatment, even in
patients with BCG refractory CIS.
A third option for patients failing BCG is the combina-
tion of BCG and interferon alpha (IFNA), as described by
Nepple and coworkers. In vitro studies have shown syner-
gism between IFNA and BCG. In their analysis the 2 year
disease free rate in 467 BCG failing patients was 45%, as
compared to 59% in BCG naive patients. Recent Wndings,
however, suggest that in BCG naive patients the additional
eVect of IFNA is at the best limited. In BCG failures, IFNA
combined with BCG may salvage especially single-course
BCG failures or late BCG relapsers, while patients relaps-
ing quickly may be destined to also fail this combination.
Finally, Hautmann and coworkers address the role of
cystectomy in T1G3 patients, which indeed is in the EAU
guidelines as potential therapy in these patients. One of the
comparisons they make is the long term outcome in patients
with an initial T1 G3 tumor (n = 124) treated with radical
cystectomy within 90 days after TUR in their institution,
versus 99 patients that had T1G3 recurrence after initial
conservative therapy, that were subsequently referred to
Ulm for radical cystectomy. Upstaging from the TUR to the
cystectomy specimen was found in 29.1% in the patients
with an immediate cystectomy, versus 63.6% for those with
a cystectomy at recurrence. Also the percentage of non
organ conWned disease and positive nodal disease was more
frequent in the deferred cystectomy patients. Most impor-
tantly, tumor speciWc survival after 10 years was 78.9 ver-
sus 64.5% in favor of early cystectomy. In spite of the
obvious limitations of a retrospective study, as nicely
pointed out by the authors, a randomized trial is not avail-
able. This means that results from expert centers like Ulm
might very well be the best we will ever have. In all, these
results seem to support the EAU guideline advice that a
cystectomy is one of the treatment options in T1G3
patients.
In summary, the above manuscripts give an insight in
current limitations and subsequent developments in the
diagnosis and treatment of NMIBC. Moreover, the practic-
ing urologist will deWnitely Wnd practical advises for high
risk and BCG failing patients.
Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution Noncommercial License which permits any
noncommercial use, distribution, and reproduction in any medium,
provided the original author(s) and source are credited.123


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