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EUROPEAN UROLOGY 62 (2012) 126–129
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Referring to the article published on pp. 118–125 of this issue
Prognosis of T1G3 Bladder Cancer: How Well Can We Predict
Progression?
J. Alfred Witjes *
Department of Urology (659), Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
Palou and colleagues report on a difficult group of bladder
cancer patients, namely, those with high-risk non–muscleinvasive bladder cancer (NMIBC), and more specifically in
this case, high-grade T1 disease with carcinoma in situ (CIS)
in the majority of patients [1].
The treatment choice for such patients is difficult. On the
one hand, there is a conservative approach, like intravesical
maintenance bacillus Calmette-Guérin (BCG) instillations.
The advantage of instillation therapy is obvious, since the
bladder is spared and therapy does not involve radical
surgery with all its morbidity and mortality. On the other
hand, cystectomy is already considered in both the European
and American guidelines. The advantage is the optimal
chance of cure, but the disadvantage is overtreatment in a
substantial percentage of patients. Furthermore, when
patients experience progression to muscle-invasive disease,
a significant window of opportunity is missed, with a
reported 4-yr cancer-specific survival of only 35% (reference
6 in Palou et al. [1]) [2]. The results of this series of patients
appear to be in the same range: 25 patients experienced
progression, and 18 died of the disease. This translates into
72% cancer-specific mortality, assuming one will not die of
bladder cancer that has not progressed. The authors mention
that 11 patients did not undergo cystectomy for several
reasons. Still, if half of these had died of bladder cancer, even
after cystectomy—a realistic assumption in cases of muscleinvasive disease—cancer-specific mortality would be >50%!
The search for prognostic markers that can help in
treatment decision making for these high-risk patients is an
unmet but very important clinical need. This report was
able to identify two additional factors in the high-risk group
for recurrence, progression, and death due to bladder
cancer, namely, female gender or the presence of CIS in the
prostatic urethra [1].
This series has several strengths [1]. It is a singleinstitution series, and the institution is well known for its
work on bladder cancer. Treatment was the same for all
patients, with a complete and radical transurethral resection (TUR), bladder mapping, and a course of BCG. The
median follow-up of 8.7 yr allows meaningful conclusions
with respect to recurrence as well as to progression and
cancer-related mortality.
The series also has clear limitations that are not all
discussed. First, none of these patients had a re-TUR or a TUR
with fluorescence techniques, although it has been clearly
demonstrated that a good TUR is of importance for
recurrence and progression, especially in high-risk or T1
patients [3,4]. As is often noted, we cannot compensate for an
incomplete resection with intravesical instillation therapy.
Second, the instillation therapy itself, a course of BCG, is
neither optimal nor guideline therapy. Currently, maintenance BCG is what should be given, at least to reduce the
recurrence rates [5]. Third, the number of patients is still only
146, of which only 14 had involvement of the prostatic
urethra and only 18 were female (12.3%). However, more
Spanish studies on bladder cancer have a significant male
predominance (11% in a series of 1529 patients and 10.5% in a
study of 1062 patients, according to references 2 and 3,
respectively, in Palou et al. [1]). Finally, although the
pathologist of this study is world famous (FA), I am not sure
whether a separate pathology review has been done for the
purpose of this study or whether the specimens have been
reviewed by one pathologist over time. Review pathology
might have identified patients that initially were over- or
understaged. Although these choices are defensible in light of
the era in which these patients were treated, we do not know
the results of this prognostic factor analysis with a second
TUR, review pathology, and maintenance BCG.
DOI of original article: 10.1016/j.eururo.2011.10.029
* Tel. +31 24 3613735; Fax: +31 24 3541031.
E-mail address: [email protected].
0302-2838/$ – see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EUROPEAN UROLOGY 62 (2012) 126–129
What we also do not know is whether the results of the
patients treated in this study could have been improved with
these current standards, since the reported results are
surprisingly good. The recurrence and progression rates at
first cystoscopy in this study, for example, are only 8.2% and
0.5%, respectively, which seem very low and good in the
context of no re-TUR. Furthermore, the probability of
recurrence at 1 yr and 4 yr is 21.9% and 41.1%, respectively.
In view of the fact that all patients had pT1G3 tumors, 65.1%
had concomitant CIS, and no one had maintenance BCG, these
figures are lower than one might expect. The authors [1]
admit that these results compare favorably to, for example,
the European Organization for Research and Treatment of
Cancer (EORTC) and Club Urológico Español De Tratamiento
Oncológico tables. Their explanation is the fact that all
patients had a wide and deep resection with muscle in the
specimen, minimizing the risk of understaging.
I am also surprised by the lack of prognostic value of
bladder CIS for progression, since it is the most important
factor for progression in the EORTC risk score [6]. Especially
in this homogeneous group, the value of CIS could have been
confirmed.
Some clinical and pathologic factors that could or even
should have been available should have been added to this
analysis. First, the 3-mo recurrence rate is mentioned as an
important prognostic factor (reference 24 in Palou et al. [1])
but was not added to the analysis. The authors mention
their recurrence and progression rates at first cystoscopy
(8.2% and 0.5%, respectively). Maybe these number are too
low to be added to the analysis, but then, the numbers of
females (12.3%) and of patients with CIS in the prostatic
urethra (9.6%) are similar. In contrast, 6 (50%) of the 12
patients that recurred at 3 mo progressed to muscleinvasive disease compared with 19 (14.2%) of 134 patients
without 3-mo recurrence, which is mentioned as highly
significant ( p = 0.002). This means that, although it is not
added in this analysis, the 3-mo recurrence rate is
important for these high-risk patients.
Second, pT1 substaging should have been included in the
prognostic factor analysis. This could have been done in a
pathology review. The authors [1] confirm that increasing
depth of involvement of the lamina propria by tumor is
correlated with a higher rate of progression and decreased
survival [7]. Although there is no information on substaging
in this report, the authors state in the discussion that the
value of substaging was not confirmed in their series. A
potential explanation is that substaging was not possible in
36.3% of the patients. Considering their apparent thorough
and deep resection, the experienced pathologist, and our
own experience [8], this percentage seems rather high.
However, because of difficulties with substaging, the World
Health Organization has not recommended substaging to be
included as a prognostic factor in high-risk NMIBC
(reference 20 in Palou et al. [1]).
In all, the authors [1] have confirmed the importance of
gender and prostatic urethra involvement as prognostic
factors for recurrence, progression, and cancer-specific
survival in a homogeneous group of high-risk NMIBC
127
patients, in this case, a group of pT1G3 bladder cancer
patients. The most important limitation is the lack of
current therapy standards such as re-TUR and maintenance BCG. The low recurrence and progression rates
suggest an effective initial treatment with a deep TUR and
a course of BCG. The authors, unfortunately, do not
attempt to answer the question of why women do worse
(reference 18 in Palou et al. [1]). Current thoughts include
the anatomy of the female bladder (a much thinner wall)
and the potential influence of hormones and hormone
receptors on tumor cells. In their discussion, the authors
give practical advice on when to take biopsies from the
prostatic urethra, namely, in all patients suspected of
having either high-grade tumor or CIS in the bladder. If
this has not been done at the initial TUR, it should be done
at re-TUR. In conclusion, together with some factors that
might be of value, like 3-mo recurrence and T1 substaging,
gender and CIS in the prostatic urethra can help in daily
practice to differentiate pT1G3 patients that can be treated
with intravesical instillation therapy or with radical
surgery.
Conflicts of interest: The author has nothing to disclose.
References
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