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Reply from Authors re: J. Alfred Witjes. Prognosis ofT1G3 Bladder Cancer: How Well Can We Predict

Progression? Eur Urol 2012;62:126–7

Joan Palou *, Oscar Rodrıguez Faba, Juan Antonio Pena

Department of Urology, Fundacio Puigvert, Universitat Autonoma de

Barcelona, Barcelona, Spain

We have read with interest the comments in Witjes’

editorial [1] about our paper relating to female gender and

carcinoma in situ (CIS) of the prostatic urethra as prognostic

factors for disease progression [2].

We agree that the main concern in the conservative

approach to high-grade T1 urothelial carcinoma of the

bladder is progression of the disease because when progres-

sion occurs, the likelihood of cure is reduced. In our series,

72% of the patients who showed disease progression died

of bladder cancer, and the global disease-specific mortality

was 8.2% at 4 yr [2]. This is a series with a very long follow-up

that comprises patients treated >10 yr ago, when radical

treatment was used less often in the elderly and when

associated comorbidities were more frequent than is the case

today. This is why 11 of the 25 patients with disease

progression did not undergo cystectomy. We are less

reluctant to perform radical cystectomy today, and we more

often undertake radical surgery in elderly people [3].

On the basis of the currently available data, it is well

known that at repeat transurethral resection (TUR) in non–

muscle-invasive disease, tumor is observed in 33–53% of

patients and muscle-invasive disease is detected in 4–25%

[4]. In our series, however, the patients were treated before

repeat TUR was an established approach. We recently

analyzed a series of 47 patients with mainly cTx and cT1

tumors who underwent a second TUR at our center.

Residual disease was present in 17%, and understaging

was detected only in those with a high-grade Tx stage at

primary resection, the rate being 4% (unpublished data). In

2001 we published a series of 114 patients with G3T1 [5] in

which we observed progression in 4.3% during the first 6 mo

and a recurrence rate of 15.7% at 3–6 mo; these results are

similar to those obtained in the present study with more

patients and longer follow-up, in which the rate of

progression at 1 yr was 7.5%.

Because substaging was not always initially done at our

center, a single pathologist (F. Algaba) at the center

reviewed the biopsy slides of all patients for the purpose

of our study, and all of the patients were confirmed to have

cT1G3 disease with muscle in the specimen.

We know that in the European Organization for Research

and Treatment of Cancer (EORTC) risk score, the presence of

CIS is the most important factor for progression (+6), but we

DOIs of original articles: 10.1016/j.eururo.2011.10.029,10.1016/j.eururo.2011.11.001* Corresponding author. Cartagena 340, 08025 Barcelona, Spain.Tel. +34 93 4169732; Fax: +34 93 4169730.E-mail address: jpalou@fundacio-puigvert.es (J. Palou).

also know that in the studies that were used for the

development of these risk score tables, only 4.4% of patients

had CIS, only 10.4% had high-grade tumors, and only 21.6%

were treated with bacillus Calmette-Guerin (BCG) [6].

Recently, the Club Urologico Espanol De Tratamiento

Oncologico published [7] its risk scores based on data

analysis in 1062 patients with non–muscle-invasive blad-

der cancer. In that series, there was a 10.3% incidence of CIS

and a 23.5% incidence of high-grade tumors, all patients

were treated with BCG (although 45.1% received low-dose

BCG), and the risk score for CIS was only +1. It is clear that if a

patient is treated with BCG, the risk of progression is not as

high as it is in the EORTC tables. One of the main drawbacks of

both of the aforementioned series is that multiple biopsies of

the bladder were not done routinely in either study;

consequently, the real incidence of CIS in the bladder and

the prostate was not known, unlike in our series. Probably, as

demonstrated in our study [2], CIS in the prostatic urethra is a

stronger predictive factor than CIS in the bladder alone, with

multifocality being associated with more aggressive disease

behavior when there is extravesical involvement.

The 3-month recurrence rate was also analyzed in our

series and was found to be a prognostic factor for

progression: Along with female gender and CIS in the

prostatic urethra, it was still significant in multivariate

analysis. We did not include further reference to the 3-mo

recurrence rate because it is already well known to be a

predictive factor for progression and because we only wanted

to consider risk factors at the time of primary diagnosis,

before the initiation of endovesical BCG treatment.

Several clinical prognostic factors may help in the

decision of whether to proceed to radical surgery. The

problem is that each individual factor is of limited

predictive value, and there may still be overtreatment or

undertreatment depending on the tumor characteristics.

Probably the combination of several clinical prognostic

factors could improve the predictive capacity [8], but

molecular markers are the future, and further studies will

need to be done to facilitate decision making.

With a view to better identifying those patients at risk of

progression, our group has been working with several

markers and addressing aspects such as galectin-3 expres-

sion, methylation status of tumor suppressor genes, and

expression patterns of ezrin protein in high-grade tumors

[9,10]. It appears that lack of expression of ezrin protein is a

promising marker of progression; our findings clearly

indicate that those patients who have the protein rarely

show disease progression, but studies in other series of

patients are needed to corroborate these results.

Conflicts of interest: The authors have nothing to disclose.

References

[1] Witjes JA. Prognosis of T1G3 bladder cancer: how well can we

predict progression? Eur Urol 2012;62:126–7.

[2] Palou J, Sylvester RJ, Rodrıguez Faba O, et al. Female gender and

carcinoma in situ in the prostatic urethra are prognostic factors for

E U R O P E A N U R O L O G Y 6 2 ( 2 0 1 2 ) 1 2 6 – 1 2 9 129

recurrence, progression, and disease-specific mortality in T1G3

bladder cancer patients treated with bacillus Calmette-Guerin.

Eur Urol 2012;62:118–25.

[3] Rodriguez Faba O, Palou J, Urdaneta G, et al. Invasive bladder cancer

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[4] Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on non–

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[5] Pieras E, Palou J, Rodriguez L, et al. Seguimiento cistoscopico de los

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[6] Sylvester RJ, van der Meijden APM, Oosterlinck W, et al. Predicting

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[8] Palou J. Patient risk profiles: prognostic factors of recurrence and

progression. Eur Urol Suppl 2006;5:648–53.

[9] Agundez M, Grau L, Palou J, et al. Evaluation of the methylation

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Eur Urol 2011;60:131–40.

[10] Palou J, Algaba F, Vera I, et al. Protein expression patterns of ezrin

are predictors of progression in T1G3 bladder tumours treated with

nonmaintenance bacillus Calmette-Guerin. Eur Urol 2009;56:

829–36.

doi:10.1016/j.eururo.2011.11.055