Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
EUROPEAN UROLOGY 62 (2012) 126–129 available at www.sciencedirect.com journal homepage: www.europeanurology.com Platinum Priority – Editorial and Reply from Authors 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 [1] Palou J, Sylvester RJ, Rodrı́guez Faba O, et al. Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with bacillus Calmette-Guérin. Eur Urol 2012;62:118–25. [2] van den Bosch S, Witjes JA. Long-term cancer specific survival in patients with high-risk non–muscle-invasive bladder cancer and tumour progression: a systematic review. Eur Urol 2011;60:493–500. [3] Divrik RT, Şahin AF, Yildirim Ü, Altok M, Zorlu F. Impact of routine second transurethral resection on the long-term outcome of patients with newly diagnosed pT1 urothelial carcinoma with respect to recurrence, progression rate, and disease specific survival: a prospective randomised clinical trial. Eur Urol 2010;58:185–90. [4] Stanislaus P, Zaak D, Stadler T, et al. Photodynamic diagnosis in patients with T1G3 bladder cancer: influence on recurrence rate. World J Urol 2010;28:407–11. [5] Malmström P-U, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guérin for non–muscle-invasive bladder cancer. Eur Urol 2009;56:247–56. [6] Sylvester RJ, van der Meijden APM, 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 seven EORTC trials. Eur Urol 2006;49:466–77. [7] Orsola A, Trias I, Raventós CX, et al. Initial high-grade T1 urothelial cell carcinoma: feasibility and prognostic significance of lamina propria invasion microstaging (T1a/b/c) in BCG-treated and BCGnon-treated patients. Eur Urol 2005;48:231–8. [8] Smits G, Schaafsma E, Kiemeney L, Caris C, Debruyne F, Witjes JA. Microstaging of pT1 transitional cell carcinoma of the bladder; identification of subgroups with distinct risks for progression. Urology 1998;52:1009–14. doi:10.1016/j.eururo.2011.11.001