Patient Risk Profiles: Prognostic Factors of Recurrence and Progression

european urology supplements 5 (2006) 648 653 available at www.sciencedirect.com journal homepage: www.europeanurology.com Review Patient Risk Profiles: Prognostic Factors of Recurrence and Progression Dr. Juan Palou is a urologist in the Urology Department and Chief of Urological Oncology at Fundació Puigvert, Barcelona, Spain. He is an associate professor of urology at Universidad Autónoma de Barcelona, and a member of the Spanish, European, American, and International Urological Associations, and the European Society of Infection in Urology (ESIU). His publications include 15 chapters in medicine and urology books, and he has participated in more than 100 articles in Spanish urologic journals and more than 80 in international journals. His clinical research in oncology focuses on transitional cell carcinomas, specifically, superficial bladder cancer and upper urinary tract tumours. Juan Palou * Fundació Puigvert, Cap de la Unitat d Urologia Oncologica, Servei d Urologia, Cartagena, 340-350, 080255 Barcelona, Spain Article info Published online ahead of print on June 4, 2006 Keywords: Urothelial carcinoma Prognostic factors Recurrence Progression Please visit www.eu-acme.org to read and answer the EU-ACME questions on-line. The EU-ACME credits will then be attributed automatically. Abstract A vast array of pathologic features has been considered in the outcome of patients with Ta and T1 urothelial carcinoma. The problem, when analysing the factors related to recurrence, is that the published series may present different methodologic bias: short follow-up, small number of patients, different treatments, factors considered, and other. In addition, different clinical factors related to recurrence have been mentioned: multiplicity, size and location of the tumour, response to intravesical instillations, recurrence rate, and anaplasia. Related to progression, factors such as grade, association with carcinoma in situ (CIS), size of the tumour, and early recurrence have been considered. The author s experience with clinical prognostic factors of recurrence and progression is presented in order to decide on the best therapeutic approach. Experience shows that risk groups for recurrence may differ from those adopted for progression. For patients with low-grade tumors (grade 1 and the majority of grade 2 tumours) multiplicity is the main prognostic factor of recurrence and the main variable to consider when deciding on treatment. Once low-grade tumors become high grade, or in the case of CIS, progression has to be considered, and the tumour should be treated accordingly. In the case of highgrade tumours, although they may recur, progression is the main concern. Clinical prognostic factors may help to decide whether to manage them conservatively (bacillus Calmette-Guérin) or with radical cystectomy. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Tel. +11 934 169 7000; Fax: +11 934 169 730. E-mail address: jpalou@fundacio-puigvert.es. 1569-9056/$ see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2006.04.006

european urology supplements 5 (2006) 648 653 649 1. Introduction A vast array of clinical and pathologic features has been considered in the outcome of patients with urothelial carcinoma. Prognostic factors can be used as a potential means of predicting the course of bladder cancer in individual patients. Risk groups for cancer recurrence and progression can be used to help decide on the best therapeutic approach. Risk group classification adopted for recurrence, however, may differ from risk groups for progression. The challenge, when analysing factors related to recurrence, is that the published series may present different methodologic bias: short follow-up, small number of patients, different treatments, and other issues. In addition, different clinical factors have been mentioned in relation to recurrence: multiplicity, size of the tumour, tumour location, response to intravesical instillations, recurrence rate, and anaplasia. With respect to progression, factors such as grade, association with carcinoma in situ (CIS), size of the tumour, and early recurrence have been considered. Recently, a combined analysis of 2596 patients included in seven European Organization for Research and Treatment of Cancer (EORTC) trials of patients treated with or without intravesical chemotherapy has provided tables to calculate recurrence and progression. This is an important step towards improving the management of patients with Ta and T1. But it has to be considered however, that we do not know the real incidence of CIS (no random biopsies) and very few patients were treated with bacillus Calmette-Guérin (BCG), which may bias the results of intermediateand high-risk groups [1]. 2. Prognostic factors for recurrence Prognostic factors for recurrence have been investigated by several clinical groups. The most frequent factor related to recurrence, in almost all the series, has been multiplicity. Intravesical instillation has been defined as a protective factor (Table 1). Kurth et al. [11] reported on factors affecting recurrence and progression from the data of two trials involving 576 patients. The trials considered factors such as tumour size, grade, and recurrence rate per year, and concluded that the most significant prognostic factors for recurrence were multiplicity, recurrence at 3 mo, size of the tumour, and anaplasia. Based on the prognostic factors investigated by various clinical groups, the following risk groups were developed by the European Association of Urology (EAU) related to recurrence and progression [15]: Low-risk tumors: single, Ta, G1, <3 cm diameter High-risk tumors: T1, G3, multifocal or highly, CIS Table 1 Prognostic factors for recurrence (modified from Millan et al. [34]) Author and year Study type Tumor status No. of cases Grade T stage Associated CIS Multiplicity Tumour size Intravesical instillations Loening 1980 [2] Retrospective Primary Narayana 1983 [3] Prospective Primary Recurrent Dalesio 1983 [4] Prospective Primary 178 No Yes No No 468 No Yes Yes No Yes Yes Yes No No 308 No Yes Yes Parmar 1989 [5] Prospective Primary 305 No No Yes No Witjes 1992 [6] Prospective Primary 1026 No Yes No No Yes Kiemeney 1993 [7] Prospective Primary 1674 No Yes No Yes Yes Kiemeney 1994 [8] Prospective Primary 1674 Yes Yes No Yes Witjes 1994 [9] Prospective Primary 469 No No Yes No Mulders 1994 [10] Prospective Primary 371 No No Yes No Kurth 1995 [11] Retrospective Primary 576 Yes No Yes No Pawinski 1996 [12] Meta-analysis Primary 2535 Yes Shinka 1997 [13] Prospective Primary 141 No Yes No No Yes Millán 2000 [14] Retrospective Primary 1529 No No Yes Yes Yes Yes CIS = carcinoma in situ.

650 european urology supplements 5 (2006) 648 653 Intermediate-risk tumors: all other tumors, Ta-1, G1-2, multifocal, >3 cm diameter Fitzpatrick et al. [16] found that a patient with a negative cystoscopy at 3 mo had a 79% chance of being free of disease for 10 yr; conversely, 90% of patients with tumour at first cystoscopy had a recurrence. Parmar et al. [17] considered multiplicity and recurrence at 3 mo as the main prognostic factors in recurrence. These two parameters provided the most predictive information related to recurrence, and they were independent of the stage. The following risk groups were proposed: Good risk (60% of the cases): solitary tumour at presentation and no new occurrence at first cystoscopy. Recurrence rate of 20% at 1 yr. Medium risk (30% of the cases): patients who had either multiple transitional cell carcinoma of the bladder (TCCB) at diagnosis, and who were tumour free at first cystoscopy, or had solitary TCCB with new occurrence at first cystoscopy. Recurrence risk of 40% at 1 yr and 60% at 2 yr. Poor risk (10% of the cases): patients having multiple TCCB at presentation and new occurrence at first cystoscopy. Recurrence rate of 50% at 6 mo and 90% by 1 2 yr. Table 2 Bladder cancer grading WHO = World Health Organization; ISUP = International Society of Urologic Pathology; TCC = transitional cell carcinoma; PUNLMP = papillary urothelial neoplasm of low malignant potential; UNLMP = urothelial neoplasm of low malignant potential. Although the above Medical Research Council classification is useful to predict the risk of recurrence, it is not useful from the viewpoint of progression. Hall et al. [18] considered T1G3 TCCB of particularly poor prognosis, because 29% progressed, and they suggested that these tumours would have to be considered as a different group in the classification scheme of Parmar et al. [17]. When considering all these classifications, it becomes clear that in low-grade tumours, multiplicity and recurrence at 3 mo allow us to establish groups of risk related to recurrence [15,19,20]. In high-grade tumours, recurrence at 3 mo is a significant risk factor, but for progression [21]. Establishing prognostic factors for progression, however, is more problematic. Another point to consider for the establishment and management of risks groups is the introduction of the World Health Organization/International Society of Urologic Pathology (WHO/ISUP) 2003 classification for grading of bladder tumours in papilloma, and papillary urothelial tumours of low malignant potential, low and high grade tumours. Under the new classification [22], tumours that were classified as grade 1 based on the 1973 WHO/ISUP classification are now named papillary urothelial neoplasm of low malignant potential (PUNLMP), grade 2 tumours are now classified mostly as low-grade tumours, with a few of them classified as high grade, and grade 3 tumors are now all classified as high-grade carcinoma (Table 2). This new classification will have to be considered in future studies and results when establishing risks groups related to recurrence and progression. 3. Prognostic factors for progression Grade, associated CIS, and stage are factors globally related to progression in the series that have investigated prognostic factors (Table 3). At Fundació Puigvert, based on 1529 patients with primary superficial bladder cancer, three risk groups were developed. The trial used recurrence prognostic factors such as multiplicity, tumour size, and CIS and progression prognostic factors such as grade, CIS, and multiplicity. The risk groups developed, however, were more useful in evaluating progression than recurrence [14]: Low risk: solitary G1 Ta-T1 without CIS. Risk of recurrence of 37% and progression of 0%. Medium risk: multiple G1T1, G2Ta, solitary G2T1 without CIS. Risk of recurrence of 45% and progression of 1.8%. High risk: multiple G2T1, G3 Ta-T1, primary CIS, or any tumour associated to CIS. Risk of recurrence of 54% and progression of 15%. The presence of mucosal abnormalities, such as CIS, has been associated with progression [24,25]. Clearly, high grade is related to progression [14], and this is the main concern in the conservative (BCG) management of superficial bladder cancer. It should be noted that Murphy [26] advocated avoiding talking about superficial disease because in some patients this apparently low risk disease may end as a life-threatening invasive and metastatic cancer.

european urology supplements 5 (2006) 648 653 651 Table 3 Prognostic factors for progression (modified from Millan et al. [34]) Author and year Study Tumor status No. of cases Grade T stage Associated CIS Multiplicity Tumour size Intravesical instillations Herr 1989 [23] Primary 221 Yes Kiemeney 1993 [7] Prospective Primary 1674 Yes Yes Yes Yes No Kiemeney 1994 [8] Prospective Primary 1674 Yes Yes Yes No Kurth 1995 [11] Retrospective Primary 576 Yes No Yes Pawinski 1996 [12] Meta-analysis Primary 2535 No Millán 2000 [14] Retrospective Primary 1529 Yes No Yes Yes Yes Yes CIS = carcinoma in situ. 4. Progression in G2T1 Grade 2 T1 tumours, even though they invade the submucosa, do not behave as aggressively as G3T1 tumours. In our experience at Fundació Puigvert with 565 patients with primary G2T1 bladder tumours, only 5.2% progressed. With the introduction of the new classification grading system (low and high grade), a lower proportion will progress, because disease in some of the G2 patients will be classified as high grade. Very seldom does a patient with a G2T1 tumour, without CIS, progress to invasive disease, without any previous high-grade superficial recurrence. In our study only one patient who had an initial G2T1 tumour developed an invasive bladder carcinoma in the first recurrence. Therefore, in G2T1 tumours initially we have to worry more about recurrence than progression. Patients with multiple G2T1 tumours, however, may be at a higher risk of progression and, indeed, in the EAU guidelines they are considered a high-risk group. Furthermore, an increase in grade or presence of CIS in the first recurrence also increases risk; from 30% to 40% will progress with a relative risk of 12.9 (95% confidence interval, 1.4 118.7) [27]. 5. Progression in G3T1 And what about G3T1? Multiple articles have mentioned risk factors [25,28] but since the introduction of better resection and staging of disease in these patients, and endovesical treatment with BCG, the global results have improved [29]. Some variables have been used to analyse progression: association with CIS [14,24], multiplicity [14], morphology (papillary or solid), tumour size (< or >3 cm) [11], early or late recurrence (3/6 months) [30], sex and age (< or >65 yr), CIS of the prostatic urethra [23], and substaging [31]. We analysed a series of 243 Fundació Puigvert patients diagnosed with primary T1G3 bladder carcinoma, 146 of whom were treated with BCG, and with a median follow-up of 86 mo. Because there was a clear difference in recurrence and progression [25] of patients with T1G3 bladder carcinoma based on treatment, we analysed only the group of patients treated with BCG to determine clinical prognostic factors to decide on the best therapeutic approach. The analysis showed that when we consider patients with T1G3 (treated with BCG) and factors such as association with CIS, tumour size, or multiplicity, progression varies from 11% to 19%. That means that almost 80% of patients will not progress and, therefore, it may not be correct to decide on an aggressive treatment based on these factors alone, even though all of them have to be considered high-risk group patients [15]. The most recent series in T1G3 bladder tumours treated with BCG confirm these results, with a global decrease of progression [32]. One prognostic factor that has established a clear difference in progression is recurrence at 3 mo [30]. CIS in the prostatic urethra is also being considered as a parameter to take into account in the final decision of whether to proceed with conservative or aggressive treatment [33]. Consideration of the association of factors, as in Sylvester et al. [1], may be a better approach for predicting the progression of disease. But with the changing patterns of recurrence and progression with endovesical BCG, only those treated with BCG have to be considered in the decision tables in Ta, T1 high-grade urothelial carcinoma of the bladder. For example, in our experience with BCG, for a patient with a papillary tumour, <3 cm, and no CIS, the probability to progress is <5%, and for a patient with CIS in the prostatic urethra and recurrence at 3 mo the probability is almost 100% (Fig. 1). Future validation of these results will allow for a more appropriate management of these patients.

652 european urology supplements 5 (2006) 648 653 Fig. 1 Prognostic factors related to progression in T1G3 urothelial carcinoma treated with bacillus Calmette- Guérin. PAP = papillary; solid = solid aspect; PU = prostatic urethra; Rec3m = recurrence at 3 mo; CIS = carcinoma in situ; T1b and T1c = substaging in T1. 6. Conclusion For patients with low-grade tumours (grade 1 and the majority of grade 2 tumours) multiplicity is the main prognostic factor of recurrence and one of the main variables to consider when deciding on treatment. Once low-grade tumours become high grade, or in the case of CIS, progression has to be considered, and the tumour should be treated accordingly. High-grade tumours may recur, but progression is the main concern. Clinical prognostic factors may help to decide whether to manage them conservatively (BCG) or with radical cystectomy. The evaluation of the response at 3 mo is an important step as a prognostic factor in recurrence and progression in the management of patients with Ta, T1, and CIS. References [1] Sylvester RJ, van der Meijden AP, Oosterlink 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. [2] Loening S, Narayana A, Yoder L, Slymen D, Penick G, Culp D. Analysis of bladder tumor recurrence in 178 patients. Urology 1980;16:137 41. [3] Narayana AS, Loening SA, Slymen DJ, Culp DA. Bladder cancer: factors affecting survival. J Urol 1983;130:56 60. [4] Dalesio O, Schulman CC, Sylvester R, et al. Prognostic factors in superficial bladder tumors. A study of the European Organization for Research on Treatment of Cancer: Genitourinary Tract Cancer Cooperative Group. J Urol 1983;129:730 3. [5] Parmar H, Charlton C, Phillips RH, Lightman SL. Management of advanced prostatic cancer. Lancet 1989;2:1338 9. [6] Witjes JA, Kiemeney LA, Oosterhof GO, Debruyne FM. Prognostic factors in superficial bladder cancer. A review. Eur Urol 1992;21:89 97. [7] Kiemeney LA, Witjes JA, Heijbroek RP, Verbeek AL, Debruyne FM. Predictability of and progressive disease in individual patients with primary superficial bladder cancer. J Urol 1993;150:60 4. [8] Kiemeney LA, Witjes JA, Heijbroek RP, Debruyne FM, Verbeek AL. Dysplasia in normal-looking urothelium increases the risk of tumour progression in primary superficial bladder cancer. Eur J Cancer 1994;30:1621 5. [9] Witjes JA, Kiemeney LA, Schaafsma HE, Debruyn FM. The influence of review pathology on study outcome of a randomized multicentre superficial bladder cancer trial. Members of the Dutch South East Cooperative Urological Group. Br J Urol 1994;73:172 6. [10] Mulders PF, Meyden AP, Doesburg WH, Oosterhof GO, Debruyne FM. Prognostic factors in pta-pt1 superficial bladder tumours treated with intravesical instillations. The Dutch South-Eastern Urological Collaborative Group. Br J Urol 1994;73:403 8. [11] Kurth KH, Denis L, Bouffioux C, et al. Factors affecting recurrence and progression in superficial bladder tumours. Eur J Cancer 1995;31:1840 6. [12] Pawinski A, Sylvester R, Kurth KH, et al. A combined analysis of European Organization for Research and Treatment of Cancer, and Medical Research Council randomized clinical trials for the prophylactic treatment of stage TaT1 bladder cancer. European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council Working Party on Superficial Bladder Cancer. J Urol 1996;156:1934 40. [13] Shinka T, Matsumoto M, Ogura H, Hirano A, Ohkawa T. Recurrence of primary superficial bladder cancer treated with prophylactic intravesical Tokyo 172 bacillus Calmette-Guérin: a long-term follow-up. Int J Urol 1997;4:139 43. [14] Millán-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J, Palou J, Algaba F, Vicente-Rodriguez J. Primary superficial bladder cancer risk groups according to progression, mortality and recurrence. J Urol 2000;164:680 4. [15] Oosterlinck W, Lobel B, Jakse G, Malmstrom PU, Stockle M, Sternberg C. European Association of Urology (EAU) Working Group on Oncological Urology. Guidelines on bladder cancer. Eur Urol 2002;41:105 12. [16] Fitzpatrick JM, West AB, Butler MR, Lane V, O Flynn JD. Superficial bladder tumors (stage pta, grades 1 and 2): the importance of recurrence pattern following initial resection. J Urol 1986;135:920 2. [17] Parmar MK, Freedman LS, Hargreave TB, Tolley DA. Prognostic factors for recurrence and followup policies in the treatment of superficial bladder cancer: report from the British Medical Research Council Subgroup on Superficial Bladder Cancer (Urological Cancer Working Party). J Urol 1989;142:284 8.

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