European Urology European Urology 41 2002) 105±112

Guidelines on Bladder Cancer$ Willem Oosterlincka,*, Bernard Lobelb, Gerhard Jaksec, Per-Uno MalmstroÈmd, Michael StoÈcklee, Cora Sternbergf The EAU Working Group on Oncological Urology$$ aDepartment of Urology, University Hospital Ghent, De Pintelaan 185, B-9000 Gent, Belgium bCHRU Pontchaillou, Rennes, France cUniversity Clinics RWTH, Aachen, Germany dUniversity Hospital, Uppsala, Sweden eUniversity Saarland, Homburg, Saar, Germany fClinic Pio XI, Rome, Italy

Abstract Objectives: On behalf of the European Association of Urology EAU) guidelines for diagnosis, therapy and follow- up of bladder cancer patients were established. Criteria for recommendations were evidence based, and included aspects of cost-effectiveness and clinical feasibility. Method: A systematic literature research using Medline Services was conducted. References were weighted by a panel of experts. Results: TNM 1997 classi®cation and WHO grading 1998 are recommended. Recommendations are developed for diagnosis for bladder cancer in general, treatment of super®cial and in®ltrative bladder cancer, and follow-up after different types of treatment modalities, such as intravesical instillations, radical , urinary diversions, radiotherapy and chemotherapy. # 2002 Elsevier Science B.V. All rights reserved.

Keywords: Bladder cancer; Super®cial bladder cancer; Guidelines

1. Classification of bladder cancer transurethral resection TUR), imaging studies and histopathological ®ndings. The use of the TNM classi®cation 1997 and WHO There is also important inter observer variability in grading, 1999, is encouraged, as it corresponds best classifying stage T1 versus Ta tumours and grading with the clinical outcome of the tumours [1]. tumours [2]. More than 90% of bladder cancers are transitional cell carcinoma TCC); the remainder are squamous cell or adenocarcinoma. 2. Diagnosis Bladder tumours are considered super®cial TIS-Ta- T1) or in®ltrative T2-T3-T4) based on , 2.1. Early detection Early symptom recognition in bladder tumours is a key to better prognosis [6,7]. Haematuria is the most common ®nding in bladder cancer. The degree of haematuria does not correlate with the extent $ For more extensive information consult the EAU Guidelines presented of the disease. at the XVI EAU Annual Congress, Geneva, Switzerland ISBN: Bladder cancer may also present with voiding irritability. 90-806179-3-9). $$ EAU Working Group on Oncological Urology Chairman: Prof. Dr. C.C. Abbou): Membersof the EAU Working Group on 2.2. Imaging Oncological Urology are the EAU Working Groupson Bladder Intravenous pyelography is considered as an important exam- Cancer, Penile Cancer, Cancer and Testis Cancer. ination to evaluate haematuria but the necessity to perform routi- * Corresponding author. Tel. ‡32-9-240-2276; Fax: ‡32-9-240-3889. nely is now questioned because of the low incidence of important E-mail address: [email protected] W. Oosterlinck). ®ndings obtained [3]. Ultrasonography combined with plain

0302-2838/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved. PII:S0302-283801)00026-4 106 W. Oosterlinck et al. / European Urology 41 52002) 105±112 abdominal ®lm was found to be as accurate in the diagnosis of the progression, side effects and cost-effectiveness. The cause of haematuria as IVP. recurrence rate of super®cial bladder cancer SBC), Computed tomography scanning may be part of the evaluation of even after adequate treatment, is widely documented invasive bladder tumours and the evaluation of pelvic and abdom- inal lymph node metastasis. Its usefulness in predicting the local [6,7]. The riskof progression to invasive cancer is extent of the disease is reduced by artefactual abnormalities in the low in the majority of cases, but goes up to 50% in perivesical tissues. high-grade T1G3 [7,8], which represents around 10% The signi®cance of routine bone scans before total cystectomy in of cases. in®ltrative tumours is questionable. The riskof recurrence and progression can be pre- dicted on the basis of clinical and pathological data. 2.3. Urinary cytology Examination of a voided urine or bladder barbotage specimen for exfoliated cancer cells is particularly useful when a high-grade 3.1.1. Prognostic factors malignancy or CIS is present. It remains often negative in low- The prognostic factors for recurrence in descending grade tumours. importance) [9,10] are the following.

2.4. Cystoscopy and TUR 1. The number of tumours present at diagnosis. A bimanual examination should be performed ®rst to assess 2. Recurrence rate in the previous period; a recur- whether or not a mass is palpable in the bladder and, if so, whether rence at 3 months. it is ®xed to the pelvic wall. TUR of the bladder tumour should be 3. Size of the tumour: the larger the tumour, the done so as to maximise the preservation of architectural detail and the relation of the tumour to the various layers of the bladder wall. higher the riskof recurrence. The more super®cial component of the tumour should be 4. Anaplasia grade of the tumour. resected separately from its deeper component. Biopsy specimens of the tumour and suspected area should be For evolution to invasive disease, anaplasia grade taken to map the extent of the disease. Random biopsies of normal and the T-category are of outmost importance. mucosa are indicated in the presence of positive cytology, even in Based on the prognostic factors, SBC can be divided the absence of a tumour, or in any non-papillary tumour. Random into the following riskgroups: biopsies in patients with solitary papillary lesions are not indicated because of the absence of additional information [4] and because it  Low-risktumours: single, Ta, G1, 3 cm diameter. may be nocious, as lesions to the mucosa can provoke implantation  High-risktumours: T1, G3, multifocal or highly of tumour cells. Prostatic biopsies by TUR are indicated for recurrent, CIS TIS). suspicion of TIS of the bladder in view of the high frequency of  Intermediate: all other tumours, Ta-1, G1-2, multi- involvement of the prostatic urethra [5]. focal, >3 cm diameter. Immediate instillation after TUR with a chemother- 3. Treatment apeutic agent should be encouraged in all cases as it is able to reduce recurrence rate by about 50% [11,12]. In  Ta-1 are superficial bladder tumours. Treatment will intermediate risktumours that needs a further instilla- be directed towards the prevention of recurrence and tion, an early instillation can reduce the need for progression of the disease. maintenance therapy [13]. Low-risktumours need no  T1G3 has a high tendency to progression. The role of further treatment. early cystectomy still is a matter of debate. Tumours with a higher riskof recurrence should be  TIS is a potential highly malignant disease that can treated with a 4±8-week-course of bladder instillation. still be treated in the majority of cases with bladder Severe bladder irritation is a reason to delay or stop the instillations of BCG. A cystectomy is necessary treatment to avoid invalidating symptoms for the when this fails to cure the disease after two cycles patient and later bladder contraction. Side effects are of six weekly instillations. related to the intensity of the treatment regimen.  Tumours of T2 or higher category are infiltrating The usefulness of repeated instillations with che- tumours and cystectomy will be necessary in the motherapeutic agents is not clearly de®ned. majority of cases. Bladder preservation can be an There is no proof that chemotherapeutic instillations option in selected cases. longer than 6 months are worthwhile, if no recurrence  N‡ and metastatic diseases needs additional ther- is noticed. Intravesical therapy may be effective mainly apeutic approaches. by reducing the hazard of recurrence in the ®rst phase after therapy. 3.1. Treatment of Ta and T1 lesions On recurrence, the initial instillation schedule is The therapeutic regimen for a Ta and T1 tumour restarted. In case of highly recurrent SBC or multiple will take into account the risk of recurrence and recurrences it is advocated to change to BCG therapy W. Oosterlinck et al. / European Urology 41 52002) 105±112 107 because of its proven results in these circumstances 4.1. Indications [14]. Progression of T1 tumours involves muscle The indication for cystectomy is a patient with in®ltration and should be treated accordingly. muscle-invasive bladder cancer T2-T4a, N0-NX, M0. Other indications are patients with high-risksuper®cial 3.1.2. BCG tumours and BCG resistant TIS and T1G3 and exten- It has been found more effective in high-riskSBC sive papillary disease that cannot be controlled with BCG is able to prevent progression. conservative measures. Six weekly induction instillations of BCG are neces- sary to provoke an immunological response and three 4.2. Technique cycles are necessary as a booster to obtain the same Radical cystectomy consists of removal of the blad- immunological reaction. In papillary T1-a G1-2 der and neighbouring organs, such as the prostate and lesions, one can reduce the dose to 25% with the same in men and uterus and adnexa in effectiveness as the full dose and less general side women. The distal part of the is also usually effects [15]. resected and in cases with CIS a frozen section of the BCG is not indicated in low-riskgroups in which the margin is advisable. The indications for urethrectomy potential danger of BCG does not counterbalance its are controversial. Currently, urethrectomy is recom- advantage. mended if the tumour involves the bladder neckin Lower recurrence rates have been reported after women and the prostatic urethra in men. maintenance therapy of up to 3 years [14]. Whether A radical cystectomy also includes a dissection of or not this heavy schedule is necessary for all patients is the regional lymph nodes, which will give valuable uncertain. prognostic information. No controlled studies exist supporting the curative value of lymph node dissection 3.2. Treatment of TIS [16]. Cystoscopy has a mortality from 1 to 4% and an Standard treatment of TIS consists of BCG instilla- important early morbidity. Late morbidity is nearly due tions given over a 6-week-period. Complete remission to the . is obtained in up to 70% of cases. If cytology and The 5-year-survival rate is usually reported to be biopsies remains positive, another cycle may produce in the range of 40±60% and has not improved sig- an additional 15% complete remission. Maintenance ni®cantly in recent times. The use of pre-operative therapy with booster cycles up to 36 months is advo- radio- or chemotherapy [17,18] has not changed the cated to prevent recurrence. If cure is not achieved after outcome. this second cycle or there is early recurrence, cystect- Tumour stage and nodal involvement are the only omy with urethrectomy is indicated. independent predictors of survival [19].

3.3. Treatment of T1G3 bladder tumours The T1G3 bladder tumours have a high tendency to 5. Urinary diversion after radical cystectomy progress and therefore some experts tend to do early cystectomy. Nevertheless, it has been demonstrated Four alternatives are used presently after cystectomy, that 50% of patients can conserve their bladder with ileal conduit, continent pouch, a bladder reconstruction bladder instillations of chemotherapeutic agents or and . The latter is only used in BCG. selected centres. The ileal conduit is a reliable option with well- known good results. However, after long-term fol- 4. Treatment: radical cystectomy low-up 20% develop stomal complications and 30% of the renal units become dilated [20]. Radical cystectomy is the standard treatment in A variety of continent reservoirs have been intro- most countries for muscle-invasive bladder tumour. duced, the majority of these used either ileal segments, However, renewed interest in quality-of-life issues ileocecal segments or the sigmoid colon [21]. Follow- has increased interest in bladder preservation treat- ing continent urinary diversion early and late compli- ments. But radiotherapy is still a choice in several cations have been encountered in 12 and 37% of the countries. Also, performance status and age can in¯u- patients, respectively [22]. Late complications seen ence the choice of therapy, with cystectomy being included ureteral stricture/obstructions, incontinence, reserved for younger patients without concomitant dif®culty in catheterization, and urinary stones. Meta- disease. bolic complications are common but in the majority of 108 W. Oosterlinck et al. / European Urology 41 52002) 105±112 cases, and with correct patient selection and education, 6.1. Complications problems may be minimised [23]. The majority of patients undergoing radical radiation Orthotopic bladder replacement have been per- of the true pelvis will experience enteritis, proctitis, or formed in men for more than a decade and in women ``cystitis'', which are usually easily controllable and more recently. The main advantage is that no stoma is self-limiting. Late toxic effects of signi®cance are less necessary. Disadvantages include nocturnal leakage in prominent in modern series [28,29]. Erectile dysfunc- one-third of the patients and problems with voiding tion will occur in more than two-thirds of male patients requiring self-intermittent catheterization. As it con- [33]. Sexual function in females seems not compro- cerns major surgery early and late complications mised [34]. remains frequent, requiring reoperation in about 22% of the patients [24]. 6.2. Prognostic factors Contra-indications to more complex procedures are Although the 5 year survival rate is acceptable, local debilitating neurological and psychiatric illnesses, short recurrence will occur in about 50% of patients [28]. A life expectancy and impaired liver or renal function. small proportion of these patients can undergo salvage For continent urinary diversion the patient has to have cystectomy [28,35]. the motivation and skill to learn self-catheterization. Contra-indications to orthotopic bladder substitutes are TCC of the prostatic urethra, widespread CIS, 7. Chemotherapy high-dose pre-operative irradiation, complex urethral stricture and intolerance to incontinence. Response rates of 40±70% with cisplatin-containing Studies of quality-of-life outcomes show that regard- combination regimens have led to their use for the less of type of urinary diversion the majority of patients treatment of locally invasive disease in combination reported good overall quality-of-life, little emotional with cystectomy or radiotherapy, either as neo-adjuvant distress and few problems with social, physical or or adjuvant therapy [36±38]. functional activities [25]. Problems with urinary diver- Randomised trials with neo-adjuvant chemotherapy sion and sexual functioning were identi®ed as the most have not yet proven a survival bene®t with neo- common. adjuvant chemotherapy [39]. However, response to By many experts and several national guidelines, it is chemotherapy is an important predictor of survival recommended to centralise continent pouch and blad- [40,41]. der replacement operations in centres doing this inter- vention regularly, because this major surgery requires 7.1. Neo-adjuvant chemotherapy and bladder experience and teamwork. preservation Selected patients with invasive bladder tumours after neo-adjuvant chemotherapy may still have their blad- 6. Radiotherapy ders preserved, although the approach is highly con- troversial [41,42]. Bladder preservation may be De®nitive radiotherapy with curative intent and the possible with an integrated approach using chemother- aim of bladder preservation is performed in T1±T4, N0, apy and radiotherapy [43]. M0 transitional cell bladder cancer [26±29]. Prognostic factors for local curability were small The decision for or against radiotherapy should be tumour size, absence of hydronephrosis, papillary his- based on prognostic factors, patients desire and will be tology, visible complete TUR and a complete response heavilyin¯uenced bythe physician's preference [27,35]. to induction chemotherapy. Patients who are suitable for this treatment should have: adequate bladder capacity; normal bladder func- 7.2. Adjuvant chemotherapy tion; no recurrent urinary infections; previous in¯am- Several trials with combination chemotherapy mation or surgery of the true pelvis with consecutive appeared to show a difference in favour of chemother- adhesion [26,27]. apy. Yet the results are controversial [44]. External beam radiotherapy is the most common form of radiotherapy. The use of simultaneous chemotherapy 7.3. Metastatic disease to induce high control is investigated [30,31]. Two prospective randomised trials have proven the is an alternative radiotherapeutic superiority of M-VAC methotrexate, vinblastine, dox- approach in selected patients with small solitary orubicin and cisplatin) [45,46]. Unfortunately, the use tumours of less than 5 cm in diameter [32]. of this combination chemotherapy is associated with W. Oosterlinck et al. / European Urology 41 52002) 105±112 109 signi®cant toxicity and produces long-term survival in all other cases, yearly follow-up is advisable for up to only, approximately 15±20% of patients. The median 10 years, with lifelong follow-up for the high-risk survival duration is only 13 months and long-term group [54]. survival is attained in, approximately 15% of patients with metastases in visceral sites and 30% of those with nodal disease. 9. IVP Novel chemotherapeutic agents such as gemcitabine and the taxanes obtain similar overall survival, time to The development of an upper urinary tract tumour progressive disease, time to treatment failure, and during follow-up of SBC is very rare, and therefore IVP response rate but gemcitabine ‡ cisplatinum appears should not be carried out routinely [55]. to have a reduced toxicity pro®le compared to M-VAC The highest frequency can be expected in CIS and [47,48]. therefore IVP should be carried out when cytology The combination of gemcitabine and taxol has been remains positive during follow-up [56,57]. shown to be highly effective in patients who have failed prior M-VAC [49]. When cisplatin gemcitabine and taxol were given to untreated patients, high overall 10. Follow-upafter radical cystectomy response rates were observed [50]. The riskof tumour progression after radical cystect- 7.4. Prognostic factors omy strongly depends on histopathological tumour The reported prognostic factors predictive of poor stage [58]. Progression riskis highest within the ®rst response to chemotherapy include elevated alkaline 24 months following cystectomy. Tumour progression phosphatase level, age greater than 60 years and per- may occur locally in the true pelvis, in regional or formance status [51]. juxtaregional lymph nodes or as distant metastases. Furthermore, urothelial remnants in the upper tract and/or the urethra need to be checked for intraluminal 8. Follow-upafterTUR in SBC tumour recurrences.

Incomplete resection, implantation at traumatised 10.1. Therapeutic consequences of follow-up sites in the bladder or rapid growth of epithelial investigations 5role of salvage therapy) malignancy are responsible for the higher recurrence No prospective data are available for salvage treat- rate of SBC after TUR at 3 months. Therefore, an early ment comparing asymptomatic tumour relapse. cystoscopy is advisable in all cases of SBC. In high- Patients with symptomatic tumour relapse often are grade lesions T1, G2 and 3), a second resection at the characterised by a reduced general condition [59]. A site of the TUR is advised earlier than 3 months [52]. reduced performance status is a predictor of a poor outcome. It does seem likely that efforts aiming at early 8.1. Frequency of later detection of tumour progression may lead to an This should be adapted to the prognostic factors of improved success rate of salvage therapy. the tumour. In low-risktumours with no recurrence at 3 months, a follow-up cystoscopy can be delayed until 10.2. Anatmical sites 9 months later and then yearly up to 5 years because of Of all cases with relapse, 15±20% are found in the the very low recurrence rate of the tumour [53]. In case true pelvis, another 10±15% in the pelvic or retro- of recurrence, the histological ®ndings are the same as peritoneal lymph nodes. Local recurrences after those of the primary TUR in over 95% of cases. cystectomy are reported for pT2a, 2b, and pT3 tumour In patients with high-risktumours, a cystoscopy every at 6, 18 and 51%, respectively [60]. 3 months during the ®rst 2 years remains the most Distant metastases are mainly located in lever 38%), commonly adapted follow-up schedule. Cystoscopy lung 36%) and bone 28%). More than 50% of all shouldthenfollow every 4 monthsinthe thirdyear, every patients with tumour progression have distant metas- 6 months thereafter for up to 5 years and then yearly. The tases. schedule of follow-up in the intermediate group lies in The most probable site of intraluminal disease recur- between. With any recurrence, the schedule of cystos- rence is the male urethra, if it is not prophylactically copies is restarted from the beginning. removed at the time of the cystectomy. The incidence It seems advisable to stop follow-up in single TaG1 of a urethral recurrence is 5±13% [61]. Tumour invol- tumours in the absence of recurrence during 5 years. In ving the bladder neckor prostate and those with TIS are 110 W. Oosterlinck et al. / European Urology 41 52002) 105±112 at highest risk. Some contemporary series report a grams are limited by the low frequency of upper tract lower riskof urethral recurrences as compared to tumours and may therefore be partially replaced by historical series [62]. ultrasound and urinary cytology [63]. Upper tract intraluminal recurrences are even less Time schedule for follow-up after radical cystect- frequent, the cost-bene®t of regular intravenous pyelo- omy and urinary diversion.

Time min) Mandatory Optional 3USa or IVP Blood Chemb Ph. Examc 6 Blood Chem Ph. Exam CT Ch X-rayd urethrae 12 US or IVP Blood Chem Ph. Exam CT Ch X-ray urethra 18 Blood Chem Ph. Exam 24 US KUBf Blood Chem Ph. Exam CT Ch X-ray urethra 36 Blood Chem Ph. Exam CT Ch X-ray urethra 48 US KUB Blood Chem Ph. Exam 60 Blood Chem Ph. Exam urethra 72 US KUB Blood Chem Ph. Exam Endoscopy urethra 96 US KUB Blood Chem Ph. Exam Endoscopy urethra 120 US KUB Blood Chem Ph. Exam Endoscopy urethra a US: ultrasound of the kidneys. b Blood Chem: liver and tests, electrolytes, base excess also vit. B12 after 4 years). c Ph. Exam: physical examination including DRE, endoscopy of bladder substitute or reservoir. d Ch X-ray: chest X-ray. e Urethra: scopy and/or wash. f KUB: plain abdominal X-ray.

References

[1] Epstein J, Amin M, Reuter V, Mostofi F and the Bladder Consensus progression in superficial bladder tumors. Eur J Cancer 1995;31 Conference Committee. The World Heath Organization/International A11):1840±6. Society of Urological Pathology consensus classification of urothelial [10] Millan-Rodriguez F, CheÂcille-Toniolo G, Salvador-Bayarri J, Palou J, transitional cell) neoplasms of the . Am J Surg Pathol Vincente-Rodriguez J. Multivariate analysis of the prognostic factors 1998;22:1435±48. of primary superficial bladder cancer. J Urol 2000;163:73±8. [2] Tosini I, Wagner U, Sauter G, Egloff M, KnoÈgagil H, Alund G, [11] Tolley DA, Parmar MKB, Grigor KM, Lallemand G, Benyon LL, Bannwart F, Mihatshg MJ, Gasser TC, Maurer R. Clinical Fellows J, Freedman LS, Grigor KN, Hall RR, Hargrave TB, Munson significance of interobserver differences in the staging and grading K, Newling DW, Richar B, Robinson MR, Ros MB, Smith PH, Willic of superficial bladder cancer. BJU Int 2000;85:48±53. JL, Whelan P. The effect of intravesical mitomycin C on recurrence [3] Goessl C, Knispel HH, Miller K, Magnusson A. Is routine excretory of newly diagnosed superficial bladder cancer: A further report with urography necessary at first diagnosis of bladder cancer. J Urol 7 years of follow-up. J Urol 1996;155:1233±8. 1997;157:480±1. [12] OosterlinckW, Kurth KH, Schroder F, BultinckJ, Hammond B, [4] Vander Meijden A, OosterlinckW, Brausi M, Kurth KH, Sylvester R, Sylvester R and members of the European Organization for Research de Balincourt C. Significance of bladder biopsies in Ta, T2 bladder and Treatment of Cancer Genitourinary Group. A prospective European tumours: A report from the EORTC GU Group. Eur Urol Organization for Research and Treatment of Cancer genitourinary 1999;35:267±71. Group randomized trial comparing transurethral resection followed by [5] Solsona E, Iborra IV, Mouros JL, Casanova JL, Almenar S. The a single intravesical instillation of Epirubicin or water in single stage prostate involvement as prognostic factor in patients with superficial Ta, T1 papillary carcinoma of the bladder. J Urol 1993;149:749±52. bladder tumours. J Urol 1995;154:1740±3. [13] Bouffioux CH, Kurth KH, Bono A, OosterlinckW, Kruger CB, De [6] Pawinsky A, Sylvester R, Kurth K, Bouffioux C, van der Meijden A, Pauw H, Sylvester R. Intravesical adjuvant chemotherapy for Pasnar MK, Bijnens L. A combined analysis of EORTC and MRC superficial transitional cell bladder carcinoma: Results of 2 European randomized clinical trials for the prophylactic treatment of Ta, T1 organization for research and treatment of cancer randomized trials bladder cancer. J Urol 1996;156:1934±41. with mitomycin C and doxorubicin comparing early versus delayed. [7] Cookson MS, Herr HW, Zhang ZF, Soloway S, Sogani P, Fair W. The Instillations and short-term versus long-term treatment.. J Urol treated natural history of high-risksuperficial bladder cancer: 15-year 1995;153:934±41. outcome. J Urol 1997;158:62±7. [14] Lamm DL, Blumenstein B, Crissman JD, Montie JE, Gottesman JE, [8] Herr HW. Tumour progression and survival in patients with T1G3 Lowe BA, Sarosdy G, Bohl RD, Grossman HB, BeckTM, Leimers bladder tumours: 15 years outcome. Br J Urol 1997;80:162±765. JT, Crawford ED. Maintenance BCG immunotherapy for recurrent [9] Kurth KH, Denis L, Bouffioux C, Sylvester R, Debruyne FM, Ta, T1 and TIS transitional cell carcinoma of the bladder: A Pavone-Macaluso M, OosterlinckW. Factors affecting recurrence and randomized SWOG group study. J Urol 2000;163:1124±9. W. Oosterlinck et al. / European Urology 41 52002) 105±112 111

[15] MackD, FrickJ. Low-dose BCG therapy in superficial high risk [35] Greven KM, Solin LJ, Hanks GE. Prognostic factors in patients with bladder cancer: A phase II study with the BCG strain, Connaught bladder carcinoma treated with definitive irradiation. Cancer Canada. Br J Urol 1995;75:185±7. 1990;65:908±12. [16] Leissner J, Hohenfellner R, ThuÈroff JW, Wolf HK. Lymphadenect- [36] Sternberg CN, Calabro F. Chemotherapy and management of bladder omy in patients with transitional cell carcinoma of the urinary tumors. Br J Urol 2000;855):599±610. bladder, significance for staging and prognosis. BJU 2000;85:817± [37] Sternberg CN, Raghavan D, Ohi Y. Neo-adjuvant and adjuvant 23. chemotherapy in locally advanced disease: What are the effects on [17] EORTC-GU Group. Neoadjuvant cisplatin, methotrexate, and vinblas- survival and prognosis. Int J Urol 1995;22):76±88. tine chemotherapy for muscle-invasive bladder cancer: A randomised [38] Donat SM, Herr HW, Bajorin DF, Fair WR, Sogani PC, Russo P, controlled trial, Lancet 1999;354:533±40. Sheinfeld J, Scher I. Methotrexate, vinblastine, doxorubicin and [18] Hellsten S, Rintala E, Wahlqvist R, Malmstrom PU. Nordic cisplatin chemotherapy and cystectomy for unresectable bladder prospective trials of radical cystectomy and neoadjuvant chemother- cancer. J Urol 1996;156:368±71. apy. The Nordic Cooperative Bladder Cancer Study Group. Eur Urol [39] Anonymous. Neoadjuvant cisplatin, methotrexate, and vinblastine 1998;33Suppl 4):35±8. chemotherapy for muscle-invasive bladder cancer: A randomised [19] Bassi P, Ferrante GD, Piazza N, Spinadin R, Carando R, Pappagallo controlled trial. Lancet 1999;354:533±40. G, Pagano F. Prognostic factors of outcome after radical cystectomy [40] Splinter TA, Scher HI, Denis L, Bulkowski R, Simon S, Klimberg I, for bladder cancer: A retrospective study of a homogeneous patient Soloway M, Vogelzang NJ, Van Tinteren H, Herr H. The prognostic cohort. Urology 1999;161:1494±7. value of the pathological response to combination chemotherapy [20] Neal DE. Complication of ileal conduit diversion in adults with before cystectomy in patients with invasive bladder cancer. European cancer followed up for at least five years. Br Med J 1985;290:1695±7. Organization for Research on Treatment of Cancer±Genitourinary [21] Benson MC, Olsson CA. Continent urinary diversion. Urol Clin Group. J Urol 1992;147:606±8. North Am 1999;26:125±47. [41] Sternberg CN, Pansadoro V, Calabro F, Marini L, van Rijn A, Carli [22] Lampel A, Fisch M, Stein R, Schulz-Lampel D, Hohenfellner M, PD, Giannarelli D, Platania A, Rossetti A. Neo-adjuvant chemother- Eggersmann C, Hohenfellner R, ThuÈroff JW. Continent diversion apy and bladder preservation in locally advanced transitional cell with the Mainz pouch. World J Urol 1996;14:85±91. carcinoma of the bladder. Ann Oncol 1999;10:1301±5. [23] Mills RD, Studer UD. Metabolic consequences of continent urinary [42] Herr HW, Bajorin DF, Scher HI. Neoadjuvant chemotherapy and diversion. J Urol 1999;161:1057±66. bladder sparing surgery for invasive bladder cancer: Ten-year [24] Hautmann RE, de Petriconi R, Gottfried HW, Kleinschmidt K, outcome. J Clin Oncol 1998;164):1298±301. Mattes R, Paiss T. The ileal neobladder: Complications and [43] Sternberg CN, Calabro F. Neo-adjuvant chemotherapy in invasive functional results in 363 patients after 11 years of follow-up. J Urol bladder cancer. World J Urol 2001;192):94±8. 1999;161:422±7. [44] Sylvester R, Sternberg C. The role of adjuvant combination [25] Mansson A, Mansson W. When the bladder is gone: Quality of life chemotherapy after cystectomy in locally advanced bladder cancer. following different types of urinary diversion. World J Urol What we do not know and why? Ann Oncol 2000;11:851±6. 1999;17:211±8. [45] Logothetis CJ, Dexeus F, Finn L, Sella A, Amato RJ, Ayala AG, [26] Fossa SD, Waehre H, Aass N, Jacobsen AB, Olsen DR, Ous S. Kibourn RG. A prospective randomized trial comparing CISCA to Bladder cancer definitive radiation therapy of muscle-invasive MVAC chemotherapy in advanced metastastic urothelial tumors. bladder cancer. Cancer 1993;15:3036±42. J Clin Oncol 1990;8:1050±5. [27] Shipley WU, Van der Schueren E, Kitagawa T, Gospodarowicz MK, [46] Loehrer P, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock Fromhold M, Magno L, Mochizuki S, Van den Bogaert W and Van I. A randomized comparison of cisplatin alone or in combination der Werf-Messing B. Guidelines for radiation therapy in clinical with methotrexate, vinblastine, and doxorubicin in patients with research in bladder cancer, In: Shipley W.U., editor, Developments in metastatic urothelial carcinoma: A Cooperative Group Study. J Clin Bladder Cancer, Alan R Liss, New York, 1986. pp. 109±21. Oncol 1992;10:1066±73. [28] Gospodarowicz MK, Hawkins NV, Rawlings GA, Connolly JG, [47] Sternberg CN. Gemcitabine in Bladder Cancer. Semin Oncol Jewett MA, Thomas GM, Herman JG, Garnett G, Chua T, Duncar W. 2000;27:31±9. Radical radiotherapy for the muscle invasive transitional cell [48] von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, carcinoma of the bladder: Failure analysis. J Urol 1989;142:1448±54. Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, [29] PollackA, Zagars GK. Radiotherapy for stage T3b transitional cell Sanchez-Rovira P, Wersall P, Cleall SP, Roychowelhury DF, Tomlin carcinoma of the bladder. Semin Urol Oncol 1996;14:86±95. I, Visseren-Crul CM, Conte PF. Gemcitabine and cisplatin versus [30] Coppin C, Gospodarowicz MK, James K, TannockIF, Zee B, Casson methotrexate, vinblastine, doxorubicin, and cisplatin in advanced J, Pater J, Sullivan LD. The NCI-Canada trial of concurrent cisplatin or metastatic bladder cancer: results of a large, randomized, and radiotherapy for muscle invasive bladder cancer. J Clin Oncol multinational, multicenter, phase III study. J Clin Oncol 2000;18: 1996;14:2901±7. 3068±77. [31] Sauer R, Birkenhake S, KyÈhn R, Wittekind C, Schrott KM, Martus P. [49] Sternberg CN, Sella A, Calabro F, Pizzocaro G, Marini L. Second- Efficacy of radiochemotherapy with platin derivatives compared to line chemotherapy with every 2-weekgemcitabine and paclitaxel in radiotherapy alone in organ-sparing treatment of bladder cancer. Int J previously treated patients with transitional cell carcinoma. J Urol Radiat Oncol Biol Phys 1998;40:121±7. 2000;163:236. [32] Moonen LM, van Horenblas S, Van der Voet JC, Nuyten M, [50] Bellmunt J, Guillem V, Paz-Ares L, Gonzalez-Larriba JL, Carles J, BartelinkH. Bladder conservation in selected T1G3 and muscle- Batiste-Alentorn E, Saenz A, Lopez-Brea M, Font A, Nogue M, invasive T2-T3a bladder carcinoma using combination therapy of Bastus R, Climert MA, de la Cruz JJ, Albanell J, Banus JM, Gallardo surgery and iridium-192 implantation. Br J Urol 1994;74:322±7. E, Diaz-Rubio E, Cortes-Funes H, Baselga J. A phase I±II study of [33] Little FA, Howard GCW. Sexual function following radical radio- paclitaxel, cisplatin and gemcitabine in advanced transitional cell therapy for bladder cancer. Radiother Oncol 1998;49:157±61. carcinoma of the urothelium. J Clin Oncol 2000;18:3247±55. [34] Kachnic LA, Shipley WU, Griffin PP, Zietman AL, Kaufman DS, [51] Geller NL, Sternberg CN, Penenberg D, Scher H, Yagoda A. Althausen AF, Heney NM. Combined modality treatment with Prognostic factors for survival of patients with advanced urothelial selective bladder conservation for invasive bladder cancer: Long-term tumors treated with methotrexate, vinblastine, doxorubicin, and tolerance in the female patient. Cancer J Sci Am 1996;2:79±84. cisplatin chemotherapy. Cancer 1991;67:1525±31. 112 W. Oosterlinck et al. / European Urology 41 52002) 105±112

[52] Brauers A, Buettner R, Jakse G. Second resection and pmrognosis of [58] StoÈckle M, Wellek S, Meyenburg W, Voges GE, Fisher U, Gertenbach primary high risksuperficial bladder cancer: Is cystectomy often too U, ThuÈroff JW, Huber C, Hohenfellner R. Radical cystectomy with or early? J Urol 2001;165:808±10. without adjuvant polychemotherapy for non-organ-confined transi- [53] Morris SB, Gordon EM, Shearer RJ, Woodhouse CRJ. Superficial tional cell carcinoma of the urinary bladder: Prognostic impact of bladder cancer: For how long should a tumour-free patient have lymph node involvement. Urology 1996;48:868±75. checkcystoscopies? Br J Urol 1995;75:193±6. [59] Sengelov L, Nielsen OS, Kamby C, von der Maase H. Platinum [54] Holmang S, Hedelin H, Anderstrom C, Johansson SL, Walzer Y, analogue combination chemotherapy, carboplatin, and methotrexate Soloway MS. The relationship among multiple recurrences, progres- in patients with metastatic urothelial tract tumors. A phase II trial sion and prognosis of patients with stages Ta and T1, transitional cell with evaluation of prognostic factors. Cancer 1995;76:1797±803. cancer of the bladder followed for at least 20 years. J Urol [60] Greven KM, Spera JA, Solin LJ, Morgan T, Hanks GE. Local 1995;153:1823±7. recurrence after cystectomy alone for bladder carcinoma. Cancer [55] Holmangs S, Hedelin H, Anderstrom C, Holmberg E, Johansson L. 1992;69:2767±70. Long-term follow-up of a bladder carcinoma cohort: Routine follow- [61] ClarkPB. Urethral carcinoma after cystectomy: The case for routine up urography is not necessary. J Urol 1998;160:45±8. urethrectomy. J Urol 1984;90:173. [56] Solsona E, Iborra IV, Ricos JV, Dumont R, Casanova JL, Calabouig [62] Freeman JA, Esrig D, Stein JP, Skinner DG. Management of the C. Upper urinary tract involvement in patients with bladder carcinoma patient with bladder cancer: Urethral recurrence. Urol Clin North Am in situ: Its impact on management. Urology 1997;49:347±52. 1994;21:645±51. [57] Millan-Rodriguez F, CheÂchile-Toniolo G, Salvador-Bayarri J, [63] Hastie KJ, Hamdy FC, Collins MC, Williams JL. Upper tact tumours Huguet-PeÂreÂz J, Vicente-Rodriguez J. Upper urinary tract tumors following cystectomy for bladder cancer. Is routine intravenous after primary superficial bladder tumors: Porgnostic factors and risk urography worthwhile? Br J Urol 1991;67:29±31. groups. J Urol 2000;164:1183±7.