European Association of Urology. Pocket Guidelines edition

Transcription

1 European Association of Urology Pocket Guidelines 2012 edition

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3 Introduction The EAU Guidelines Office is pleased to present the 2012 edition of the Pocket Guidelines. These ultra-short versions of Europe s most read and used urological clinical Guidelines have been updated and improved to meet the high standards of the EAU and its members. To maintain this quality, we advise that the Pocket Guidelines should be used in combination with the extended documents of the clinical Guidelines, which are available in hard copy, on CD, and at the EAU website. Over 160 contributors have worked throughout the year to integrate the latest scientific research into the recommendations found in these Pocket Guidelines. Their dedication and perseverance has resulted in this updated publication; without them none of this would have been possible. We are extremely grateful to all contributing panel members who devote their time and energy to the guidelines project. The Pocket Guidelines are also published online, at to facilitate consultation of all Guidelines on computer, tablet device, or smartphone. 1

4 The Guidelines Office Board and contributors endeavour to compile a user-friendly and informative document. We hope that we have succeeded in making these latest Pocket Guidelines helpful to you and, ultimately, your patients. On behalf of the Guidelines Office Board, Mr. K.F. Parsons Chairman EAU Guidelines Office Board Prof.Dr. J. Irani, Vice-Chairman Prof.Dr. C.R. Chapple Prof. M. Fall Prof.Dr. T. Hánuš Prof.Dr. C. Llorente Abarca Prof.Dr. T. Loch Prof.Dr. D. Mitropoulos Prof.Dr. J. N Dow Prof.Dr. H-P. Schmid Prof.Dr. R. Sylvester 2

5 The European Association of Urology use the following rating system: Table 1: Level of evidence* Level Type of evidence 1a Evidence obtained from meta-analysis of randomised trials 1b Evidence obtained from at least one randomised trial 2a Evidence obtained from one well-designed controlled study without randomisation 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities *Modified from Sackett et al. (1) It should be noted, however, that when recommendations are graded, the link between the level of evidence and grade of recommendation is not directly linear. Availability of RCTs may not necessarily translate into a grade A recommendation where there are methodological limitations or disparity in published results. Alternatively, absence of high level evidence does not necessarily preclude a grade A recommendation, if there is overwhelming clinical experience and consensus. In addition, there may be exceptional situations where corroborating Introduction 3

6 studies cannot be performed, perhaps for ethical or other reasons and in this case unequivocal recommendations are considered helpful for the reader. Whenever this occurs, it has been clearly indicated in the text with an asterix, as upgraded based on panel consensus. The quality of the underlying scientific evidence - although a very important factor - has to be balanced against benefits and burdens, values and preferences and cost when a grade is assigned (2-4). Table 2: Grade of recommendation* Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial B Based on well-conducted clinical studies, but without randomised clinical trials C Made despite the absence of directly applicable clinical studies of good quality *Modified from Sackett et al. (1) References 1. Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2009). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November Updated by Jeremy Howick March [Access date January 2012] 2. Atkins D, Best D, Briss PA, et al; GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004 Jun 19;328(7454): Guyatt GH, Oxman AD, Vist GE et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650): Guyatt GH, Oxman AD, Kunz R et al; GRADE Working Group. Going from evidence to recommendations. BMJ 2008 May 10;336(7652):

7 Page 7 Page 21 Page 30 Page 48 Page 70 Page 89 Page 102 Page 123 Page 145 Page 167 Page 176 Page 189 Page 200 Page 224 Page 242 Page 254 Page 278 Page 304 Page 329 Page 365 Page 377 Non-muscle Invasive Bladder Cancer Upper Urinary Tract Urothelial Cell Carcinomas Muscle-invasive and Metastatic Bladder Cancer Prostate Cancer Renal Cell Carcinoma Penile Cancer Testicular Cancer Management of Male LUTS, incl. benign prostatic obstruction Male Sexual Dysfunction: Erectile Dysfunction and Premature Ejaculation Penile Curvature Male Infertility Male Hypogonadism Urinary Incontinence Urological Infections Neurogenic Lower Urinary Tract Dysfunction Urological Trauma Pain Management in Urology Chronic Pelvic Pain Urolithiasis Renal Transplantation Paediatric Urology 5

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9 GUIDELINES ON NON-MUSCLE- INVASIVE BLADDER CANCER (Limited text update December 2010) M. Babjuk, W. Oosterlinck, R. Sylvester, E. Kaasinen, A. Böhle, J. Palou, M. Rouprêt Eur Urol 2011 Apr;59(4): Introduction The EAU Working Group on Non-muscle-invasive Bladder Cancer has published a short and long version of guidelines on non-muscle-invasive bladder cancer which contains information on its background, classification, risk factors, diagnosis, prognostic factors, and treatment. The current recommendations for non-muscle-invasive bladder cancer are ultra short and are based on the current literature (until end of 2010), with emphasis being placed on (evidence based) results from randomised clinical trials and meta-analyses. These guidelines can be used as a quick reference on the management of patients with non-muscleinvasive bladder cancer. The recommendations of this working panel apply to patients with papillary stage Ta and T1 tumours as well as to carcinoma in situ (CIS), a flat neoplasm. The classification of non-muscle-invasive tumours (Ta, T1, and CIS) is given in Non-muscle-invasive Bladder Cancer 7

10 the TNM Classification of Malignant Tumours, 7 th Edition, 2009 (Table 1). Table 1: TNM classification 2009 for urinary bladder T - Primary Tumour Ta Non-invasive papillary carcinoma Tis Carcinoma in situ: flat tumour T1 Tumour invades subepithelial connective tissue T2 Tumour invades muscularis T2a Superficial muscle (inner half) T2b Deep muscle (outer half) T3 Tumour invades perivesical tissue (beyond muscularis) T3a Microscopically T3b Macroscopically (extravesical mass) T4 Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall T4a Prostate, uterus, or vagina T4b Pelvic wall or abdominal wall N - Lymph Nodes NX N0 N1 N2 N3 Regional lymph nodes cannot be assessed No regional lymph node metatstases Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac, or presacral) Mestastasis in multiple lymph nodes in the true pelvis (hypogastric, obturator, external iliac, or presacral) Metastasis in a common iliac lymph node(s) 8 Non-muscle-invasive Bladder Cancer

11 M - Distant Metastasis MX Metastasis not assessed M0 No distant metastasis M1 Distant metastasis Characteristics of stages Ta, T1, and CIS Stage Ta tumours are confined to the urothelium, have a papillary configuration of their exophytic part, and do not penetrate from the urothelium into the lamina propria or detrusor muscle. Stage T1 tumours originate from the urothelium but penetrate the basement membrane which separates the urothelium from the deeper layers. T1 tumours invade into the lamina propria, but are not so deep that they reach the detrusor muscle. Carcinoma in situ (CIS) is a high-grade (anaplastic) carcinoma confined to the urothelium, but with a flat non-papillary configuration. Unlike a papillary tumour, CIS appears as reddened and velvety mucosa and is slightly elevated but sometimes not visible. CIS can be local or diffuse. Three types of CIS are distinguishable; primary CIS (no previous or concurrent papillary tumours); secondary CIS (with a history of papillary tumours); concurrent CIS (in the presence of papillary tumours). Characteristics of grade 1973 WHO classification Apart from their architecture, the individual cells show dif- Non-muscle-invasive Bladder Cancer 9

12 ferent degrees of anaplasia: Grade 1: well differentiated tumour Grade 2: moderately differentiated tumour Grade 3: poorly differentiated tumour 2004 WHO Classification A new classification system was initially proposed by the WHO/ISUP in 1998 and updated by the WHO in For non-invasive urothelial neoplasias, the categories described in Table 2 are used. Table 2: 2004 WHO classification of non-invasive urothelial neoplasia Flat lesions Hyperplasia (flat lesion without atypia or papillary) Reactive atypia (flat lesion with atypia) Atypia of unknown significance Urothelial dysplasia Urothelial carcinoma in situ (CIS) Papillary lesions Urothelial papilloma (a completely benign lesion) Papillary urothelial neoplasm of low malignant potential (PUNLMP) Low-grade papillary urothelial carcinoma High-grade papillary urothelial carcinoma The 2004 WHO grading system defines CIS as a non-papillary, i.e. a flat, lesion in which the surface epithelium contains cells that are cytologically malignant. Papillary tumours are classified as either papillary urothelial neoplasms of low 10 Non-muscle-invasive Bladder Cancer

13 malignant potential (PUNLMP) or as urothelial carcinomas, with the latter being subdivided into two grades: low grade and high grade (Table 2). The intermediate group (G2) has been eliminated; this group was the subject of controversy in the 1973 WHO classification. Use of the 2004 WHO classification is advocated, as this should result in less diagnostic variability among pathologists. However until the 2004 WHO classification has been validated clinically, both classifications can be used. The majority of clinical trials published so far on TaT1 bladder tumours have been performed using the 1973 WHO classification, and therefore the following guidelines are based on the 1973 WHO grade classification. Diagnosis and initial treatment steps The diagnosis mainly depends on the cystoscopic examination of the bladder, biopsy, and urine cytology. To date, molecular urinary markers have not improved the combination of cystoscopy and cytology. The standard initial therapy for Ta and T1 papillary bladder tumours is complete macroscopic transurethral resection (TUR) including a part of the underlying muscle. A second TUR should be considered if there is a suspicion that the initial resection was incomplete, e.g. when multiple or large tumours are present, or when the pathologist reported no muscle tissue in the specimen, or when a high-grade tumour or a T1 tumour was detected. The technique of TUR is described in the EAU guidelines on non-muscle- Non-muscle-invasive Bladder Cancer 11

14 invasive urothelial carcinoma of the bladder (Eur Urol 2011 Jun;59(6): ). The diagnosis of CIS is based on the histology of biopsies from the bladder wall. Biopsies are taken from suspect areas. In patients with positive urine cytology and no papillary tumour, multiple biopsies from normal looking mucosa including prostatic urethra (random biopsies) are recommended. Fluorescence cystoscopy is recommended in these cases as it improves the detection rate of CIS. Urine cytology is an important tool in the diagnosis and follow-up of CIS because of its high sensitivity and specificity (over 90%). Carcinoma in situ cannot be eradicated by TUR and further treatment is mandatory. Prognostic factors and adjuvant treatment TaT1 papillary tumours Since there is considerable risk for recurrence and/or progression of tumours after TUR, adjuvant intravesical therapy is recommended for all stages (Ta, T1, and CIS). All patients should receive an immediate post-operative instillation of chemotherapy within 6 hours after TUR, except in cases of bladder perforation or severe bleeding. An immediate instillation is considered as standard, the choice of drug (mitomycin C, epirubicin, or doxorubicine) is optional. The choice of further intravesical adjuvant therapy depends on the patient s risk of recurrence and/or progression which can be assessed using the European Organization for the Research and Treatment of Cancer (EORTC) scor- 12 Non-muscle-invasive Bladder Cancer

15 ing system (Table 3) and risk tables (Table 4). Patients with multiple tumours, large tumours (> 3 cm), and highly recurrent tumours (> 1 recurrence/year) are at the highest risk of recurrence while patients with stage T1 tumours, high grade tumours, and CIS have the highest risk of progression. Intravesical chemotherapy reduces the risk of recurrence but not progression and is associated with minor side-effects. Intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) (induction and maintenance) is superior to intravesical chemotherapy in reducing recurrences and in preventing or delaying progression to muscle-invasive bladder cancer. However, intravesical BCG is more toxic. Recommendations for low risk tumours Patients with a single, small, low grade Ta tumour GR without CIS, who are at low risk for both recurrence and progression, should receive: 1. A complete TUR. A 2. An immediate single post-operative instillation with A a chemotherapeutic agent (drug optional). 3. No further treatment is recommended prior to A recurrence. Recommendations for high risk tumours Patients with TaT1 high grade tumours with or without CIS and those with CIS alone are at high risk of progression. Treatment should consist of: GR Non-muscle-invasive Bladder Cancer 13

16 1. Complete TUR of papillary tumours followed by an C immediate post-operative instillation with a chemotherapeutic agent (drug optional). 2. A second TUR after 4 6 weeks. B 3. Adjuvant intravesical immunotherapy with BCG A (full dose or reduced dose in case of side-effects). Maintenance therapy for at least 1 year is necessary although the optimal maintenance scheme has not yet been determined. 4. Immediate cystectomy may be offered to patients at C highest risk of tumour progression. 5. In patients with BCG failure, cystectomy is recommended. B BCG = Bacillus Calmette-Guérin; CIS = carcinoma in situ; TUR = transurethral resection. Intermediate risk tumours In the remaining intermediate risk patients, adjuvant intravesical therapy is necessary but no consensus exists regarding the optimal drug and the most appropriate scheme. BCG is more effective than chemotherapy in both reducing recurrence and progression but it is associated with more systemic and local side-effects. Recommendations for intermediate risk tumours The major issue in the management of intermediate risk tumours is to prevent recurrence and progression, of which recurrence is clinically the most frequent. Treatment should include: GR 14 Non-muscle-invasive Bladder Cancer

17 1. Complete TUR followed by an immediate postoperative instillation with a chemotherapeutic agent (drug optional). 2. A second TUR after 4 6 weeks when the initial resection was incomplete. 3a Adjuvant intravesical chemotherapy (drug optional), schedule: optional although the duration of treatment should not exceed 1 year. Or 3b Adjuvant intravesical immunotherapy with BCG (full dose or reduced dose in case of side-effects). Maintenance therapy for at least 1 year is necessary although the optimal maintenance schedule has not yet been determined. BCG = Bacillus Calmette-Guérin; CIS = carcinoma in situ; TUR = transurethral resection. A B A A Table 3: Calculation of recurrence and progression scores Factor Recurrence Progression Number of tumours Single 2 to 7 > 8 Tumour diameter < 3 cm > 3 cm Prior recurrence rate Non-muscle-invasive Bladder Cancer 15

18 Primary < 1 recurrence/year > 1 recurrence/year Category Ta T1 Concomitant CIS No Yes Grade (1973 WHO) G1 G2 G Total Score CIS = carcinoma in situ; WHO = World Health Organization. Table 4: Probability of recurrence and progression according to total score Recurrence score Prob. recurrence 1 year Prob. recurrence 5 years Recurrence risk group 0 15% 31% Low risk % 46% Intermediate % 62% risk % 78% High risk Progression score Prob. progression 1 year Prob. progression 5 years Progression risk group 0 0.2% 0.8% Low risk 16 Non-muscle-invasive Bladder Cancer

19 2-6 1% 6% Intermediate risk % 17% % 45% High risk Note: electronic calculators for Tables 3 and 4 are available at Eur Urol 2006;49(3): Carcinoma in situ Carcinoma in situ has a high risk of progression to muscleinvasive disease which exceeds 50% in some studies. BCG intravesical immunotherapy (induction and maintenance) is superior to intravesical chemotherapy in increasing the complete response rate and the overall percent of patients remaining tumour free. Moreover, BCG reduces the risk of progression as compared to either intravesical chemotherapy or a different immunotherapy. Early radical cystectomy at the time of diagnosis provides excellent disease-free survival, but over-treatment occurs in up to 50% of patients. Recommendations for the treatment of CIS 1. In concurrent CIS, the initial strategy (TUR, early intravesical instillation, a second TUR) is based on the features of the papillary tumour. 2. Intravesical BCG immunotherapy including at least 1 year maintenance. GR A Non-muscle-invasive Bladder Cancer 17

20 3. After the 6 week induction course, a second course of 6 weekly BCG instillations or maintenance cycles consisting of 3 weekly instillations may be considered in non-responders since about 40-60% of these patients will respond to additional treatment with BCG. 4. In BCG non-responders at 6 months radical cystectomy is recommended. BCG = Bacillus Calmette-Guérin; CIS = carcinoma in situ; TUR = transurethral resection. Follow-up for non-muscle-invasive bladder tumours Patients with non-muscle-invasive bladder tumours need to be regularly followed up because of the risk of recurrence and progression; however, the frequency and duration of cystoscopies should reflect the individual patient s degree of risk. Using the risk tables (Tables 3 and 4), the short-term and long-term risks of both recurrence and progression in individual patients can be predicted and the follow-up schedule adapted accordingly: a. The prompt detection of muscle-invasive and high-grade non-muscle-invasive recurrences is critical since a delay in diagnosis and therapy threatens a patient s life. b. Tumour recurrence in the low-risk group is nearly always low stage and low grade. Small, non-invasive (Ta), low grade papillary recurrences do not present an immediate danger to the patient and their early detection is not essential for successful therapy. c. The result of the first cystoscopy after TUR at 3 months is B B 18 Non-muscle-invasive Bladder Cancer

21 a very important prognostic factor for recurrence and for progression. The first cystoscopy should thus always be performed 3 months after TUR in all patients with nonmuscle-invasive bladder tumour. The following recommendations are only based on retrospective experience. Recommendations for follow-up cystoscopy Patients with tumours at low risk of recurrence and progression should have a cystoscopy at 3 months. If negative, the following cystoscopy is advised at 9 months and consequently yearly for 5 years. Patients with tumours at high risk of progression should have a cystoscopy and urinary cytology at 3 months. If negative, the following cystoscopies and cytologies should be repeated every 3 months for a period of 2 years, every 4 months in the third year, every 6 months thereafter until 5 years, and yearly thereafter. A yearly exploration of the upper tract is recommended. Patients with intermediate-risk of progression (about one-third of all patients) should have an in-between follow-up scheme using cystoscopy and cytology, adapted according to personal and subjective factors. GR C C C Non-muscle-invasive Bladder Cancer 19

22 Patients with CIS should be followed up for life due to the high risk of recurrence and progression, both within the bladder and extravesically. Urine cytology together with cystoscopy (and bladder biopsies in cytology positive cases) is essential for monitoring of treatment efficacy. The follow-up schedule is the same as for patients with high-risk tumours. C This short booklet text is based on the more comprehensive EAU guidelines (ISBN ), available to all members of the European Association of Urology at their website, 20 Non-muscle-invasive Bladder Cancer

23 GUIDELINES ON UPPER URINARY TRACT UROTHELIAL CELL CARCINOMAS M. Rouprêt, R. Zigeuner, J. Palou, A. Boehle, E. Kaasinen, M. Babjuk, R. Sylvester, W. Oosterlinck Eur Urol 2011 Apr;59(4): Introduction The EAU Working Group for upper urinary tract urothelial cell carcinomas (UUT-UCCs) has recently updated guidelines for this tumour type. This document provides a brief overview of the updated EAU guidelines. UUT-UCCs are uncommon and account for only 5-10% of UCCs. The estimated annual incidence of UUT-UCCs in Western countries is about 1-2 new cases per 100,000 population. Pyelocaliceal tumours are about twice as common as ureteral tumours. The principal environmental factors which contribute to the development of UUT-UCCs are similar to those associated with bladder cancer, namely tobacco and occupational exposure. Other environmental factors that are specifically associated with UUT-UCCs include phenacetin, aristolochic acid nephropathy, and blackfoot disease. Upper Urinary Tract Urothelial Cell Carcinomas 21

24 The morphology of UUT-UCCs is similar to those of bladder carcinomas. Over 95% of UCCs are derived from the urothelium, comprising of either UUT-UCCs or bladder carcinomas. Classification The classification of UUT-UCCs is given in the TNM classification of Malignant Tumours 7 th edition, Table 1: TNM classification 2009 for renal pelvis and ureter* T - Primary tumour TX T0 Ta Tis T1 T2 T3 T4 Primary tumour cannot be assessed No evidence of primary tumour Non-invasive papillary carcinoma Carcinoma in situ Tumour invades subepithelial connective tissue Tumour invades muscularis (Renal pelvis) Tumour invades beyond muscularis into peripelvic fat or renal parenchyma (Ureter) Tumour invades beyond muscularis into periureteric fat Tumour invades adjacent organs or through the kidney into perinephric fat 22 Upper Urinary Tract Urothelial Cell Carcinomas

25 N - Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node 2 cm or less in the greatest dimension N2 Metastasis in a single lymph node more than 2 cm but not more than 5 cm in the greatest dimension or multiple lymph nodes, none more than 5 cm in greatest dimension N3 Metastasis in a lymph node more than 5 cm in greatest dimension M - Distant metastasis M0 No distant metastasis M1 Distant metastasis * All EAU guidelines advocate the TNM system of tumour classification. Tumour grade Until 2004, the most common classification used for UUT- UCCs was the WHO classification of 1973, which distinguishes among three grades (G1, G2 and G3). Since 2004, the new WHO classification distinguishes among three groups of non-invasive tumours: papillary urothelial neoplasia of low malignant potential, low-grade carcinomas, and high-grade carcinomas. Both classifications are in use currently for UUT-UCCs. There are almost no tumours of low malignant potential in the UUT. Diagnosis The diagnosis of a UUT-UCC depends on imaging, cystoscopy, urinary cytology, and diagnostic ureteroscopy. Upper Urinary Tract Urothelial Cell Carcinomas 23

26 Recommendations for diagnosis of UUT-UCC Urinary cytology Cystoscopy to rule out a concomitant bladder tumour MDCT urography MDCT = multidetector computed tomography. GR A A A In addition, the possible advantages of ureteroscopy should be discussed in the preoperative assessment of any UUT- UCC patient. Prognostic factors UUT-UCCs that invade the muscle wall usually have a very poor prognosis. The recognised prognostic factors in decreasing order of importance include: tumour stage and grade; concomitant carcinoma in situ (CIS); age; lymphovascular invasion; tumour architecture; extensive tumour necrosis; molecular markers; tumour location; gender. Treatment Localised disease The radical management of UUT-UCC consists of radical nephroureterectomy (RNU) by open surgery with excision of the bladder cuff. This is the gold standard treatment for UUT-UCC, regardless of the location of the tumour in the UUT. Resection of the distal ureter and its orifice is per- 24 Upper Urinary Tract Urothelial Cell Carcinomas

27 formed because this part of the urinary tract carries a considerable risk of recurrence. Lymph node dissection associated with RNU is of therapeutic interest and allows for optimal staging of the disease. Recommendations for radical management of UUT-UCC: RNU Indications for radical management of UUT-UCC GR Suspicion of infiltrating UUT-UCC (imaging) B High-grade tumour (urinary cytology) B Multifocality (with two functional kidneys) B Techniques for RNU in UUT-UCC Open and laparoscopic access are equally effective B Bladder cuff removal is imperative A Several techniques for bladder cuff excision are C acceptable, except stripping Lymphadenectomy is recommended in the case of C invasive UUT-UCC RNU = radical nephroureterectomy. The conservative management of low-risk UUT-UCC consists of conservative surgery, which allows for preservation of the upper urinary renal unit. Conservative management of UUT-UCC can be considered in imperative cases (renal insufficiency, solitary functional kidney) or in selected elective cases (functional contralateral kidney) for low-grade, low-stage tumours. The choice of technique (ureteroscopy, segmental resection, percutaneous access) depends on technical constraints, the anatomical location of the tumour, and the experience of the surgeon. Upper Urinary Tract Urothelial Cell Carcinomas 25

28 Recommendations for conservative management of UUT-UCC Indications for conservative management of UUT- UCC Unifocal tumour Small tumour (size < 1cm) Low-grade tumour (cytology or biopsies) No evidence of an infiltrative lesion on MDCT urography Understanding of close follow-up Techniques used for conservative management of UUT-UCC Laser should be used in the case of endoscopic treatment Flexible ureteroscopy is preferable to rigid ureteroscopy Open partial resection is an option for pelvic ureteral tumours A percutaneous approach is an option for small, lowgrade, caliceal tumours unsuitable for ureteroscopic treatment MDCT = multidetector computed tomography. GR B B B B B C C C C The instillation of Bacillus Calmette-Guérin (BCG) or mitomycin C in the urinary tract by percutaneous nephrostomy or via a ureteric stent is technically feasible after conservative treatment of UUT-UCCs. However, benefits have not been confirmed. 26 Upper Urinary Tract Urothelial Cell Carcinomas

29 Advanced disease There are no benefits of RNU in metastatic (M+) disease, although it can be considered as a palliative option. As UUT-UCCs are urothelial tumours, platinum-based chemotherapy is expected to produce similar results to those seen in bladder cancer. Currently, insufficient data are available to provide any recommendations. Radiation therapy appears to be scarcely relevant nowadays both as a unique therapy and associated with chemotherapy as tumour adjuvant. Follow-up Strict follow-up of UUT-UCC patients after radical management is necessary in order to detect metachronous bladder tumours (in all cases), local recurrence and distant metastases (in the case of invasive tumours). With conservative management, the ipsilateral UUT requires careful follow-up due to the high risk of recurrence. Recommendations for follow-up of UUT-UCC patients after initial treatment After radical management, over at least 5 years GR Non-invasive tumour Cystoscopy/urinary cytology at 3 months and then C yearly MDCT urography yearly C Invasive tumour Cystoscopy/urinary cytology at 3 months and then C yearly Upper Urinary Tract Urothelial Cell Carcinomas 27

30 MDCT urography every 6 months for 2 years and then yearly After conservative management, over at least 5 years Urinary cytology and MDCT urography at 3 months, 6 months and then yearly Cystoscopy, ureteroscopy and cytology in situ at 3 months, 6 months, every 6 months for 2 years and then yearly C C C MDCT = multidetector computed tomography; RNU = radical nephroureterectomy. 28 Upper Urinary Tract Urothelial Cell Carcinomas

31 Figure 1: Proposed flowchart for the management of UUT- UCC UUT-UCC Diagnostics evaluation: CT-urography, urinary cytology, cystoscopy (± ureteroscopy with biopsies) - Unifocal tumour - Size < 1 cm - Low-grade tumour - Superficial aspect on MDCTU Gold standard treatment: Radical nephroureterectomy Conservative management: ureteroscopy, segmental resection, percutaneous approach Recurrence Open Laparoscopic Close and stringent follow-up MDCT = multidetector computed tomography. This short booklet text is based on the more comprehensive EAU guidelines (ISBN: ), available to all members of the European Association of Urology at their website, Upper Urinary Tract Urothelial Cell Carcinomas 29

32 MUSCLE-INVASIVE AND METASTATIC BLADDER CANCER (Text update February 2012) A. Stenzl (chairman), J.A. Witjes (vice-chairman), E. Compérat, N.C. Cowan, M. De Santis, M. Kuczyk, T. Lebret, M.J. Ribal, A. Sherif Introduction Publications concerning muscle-invasive and metastatic bladder cancer are mostly based on retrospective analysis, including some larger multicentre studies and well-designed controlled studies. The studies underpinning the current guidelines were identified through a systematic literature research. It is evident that optimal treatment strategies for MIBC require the involvement of a specialist multidisciplinary team and a model of integrated care to avoid fragmentation of patient care. Staging system The UICC 2009 TNM (Tumour, Node, Metastasis Classification) is used for staging (Table 1). 30 Muscle-invasive and Metastatic Bladder Cancer

33 Table 1: 2009 TNM classification of urinary bladder cancer T - Primary tumour TX T0 Ta Tis T1 T2 T3 T4 Primary tumour cannot be assessed No evidence of primary tumour Non-invasive papillary carcinoma Carcinoma in situ: flat tumour Tumour invades subepithelial connective tissue Tumour invades muscle T2a Tumour invades superficial muscle (inner half) T2b Tumour invades deep muscle (outer half) Tumour invades perivesical tissue T3a Microscopically T3b Microscopically (extravesical mass) Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall T4a Tumour invades prostate, uterus or vagina T4b Tumour invades pelvic wall or abdominal wall N - Lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac or presacral) N2 Metastasis in multiple lymph nodes in the true pelvis (hypogastric, obturator, external iliac or presacral) N3 Metastasis in a common iliac lymph node(s) M - Distant metastasis M0 M1 No distant metastasis Distant metastasis Muscle-invasive and Metastatic Bladder Cancer 31

34 Table 2: WHO grading 1973 and 2004 (Both classifications are used for the current guidelines since most of the retrospective studies were based on the old WHO 1973 grading system) WHO grading Urothelial papilloma Grade 1: well differentiated Grade 2: moderately differentiated Grade 3: poorly differentiated 2004 WHO grading Urothelial papilloma Papillary urothelial neoplasm of low malignant potential (PUNLMP) Low-grade papillary urothelial carcinoma High-grade papillary urothelial carcinoma Morphological subtypes can be important for helping with prognosis and treatment decisions. Currently the following differentiation is used: 1. urothelial carcinoma (more than 90% of all cases) 2. urothelial carcinomas with squamous and/or glandular partial differentiation; 3. micropapillary urothelial carcinoma; 4. small-cell carcinomas; 5. some urothelial carcinomas with trophoblastic differentiation; 6. nested carcinoma: 7. spindle cell carcinomas. 32 Muscle-invasive and Metastatic Bladder Cancer

35 Specific recommendations for primary assessment of presumably invasive bladder tumours (General information for assessment of bladder tumours, see EAU Guidelines on Non-muscle-invasive Bladder cancer) Recommendations Cystoscopy should describe all macroscopic features of the tumour (site, size, number and appearance) and mucosal abnormalities. A bladder diagram is recommended. Biopsy of the prostatic urethra is recommended for cases of bladder neck tumour, when bladder CIS is present or suspected, when there is positive cytology without evidence of tumour in the bladder, or when abnormalities of the prostatic urethra are visible. If biopsy is not performed during the initial procedure, it should be completed at the time of the second resection. In women undergoing a subsequent orthotopic neobladder, procedure information is required (including a histological evaluation) of the bladder neck and urethral margin, either prior to, or at the time of cystoscopy The pathological report should specify the grade, the depth of tumour invasion and whether the lamina propria and muscle tissue are present in the specimen. GR C C C C Muscle-invasive and Metastatic Bladder Cancer 33

36 Recommendations for staging of verified bladder GR tumour Computed tomography (CT) or magnetic resonance imaging is recommended if there is suspicion of locally advanced or metastatic disease precluding radical treatment. In patients considered eligible for radical treatment, B for optimal T-staging, either MR imaging with fast dynamic contrast-enhancement or multidetector computed tomography with contrast enhancement are recommended In patients with confirmed muscle-invasive bladder B cancer, computed tomography of the chest, abdomen and pelvis is the optimal form of staging, including CT urography for complete examination of the upper urinary tracts. If CT is not available, lesser alternatives are excretory urography and a chest X-ray. In patients with a verified muscle invasive lesion C (TUR), abdominal pelvis and chest imaging is mandatory. MR imaging and CT are equivalent in diagnosing local and distant abdominal metastases. Computed tomography is preferred to magnetic C resonance imaging for the detection of pulmonary metastases. MR = magnetic resonance; CT = computed tomography. 34 Muscle-invasive and Metastatic Bladder Cancer

37 Treatment failure of non-muscle invasive bladder tumours Recommendations for treatment failure of nonmuscle invasive bladder cancer In all T1 tumours at high risk of progression (i.e. high grade, multifocality, carcinoma in situ, and tumour size, as outlined in the EAU guidelines for Non-muscle-invasive bladder cancer), immediate radical cystectomy is an option. In all T1 patients failing intravesical therapy, cystectomy should be performed. GR B B Muscle-invasive bladder cancer - standard treatment Radical Surgery and Urinary Diversion Conclusions For muscle-invasive bladder cancer radical cystectomy is the curative treatment of choice A higher case load reduces morbidity and mortality of cystectomy. Radical cystectomy includes removal of regional lymph nodes, the anatomical extent of which has not been sufficiently defined. Radical cystectomy in both sexes must not include the removal of the entire urethra in all cases, which may then serve as outlet for an orthotopic bladder substitution. Terminal ileum and colon are the intestinal segments of choice for urinary diversion. LE Muscle-invasive and Metastatic Bladder Cancer 35

38 The type of urinary diversion does not affect oncological outcome. Laparoscopic and robotic-assisted laparoscopic cystectomy is feasible but still investigational. In patients with invasive bladder cancer older than 80 years cystectomy is an option. Co-morbidity, age, previous treatment for bladder cancer or other pelvic diseases, surgeon and hospital volume of cystectomy, and type of urinary diversion influence surgical outcome. Surgical complications of cystectomy and urinary diversion should be reported in a uniform grading system. Currently, the best-adapted, graded system for cystectomy is the Clavien grading system Contraindications for orthotopic bladder substitution are positive margins at the level of urethral dissection, positive margins anywhere on the bladder specimen (in both sexes), if the primary tumour is located at the bladder neck or in the urethra (in women), or if tumour extensively infiltrates the prostate (in men). Recommendations for radical cystectomy Radical cystectomy is recommended in T2-T4a, N0 M0, and high risk non-muscle-invasive BC (as outlined above). Do not delay cystectomy more than 3 months since it increases the risk of progression and cancer-specific death. GR A* B 36 Muscle-invasive and Metastatic Bladder Cancer

39 Pre-operative radiotherapy is not recommended in case of subsequent cystectomy with urinary diversion. Lymph node dissection should be an integral part of cystectomy, but the extent of the dissection has not been established. The urethra can be preserved if margins are negative. If no bladder substitution is attached, the urethra must be checked regularly. Laparoscopic and robot-assisted laparoscopic cystectomy are both options. However, current data have not sufficiently proven the advantages or disadvantages for both oncological and functional outcomes of laparoscopic and robotic-assisted laparoscopic cystectomy. Before cystectomy, the patient should be fully informed about the benefits and potential risks of all possible alternatives, and the final decision should be based on a balanced discussion between patient and surgeon. Pre-operative bowel preparation is not mandatory, fast track measurements may reduce the time of bowel recovery. An orthotopic bladder substitute should be offered to male and female patients lacking any contraindications and who have no tumour in the urethra and at the level of urethral dissection. A B B C B C B *Upgraded following panel consensus Neoadjuvant chemotherapy Neoadjuvant cisplatin-containing combination chemotherapy improves overall survival, irrespective of the type of defini- Muscle-invasive and Metastatic Bladder Cancer 37

40 tive treatment (LE: 1a). It has its limitations regarding patient selection, current development of surgical technique, and current chemotherapy combinations. Recommendations Neoadjuvant chemotherapy should always be cisplatinum based. Neoadjuvant chemotherapy is not recommended in patients with PS > 2 and/or impaired renal function. GR A B Neoadjuvant/adjuvant radiotherapy in muscle-invasive bladder cancer Conclusions LE No data exist to support that pre-operative radiotherapy for operable muscle-invasive bladder cancer 2 increases survival Pre-operative radiotherapy for operable muscleinvasive bladder cancer, using a dose of Gy in 2 fractions of Gy results in down-staging after 4-6 weeks. Pre-operative radiotherapy with a dose of Gy in 3 fractions of Gy does not significantly increase toxicity after surgery. There are suggestions in older literature that preoperative radiotherapy decreases local recurrence of 3 muscle-invasive bladder cancer. 38 Muscle-invasive and Metastatic Bladder Cancer

41 Figure 1: Flowchart for the management for T2-T4a N0M0 urothelial bladder cancer Diagnosis Cystoscopy and tumour resection Evaluation of urethra CT imaging of abdomen, chest, UUT MR can be used for local staging 1 - males: biopsy apical prostatic urethra or frozen section during surgery 1 - females: biopsy of proximal urethra or frozen section during surgery Findings: pt2-3, clinical N0M0 urothelial carcinoma of the bladder pt2n0m0 selected patients - Multimodality bladder sparing therapy can be considered for T2 tumours (Note: alternative, not the standard option) Neoadjuvant chemotherapy Should be considered in selected patients 5-7% 5 year survival benefit 2 - neoadjuvant radiotherapy is not recommended Radical cystectomy Know general aspects of surgery o Preparation o Surgical technique o Integrated node dissection o Urinary diversion o Timing of surgery A higher case load improves outcome Direct adjuvant chemotherapy Not indicated after cystectomy Bladder-sparing treatments for localised disease Transurethral resection of bladder tumour (TURB) TURB alone is only possible as a therapeutic option if tumour growth is limited to the superficial muscle layer and if re-staging biopsies are negative for residual tumour. Muscle-invasive and Metastatic Bladder Cancer 39

42 External beam radiotherapy External beam radiotherapy alone should only be considered as a therapeutic option when the patient is unfit for cystectomy or a multimodality bladder-preserving approach. Radiotherapy can also be used to stop bleeding from the tumour when local control cannot be achieved by transurethral manipulation because of extensive local tumour growth (LE: 3). Surgically non-curable tumours Palliative cystectomy for metastatic disease Primary radical cystectomy in T4b bladder cancer is not a curative option. If there are symptoms, radical cystectomy may be a therapeutic/palliative option. Intestinal or nonintestinal forms of urinary diversion can be used, with or without, palliative cystectomy. Recommendations LE GR In patients with inoperable locally advanced B tumours (T4b), primary radical cystectomy is a palliative option and cannot be offered as curative treatment. In patients with symptoms palliative cystectomy may be offered. Prior to any further interventions, surgeryrelated morbidity and quality-of-life should be fully discussed with the patient. 3 B Chemotherapy and best supportive care Urothelial carcinoma is a chemo-sensitive tumour. With cisplatin-based chemotherapy as primary therapy for locally advanced tumours in highly selected patients, complete and 40 Muscle-invasive and Metastatic Bladder Cancer

43 partial local responses have been reported. (LE: 2b). Recommendation Chemotherapy alone is not recommended as primary therapy for localised bladder cancer. GR A Adjuvant Chemotherapy Adjuvant chemotherapy is under debate. Neither randomised trials nor a meta-analysis have provided sufficient data to support the routine use of adjuvant chemotherapy (LE: 1a). Recommendation Adjuvant chemotherapy is advised within clinical trials, but not as a routine therapeutic option. GR A Multimodality treatment Conclusions In a highly selected patient population, long-term survival rates of multimodality treatment are comparable to those of early cystectomy. Delay in surgical therapy can compromise survival rates. LE 3 2b Muscle-invasive and Metastatic Bladder Cancer 41

44 Recommendations GR Transurethral resection of bladder tumour (TURB) B alone cannot be offered as a standard curative treatment option in most patients. Radiotherapy alone is less effective than surgery and B is only recommended as a therapeutic option when the patient is unfit for cystectomy or a multimodality bladder-preserving approach. Chemotherapy alone is not recommended as primary A therapy for muscle-invasive bladder cancer. Surgical intervention or multimodality treatment are B the preferred curative therapeutic approaches since they are more effective than radiotherapy alone. Multimodality treatment could be offered as an alternative in selected, well-informed, well selected and B compliant patients, especially for whom cystectomy is not an option. Metastatic disease Conclusions for metastatic disease LE Performance status and the presence or absence of 3 visceral metastases are independent prognostic factors for survival. These factors are at least as important as the type of chemotherapy administered. Cisplatin-containing combination chemotherapy is 1b able to achieve a median survival of up to 14 months, with long-term disease-free survival reported in about 15% of patients with nodal disease and good performance status. 42 Muscle-invasive and Metastatic Bladder Cancer

45 Single-agent chemotherapy provides low response rates of usually short duration. Carboplatin-combination chemotherapy is less effective than cisplatin-based chemotherapy in terms of complete response and survival. Non-platinum combination chemotherapy has produced substantial responses in first- and secondline use, but has not been tested against standard chemotherapy in fit patients or in a purely unfit patient group. To date, there is no defined standard chemotherapy for unfit patients with advanced or metastatic urothelial cancer. Vinflunine reached the highest level of evidence ever reported for second-line use. Post-chemotherapy surgery after a partial or complete response may contribute to long-term disease-free survival. Zoledronic acid and denusomab have been studied and approved for all cancer types including urothelial cancer, as they have been shown to reduce and delay skeletal-related events in metastatic bone disease. Recommendations for metastatic disease The selection of treatment should be guided by prognostic factors. First-line treatment for fit patients: Use cisplatin-containing combination chemotherapy with GC, MVAC, preferably with GCSF, or HD-MVAC with GCSF. Carboplatin and non-platinum combination chemotherapy are not recommended. 2a 2a 2a 2b 1b 3 1 GR B A B Muscle-invasive and Metastatic Bladder Cancer 43

46 First-line treatment in patients ineligible ( unfit ) for cisplatin: Use carboplatin combination chemotherapy or single C agents. For cisplatin-ineligible patients ( unfit ) with either A PS 2 or impaired renal function, or with 0-1 poor Bajorin prognostic factors, first-line treatment is carboplatin-containing combination chemotherapy, preferably with gemcitabine/carboplatin. Second-line treatment: In patients progressing after platinum-based combination chemotherapy for metastatic disease, vin- A* flunine should be offered. Alternatively, treatment within a clinical trial setting may be offered. Zoledronic Acid or denosumab, are recommended for B the treatment of bone metastases. *Grade A recommendation is weak by a problem of statistical significance. Recommendation for the use of biomarkers Currently, no biomarkers can be recommended in daily clinical practice since they have no impact on predicting outcome, treatment decisions or monitoring therapy in muscle-invasive bladder cancer. *Upgraded following panel consensus. GR A 44 Muscle-invasive and Metastatic Bladder Cancer

47 Figure 2: Flowchart for the management of metastatic urothelial cancer Patient characteristics: PS 0-1/ 2/ >2 GFR >/< 60ml/min Comorbidities C I S P L A T I N? YES NO NO PS 0-1 and GFR > 60ml/min STANDARD GC MVAC HD MVAC PS 2 or GFR < 60ml/min comb. chemo: Carbo- based PS > 2 and GFR < 60ml/min NO comb.chemo studies, monotherapy, BSC Second-line treatment PS 0-1 PS > 2 1. Progression > 6-12 months after first-line chemotherapy, adequate renal function a. re-exposition to first line treatment (cisplatin based) b. clinical study 2. Progression > 6-12 months after first-line chemotherapy, PS 0-1, impaired renal function a. Vinflunine b. clinical study 3. Progression < 6-12 months after first-line chemotherapy, PS 0-1 a. Vinflunine b. clinical study a. best supportive care b. clinical study Health-related quality-of-life (HRQoL) No randomised, prospective HRQoL study has evaluated the different forms of definitive treatment for muscle-invasive bladder cancer. Important determinants of (subjective) quality of life are a patient s personality, coping style and social support. Muscle-invasive and Metastatic Bladder Cancer 45

48 Recommendations for HRQoL GR The use of validated questionnaires is recommended B to assess HRQoL in patients with muscle-invasive bladder cancer. Unless a patient s co-morbidities, tumour variables C and coping abilities present clear contra-indications, a continent urinary diversion should be offered. Pre-operative patient information, patient selection, surgical techniques, and careful post-operative C follow-up are the cornerstones for achieving good long-term results. Patient should be encouraged to take active part in C the decision-making process. Clear and exhaustive information on all potential benefits and side-effects should be provided, allowing them to make informed decisions. Recommendations for general follow-up Follow-up is based on the stage of initial tumour after cystectomy. At every visit, the following should be performed: history; physical examination; bone scan only when indicated. Tables have been set up (see EAU Guidelines 2012 version), based on expert opinion which, however, do not include non-oncological follow-up. They comprise a minimum set of tests that must be performed during follow-up (GR: C; LE: 4). After 5 years of follow-up, stop oncological surveillance and continue with functional surveillance. 46 Muscle-invasive and Metastatic Bladder Cancer

49 This short booklet text is based on the more comprehensive EAU guidelines (ISBN ), available to all members of the European Association of Urology at their website, Muscle-invasive and Metastatic Bladder Cancer 47