European Association of Urology. Pocket Guidelines edition

Transcription

1 European ssociation of Urology Pocket Guidelines 2015 edition

2 European ssociation of Urology Pocket Guidelines 2015 edition

3 Introduction We are honoured and privileged to introduce you to the short summaries of the 2015 update of the EU Guidelines. The EU Guidelines Office oversees the production of 20 International Guidelines across 20 Guideline Panels. Our Guideline panels have some of the most respected, talented and dedicated urologists from across the breadth of Europe and beyond that work on a voluntary basis for the Guidelines Office. In mapping out the future of the EU Guidelines over the next 5 years, our readership will witness increasing standardisation of the structure of the guidelines, high quality systematic reviews underpinning key recommendations, and increasing standardisation in phrasing of actionable recommendations. Strengthening our evidence base that underpin EU Guidelines recommendations and improving the transparency from evidence to recommendations is a critical area the EU Guidelines Office must continue to be vigilant about. More meaningful involvement of patients in the development of the EU guidelines is another area that the EU is investing in. The EU Guidelines Office is embracing New Media tools (Facebook and Twitter - #eauguidelines) as a means to enhance not only the dissemination of the EU guidelines but also to promote discussion and feedback from our users. We are counting on your active engagement in helping us with this endeavor. The yearly publication of the EU Guidelines would not be possible without the trust and support of each and every user Introduction 1

4 of the Guidelines globally, our EU membership, our valued Guideline panels, the young Guideline ssociates, the EU Executive Committee & Management team, our EU National Societies, and importantly, the Guidelines Office staff (especially Karin Plass, Esther Robijn and Eva Lowther). So, on behalf of the EU Guidelines Office Board, thank you for your support and inspiration. We hope you enjoy using the 2015 update of the EU Guidelines! Prof.Dr. James N Dow Chairman EU Guidelines Office EU Guidelines Office Board members Prof.Dr. J. Irani (Vice-chair) Prof.Dr. T. Knoll Prof.Dr. C. Llorente Prof.Dr. T. Loch Prof.Dr. M. De Santis Prof.Dr. R. Sylvester Prof.Dr. H. Van Poppel (ex-officio) 2 Introduction

5 The EU Guidelines Office 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 CEMB (1). It should be noted, however, that when recommendations are graded, the link between the level of evidence (LE) and grade of recommendation (GR) is not directly linear. vailability of RCTs may not necessarily translate into a grade recommendation where there are methodological limitations or disparity in published results. lternatively, absence of high level evidence does not necessarily preclude a grade recommendation, if there is overwhelming clinical experience and consensus. In addition, there may be exceptional situations where corroborating studies cannot be performed, perhaps for ethical or other reasons and in this case unequivocal recommendations are Introduction 3

6 considered helpful for the reader. Whenever this occurs, it has been clearly indicated in the text with an asterix, as upgraded following 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. Table 2: Grade of recommendation* Grade Nature of recommendations 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 CEMB (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 [ccess date February 2013] 2. tkins D, Best D, Briss P, et al; GRDE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004 Jun 19;328(7454): Guyatt GH, Oxman D, Vist GE et al. GRDE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650): Guyatt GH, Oxman D, Kunz R et al; GRDE Working Group. Going from evidence to recommendations. BMJ 2008 May 10;336(7652): Introduction

7 Page 7 Page 24 Page 32 Page 47 Page 74 Page 96 Page 110 Page 130 Page 145 Page 161 Page 172 Page 182 Page 198 Page 210 Page 237 Page 258 Page 271 Page 289 Page 315 Page 347 Non-muscle Invasive Bladder Cancer Urothelial Carcinomas Of The Upper Urinary Tract Muscle-invasive and Metastatic Bladder Cancer Prostate Cancer Renal Cell Carcinoma Penile Cancer Testicular Cancer Non-neurogenic Male LUTS, incl. benign prostatic obstruction (BPO) Male Sexual Dysfunction: Erectile Dysfunction and Premature Ejaculation Priapism Penile Curvature Male Infertility Male Hypogonadism Urinary Incontinence Urological Infections Neuro-Urology Urological Trauma Chronic Pelvic Pain Urolithiasis Paediatric Urology 5

8 GUIDELINES ON NON-MUSCLE INVSIVE (Ta, T1, CIS) BLDDER CNCER (Limited text update March 2015) M. Babjuk (Chair),. Böhle, M. Burger, E. Compérat, E. Kaasinen, J. Palou, B.W.G. van Rhijn, M. Rouprêt, S. Shariat, R. Sylvester, R. Zigeuner Eur Urol 2011 pr;59(4): Eur Urol 2013 Oct;64(4): Introduction The EU Working Group has published guidelines on nonmuscle-invasive bladder cancer (NMIBC). It comprises Ta and T1 tumours as well as carcinoma in situ (CIS). Staging and classification systems The TNM Classification of Malignant Tumours, 7th Edition, 2009 will apply (Table 1). Non-muscle invasive (Ta, T1, CIS) Bladder Cancer 7

9 Table 1: TNM Classification 2009 T - Primary Tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Carcinoma in situ: flat tumour T1 Tumour invades subepithelial connective tissue T2 Tumour invades muscle T2a Tumour invades superficial muscle (inner half) T2b Tumour invades deep muscle (outer half) T3 Tumour invades perivesical tissue: T3a Microscopically T3b Macroscopically (extravesical mass) T4 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 MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis 8 Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

10 Carcinoma in situ classification CIS is classified into the following clinical types: Primary: isolated CIS with no previous or concurrent papillary tumours and no previous CIS; Secondary: CIS detected during follow-up of patients with a previous tumour that was not CIS; Concurrent: CIS in the presence of any other urothelial tumour in the bladder. Currently, two grading systems for NMIBC are available, WHO 1973 and WHO 2004 (Table 2). The prognostic value of both WHO 1973 and 2004 grading systems has been confirmed. The WHO 2004 system has not yet been fully incorporated into prognostic models. Most clinical trials published to date on Ta, T1 bladder tumours have been performed using the 1973 WHO classification, and the following guidelines are therefore based on this version. Non-muscle invasive (Ta, T1, CIS) Bladder Cancer 9

11 Table 2: WHO grading in 1973 and in WHO grading Urothelial papilloma Grade 1: well differentiated Grade 2: moderately differentiated Grade 3: poorly differentiated 2004 WHO grading system Papillary lesions: Urothelial papilloma (completely benign lesion) Papillary urothelial neoplasm of low malignant potential (PUNLMP) Low-grade (LG) papillary urothelial carcinoma High-grade (HG) papillary urothelial carcinoma Flat lesions: Hyperplasia (flat lesion without atypia or papillary aspects) Reactive atypia (flat lesion with atypia) typia of unknown significance Urothelial dysplasia Urothelial CIS is always high-grade Diagnosis comprehensive patient history is mandatory. Haematuria is the most common finding. Physical examination will not reveal NMIBC. 10 Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

12 Guidelines for primary assessment of NMIBC GR Patient history should be taken. Renal and bladder US may be used during the initial C work-up in patients with haematuria. t the time of the initial diagnosis of NMIBC, CT urography (or IVU) should be performed only in selected B cases (e.g., tumours located in the trigone, multiple- or high-risk tumours). Cystoscopy is recommended in all patients with symptoms suggestive of BC. It cannot be replaced by cytology or by any other non-invasive test. Cystoscopy should describe all macroscopic features C of the tumour (site, size, number and appearance) and mucosal abnormalities. bladder diagram is recommended. Voided urine cytology is advocated to predict HG C tumour before TURB. Cytology should be performed on fresh urine with C adequate fixation. Morning urine is not suitable because of the frequent presence of cytolysis. BC = bladder cancer; CT = computed tomography; GR = grade of recommendation; HG = high-grade; IVU = intravenous urography; US = ultrasound; NMIBC = non-muscle invasive bladder cancer; TURB = transurethral resection of the bladder. Papillary (Ta, T1) tumours The diagnosis of papillary BC ultimately depends on cystoscopic examination of the bladder and histological evaluation of the resected tissue. Transurethral resection (TURB) of Ta, T1 tumours TURB is a crucial procedure in the diagnosis and treatment of BC. It should be performed systematically in individual steps Non-muscle invasive (Ta, T1, CIS) Bladder Cancer 11

13 (see recommendations below). The strategy of resection depends on the size of the lesion. In selected cases, due to the risk of tumour persistence and understaging after initial TURB, a second resection (2nd TURB) is recommended. Carcinoma in situ CIS is diagnosed by a combination of cystoscopy, urine cytology, and histological evaluation of multiple bladder biopsies. Carcinoma in situ cannot be eradicated by TURB and further treatment is mandatory. Guidelines for TURB and/or biopsies, tumour classification and pathology report TURB should be performed systematically in individual steps: bimanual palpation under anaesthesia; insertion of the resectoscope, under visual control with inspection of the whole urethra; inspection of the whole urothelial lining of the bladder; biopsy from prostatic urethra (if indicated); cold-cup bladder biopsies (if indicated); resection of the tumour; protocol formulation; surgical report formulation precise description of the specimen for pathological evaluation. Individual steps: Perform resection in one piece for small papillary tumours (< 1 cm), including part from the underlying bladder wall. GR C B 12 Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

14 Perform resection in fractions including the exophytic B part of the tumour, the underlying bladder wall with the detrusor muscle, and the edges of the resection area for tumours > 1 cm in diameter. void cauterization as much as possible during TURB C to avoid tissue deterioration. Take biopsies from abnormal-looking urothelium. C Biopsies from normal-looking mucosa (trigone, bladder dome, and right, left, anterior and posterior bladder walls) are recommended only when cytology is positive or when high-risk exophytic tumour is expected (non-papillary appearance). Take biopsy of the prostatic urethra in cases of bladder C 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. Take the biopsy from abnormal areas in the prostatic C urethra and from the precollicular area (between 5 and 7 o clock position) using a resection loop. In primary non-muscle-invasive tumours when stromal invasion is not suspected, the cold-cup biopsy with forceps can be used. If equipment is available, use fluorescence-guided B (PDD) biopsy instead of random biopsies when bladder CIS or HG tumour is suspected (e.g., positive cytology, recurrent tumour with previous history of a HG lesion). Refer the specimens from different biopsies and resection fractions to the pathologist in separate containers C and label them separately. Non-muscle invasive (Ta, T1, CIS) Bladder Cancer 13

15 TURB protocol must describe tumour appearance, all steps of the procedure, as well as the extent and completeness of resection. In patients with positive cytology, but negative cystoscopy, exclude a UTUC, CIS in the bladder (random biopsies or PDD targeted biopsies) and tumour in the prostatic urethra (prostatic urethra biopsy). Perform a second TURB in the following situations: after incomplete initial TURB; if there is no muscle in the specimen after initial resection, with the exception of Ta G1 tumours and primary CIS; in all T1 tumours; in all G3 tumours, except primary CIS. If indicated, perform a second TURB within 2-6 weeks after initial resection. It should include resection of the primary tumour site. Classification and pathological report For classification of the depth of tumour invasion (staging) use the 2009 TNM system. For histological classification, use both the 1973 and 2004 WHO grading. Do not use the term Superficial BC. Whenever using the terminology NMIBC in individual cases, mention the tumour stage and grade. The pathological report should specify tumour location, tumour grade, depth of tumour invasion, presence of CIS, and whether the detrusor muscle is present in the specimen. The pathological report should specify the presence of LVI or unusual (variant) histology. C C C C 14 Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

16 In difficult cases, consider an additional review by an B experienced genitourinary pathologist. BC = bladder cancer; CIS = carcinoma in situ; CT = computed tomography; LVI = lymphovascular invasion; PDD = photodynamic diagnosis; TNM = Tumour, Node, Metastasis; TURB = transurethral resection of the bladder; WHO = World Health Organisation. Predicting disease recurrence and progression fter TURB, patients should be stratified, according to prognostic factors, into risk groups which will facilitate treatment recommendations. Their definition, which takes into account the EORTC risk tables probabilities of recurrence and especially progression, can be found in Table 3. For individual prediction of the risk of tumour recurrence and progression at different intervals after TURB, application of EORTC risk tables and calculator ( is strongly recommended. For BCG-treated patients, a scoring model was created by the Club Urológico Español de Tratamiento Oncológico (CUETO). The CUETO risk calculator is available at: Non-muscle invasive (Ta, T1, CIS) Bladder Cancer 15

17 Table 3: Treatment recommendations in Ta, T1 tumours and CIS according to risk stratification Low-risk tumours Risk category Definition Treatment recommendation Intermediaterisk tumours High-risk tumours Primary, solitary, Ta, LG/G1,< 3 cm, no CIS ll cases between categories of low and high risk ny of the following: T1 tumours; HG/G3 tumours; CIS; Multiple and recurrent and large (> 3 cm) Ta G1G2 tumours (all these conditions must be presented). One immediate instillation of chemotherapy. One immediate instillation of chemotherapy followed by further instillations, either chemotherapy for a maximum of 1 year or 1-year fulldose BCG. Intravesical fulldose BCG instillations for 1-3 years or cystectomy (in highest-risk tumours). 16 Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

18 Subgroup of highest-risk tumours T1G3 associated with concurrent bladder CIS, multiple and/or larget1g3 and/or recurrent T1G3, T1G3 with CIS in prostatic urethra, unusual histology of urothelial carcinoma, LVI. BCG failures Radical cystectomy (RC) should be considered. In those who refuse RC, intravesical full-dose BCG instillations for 1-3 years. Radical cystectomy is recommended. BCG = bacillus Calmette-Guérin; CIS = carcinoma in situ; HG = high-grade: LG = low-grade; LVI = lymphovascular invasion. Recommendations for stratification of NMIBC GR Stratify patients into three risk groups. B pply the EORTC risk tables and calculator for individual prediction of the risk of tumour recurrence and B progression in different intervals after TURB. In patients treated with BCG, use the CUETO risk B tables for individual prediction of the risk of tumour recurrence and progression. BCG = Bacillus Calmette-Guérin; CUETO = Club Urológico Español de Tratamiento Oncológico; GR = grade of recommendation; EORTC = European Organization for Research and Treatment of Cancer; TURB = transurethral resection of the bladder. Disease management djuvant treatment Since there is considerable risk for recurrence and/or progres- Non-muscle invasive (Ta, T1, CIS) Bladder Cancer 17

19 sion of tumours after TURB, adjuvant intravesical therapy is recommended for all stages (Ta, T1, and CIS). Immediate single post-operative instillation of chemotherapy within 6 hours after TURB is recommended in tumours presumed to be at low or intermediate risk, except in cases of bladder perforation or severe bleeding. The choice of drug (mitomycin C, epirubicin, or doxorubicin) is optional. Further chemotherapy instillations can improve RFS in intermediate-risk tumours, but do not prevent progression. These instillations are 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. The individual choice of further intravesical adjuvant therapy depends on the patient s risk (Table 3). In patients at highest risk of progression, radical cystectomy (RC) should be considered. Patients with BCG failure are unlikely to respond to further BCG therapy; RC is therefore the preferred option. Recommendations for adjuvant therapy in Ta, T1 tumours and for therapy of CIS Smokers with confirmed NMIBC should be counseled to stop smoking. The type of intravesical therapy should be based on risk groups. In patients with tumours presumed to be at low- or intermediate risk, one immediate chemotherapy instillation is recommended. GR B 18 Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

20 In patients with low-risk tumours, one immediate instillation of chemotherapy is recommended as the complete adjuvant treatment. In patients with intermediate-risk tumours, one immediate instillation of chemotherapy should be followed by 1-year full-dose BCG treatment, or by further instillation of chemotherapy for a maximum of 1 year. The final choice should reflect the individual patient s risk of recurrence and progression as well as the efficacy and side effects of each treatment modality. In patients with high-risk tumours, full-dose intravesical BCG for 1-3 years is indicated. The additional beneficial effect of the second and third years of maintenance should be weighed against its added costs and inconvenience. In patients with CIS in the epithelial lining of the prostatic urethra, TUR of the prostate followed by intravesical instillation of BCG can be offered. In patients at highest risk of tumour progression, immediate radical cystectomy should be considered. In patients with BCG failure, radical cystectomy is indicated. Intravesical chemotherapy One immediate instillation should be administered within 24 hours after TURB. One immediate instillation of chemotherapy should be omitted in any case of overt or suspected intra- or extra-peritoneal perforation (after extensive TURB, or bleeding requiring bladder irrigation). Give clear instructions to the nursing staff to control the free flow of the bladder catheter at the end of the immediate instillation. C C B C C C Non-muscle invasive (Ta, T1, CIS) Bladder Cancer 19

21 The optimal schedule of further intravesical chemotherapy instillation and its duration is not defined, but C it should not exceed 1 year. If intravesical chemotherapy is given, it is advised to B use the drug at its optimal ph and to maintain the concentration of the drug by reducing fluid intake before and during instillation. The length of an individual instillation should be 1-2 C hours. BCG intravesical immunotherapy bsolute contraindications of BCG intravesical C instillation are: during the first 2 weeks after TURB; in patients with visible haematuria; after traumatic catheterisation; in patients with symptomatic urinary tract infection. The management of side effects after BCG intravesical C instillation should reflect their type and grade. BCG = bacillus Calmette-Guérin; CIS = carcinoma in situ; GR = grade of recommendation; MMC = mitomycin C; TUR = transurethral resection; TURB = transurethral resection of the bladder. Follow-up s a result of the risk of recurrence and progression, patients with NMIBC need to be followed up. However, the frequency and duration of cystoscopy and imaging should reflect the individual patient s degree of risk. When planning the follow-up schedule and methods, the following aspects should be considered: The prompt detection of muscle-invasive and HG/G3 nonmuscle-invasive recurrence is crucial because a delay in 20 Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

22 diagnosis and therapy can be life-threatening. Tumour recurrence in the low-risk group is nearly always low stage and LG/G1. Papillary recurrence does not present an immediate danger to the patient and early detection is not essential for successful therapy. Fulguration of small papillary recurrences on an outpatient basis could be a safe option that reduces the therapeutic burden. The first cystoscopy after TURB at 3 months is a very important prognostic indicator for recurrence and progression. Therefore, the first cystoscopy should always be performed 3 months after TURB in all patients with Ta, T1 tumours and CIS. In tumours at low risk, the risk of recurrence after 5 recurrence-free years is low. Discontinuation of cystoscopy or its replacement with lessinvasive methods can be considered. In tumours originally intermediate- or high-risk, recurrences after 10 years tumour-free are not unusual. Therefore, life-long follow-up is recommended. The follow-up strategy must reflect the risk of extravesical recurrence (prostatic urethra in men and UUT). The risk of UUT recurrence increases in patients with multiple and high-risk tumours. Positive urine test results have a positive impact on the quality of performed follow-up cystoscopy). It supports the adjunctive role of urine tests during follow-up. The following recommendations are based on retrospective experience only. Non-muscle invasive (Ta, T1, CIS) Bladder Cancer 21

23 Recommendations for follow-up GR The follow-up of Ta, T1 tumours and CIS is based on regular cystoscopy. Patients with low-risk Ta tumours should undergo C cystoscopy at 3 months. If negative, subsequent cystoscopy is advised 9 months later, and then yearly for 5 years. Patients with high-risk tumours should undergo C cystoscopy and urinary cytology at 3 months. If negative, subsequent cystoscopy and cytology should be repeated every 3 months for a period of 2 years, and every 6 months thereafter until 5 years, and then yearly. Patients with intermediate-risk Ta tumours should C have an in-between follow-up scheme using cystoscopy and cytology, which is adapted according to personal and subjective factors. Regular (yearly) upper tract imaging (CT-IVU or IVU) is C recommended for high-risk tumours. Endoscopy under anaesthesia and bladder biopsies B should be performed when office cystoscopy shows suspicious findings or if urinary cytology is positive. Consider R-biopsies or biopsies with PDD after C intravesical treatment (at 3 or 6 months) in patients with CIS. During follow-up in patients with positive cytology and B no visible tumour in the bladder, R-biopsies or biopsies with PDD (if equipment is available) and investigation of extravesical locations (CT urography, prostatic urethra biopsy) are recommended. CIS = carcinoma in situ; CT-IVU = computed tomography intravenous urography; GR = grade of recommendation; IVU = intravenous urography; PDD = photodynamic diagnosis; R-biopsies = random biopsies. 22 Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

24 This short booklet text is based on the more comprehensive EU Guidelines (ISBN ), available to all members of the European ssociation of Urology at their website: Non-muscle invasive (Ta, T1, CIS) Bladder Cancer 23

25 GUIDELINES ON UROTHELIL CRCINOMS OF THE UPPER URINRY TRCT (UTUCs) (Limited text update March 2015) M. Rouprêt, M. Babjuk, E. Compérat, R. Zigeuner, R. Sylvester, M. Burger,. Böhle, B.W.G. Van Rhijn, E. Kaasinen, J. Palou, S.F. Shariat Eur Urol 2011 pr;59(4): Eur Urol 2013 Jun;63(6): Epidemiology UTUCs are uncommon and account for only 5-10% of urothelial cell carcinomas. They have a similar morphology to bladder carcinomas and nearly all UTUCs are urothelial in origin. Staging and grading systems The UICC 2009 TNM (Tumour, Node, Metastasis Classification) for renal pelvis and ureter is used for staging (Table 1). Tumour grade There are currently two main classifications used for UTUCs; the 1973 WHO classification, which classifies tumours into three grades, G1, G2 and G3, and the 2004 WHO classification, which classifies tumours into three groups: Papillary urothelial neoplasia of low malignant potential; Low-grade carcinomas; High-grade carcinomas. Upper urinary tract tumours with low malignant potential are very rare. 24 Urothelial Carcinomas Of The Upper Urinary Tract

26 Table 1: TNM Classification 2009 T - Primary Tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Carcinoma in situ T1 Tumour invades subepithelial connective tissue T2 Tumour invades muscularis T3 (Renal pelvis) Tumour invades beyond muscularis into peripelvic fat or renal parenchyma (Ureter) Tumour invades beyond muscularis into periureteric fat T4 Tumour invades adjacent organs or through the kidney into perinephric fat 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 Diagnosis UTUCs are diagnosed using imaging, cystoscopy, urinary cytology and diagnostic ureteroscopy. The benefits of Urothelial Carcinomas Of The Upper Urinary Tract 25

27 ureteroscopy for pre-operative assessment should also be discussed with the patient. Recommendations for the diagnosis of UTUCs Urinary cytology should be performed as part of a standard diagnostic work-up. cystoscopy should be done to rule out concomitant bladder tumour. CTU must be part of the diagnostic work-up. Diagnostic ureteroscopy and biopsy should be performed, certainly in cases where additional information will impact treatment decisions. Retrograde ureteropyelography is an optional tool for the detection of UTUC. CTU = Computed tomography urography; GR = grade of recommendation. GR C C Prognosis UTUCs invading the muscle wall usually have a very poor prognosis. Recognised prognostic facts, as listed in Figure Urothelial Carcinomas Of The Upper Urinary Tract

28 Figure 1: UTUCs - Prognostic factors UTUC Prognostic factors Pre-operative Major impact on survival Post-operative size > 3 cm multifocality grade (biopsy, cytology) advanced age tobacco consumption distal ureter management ECOG- PS > 1 co-morbidity (S score) systemic revealing symptoms hydronephrosis delay surgery > 3 months tumour location fro-merican race BMI > 30 gender stage grade carcinoma in situ bladder cuff excision lymphovascular invasion lymph node involvement tumour architecture positive surgical margins temour necrosis molecular marker histological variant Minor impact on survival S = merican Society of nesthesiologists; BMI = body mass index: ECOG = Eastern Cooperative Oncology Group. Risk stratification It is necessary to risk-stratify UTUC cases before treatment to identify those patients (and tumours) who are more suitable for kidney-sparing management rather than radical extirpative surgery. Urothelial Carcinomas Of The Upper Urinary Tract 27

29 Figure 2: UTUCs - Risk stratification UTUC Low-risk UTUC* High-risk UTUC** - Unifocal disease - Tumour size < 1 cm - Low-grade cytology - Low-grade URS biopsy - No invasive aspect on MDCT-urography - Hydronephrosis - Tumour size > 1 cm - High-grade cytology - High-grade URS biopsy - Multifocal disease - Previous radical cystectomy for bladder cancer * ll of these factors need to be present ** ny of these factors need to be present MDCT = multidetector-row computed tomography; URS = ureterorenoscopy. Disease management Localised disease Kidney-sparing surgery (low-risk UTUCs) Conservative management of low-risk UTUCs consists of surgery preserving the upper urinary renal unit. It is used in imperative cases (renal insufficiency, solitary functional kidney). It can also be discussed in low-risk patients in case of a functional contralateral kidney. Kidney-sparing surgery in low-risk UTUCs potentially allows avoiding the morbidity associated with open radical surgery without compromising oncological outcomes and kidney function. 28 Urothelial Carcinomas Of The Upper Urinary Tract

30 Recommendations for the kidney-sparing management of low-risk UTUCs Indications GR Unifocal tumour. B Small tumour (size < 1 cm). B Low-grade tumour (cytology or biopsies). B No evidence of an infiltrative lesion on CTU. B Understanding of close follow-up. B Techniques used according to location Laser should be used for endoscopic treatment. C Flexible is preferable to rigid ureteroscopy; renal pelvic, distal-, mid- and proximal ureter. C Percutaneous approach is an option for low-grade C tumours not accessible by ureteroscopic approach. Surgical open approach Renal pelvis or calyces: C Partial pyelectomy or partial nephrectomy is seldom indicated. Ureter-Mid & proximal: C Ureteroureterostomy is indicated for tumours that cannot be removed completely endoscopically. Distal: C Complete distal ureterectomy and neocystostomy are indicated for tumours in the distal ureter that cannot be removed completely endoscopically. CTU = computed tomography urography; GR = grade of recommendation. The instillation of Bacillus Calmette-Guérin or mitomycin C in the urinary tract by percutaneous nephrostomy or via a ureteric stent is technically feasible after conservative treatment of UTUCs. However, the benefits have not been confirmed. Urothelial Carcinomas Of The Upper Urinary Tract 29

31 dvanced disease RNU has no benefit in metastatic (M+) disease, but may be used in palliative care. s UTUCs are urothelial tumours, platinum-based chemotherapy should give similar results to those in bladder cancer. Currently, insufficient data are available to provide any recommendations. Radiotherapy is scarcely relevant nowadays, both as a unique therapy and associated with chemotherapy as a tumour adjuvant. Follow-up after initial treatment In all cases, there should be strict follow-up after radical management to detect metachronous bladder tumours, as well as invasive tumours, local recurrence and distant metastases. In conservative management, the ipsilateral upper urinary tract requires careful follow-up due to the high risk of recurrence. Recommendation for follow-up of UTUC after initial treatment fter radical management, over at least 5 years Non-invasive tumour Cystoscopy/urinary cytology at 3 months and then yearly. CT every year. Invasive tumour Cystoscopy/urinary cytology at 3 months and then yearly. CTU every 6 months for 2 years and then yearly. fter conservative management, over at least 5 years Urinary cytology and CTU at 3 months, 6 months and then yearly. GR C C C C C 30 Urothelial Carcinomas Of The Upper Urinary Tract

32 Cystoscopy, ureteroscopy and cytology in situ at 3 months, 6 months, every 6 months for 2 years and then yearly. CTU = computed tomography urography; GR = grade of recommendation. C Figure 3: Proposed flowchart for the management of UTUC UTUC Diagnostic evaluation: CTU, urinary cytology, cystoscopy +/- Flexible ureteroscopy with biopsies Low-risk UTUC High-risk UTUC* RNU Kidney-sparing surgery: flexible ureteroscopy or segmental resection or percutaneous approach Open Laparoscopic Recurrence Close and stringent follow-up * in patients with solitary kidney consider more conservative approach Single postoperative dose of intravesical chemotherapy CTU = computed tomography urography; RNU = nephroureterectomy. This short booklet text is based on the more comprehensive EU Guidelines (ISBN: ), available to all members of the European ssociation of Urology at their website: Urothelial Carcinomas Of The Upper Urinary Tract 31

33 MUSCLE-INVSIVE ND METSTTIC BLDDER CNCER (Text update March 2015) J.. Witjes (Chair), E. Compérat, N.C. Cowan, M. De Santis, G. Gakis, N. James, T. Lebret,. Sherif,.G. van der Heijden, M.J. Ribal Guidelines ssociates: M. Bruins, V. Hernandez, E. Veskimäe Eur Urol 2011 Jun;59(6): Eur Urol 2014 Mar;65(3): Introduction Optimal treatment strategies for Muscle-invasive Bladder Cancer (MIBC) require the involvement of a specialist multidisciplinary team and a model of integrated treatment strategies to avoid fragmentation of patient care. Staging and grading systems The UICC 2009 TNM (Tumour, Node, Metastasis Classification) is used for staging. For grading, the 1973 and 2004 WHO grading classifications are used. 32 Muscle-invasive and Metastatic Bladder Cancer

34 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 stroma, seminal vesicles, ureterus, vagina, pelvic wall, abdominal wall T4a Tumour invades prostate stroma, seminal vesicles, uterus or vagina T4b Tumour invades pelvic wall or abdominal wall N - Lymph nodes NX N0 N1 N2 N3 M - Distant metastasis M0 M1 Regional lymph nodes cannot be assessed No regional lymph-node metastasis Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac or presacral) Metastasis in multiple lymph nodes in the true pelvis (hypogastric, obturator, external iliac or presacral) Metastasis in a common iliac lymph node(s) No distant metastasis Distant metastasis Muscle-invasive and Metastatic Bladder Cancer 33

35 Table 2: WHO grading in 1973 and in 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 Flat lesions Hyperplasia (flat lesion without atypia or papillary aspects) Reactive atypia (flat lesion with atypia) typia of unknown significance Urothelial dysplasia Urothelial CIS (always high-grade [HG]) Papillary lesions Urothelial papilloma (completely benign lesion) Papillary urothelial neoplasm of low malignant potential (PUNLMP) Low-grade papillary urothelial carcinoma High-grade papillary urothelial carcinoma Pathology of MIBC Determination of morphological subtypes can be helpful in assessing the prognosis and treatment options of high-grade urothelial carcinomas (grade II or grade III) as discussed in these guidelines. 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; 34 Muscle-invasive and Metastatic Bladder Cancer

36 4. Nested carcinoma; 5. Some urothelial carcinomas with trophoblastic differentiation; 6. Small-cell carcinomas; 7. Spindle cell carcinomas. Mandatory evaluations Depth of invasion (categories pt2 vs pt3a, pt3b or pt4). Margins with special attention paid to the radial margin, prostate, ureter, urethra and peritoneal fat and uterus and vaginal top. Histological subtype, if it has clinical implications. Extensive lymph node representation (more than nine). Optional evaluations Bladder wall blood vessel invasion. Pattern of muscle invasion. Specific recommendations for the primary assessment of presumably invasive bladder tumours* Cystoscopy should describe all macroscopic features of the tumour (site, size, number and appearance) and mucosal abnormalities. 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. GR C C Muscle-invasive and Metastatic Bladder Cancer 35

37 In women undergoing a subsequent orthotopic neobladder, procedure information is required (including a C 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 C depth of tumour invasion and whether the lamina propria and muscle tissue are present in the specimen. * For general information on the assessment of bladder tumours, see EU Guidelines on Non-muscle-invasive bladder cancer. 36 Recommendations for staging of MIBC GR In patients with confirmed MIBC, CT of the chest, B abdomen and pelvis is the optimal form of staging, including excretory-phase CT urography for complete examination of the upper urinary tract. Excretory-phase CT urography is preferred to MR C urography for diagnosis of UTUC in terms of greater diagnostic accuracy, less cost, and greater patient acceptability. MR urography is used when CT urography is contraindicated for reasons related to contrast administration or radiation dose. Ureteroscopic-guided biopsy is recommended for C histopathological confirmation of preoperative diagnosis of UTUC. CT or MRI is recommended for staging locally B advanced or metastatic disease in patients in whom radical treatment is being considered. CT and MRI are generally equivalent in diagnosing C local and distant abdominal metastases but CT is preferred for diagnosing pulmonary metastases. CIS = carcinoma in situ; CT = computed tomography; MRI = magnetic resonance imaging; UTUC = upper urinary tract urothelial carcinoma. Muscle-invasive and Metastatic Bladder Cancer

38 Disease management Treatment failure of non-mibc Recommendations for treatment failure of non-mibc In all T1 tumours at high-risk of progression (i.e. high grade, multifocality, carcinoma in situ, and tumour size, as outlined in the EU guidelines for Non-muscle invasive bladder cancer), immediate radical treatment is an option. In all T1 patients failing intravesical therapy, radical treatment should be offered. GR C B Neoadjuvant chemotherapy (NC) Neoadjuvant cisplatin-containing combination chemotherapy improves OS (5-8% at 5 years), irrespective of the type of definitive treatment used. Currently, no tools are available to select patients who have a higher probability of benefitting from neoadjuvant chemotherapy (NC). However, NC has its limitations regarding patient selection, current development of surgical techniques, and current chemotherapy combinations. Recommendations for neoadjuvant chemotherapy Neoadjuvant chemotherapy is recommended for T2-T4a, cn0m0 bladder cancer and should always be cisplatin-based combination therapy. Neoadjuvant chemotherapy is not recommended in patients who are ineligible for cisplatin-based combination therapy. GR Muscle-invasive and Metastatic Bladder Cancer 37

39 Radical surgery and urinary diversion Conclusions For MIBC, radical cystectomy is the curative treatment of choice. higher case load reduces morbidity and mortality of cystectomy. Radical cystectomy includes removal of regional lymph nodes. There are data to support that an extended LND (vs. standard or limited LND) improves survival after radical cystectomy. Radical cystectomy in both sexes must not include the removal of the entire urethra in all cases, which may then serve as an outlet for an orthotopic bladder substitution. Terminal ileum and colon are the intestinal segments of choice for urinary diversion. The type of urinary diversion does not affect oncological outcome. Laparoscopic- and robotic-assisted laparoscopic cystectomy are feasible but still investigational. Current best practice is open radical cystectomy. In patients aged > 80 years with MIBC, cystectomy is an option. Surgical outcome is influenced by comorbidity, age, previous treatment for bladder cancer or other pelvic diseases, surgeon and hospital volume of cystectomy, and type of urinary diversion. 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. LND = lymph node dissection. LE Muscle-invasive and Metastatic Bladder Cancer

40 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 and urinary diversion Radical cystectomy is recommended in T2-T4a, N0M0, and high-risk non-mibc. Do not delay cystectomy for > 3 months because it increases the risk of progression and cancer-specific mortality. Preoperative radiotherapy is not recommended in case of subsequent cystectomy with urinary diversion. 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 management options. However, current data have not sufficiently proven the advantages or disadvantages for oncological and functional outcomes. 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. GR * B B C B C Muscle-invasive and Metastatic Bladder Cancer 39

41 n 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. *Upgraded following panel consensus. B Fig. 1: Flowchart for the management of T2-T4a N0M0 urothelial bladder cancer Diagnosis Cystoscopy and tumour resection Evaluation of urethra CT imaging of abdomen, chest, UUT MRI can be used for local staging 1 - males: biopsy of apical prostatic urethra or frozen section during surgery 1 - females: biopsy of proximal urethra or frozen section during surgery Findings pt2-4a, 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 higher case load improves outcome Direct adjuvant chemotherapy Not indicated after cystectomy CT = computed tomography; MRI = magnetic resonance imaging; UUT = upper urinary tract. 40 Muscle-invasive and Metastatic Bladder Cancer

42 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 restaging biopsies are negative for residual tumour. External beam radiotherapy (EBRT) EBRT 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 due to extensive local tumour growth. Chemotherapy and best supportive care With cisplatin-based chemotherapy as primary therapy for locally advanced tumours in highly selected patients, complete and partial local responses have been reported. Multimodality treatment 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. Recommendations for bladder-sparing treatments for localised disease Transurethral resection of bladder tumour alone is not a curative treatment option in most patients. Radiotherapy alone is not recommended as primary therapy for localised bladder cancer. Chemotherapy alone is not recommended as primary therapy for MIBC. GR B B Muscle-invasive and Metastatic Bladder Cancer 41

43 Surgical intervention or multimodality treatments are the preferred curative therapeutic approaches as they are more effective than radiotherapy alone. Multimodality treatment could be offered as an alternative in selected, well-informed, well-selected and compliant patients, especially for whom cystectomy is not an option. B B 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 non-intestinal forms of urinary diversion can be used, with or without palliative cystectomy. Recommendations In patients with inoperable locally advanced tumours (T4b), primary radical cystectomy is a palliative option. In patients with symptoms, palliative cystectomy may be offered. GR B djuvant Chemotherapy Recommendation GR djuvant cisplatin-based combination chemotherapy C may be offered to patients with pt3/4 or pn+ disease if no neoadjuvant chemotherapy has been given. 42 Muscle-invasive and Metastatic Bladder Cancer

44 Metastatic disease Conclusions for metastatic disease In a first-line setting, PS and the presence or absence of visceral metastases are independent prognostic factors for survival. In a second-line setting, prognostic factors are: liver metastasis, PS 1 and low haemoglobin (< 10 g/dl). Cisplatin-containing combination chemotherapy can achieve median survival of up to 14 months, with longterm disease-free survival reported in 15% of patients with nodal disease and a good PS. 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 produces substantial responses in first- and second-line settings. Non-platinum combination chemotherapy has not been tested against standard chemotherapy in patients who are fit or unfit for cisplatin combination chemotherapy. 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 partial or complete response may contribute to long-term disease-free survival. LE 1b 1b 1b 2a 2a 2a 4 2b 1b 3 Muscle-invasive and Metastatic Bladder Cancer 43