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I Curso de Tumores da Bexiga
Diagnóstico e factores de prognóstico
Miguel Carvalho
Assistente Hospitalar Graduado de Urologia
Serviço de Urologia – H. Garcia de Orta – Almada
Hotel Júpiter, Lisboa
26 Novembro 2016
BLADDER CANCER: INCIDENCE/MORTALITY 2016
RELEVANT DATA
 76 960 new cases
 16 390 deaths
 4:1 male:female ratio
 89% of US patients ≥ 55 years old
 4th most common cancer in men
 10th most common cancer in women
 Lifetime risk 2.41%
 Cost per patient: most expensive cancer
from diagnosis to death
Siegel , R. et al. CA Cancer J Clin. 2016 Jan-Feb;66(1):7-30.
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BLADDER CANCER: GEOGRAPHIC DISTRIBUTION
RELEVANT DATA
 Urothelial carcinoma is the predominant
histologic type in the United States and
Western Europe, where it accounts for
approximately 90 percent of bladder
cancers.
 In other areas of the world, such as the
Middle East, non-urothelial histologies
are more frequent, due at least in part to
the prevalence of schistosomiasis.
- Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65:87.
- Marcos-Gragera R, Mallone S, Kiemeney LA, et al. Urinary tract cancer survival in Europe 1999-2007: Results of the populationbased study EUROCARE-5. Eur J Cancer 2015.
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BLADDER CANCER: EPIDEMIOLOGY
AGE, SEX AND RACE
 Older individuals, with a median age at diagnosis of 69 years in men
and 71 in women
 The incidence increases with age
 The age of onset is younger in current smokers than in never-smokers
 In children and young adults  low-grade, non-invasive disease
 In the US, white males have the highest risk with roughly twice the
incidence seen in African-American and Hispanic men
 Variations in acetylator phenotypes among different racial/ethnic
groups and occupational differences among minorities that influence
exposure to industrial carcinogens
- Lynch CF, Cohen MB. Urinary system. Cancer 1995; 75:316.
- Scosyrev E, Noyes K, Feng C, Messing E. Sex and racial differences in bladder cancer presentation and mortality in the US. Cancer 2009;
115:68.
- Hinotsu S, Akaza H, Miki T, et al. Bladder cancer develops 6 years earlier in current smokers: analysis of bladder cancer registry data
collected by the cancer registration committee of the Japanese Urological Association. Int J Urol 2009; 16:64.
- Linn JF, Sesterhenn I, Mostofi FK, Schoenberg M. The molecular characteristics of bladder cancer in young patients. J Urol 1998; 159:1493.
- Ryerson AB, Eheman CR, Altekruse SF, et al. Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing
incidence of liver cancer. Cancer 2016; 122:1312.
- Schulz MR, Loomis D. Occupational bladder cancer mortality among racial and ethnic minorities in 21 states. Am J Ind Med 2000; 38:90.
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BLADDER CANCER: RISK FACTORS
RELEVANT DATA
 Tobacco smoking
 50% of all cases
 3-fold risk in incidence
 Occupational exposure
 10% of all cases
 Pelvic RT
 Chronic inflammation (SCC)
 Bladder stone
 Long-term Foley
 Schistosoma haematobium
 Drugs – phenacetin, cyclophosphamide
Pelucchi C, Bosetti C, Negri E, et al. Mechanisms of disease: The epidemiology of bladder
cancer. Nat Clin Pract Urol 2006; 3:327.
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BLADDER CANCER: CLINICAL AND MOLECULAR STAGING
Goebell PJ, Knowles MA. Urol Oncol. 2010 Jul-Aug;28(4):409-28
Knowles MA, Hurst CD.Nat Rev Cancer. 2015 Jan;15(1):25-41
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BLADDER CANCER: CLINICAL AND MOLECULAR STAGING
RELEVANT DATA
 Main karyotypic change
 Cr 9 (> 50% of tumour)
 Cr 13 (retinoblastoma gene loci)
 Cr 17 (p53 loci)
 NMIBC
 Loss of Rb gene expression
 Ha-ras activation
 Over expression of telomerase
 MIBC
 p53 mutation (Cr 17)
 FGF and VEGF over-expression
 Clonal vs. Field change/oligoclonal theory
Knowles MA, Hurst CD.Nat Rev Cancer. 2015 Jan;15(1):25-41
.
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BLADDER CANCER – CLINICAL PRESENTATION
HEMATURIA
Intermittent, gross, painless, and present throughout
micturition; some studies diagnosing bladder cancer in
10 to 20 percent of patients with gross hematuria
PAIN
locally advanced or metastatic
tumors; flank pain  obstrution;
suprapubic, perineal, hypogastric
and presacral pain  locally
advanced disease; bone pain;
headache
LUTS
CLINICAL
PRESENTATION
Storage  1/3 cases
Dysuria, frequency, urgency  CIS ?
Voiding  less common
bladder neck or prostatic urethra
cancer
CONSTITUTIONAL SYMPTOMS
fatigue, weight loss, anorexia  advanced or metastatic BC  poor prognosis.
renal failure caused by bilateral ureteral obstruction  possible but rare
Kolodziej, A. et al. Cent European J Urol. 2016; 69: 150-156
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BLADDER CANCER – CLINICAL PRESENTATION
PHYSICAL EXAMINATION
 Unremarkable in most patients
 Abnormal findings that can be seen
 A solid pelvic mass advanced cases
 Induration of the prostate gland  bladder neck / prostate invasion
 Inguinal adenopathy can be present, although the inguinal region is not a
common site of node metastases
 Nodularity in the periumbilical region  dome of the bladder. This is often
seen with urachal cancers (adenocarcinomas)
 Abdominal examination  enlarged para-aortic lymph nodes or hepatic
metastases.
Khadra MH, et al. A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. J Urol 2000; 163:524.
Mariani AJ, et al. The significance of adult hematuria: 1,000 hematuria evaluations including a risk-benefit and cost-effectiveness analysis. J Urol 1989; 141:350.
Messing EM, et al. Home screening for hematuria: results of a multiclinic study. J Urol 1992; 148:289.
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BLADDER CANCER DIAGNOSIS - IMAGING
ULTRASOUND
CT UROGRAPHY
 Renal masses, hydronephrosis
 Filling defects, hydronephrosis
 Intraluminal lesions of the bladder
 Lymph node status/other organs
 Good as 1st approach in haematuria
 Incidence of UTUC (1,8%) – questioned
 Cannot exclude UTUC / replace CT
 If trigonal BC  7,5% UTUC  CT scan
Imaging is poor for local staging and tipically understages
EAU Guidelines 2015
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BLADDER CANCER DIAGNOSIS – URINARY CITOLOGY
PROS
LIMITATIONS
 High sensitivity in G3 tumours
 Low sensitivity in G1 tumours
 Sensitivity in CIS detection – 28-100%
 If negative does not exclude UC
 Adjunct to cystoscopy (G3 / CIS present)
 User-dependent
 If positive can indicate UC anywhere UT
 UTI, stones, iv chemo.
EAU Guidelines 2015
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BLADDER CANCER: GRADING AND STAGING
Knowles MA, Hurst CD.Nat Rev Cancer. 2015 Jan;15(1):25-41
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BLADDER CANCER: 2009 TNM CLASSIFICATION
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BLADDER CANCER: PATHOLOGICAL PRESENTATION
Ta (70%)
5-year recurrence
rate > 50%
NMIBC (75%)
T1 (20%)
Bladder
tumor
5-year progression
rate 30%
MIBC (25%)
CIS (10%)
5-year mortality rate – 38%
Mbeutcha A, Lucca I, et . al, Urol Clin N Am 43 (2016) 47-62
.
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STAGING OF UROTHELIAL CARCINOMA
CLINICAL STAGING
PATHOLOGICAL
 Bimanual examination
 Gold-standard
 Cystoscopy
 Limited by the quality of the TUR
specimen
 Cross-sectional radiographic assessment
 Notoriously innacurate
Kamat, A. M., Hahn, N. M., & Efstathiou, J. A. Bladder cancer. Lancet 2016
 Difficulty differentiating stage T1 from T2
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BLADDER CANCER DIAGNOSIS – TURBT
GOALS
LIMITATIONS
 Eradicate all visible tumors
 Visualization (CIS, small lesions)
 Prevent tumour rcurrence
 Lateral bladder wall, ureteral orifice
 Prevent tumour progression (≥T2 / M1)
 Bleeding, perforation, hydronephrosis
 Diagnose, stage, treat visible tumors
 If obese patient – anterior/posterior wall
Michael Jurewicz, Mark S. Soloway. Turkish Journal of Urology 2014; 40(2): 73-7
I Curso de Tumores da Bexiga , Lisboa 2016 - MC©
BLADDER CANCER – APPROACHING THE OPTIMAL TURBT
PRIOR TO TURBT …
 Use a systematic way of performing it
 Urine should be sent for citology
 Bimanual palpation
 Pancystoscopy – bladder diagram/photo
 Location, size, configuration
 Bladder volume should be mantained at
50-70%
 Avoid overdistention  perforation
 Improves CIS visualization
Michael Jurewicz, Mark S. Soloway. Turkish Journal of Urology 2014; 40(2): 73-7
I Curso de Tumores da Bexiga , Lisboa 2016 - MC©
BLADDER CANCER – APPROACHING THE OPTIMAL TURBT
THE “IDEAL” TURBT
 Monopolar vs. bipolar TUR ?
 Minimize cautery artifact
 Balance: identifying muscle/risk perforation
 Send separate specimens
 Tumour, base, margins
 Quality of margin size
 8 mm of tumour-free urothelium
 Recurrence 58%  19%
 Adequate hemostasis / ensure no tumour remains
Complication rate 5-43%  majority < 15%
Perforation  3,5%; haematuria/transfusion  2,5%
Michael Jurewicz, Mark S. Soloway. Turkish Journal of Urology 2014; 40(2): 73-7
I Curso de Tumores da Bexiga , Lisboa 2016 - MC©
BLADDER CANCER – ROLE OF BLADDER RANDOM BIOPSIES
AVAILABLE EVIDENCE
 Recommended  Bx abnormal urothelium
 Random Bx  not routine
 Likelihood of CIS  if low-risk BC < 2%
 Indication
 cytology+ and normal mucosa
 Non-papillary appearance in TaT1 BC
 Biopsy:
 Trigone, bladder dome
 Left, right, anterior, posterior walls
 Separate containers
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WHITE LIGHT CYSTOSCOPY - LIMITATIONS
EVIDENCE
 Does not allow for cancer grading / infiltration status
 Can be indequate in identifying small or flat solid tumors (CIS)
 Detection rates  58 – 68%  incorrect conservative treatment
 Does not allow for examination of surgical margins/small satellite tumors
 40 – 70% rates of residual tumors found in re-TUR 4-6 wk
 Emergence of new optical imaging techniques




Optimize detection and ressection
Fluorescence cystoscopy, Narrow band imaging, microscopic imaging
Raman and multiphoton spectroscopy, scanning fiber endoscopy
Ultraviolet autofluorescence, molecular imaging
Kolodziej, A. et al. Cent European J Urol. 2016; 69: 150-156
I Curso de Tumores da Bexiga , Lisboa 2016 - MC©
BLADDER CANCER – IMPROVING THE OPTIMAL TURBT
WHAT IS FLUORESCENT CYSTOSCOPY ?
 Photodynamic diagnosis (PDD) or blue light
cystoscopy
 Uses a photosensitizing agent  taken up 20x
in UC cells
 HAL (hexylkaminolevulinic acid) or 5-ALA (5aminolevulinic acid)
 Precursor of porphyrins –> emit red light
under blue light
 Metabolized within 24h and back to N levels
 Instilled 1hr pre TURBT into empty bladder
 Used with rigid cystoscopy !
Michael Jurewicz, Mark S. Soloway. Turkish Journal of Urology 2014; 40(2): 73-7
Image showing (a) an inconspicuous left
ureteral orifice in white-light cystoscopy,
and (b) two spots of carcinoma in situ that
were detected by hexyl aminolevulinate
fluorescence cystoscopy.
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BLADDER CANCER – IMPROVING THE OPTIMAL TURBT
FC vs. WLC
FLUORESCENT CYSTOSCOPY – SUMMARY OF EVIDENCE
 INDICATIONS
 Unexplained positive cytology; suspicion of and/or history of CIS
 High-grade disease with sessile appearing tumour
 CONTRAINDICATIONS
 Porphyria; allergic to ALA, HAL ; gross heamaturia; pregnancy
 Advantage of HAL over 5-ALA
 5-ALA – highly charged; 3hr to pass lipid cell membrane
 HAL – lipophilic, urine soluble and ↑ protoporphyrin IX
 HAL 1 hour  ↓ concentration needed; faster and ↑
protopotphyrin IX level
 Disadvantages
 Photosensitivity, bladder spasm/pain, dysuria (~3%)
 Avoid in inflammation (e.g. post IVBCG); expensive, time
 Tangential view (BN, trigone, prostatic urethra)
Michael Jurewicz, Mark S. Soloway. Turkish Journal of Urology 2014; 40(2): 73-7
 Detection rate
 ↑ 11% Ta
 ↑ 24-44% CIS
 Residual tumour
 11% FC
 31% WLC
 Recurrence FS
 WLC 9,6 mo
 FC 16,4 mo
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BLADDER CANCER – IMPROVING THE OPTIMAL TURBT
WHAT IS NARROW BAND IMAGING?
 Based on the phenomen that depth of light
penetratation increses with wavelenght
 White light is filtered into 2 bands – 415 nm
(blue) and 540 nm (green)
 Both abserved by Hb more strongly
 Blue light  enhance superficial vessels
 Green light  enhance deeper vessels
 Enhances contrast between mucosa and
microvessels without the use of a dye
 Can be used in flexible scope
Follow-up NBI cystoscopy revealing a recurrent
pTaG3 lesion missed during standard WLC
Michael Jurewicz, Mark S. Soloway. Turkish Journal of Urology 2014; 40(2): 73-7
I Curso de Tumores da Bexiga , Lisboa 2016 - MC©
BLADDER CANCER – IMPROVING THE OPTIMAL TURBT
NBI – SUMMARY OF EVIDENCE
 Evidence: compare with WLC (Herr, BJUI 2008)




15% more patients detected with BC with NBI
55% more tumours detected with NBI
No learning curve
NBI more accurate at identifying post-BCG recurrence
 Better sensitivity than urine cytology (95% vs. 50%)
 Re-TURBT with NBI can detect 15% more cases of residual tumour
 Naseli a, et al. BJUI 2010
 Potential use for Dx of IC
Michael Jurewicz, Mark S. Soloway. Turkish Journal of Urology 2014; 40(2): 73-7
I Curso de Tumores da Bexiga , Lisboa 2016 - MC©
BLADDER CANCER – SUMMARY OF ACCURACY OF DIFFERENT
DIAGNOSTIC METHODS
METHOD
WLC
CYTOLOGY
FC/PDD
NBI
Sensitivity
70%
50%
90%
95%
Specificity
70%
95%
60%
80%
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BLADDER CANCER - HIGH RISK NMIBC
PREDICTORS OF UNDERSTAGING
 Incomplete TUR
 No muscle in the TUR specimen
 Multifocal or large lesions
 Associated carcinoma in situ
 Lymphovascular invasion
 Mass on bimanual exam
 Hydronephrosis
 Prostatic urethra involvement
Ark JT, Keegan KA, Barocas DA, et al. Incidence and Predictors of Understaging in Patients with Clinical T1
Urothelial Carcinoma Undergoing Radical Cystectomy. BJU international. 2014;113(6):894-899.
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BLADDER CANCER - HIGH RISK NMIBC
PREDICTORS OF UNDERSTAGING
 Incomplete TUR
 No muscle in the TUR specimen
 Multifocal or large lesions
 Associated carcinoma in situ
 Lymphovascular invasion
 Mass on bimanual exam
 Hydronephrosis
 Prostatic urethra involvement
Ark JT, Keegan KA, Barocas DA, et al. Incidence and Predictors of Understaging in Patients with Clinical T1
Urothelial Carcinoma Undergoing Radical Cystectomy. BJU international. 2014;113(6):894-899.
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BLADDER CANCER – Re-STAGING T1
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BLADDER CANCER – Re-STAGING T1
Bladder cancer specific death according to
stage from restaging TUR
STUDY DATA
DOD – death from BC
 Retrospective review 1990-2007
 523 patients initial T1  re-staging TUR
 Muscle in initial TURBT  47%
44% (95% CI, 35-56%)
 Muscle in re-TURBT  84%
 20% upstaged to ≥ T2
 Patients upstaged to T2 disease had the
worst disease-specific survival
Dalbagni G, Vora K, Kaag M, Cronin A, Bochner B, Donat SM, Herr HW.Eur Urol. 2009 Dec;56(6):903-10
10% (95% CI,5%-17%)
8% (95% CI,5%-13%)
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BLADDER CANCER – Re-STAGING T1
STUDY DATA
 Prospective – Jan 2001 – Jan 2005
 210 newly diagnosed T1 BC
 Group 1 – re-TUR 2-6 wk after 1st TUR
 Group 2 – no re-TUR
 All groups – single instillation MMC
 Residual tumour  35/105 Group 1
 8/35  pT2
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BLADDER CANCER – Re-STAGING T1
Divrik RT, Sahin AF, Yildirim U, Altok M, Zorlu F. Eur Urol. 2010 Aug;58(2):185-90.
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BLADDER CANCER – Re-STAGING T1
Divrik RT, Sahin AF, Yildirim U, Altok M, Zorlu F. Eur Urol. 2010 Aug;58(2):185-90.
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BLADDER CANCER – Re-STAGING T1
Divrik RT, Sahin AF, Yildirim U, Altok M, Zorlu F. Eur Urol. 2010 Aug;58(2):185-90.
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BLADDER CANCER: Re-TUR FOR HIGH-GRADE Ta, T1
GUIDELINES
 EAU
 Ta – any incomplete TUR, large,
multifocal, no muscle
 All T1 tumours
 AUA
 Selected Ta patients; all T1 patients
EAU GUIDELINES 2015; AUA GUIDELINES 2016
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BLADDER CANCER - HIGH RISK NMIBC
PREDICTORS OF UNDERSTAGING
 Incomplete TUR
 No muscle in the TUR specimen
 Multifocal or large lesions
 Associated carcinoma in situ
 Lymphovascular invasion
 Mass on bimanual exam
 Hydronephrosis
 Prostatic urethra involvement
Ark JT, Keegan KA, Barocas DA, et al. Incidence and Predictors of Understaging in Patients with Clinical T1
Urothelial Carcinoma Undergoing Radical Cystectomy. BJU international. 2014;113(6):894-899.
I Curso de Tumores da Bexiga , Lisboa 2016 - MC©
BLADDER CANCER – ROLE OF PROSTATE BIOPSIES
WHICH PATIENTS ARE AT RISK FOR PROSTATIC UC
 CIS of the bladder
 32% of patients with CIS vs. 5%
 Multifocal disease
 35% with multifocal disease s. 4%
 Involvement of trigone or bladder neck
 Prior intravesical therapy (failure of therapy)
 History of higher stage bladder cancer
 Previous involvement of the prostate
Mazzucchelli R, et al. Urology. 2009 Aug;74(2):385-90
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BLADDER CANCER – ROLE OF PROSTATE BIOPSIES
AVAILABLE EVIDENCE
 Indications
 Visible abnormality in prostatic urethra
 Cytology+ with negative cystoscopy
 Tumor at trigone or bladder neck
 Concomitant bladder CIS
 Multifocal tumor
 Site & technique
 With ressection loop
 Abnormal area
 Precolicular area near verumontanum (5&7 oc)
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BLADDER CANCER – ROLE OF PROSTATE BIOPSIES
RELEVANT DATA
 Fundació Puigvert, Barcelona, Spain
 BCG treatment failed in 62 high-risk
cases
 Prostatic urethra TCC most important
predictor of muscle-invasive cancer
 HR, 12,2 (2,2 – 65,5), p=0.003
 Sampling from the urethra in high-risk
patients is essential
Huguet, J. et al. Eur Urol. 2005; 48: 53-59.
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BLADDER CANCER – ROLE OF PROSTATE BIOPSIES
Huguet, J. Actas Urol Esp. 2012;36(9):545---553
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BLADDER CANCER: PROGRESSION OF NMIBC
AVAILABLE EVIDENCE
 Recurrence rate  70% within 5yr
 Progression  10 - 20%
 Mortality  1 - 15%
 Upper tract tumor  2%
 Stage Ta  70%
 50% will recur; 50% never recur
 If first f/u cystoscopy + recurrence  risk of further recurrence = 90%
 5% progress
 Stage T1  30%
 20% 5yr mortality
 80% recur, 30% of T1 HG progress
 High progression 80% if concomittent CIS
 30% of T1 HG is understaged at RC
 Become T2 if untreated in 2 years
 50% will progress to muscle-invasive disease
 CIS: 5% primary, 20% with tumor present
Sylvester RJ, J Urol 2002;
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BLADDER CANCER: PREDICTING RECURRENCE AND PROGRESSION
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BLADDER CANCER: PREDICTING RECURRENCE AND PROGRESSION
RELEVANT DATA
 Combine analysis of 2596 patients from
7 EORTC trials to predict recurrence and
progression in patient with stage Ta T1
bladder cancer
 Note: patient does not have 2nd TUR or
maintenance BCG
 Recurrence
 Number of tumors
 Size (< 3 cm vs. > 3 cm)
 Prior recurrence rate
 Progression
 T stage
 Grade
 Presence of CIS (Yes/No)
Sylvester RJ, et al., Eur Urol 2006 Mar;49(3):466-5.
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BLADDER CANCER: PREDICTING RECURRENCE AND PROGRESSION
Sylvester RJ, et al., Eur Urol 2006 Mar;49(3):466-5.
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BLADDER CANCER: PREDICTING RECURRENCE AND PROGRESSION
Sylvester RJ, et al., Eur Urol 2006 Mar;49(3):466-5.
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BLADDER CANCER: RISK GROUP STRATIFICATION (EAU 2015)
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BLADDER CANCER: IMPLICATIONS OF RISK STRATIFICATION
AVAILABLE EVIDENCE
 At a low risk of tumour recurrence and progression
 One immediate instillation of chemotherapy is strongly
recommended as the complete adjuvant treatment
 At an intermediate or high risk of recurrence and an intermediate risk
of progression
 One immediate instillation of chemotherapy should be followed by
further instillations of chemotherapy or a minimum of 1 year of
BCG
 At high risk of tumour progression
 Intravesical BCG for at least 1 year
 Radical cystectomy may be offered to the highest risk patients
EAU GUIDELINES 2015;
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I Curso de Tumores da Bexiga
Diagnóstico e factores de prognóstico
Miguel Carvalho
OBRIGADO