Tobacco smoking and occupational exposure to chemicals are the most important risk factors for non-muscle-invasive bladder cancer. Diagnosis involves cystoscopy, urinary cytology, and biopsy of any lesions found. Tumors are graded based on histology. Carcinoma in situ is diagnosed through cystoscopy and random bladder biopsies. Resection of tumors aims to completely remove all visible lesions while obtaining detrusor muscle in specimens. New techniques like photodynamic diagnosis and narrow-band imaging aid in visualizing lesions.

1. EAU GUIDELINES ON
NON-MUSCLE-
INVASIVE BLADDER
CANCER (Ta,T1 AND
CIS)

2. EPIDEMIOLOGY, AETIOLOGY AND
PATHOLOGY
• TOBACCO SMOKING IS THE MOST IMPORTANT RISK
FACTOR FOR BC, ACCOUNTING FOR APPROXIMATELY 50%
OF CASES. TOBACCO SMOKE CONTAINS AROMATIC AMINES
AND POLYCYCLIC AROMATIC HYDROCARBONS, WHICH ARE
EXCRETED IN URINE.

3. • OCCUPATIONAL EXPOSURE TO AROMATIC AMINES,
POLYCYCLIC AROMATIC HYDROCARBONS AND
CHLORINATED HYDROCARBONS IS THE SECOND MOST
IMPORTANT RISK FACTOR FOR BC, ACCOUNTING FOR
ABOUT 10% OF ALL CASES
• THIS TYPE OF OCCUPATIONAL EXPOSURE OCCURS MAINLY
IN INDUSTRIAL PLANTS, WHICH PROCESS PAINT, DYE,
METAL AND PETROLEUM PRODUCTS

4. • THE CHLORINATION OF DRINKING WATER AND SUBSEQUENT
LEVELS OF TRIHALOMETHANES ARE POTENTIALLY
CARCINOGENIC, ALSO EXPOSURE TO ARSENIC IN DRINKING
WATER INCREASES RISK.
• EXPOSURE TO IONIZING RADIATION IS CONNECTED WITH
INCREASED RISK; WEAK ASSOCIATION WAS ALSO SUGGESTED
FOR CYCLOPHOSPHAMIDE AND PIOGLITAZONE.
• SCHISTOSOMIASIS, A CHRONIC ENDEMIC CYSTITIS BASED ON
RECURRENT INFECTION WITH A PARASITIC TREMATODE, IS
ALSO A CAUSE OF BC

5. • WHILE FAMILY HISTORY SEEMS TO HAVE LITTLE IMPACT
AND, TO DATE, NO OVERT SIGNIFICANCE OF ANY GENETIC
VARIATION FOR BC HAS BEEN SHOWN, GENETIC
PREDISPOSITION HAS AN INFLUENCE ON THE INCIDENCE OF
BC VIA ITS IMPACT ON SUSCEPTIBILITY TO OTHER RISK
FACTORS

6. STAGING AND CLASSIFICATION
SYSTEMS
• DEFINITION OF NON-MUSCLE-INVASIVE BLADDER CANCER
-PAPILLARY TUMOURS CONFINED TO THE MUCOSA AND
INVADING THE LAMINA PROPRIA ARE CLASSIFIED AS STAGE
Ta AND T1, RESPECTIVELY.
-FLAT, HIGH GRADE TUMOURS THAT ARE CONFINED TO
THE MUCOSA ARE CLASSIFIED AS CIS (TIS)

8. HISTOLOGICAL GRADING OF
NON-MUSCLE-INVASIVE BLADDER
UROTHELIAL CARCINOMAS
• 1973 WHO GRADING
- GRADE 1: WELL DIFFERENTIATED
- GRADE 2: MODERATELY DIFFERENTIATED
- GRADE 3: POORLY DIFFERENTIATED
• 2004 WHO GRADING SYSTEM (PAPILLARY LESIONS)
-PAPILLARY UROTHELIAL NEOPLASM OF LOW MALIGNANT POTENTIAL
(PUNLMP)
-LOW-GRADE (LG) PAPILLARY UROTHELIAL CARCINOMA
- HIGH-GRADE (HG) PAPILLARY UROTHELIAL CARCINOMA

9. CARCINOMA IN SITU AND ITS
CLASSIFICATION
• CARCINOMA IN SITU (CIS) IS A FLAT, HIGH-GRADE, NON-
INVASIVE UROTHELIAL CARCINOMA.
• CARCINOMA IN SITU IS OFTEN MULTIFOCAL AND CAN
OCCUR IN THE BLADDER, BUT ALSO IN THE UPPER URINARY
TRACT (UUT), PROSTATIC DUCTS, AND PROSTATIC
URETHRA .

10. CLASSIFICATION OF CIS ACCORDING TO CLINICAL TYPE:
• 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.

12. DIAGNOSIS
• PATIENT HISTORY
• SIGNS AND SYMPTOMS
-HAEMATURIA IS THE MOST COMMON FINDING IN NMIBC.
-VISIBLE HAEMATURIA WAS FOUND TO BE ASSOCIATED
WITH HIGHER STAGE DISEASE COMPARED TO NONVISIBLE
HAEMATURIA AT FIRST PRESENTATION
-CARCINOMA IN SITU MIGHT BE SUSPECTED IN PATIENTS
WITH LOWER URINARY TRACT SYMPTOMS, ESPECIALLY
IRRITATIVE VOIDING.

13. IMAGING
• ULTRASOUND (US)
-TRANSABDOMINAL US PERMITS CHARACTERISATION OF
RENAL MASSES, DETECTION OF HYDRONEPHROSIS, AND
VISUALISATION OF INTRALUMINAL MASSES IN THE BLADDER
.
-HOWEVER, IT CANNOT EXCLUDE THE PRESENCE OF UTUC
AND CANNOT REPLACE CT UROGRAPHY IN BLADDER
CANCER DETECTION.

14. • COMPUTED TOMOGRAPHY UROGRAPHY AND INTRAVENOUS
UROGRAPHY
-COMPUTED TOMOGRAPHY (CT) UROGRAPHY IS USED TO
DETECT PAPILLARY TUMOURS IN THE URINARY TRACT,
INDICATED BY FILLING DEFECTS OR HYDRONEPHROSIS.
-INTRAVENOUS UROGRAPHY (IVU) IS AN ALTERNATIVE IF CT
IS NOT AVAILABLE, BUT PARTICULARLY IN MIBC AND IN
UTUCS, CT UROGRAPHY GIVES MORE INFORMATION THAN
IVU (INCLUDING STATUS OF LYMPH NODES AND
NEIGHBOURING ORGANS).

15. • THE NECESSITY TO PERFORM A BASELINE CT UROGRAPHY
OR IVU ONCE A BLADDER TUMOUR HAS BEEN DETECTED IS
QUESTIONABLE DUE TO THE LOW INCIDENCE OF
SIGNIFICANT FINDINGS OBTAIN.
• THE INCIDENCE OF UTUCS IS LOW (1.8%), BUT INCREASES
TO 7.5% IN TUMOURS LOCATED IN THE TRIGONE.
• THE RISK OF UTUC DURING FOLLOW UP INCREASES IN
PATIENTS WITH MULTIPLE- AND HIGH-RISK TUMOURS

16. • THE DIAGNOSIS OF CIS CANNOT BE MADE WITH IMAGING
METHODS (CT UROGRAPHY, IVU OR US)

17. URINARY CYTOLOGY
• THE EXAMINATION OF VOIDED URINE OR BLADDER-
WASHING SPECIMENS FOR EXFOLIATED CANCER CELLS HAS
-HIGH SENSITIVITY IN G3 AND HIGH-GRADE TUMOURS (84%)
-LOW SENSITIVITY IN G1 AND LOW-GRADE TUMOURS (16%).
-THE SENSITIVITY IN CIS DETECTION IS 28-100%

18. • POSITIVE VOIDED URINARY CYTOLOGY CAN INDICATE A
UROTHELIAL TUMOUR ANYWHERE IN THE URINARY TRACT;
NEGATIVE CYTOLOGY, HOWEVER, DOES NOT EXCLUDE THE
PRESENCE OF A TUMOUR.

19. EVALUATION CAN BE HAMPERED BY
- LOW CELLULAR YIELD
- URINARY TRACT INFECTIONS
- STONES
- INTRAVESICAL INSTILLATIONS,

20. • A STANDARDISED REPORTING SYSTEM REDEFINING
URINARY CYTOLOGY DIAGNOSTIC CATEGORIES WAS
PUBLISHED IN 2016 BY THE PARIS WORKING GROUP:
-ADEQUACY OF URINE SPECIMENS (ADEQUACY).
-NEGATIVE FOR HIGH-GRADE UROTHELIAL CARCINOMA
(NEGATIVE).
-ATYPICAL UROTHELIAL CELLS (AUC).
-SUSPICIOUS FOR HIGH-GRADE UROTHELIAL CARCINOMA
(SUSPICIOUS).
-HIGH-GRADE UROTHELIAL CARCINOMA (HGUC).
-LOW-GRADE UROTHELIAL NEOPLASIA (LGUN)

21. URINARY MOLECULAR MARKER
TESTS
NONE OF THESE MARKERS HAVE BEEN ACCEPTED FOR
DIAGNOSIS OR FOLLOW-UP IN ROUTINE PRACTICE OR
CLINICAL GUIDELINES.
VARIOUS MARKERS ARE
1-UROVYSION
2 MICROSATELLITE ANALYSIS
3 NMP 22
4 BTA STAT
5 CYTOKERATIN

22. THE FOLLOWING CONCLUSIONS CAN BE DRAWN REGARDING
THE EXISTING TESTS:
• SENSITIVITY IS USUALLY HIGHER AT THE COST OF LOWER
SPECIFICITY, COMPARED TO URINE CYTOLOGY.
• BENIGN CONDITIONS AND PREVIOUS BACILLUS CALMETTE-
GUÉRIN (BCG) INSTILLATIONS INFLUENCE MANY URINARY
MARKER TESTS.

23. • REQUIREMENTS FOR SENSITIVITY AND SPECIFICITY OF A
URINARY MARKER TEST LARGELY DEPEND ON THE CLINICAL
CONTEXT OF THE PATIENT (SCREENING, PRIMARY
DETECTION, FOLLOW UP [HIGH RISK, LOW/INTERMEDIATE
RISK]).
• LOW REPRODUCIBILITY MAY BE EXPLAINED BY PATIENT
SELECTION AND COMPLICATED LABORATORY METHODS
REQUIRED.
• POSITIVE RESULTS OF CYTOLOGY AND MARKER IN
PATIENTS WITH NEGATIVE CYSTOSCOPY AND UPPER TRACT
WORK-UP, MAY IDENTIFY PATIENTS MORE LIKELY TO
EXPERIENCE RECURRENCE AND POSSIBLY PROGRESSION

24. POTENTIAL APPLICATION OF
URINARY CYTOLOGY AND
MARKERS
• SCREENING OF THE POPULATION AT RISK OF BLADDER
CANCER
-DUE TO THE LOW INCIDENCE OF BC IN THE GENERAL
POPULATION AND THE SHORT LEAD-TIME, ROUTINE
SCREENING FOR BC IS NOT RECOMMENDED.
• EXPLORATION OF PATIENTS AFTER HAEMATURIA OR OTHER
SYMPTOMS SUGGESTIVE OF BLADDER CANCER (PRIMARY
DETECTION)
-URINARY CYTOLOGY IS HIGHLY SPECIFIC, BUT URINARY
MARKERS LACK SUCH HIGH SPECIFICITY AND ARE NOT
RECOMMENDED FOR PRIMARY DETECTION.

25. • FOLLOW-UP OF HIGH-RISK NON-MUSCLE-INVASIVE
BLADDER CANCER
- THE BEST SURVEILLANCE STRATEGY FOR THESE PATIENTS
WILL CONTINUE TO INCLUDE FREQUENT CYSTOSCOPY AND
CYTOLOGY.

26. CYSTOSCOPY
• THE DIAGNOSIS OF PAPILLARY BC ULTIMATELY DEPENDS
ON CYSTOSCOPIC EXAMINATION OF THE BLADDER AND
HISTOLOGICAL EVALUATION OF SAMPLED TISSUE BY EITHER
COLD-CUP BIOPSY OR RESECTION.
• CARCINOMA IN SITU IS DIAGNOSED BY A COMBINATION OF
CYSTOSCOPY, URINE CYTOLOGY, AND HISTOLOGICAL
EVALUATION OF MULTIPLE BLADDER BIOPSIES.

28. TRANSURETHRAL RESECTION OF
Ta,T1 BLADDER TUMOURS
• STRATEGY OF THE PROCEDURE
-THE GOAL OF TURB IN TaT1 BC IS TO MAKE THE CORRECT
DIAGNOSIS AND COMPLETELY REMOVE ALL VISIBLE
LESIONS.
IT IS A CRUCIAL PROCEDURE IN THE DIAGNOSIS AND
TREATMENT OF BC.

29. • SURGICAL AND TECHNICAL ASPECTS OF TUMOUR
RESECTION
- A COMPLETE RESECTION CAN BE ACHIEVED BY EITHER
FRACTIONED OR EN-BLOC RESECTION .
RESECTION IN FRACTIONS (SEPARATE RESECTION OF THE
EXOPHYTIC PART OF THE TUMOUR , THE UNDERLYING
BLADDER WALL AND THE EDGES OF THE RESECTION AREA)
PROVIDES GOOD INFORMATION ABOUT THE VERTICAL AND
HORIZONTAL EXTENT OF THE TUMOUR.
EN-BLOC RESECTION USING MONOPOLAR OR BIPOLAR
CURRENT, THULIUM-YAG OR HOLMIUM-YAG LASER IS
FEASIBLE IN SELECTED EXOPHYTIC TUMOURS. IT PROVIDES
HIGH QUALITY RESECTED SPECIMENS WITH THE PRESENCE
OF DETRUSOR MUSCLE IN 96-100% OF CASES

30. • EVALUATION OF RESECTION QUALITY
-IT HAS BEEN CONFIRMED THAT THE ABSENCE OF
DETRUSOR MUSCLE IN THE SPECIMEN IS ASSOCIATED WITH
A SIGNIFICANTLY HIGHER RISK OF RESIDUAL DISEASE,
EARLY RECURRENCE AND TUMOUR UNDERSTAGING .
-THE PRESENCE OF DETRUSOR MUSCLE IN THE SPECIMEN IS
CONSIDERED AS THE SURROGATE CRITERION OF THE
RESECTION QUALITY AND IS REQUIRED (EXCEPT OF
TAG1/LG TUMOURS)

31. • RESECTION OF SMALL PAPILLARY BLADDER TUMOURS AT
THE TIME OF TRANSURETHRAL RESECTION OF THE
PROSTATE (TURP)
-ONLY LIMITED, RETROSPECTIVE, DATA EXIST ON THE
OUTCOME OF INCIDENTALLY DETECTED PAPILLARY
BLADDER TUMOUR DURING CYSTOSCOPY AS THE INITIAL
STEP OF TURP.
-PROVIDED THESE TUMOURS ARE PAPILLARY BY ASPECT,
RATHER SMALL AND NOT EXTENSIVELY MULTIFOCAL, IT
SEEMS FEASIBLE TO RESECT THESE TUMOURS AND
CONTINUE WITH THE RESECTION OF THE PROSTATE.

32. • BLADDER AND PROSTATIC URETHRAL BIOPSIES
-CARCINOMA IN SITU CAN PRESENT AS A VELVET-LIKE,
REDDISH, AREA INDISTINGUISHABLE FROM INFLAMMATION,
OR IT MAY NOT BE VISIBLE AT ALL.
-FOR THIS REASON, THE STRATEGY OF TAKING BIOPSIES
FROM ABNORMAL UROTHELIUM AND BIOPSIES FROM
NORMAL-LOOKING MUCOSA (RANDOM/MAPPING BIOPSIES)
IS RECOMMENDED.

33. • PHOTODYNAMIC DIAGNOSIS (PDD) IS A USEFUL TOOL TO
TARGET THE BIOPSY

34. • INVOLVEMENT OF THE PROSTATIC URETHRA AND DUCTS IN
MEN WITH NMIBC HAS BEEN REPORTED.
• PALOU ET AL. SHOWED THAT IN 128 MEN WITH T1G3 BC,
THE INCIDENCE OF CIS IN THE PROSTATIC URETHRA WAS
11.7% .
• THE RISK OF PROSTATIC URETHRA OR DUCT
INVOLVEMENT IS HIGHER IF THE TUMOUR IS LOCATED AT
THE TRIGONE OR BLADDER NECK, IN THE PRESENCE OF
BLADDER CIS AND MULTIPLE TUMOURS

35. NEW METHODS OF TUMOUR
VISUALISATION
• PHOTODYNAMIC DIAGNOSIS (FLUORESCENCE CYSTOSCOPY)
• NARROW-BAND IMAGING

36. PHOTODYNAMIC DIAGNOSIS
(FLUORESCENCE CYSTOSCOPY)
• PHOTODYNAMIC DIAGNOSIS (PDD) IS PERFORMED USING
VIOLET LIGHT AFTER INTRAVESICAL INSTILLATION OF 5-
AMINOLAEVULINIC ACID (ALA) OR HEXAMINOLAEVULINIC
ACID (HAL).
• IT HAS BEEN CONFIRMED THAT FLUORESCENCE-GUIDED
BIOPSY AND RESECTION ARE MORE SENSITIVE THAN
CONVENTIONAL PROCEDURES FOR THE DETECTION OF
MALIGNANT TUMOURS, PARTICULARLY FOR CIS.

37. • PDD HAD HIGHER SENSITIVITY THAN WHITE LIGHT
ENDOSCOPY IN THE POOLED ESTIMATES FOR ANALYSES AT
BOTH THE PATIENT-LEVEL (92% VS.71%) AND BIOPSY-LEVEL
(93% VS. 65%)
• PHOTODYNAMIC DIAGNOSIS HAD LOWER SPECIFICITY
THAN WHITE-LIGHT ENDOSCOPY (63% VS. 81%)

38. • FALSE-POSITIVITY CAN BE INDUCED BY
-INFLAMMATION
-RECENT TURB
-DURING THE FIRST THREE MONTHS AFTER BCG
INSTILLATION

39. NARROW-BAND IMAGING
• IN NARROW-BAND IMAGING (NBI), THE CONTRAST
BETWEEN NORMAL UROTHELIUM AND HYPER-VASCULAR
CANCER TISSUE IS ENHANCED.
• COHORT STUDIES HAVE DEMONSTRATED IMPROVED
CANCER DETECTION BY NBI FLEXIBLE CYSTOSCOPY AND
NBI-GUIDED BIOPSIES AND RESECTION.
• THE REDUCTION OF RECURRENCE RATE IF NBI IS USED
DURING TURB HAS BEEN CONFIRMED AFTER THREE AND
TWELVE MONTHS FOR LOW-RISK TUMOURS (PTALG, < 30
MM, NO CIS)

40. SECOND RESECTION
• THE SIGNIFICANT RISK OF RESIDUAL TUMOUR AFTER
INITIAL TURB OF TaT1 LESIONS HAS BEEN DEMONSTRATED.
• PERSISTENT DISEASE
• AFTER RESECTION OF T1 TUMOURS HAS BEEN OBSERVED IN
33-55% OF PATIENTS,
• AFTER RESECTION OF TAG3 TUMOUR IN 41.4% OF PATIENTS.

41. • THE TUMOUR IS OFTEN UNDERSTAGED IN THE INITIAL
RESECTION.
• THE LIKELIHOOD THAT MUSCLE-INVASIVE DISEASE IS
DETECTED BY SECOND RESECTION OF INITIALLY T1
TUMOUR RANGES FROM 1.3-25%, AND INCREASES TO 45%
IF THERE WAS NO MUSCLE IN THE INITIAL RESECTION

42. • RETROSPECTIVE EVALUATION SHOWED THAT A SECOND
RESECTION PERFORMED 14-42 DAYS AFTER INITIAL
RESECTION PROVIDES LONGER RFS AND DFS COMPARED TO
SECOND RESECTION PERFORMED AFTER 43-90 DAYS.
• BASED ON THESE ARGUMENTS, A SECOND TURB IS
RECOMMENDED IN SELECTED CASES TWO-SIX WEEKS AFTER
INITIAL RESECTION

43. • IT HAS BEEN DEMONSTRATED THAT A SECOND TURB CAN
INCREASE RECURRENCE-FREE SURVIVAL, IMPROVE
OUTCOMES AFTER BCG TREATMENT AND PROVIDE
PROGNOSTIC INFORMATION.
• THE RESULTS OF THE SECOND RESECTION (RESIDUAL
TUMOURS AND UNDERSTAGING) REFLECT THE QUALITY OF
THE INITIAL TURB

47. RISK GROUP STRATIFICATION

48. DISEASE MANAGEMENT
• COUNSELLING OF SMOKING CESSATION
-STILL CONTROVERSIAL WHETHER SMOKING CESSATION IN
BC WILL FAVOURABLY INFLUENCE THE OUTCOME OF BC
TREATMENT, PATIENTS SHOULD BE COUNSELLED TO STOP
SMOKING DUE TO THE GENERAL RISKS CONNECTED WITH
TOBACCO SMOKING

49. INTRAVESICAL CHEMOTHERAPY
• IT IS BELIEVED THAT TUMOR CELL IMPLANTATION
IMMEDIATELY AFTER RESECTION IS RESPONSIBLE FOR MANY
EARLY RECURRENCES, AND THIS HAS BEEN USED TO
EXPLAIN THE OBSERVATION THAT INITIAL TUMORS ARE
MOST COMMONLY FOUND ON THE FLOOR AND LOWER
SIDEWALLS OF THE BLADDER, WHEREAS RECURRENCES ARE
OFTEN LOCATED NEAR THE DOME AS A RESULT OF
“FLOTATION” (HENEY ET AL, 1981).
• THUS, INTRAVESICAL CHEMOTHERAPY TO KILL SUCH
CELLS BEFORE IMPLANTATION HAS BEEN USED FOR
DECADES.

50. • MITOMYCIN C (MMC) APPEARS TO BE THE MOST EFFECTIVE
ADJUVANT INTRAVESICAL CHEMOTHERAPEUTIC AGENT
PERIOPERATIVELY, ALTHOUGH EPIRUBICIN IS USED IN
EUROPE AND DIRECT COMPARATIVE STUDIES ARE LACKING
(WITJES AND HENDRICKSEN, 2008).
• CONSISTENT WITH ITS PROPOSED MECHANISM OF ACTION
TO PREVENT TUMOR CELL IMPLANTATION, A SINGLE DOSE
ADMINISTERED WITHIN 6 HOURS LESSENS RECURRENCE
RATES, WHEREAS A DOSE 24 HOURS LATER DOES NOT.

51. • LEVEL 1 DATA DEMONSTRATE CLEARLY
THAT SINGLE-DOSE MMC OR EPIRUBICIN
IMMEDIATELY AFTER RESECTION REDUCES
TUMOR RECURRENCE, PARTICULARLY FOR
THE INITIAL PRESENTATION OF A
SOLITARY PAPILLARY LOW-GRADE TUMOR

53. • ALTHOUGH LOCAL IRRITATIVE SYMPTOMS ARE
THE MOST COMMON COMPLICATIONS OF
POSTOPERATIVE INSTILLATION, SERIOUS
SEQUELAE AND RARE DEATHS HAVE OCCURRED,
ESPECIALLY IN PATIENTS WITH PERFORATION
DURING RESECTION .
• OTHER REPORTED CONDITIONS ASSOCIATED
WITH INTRAVESICAL CHEMOTHERAPY (WITH
PERIOPERATIVE OR MULTIDOSE REGIMENS)
INCLUDE CHEMICAL CYSTITIS, CUTANEOUS
DESQUAMATION, DECREASED BLADDER
CAPACITY AS A RESULT OF CONTRACTURES,
CALCIFIED ESCHARS, AND COMPLICATIONS OR

54. • CHEMOTHERAPY SHOULD BE WITHHELD IN PATIENTS WITH
EXTENSIVE RESECTION OR WHEN THERE IS CONCERN
ABOUT PERFORATION
• THE INCREMENTAL BENEFIT IN PATIENTS WITH RECURRENT
OR MULTIPLE TUMORS IS LIMITED.
• NO BENEFIT HAS BEEN FOUND IN PATIENTS WITH HIGH-
GRADE DISEASE

55. DEVICE-ASSISTED INTRAVESICAL
CHEMOTHERAPY
• MICROWAVE-INDUCED HYPERTHERMIA
• HYPERTHERMIC INTRAVESICAL CHEMOTHERAPY
• ELECTROMOTIVE DRUG ADMINISTRATION (EMDA)

57. INTRAVESICAL IMMUNOTHERAPY
• BCG IS AN ATTENUATED MYCOBACTERIUM
DEVELOPED AS A VACCINE FOR TUBERCULOSIS
THAT HAS DEMONSTRATED ANTITUMOR
ACTIVITY IN SEVERAL DIFFERENT CANCERS .

58. • BCG POWDERED VACCINE IS RECONSTITUTED WITH 50 ML OF
SALINE AND SHOULD BE ADMINISTERED THROUGH A
URETHRAL CATHETER UNDER GRAVITY
• TREATMENTS ARE TYPICALLY BEGUN 2 TO 4 WEEKS AFTER
TUMOR RESECTION, ALLOWING TIME FOR RE-
EPITHELIALIZATION, WHICH MINIMIZES THE POTENTIAL FOR
INTRAVASATION OF LIVE BACTERIA.
• FOR THE SAME REASON, A URINALYSIS IS USUALLY
PERFORMED IMMEDIATELY BEFORE INSTILLATION TO FURTHER
CONFIRM ABSENCE OF INFECTION OR SIGNIFICANT BLEEDING
TO DECREASE THE LIKELIHOOD OF SYSTEMIC UPTAKE OF BCG.
• IN THE EVENT OF A TRAUMATIC CATHETERIZATION, THE
TREATMENT SHOULD BE DELAYED FOR SEVERAL DAYS TO 1
WEEK, DEPENDING ON THE EXTENT OF INJURY.

59. • ACTIVE URINARY TRACT INFECTION IS OFTEN CONSIDERED
AN INDICATION TO DELAY TREATMENT UNTIL IT HAS BEEN
MANAGED, BUT RECENT PUBLICATIONS QUESTION THE
NEED TO AVOID BCG IN THE PRESENCE OF ASYMPTOMATIC
BACTERIURIA.
• AFTER INSTILLATION, THE PATIENT SHOULD RETAIN THE
SOLUTION FOR AT LEAST 2 HOURS.
• SOME CLINICIANS HAVE ADVOCATED THAT THE PATIENT
TURN FROM SIDE TO SIDE TO BATHE THE ENTIRE
UROTHELIUM, BUT THERE IS NO SCIENTIFIC SUPPORT FOR
THIS PRACTICE.

60. • FLUID, DIURETIC, AND CAFFEINE RESTRICTION BEFORE
INSTILLATION LIMITS DILUTION OF THE AGENT BY URINE
AND FACILITATES ADEQUATE RETENTION OF THE AGENT
FOR 2 HOURS (LAMM ET AL, 2000B).
• PATIENTS ARE USUALLY INSTRUCTED TO CLEAN THE
TOILET WITH BLEACH, ALTHOUGH THERE IS NO
DEMONSTRABLE RISK OF CLOSE CONTACT INFECTION

61. MECHANISM OF ACTION
• INTRAVESICAL IMMUNOTHERAPY RESULTS IN A MASSIVE
LOCAL IMMUNE RESPONSE CHARACTERIZED BY INDUCED
EXPRESSION OF CYTOKINES IN THE URINE AND BLADDER
WALL AND BY AN INFLUX OF GRANULOCYTES AND
MONONUCLEAR AND DENDRITIC CELLS
• THE INITIAL STEP APPEARS TO BE DIRECT BINDING TO
FIBRONECTIN WITHIN THE BLADDER WALL, SUBSEQUENTLY
LEADING TO DIRECT STIMULATION OF CELL-BASED
IMMUNOLOGIC RESPONSE AND AN ANTIANGIOGENIC STATE

63. • THE OBSERVED PATTERN OF CYTOKINE INDUCTION WITH
PREFERENTIAL UPREGULATION OF IFN-Γ, IL-2, AND IL-12
REFLECTS INDUCTION OF A T-HELPER TYPE-1 (TH1)
RESPONSE.
• THIS IMMUNOLOGIC RESPONSE ACTIVATES CELL-MEDIATED
CYTOTOXIC MECHANISMS THAT ARE BELIEVED TO UNDERLIE
THE EFFICACY OF BCG AND OTHER AGENTS IN THE
PREVENTION OF RECURRENCE AND PROGRESSION (BOHLE AND
BRANDAU, 2003).
• BCG MAY CONCOMITANTLY STIMULATE IL-10, RESULTING IN
THE SUPPRESSIVE TH2 RESPONSE

64. BACILLE CALMETTE-GUÉRIN
TREATMENT OF CARCINOMA IN
SITU
• THE AUA GUIDELINES PANEL SUPPORTED BCG AS
THE PREFERRED INITIAL TREATMENT OPTION FOR
CIS (HALL ET AL, 2007).

65. BACILLE CALMETTE-GUÉRIN
TREATMENT OF RESIDUAL TUMOR
• INTRAVESICAL BCG CAN EFFECTIVELY TREAT RESIDUAL
PAPILLARY LESIONS BUT SHOULD NOT BE USED AS A
SUBSTITUTE FOR SURGICAL RESECTION.
• INVESTIGATORS HAVE DEMONSTRATED A NEARLY 60%
RESPONSE BY RESIDUAL TUMOR WITH INTRAVESICAL BCG
ALONE.
• CARCINOMA OF THE MUCOSA OR THE SUPERFICIAL DUCTS
OF THE PROSTATE CAN BE ADEQUATELY TREATED BY BCG
WITH A 50% TUMOR-FREE RATE

66. BACILLE CALMETTE-GUÉRIN
PROPHYLAXIS TO PREVENT
RECURRENCE
• EARLY SINGLE-CENTER STUDIES DEMONSTRATED AN ADVANTAGE
IN DECREASED TUMOR RECURRENCE OF APPROXIMATELY 30%
WHEN A 6-WEEK COURSE OF BCG WAS ADMINISTERED AFTER
RECOVERY FROM TURBT
• TA, T1, AND/OR CIS DISEASE FOUND THAT PATIENTS RECEIVING
MAINTENANCE BCG HAD A STATISTICALLY DECREASED RATE OF
RECURRENCE COMPARED WITH THOSE RECEIVING INDUCTION
THERAPY ALONE .
• THE EFFICACY OF BCG AFTER TURBT FOR HIGH-RISK PAPILLARY
DISEASE HAS BEEN DEMONSTRATED IN SEVERAL SERIES OF T1
LESIONS, WITH RECURRENCE RATES OF 16% TO 40% AND
PROGRESSION RATES OF 4.4% TO 40%, A SUBSTANTIAL
IMPROVEMENT COMPARED WITH TUR ALONE

67. OPTIMUM BACILLE CALMETTE-
GUÉRIN TREATMENT SCHEDULE
• SEVERAL STUDIES SUGGEST THAT A 6-WEEK INDUCTION
COURSE ALONE IS INSUFFICIENT TO OBTAIN AN OPTIMAL
RESPONSE IN MANY PATIENTS AND THAT MAINTENANCE
THERAPY IS REQUISITE .
• BOHLE AND OTHERS REPORTED THAT 6 WEEKS WERE IDEAL
FOR MAXIMUM RESPONSE TO BCG, ALTHOUGH WE NOW
KNOW THAT MAINTENANCE DOSING ENHANCES RESPONSE
EVEN FURTHER.
• THE AVERAGE ADDITIONAL RESPONSE TO A SECOND
INDUCTION COURSE IS 25% IN THOSE PATIENTS TREATED
FOR PROPHYLAXIS AND 30% IN CIS PATIENTS

68. • ADDITIONAL COURSES OF BCG TO TREAT REFRACTORY
PATIENTS AFTER A SECOND 6-WEEK COURSE ARE
ACCOMPANIED BY A SIGNIFICANT RISK OF TUMOR
PROGRESSION IN 20% TO 50% OF PATIENTS
• RESPONSE TO BCG AT 6 MONTHS CAN BE USED AS A
PREDICTOR OF PROGNOSIS, WITH THE NUMBER OF PATIENTS
DEVELOPING PROGRESSIVE DISEASE BEING SIGNIFICANTLY
HIGHER AMONG NONRESPONDERS

69. • THE SOUTHWEST ONCOLOGY GROUP (SWOG) REPORTED
THE MOST SIGNIFICANT IMPACT OF MAINTENANCE
THERAPY. PATIENTS RECEIVED A 6-WEEK INDUCTION
COURSE FOLLOWED BY THREE WEEKLY INSTILLATIONS AT 3
AND 6 MONTHS AND EVERY 6 MONTHS THEREAFTER FOR 3
YEARS. ESTIMATED MEDIAN RECURRENCE-FREE SURVIVAL
WAS 76.8 MONTHS IN THE MAINTENANCE ARM AND 35.7
MONTHS IN THE CONTROL ARM (P = .0001).

70. • ANTIBIOTIC THERAPY MAY HAVE A BENEFICIAL EFFECT IN
TREATING OR PREVENTING SYSTEMIC SIDE EFFECTS OF BCG
THERAPY, YET IT MAY ALSO INHIBIT THE EFFECTIVENESS OF
BCG THERAPY IF IT IS GIVEN ROUTINELY FOR URINARY
TRACT PROPHYLAXIS DURING A COURSE OF BCG THERAPY
• QUINOLONES IN PARTICULAR MAY AFFECT THE VIABILITY
OF BCG AND SHOULD BE AVOIDED IF POSSIBLE DURING THE
COURSE OF BCG TREATMENTS

71. • CUETO SUGGESTED THAT IN HIGH-RISK TUMOURS, THE
MAINTENANCE SCHEDULE WITH ONLY ONE INSTILLATION
EVERY THREE MONTHS FOR THREE YEARS MAY BE
SUBOPTIMAL

75. SPECIFIC ASPECTS OF TREATMENT
OF CARCINOMA IN SITU
• TREATMENT STRATEGY
-THE DETECTION OF CONCURRENT CIS INCREASES THE RISK
OF RECURRENCE AND PROGRESSION OF TaT1 TUMOURS.
- CARCINOMA IN SITU CANNOT BE CURED BY AN ENDOSCOPIC
PROCEDURE ALONE.
- HISTOLOGICAL DIAGNOSIS OF CIS MUST BE FOLLOWED BY
FURTHER TREATMENT, EITHER INTRAVESICAL BCG
INSTILLATIONS OR RC .
- TUMOUR-SPECIFIC-SURVIVAL RATES AFTER IMMEDIATE RC
FOR CIS ARE EXCELLENT, BUT AS MANY AS 40-50% OF
PATIENTS MIGHT BE OVER TREATED

76. • IN RETROSPECTIVE EVALUATIONS OF PATIENTS WITH CIS, A
COMPLETE RESPONSE RATE OF 48% WAS ACHIEVED WITH
INTRAVESICAL CHEMOTHERAPY AND 72-93% WITH BCG

77. TREATMENT OF CIS IN PROSTATIC
URETHRA AND UPPER URINARY
TRACT
• SOLSONA ET AL. FOUND THAT 63% OF PATIENTS WITH CIS
DEVELOPED EXTRAVESICAL INVOLVEMENT INITIALLY OR
DURING FOLLOW-UP.
• PATIENTS WITH EXTRAVESICAL INVOLVEMENT HAD WORSE
SURVIVAL THAN THOSE WITH BLADDER CIS ALONE

78. • IN THE PROSTATE, CIS MIGHT BE PRESENT ONLY IN THE
EPITHELIAL LINING OF THE PROSTATIC URETHRA OR IN THE
PROSTATIC DUCTS.
• THESE SITUATIONS SHOULD BE DISTINGUISHED FROM TUMOUR
INVASION INTO THE PROSTATIC STROMA (STAGE T4A IN
BLADDER TUMOURS), AND FOR WHICH IMMEDIATE RADICAL
CYSTOPROSTATECTOMY IS MANDATORY.
• PATIENTS WITH CIS IN THE EPITHELIAL LINING OF THE
PROSTATIC URETHRA CAN BE TREATED BY INTRAVESICAL
INSTILLATION OF BCG. TRANSURETHRAL RESECTION OF THE
PROSTATE CAN IMPROVE CONTACT OF BCG WITH THE
PROSTATIC URETHRA.

79. • IN PATIENTS WITH PROSTATIC DUCT INVOLVEMENT, THERE
ARE PROMISING RESULTS OF BCG, BUT ONLY FROM SMALL
SERIES.
• THE DATA ARE INSUFFICIENT TO PROVIDE CLEAR
TREATMENT RECOMMENDATIONS AND RADICAL SURGERY
SHOULD BE CONSIDERED

81. TREATMENT OF FAILURE OF
INTRAVESICAL THERAPY
• FAILURE OF INTRAVESICAL CHEMOTHERAPY
-PATIENTS WITH NMIBC RECURRENCE AFTER A
CHEMOTHERAPY REGIMEN CAN BENEFIT FROM BCG
INSTILLATIONS.
-PRIOR INTRAVESICAL CHEMOTHERAPY HAS NO IMPACT
ON THE EFFECT OF BCG INSTILLATION

82. CATEGORIES OF UNSUCCESSFUL
TREATMENT WITH INTRAVESICAL
BCG

83. TREATMENT OF BCG FAILURE AND
RECURRENCES AFTER BCG

84. RADICAL CYSTECTOMY FOR
NMIBC
• THERE ARE SEVERAL REASONS TO CONSIDER IMMEDIATE RC
FOR SELECTED PATIENTS WITH NMIBC:
-THE STAGING ACCURACY FOR T1 TUMOURS BY TURB IS LOW
WITH 27-51% OF PATIENTS BEING UPSTAGED TO MUSCLE-
INVASIVE TUMOUR AT RC.
-SOME PATIENTS WITH NMIBC EXPERIENCE DISEASE
PROGRESSION TO MUSCLE-INVASIVE DISEASE.
-PATIENTS WHO EXPERIENCE DISEASE PROGRESSION TO
MUSCLE-INVASIVE STAGE, HAVE A WORSE PROGNOSIS THAN
THOSE WHO PRESENT WITH ‘PRIMARY’ MUSCLE-INVASIVE
DISEASE .

90. THANK YOU