Approach to non- muscle invasive bladder cancer and management .Details about Risk Stratification , TURBT & Intravesical Therapy.

1. Dr.Bhavin Vadodariya
Management of
Non- Muscle Invasive Urinary bladder

2. OUTLINE
 EPIDEMIOLOGY
 RISK FACTORS
 STAGING
 GRADING
 DEFINITION OF NMIBC
 CIS
 DIAGNOSIS
 MOLECULAR MARKERS
 ENDOSCOPIC RESECTION
 HISTOPATHOLOGY REPORT
 PREDICTING RECURRENCE AND PROGRESSION
 ADJUVANT TREATMENT

3. Epidemiology

5. Epidemiology
 Bladder cancer is the 10th most common form of cancer
worldwide, with an estimated 549,000 new cases and
 200,000 deaths (Table 1).
 Bladder cancer is more common in men than in women, with
respective incidence and mortality rates of 9.6 and 3.2 per
100,000 in men: about 4 times those of women globally .
 Thus the disease ranks higher among men, in whom it is the
sixth most common cancer and ninth leading cause of cancer
death
National Cancer Institute, Bladder cancer

6.  Incidence rates in both sexes are highest in Southern Europe
(Greece, with the highest incidence rate in men globally;
Spain; Italy), Western Europe (Belgium and the Netherlands),
and Northern America, although the highest rates are
estimated in Lebanon among women .

7.  Other than certain occupational exposures to
chemical and water contaminants, cigarette smoking
is the main risk factor for bladder cancer and, with the
rising prevalence of smoking among women, the
attributable risk, at least in the United States, has
reached that among men, with 50% of bladder cancer
cases attributable to smoking in both sexes

8. Risk Factors

10. Staging

11. Dr chanchal
Management of
Carcinoma Urinary bladder

12. Superficial Locally Invasive Metastatic
Bladder Cancer
70% 25% 5%

13. Bladder Anatomy
 The urinary bladder has 3 distinct histologic layers
 Urothelium
 Lamina Propria
 Detrusor (Muscularis Propria)

17. CIS
 Multifocal and can occur in the upper urinary
tract
 54% - progress to muscle-invasive disease
 Response to intravesical treatment with BCG or
chemotherapy is an important prognostic
factor
 Carcinoma in situ is classified into
 Primary: isolated CIS with no previous or
concurrent exophytic tumours;
 Secondary: CIS detected during the follow-up of
patients with a previous tumour;
 Concurrent: CIS in the presence of exophytic
tumours.[worse prognosis]

18. Diagnosis of non muscle invasive
Bladder Cancer

19. Clinical Presentation
 Hematuria: 80% of TCCs
 Gross- in 85%
 Microscopic( in all patients)
 Degree of hematuria is independent of disease grade/stage
 Often asymptomatic
 Bladder irritability
 Most common with CIS
 Frequency
 Urgency
 Dysuria

20. When is Hematuria a symptom of bladder
cancer?
 Gross painless hematuria
20%- will have urological malignancy
12%- will have bladder cancer
 Microscopic hematuria
5.4% -have a urological malignancy
4.1%- have bladder cancer
 Many benign conditions associated with hematuria
 Symptoms help to distinguish
 Bladder cancer workup indicated if persistently >3-5 RBCs/high-power field
on microscopic examination
 Some feel workup indictaed for any hematuria Tumer AG et al. BMJ.1997;2:29
Carson CC et al. JAMA.1979;241:149
Amling CL. Curr Pronl Cancer.2001;25:219

21. EVALUATION OF HEMATURIA
GROSS HEMATURIA
• CYSTOSCOPY
• URINE CYTOLOGY
• UPPER URINARY TRACT
IMAGING[CT SCAN]
• Sr.PSA [10% will have prostatic
cancer]
MICROSCOPIC
HEMATURIA[AUA]
• CYSTOSCOPY
• UPPER TRACT IMAGING
• URINE CYTOLOGY
• REPEAT EVALUATION Every 6
months for high risk patients

22. Cystoscopy
 Gold standard
 Complete visualization of urethral and bladder mucosa: allows
biopsy/resection of any lesion
 Invasive
 Can be performed with minimal discomfort with topical local
anaesthesia in the urethra
 Standard schedule (q3-4mo) not based on clinical validation
 Expensive
 Sensitivity: 73%, specificity: 68.5%
 Can be enhanced to 97% sensitivity with 5-aminolevulinic acid –
indiuced fluorescence, but not widely practiced
Kriegmair M et al. J Urol.1996;155:105

23. Endoscopic Assessment
At initial diagnostic cystoscopy it is necessary to document the foll:
Tumor – Size, Number, Position
Growth pattern ( Papillary or Solid)
Mucosa – Normal, red areas or area of red,
irregular mucosa
Lower tract – The Urethra, The Prostate
Bimanual - Is there mass before resection ?
exam Is there mass after resection ?
Size of mass and mobility

24. Examples of Cystoscopic
Imaging

25. Carcinoma in Situ

26. FLUORESCENT CYSTOSCOPY
 5-aminolevulinic acid (5-ALA)
 A precursor to heme biosynthesis is instilled into the bladder
 Taken up by neoplasms
 Blue light excites the agent and can detect otherwise unseen CIS on white
light
 Additional detection rate
20% - for all tumors
23% - for CIS
9% - Reduction in risk of recurrence at 9 months
 Many false + due to inflammatory lesions

27. Fluorescent Cystoscopy

28. Fluorescent Cystoscopy

29. Urine Cytology
 Standard, non-invasive, tumor-specific marker test
 Adjunct to cystoscopy
 Major role
 Detect high-grade tumors
 Detect carcinoma in situ
 Defined criteria for malignant cells
 Increased nuclear to cytoplasmic ratio
 Prominent nucleoli
 Requires trained cytopathologist
 Significant interpretation variability

30. Urine Cytology…
 Sensitivity: 38-60%
 Misses low grade tumors
 Specificity: 95-100%
 Excellent for high-grade tumors
 Bladder wash vs voided urine
 Increase exfoliated cells
 Invasive
 Instrument artifact
 Not cost-effective
 No significant difference Raitanen MP et al. Eur Urol.2002;41(3):284-289
Amling CL. Curr Pronl Cancer.2001;25:219
Ramakumar S et al. J Urol.1999;161:388-394

31. Markers
It is generally accepted that none of the currently available tests
can replace cystoscopy. However, urinary
cytology or biomarkers can be used as an adjunct to
cystoscopy to detect invisible tumours, particularly CIS

32. IMAGING
 INTRAVENOUS UROGRAPHY
detect filling defects in the calyces, renal pelvis and ureters, and
hydronephrosis
 CT SCAN
in muscle-invasive tumours of the bladder
in upper tract tumours
tumors located in trigone
 USG
characterisation of renal masses,
detection of hydronephrosis and
visualisation of intraluminal masses in the bladder

33. Imaging- CT vs. MRI

■ CT is unreliable for staging tumours confined to the bladder wall
■ CT is accurate for staging advanced disease
■ MR imaging is superior to CT for staging early tumours
■ Contrast-enhanced MR is probably superior to unenhanced MR for staging
bladder cancer
■ CT and MR both have important limitations leading to over staging and under
staging.
■ CT and MR are equal in their ability to detect lymph node involvement
■ CT and MR may be useful for monitoring response
■ CT and MR are valuable for detection of recurrence

34. Treatment of Superficial Bladder
Cancer

35. Treatment options
 Transurethral resection (TUR)
 Laser treatment
 Photodynamic therapy
 Intravesical therapy
 Chemotherapy
 BCG
 Interferon
 BCG + interferon
• Role of cystectomy

36. TURBT
 TURBT under regional or general anaesthesia is the initial treatment
for visible lesions and is performed to
(1) remove all visible tumours and
(2) provide specimens for pathologic examination to accurately
determine stage and grade.

37. Before TURBT
 Urine cytology
 Bimanual Examination
 Pan cystoscopy- lesion evaluation
 Avoid over distension- (50-70%)- prevent perforation and improve
visibility of CIS

38. Bimanual Examination
 Under GA , before painting and draping
 Should be done before and after resection.
 Fixation or persistence of a palpable mass after resection suggests
locally advanced disease.
 Not necessary if the tumor is clearly small and noninvasive, and is
repeated

39. Anaesthesia
 The use of general anesthesia with muscle-paralyzing agents also
prevents obturator reflex.
 A direct injection of 20 to 30 mL of local anesthetic (lidocaine) into the
obturator nerve and its canal can also help.

40. Surgical principles
 Fexible cystoscope or preferably the 70-degree rigid rod lens, which
allows maintenance of the anatomic relationships .
 low-grade tumours can often be removed without the use of electrical
energy .
 Lifting the tumour edge away from detrusor lessens the chance of
perforation
 After all visible tumour has been resected, an additional pass of the
cutting loop or a cold-cup biopsy can be obtained to send to pathology
separately to determine the presence of muscle invasion of the
tumour base

41. Cauterization
 Monopolar electrode can transmit and disperse energy through normal saline
so sterile water or gylcine should be used.
 Introduction of bipolar electroresection is reported to allow TUR in saline and
to minimize the risk of the obturator reflex, which can predispose to bladder
perforation
 A successful cauterization method involves placing the electrode inside the
biopsy site with the bladder under minimal distention.

42. Cauterization
 When the electrode touches the cut surface of the biopsy crater, the
electrical energy will cause the mucosa to contract around the electrode
unless the bladder is full.
 Light irrigation clears the area of blood and vaporization bubbles created
during fulguration.
 Visualizing a small (1 to 2 mm) ring of white coagulation confrms
hemostasis and yields less damage to the bladder than that occurring
when the biopsy area is “painted” with cautery.

43. Diverticular tumours
 Signifcant risk of bladder wall perforation, and accurate staging is diffcult to
achieve because the underlying detrusor is absent.
 Low-grade diverticular tumors are best treated with a combination of
resection and fulguration of the base.
 Conservative resection can be followed with subsequent repeat resection if
the final pathologic interpretation is high grade.
 High-grade tumors require adequate sampling of the tumor base, often
including perivesical fat, despite the near certainty of bladder perforation.
 Partial or radical cystectomy should be strongly considered for high-grade
diverticular lesions.

44. Anterior wall tumours and tumours at
the dome
 These tumours in patients with large bladders can be difficult to reach.
 Minimal bladder filling combined with manual compression of the lower
abdominal wall to bring the tumor toward the resectoscope facilitates
removal. However, modern resectoscopes are long enough to reach the
entirety of most bladders.
 Creation of a temporary perineal urethrostomy offers deeper access but is
rarely necessary except in the obese patient with an inaccessible tumor.
 Digital manipulation through the rectum or vagina can occasionally
facilitate resection

45. URETERAL ORIFICES
 Care must be taken during resection near the ureteral orifIce to
prevent obstruction from scarring after fulguration.
 Pure cutting current causes minimal scarring and may be safely
performed, including resection of the orifce if necessary.
 Resection of the intramural ureter can sometimes lead to complete
eradication of the tumor but risks reflux of malignant cells.
 The clinical implications of this are unclear

46. Pathologist should comment on:
 Size
 Tumour grade
 Depth of tumour invasion,
 Presence of CIS
 Whether the muscle is present in the specimen.
 Specify the presence of LVI or unusual (variant) histology
If there is uncertainty over the pathology, a further early reresection should be done
within 6 wk.

47. Endoscopic Management
Complications
 Obturator reflex perforation
 Bleeding
 TUR Syndrome
 UO Obstruction
 Unrecognized disease
 Perforation
 Extraperitoneal
 Intraperitoneal

48. ROLE OF ‘R’ BIOPSIES
 RANDOM BIOPSY FROM BLADDER
 Positive urinary cytology and absence of visible tumour in the bladder.
 Exophytic tumour has a non-papillary appearance.
Trigone, bladder dome and from right, left, anterior and posterior bladder
walls.
 PROSTATIC URETHRAL BIOPSY- 11% synchronous malignancy
 Tumour is located on the trigone or bladder neck
 In the presence of bladder CIS
 Multiple tumour
 Abnormalities of prostatic urethra are visible
Biopsy is taken from abnormal areas and from the precollicular area (between 5 and
7o’clock position) using a resection loop.

49. Second look TURBT?
Indications
 Residual disease after initial TURBT.
 When specimen contained no muscle.
 High-grade and/or T1 tumor.
Timing and strategy:
 Most recommend within 6 weeks after initial TUR.
 Should include complete resection of primary tumor site.
Evidences for the need of 2nd look TURBT in T1 /HG tumor-
 1/2 will have residual disease on 2nd look [EAU 2010]
 Under stage is more likely if muscle is absence (50% vs 15%) [Herr JU 1999]
 1/4 will have upstage [Herr JU1999]
 1/3 will have to change management [Herr JU 1999]
 20% increase 5yr DFS in pts with complete TURBT[Germen observational study
2003]
European Association of Urology Guidelines.

50. What Next?- Risk Stratification &
Normograms

51. Treatment recommendations in Ta, T1 tumours and CIS
according to risk stratification-EAU 2018

53. Predicting recurrence and progression
EORTC Tables

56. CUETO - http://www.aeu.es/Cueto.html.
 A scoring model for BCG-treated patients that predicts the
short- and long-term risks of recurrence and progression has
been published by the Club Urológico Español de
Tratamiento Oncológico (CUETO)
 Gender;
 Age;
 Prior recurrence status;
 Number of tumours;
 T category;
 Associated CIS;
 Tumour grade.

57. Principles of Intravesical treatment

58. Why Intravesical ?
 It permits high local concentrations of a therapeutic
agent within the bladder
 It can potentially destroying viable tumor cells that
remain following transurethral resection of all visible
bladder tumor (TURBT).

61. Superficial Bladder Cancer
Intravesical Therapy
Chemotherapy
Thiotepa
Doxorubicin
Epirubicin
Mitomycin
Ethoglucid
Immunotherapy
BCG
Interferon
Interleukin-2
KLH

62. Perioperative intravesical Mitomycin C
 The standard dosage of Mitomycin C is 40 mg in 20 cc sterile water.
 Best time to install is first 6 hrs, can be given within 24 hrs.
 Overnight dehydration,
 Ultrasound-confirmed complete bladder emptying,
 Alkalinization using 1.3 g of sodium bicarbonate the night before,
morning of, and 30 minutes prior to treatment.
 As Mitomycin C is inactivated by acid urine (Au et al. 2001).

63. Contraindications to perioperative MMC
 Hypersensitivity,
 Bladder perforation,
 Hematuria
 Myelosuppression,
 Thrombocytopenia.

65. Conclusion-
 An immediate single instillation of MMC within 24 h
after TURBT reduces the recurrence risk and prolongs
the time to recurrence compared with a single
delayed instillation of MMC 2 wk after TURBT in
patients with NMIBC.
 Patients treated with adjuvant schedules of
chemotherapy also benefit from an immediate
instillation.

66. Timing of Perioperative Mitomycin C (MMC)
 205 patients with frequently recurrent stage Ta or T1 tumors
in FinnBladder IV treated with 2 chemoimmunotherapy
regimens
-Kaasinen E et al. Eur Urol.2002;42:167

68.  N=495,
 Recurrent ,multifocal Ta & T1 all grades- Intermediate & High
Risk
 Group 1- BCG RIVM 2 108 CFU weekly for 6 wk,
 Group 2- MMC 20 mg weekly for 6 wk,
 Group 3- MMC 20 mg weekly for 6 wk followed by monthly
instillations for 3 yr

69.  Long-term MMC significantly reduced the risk of
tumour recurrence without enhanced toxicity
compared with both short-term BCG and MMC in
patients with intermediate- and high-risk non–muscle-
invasive bladder carcinoma

70. Intravesical Chemotherapy After TUR
Net Effect on Recurence rate.
-Lamm DL et al, J Urol; 1995; 153(5):1444-50.

71. Benefits of Intravesical Chemo
 Modest decrease in short term tumour recurrence (up to 2-3 years)
 Recurrences same as in controls at 5 years or later
 No reduction in risk of stage progression
 Does not improve patient survival

72. Bacillus Calmette-Guerin
 Live attenuated vaccine produced by serial sub culturing of bovine
tubercle bacilli in which the bacilli maintain their antigenicity but virulence
is nearly lost.

73. Immunotherapy
Bacillus Calmette Guerin (BCG)-
 Developed from live attenuated strain of M. bovis
 Stains commonly used in US
 Tice
 TheraCYS
 Stains commonly used in India-
 Danish 1331
 Tokyo 172
Mechenism of action-
 Acts as immune stimulant: stimulates cellular immune response
releasing cytokines IL-1,2,6,8,TNF and IFN gamma.
 Activation of resting NK cells which further kill the malignant cells via
perforin.

74. Mechanism of action of BCG
 Induces massive local immune response
 1ststep-direct binding to fibronectin on bladder mucosa
 Cytokine induction:IFN-g,IL1,IL2,IL5,IL6, IL8, IL10,IL12,IL18
 Th 1 response, influx of granulocytes and mononuclear cells.
 Cell mediated cytotoxic mechanisms which underlie efficacy of BCG.
-Bohle and Brandau, J Urol 2003; 170:964-969.

75. Mechanism of Action of Intravesical BCG

76. Why BCG
 BCG is the most commonly used agent for intravesical
therapy.
 A number of other intravesical agents have been
compared with BCG, but most are inferior, and none
has consistently proven to be superior .

77. EAU,AUA,CUA Recommendations
 For all patients with high-risk non-muscle invasive
bladder cancer, a course of intravesical BCG following
a restaging TURBT is indicated rather than intravesical
chemotherapy.
 Intravesical BCG is also an option for appropriately
selected patients with intermediate-risk disease.

80. Immunotherapy
Dose and schedule of BCG-
 Initiated 3-4 weeks after resection.
 Induction therapy as weekly for 6 cycles f/b maintenance as 3 weekly for a 1-3 year
(3yr better for high risk cases).
 50 mg of TICE or 80 Mg Denish 1331 in 50cc of 0.9% NS is instilled via catheter.
 Catheter must be removed immediately.
 Ask the pt to hold the urine for 2 hr.
S/E :
 Urinary frequency ,dysuria, hematuria.
 Arthralgia, rash, fever.
 Pneumonitis, hepatitis, prostatitis, sepsis.

82. Trails for BCG dose and schedule
EORTC phase III trial – Dose – 1/3 dose V/S a full dose
Duration - 1-year V/S 3-year treatment
 Four different arms were made as per doses and duration regarding
schedules of BCG maintenance therapy.
Conclusion-
 No meaningful differences in toxicity, progression recurrence and
survival were observed in low risk patients.
 However, the recurrence rate was lowest in high-risk patients treated
with the full dose therapy for 3 years, supporting current treatment
recommendations.

83. Eortc conclusion
 There were no significant differences in the toxicity
profiles between full and reduced doses of BCG.
 There was no additional benefit to three years of
maintenance treatment compared with one year for
patients with intermediate-risk disease given full-dose
BCG.

84. Trails for BCG dose and schedule
SWOG trial-
 Compared Induction Vs Induction +3 wkly BCG maintenance therapy.
 6 cycle of weekly induction therapy.
 3 weekly maintenance therapy at 3, 6, 12, 18, 24, 30, 36 months (3 yrs).
 No difference in overall 5 yr survival.
 Improvement in:
 Recurrence free survival (60% vs 41%)
 Progession free survival(76% vs 70%)
 But only 16% tolerated full dose 3 yr therapy.

85. Maintenance BCG
SWOG TRIAL(1995)

86. Effect of Intravesical BCG on
Disease Progression
 Reduces stage progression rate
 Reduces progression to muscle invasion
 Increases progression-free interval
 Reduces no of patients requiring cystectomy
 Increases period of bladder preservation
 Reduces no of deaths from disease
 Increases disease specific survival

87. Instructions to the patients after BCG
therapy

88. FDA Package insert- Patient instructions
 Limit Fluid intake for 4 hrs prior to concentrate urine.
 Empty bladder and get done Urine routine micro
 Catheterisation upn to 2 hrs post procedure.
 Sit down on toilet to urinate so avoid splashing of
urine on restroom surface and avoid surface
contamination.

89. FDA Package insert- Patient instructions
 After 6 hrs, pour household bleach into toilet or 20
minutes ,do this after every frequency.
 Wash hands and genitals after each frequency.
 For 24-72 hours patient may experience burning
micturition,frequency and urgency.
 Contact doctor if fever, rash , arthralgia or hematuria

90. Toxicity of BCG
 Toxicity can be Acute or Late Onset
 Acute toxicity can be Local or Systemic.
 Local toxicity- cystitis , frequency , urgency, gross hematuria ,
suprapubic pain , urge incontinence , passage of shreds in
urine , perineal pain , penile pain.

91. Systemic toxicity
 Flu like symptoms – fever ,malaise ,chills, myalgia, headache ,
arthralgia ,anorexia, diarrhea, nausea.
 Polyarthritis
 Deranged LFT’s
 Lung infiltrates
 Non BCG acid fast bacilli infection
 Severe hypersensitivity reaction with shock
 Death

92. Late toxicity of BCG
 Increased bladder irritability
 Reduced bladder capacity
 Granulomatous cystitis
 Bladder contracture
 Prostatic urethritis
 Granulomatous prostatitis

93. Cleveland Clinic Guidelines for management of BCG toxicity
Grade 1: Mild to moderate irritative voiding symptoms,
Mild hematuria,
Fever<38.5C
All symptoms for <48 hrs.
Management: Symptomatic only.
Anticholinergics ,
Topical anti spasmodics(phenazopyridine)
Analgesics and NSAIDS .

94.  Grade II toxicity
 Severe irritative voiding symptoms ,
 Gross hematuria or any symptoms > 48 hrs.
 Assessment : Urine C/S, CXR , LFT
 Management :
 Symptomatic Rx +
 Treat C/S report with appropriate antibiotics.
 Start INH 300mg with R’cin 600mg PO till symptoms resolve.
Cleveland Clinic Guidelines for Mx of BCG toxicity

95.  Grade III toxicity
 Serious complications with persistant high grade fever,
 Hemodynamic changes,
 Allergic reactions (joint pains),
 Solid organ involvement (epididymitis,osteomyelitis, lung ,liver ,
kidney,prostate involvement)
 Management : All maneuvers for gr.I & II
 INH 300mg + R’cin600mg for 3-6 mths.
 Ethambutol 15mg/kg/day if solid organ involvement
 Prednisone 40 mg/day if response inadequate
 IV steroids(with antibiotic cover) in septic shock
Cleveland Clinic Guidelines for mx of BCG toxicity

96. Contraindications to BCG
Absolute contraindications
 Immunocompromised patients
 Immediately after TURBT(
intravasation and septic death)
 Gross hematuria(intravasation risk)
 Traumatic catheterisation
 Total incontinence(patient will not
retain the agent)
 Past h/o BCG sepsis
Relative contraindications
 UTI (intravasation risk)
 Liver disease (cannot give INH if
sepsis occurs)
 Personal H/O TB
 Poor performance status
 Advanced age( especially >80yrs)

98. Specific scenario
On follow up if Cytology +ve
with Cystoscopy –ve 
Cystoscopy plus-
 Imaging of urinary tract
 Mapping biopsies
 TUR biopsy of prostate
 Cytology of upper tract
 Ureteroscopy
If biopsy +ve then treat
accordingly-
Upper tract positive
Prostate positive.
Prostatic urethra positive.
If biopsy –ve close follow up

99. FOUR SUBTYPES OF BCG FAILURE
BCG refractory disease -Failure to achieve a disease free state by 6 mon. after initial
BCG therapy
OR
-Either maintenance or re-t/t at 3 mon. due to either persistent or
rapidly recurrent disease
-Also include any progression in stage or grade or disease extent by
3 mon after the 1st cycle of BCG (non-improving or worsening the
dis)
BCG resistant disease -Persistence of disease at 3 mon after induction cycle
BUT
- It is of lesser degree / stage / grade & no longer +nt after 6 mon
of BCG re-t/t with or without TUR
BCG relapse disease Recurrence of tumor after disease free status of 6 mon of BCG 
EARLY - < 12 mon
INTERMEDIATE – 12-24 mon
LATE - > 24 mon
BCG intolerant disease Therapy needed to be terminated due to BCG related serious
adverse event before adequate therapy.

101. FACTORS ASSOCIATED WITH RISK OF
BCG FAILURE
Pathological factors
 Multifocality,
 Recurrent tumours,
 Associated CIS (particularly in the prostatic urethra),
 Lymphovascular invasion,
 Detectable disease at 3-month cystoscopy,
 Depth of lamina propria invasion,
 Timing of failure (early vs. Late), and
 Two or more prior courses of BCG
Yates D et al. Eur Urol 2012

102. FACTORS ASSOCIATED WITH BCG
FAILURE
 Micrometastatic disease diagnosis is notoriously
suboptimal.
 Patients with NMIBC may already harbour
micrometastatic disease.
 Long- term outcome of patients initially receiving
cystectomy at the T1 stage ….. the prevalence of
micrometastatic disease often underappreciated.
Patard et al. Eur Urol 2002

103. Post Rx Recurrence

104. EAU 2018- Rx options BCG Failure

105. Post Rx Recurrence
Two groups of patients presented with recurrence-
 Who were under observation after initial TURBT—
 Repeat TURBT f/b intravesical therapy
 Then followed at 3 months interval.
 Recurrence following intravesical Rx.—
 Can be given a second induction course of BCG or mitomycin C.
No more than 2 consecutive induction course should be given because
such patients will fail 80% of time and presented with rapid disease
progression.

106. If after second course of BCG , residual ds
is seen at 3month follow-up TURBT
 If Tis or cTa–
 Different intravesical agent OR cystectomy.
 Options for further intravesical treatment after BCG failure include
-low dose BCG (1/3 rd dose) plus IFNα-2B
- gemcitabine
- valrubicin
- docetaxel
 If high grade cT1—
 Cystectomy

107. If after second course of BCG , residual disease is NOT seen at
3month follow-up --
 Maintenance therapy with BCG
 Maintenance therapy for 1 to 3 years.
 In high risk pts 3 year therapy had better results-
 Better reduction in local recurrence rate.
BUT
 Not impact progression or survival.

108. Post Rx Recurrence
When the disease is found to progress into the muscularis
propria (T2 or greater)-
 Radical cystectomy is indicated.

109. Indications for cystectomy
 T1 tumors with lymphovascular invasion or
micropapillary features
 Large/diffuse T1 grade 3 tumors are unable to be
completely resected
 Pure squamous cell, or adenocarcinoma histology
 Prostatic duct/acinar carcinoma in situ (CIS)
 Women with bladder neck and/or urethral CIS

110. Relative indications for cystectomy
 Ta or T1 grade 3 associated with Tis; T1b tumors (ie,
deep or extensive involvement of lamina propria)
 Persistent T1 grade 3 tumors identified on re-resection
 Recurrent or persistent disease within 6 to 12 months
of initiating treatment with Bacillus Calmette-Guerin
(BCG)
 Large-volume high-grade disease

111. Patients unsuitable or unwilling for cystectomy*
 Combination of INF alfa with dose reduced BCG
 Partial cystectomy
 Photodynamic therapy
 Radiation therapy(only for palliative purposes)
 *most of the therapies are investigational
Management of BCG failure

112. Radical cystectomy remains the gold standard for recurrent
BCG refractory T1 disease.
Justification for this approach-
 Ten-year cancer-specific survivals is 80% as compared with 50% in
patients in whom the cystectomy is performed when the disease
progresses to involve the muscularis propria.
 There is an open protocol RTOG 0926 - evaluating chemoradiation
for T1 lesions.

113. When to consider IFN and BCG
 BCG failure occurred > 1year after BCG treatment
 Multi-focality
 Stage: T1 vs Ta
 Large tumour size: >5cm vs 1cm
 Age ; 80 yrs vs 61-70 yrs,
39% 2-year CFS vs 61% CFS

114. Valrubicin
 FDA- approved treatment of BCG refractory CIS in
patients who are not candidates for cystectomy

115. Valrubicin
 Six weekly instillations of 800 mg intravesical valrubicin
 90 patients with recurrent CIS after BCG;
 21% had a Complete Response with a median follow-up of 30
months,
 but only seven (8%) remained disease-free at the end of the
study.
 In all, 56% had a Radical Cystectomy, including 15% with ≥ T3
disease
Steinberg et al; The Valrubicin Study Group. J Urol 2000; 163:
761–7

116. GEMCITABINE
 Dalbagni et al.
 Phase 2 study of 30 patients with NMIBC who were deemed ‘BCG
failures’.
 The patients received two courses of intravesical gemcitabine twice
weekly at a dose of 2000 mg/100 mL for three consecutive weeks.
 The median follow-up was 19 months.
 The complete response rate -50%
 1-year recurrence-free survival rate - 21%.
 37% ultimately required a radical cystectomy

118. High Risk Management

122. CONCLUSION
 BCG failure group is a heterogeneous group; no universally agreed
definition
 Combination of clinical, pathological factors to predict BCG response
 Cystectomy remains the standard of care for high-risk patients who fail
BCG therapy
 Responses to salvage intra-vesical treatments after BCG failure vary;
considered investigational
 There is limited evidence on which option is most beneficial. Induction
vs maintenance