2. MODERATORS:
Professors:
Prof. Dr. G. Sivasankar, M.S., M.Ch.,
Prof. Dr.A. Senthilvel, M.S., M.Ch.,
Asst Professors:
Dr. J. Sivabalan, M.S., M.Ch.,
Dr. R. Bhargavi, M.S., M.Ch.,
Dr. S. Raju, M.S., M.Ch.,
Dr. K. Muthurathinam, M.S., M.Ch.,
Dr. D.Tamilselvan, M.S., M.Ch.,
Dr. K. Senthilkumar, M.S., M.Ch.
DEPT OF UROLOGY, GRH AND KMC, CHENNAI. 2
3. DEFINITION
Malignant urothelial tumors that have not invaded the detrusor
Traditionally – superficial bladder cancer
3
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
4. NMIBC
CIS – High grade, flat
malignancy confined to
urothelium
Ta – papillary tumor
confined to urothelium
T1 – Papillary tumors
invading lamina propira 4
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
5. NON MUSCLE INVASIVE ≠ NON INVASIVE
T1 and CIS, as compared toTa, have high malignant potential
“Superficial tumors” – misleading
T1 – invasive with lamina propria invasion
Deep lamina propria invasion with muscularis mucosa –
Subcategorised as T1b
EAU 2018 – do not use the term “superficial bladder cancer”
5
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
6. INCIDENCE
70% - non-muscle invasive at presentation
70% - Ta
20% - T1
10% CIS
6
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
7. PATHOLOGIC GRADING
1973WHO 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
7
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
9. OTHER PROGNOSTIC FACTORS
Tumor size
Multiplicity
Papillary versus sessile configuration
Presence or absence of lymphovascular invasion
Status of remaining urothelium
9
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
10. GENETICS
Dual molecular lines
Low grade
Few chromosomal abnormalities
Loss of all or part of chromosome 9q
FGFR3 mutations
High grade
Numerous and greatly variable chromosomal gains / losses
Loss of all or part of chromosome 9q
Aneuploidy of chromosomes 7,9 and 17
TP53, RB mutations 10
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
11. PUNLMP
Papillary urothelial neoplasm of low malignant potential
Low risk
Unlikely to progress
Considered benign
Orderly cellular arrangement, minimal architectural abnormalities, minimal
nuclear atypia
WHO recommendation for Pathology report
“Patients with these tumors are at risk of developing new bladder tumors
(‘recurrence”), usually of similar histology; However occasionally these
subsequent lesions manifest as UC, such that follow-up is warranted” 11
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
12. HISTOLOGICAL CLASSIFICATION OF FLAT
LESIONS – WHO 2004
Urothelial proliferation of uncertain malignant potential (flat
lesion without atypia or papillary aspects).
Reactive atypia (flat lesion with atypia).
Atypia of unknown significance.
Urothelial dysplasia.
Urothelial CIS - always high grade
12
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
13. CIS
Flat, high-grade, non-invasive urothelial carcinoma.
Precursor of invasive high-grade cancer
Missed or misinterpreted as an inflammatory lesion during
cystoscopy if not biopsied.
Often multifocal - in the bladder, but also in the upper urinary
tract (UUT), prostatic ducts, and prostatic urethra
13
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
14. CIS – CLASSIFICATION
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
14
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
15. CIS
Composed of severely dysplastic urothelium
Disorderly histology with nuclear atypia characteristic of high
grade malignancy
40 – 83% - develop muscle invasion if untreated, especially if
associated with papillary tumors
CIS – second most important prognostic factor after grade
15
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
16. TA
Low grade
Recurrence common
Progression rare
2.9 – 18 % - high grade
16
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
17. T1
Usually papillary with narrow stalk
Nodular / sessile → deeper invasion
Increased risk of recurrence/progression with
Deep penetration involving muscularis mucosae
Lymphovascular invasion
Bladder neck involvement
17
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
18. RISK OF UNDERSTAGING
Significant potential for understaging high-grade, apparently
NMIBC
Many tumors – more extensive / muscle invasive thanTUR
specimen when cystectomy is performed
18
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
20. CLINICAL FEATURES
Haematuria - most common finding
Visible haematuria was found to be associated with higher stage
disease compared to nonvisible haematuria at first presentation
Carcinoma in situ - lower urinary tract symptoms, especially
irritative voiding.
20
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
21. DIAGNOSIS
Physical examination does not reveal NMIBC
Transabdominal US
Permits characterisation of renal masses, detection of hydronephrosis,
and visualisation of intraluminal masses in the bladder
For detection of obstruction in patients with haematuria.
Cannot exclude the presence of UTUC and cannot replace CT
urography in bladder cancer detection.
21
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
22. CT UROGRAPHY
Detect papillary tumours in the urinary tract – filling defects
Tumours located in the trigone
Multiple tumors
High-risk tumours
Intravenous urography (IVU) - Alternative
22
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
23. CT UROGRAPHY
Upper tract imaging usually performed beforeTUR
To identify other sources of hematuria
To assess the extravesical urothelium because of the field change
nature of UC
Retrograde pyelography or ureteroscopy can be planned for any
upper tract abnormalities identified.
The diagnosis of CIS cannot be made with imaging methods (CT urography,
IVU or US) 23
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
24. URINE CYTOLOGY
The examination of voided urine or bladder-washing specimens
for exfoliated cancer cells
High sensitivity in high-grade tumours (84%)
Low sensitivity in low-grade tumours (16%)
Sensitivity in CIS detection is 28-100%
24
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
25. URINE
CYTOLOGY
Positive voided urinary cytology can
indicate an urothelial tumour anywhere
in the urinary tract
Negative cytology, however, does not
exclude the presence of a tumour.
Evaluation can be
hampered by
Low cellular yield
Urinary tract infections
Stones
Intravesical instillations
25
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
26. PARIS REPORTING SYSTEM
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).
26
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
30. RISK
STRATIFICATION
AUA
Low risk Intermediate risk High risk
LG SOLITARYTa <
3CM
LG Ta Recurrence
within 1year
HGT1
PUNLMP SOLITARY LGTa
>3CM
Any recurrent HGTa
LG Ta,
MULITFOCAL
HGTa, >3CM or multifocal
HGTa < 3CM Any CIS
LG T1 Any BCG failure in HG
Any variant histology
Any LVI
Any HG prostatic urethral
involvement
30
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
31. RISK
STRATIFICATION
EAU
Low risk Intermediate risk High risk
Primary, solitary
LG/G1 <3cm, No
CIS
All tumors not
defined in two
adjacent categories
T1 tumors
HG/G3 tumors
CIS
Multiple, Recurrent,
>3cm,Ta G1G2
tumors (all
conditions must be
present)
31
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
32. TURBT
INITIAL TREATMENT OF
VISIBLE LESIONS
• Remove all visible tumors
• Provide specimens for pathologic examination to accurately
stage and grade
Goal:
32
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
33. BIMANUAL EXAMINATION
Bimanual examination of the bladder is often performed
with the patient under anesthesia before preparation and draping
unless the tumor is clearly small and noninvasive
Repeated after resection.
Fixation or persistence of a palpable mass after resection suggests locally
advanced disease
Additional value of this maneuver in the era of modern imaging appears
limited and may even be misleading
33
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
34. Resection is performed using a 12- or 30-degree lens
Continuous irrigation with the bladder filled only enough to
visualize its contents
Minimizes bladder wall movement
Lessens thinning of the detrusor through overdistention
Reduce the risk of perforation
34
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
35. Resection is performed piecemeal, delaying transection of any
stalk until most tumor has been resected, to maintain
countertraction.
Friable, low-grade tumors can often be removed without the
use of electrical energy because the nonpowered cutting loop
will break off many low-grade tumors.
35
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
36. TURBT
Higher-grade, more solid tumors and the base of all tumors require
the use of cutting current
Lifting the tumor edge away from detrusor lessens the chance of
perforation
Cautery yields hemostasis once the entire tumor has been
resected.
Repeated slow fulguration may complicate the ability of the
pathologist to determine grade or invasion status.
36
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
37. MUSCLE BIOPSY
After all visible tumor 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 tumor base.
37
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
38. OBTURATOR REFLEX
Obturator nerve passes near the inferolateral bladder wall,
bladder neck and lateral prostatic urethra.
Stimulated by lateral wall resection
Minimised by
TUR in saline
Use of general anesthesia with muscle-paralyzing agents
Obturator block - by direct injection of 20 to 30 mL of local
anesthetic (lidocaine) into the obturator nerve and its canal
38
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
40. TURBT IN DIVERTICULAR
TUMORS Significant risk of bladder wall perforation
Accurate staging is difficult to achieve - underlying
detrusor is absent.
Invasion beyond the diverticular lamina propria
immediately involves perivesical fat (stageT3a by
definition)
40
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
41. DIVERTICULARTUMORS
• 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.
Low-grade
diverticular 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.
High-grade
diverticular tumors
An indwelling catheter usually allows healing within a few days.
41
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
42. ANTERIOR WALL TUMORS
Anterior wall tumors and tumors at the dome in patients with large bladders can
be difficult to reach.
Maneuvers to facilitate resection
Minimal bladder filling combined with manual compression of the lower
abdominal wall
Long resectoscopes
Temporary perineal urethrostomy - rarely necessary except in the obese
patient with an inaccessible tumor.
Digital manipulation through the rectum or vaginal wall
42
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
43. ADJACENTTO URETERAL ORIFICE
Care to prevent obstruction from scarring after fulguration.
Pure cutting current causes minimal scarring and may be safely
performed, including resection of the orifice if necessary.
Resection of the intramural ureter can sometimes lead to
complete eradication of the tumor but risks reflux of malignant
cells.
43
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
44. RESECTION WITH COLD CUP BIOPSY FORCEPS
Small tumors
In elderly women, who are predisposed to perforation owing
to their thin-walled bladders.
If perforation occurs, the cup causes a smaller hole than does
the cutting loop.
44
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
45. HEMOSTASIS AFTER TURBT
A Bugbee electrode facilitates hemostasis.
Involves placing the Bugbee electrode inside the biopsy site with the bladder under minimal
distention.
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 confirms hemostasis and yields less
damage to the bladder than that occurring when the biopsy area is “painted” with cautery.
Removing the electrode from the site before discontinuing the energy current lessens the chance
of pulling the fresh clot off as the Bugbee electrode separates from the urothelium.
45
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
46. MUSCLE BIOPSY
If a tumor appears to be muscle invasive, biopsies of the
borders and base to establish invasion may be performed in lieu
of complete resection
Failure to demonstrate invasion necessitates repeat resection
unless the decision is made to proceed to cystectomy based on
factors other than muscle invasion.
46
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
47. EVALUATION OF RESECTION
Detrusor muscle in the specimen is considered as the surrogate
criterion of the resection quality and is required (except of
TaG1/LG tumours).
47
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
48. COMPLICATIONS
Immediate postoperative period – minor bleeding and irritative
symptoms
Major – 5%
Uncontrolled hematuria
Bladder perforation
As long as resection of the ureteral orifice is performed with pure
cutting current, scarring is minimal and obstruction unlikely.
48
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
49. REPEAT TURBT
High-grade tumor
T1 tumors
No evidence of muscle invasion is identified on the initial resection
in pT1 and many high-gradeTa tumors
Timing: 1 to 6 weeks after the initial resection
Residual tumor is identified at the site of the initial resection at
least 40% of the time
49
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
51. RANDOM / ADDITIONAL BIOPSIES
Biopsies from normal looking mucosa / abnormal epithelium
Indications:
CIS indistinguishable from inflammation/ not visible
Multiple tumors
Positive cytology / High risk tumor (non- papillary appearance) – trigone,
bladder dome and right, left, anterior and posterior bladder wall
Tumors in trigone / bladder neck, CIS – prostatic urethra / duct
involvement higher
Prostatic urethral biopsy - if neobladder creation is anticipated for high-
risk disease
51
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
52. LASER THERAPY
Laser coagulation allows minimally invasive ablation of tumors up to 2.5 cm
in size.
The neodymium : yttrium-aluminum-garnet (Nd :YAG) laser has the best
properties for use in bladder cancer.
Lesions can be coagulated until nonviable through protein denaturation
using a straight or 90-degree noncontact “free beam” laser using power
output of up to 60W.
No tissue available for pathologic inspection - the optimal candidate is
patient with recurrent, low-grade lesions whose biology is already known. 52
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
53. COMPLICATIONS OF LASER
Injury to Adjacent Structures
Due to forward scatter of laser energy to adjacent structures,
resulting in perforation of a hollow, viscous organ such as
overlying bowel.
Rare but most commonly occurs with the Nd :YAG laser
because of its deeper tissue penetration than with holmium
(Ho):YAG and potassium titanyl phosphate (KTP) lasers
53
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
54. COMPLICATIONS OF LASER
Bladder wall perforation
Unless higher energy is necessary for a very large tumor,
limiting energy to 35W precludes exceeding 60°C on the
outer bladder wall, minimizing the risk of perforation
The most efficient delivery appears to be an end-fire
noncontact fiber with a 5- to 15-degree angle of divergence,
which allows variable penetration depth up to 5 mm
54
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
55. COMPLICATIONS OF LASER
Extravesical injury
Treatment should be under direct visualization and should
discontinue as soon as protein denaturation is evident by the
white appearance of the treated tissue. Persistence after this
occurs, risks extravesical injury.
55
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
56. LASER THERAPY
More expensive - cost of laser fibers
Bleeding is negligible
No risk of obturator reflex.
Small lesions can be treated easily using intravesical anesthesia.
56
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
59. PERIOPERATIVE INTRAVESICALTHERAPY
Rationale
Tumor cell implantation immediately after resection is
responsible for many early recurrences
Explains 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).
Intravesical chemotherapy kill such cells before implantation
59
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
60. INTRAVESICAL CHEMOTHERAPY
Single dose administered within 6 hours lessens recurrence
rates, whereas a dose 24 hours later does not
The number needed to treat (NNT) to prevent one recurrence
in the meta-analysis was 8.5
60
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
61. PERIOPERATIVE
ADMINISTRATION
OF INTRAVESICAL
CHEMOTHERAPY
Confirm absence of clinical perforation
Place three way catheter into bladder while patient is still in operating
room
Attach inflow port to saline infusion bag and clamp inflow
Administer chemotherapeutic agent through catheter outflow port in
recovery room within 6 hrs of surgery and clamp outflow tubing to allow
retention
Open outflow 1 hour after administration and for irrigation, to be opened
to gravity drainage for next 30 to 60 mins
Remove foley’s catheter and discard in biohazard container
61
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
62. COMPLICATIONS
Local irritative symptoms
Chemical cystitis
Cutaneous desquamation,
Decreased bladder capacity as a result of contractures, calcified
eschars
Added difficulty of subsequent cystectomy
Serious sequelae and rare deaths have occurred, especially in
patients with perforation during resection 62
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
63. MITOMYCIN C
Alkylating agent
Inhibits DNA synthesis
Instilled weekly for 6 to 8 weeks at dose ranges from 20 to 60 mg
Optimisation of delivery by:
Eliminating residual urine
Fasting overnight
Sodium bicarbonate to reduce drug degradation
Increasing concentration to 40 mg in 20 ml
Local microwave therapy
Electromotive intravesical therapy
63
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
64. DOXORUBICIN
Anthracyline antibiotic
Binds to DNA base pairs → inhibits topoisomerase II & protein synthesis
Principal AE: chemical cystitis
Derivatives
Epirubicin – available only in Europe for UC treatment
Valrubicin – semisynthetic analog
Approved by FDA for BCG refractory CIS in patients who
cannot tolerate cystectomy
64
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
65. THIOTEPA
Triethylenethiophosphoramide
Only chemotherapeutic approved by FDA specifically for intravesical
treatment of papillary bladder cancer
Alkylating agent
Not cell cycle specific
Systemic side effects – low molecular weight (half of administered
doses being absorbed) risking hemopoietic toxicity
65
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
66. NOVEL AGENTS
Gemcitabine
Intravesically – either weekly or twice weekly for 6 to 8
treatments
Reduction of recurrence
Taxanes – paclitaxel, docetaxel
Modest efficacy
Data limited to preclinical studies 66
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
67. COMBINATION THERAPY
MMC (20mg) – day 1 + Doxorubicin (40mg) – day 2 / week X 5
weeks
Chemotherapy + BCG
No clear advantage
67
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
68. IMMUNOTHERAPY
BCG
Interferon alpha
Investigational agents – KLH, IL 2, Mycobacterial cell wall DNA
68
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
69. BCG
Attenuated mycobacterium
Antitumor activity in several different cancers including UC
STANDARD DOSE: 120 mg
LOW DOSE: 40 / 80 mg
Reconstituted with 50 mL of saline
Administered through a urethral catheter under gravity.
Retain the solution for atleast 2 hours
69
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
70. INTRAVESICAL
BCG
2 to 4 weeks after tumor resection
Allowing time for re-epithelialization
Urinalysis is usually performed
immediately before instillation
In the event of a traumatic
catheterization, the treatment should be
delayed for several days to 1 week
70
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
72. BCG
In carcinoma in situ
Intital tumor free response rate – 84%
50% - durable response for median period of 4 years
30% free of progression or recurrence – over 10 years
AUA – BCG as the preferred initial treatment in CIS
Residual tumor
Effectively treat residual papillary lesions
Should not be used as a substitute for surgical resection
60% response rate
72
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
73. BCG
To prevent recurrence
Maintenance BCG
3years maintenance therapy
Intermediate risk – 1 year
Impact on progression
Delay progression of high risk cancer
No chemotherapy trials achieved significant reduction in
progression when compared to BCG
73
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
74. LAMMS/SWOG REGIMEN
Induction therapy – 6 weeks
Maintenance therapy – 3 years
3 weekly instillations at 3 and 6 months and every 6 months
thereafter
74
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
79. BCG FAILURE
Recurrent or persistent disease after an initial 6 week course of BCG = BCG
failure
BCG REFRACTORY - non improving or worsening despite BCG
BCG RESISTANT – recurrence or persistence of lesser degree, stage, or grade
after an initial course, which then resolves with further BCG
BCG RELAPSING – recurrence after initial resolution with high risk group
Should be strongly considered for immediate cystectomy if young and in
generally good health
79
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
80. Declaring failure may take upto 6 months
Response rate for patients with high grade with BCG rose
from 57 to 80% 3 to 6 months after therapy
Tumoricidal activity continued after cessation of therapy for
some period
80
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
81. INTERFERON
Glycoproteins produced in response to antigenic stimuli
Anti-tumor Actions:
Inhibition of nucleotide synthesis
Upregulation of tumor antigens
Antiangiogenic properties
Stimulation of cytokine release with enhancedT and B cell activation
Enhanced natural killer cell activity
81
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
82. INTERFERON
Most active in doses of at least 100 million units
Optimal dose and administration schedule – unclear
Expensive
Less effective than BCG or Intravesical chemotherapy (in residual disease,
preventing recurrence and in CIS)
Occasionally be effective in BCG failure
Additive effects with epirubicin or MMC
Trials – BCG + IFN → superiority with possibility of dose reduction of BCG
82
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
83. INVESTIGATIONAL IMMUNOTHERAPEUTIC AGENTS
KLH
Keyhole limpet hemocyanin
From hemolymph of mollusk Megathura crenulata
Non specific immune stimulant
No clear superiority to available agents
Mycobacterial cell wall DNA extract
Good tolerability with success rates less than BCG
IL 2
Highly expressed after BCG stimulation
Key component of Th1 immune response
Trials – potential benefit; less toxicity
83
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
84. REFRACTORY HIGH GRADE DISEASE
Initial 6 week course of
intravesical therapy for
high risk
(BCG / chemotherapy)
Persistent after first
course
Initial chemotherapy –
BCG
Initial BCG – 2nd course
Cannot tolerate BCG →
salvage chemotherapy
(risk of progression &
failure high)
Further courses beyond
two are not
recommended
Fail 80% of the time
Salvage chemotherapy
Investigational protocols
IFN alone or in
combination with BCG
84
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
85. ALTERNATIVE OPTIONS FOR REFRACTORY
DISEASE
Photodynamic therapy
Administering photosensitizing agent (porfimer sodium iv or HAL, hypericin, radachlorin
intravesically)
2 to 3 days after the substance cleared from normal tissue (for Photofrin), intravesical
treatment with red laser light (630nm) for 12 to 20 mins
After excitation by light, the photosensitiser reacts with molecular oxygen to form free
radical and reactive singlet oxygen → cytotoxic
Side effects: bladder contracture, irritative LUTS, dermal sensitivity
Radiation therapy
Restricted to patients who refuse cystectomy after failure of intravesical therapy or who
are unsuitable for major surgery
Limited role other than palliative purpose 85
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
87. ROLE OF EARLY CYSTECTOMY
“Early” cystectomy - performed before traditional surgical indication of documented muscle
invasion
Considered in
High grade NMIBC
Deep invasion into lamina propria
Lymphovascular invasion
Associated with diffuse CIS
Tumors in diverticula, distal ureters, prostatic urethra
Tumors refractory to initial therapy
Too large or anatomically inaccessible to be removed in their entirety endoscopically 87
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.
88. RATIONALE FOR EARLY CYSTECTOMY
Early (3 month) failure for T1 tumors after BCG – 82% progression rate
Upto 20% of CIS – die of UC within 10 years
Each occurrence ofT1 tumors associated with 5-10% chance of metastasis
Residual tumor on repeat TUR – associated with 82% chance of muscle
invasion
50% of presumed high grade NMIBC who undergo cystectomy – muscle
invasion+
Delay in cystectomy even by 12 weeks – poorer survival
Pts who progress to muscle invasion have poorer prognosis than with muscle
invasiveness at presentation
More accurate pathological staging
88
DEPT OF UROLOGY, GRH AND KMC, CHENNAI.