This document describes risk stratification groups for non-muscle invasive bladder cancer (NMIBC) based on clinical and pathological factors. It defines low, intermediate, high, and very high risk groups based on features like tumor stage, grade, size, number, presence of carcinoma in situ, and patient age. For patients in the high and very high risk groups, bacillus Calmette-Guérin (BCG) immunotherapy is recommended as first-line treatment due to its ability to reduce recurrence rates and risk of progression compared to other options like chemotherapy. BCG is most effective when given as a multi-dose induction course followed by years of maintenance therapy. Cystectomy may be considered for cases of early

1. • Clinical composition of the new EAU NMIBC prognostic factor
risk groups based on the WHO 2004/2016 or the WHO 1973
grading classification systems
• Additional clinical risk factors are:
• age > 70;
• multiple papillary tumours;
• tumour diameter > 3 cm.

2. Risk group
Low Risk • A primary, single, Ta/T1 LG/G1 tumour < 3 cm in diameter
without CIS in a patient
< 70 years
• A primary Ta LG/G1 tumour without CIS with at most ONE of the
additional clinical
risk factors (see above*)
Intermediate Risk Patients without CIS who are not included in either
the low, high or very high-risk groups
High Risk • All T1 HG/G3 without CIS, EXCEPT those included in the
very high-risk group
• All CIS patients, EXCEPT those included in the very high-risk group
Stage, grade with additional clinical risk factors:
• Ta LG/G2 or T1 G1, no CIS with all 3 risk factors
• Ta HG/G3 or T1 LG, no CIS with at least 2 risk factors
• T1 G2 no CIS with at least 1 risk factor
Very High Risk Stage, grade with additional clinical risk factors:
• Ta HG/G3 and CIS with all 3 risk factors
• T1 G2 and CIS with at least 2 risk factors
• T1 HG/G3 and CIS with at least 1 risk factor
• T1 HG/G3 no CIS with all 3 risk factors

4. EAU NMIBC RISK CALCULATOR
1. Age
1. ≤ 70 years >70 years
2. Tumor Status
1. Primary Recurrent
3. Number of Tumors
1. Single Multiple
4. Maximum Tumor Diameter
1. <3 cm ≥3 cm
5. Stage
1. Ta T1
6. Concomitent CIS
1. NO Yes
Select Classification System
1. WHO Grade 2004/2016
1. LMP-LG HG
2. WHO Grade 1973
1. G1 G2 G3

8. Whenever a MIBC is detected during follow-up.
BCG-refractory tumour
1. If T1G3/HG tumour is present at 3 months [196, 291, 294] (LE: 3).
2. If TaG3/HG tumour is present after 3 months and/or at 6 months, after either re-
induction or first course of
maintenance [43] (LE: 4).
3. If CIS (without concomitant papillary tumour) is present at 3 months and persists at
6 months after either
re-induction or first course of maintenance. If patients with CIS present at 3 months,
an additional BCG
course can achieve a complete response in > 50% of cases [43, 44, 284] (LE: 1b).
4. If HG tumour appears during BCG maintenance therapy*.
BCG-relapsing tumour
Recurrence of G3/HG (WHO 1973/2004) tumour after completion of BCG
maintenance, despite an initial
response [288] (LE: 3).
BCG unresponsive tumour
Recurrence of G3/HG (WHO 1973/2004) tumour after completion of BCG
maintenance, despite an initial
response [295] (LE: 3).
BCG intolerance
Severe side effects that prevent further BCG instillation before completing treatment
[266].

12. Guidelines for the treatment of TaT1 tumours and carcinoma in situ
according to risk stratification

13. Treatment options for the various categories of BCG failure

14. 14
Progression of NMIBC
• Recurrenace rate: 70% within 5yr
• Progression: 10-20%
• Mortality 1-15%
• Upper tract tumor: 2%
• Stage Ta: 70%
–
–
–
50% will recur , 50% never recur
If FC 3/12 show recurrence , risk of further recurrence 90%
5% progress
• Stage T1: 20%
– 20% 5yr mortality
– 80% recur
– 30% T1G3 progress
– high progression 80% if concomittent CIS
– 30% T1G3 is understage at RC
– Become T2 if untreated in 2 years
– 50% will progress to muscle invasive
•
•
•
CIS: 10% primary , 20% with tumor present
Percentage of occult metastasis of T2 disease - 33%
Percentage of patients submitted to radical cystectomy present with lymph
node involvement at the time of surgery - 25%

15. 15
Intravesical chemotherapy

16. 16
Adjuvant Intravesical
Chemotherapy
• One immediate post-op intravesical
instillation
• Additional intravesical chemo instillations
• Optimizing intravesical Chemo
• Adj IVBCG (indication)
• Optiomal BCG schedule
• BCG toxicity

17. Role of one, immediate, post-operative
intravesical instillation of chemotherapy
• Indication: everyone
–
–
–
As sole intravesical txn in low risk of recurrence and progression
As initial stage of further intavesical therapy in intermediate risk
Also indicated in high risk gp to reduce recurrence, although
subsequent BCG is essential
• MOA: Mitomycin C
–
–
Alkylating and intercalating agent of DNA in bladder tumor cell
Destruction of circulating tumour cells and chemoresection of
residual microscopic tumor at the site of TURBT
• Timing: Within 24 hours, EORTC: <6hrs
Dosage: 40mg in 40ml NS/H20
Procedure:
– Instill into empty bladder, clamp for 1hr then release
•
•

18. 18
To further improve the efficacy of
intravesical chemotherapy
• Completely bladder emptying
• Changing the position of the patient
• 6-h fasting period (do not drink in the
morning)
– Decreases urinary output
– Prevents up to 20% drug dilution
• Oral sodium bicarbonate (urine pH > 7)
– Improve drug stability, cell uptake &
penetration

19. 19
Local microwave hyperthermia
• Induces bladder wall hyperthermia around 40C with a
special catheter
• Internal thermocouples to monitor the temperature
• Used in combination with intravesical MMC
(thermochemotherapy) showed superiority over MMC
alone
• Significantly more side-effects, though moderate
and transient
• Approved in US
Colombo R et al. Multicentric study comparing intravesical chemotherapy alone and with local microwave
hyperthermia for prophylaxis of recurrence of superficial transitional cell carcinoma. J Clin Oncol
2003;21:4270–6

20. 20
Intravesical BCG

21. 21
Mechanism of IVBCG
•
•
•
First use in TCC bladder by Morales in 1976
Live attenuated Mycobacterium bovis
Many strains (Pasteur, Connaught, Tice, Tice / RIVM, RIVM, A.
Frappier) - All strains same
MOA:
•
–
–
–
–
–
Precise mechanism remains unknown
Attachment of BCG to urothelial cell
Promotes a local acute inflammatory & sub-acute granulomatous
reaction with macrophage
leukocyte infiltration in the urothelium and lamina propria
Local inflammatory effects are associated with an elimination or
reduction of superficial cancerous lesions of the urinary bladder
– Induces accumulation of granulocytes and the influx of macrophages
and lymphocytes into urothelium (maintainence therapy)
• BCG granuloma consists of epitheloid cells, Langerhan’s giant cell
and lymphocytes
More recent evidence suggests that an increase nitric oxide
synthetase activity may be implemented
•

22. 22
Indication of IVBCG
• Low risk disease → No; due to over-treatment
• High risk disease → Yes
– First line treatment for high risk bladder TCC, CIS,
G3pT1 and multifocal G2pT1
• Intermediate-risk disease → Yes
– BCG with 1 yr of maintenance is more effective then
chemo for preventing recurrence
– However , BCG has more side effect then chemo
– Thus both BCG & chemo remains an options

23. Contra-Indication of IVBCG

24. 24
BCG
• Adjuvant therapy – 2-4 week after TURBT
• Connaught strain : 81mg in 50ml NS
• Instillation via catheter, immediately
removed
• BCG held in bladder to up to 2 hour
• After 2hour: increase fluid intake and void
regularly

25. 25
BCG evidence: Better than TURBT alone
• In terms of recurrence : Yes
– Reduced time to first recurrence [Shelly BJU 2001]
– Reduced recurrence rate by 47% [Meta-analysis of 6
trial, Shelley, BJU 2001]
• In terms of progression:
– Cannot conclude effect of BCG on tumor progression
[Shelley BJU 2001]
• Thus meta-analysis on progression is needed

26. 100
BCG evidence: Reduce risk of
Progression
•
•
•
Meta-analysis of 24 trial EORTC [Sylvester JU 2002]
TUR + BCG vs TUR alone vs other txn
Result:
–
–
4% absolute risk reduction of progression (13%vs 9%)
27% relative risk reduction of progression
•
•
•
Only pt receiving maintenance BCG benefit
The benefit of BCG is the same for papilary Ca and CIS
NO significant difference in treatment effect for OS or death due to
CaB
Conclusion:
•
–
– BCG significantly reduces the risk of progression to muscle invasive
disease after transurethral resection in patients with NMIBC who
receive maintenance BCG
BCG is considered to be the drug of choice for adjuvant treatment after
transurethral resection in intermediate and high risk patients with
papillary tumors and is the best intravesical treatment for carcinoma in
situ.

27. 27
BCG evidence: BCG better then MMC
• In terms of recurrence: Yes
– Absolute risk reduction of 20% & relative risk reduction of recurrence of 60% [MA
Sylvester JU2005]
– Only in those patients at high risk of tumour recurrence [Cochrane 2008]
– Only with BCG maintenance: 32 % reduction in the risk of recurrence [MA
Sylvester EU2009]
• In terms of progression: Yes
– 4% decrease in preventing tumor progression , but only if maintenance is given
[MA of 9 trial Bohle JU2004]
– 26% reduction in the risk of progression [MA Sylvester 2005]
– However, no difference in term of progression in one MA [Sylvester EU2009]
• In terms of overall survival and cancer specific survival
– No difference [Sylvester EU2009]
• In particular , BCG is more effective than MMC in CIS:
–
–
Response rate: 70% vs 50%
Overall disease free rate: 50% in BCG group and 25% in chemo group
(median Fu 4yr)

28. 28
BCG evidence: Maintenance
•
•
•
•
SWOG 85-07 (RCT by Lamm, J Uro 2000)
Ta/1 high risk pt
Receive primary treatment + 6w induction → randomized if no recurrence
Randomized:
– Maintenance: 3 weekly BCG @ 3, 6, 12, 18, 24, 30, 36m
– No maintenance
• Result: Maintenance therapy is able to:
–
–
–
Reduce and delay recurrence
Delay time to progression
Suggestion of survival benefit : 5yr OS (83% vs 78%)
• Only patients receiving maintenance BCG benefited in terms of recurrence
and progression
• The downside of that study was that only 16% of patients randomized to
maintenance BCG completed the full course

29. 29
Lamm’s Regime
•
•
•
•
Post –TURBT : 6-week induction course
3-week course at 3 months
3-week course at 6 months
3 week course every 6 months up to 3 years (total 27)
– cytokine response with second 6 week course peaks
by week three and may be suppressed during weeks
4-6
– Lymphocytic infiltration and delayed cutaneous
hypersensitivity response weaken after 6 month
– Repeated stimulation of immune system

30. 30
Rationale - 3 weekly maintanence
• After exposure to an antigen, the secondary immune
response occurs more rapidly and is more vigorous.
• Induction course: 6 week for peak immune response
(urinary cytokine excretion)
• Maintanence course: 3 weeks for peak immune
response (and is suppressed in week 4,5 and 6)

31. 31
Rationale – 6 monthly afterwards
• Duration of immune stimulation and protection from
recurrence following BCG instillation appears to be
long term
• However, lymphocytic infiltration, delayed cutaneous
hypersensitivity response and immunoproliferative
response persist as little as 6 months
• TF: 6 monthly maintenance schedule may be biological
significance

32. 32
Rationale – 3 years
• Should consider, safety, cost and biology of the
immune response
• In an RCT of 1,355 patients, the EORTC has shown
that when BCG is given at full dose, three years'
maintenance (3-weekly instillations 3, 6, 12, 18, 24,
30 and 36 months) reduces the recurrence rate
compared to one year in high - but not in
intermediate-risk patients.

33. 33
2nd Induction course
• The complete response of those who failed to
respond to the first course of BCG was 60% by
a second course

34. 34
Conclusion
• Most effective intravesical agent for preventing
NMIBC recurrence
• Role in progression still controversial
• BCG as alternative to IVCT in intermediate risk
NMIBC
• Recommended as standard of care for high risk
NMIBC
• Reduction in risk of progression in high and
intermediate risk [EAU 2020]
• Requires maintenance schedule for benefit
• No maintenance → no benefit in High Risk

35. 35
Role of reduced dosage of IVBCG
•
•
Connaught 81mg vs 27mg
The Spanish CUETO trial concluded that low dose BCG is equally
effective to high dose BCG.
Except marginal superiority of standard dose in G3 and high risk
tumours of full dose
Reduced toxicity in reduced dose arm
Although fewer patients reported toxicity with the reduced dose,
the incidence of severe systemic toxicity was similar in the
standard- and reduced-dose groups
This group suggested one-third of the standard dose of BCG may
be the minimum effective dose in intermediate-risk tumours
•
•
•
•

39. 39
Precautions after IVBCG
1. Sitting down to void in order to avoid splashing
2. Hand washing after voiding
3. Rinsing toilet with undiluted bleach
4. Theoretical risk of BCG infection through genital
tract during intercourse
–
–
Should not have sex 48 hours after each treatment
A condom is advised during the treatment till 6 weeks
afterwards
5. Quinolones should be avoided due to anti-TB
activity
6. BCG can be used in joint and valvular prosthesis
with antibiotic cover for urethral instrumentation

40. 40

41. 41
Role of 2nd Induction therapy after
failure of induction
After induction BCG in CIS:
• If Recurrence at 3m
– Re-induction → 50% complete response
• If Recurrence at 3m and 6m (i.e. BCG - refractory)
– 30% progress, 50% metastasis
• If Late recurrence after >6m success
– Re-induction → 80% complete response at 6m,
→ 50% at 5yr
In T1 failure:
– re-BCG → 70% progress to MI
– No evidence that repeat induction improve out come of T1G3

42. 42
BCG failure Options
• Early Cystectomy (80% cure before MI)
– Early cystectomy show survival benefit than conservative
treatment (don’t wait till MI) [Raj JU2007]
– Cystectomy also better in primary MI gp than progression to
MI gp
• Intravesical chemotherapy
– Gemcitabine, docetaxel (investigational)
• Device assisted instillation
– EMDA, HYMN (recurrence 15% at 1 year)
• Immunotherapy (interferon + BCG 45% tumor free at 4yr)

43. 43
Indication of cystectomy for
NIMBC
• High risk of progression. According to the risk tables of the EORTC
1. Multiple recurrent HG tumors: risk of progression ↑ to 80%
2. T1HG
3. HG tumor with concurrent CIS
4. BCG failure
5. Lymphovascular invasion
6. Involvement of distal ureters or prostatic urethra
7. Too large or anatomically inaccesible to be removed in
their entirety endoscopically
•
A delay in cystectomy increases the risk of progression and
cancer-specific death
–
Herr HW, et al. Does early cystectomy improve the survival of patients with
high risk superficial bladder tumors?. J Urol 2001;166(4):1296-9.

44. 44
FU of patients with T1Ta disease
• Result of 1stcystoscopy is a very important prognostic factor for recurrence and
progression
1stcystoscopy should always performed 3m after TUR
EAU 2020
low risk tumor after TURBT
•
•
– Recurrence 20% at 1 year
– Cystoscopy at 3 months
– If –ve: FC 9 months later then yearly for 5 years.
•
Intermediate risk tumor after TURBT
– Recurrence 40%@1year, 60%@2yr
– In-between follow-up scheme using cystoscopy and cytology
•
High risk tumor after TURBT:
–
–
–
Recurrence 50% at 6m, 90% @1year
Cystoscopy + cytology at 3m
If –ve: FC+ Cytology Q3m x 2 year
FC + Cytology Q6m x 3 year (till 5yr)
FC + cytology yearly + upper tract imaging yearly
• AUA
:
– 3 monthly x 2yr
– then 6 monthly x 2-3 yr
– then yearly
•

45. 45
CIS
•
•
•
Definition: Flat, non invasive high grade malignancy of the bladder
5-10% of NMIBC
Classified:
–
–
–
Primary CIS: isolated CIS
2nd CIS: CIS with previous papillary tumor
Concurrent CIS: CIS in the presence of papillary tumors
• How does it behave?
–
–
–
–
–
Lead to invasive disease in 2 yr if not treated
With BCG: complete response 70%
14% progress to T1
Progression: 50% if alone, 80% if with G3 disease
7% dies of Ca bladder
• Dx:
–
–
–
Cytology : SV 94% , SP 96%
White light FC: 53% of CIS missed
Fluoresence FC: improve detection rate of CIS > 95%

46. 46
• Treatment:
–
–
–
–
–
–
Mainstay of treatment is IVBCG
With MIBC → treat as MIBC
With Ta/T1→ TURBT + BCG
Early cystectomy : 50% overtreatment RT:
not an option
BCG with maintenance up to 3 yr is more effective than MMC :
[Sylvester JU 2005]
• Response rate: 70% vs 50%
• 5 yr Overall disease free rate: 50% vs 25%
• 30% remain disease free at 10 yr
– BCG reduced risk of progression by 35% vs MMC [Sylvester JU 2002]
50% who do not response to initial induction BCG will response to 2nd
induction course (6 weekly)
Alternating schedule of MMC and BCG is not superior to BCG alone
[Nordic trail]
Conclusion: BCG increase complete response rate, overall disease free
rate & reduce progression in patient with CIS
Upper tract CIS: txn with BCG asso with more BCS Cx as more
systemic absorption
•
•
•
•

47. 47

54. 54
Micropapillary Variant
•
•
•
Male-predominant (5:1)
Aggressive tumor, 85% present as metastasis
Gross pathology
– Highly variable, from a strikingly ulcerated mass to seemingly
benign granular mucosa
Not responsive to BCG
Mostly with lymphovascular invasion
•
•
•
•
Cystectomy treatment of choice
5-year and 10-year overall survival: 51% and 24%
– MD Anderson Cancer Cancer: review of micropapillary Ca bladder (Cancer 2007)

55. 55
Risk of LN met according to T stage
• Ta 6%
• T1 10%
• T2/3a 18%
• T3b/4 30%

56. 56
SCC
• Bilharzial (Schistosomasis )
–
–
–
–
–
Exophytic, nodular, fungating lesions
usually well differentiated & present as low grade disease
relatively low incidence of lymph node and distant metastases.
Ureteric involvement complicates 25% of cases of bladder bilharzias.
The lower third of the ureter is most commonly affected (80%) and is
usually bilateral
• Nonbilharzial SCCs
– caused by chronic irritation from urinary calculi, long-term indwelling catheters,
chronic urinary infections, or bladder diverticula
– Prognosis is poor because most patients have advanced disease at the time of
diagnosis
• Histology
– Characteristically of keratinized islands that contain eccentric
aggregates of cells called squamous pearls
Cystoscopy: invasive ulcerative lesion at trigone or lateral wall
Treatment: cystectomy
10% present as metastasis
5yr survival: 50%
•
•
•
•

57. 57
Adenocarcinoma
•
•
<1% of bladder cancer
2 types:
–
–
Primary: de novo (trigone, or post wall)
Secondary: metastatic (bowel) or urachal remnant
• Risk factor:
–
–
–
Bladder extrophy / bowel augmentation / bladder substitution ( after 10-20yr)
Patent urachus
Association with cystitis glandularis
• Urachal tumor:
–
–
–
–
More common in female
Presentation: hematuria + mucous discharge from urachus
Sharp demarcation between tumour and urothelium
Histologically, adenoca (85%), sarcoma (8%), SCC (3%) or even TCC (3%)
• 25% of bladder adenoca
Radiologically (CT scan) there is a stipples calcification in 50% of them, when
present is almost pathognomonic
Treatment: either extended partial or radical cystectomy + excision of the
urachus and umbilicus depending on the clinical staging
Overall 5 year survival rate is 50%
–
–
–

58. 58

59. 59
Evidence of fluorescence Cystoscopy
for Ca Bladder
• Meta-analysis [Kausch, EU 2010]
– More sensitive than conventional procedures in detecting
malignant tumour
– 20% (95% CI, 8–35) more tumor-positive patients were detected
with PDD in NMIBC
– 40% (CI, 23–57) more in subgroup CIS only
– Residual tumor was significantly less often found after PDD
(odds ratio: 0.28; 95% CI, 0.15–0.52; p < 0.0001)
– Recurrence-free survival was higher at 12 and 24mo in the
fluorescence-guided TUR than in the WLI-only groups
(p<0.0002)
fluorescence guided TUR reduced recurrence up to 5
years (ALA)
– Recurrence rate at 5 years 75% vs 59% (Danitchenko J Urol
2005)
•