1. N.N. Alexandrov National Cancer Centre
Fluorescent cystoscopy-assisted TUR: does it affect outcome in NMIBC patients?
Sergey Polyakov, MD, PhD
N.N. Alexandrov National Cancer Centre
Minsk, Belarus
First of all I would like to thank organizing committee for inviting me
This is the first time Belarusian urologists have an opportunity to give a presentation at this Baltic meeting

2. N.N.Alexandrov National Cancer Centre
Oncological Urology
55 beds
4 OR
16 physicians
1600 surgeries / year
(350 RP, 60 RC, 400 TURBTs 200 RN, 250 PN)
Let me introduce my centre were I have been practicing for 20 years (come from)
This is National Cancer Centre named after Nikolay Alexandrov
Which is located not far from Minsk – the capital of Belarus
We are the major referral center for cancer patients in the country
Our department occupies this building
We have 55 beds inpatient department with 4 operation rooms and 16
We do ….

3. NMIBC challenges Recurrences 50-70% Progression 20-30% Causes:
repeat TURBT / instillations
cost
Progression 20-30%
high death rate
Causes:
incomplete TURBT
Ca cell implantation
TURBT understaging
“new primaries”
high-grade cancer
CIS
Challenges in the NMIBC treatment are the same for many years
They are high rate of recurrence
and possibility for progression which is main source of deaths from BC (cause specific mortality)
The causes of this events in great part are connected with poor quality of surgical removal of the cancer tissue

4. Completeness of TURBT Variability in 3-moths RR1 single: 0-21%
multiple: 7-46%
Re-TURB2:
residual tumor: 33-76%
muscle invasion: 4-28%
Absence of muscle in the specimen in T13,4
30-40%
We know that there are many issues with completeness of TUR in this disease
We have a number of proofs for this
Dr Brausi showed us high variability in early RR after TUR between different institutions in Europe
From the repeat TUR series we know that in selected cases we could find residual cancer in up to 76% of pts
And could significantly understage up to quarter of cases
There was recent analysis of American SEER database indicating that 30% of T1 cases in common practice did not have muscle tissue in the specimen
And this mean that TUR was too gentle and possibly incomplete
And finally a number of mapping studies showed that many bladder tumors recur at the same site
1 Brausi et al., 2002
2 Naselli et al., 2017
3 Chamie et al., 2015
4 Herr, 1999

5. Completeness of TURBT
Variability in 3-moths RR1
single: 0-21%
multiple: 7-46%
Re-TURBT2:
residual tumor: 33-76%
muscle invasion: 4-28%
Absence of muscle in the specimen in T13,4
30-40%
Mapping studies5
same site recurrences
… quality of surgery is often suboptimal and … urologists should know their personal bladder tumour recurrence rates.
Griffiths  Kockelbergh, 2014
So the quality of surgery is often suboptimal and … urologists should know their personal bladder tumour recurrence rates
As Griffiths  Kockelbergh (British) wrote in their editorial in European Urology
1 Brausi et al., 2002
2 Naselli et al., 2017
3 Chamie et al., 2015
4 Herr, 1999
5 Herr  Donat, 2008

6. Quality of TURBT: personal RR
Retrospective analysis: 949 consecutive TURBTs in 773 pts; 5 staff surgeons with comparable experience
Variable
HR (95%CI) Р
Risk group
<0.0001
Low
1.00
Intermediate
1.61 ( )
High
2.96 ( )
Surgeon
0.001
Surgeon 1
Surgeon 2
1.17 ( )
0.27
Surgeon 3
1.46 ( )
0.05
Surgeon 4
1.71 ( )
0.002
Surgeon 5
1.70 ( )
reTURBT
1.72 ( )
0.014
Intravesical therapy No
BCG
0.64 ( )
Chemo
1.27 ( )
0.56
And we followed their advice
And compared RFS in 5 staff surgeons mostly involved in the endoscopic bladder surgery
As you see there was (We found) high variability in RR between different surgeons
And this differences persisted after adjustment for the risk group and use of adjuvant therapy
Surgeon-specific outcome
Median f-u 5.4 years
Rolevich et al., CEJU, 2016

7. Personal RR: implications
TURBT is not a “simple” surgery
Surgeon/Clinic volume1
cystectomy – volume matters
nephrectomy – does not
Surgeon in important variable
underecognized / not used in clinical trials
may modify any therapy results
“Best” vs “Worst” – HR 0.60
single chemo – HR
maintenance BCG vs MMC – HR
What are the implications of these results?
first - TURB is not a “simple” surgery as regarded by many
As all story with Surgeon or Clinic volume tells us – in simple surgery experience does not play significant role for providing better results
Second – the surgeon in important variable
And this fact is underecognized in clinical trials but may modify treatment results
As impact of the surgeon is in the range of efficacy of intravesical therapy
Ad third – Early RR is important quality indicator
Early RR is important quality indicator
1 Birkmeyer et al., 2002
2 Sylvester et al., 2016
3 Malmstrom et al., 2009

8. Personal RR: implications
TURBT is not a “simple” surgery
Surgeon/Clinic volume1
cystectomy – volume matters
nephrectomy – does not
…Although TURBT is an essential procedure familiar to urologists, it is a difficult operation to do well.
H.W. Herr
Surgeon in important variable
underecognized / not used in clinical trials
may modify any therapy results
“Best” vs “Worst” – HR 0.60
single chemo – HR
maintenance BCG vs MMC – HR
In other words we (validated) found proof of this quotation (statement) made by Harry Herr
That I like a lot
Early RR is important quality indicator
1 Birkmeyer et al., 2002
2 Sylvester et al., 2016
3 Malmstrom et al., 2009

9. How to improve quality of TURBT?
Surgical issues Technical solutions
How could we improve this situation
There are some surgical issues
However there are some technical solutions that could help surgeons to improve their performance
And Blue Light cystoscopy is one of the best studied techniques
From Lerner & Goh, 2014

10. 5-ALA 5-aminolevulinic acid
HAL
hexaminolevulinate
Natural metabolite Hydrophilic Poor intracellular penetration Long intravesical exposure (2h) 50 EUR Not registered
Hexyl ester of ALA
Lipophilic
Better membrane penetration
Short exposure (1h)
400 EUR
EMA  FDA registered
There are 2 photosensitizers that work in the bladder
The difference between them is this modification of the molecule
That makes HAL more lypophilic with better ability to penetrate membranes
This allows to reduce time of intravesical instillation which is convenient
But also makes it much more expensive

11. Does it affect outcome? The main question is - does it affect outcome?
Ant there is lot of confusion when answering this question
Since almost all review on this topic find it very useful with very minor critique
As example In 2014 an Expert recommendation was given by the panel of international experts that ……………….
However almost the same set of experts in 2017 provided Europ Guidelines
that did not mention FC in the initial management of NMIBC patients

12. Evidence of FC efficacy
26 years history with bladder PDD
1992 – first PDD with ALA1
Diagnostic studies2,3
20% increase in sensitivity
additional detection CIS (40%), Tа (15%), T1 (11%)
10% decrease in specificity
false positives 1-26%
FC is good for CIS detection
Residual tumor rate at reTURB
15% vs 35% (20% decrease)2
not substitute for recurrence / progression
“Therapeutic” studies
if FC good for recurrence prevention?
mostly positive, but not all
This year we could celebrate 25th anniversary since landmark Kriegmair publication
Since then there were numerous diagnostic studies
showing better sensitivity then standard WL cystoscopy
With greatest benefit in the additional detection of CIS but also papillary tumors
The cost for this is decrease in specificity, however the rate of FN may be reduced with some experience
This data clearly shows that …. (no discussion)
Also there were some studies assessing residual tumors at repeat TUR
This studies uniformly showed decrease in residuals for the same 20%
However it may be regarded as a proof of concept but not real benefit
As this is not a substitute for REC or PRO and all patients get reTURB anyway
And finally there were some “therapeutic” studies
Answering the question if FC good for recurrence prevention?
Most of them were positive but not all
Today we probably could find few enthusiastic urologists on this technique. Out of favor for the most urologists
1 Kriegmair et al., 1992
2 Kausch et al., 2010
3 Burger et al., 2013

13. No rando-mized / evaluable
5-ALA studies
Publication, year
No of centers,
place
No rando-mized / evaluable
Follow-up, months
Single instillation
reTURB
BCG / MMC
Findings
Riedl, 2001; Daniltchenko, 2005
Vienna – Berlin
115 / 102
39-42 No
All
Positive (treated positive reTURB as “recurrences”)
Filbeck, 2002; Denzinger, 2007
Regensburg
301 / 191
83-86
Yes
Positive
(most impressive)
Babjuk, 2005
Prague
128 / 122
21-22
Schumacher, 2010
5 (Sweden)
300 / 279 12
Negative
Stenzl, 2011
8 (Austria-Germany)
381 / 359
So lets start with ALA studies
There were only 5 published trials – 3 positive and 2 negative
Urologiia Aug;(4): Russian

14. No rando-mized / evaluable No rando-mized / evaluable
5-ALA studies
Publication, year
No of centers,
place
No rando-mized / evaluable
Follow-up, months
Single instillation
reTURB
BCG / MMC
Risk of bias
Riedl, 2001; Daniltchenko, 2005
Vienna – Berlin
115 / 102
39-42 No
All
High
Filbeck, 2002; Denzinger, 2007
Regensburg
301 / 191
83-86
Yes
Babjuk, 2005
Prague
128 / 122
21-22
Unknown
Schumacher, 2010
5 (Sweden)
300 / 279 12
Low
Stenzl, 2011
8 (Austria-Germany)
381 / 359
Publication, year
No of centers,
place
No rando-mized / evaluable
Follow-up, months
Single instillation
reTURB
BCG / MMC
Risk of bias
Riedl, 2001; Daniltchenko, 2005
Vienna – Berlin
115 / 102
39-42 No
All
High
Filbeck, 2002; Denzinger, 2007
Regensburg
301 / 191
83-86
Yes
Babjuk, 2005
Prague
128 / 122
21-22
Unknown
Schumacher, 2010
5 (Sweden)
300 / 279 12
Low
Stenzl, 2011
8 (Austria-Germany)
381 / 359
They differed by
number of centers (multicentre and single or 2 center)
Length of follow up
And risk of bias
So we split them into 2 subgroups
With subgroup 1 pooling ….
And the rest 2 trial were
Urologiia Aug;(4): Russian

15. 5-ALA studies
We performed a meta-analysis of these trials
And found no statistically significant differences in the effect of FC-assisted TUR
However the heterogeneity between different trials was very high
and subgroup analysis allowed to decrease it significantly
So in the 2nd subgroup the were no differences
But in the 1st subgroup the was a considerable effect with HR 0.51
So we found efficacy in trials with high risk of bias / 1-2 center / long follow-up
It was not possible to come to definite conclusions from this
Efficacy in trials with high risk of bias / 1-2 center / long follow-up
Urologiya Aug;(4): Russian

16. No rando-mized / evaluable
HAL studies
Publication, year
No of centers,
place
No rando-mized / evaluable
Follow-up, months
Single instillation
reTURB
BCG / MMC
Findings
Stenzl, 2010; Grossman, 2012
28 (USA, Canada, Europe)
814 / 516
53-55 No
Yes
Positive
Hermann, 2011
2 (Denmark)
233 / 145 12
Drăgoescu, 2011
Craiova
44 / 44
Geavlete, 2012
Bucharest
362 / 269 24
Karaolides, 2012
Athens
102 / 86
14-18
Gkritsios, 2013
Thessaloniki
130 / 85
NA (40?)
Negative
O'Brien, 2013
London
249 / 185
What about Hexaminolevulinate studies
There were 7 with 5 positive and 2 negative
Most important in my view was the first which was international multicenter, the largest and well done

17. J. Urol., 2012 Recurrence-free 32% vs 38% (P=0.14)
Median RFS 9.4 vs 16.4 months (P=0.04)
Most benefit in TaG1 / TaG2
There was a publication assessing long-term RFS with median FU 4.5 years
The rate of recurrences was nearly the same 32 and 38% (6% difference)
However time to recurrence was significantly prolonged from 9.4 to 16.4 months
Most benefit was in low risk subgroup
Median FU months
J. Urol., 2012

18. No rando-mized / evaluable
HAL studies
Publication, year
No of centers,
place
No rando-mized / evaluable
Follow-up, months
Single instillation
reTURB
BCG / MMC
Findings
Stenzl, 2010; Grossman, 2012
28 (USA, Canada, Europe)
814 / 516
53-55 No
Yes
Positive
Hermann, 2011
2 (Denmark)
233 / 145 12
Drăgoescu, 2011
Craiova
44 / 44
Geavlete, 2012
Bucharest
362 / 269 24
Karaolides, 2012
Athens
102 / 86
14-18
Gkritsios, 2013
Thessaloniki
130 / 85
NA (40?)
Negative
O'Brien, 2013
London
249 / 185
Interesting suggestion was to explain differences in the trials by use of single instillation of MMC
As both negative studies used it and Stenzl trial did not used
We will address this question later on

19. Impact on progression Definition muscle invasion / metastases
2014 IBCG:
Ta → T1
low grade → high grade
Older definition
impact not shown
not designed to assess progression
Progressed 12% (HAL) vs 18% (WL)
TTP: p = 0.05
What about impact on progression
It is depended on the definition
Older was muscle invasion or metastases
In 2014 new (more liberal) definition by International Group was proposed which includes progression from Ta to T1 and from low grade to high grade
No any trial showed impact on older definition of progression
It is not а surprise because no any trial was designed to asses PRO (However we should admit that this is very difficult to do)
Kamat with colleagues reassessed Stenzl HAL trial with new definition of progression and found benefit of FC however with marginal statistical significance
New definition
Kamat et al., 2016

20. Impact on progression Gakis & Fahmy, 2016 Chou et al., 2017
Two recent metaanalyses evaluated risk of progression
Gakis found benefit of HAL, however he included Kamat study with different definition
In Chou meta analysis with older definition - there were not statistically significant differences in ALA subgroup but in HAL subgroup there was a benefit

21. Our study… Rationale: impact of FC-TUR with ALA on RR is inconclusive
interaction with single instillation not studied
Design:
prospective randomised open-label trial
22 factorial design
And finally our study
The rationale was
To demonstrate Impact of FC-TUR with ALA on RR as it is inconclusive from the literature
And to asses possible interaction between with single instillation and FC
So we designed a …..
World J Urol (2017) 35:745–752

22. Suspicion of primary / recurrent NMIBC (US / cysto), 2008-2012
Inclusion criteria:
suspicion of primary / recurrent NMIBC
age ≥18 years;
adequate bladder capacity
life expectancy > 3 years
informed consent
no hydronephrosis
no treatment < 6 months
Suspicion of primary / recurrent NMIBC (US / cysto),
Randomization
FC-TURBT
DOX
No DOX
reTURB / BCG at physician discretion
Follow-up outside the center (cysto / US)
Outcome: primary – RFS, secondary – PFS, CSS, OS
Eligibility: confirmed NMIBC / benign after complete TUR (no MIBC, no incomplete, no without f-u)
WL-TURBT
From 2008 to 2012 all the patients hospitalized at our institution with a suspicion of primary or recurrent NMIBC were offered to take part in a prospective open-label randomized study.
If they agreed to participate they were randomized into four study arms.
Patients in the first arm (PDD+D) underwent PDD-assisted TUR with 5-ALA. Subsequently, those patients with macroscopically complete TUR and without signs of bladder perforation within 6 hours after TUR received an intravesical instillation of 50 mg of doxorubicin.
The second arm (WL+D) underwent white light TUR plus single doxorubicin instillation (as described above).
The third arm (PDD+0) received PDD-assisted TUR without instillation.
And the forth control arm underwent standard TUR without doxorubicin.
The patients were considered ineligible if they underwent incomplete TUR or histological analysis of removed specimen showed tumor invasion of the muscle tissue.
The subsequent treatment, if necessary, was administered to these patients depending on extent of the disease and local guidelines.

23. Patient`s flow 377 patients World J Urol (2017) 35:745–752
Randomized: N=525
WL+0: N=132
Analyzed: N=104
Non-evaluable:
MI: 20 (15%)
incomplete: 10 (8%)
no f-u: 8 (6%)
Total: 38 (29%)
WL+D: N=141
Analyzed: N=109
MI: 17 (12%)
incomplete: 8 (6%)
no f-u: 7 (5%)
Total: 32 (23%)
FC+0: N=128
Analyzed: N=90
MI: 11 (9%)
incomplete: 16 (13%)
no f-u: 11 (9%)
Total: 38 (30%)
FC+D: N=124
Analyzed: N=84
MI: 19 (15%)
incomplete: 11 (9%)
no f-u: 10 (8%)
Total: 40 (32%)
525 patients were randomised.
From 23% to 32% of patients were non-evaluable (that mean they had MI disease, incomplete TURB or no FU)
A total of 377 patients could be assessed
377 patients
World J Urol (2017) 35:745–752

24. RFS by intervention FC vs no FC DOX vs no DOX
HR 0.77
95%CI
p = 0.13
HR %CI p = 0.002
With median fu of 55 months
there was statistically significant benefit of FC over WL TUR
With HR 0.56
The single instillation was associated with increase in RFS but not statistically significant
Median f-u 55 months
World J Urol (2017) 35:745–752

25. PFS by intervention FC vs no FC DOX vs no DOX
HR 0.65
95%CI
p = 0.32
HR 0.33
95%CI
p = 0.032
Interestingly PFS was significantly better in FC group
Median f-u 55 months
World J Urol (2017) 35:745–752

26. Subgroup analysis World J Urol (2017) 35:745–752
In the subgroup analysis the only significant interacting factor with the efficacy of FC was the surgeon
World J Urol (2017) 35:745–752

27. “Experienced” surgeons “Less experienced” surgeons
RFS by quality of TURBT
“Experienced” surgeons
“Less experienced” surgeons FC FC
No FC
No FC
If the surgery was done by more experienced surgeons we see some prolongation of RFS but not significant
In less experienced surgeons there was very large and stat significant benefit of FC (white light TUR) with
HR 0.81
95%CI
p = 0.34
HR 0.31
95%CI
p = 0.001

28. Conclusions FC-assisted TURBT decreases recurrences
baseline quality of TURBT is significant interacting factor
FC could facilitate mastering of high quality TURB
Benefit of FC-assisted TURBT >> single instillation
FC and single instillation probably have no interaction (additive effect)
FC-assisted TURBT decreases progression
less intensive follow-up may increase the benefit
In conclusions
FC-assisted TURB decreases recurrences
According to our data baseline quality of TURB is significant interacting factor
In less experienced surgeons FC could facilitate mastering of high quality TURB
Benefit of FC-assisted TURB exceeds single instillation
FC and single instillation probably have additive effect / and no interaction between them
FC-assisted TURB decreases progression
and less intensive follow-up may increase the benefit as we think happened in our study

29. Take home messages Do high quality TURBT slowly systematically
aggressively
understand disease you treat (TaLG vs T1HG)
check and crosscheck completeness
Know your recurrence rate
Use FC (ALA or HAL)
Limited resources?
Invest in your surgical skills
My final messages to the audience are
Do high quality TURB slowly, systematically, and rather aggressively
understand disease you treat (that is mean modify your technique according to risk)
check and crosscheck completeness of surgery
Know your recurrence rate
Use FC (ALA or HAL) they are probably nearly the same
If Limited resources? Invest in your surgical skills