Bladder Preservation for muscle

invasive diseaseNicholas James

@Prof_Nick_James

1

Overview

• Evidence base for bladder preservation

as alternative to surgery

• Comparison to other primary sites

• Optimising bladder preservation –

diagnostic pathways

Rafael Marcos-Gragera, et al Urinary tract cancer survival in Europe 1999–2007: Results of the population-based study

EUROCARE-5 European Journal of Cancer, Volume 51, Issue 15, 2015, 2217–2230 http://dx.doi.org/10.1016/j.ejca.2015.07.028

Outcomes are staticAge-standardised 5-year survival for bladder cancer 1999––2007

N Europe

Central Europe

Eastern Europe

Ireland and UK

Southern Europe

Europe

Surgery has been optimised

• Bladder cancer outcomes have not significantly

improved for 30 yearsZehnder P, Studer UE, Skinner EC, Thalmann GN, Miranda G, Roth B, Cai J, Birkhauser FD, Mitra AP,

Burkhard FC, Dorin RP, Daneshmand S, Skinner DG, Gill IS. Unaltered oncological outcomes of radical

cystectomy with extended lymphadenectomy over three decades. BJU Int 2013;112:E51-8

Presented by: Nick James

IS SURVIVAL BETTER AFTER

SURGERY?

Survival remains poor with death from

metastasis

• 453 UK pts, 1993-

1996

• Ratio

RT:cystectomy 3:1

• 10 year survival RT

22% Surgery 24%

Munro NP, Sundaram SK, Weston PM, et al. A 10-year retrospective review of a nonrandomized cohort of 458 patients

undergoing radical radiotherapy or cystectomy in Yorkshire, UK. Int J Radiat Oncol Biol Phys 2010;77:119-24.

Bladder cancer is a systemic disease

• No plateau in survival curves

– Patients die from metastases

Treatment needs to address local control and distant

metastases:

• Local control

– Surgery or RT

• Metastases

– Systemic therapy

WHAT CAN WE LEARN FROM

OTHER CANCERS – BREAST

CANCER?

Breast cancer therapy

1880 1900 1920 1940 1960 1980 2000 2020

Radical

mastectomy -

Halstead

Adjuvant RT

Adjuvant

hormone

therapy

Adjuvant

chemotherapy

Adjuvant

HER2

targetingAdjuvant

aromatase

inhibitors

Breast cancer

Mortality Rates From Breast Cancer

IMPROVED OUTCOMES

DEPEND ON NEW SYSTEMIC

THERAPIES

T Powles et al. Nature 515, 558-562 (2014) doi:10.1038/nature13904

PD-L1 prevalence and response rates in patients with UBC.

T Powles et al. Nature 515, 558-562 (2014) doi:10.1038/nature13904

MPDL3280A anti-tumour activity in patients with UBC.

WHAT CAN WE LEARN FROM

OTHER CANCERS – ANAL

CANCER?

Anal cancer

• Primary therapy was surgery up until mid-1980s

• Various chemo-RT regimens showed high activity

with range of agents including 5FU, MMC,

cisplatinum during 1970s

• “…surgery as the primary therapeutic modality

has been abandoned.”Anal cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and

follow-up Ann Oncol (2014) 25 (suppl 3):iii10-iii20.doi: 10.1093/annonc/mdu159

CAN WE SALVAGE LOCAL

FAILURES?

Primary vs Salvage Cystectomy

Addla et al. The Journal of Urology Vol. 181, Issue 4, Supplement, Page 633

Are complication rates higher

with salvage cystectomy?

• 426 primary and 420 salvage cystectomies

• Single institution

• 1970-2005

Differential Complication Rates Following Radical Cystectomy in the Irradiated and Nonirradiated Pelvis Vijay A.C. Ramani, Satish B. Maddineni, Ben R. Grey, Noel W. Clarke. Eur Urol 57 (2010) 1058–1063

Are complication rates higher with salvage

cystectomy?

Differential Complication Rates Following Radical Cystectomy in the Irradiated and Nonirradiated Pelvis Vijay A.C. Ramani, Satish B. Maddineni, Ben R. Grey, Noel W. Clarke. Eur Urol 57 (2010) 1058–1063

IS SURGERY APPLICABLE TO

THE WHOLE POPULATION?

Age at diagnosis

0

200

400

600

800

1000

1200

1400

1600

0-4 5-9 10-

14

15-

19

20-

24

25-

29

30-

34

35-

39

40-

44

45-

49

50-

54

55-

59

60-

64

65-

69

70-

74

75-

79

80-

84

85+

Male cases

Female casesMedian age in

BA06 & SWOG 8710

Median age in

BC2001 and BCON

Median age in

USC series

Choice of treatment

• Surgery and radiotherapy data relate to

different segments of the population

• Hence age/fitness is important factor in

treatment decisions

CHEMORADIOTHERAPY

OUTCOMES

Radio-sensitisation

• Numerous phase I/II studies showing

feasibility and safety

• Three phase III studies

– RT vs RT + Cisplatinum (NCIC)

– RT vs RT + nicotinamide/carbogen (BCON)

– RT vs RT + 5FU/MMC (BC2001)

Radio-sensitisation

• Numerous phase I/II studies showing

feasibility and safety

• Three phase III studies

– RT vs RT + Cisplatinum (NCIC)

– RT vs RT + nicotinamide/carbogen (BCON)

– RT vs RT + 5FU/MMC (BC2001)

10 YEAR OUTCOMES BC2001

N at risk (events)

HR (95% CI) = 0.55 (0.36-0.84)Stratified logrank p=0.006

0.0

00.2

50.5

00.7

51.0

0

Invasiv

e L

oco-R

eg

ional C

on

tro

l

178 88(50) 63(4) 51(1) 37(2) 15(1)No CT (0)182 94(27) 77(3) 66(1) 37(1) 13(1)CT (0)

0 24 48 72 96 120

Months since randomisation

CT

No CT

N at risk (events)

HR (95% CI) = 0.61 (0.43-0.86)Stratified logrank p=0.004

0.0

00.2

50.5

00.7

51.0

0

Lo

co

-Re

gio

nal C

ontr

ol

178 72(71) 53(5) 38(5) 28(2) 13(1)No CT (0)182 77(48) 65(4) 54(2) 28(0) 8(1)CT (0)

0 24 48 72 96 120

Months since randomisation

CT

No CT

Loco-Regional Control (LRC)Invasive Loco-Regional Control

(ILRC)

Adjusted HR (95%CI): 0.59 (0.41 – 0.83), p=0.003 Adjusted HR (95%CI): 0.52 (0.33 – 0.81), p=0.004

Snapshot of data: July 2016, N=360, Median FUP 117.1 m

Updated results - CT comparison

Hall et al Proc ESMO 2016

N at risk (events)

HR (95% CI) = 0.79 (0.59-1.06)Stratified logrank p= 0.11

0.0

00.2

50.5

00.7

51.0

0

Bla

dder

Can

ce

r S

pecific

surv

ival

178 107(60) 73(25) 58(9) 47(3) 18(0)No CT (1)182 111(55) 88(15) 80(3) 59(4) 25(2)CT (3)

0 24 48 72 96 120

Months since randomisation

CT

No CT

N at risk (events)

HR (95% CI) = 0.88 (0.69-1.13)Stratified logrank p= 0.31

0.0

00.2

50.5

00.7

51.0

0

Overa

ll surv

ival

178 107(69) 73(33) 58(14) 47(5) 18(5)No CT (1)182 111(69) 88(20) 80(5) 59(12) 25(11)CT (6)

0 24 48 72 96 120

Months since randomisation

CT

No CT

Overall Survival Bladder Cancer specific Survival

Adjusted HR (95%CI): 0.81 (0.62 – 1.04), p=0.100 Adjusted HR (95%CI): 0.73 (0.54 – 0.99), p=0.043

Snapshot of data: July 2016, N=360, Median FUP 117.1 m

Updated results - CT comparison

Hall et al Proc ESMO 2016

N at risk (events)

HR (95% CI) = 0.54 (0.31-0.95)Stratified logrank p= 0.03

0.0

00.2

50.5

00.7

51.0

0

Cyste

cto

my Incid

ence

178 95(25) 64(3) 49(4) 41(1) 18(0)No CT (0)182 98(15) 79(3) 71(1) 51(1) 20(0)CT (0)

0 24 48 72 96 120

Months since randomisation

CT

No CT

N at risk (events)

HR (95% CI) = 0.78 (0.58-1.05)Stratified logrank p= 0.09

0.0

00.2

50.5

00.7

51.0

0

Meta

sta

ses F

ree

Surv

ival

178 95(71) 67(18) 53(6) 39(2) 17(0)No CT (1)182 101(61) 82(10) 71(2) 42(3) 15(2)CT (2)

0 24 48 72 96 120

Months since randomisation

CT

No CT

Metastasis Free Survival Salvage Cystectomy Rate

Adjusted HR (95%CI): 0.74 (0.54 – 1.00), p=0.051

2-year rate: CT 11% (7-17)

No CT17% (12-24)

Snapshot of data: July 2016, N=360, Median FUP 117.1 m

Updated results - CT comparison

Hall et al Proc ESMO 2016

rtrand1

rtrand2

rtrand3

ptds1

ptds2

neoadj1

neoadj2

Primary

ID

Study

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

Favours CT Favours no CT 1.2 .5 1 2

rtrand1

rtrand2

rtrand3

ptds1

ptds2

neoadj1

neoadj2

Primary

ID

Study

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

Favours CT Favours no CT 1.2 .5 1 2

rtrand1

rtrand2

rtrand3

ptds1

ptds2

neoadj1

neoadj2

Primary

ID

Study

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

Favours CT Favours no CT 1.2 .5 1 2

LRDFS - consistency across subgroupsHazard ratio (95% CI)

Randomised sRT 63 0.57

Randomised RHDV 58

Elect sRT 239RT dose 55Gy/20F 142 0.63

RT dose 64Gy/32F 217Neoadjuvant CT 118 0.59

No neoadjuvant CT 242Primary analysis 360

N P-value

rtrand1

rtrand2

rtrand3

ptds1

ptds2

neoadj1

neoadj2

Primary

ID

Study

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

Favours CT Favours no CT 1.2 .5 1 2

rtrand1

rtrand2

rtrand3

ptds1

ptds2

neoadj1

neoadj2

Primary

ID

Study

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

Favours CT Favours no CT 1.2 .5 1 2

rtrand1

rtrand2

rtrand3

ptds1

ptds2

neoadj1

neoadj2

Primary

ID

Study

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

Favours CT Favours no CT 1.2 .5 1 2

rtrand1

rtrand2

rtrand3

ptds1

ptds2

neoadj1

neoadj2

Primary

ID

Study

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

Favours CT Favours no CT 1.2 .5 1 2

LRDFS - consistency across subgroupsHazard ratio (95% CI)

Randomised sRT 63 0.57

Randomised RHDV 58

Elect sRT 239RT dose 55Gy/20F 142 0.63

RT dose 64Gy/32F 217Neoadjuvant CT 118 0.59

No neoadjuvant CT 242Primary analysis 360

N P-value

rtrand1

rtrand2

rtrand3

ptds1

ptds2

neoadj1

neoadj2

Primary

ID

Study

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

0.79 (0.36, 1.77)

1.01 (0.37, 2.77)

0.59 (0.38, 0.91)

0.75 (0.41, 1.37)

0.63 (0.40, 0.97)

0.58 (0.32, 1.08)

0.72 (0.47, 1.12)

0.67 (0.47, 0.95)

HR (95% CI)

Favours CT Favours no CT 1.2 .5 1 2

Patterns of recurrence after chemoRT

Any recurrence

93/182 pts

Loco-regional recurrence

53

Non-muscle invasive

25

Muscle invasive

18

Pelvic nodes

6

Distant recurrence or

second primary

40

Metastasis

29

Second primary

11

Further trials

• TUXEDO – RT/5FU/MMC + cetuximab

– Analysis complete, good toxicity, QOL, high rate

pelvic control

• RAD-IO - RT/5FU/MMC +/- durvalumab

– Neoadjuvant, synchronous + adjuvant

– Multi-stage trial – feasibility, intermediate efficacy,

proceed to phase 3 if first 2 stages successful

“But radiotherapy leaves you a

small poorly functioning bladder”

RTOG 6 month toxicity outcomes

n= 291, 145 RT only, 146 chemo-radiotherapy

0

10

20

30

40

50

60

70

80

Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Unknown

Chemo RTRT only

James et al, Radiotherapy with or without chemotherapy for invasive bladder cancer. NEJM 2012 366, 1477-1488

Change in FACT domains (all patients)

*Paired t-test,

p≤0.01

No. with data:

-4-2

02

4

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

327

6m

278

12m

230

2 years

165

3 years

144

4 years

122

5 years

104

Mean 95% CI

Physical Well-Being Change from Baseline Score

*No. with data:

-8-6

-4-2

02

46

8

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

325

6m

275

12m

227

2 years

166

3 years

143

4 years

122

5 years

106

Mean 95% CI

BLCS Change from Baseline Score

No. with data:

-8-6

-4-2

02

46

8

Mea

n ch

ange

from

bas

elin

eB/L

N

EOT

325

6m

275

12m

227

2 years

166

3 years

143

4 years

122

5 years

106

Mean 95% CI

BLCS Change from Baseline Score

No. with data:

-8-6

-4-2

02

46

8

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

325

6m

275

12m

227

2 years

166

3 years

143

4 years

122

5 years

106

Mean 95% CI

BLCS Change from Baseline Score

No. with data:

-4-2

02

4

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

317

6m

273

12m

225

2 years

162

3 years

140

4 years

117

5 years

101

Mean 95% CI

Social Well-Being Change from Baseline Score

No. with data:

-8-6

-4-2

02

46

8

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

325

6m

275

12m

227

2 years

166

3 years

143

4 years

122

5 years

106

Mean 95% CI

BLCS Change from Baseline Score

No. with data:

-8-6

-4-2

02

46

8

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

325

6m

275

12m

227

2 years

166

3 years

143

4 years

122

5 years

106

Mean 95% CI

BLCS Change from Baseline Score

No. with data:

-8-6

-4-2

02

46

8

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

325

6m

275

12m

227

2 years

166

3 years

143

4 years

122

5 years

106

Mean 95% CI

BLCS Change from Baseline Score

No. with data:

-4-2

02

4

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

324

6m

277

12m

228

2 years

165

3 years

142

4 years

120

5 years

105

Mean 95% CI

Functional Well-Being Change from Baseline Score

* No. with data:

-8-6

-4-2

02

46

8

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

325

6m

275

12m

227

2 years

166

3 years

143

4 years

122

5 years

106

Mean 95% CI

BLCS Change from Baseline Score

No. with data:

-8-6

-4-2

02

46

8

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

325

6m

275

12m

227

2 years

166

3 years

143

4 years

122

5 years

106

Mean 95% CI

BLCS Change from Baseline Score

No. with data:

-8-6

-4-2

02

46

8

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

325

6m

275

12m

227

2 years

166

3 years

143

4 years

122

5 years

106

Mean 95% CI

BLCS Change from Baseline Score

No. with data:

-4-2

02

4

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

326

6m

276

12m

229

2 years

167

3 years

142

4 years

120

5 years

104

Mean 95% CI

Emotional Well-Being Change from Baseline Score

** * *** *No. with data:

-8-6

-4-2

02

46

8

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

325

6m

275

12m

227

2 years

166

3 years

143

4 years

122

5 years

106

Mean 95% CI

BLCS Change from Baseline Score

No. with data:

-8-6

-4-2

02

46

8

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

325

6m

275

12m

227

2 years

166

3 years

143

4 years

122

5 years

106

Mean 95% CI

BLCS Change from Baseline Score

No. with data:

-8-6

-4-2

02

46

8

Mea

n ch

ange

from

bas

elin

e

B/L N

EOT

325

6m

275

12m

227

2 years

166

3 years

143

4 years

122

5 years

106

Mean 95% CI

BLCS Change from Baseline Score

Hall et al Proc ESMO 2016

CAN WE SELECT PATIENTS

FOR

CHEMORADIOTHERAPY?

Patients unsuitable for surgery

• Elderly

• Severe cardiovascular or chest problems

• Obese

• Diabetes

• Patients reluctant or unable to cope with stoma

• etc

Patients unsuitable for

(chemo)RT• Poor bladder function

• Highly symptomatic bladders

• Extensive CIS

• Prior pelvic RT

• Inflammatory bowel disease

• Certain genetic disorders

How to decide

• 3 groups:

– Fit for surgery, fit for cisplatinum

– Fit for surgery, not fit for cisplatinum

– Not fit for surgery

How should we make decisions in MIBC?Fit for

cisplatinum

Neoadjuvant

therapy

Reassess

Good response,

good bladder

function

ChemoRT

Poor response or

poor bladder

function

Surgery

Fit for surgery?

Yes No

Yes No

Good bladder

function

Consider

ChemoRT

Poor bladder

function

Consider Surgery

Fit for RT

Consider

ChemoRT

Not fit for

RT

BSC

How should we make decisions in MIBC?Fit for

cisplatinum

Neoadjuvant

therapy

Reassess

Good response,

good bladder

function

ChemoRT

Poor response or

poor bladder

function

Surgery

Fit for surgery?

Yes No

Yes No

Good bladder

function

Consider

ChemoRT

Poor bladder

function

Consider Surgery

Fit for RT

Consider

ChemoRT

Not fit for

RT

BSC

How should we make decisions in MIBC?Fit for

cisplatinum

Neoadjuvant

therapy

Reassess

Good response,

good bladder

function

ChemoRT

Poor response or

poor bladder

function

Surgery

Fit for surgery?

Yes No

Yes No

Good bladder

function

Consider

ChemoRT

Poor bladder

function

Consider Surgery

Fit for RT

Consider

ChemoRT

Not fit for

RT

BSC

How should we make decisions in MIBC?Fit for

cisplatinum

Neoadjuvant

therapy

Reassess

Good response,

good bladder

function

ChemoRT

Poor response or

poor bladder

function

Surgery

Fit for surgery?

Yes No

Yes No

Good bladder

function

Consider

ChemoRT

Poor bladder

function

Consider Surgery

Fit for RT

Consider

ChemoRT

Not fit for

RT

BSC

CHEMO-RT IN THE ELDERLY

Presence of residual mass, extent of resection and tumour size are related

The presence of residual mass was highly correlated with extent of

resection

• 96% complete resections without residual mass

• 66% incomplete resections with residual mass

Logrank test p= 0.04

0.00

0.25

0.50

0.75

1.00

0 12 24 36 48 60 72Months

Biopsy/Not resected

Complete resection

Incomplete resection

Extent of tumour resection

Logrank test p=0.005

0.00

0.25

0.50

0.75

1.00

0 12 24 36 48 60 72Months

No

Yes

Residual mass post resection

Logrank test p= 0.11

0.00

0.25

0.50

0.75

1.00

0 12 24 36 48 60 72Months

T2

T3-4

Stage

Logrank test p=0.001

0.00

0.25

0.50

0.75

1.00

0 12 24 36 48 60 72Months

<30mm

>=30mm

Unknown

Size of tumour

TURBT and residual mass

• Residual mass = high stage

• High stage = poor prognosis

• Therefore does not follow that RT only for

patients with no mass post TURBT as these

patients will do badly with surgery

• Also does not follow that TURBT actually needed

Effect of Multivariate factors on ILRC

49

0.2

.4.6

.81

Pro

port

ion

of

invas

ive

loco

-reg

ion

al c

on

trol

0 12 24 36 48 60 72Months since randomisation

No neoadjuvant CT

0.2

.4.6

.81

Pro

port

ion

of

invas

ive

loco

-reg

ion

al c

on

trol

0 12 24 36 48 60 72Months since randomisation

Neoadjuvant CT

No Res

massRT

RT+CT

RT

RT+CT

Residual

mass

No Res mass83.0%

71.4%

56.2%

35.3%

90.1%

82.9%

72.5%

56.0%

RT

RT+CT

RT

RT+CT

Residual

mass

No Res

mass

3-yr ILRC: 3-yr ILRC:

Neoadjuvant chemotherapy and synchronous

chemotherapy do different things

0.2

.4.6

.81

Over

all

Surv

ival

0 12 24 36 48 60 72Months since randomisation

WHO 0, Age 70

0.2

.4.6

.81

Over

all

Surv

ival

0 12 24 36 48 60 72Months since randomisation

WHO 1-2, Age 700

.2.4

.6.8

1O

ver

all

Surv

ival

0 12 24 36 48 60 72Months since randomisation

WHO 0, Age 80

0.2

.4.6

.81

Over

all

Surv

ival

0 12 24 36 48 60 72Months since randomisation

WHO 1-2, Age 80

Overall Survival

50RT, No Res Mass RT, Res Mass

RT+CT, No Res Mass RT+CT, Res Mass

DIAGNOSTIC PATHWAYS

The origin of TURBT

Br. J. Surgery: 1931

Low grade NMI Bladder cancer

- High rates of local recurrence

1. Does TURBT work?

Low grade

NMI

High grade

NMIMIBC

Sylvester et al. EORTC data: Eur Urol 49 (2006) 466–477

What if breast cancer specialists behaved

like urologists?

• Breast cancer would be diagnosed by 6 random

needle cores in each breast

• Initial treatment would use a hot wire to scrape the

middle of the tumour out, leaving the invasive bits

round the edge to grow for several weeks while

staging proceeds

Debulking in cancer care

• Very few disease sites use primary surgical

debulking as staging for bulky disease

• Where this has previously been the practice, now

abandoned for primary systemic therapy e.g.

– Anal cancer

– Breast cancer

– Head and neck cancer

Functions of TURBT?

• Diagnosis

• Staging

• Treatment

• Palliation of symptoms from bladder

Non-muscle invasive bladder cancer – 80% of total

TURBT

• Diagnosis

• Staging

• Treatment

• Palliation of symptoms from

bladder

✔

✔

✔

✔

Invasive bladder cancer

TURBT

• Diagnosis

• Staging

• Treatment

• Palliation of symptoms from

bladder

✔

✔ - incomplete

No - delayed

Possibly

If we could diagnose and stage a different way, treatment would be faster

Do we need TURBT for

histology?• Flexible cystoscopy can give accurate

histology

Can we replace TURBT for staging?

• TURBT is frequently inaccurate and operator

dependent – 25-40% NMIBC upstaged at

cystectomy

• Repeat TURBT in G3pT1 delays MIBC therapy if

upstaged

• A test that distinguished <=T1 vs >=T2 could

speed correct MIBC therapy

TURBT in MIBC

• 5% overt bladder perforation rate

• 50% occult bladder perforation

• Large increase in circulating tumour cells

• Around 10% of MIBC M+ at diagnosis but half of

these get metastasis

• Could TURBT be actually spreading the cancer?

Is TURBT an essential component of MIBC

treatment?

• If planning cystectomy why is it needed?

• No randomised data in bladder preservation

2. Does TURBT delay definitive treatment?

Low grade

NMI

High grade

NMIMIBC

New lesion

Radical treatment

• TURBT 2-4 weeks

• Pathology +2 weeks

• Clinic +1-2 weeks

• ?Re-Resect +6 weeks

• Decision to Radical Rx

+2-4 weeks

Total = 7-18 weeks

Average is

>112 days

RADS & Imaging

Prostate cancer: PIRADS Bladder cancer: VIRADS

Ideal new pathway?

NMIBC

• Identify on imaging and

biopsy/cytology

• Fast track to TURBT and

subsequent therapy

MIBC

• Stage with biopsy and MRI

• Fast track to definitive

therapy

• TURBT only if urgently

needed for symptoms e.g.

intractable bleeding

Problem: need to separate NMIBC from MIBC

MRI – Superficial vs invasive

Sensitivity

• T2 – 88%

• T2 + DWI 88%

• T2 + DCE 94%

• All 3 94%

Specificity

• T2 – 74%

• T2 + DWI 100%

• T2 + DCE 86%

• All 3 100%

TURBT pathological upstaging at cystectomy 40%

Takeuchi M, Sasaki S, Ito M, Okada S, Takahashi S, Kawai T, Suzuki K, Oshima H, Hara M, Shibamoto Y.

Urinary bladder cancer: diffusion-weighted MR imaging--accuracy for diagnosing T stage and estimating

histologic grade. Radiology 2009;251:112-21

BladderPath Trial

Newly presented haematuria

patients

Randomise

MRI directed pathwayStandard care pathway

Outcome measures:

Stage 1: Feasibility, safety

Stage 2: Time to primary treatment

Stage 3: Failure free survival

BladderPath

• Feasibility stage – 150 patients

• Intermediate stage – event driven, at least

20 MIBC patients (approximately 80-100

patients will need to be recruited overall).

• Final clinical stage – event driven,

(approximately 950 patients)

Patient 1

• Presented with

haematuria

• Large mass on

flexible cystoscopy

• Biopsy – G3TCC

• Proceeded direct to

chemotherapy

Patient 2

• Haematuria

• Flexible cystoscopy:

• 1.5 cm papillary

tumour on left lateral

wall

• Histology G2 TCC

• Stage T1N0M0

Patient 3

• Transplant pt

• Solid mass at dome of

bladder, partial

TURBT done

• T4 on MRI with bowel

infiltration

• Lower bowel

defunctioned

Patient 3 (cont)

• Completed 55Gy/20

fractions + 5FU/MMC

• Post RT cystoscopy –

pathological CR

• MRI gives accurate

response assessment

Conclusions• No convincing evidence surgery superior to primary

bladder preservation with salvage surgery

• Improved chemoradiotherapy schedules increase

pelvic control compared to RT alone and reduce

metastasis

• Improved systemic therapies should start to reduce

deaths from metastasis