The Role of Surgery in Metastatic Bladder

Cancer

Maurizio Brausi

Chairman ESOU

Modena, ITALY

“

”

Disclosures

� No relevant to this presentation

Metastatic/Unresectable BC: Definition

�«Bladder cancer invading into the pelvic or

abdominal wall (T4b, N+/M+)

�The vast majority of these patients have uncurable disease

Locally advanced BC: Definition

� A tumor invading all the layers of the bladder

wall and extending into the perivesical fat (T3) ,

Microscopically (T3a) or Macroscopically (T3b)

or invading adjacent organs like prostate, uterus

or adnexa (T4a) or invading the pelvic or

abdominal wall (T4b)

( TNM Classification 2007)

Metastatic Bladder Cancer

� Lymph-node metastasis diagnosed by Imaging (CT, CT-

Pet , MRI, PSMA-CT )

� Metastases in distant organs (Lung, Liver, bones….)

M+Disease: EAU Guidelines 2018 Recommendations

� Use Cis-platinum-containing combination chemotherapy with GC,MVAC, preferably with G-CSF,HD-MVAC with G-CSF or PCG (R Strong)

� Do not use Carboplatin and non-platinum combination chemotherapy

� First line treatment in patients inelegible (unfit) for Cisplatin: use check-point inhibitors Pembrolizumab or Atezolizumab (R Strong) Use carboplatin combination chemotherapy (R Weak)

� Second-line treatment : offer checkpoint inhibitors Pembrolizumab or atezolizumab to patients progressing during or after platinum-based combination chemotherapy for M+ disease. Alternatively : clinical trials (R Strong)

Surgery Alone for Locally Advanced ,N+/M+ Bladder Cancer

� Is it feasible ?

� Is it indicated ?

� Is the diagnosis always correct ?

Limitation of CT in the diagnosis of Limphnode

disease……

� In the elderly ( >75 ) ?

Clinical case: 71-y-old pt. with Tcc of the bladder involving GI tract (bowel occlusion) , enlarged pelvic LNs at CT and T invading the pelvic wall considered unresectable by a Urological Center. Stage cT4bN+

� 8.08.2017

10.9.2017

10.09.17

Surgery

Radical cysectomy with extended LND ,

terminal ileum 30 cm from cecal valve resection and end to end ileal

anastomosis. The tumor was stocked to

the pelvic bone but not infiltrating

Ureterocutaneostomy bilateral

Omentum into the pelvis

Specimen: Bladder with prostate and

seminal vesicles

Path. Report:

TCCHG of the bladder invading the

prostate and semnal vesicles bilat.

Invasion of the terminal ileum. Margins negative

47 lymphnodes: obturator, internal,

external and common iliac nodes: NO

Cancer

Stage PT4aHG(G3)R0N0Mx

Unresectable Bladder Cancer

� The definition of unresectable tumor is relative. For surgeons with a great surgical experience, able to manage vascular damages, GI tract cancer infiltration (GI resections) and also bone invasion this term may not be appropriate.

� However the question is not if the tumor is surgically resectable or not , but, if the indication for an aggressive major surgery exists

� For hese patients a multidisciplinary surgical approach is a must. This involves urologists, general and vascular surgeons and orthopedics, sometime gynecologists. MDT EVALUATION

UrologistsClinical and

medical oncologists

Urology and oncology nurse

specialists

Palliative care specialists

Radiation oncologists

PathologistsPatient

advocates

Unresectable Bladder Cancer

� PATIENTS related (co-morbidities, age)

� TUMOUR related (aggressive tumor biology or massive

adjecent organ/pelvic/abdominal wall infiltration or

N+/M+)

� SURGEON related (surgeon with insufficient experience)

and Institution Type related

Rationale for Palliative RC and LND in T4bBC

�Rationale for oncological surgery in T4b TCC

� * Debulking (removing the bladder with tumor and all the tissue in the pelvis together with the lymph-nodes) trying to have neg. margins * Reducing local recurrence * Preventing further complications (ureteral stenosis, bowel occlusion ….) * Improving Survival ???

RC and e-LND For Locally Advanced

and N+ Bladder Cancer:

Oncological Results

L

Open Radical Cystectomy: 5-10 year survival

Author(year)

N° pts P/stage OS(%)

5-10 yrs

DSS(%)

5-10 yrs

Mortality(%)

PR

Ghoneim A.

J.Urol. ’97

(5 yrs)

RC-CT-RT

1026 T1 or <=48T2= 142T3a= 709T3b= 57T4= 70N0= 838N+= 188

N.R. 7365.546.931.019.053.023.4

(’80-’97)

4

vs

13.7

(Before ’80)

N.R.

Studer U.

JCO ’03

(5-10 yrs)

RC

507 T1 or <=94T2= 151T3= 184T4= 78N0= 383N+= 124

63

32

26

76745236

33

4.5 43

Local=8

Dist=35

12 month

Hautmann

J.Urol. ’05

(5 yrs)

RC

788 T1 or <T2 T3 T4 N0 N+

N.R. 88.171.642.228.574.419.9

N.R. 30.4Local = 9.3Dist = 17.8UT = 3.3

Open Radical Cystectomy: 5-10 year survival

Author(year)

N° pts P/stage OS(%)

5-10 yrs

DSS(%)

5-10 yrs

Mortality(%)

PR

Stein J.P.

JCO ’01

(5-10 yrs)

RC-RT-CT

1054 T1 or <T2 T3a T3b T4N0 N+

76-5277-5764-4449-2944-2369-4931-23

83-7889-8778-7662-6150-4578-7535-34

3.0 30Local=

24.7Distant=

75.312-18 month

Fair W.

Eur.Urol. ’02

(5 yrs)

RC-RT-CT

686 OC = 374(<T3a)

NOC = 312N0 = 493N+ = 193G1-2 = 92G3 = 594VI 0 = 123VI + = 267

68-49.1

30.3-22.8

57-40.825-20.9

N.R.N.R.

N.R.

78.9-72.9

36.8-39.3

66.7-61.731.2-27.7

N.R

N.R.

N.R.

N.R. N.R.

Open Radical Cystectomy: 5-10 year survival

Author(year)

N° pts P/stage OS(%)

5-10 yrs

DSS(%)

5-10 yrs

Mortality(%)

PR

Nishiyama

Eur.Urol. ’04

(5 yrs)

RC

1042 T1 or < = 290T2 = 323T3 = 371 T4 = 68 N0 = 853 N+ = 163 NO LD = 121LD = 982

82.260.247.828.075.535.154.169.8

N.R. N.R. 30.4

Loc rec. = 9.3

Dist. rec. = 17.8

B = 1.1

5-Year Survival in Locally Advanced BC

after RC

� pT3 = 31% - 62%

� pT4 = 19% - 50%

� N+ = 20% - 35%

�Conclusions:RC may have a role in the treatment of these patients (also pT4b/N+)

Rationale of an E-LND

� Removing a larger number of pelvic lymph nodes during cystectomy is strongly correlated with improved overall survival both in lymph node negative and lymph node positive metastasis

� Vieweg J et al J Urol 1999 Lerner SP et al J Urol 1993 Mills RD et al J Urol 2001 Stein JP et al BJU Int 2003 Herr HW et al Urology 2003

LNDLimited : nodes of the obturator fossa

Extended: obturator, int., ext, common iliac, presacral.

Super-Extended: until the inf. mesenteric artery

Roth BEur Urol 57 : 205, 2010

Lynph node Dissection in T4b/N+

Guidelines 2012

In T4b/N+ BC LND can be extended to the

periaortic/pericaval, interaortocaval space

Survival Local Recurrence

VariableAt

Risk Deaths5-Year

Survival (%) P

No. of

Pts. % P

PLNDNoneLimitedStandard

2498

146

176379

334660

.0112227

50225

<.0001

SurgeonUrologistUrologic oncologist

153115

9861

4858

.053 338

236

.06

Institution typeAcademicCommunityVA/military

1378447

725235

575440

.05314189

102119

.02

Urinary diversionIleal ConduitContinent stoma or orthotopic

19177

12633

4863

.006 2912

1516

.93

Bladder Cancer Outcomes by Surgical and Pathologic Variables

for the 268 Patients Undergoing Cystectomy SWOG 8710

H.W. Herr et al., J Clin Oncol 22:2781-2789, 2004

Recurrence after RC in Locally

Advanced BC

� The recurrence rate in T3-T4 BCs is high even if an extended surgery

is perfomed.

� 5-y RR in 1110 patients treated with RC and LND:

For T3 = 56% T4 = 64%. Local R = 21.5% Distant R = 69%

Secondary UC =9.5% Peritoneal carinomatosis : 5.1%

� 5-y RR in

N0 patients = 33%

N1 = 62%

N2 = 75%

� About 50% of patients died within 1 year after recurrence

Median CSM after recurrence : 18 mos

(Moschini et al EJSO 2016)

surgical/radiotherapy

options

“Induction”

systemic

therapy

Post-operative

“adjuvant”

systemic therapy

Stratification according to the extent of

metastatic disease:

• T4b/cN+ (curative window?)

• cM+ (e.g., palliative cystectomy,

metastasectomy)

Locally-advanced/Metastatic UBC (T4b, TanyN+, TanyNanyM+)

Neo-Adjuvant Chemotherapy Improves Survival for

Patients with MIBC: Level 1 Evidence

Winquist et al, J Urol 171:561, 2004

Only about 20% of eligible patients receive the recommended care.

Which Chemotherapy

• DD-MVAC and GP are considered nowadays standard regimens for patients with metastatic

urothelial cancer and normal renal function (EAU-AUA Guidelines 2017-2018)

NAC Use in Europe

• A feasibility questionnaire performed for the MAGNOLIA trial among European high-volume

cystectomy centres indicated that NAC is used in only 12% of the approximately 5000 BC

patients undergoing RC annually in europe who are being considered for NAC (Burger et al Eur Urol 2012)

Is NAC For Everyone?

• Meta-analysis reveals only a modest benefit for NAC and only 20-

25% of unselected patients benefit.

• We cannot yet predict response prior to treatment and only those

that respond dramatically benefit (30-40%).

(This would be acceptable if chemo was free from cost and toxicity).

• In this era of precision medicine we should try to select patients who can be elegible for chemo

Genetic Alterations Predicting Response to Chemotherapy

� ERBB2 mutations characterize a subgroup of muscle

invasive bladder cancers with excellent response to

neo-adjuvant chemotherapy Groenendijk FH et al Eur Urol 2016;69:384

� Alterations in ATM, RB1 and FANCC correlates with

survival after NAC Van Allen, Cancer Discov 2014, Plimack, Eur Urol 2015

p=0.0205

MDACC: 3 molecular subtypes of MIBC

Choi et al, Cancer Cell 2014

Survival Days

0 2000 4000 60000

20

40

60

80

100cluster 1

cluster 2

cluster 3

Luminal

Basalp53-like

Validated in 3 independent cohorts.

Survival for Basal Tumors Improved by NAC

Siefker-Radtke et al, 2015. Black et al, AscoGU 2018

Post Chemo Surgery in Patients with Unresectable or

Regionally Metastatic Bladder Cancer Herr et al J.Urol 2001

� Population: 207 pts. with unresectable or regionally metastatic BC 80/207 (39%) received surgery after chemo (Platinum based)

� ObjectiveTo assess the CR rate and Relapse-free Survival

� Results24/80 cases (30%) had a pathologically confirmed CR after Chemo. 14/24 (58%) pts survived from 9 mos to 5 years Residual cancer was completely re-resected in 49 pts (61%) with a CR rate 20 pts (41%) survived Post-Chemo surgery did not benefit those who failed to achieve a major Complete or Partial response to chemo

� Only 1/12 pts (8%) who refused surgery remained alive

Abufaraj M, et al. Eur Urol. 2017 Nov 6. pii: S0302-2838(17)30840-0

Necchi A, et al. Eur Urol Focus. 2017 Jun 3. pii: S2405-4569(17)30125-6

No RPLND

Effectiveness of PC-LND

Surgey after chemotherapy in N+ Bladder Cancer may have a role : Prerequisites

� 1. Good response to chemotherapy

� 2. Patient fit or accepting surgery (age is important)

� 3. Expert surgeon (removal of all the lymphatic tissue..

The N of nodes removed is a surrogate of extended

surgery > 20- 30)

Metastasectomy in UC

� Cytoreduction

�“Immunosurgery“

� Subtyping

Type of study

Retrospective cohort 14

Randomized controlled trial 3

Total number of patients 412

Demographics, N (%)

Male 288 (70)

Mean age 62

Tumor location, N (%)

Bladder 309 (75)

Othera 103 (25)

Number of metastases, N (%)

Multiple 148 (36)

Single 148 (36)

Not reported 116 (28)

Sites of metastasectomy, N

Lung 181

Bone 21

Liver 16

Distant lymph nodes 118

Other 47

Peri-operative chemothereapy, N (%)

Yes 325 (79)

No 66 (16)

Not reported 21 (5)

Type of chemotherapy, N (%)

Platinum-based chemotherapy 304 (88)

Other 21 (6)

Unknown 21 (6)

Outcomes

Mean time from initial surgery to metastasectomyb 19 months

Mean time for relapse after metastasectomyc 14.3 months

V. Patel et al. / Survival after metastasectomy in UC

Conclusions

� A multidisciplinary approach to locally advanced, N+,M+ bladder cancer is a must (Onco Units)

� An accurate diagnosis of the disease extension (LNs at CT) is diffficult and sometime misleading

� NAC should be proposed as the first line treatment in these patients

� Post-Chemo RC with E-LND is the treatment of choice for patients with locally advanced BC and N+ who achieve a CR or PR

� The rationale for a palliative aggressive surgery (debulking, reducing RR and possible future complications) is strong

� Metastasectomy is an option and usefull in patients with solitary mets

�THANK YOU !!!

� OR Ausl Modena/ B- Ramazzini H Carpi