early cistectomy nei tumori della vescica pubbl...

Early cistectomy nei tumori della vescica ad alto grado

Milano, 30 Novembre 2012

Moderatore: C. Terrone

Pianist: K. TouijerShooter: R. Colombo



PianistK. Touijer

Radical Cystectomy As Early Primary Therapy for T1HG

Bladder Cancer

Karim Touijer, MD, FACSAttending Surgeon

Dept of Surgery, Urology ServiceMemorial Sloan-Kettering Cancer Center

Weill Medical College of Cornell University

Accurate staging (Pathologic classification)

Pitfalls of accurate staging

Poor orientation due to tangential sectioning.Thermal injury.Intense inflammatory response obscuring nests of invasive tumor.The nested variant of urothelial carcinoma mimicking von The nested variant of urothelial carcinoma mimicking von Brunn’s nests.Carcinoma in situ in von Brunn’s nests.Prominent muscularis mucosae can be confused with detrusor muscle.Fat in Lamina propria gives the erroneous impression of tumor involving perivesical fat

Accurate staging (Pathologic classification)

Pitfalls of accurate staging

T1G3 And TIS Bladder CancerClinical Understaging

Author P stage > T1

Amling (Duke), 1994 37%

Soloway (Florida) 1994 36% (60% for Tis)

Stein (USC) 2001 39%

10 - 15% have positive nodes at cystectomy

Risk Of Understaging Is Influenced By Presence Of Muscle In TUR Specimen

N=78

Dutta, J Urol 166:490, 2001 Herr, HW J Urol 162:74, 1999

A second TURBT required to identify extent of disease.

Accurate staging (Restaging TUR)

• Prospective randomized trial of restaging versus no restaging in newly diagnosed T1

• N=210 and mean • N=210 and mean follow-up 66 months

• RFS at 5 years was 57% versus 32%

• PFS at 5 years was 93% versus 79%

Divrik et al Eur Urol 2010; 58(2):185-90

Bladder cancer specific death

• Cumulative incidence of disease-specific death at 5 yrs was

• 8% (95% CI, 5-13%),• 8% (95% CI, 5-13%),• 10% (95% CI, 5-17%),• 44% (95% CI, 35-56%)

for those less than T1, T1 or T2 on restage.

Risk Characteristics of T1 Bladder Cancer

~ Morphologic Features ~

Papillary vs Solid appearance

Tumor size and number of T1 lesions

Tumor Location

Risk Characteristics of T1 Bladder Cancer

~ Pathologic Characteristics ~

Aberrant growth pattern

Lymphovascular invasionLymphovascular invasion

Depth of tumor invasion

Presence of CIS

pT1a, n=75

pT1b, n=26pT1b, n=26

pT1c, n=23

p

Presence of Carcinoma -in-situ

Higher risk for upstaging: 55% vs. 6% Masood et al. Int Urol Nephrol 2004;36:41-44

Higher risk of progression and poor overall

Solsona et al. BJU Int. 2004;94:1258Herr et al. B J Urol. 1997; 80:762Zieger et al. Scand J Urol Nephrol. 2002; 36:52

Higher risk of progression and poor overall prognosis

Analysis of 2596 patients with superficial bladder cancer from 7 EORTC trials.Scoring system based on: number of tumors, tumor size, prior recurrence rate, T stage, CIS and grade to determine recurrence and progression rate

Prognostic indicators (pathologic) Divergent differentiation (MP)

Non-classic morphologic features within a urothelial tumor such as glandular, small cell, glandular, small cell, micropapillary is most commonly encountered in the setting of high grade disease, and more common in invasive tumors.

T1G3 Bladder Cancer“THE FACTS”

Is a potentially lethal tumorThis is NOT a superficial tumorUnderstaging occurs frequentlyHigh recurrence rate and progression despite High recurrence rate and progression despite intravesical therapyPoor markers available to accurately identify high risk lesions Can be effectively CURED by early definitive surgery (radical cystectomy)

Management of patients with cT1 tumors

T1

Restaging TUR

≤ T1

T2

High –risk T1•Prior BCG•cT1 on restage•Multiple T1 recurrences•Multifocal T1,Extensive cis•vascular invasion

Low risk T1

Intravesical BCG

Recurrent T1 No recurrence

SurveillanceRadical cystectomy

Prognostic indicators (pathologic) The importance of the muscularis

mucosae

“There is no continuous layer of smooth muscle separating the connective tissue into two distinctive compartments but only scattered fascicles only scattered fascicles loosely associated with blood vessels. Such a poorly demarcated landmark in a mal-oriented specimen may invite to observational inaccuracies”

Murphy

Prognostic indicators (pathologic) The importance of the muscularis mucosae

• Pagano reported the importance of the depth of penetration in the lamina propria

• Patients with T1b had a higher progression rate (58% vs 36%) and death rate (45% vs 23%) compared to T1a (Holmang)T1a (Holmang)

• On a multivariate analysis, only depth of penetration and CIS were independent predictor of outcome (Bernardini)

However, the identification of muscularis mucosae is a difficult task, At the present time, standardized criteria have not been adopted by pathologists .

Conservative Management is Appropriate

Recurrence-free survivalOrsola et al Eur Urol 48:231, 2005

Study # pts Med. F/u Progression

Cookson 86 15.3 yrs 53%

Pansadoro 81 6.3 yrs 15%

Shahin 92 5.3 yrs 30 %

T1G3 Bladder CancerLong-Term Outcome Conservative

Disease Specific Outcomes

Prognostic indicators (pathologic)Grade

• Grade is the most significant tumor variable in non-muscle invasive bladder cancer (Torti)cancer (Torti)

• The National Bladder Cancer Collaborative Group A reported 2, 11 and 45% progression in Grade 1, 2 and 3(Heney)

• 10 year survival rate of 78% for T1G2 and 50% for T1G3 (Jakse)

Prognostic indicators (pathologic)Grading system

With the new classification, the majority of T1 tumors are classified as high grade and the value of the grade is greatly diminished.



ShooterR. Colombo

Early cistectomy in High Risk NMIBCIf, When and How

Dott. Renzo ColomboDott. Renzo Colombo

Dipartimento di Urologia Ospedale San Raffaele

Urological Research Institute – URI

Università Vita-Salute San Raffaele

HR- NMIBC: PRO conservative treatment

There is no definitive evidence that one approach is better than other in terms of cancer specific survival

There is evidence that QoL is reduced after radical cystectomyExtremely delayed radical cystectomy can significantly compromize

survival

There is evidence that overall 60-70% of radical cystectomies are unnecessaryConsistent peri and post-operative morbidity Not negligible introperative mortalityReduced QoL

Contemporary management of superficial bladder cancer in the USA: a pattern of care analysis

Joudi FN et al. Urology 62; 2003

A consistent proportion (73%) of surveyed urologists still opt for intravesical therapy to treat high grade T1 disease that has failed BCG

Patients with Ta-T1, high-grade disease that failed BCG twice would receive

another course of intravesical chemotherapy (35%) or immunotherapy (38%).

Only 19% of surveyed urologists preferred pursuing radical treatment in these

patients.

Urologists trained after 1985 are three times more likely to treat T1

high-grade disease with CIS that had failed BCG with RC than the remaining

Urologists working at reference high volume centres or working in a

collaborative group tend to treat HR-NMIBC who failed after BCG with RC

This can be related to availability of assistance from partners for major surgery

and management of the expected complications

intravesical therapy to treat high grade T1 disease that has failed BCG twice.

HR- NMIBC factors that may influence decision making

AGE

COMORBIDITY [[ASA ASA -- CharlsonCharlson Score]Score]

SURGICAL VOLUME

OBESITY

An elderly patient with HR-NMIBC that has failed multiple courses of

intravesical therapy who has severe comorbidities might not be not

conisidered as a surgical candidate even though cystectomy is

recognized as the optimal treatment

SURGICAL VOLUME

METHOD METHOD --TO TO --PATIENT MATCHING APPROACHPATIENT MATCHING APPROACH

ARE WE ABLE TO DEFINE THE SUBSET,AMONG THE HR-NMIBC PATIENTS, FORWHICH A CONSERVATIVE TREATMENT CANBE SAFELY PROPOSED?

Q:

2 levels of discussion

TO DATA, WHAT KIND OF CONSERVATIVESTRATEGY CAN BE PROPOSED TO THISCOHORT OF PATIENT AND WHAT ARE THECLINICAL EXPECTATIONS?

Q:

HIGH RISK

SELECTION CRITERIAFOR DECISION MAKING

GRADINGSUBEPITHELIAL

CONNECTIVETISSUE INVASION

HIGH RISK NMIBC

IMMUNOHISTOCHEMISTRY

Kind of BCG-FAILURES

TUMOR GROWTH PATTERNS

FOCALITY & DIMENSIONS

CLINICAL IMPACT OF GRADEGRADE ON BOTH RECURRENCE AND PROGRESSION IN T1 BLADDER CANCER:

A COMPARISON BETWEEN WHO 1973 AND WHO 2004 HISTOLOGICAL CLASSIFICATION

GRADING

According to our retrospective internal investigation concerning HR-NMIBC patients, the WHO 1973 grading classification system wasdocumented to be more reliable for the oncologic outcomeprediction when compared to WHO-2004 classification.

High grade Low grade

Methods – Study population

We retrospectively evaluated clinical data of 266 consecutivepatients diagnosed with first presentation of T1 stage bladdercancer at transurethral resection (TUR) between 2004-2011

All patients with concomitant CIS were excluded (n=20)All patients with concomitant CIS were excluded (n=20)

In all cases, the grade was assigned by a singleuropathologist simultaneously as high grade and as G2 or G3according to the WHO 2004 and WHO 1973 classificationsystems, respectively

All patients included in the study were submitted to Re-TURand received immunotherapy with SWOG-BCG scheduledtreatment

Results

Overall High grade266 pz

Mean follow-up period was 31,1 months (median 19; range 1–93)

G2 patients124 Pz (46.6%)

G3 patients142 pz (53.4%)

Progression free survival – Cox models

Variables Univariable Multivariable

HR 95% CI p value HR 95% CI p value

Age 0.99 0.97-1.02 0.93 1 0.97-1.03 0.91

GenderMaleFemale

[Ref.]0.64

---0.3-1.3

---0.25

---0.81

---0.37-1.77

---0.60

Focality2 or more lesions1 lesion

[Ref.]0.65

---0.34-1.25

---0.19

---0.68

---0.35-1.33

---0.26

Tumor size≥ 3 cm

< 3 cm[Ref.]0.51

---0.24-1.08

---0.08

---0.49

---0.22-1.06

---0.07

Grade WHO 1973 (G2 vs G3)G2G3

[Ref.]3.44

---1.76-6.71

---< 0.001

---3.50

---1.79-6.58

---< 0.001

HG- Recurrence free survival – G2 vs G3 Kaplan-Meier curves

1,0

0,8 G3

G2

Grade WHO 1973

High Grade WHO 2004

100806040200

Follow-up (months)

0,6

0,4

0,2

0,0

p =0,003

G25 yr RFS rate 49,1%

G35 yr RFS rate 31,8%

G2

G3

HG- Progression free survival – G2 vs G3 Kaplan-Meier curves

1,0

0,8 G3

G2

Grade WHO 1973

1,0

0,8

0,6

0,4

0,2

OverallHigh grade

High Grade WHO 2004

100806040200

Follow-up (months)

0,6

0,4

0,2

0,0

p

Grading

Based on the mono-istitutional high-volume centerexperience with a single expert uro-pathologist, theWHO 1973 classification was proved to bemore reliable as prognostic factor in T1 NMIBCpatientspatients

This should be kept in consideration in the decision makingabout conservative rather than radical treatment.

G2G2 according to WHOaccording to WHO--1973 classification may be considered 1973 classification may be considered as a factor in favour of conservative treatmentas a factor in favour of conservative treatment

What has been, the impact of the newgrading classification in treatmentdecision-making in HG-NMIBC at yourQ: decision-making in HG-NMIBC at yourInstitute and in USA?

Prognostic significance of non-papillary tumor morphology as a predictor of cancer progression and survival in patients with primary T1G3 bladder cancerJinsung Park · Cheryn Song · Jun Hyuk Hong · Bong-H ee Park · Yong Mee Cho · Choung-Soo Kim ·Hanjong Ah n

MORPHOLOGIC FEATURES

Morphology:

papillary

non-papillaryPark. J., et al. World J Urol; 2009, 27(2):277

Understaging

Tumor at prostate urethra at endoscopic staging

Huguet ,Eur Urol 48;2005

endoscopic staging is the only (or at least the major) factor associated to understaging and shorter survival

Patients without involvement of prostate urethra ma y be considered for conservative treatment

Prognostic value of histopathological tumour growth patterns at the invasion frontof T1G3 urothelial carcinoma of the bladder.

Denzinger S., et al. Scand J Urol Nephrol. 2009; 43(4):282-7

Tumor growth patterns:

205 pts

F-Um: 6.7 ys

PATHOLOGIC CHARACTERISTICS

Tumor growth patterns

nodular

infiltrative

trabecular

CSS:

Infiltrative: 59.3%

Trabecular: 86.2%

Nodular: 91.1%

KindKind ofof tumortumor growthgrowth pattern pattern maymay bebe consideredconsidered forforselectingselecting patientspatients forfor conservative treatmentconservative treatment

What is the role of the extension of lamina propria involvement as a prognostic factor?

Pathologic T1 microstaging

PATHOLOGIC CHARACTERISTICS

propria involvement as a prognostic factor?

Is the microstaging feasible and reliable?

Q:

Orsola A et al. Eur Urol 2005;48(2):231-8

T1a:superficial invasion of lamina propria

T1b:invasion at the level of (or into) the lamina propria

T1c:invasion beyond the lamina propria

The depth of invasion in the TURB specimens isan independent prognostic factor for T1 patientseven in BCG-pretreated patients

T1a microstaging patients may be suitable for conservative

treatment

T1-HR, NMIBCRole of the extension of lamina propria

involvement as a prognostic factor

van Rhijn et al. Eur Urol 2012;61(2):378-84

T1m: microfocal involvement T1e: extended involvement

T1m

T1e

Substaging according to a new system (T1m and T1e)was:

user-friendlypossible in all cases andvery predictive of T1-NMIBC behaviour.

The tumor extension of bladder submucosa (focal rather thanmassive) has been considered for long time among majorprognostic factors for decision between conservative orradical treatment in high risk NMIBC in many centres as wellas at our Institute.

Courtesy by M. Freschi

Focal pT1 Diffuse pT1

Consider focal pT1 for conservative treatment

Consider diffuse pT1 for early radical cystectomy

Is the microstaging currently assessed at your Institute?

Is there a routine closed collaboration between urologists and pathologists at your Institute?

How much this pathologic finding impact on HR-NMIBC Q:

How much this pathologic finding impact on HR-NMIBC treatment decision at your Institute?

BCG-FAILURES

� Intolerant: Stopped d/t SE

� Resistant: Not “cleaned” in 3 mo.; St/Gr ↓↓↓↓� Refractory: Not “cleaned” in 6 mo.; St/Gr ↔↔↔↔ or ↑↑↑↑

Effect of response to prior therapy

� Refractory: Not “cleaned” in 6 mo.; St/Gr ↔↔↔↔ or ↑↑↑↑

---------------------------------------------------------------

� Early Relapsing: Cleaned but Rec < 1 y

� Intermediate Relapsing: Cleaned but Rec 1-2 y

� Late Relapsing: Cleaned but Rec > 2 years

by M. O’Donnell

BCG intolerant and late relapsing patients may be considered for

conservative treatment

What is the prognostic significance of recurrence during BCG maintenance?Q:

When patients had early recurrence there was a slightly higher probability of cystectomy but not progression to muscle invasive cancer

J Urol. 2007 May;177(5):1727-31

Immunohistochemistry

Assessment of p53, p27 and Ki-67 in urothelial carcinoma of thebladder specimens improves the prediction of recurrence-free and cancer specificsurvival in patients with pT1 disease at radical cystectomy.

These markers (p53, p21, p27, pRB, survivin, Ki-67) may help stratify theheterogeneous population of patients with pT1 disease into risk groups that

Pathologic characteristics

heterogeneous population of patients with pT1 disease into risk groups thatcan be used to guide clinical decision making regarding observation vs adjuvanttherapy.

Immunohistochemical staining was performed on representative urothelialcarcinoma of the bladder specimens of 80 patients with pT1 urothelial carcinomaof the bladder treated with radical cystectomy and bilateral pelviclymphadenectomy (median followup 61.6 months)

Shariat SF et al.. J Urol 2009 ;182(1):78-84

Bertz S et. Eur Urol 2012 May 19. [Epub ahead of print]

Predictive Value of Combined Immunohistochemical Markers in PatientsWith pT1 Urothelial Carcinoma at Radical CystectomyShahrokh F. Shariat, Christian Bolenz Guilherme Godoy, Yves Fradet, Raheela Ashfaq, Pierre I. Karakiewicz, HendrikIsbarn, Claudio Jeldres, Jérôme Rigaud, Arthur I. Sagalowsky, Yair Lotan

J Urol 2009 ;182(1):78-84

Immunohistochemical independent predictors for disease specific mortality

p53, p27, Ki-67

Only one alterated marker may be considered in favour of conservative treatment

IMMUNOHISTOCHEMISTRY

We rarely use the immunohistochemistry in decision making

Vascular invasionMicropapillary urothelial

carcinoma

Courtesy by M. Freschi

Q:What is the expected

cost/effectiveness analysis?

TO DATA, WHAT KIND OF CONSERVATIVESTRATEGY CAN BE PROPOSED TO THISCOHORT OF PATIENT AND WHAT ARE THECLINICAL EXPECTATIONS?

Q:

Additional cycles with BCG o BCG+INFα

Change to ICT

Tumor CR range: 20 e 60%. EffectiveLow level of Evidence

Reduced response (

Lammers RJ et al. The role of a combined regimen with intravesical ch emotherapy and hyperthermia in the management of non-muscle-invasi ve bladder cancer: a systematic review.Eur Urol 2011 Jul;60(1):81-93

overall bladder preservation rate:86.7%

Halachmi S. Intravesical mitomycin C combined with hyperthermia for patients with T1G3 transitional cell carcinoma of the bladder.Urol Oncol 2011 May-Jun;29(3):259-64

42.9 % and 7.9% recurrence and progression rate, at median 24 month follow -up, respectively

MW-TCT Synergo® and HR -NMIBC

month follow -up, respectively

Nativ O.Combined thermo-chemotherapy for recurrent bladder cancer after bacillus Calmette-Guerin. J Urol 2009182(4):1313-7

estimated disease-free survival of 85% and 56% afte r 1 and 2 years, progression rate (3%)

Volpe A. Thermochemotherapy for non-muscle-invasive bladder cancer: s there a chance to avoid early cystectomy?Urol Int 2012;89(3):311-8

43.3% of patients were disease-free , 3 progressions

BCG-Failures –Device-assisted approaches

RF-THERMO-CHEMOTHERAPY

34 BCG refractory

•K-M: estimated disease free survival for BCG refractory Pts

2 year disease free survival: 45%

progression rate: 6.6% (3/45)

18: after 2x6 inst .

16: after 1x6 + at least 1x3

additional inst.

Di Stasi S. Sequential BCG and electromotive mitomy cin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial.Lancet Onco 2006 Jan;7(1):43-51.

sequential BCG and EMDA/MMC had a significantly lon ger disease-free interval and lower recurrence rate than those assig ned to BCG alone

Di Stasi SM , Giannantoni A , Stephen RL , Capelli G , Navarra P , Massoud R , Vespasiani G .J Urol. 2003 Sep;170(3):777-82

EMDA and HR -NMIBC

Sockett LJ, Borwell J, Symes A, Parker T, Montgomer y BSI, Barber NJ (2008) Electro-motive drug administration (EMDA) of intravesical mitomycin-C in patients with high-risk non-invasive bladder cancer and failure of BCG immunotherapy. BJU Int101(suppl 5):50 abs #U17

31% remained recurrence-free while the others recurred without progression

Q:Why the device-assisted procedures are not considered and used in USA?

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