Prof. Francesco Boccardo

University and National Cancer Research Institute of Genoa, Italy

Prof. Francesco Boccardo

University and National Cancer Research Institute of Genoa, Italy

“Neoadjuvant and adjuvant

chemotherapy for high risk

bladder cancer”

“Neoadjuvant and adjuvant

chemotherapy for high risk

bladder cancer”

Rome, May 9-Rome, May 9-10,200810,2008

Prevalence of Prevalence of infiltrating bladder infiltrating bladder

cancer in surgical seriescancer in surgical series

Prevalence of Prevalence of infiltrating bladder infiltrating bladder

cancer in surgical seriescancer in surgical series

80-90%80-90% (Kaye & Lange, (Kaye & Lange, 1982)1982)

(Hopkins et al, (Hopkins et al, 1983)1983)

57%57% (Vaidya et al, (Vaidya et al, 2001)2001)

(A) Recurrence-free survival and (B) overall survival in 1,054 patients after radical cystectomy stratified by pathologic subgroups (organ confined, extravesical, and lymph node positive.

Stein JP et al, 2001

Stein JP et al J Urol, 2003

Stein JP et al, J Urol., 2003

Nodes Nodes Examined Examined (n)(n)

Patients Patients (n)(n)

5-yr Local 5-yr Local Relapse Relapse Rate (%)Rate (%)

5-yr 5-yr Survival Survival Rate (%)Rate (%)

0-50-5 149149 1717 3333

6-106-10 152152 8.58.5 4444

11-1411-14 157157 77 7373

>14>14 179179 44 7979

Table I . Outcome by number of nodes examined (quartiles) in all patients

Herr HW, Urology, 2003

Herr H et al,JCO 2004

Neoadjuvant chemotherapyNeoadjuvant

chemotherapy PROS Early control of

micrometastasis local control

(bladder sparing) Better compliance

to CT ( acute toxicity and lethality)

Chemosensitivity (postcystectomy treatment)

Prognostic significance of T response

CONTRA Delay in local control Understaging?

(postcystectomy treatment)

Overtreatment for a definite proportion of patients (patients selection)

Investigator/GroupInvestigator/Group Type of Type of evidenceevidence

Benefit (% reduction Benefit (% reduction mortality vs mortality vs cystectomy alone)cystectomy alone)

RemarksRemarks

SWOG (NEJM, SWOG (NEJM, 2003)2003)

Multicentric Multicentric randomized randomized study (317 study (317 pts)pts)

HR HR 5yr5yr

0.67 0.67 14%14%

p=0.06 (two p=0.06 (two sided)sided)

Benefit more Benefit more evident in T3 evident in T3 or T4a ptsor T4a pts

NORDIC (Eur Urol, NORDIC (Eur Urol, 2004)2004)

Metanalysis Metanalysis of 2 of 2 randomized randomized trial (Nordic trial (Nordic I and II) I and II) (620 pts)(620 pts)

HR HR 5yr5yr

0.80 0.80 8%8%

(0.64-0.99)(0.64-0.99)

p=0.05 p=0.05

Benefit more Benefit more evident in T3 evident in T3 or <65 yr ptsor <65 yr pts

ABC Collaboration ABC Collaboration (Lancet, 2003)(Lancet, 2003)

Metanalysis Metanalysis of 9 of 9 randomized randomized trials trials (including (including MRC/EORTC MRC/EORTC (2688 pts)(2688 pts)

HR HR 5yr5yr

0.91 0.91 3%3%

0.87 0.87 5%5%

p=0.01 p=0.01

Benefit for Benefit for combination combination chemotherapchemotherapy onlyy only

CANCER CARE CANCER CARE ONTARIO ONTARIO PROGRAM (J Urol, PROGRAM (J Urol, 2004)2004)

Metanalysis Metanalysis of 11 of 11 randomized randomized trials trials (including (including MRCEORTC) MRCEORTC) (2605 pts)(2605 pts)

HR HR 5yr5yr

0.900.90

p=0.02 p=0.02

0.87 0.87 6.5%6.5%

p=0.006 p=0.006

Benefit for Benefit for combination combination chemotherapchemotherapy onlyy only

Evidence supporting the efficacy of neoadjuvant chemotherapy in MIBC

Neoadjuvant chemotherapyNeoadjuvant

chemotherapy PROS Early control of

micrometastasis local control

(bladder sparing) Better compliance

to CT ( acute toxicity and lethality)

Chemosensitivity (postcystectomy treatment)

Prognostic significance of T response

CONTRA Delay in local

control Understaging?

(postcystectomy treatment)

Overtreatment for a definite proportion of patients (patients selection)

T versus P staging for T versus P staging for radical cystectomy radical cystectomy

patientspatients

T versus P staging for T versus P staging for radical cystectomy radical cystectomy

patientspatientsT T stagestage

No. of No. of patientpatient

s*s*

Patients for Patients for whom T < P whom T < P

(%)(%)

Patients for Patients for whom T > P whom T > P

(%)(%)

T1/TisT1/Tis 124124 23 (19)23 (19) 18 (15)18 (15)

T2T2 181181 71 (39)71 (39) 45 (25)45 (25)

T3aT3a 104104 37 (36)37 (36) 19 (18)19 (18)

T3bT3b 5656 32 (57)32 (57) 23 (45)23 (45)

TotalTotal 465465 163 (35)163 (35) 105 (23)105 (23)*Combined series from Whitmore*Combined series from Whitmore19771977, Prout, Prout19771977, Richie, Richie19751975 and Skinnerand Skinner19821982

Fair WR, 1993Fair WR, 1993

Why adjuvant chemotherapy?Why adjuvant chemotherapy?

1.Pathologic staging most accurately predicts the risk of relapse

2.The risk for new tumor formation is reduced or eliminated after surgery

3.No delay in surgery

Adjuvant Chemotherapy In Muscle-invasive Bladder Cancer: A Pooled Analysis From Phase III Studies.

Overall Survival

Adjuvant Chemotherapy In Muscle-invasive Bladder Cancer: A Pooled Analysis From Phase III Studies.

Disease-Free Survival

IPDIPD11 ADAD22

RRRR 0.750.75 0.770.77

pp 0.0190.019 0.0020.002

Heter. TestHeter. Test 0.810.81 0.720.72

Absolute Absolute BenefitBenefit 9%9% 9.4%9.4%

1Vale, Eur Urol 2005; 2Ruggeri, Cancer in press

Meta-Analysis of Adjuvant Chemotherapy for Bladder Cancer:

Overall Survival: IPD vs AD

EORTCEORTC + Intergroup Trial (+ Intergroup Trial (EORTC 30994)

EarlyEarly vs vs DelayedDelayed therapy for therapy for pT3pT3--pT4, and/or N+M0 TCC of the bladderpT4, and/or N+M0 TCC of the bladder

rraannddoommiizzee

GemGem--Cis x 4 orCis x 4 orMM--VAC x 4VAC x 4HDHD--MM--VAC x 4VAC x 4

Therapy at Therapy at relapse (x6 relapse (x6 cycles)cycles)

Trial design:Trial design:

Increase in 5 yr survival from Increase in 5 yr survival from 35 to 42%.35 to 42%.

Alpha .05; Beta .20: Alpha .05; Beta .20: 1344 pts1344 pts

Accrual 5.37yrs; F/U 3 yrsAccrual 5.37yrs; F/U 3 yrs

rraannddoommiizzee

Paclitaxel/Paclitaxel/Cisplatin/Cisplatin/Gemcitabine x 4Gemcitabine x 4

Therapy at Therapy at relapse relapse

SOGUGSOGUG Trial for pT3Trial for pT3--4,NxM0;4,NxM0;pTx, N1pTx, N1--3, M0 TCC3, M0 TCC

Trial design:Trial design:

Stratify by N status and PSStratify by N status and PS

15% improvement in 15% improvement in survival at 2 years survival at 2 years

(50(50-->65%)>65%)

Alpha .05; Beta .20: Alpha .05; Beta .20: 340 pts340 pts

Accrual 28 mo.; F/U 2 yrsAccrual 28 mo.; F/U 2 yrs

CISTECTOMIA RADICALE

pT2 G3 (N0- 2),pT3- 4 (N0- 2)pN1- 2 (qualunque G)

RANDOM

FOLLOW UP CDDP/GEM

RIPRESA DI MALATTIA RANDOM

Braccio B2 Braccio B15 GEM 1000 mg/mq GEM 1000 mg/mq

CDDP/GEM 1°,8° e 15° g 1°,8° e 15° g

CDDP 70 mg/mq CDDP 70 mg/mq

2° g 15° g

ogni 28gg. X 4 cicli ogni 28 gg. X 4 cicli

Ongoing Studies

Trial Design

10% Absolute in survival

25% death risk 35% 26%

=0.05; =20% 80% ; 610 patients

Assigned treatmentsAssigned treatments

Control (delayed)Control (delayed)

n=92 (%)n=92 (%)CDDP/GEM (early)CDDP/GEM (early)

n=102 (%)n=102 (%)

Median age, years(range)Median age, years(range) 63.5 (36.0-75.0)63.5 (36.0-75.0) 64.0 (38.0-75.0)64.0 (38.0-75.0)

SexSex

MaleMale

FemaleFemale80 (87.0)80 (87.0)

12 (13.0)12 (13.0)95 (93.1)95 (93.1)

7 ( 6.9)7 ( 6.9)

Performance statusPerformance status

00

11

missingmissing

65 (70.7)65 (70.7)

21 (22.8)21 (22.8)

6 ( 6.5)6 ( 6.5)

82 (80.4)82 (80.4)

16 (15.7)16 (15.7)

4 ( 3.9)4 ( 3.9)

Tumor size (depth)Tumor size (depth)

pT1-2pT1-2

pT3-4pT3-4

missingmissing

20 (21.7)20 (21.7)

66 (71.7)66 (71.7)

6 ( 6.6)6 ( 6.6)

32 (31.4)32 (31.4)

66 (64.7)66 (64.7)

4 ( 3.9)4 ( 3.9)

Nodal statusNodal status

pN0pN0

pN1-2pN1-2

missingmissing

49 (53.3)49 (53.3)

37 (40.2)37 (40.2)

6 ( 6.5)6 ( 6.5)

48 (47.1)48 (47.1)

50 (49.0)50 (49.0)

4 ( 3.9)4 ( 3.9)

Italian study: Patients demography

N° pts Obs p= HR (95% CI) p=CONTROL 86 37 0.7 1.0 0.7 CDDP/GEM 98 42 0.92 (0.59-1.44)

CONTROL( delayed)

CDDP/GEM (early)

Years

% P

rog

ressio

n f

ree s

urv

ival

Hazard of progressionHazard of progression

Delayed favored Early favored

0.92 (0.59-1.44)

0.88 (0.53-1.47)

0.99 (0.40-2.47)

0.49 (0.17-1.45)

1.04 (0.63-1.71)

1.18 (0.54-2.61)

HR (95% CI)

0.7

0.6

p value=

0.9

0.2

0.9

0.7

All patients

PS=0

pN0

pN1-2 0.90 (0.52-1.56)

0.7

PS=1

pT1-2

pT3-4

HRHR (95% CI)(95% CI) p=p=

TreatmentTreatment

CONTROLCONTROL

CDDP/GEMCDDP/GEM1.01.0

0.980.98 (0.63-1.54)(0.63-1.54)0.90.9

Performance statusPerformance status

00

111.01.0

1.141.14 (0.68-1.92)(0.68-1.92)0.60.6

Tumor size (depth)Tumor size (depth)

pT1-2pT1-2

pT3-4 pT3-4 1.01.0

1.731.73 (0.99-2.99)(0.99-2.99)0.050.05

Nodal statusNodal status

pN0pN0

pN1-2pN1-21.01.0

3.473.47 (2.15-5.62)(2.15-5.62)0.0000.000

Multivariate Analysis – Progression-free survival

Adjuvant chemotherapy for deep muscle-invasive transitional cell bladder carcinoma – a practice guideline

Roanne Segal, MD, Eric Winquist, MD Himu Lukka, MB,ChB, Joseph L. Chin, MD, Michael Brundage, MD, MSc, BR Markman,MA

The Canadian Journal of Urology, 2002