prof. francesco boccardo university and national cancer research institute of genoa, italy prof....
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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