wilms tumour - ipso · rhabdoid tumor 35 30 25 20 15 10 5 0 5 10 15 20 25 30 35 40 graf n et al.:...
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Wilms Tumour Where we are?
Norbert Graf, Kathy Pritchard-Jones
Wilms Tumour © Norbert Graf
SIOP Nephroblastoma Trials
• SIOP 1 1971 – 1974 338 Patients
• SIOP 2 1974 – 1976 138
• SIOP 5 1977 – 1979 397
• SIOP 6 1980 – 1987 1095
• SIOP 9 1987 – 1991 852
• SIOP 93-01 1993 – 2001 2162
• SIOP 2001 2001 – 2012 4719
9701
• 28 countries
• 261 centres
Wilms Tumour © Norbert Graf
Preoperative Chemotherapy
bei Diagnose nach 4 Wochen VCR / ACT-D
Wilms Tumour © Norbert Graf
Histology preop. chemotherapy primary surgery
%
3
0,7
0,4
30,1
4,5
9,1
7,9
28,5
7,7
5,7
2,1
12
1,3
2,6
32,6
7,3
34
1,3
0
2
2,6
4
CMN
CPDN
highly diff. epithelial
mixed
epithelial predominant
blastemal predominant
stromal predominant
post-chemotherapeutic changes
anaplasia
CCSK
rhabdoid tumor
0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 40
Graf N et al.: The Role of Preoperative Chemotherapy in the Management of Wilms Tumor - The SIOP Studies. Urologic Clinics of North America, 27:443-454, 2000
Wilms Tumour © Norbert Graf
SIOP 2001 - Randomisation
• December 2009: randomisation closed: 583 patients
6% ineligible after review of stage & histology (+ 4.5% missing pathology review)
Category Doxo
(N=291)
No Doxo
(n=292)
Total
(n=583)
Brazil 62 64 126 (22%)
France 76 74 150 (26%)
Germany 45 45 90 (15%)
SIOP-NL 63 65 128 (22%)
UK 45 44 89 (15%)
Stage II 170 171 341 (58%)
Stage III 121 121 242 (42%)
Median age at diagnosis, 41 months; M:F 47%:53%
Wilms Tumour © Norbert Graf
Outcome (median follow up 47 months)
EFS by randomised treatment (ITT) OS by randomised treatment (ITT)
The difference between ‘DOX’ compared to ‘no DOX’ arms for EFS at 2 yrs is:
3.9% (97.5% lower bound -1.1%, upper bound 9.0%) ITT and,
3.1% (97.5% lower bound -2.1%, upper bound 8.3%) eligible patients only
Neither exceeded the predetermined limits (up to 10%).
Wilms Tumour © Norbert Graf
SIOP 2001 - Prognosis
SIOP-RTSG, Interim Report - Update April 2010
Wilms Tumour © Norbert Graf
Blastemal Type ?
If < 2/3 of tumour is necrotic, assign a cellular subtype
If > 2/3 of viable tumour is blastema = ‘blastemal type’
Volume after pre-op chemo
% necrosis
% blastema Histol. Risk Group
Volume Blastema
200 ml 60 70 Blastemal 56 ml
200 ml 70 90 Regressive 54 ml
Wilms Tumour © Norbert Graf
SIOP 2001 – localized WT - IR
SIOP-RTSG, Brainstorm Meeting 2010
Martingale residual
plot of blastema
volume after pre-op
chemotherapy and
EFS
log(volume blastema)
Excessiv
e r
isk (
EF
S)
20 ml
Wilms Tumour © Norbert Graf
SIOP 2001 – Stage IV
SIOP-RTSG, Brainstorm Meeting 2010
log(volume blastema)
Exce
ssiv
e r
isk (
EF
S)
time (months)
EF
S p
rob
ab
ility
Wilms Tumour © Norbert Graf
COG trials Tumor LOH Rapid
Age Weight Stage 1p and
16q Response
Risk
Group Study
< 2 yrs < 550 g I Any N/A Very Low AREN0532
Any ≥ 550 g I None N/A Low AREN0532
>2yrs Any I None N/A Low AREN0532
Any Any II None N/A Low AREN0532
> 2yrs Any I LOH N/A Standard AREN0532
Any ≥ 550 g I LOH N/A Standard AREN0532
Any Any II LOH N/A Standard AREN0532
Any Any III None Any Standard AREN0532
Any Any III LOH Any Higher AREN0533
Any Any IV LOH Any Higher AREN0533
Any Any IV None Yes Standard AREN0533
Any Any IV None No Higher AREN0533
Any Any V Any Any Bilateral AREN0534
Wilms Tumour © Norbert Graf
LOH (COG Daten)
Paul Grundy et al., JCO 2005
stage I & II
stage III & IV
Wilms Tumour © Norbert Graf
Preoperative Chemotherapy
initial after 4 weeks after 8 weeks
0
100
200
300
400
500
600
700
tumor volume [ml]
of preoperative chemotherapy
75 %
Median
25 %
stage I
65,0%
stage II N-
22,2%
stage II N+, III
12,8%
I
62,0%
II N-
25,1%
II N+, III
12,8%
Wilms´Tumor trial and study SIOP Committee Report, November 1993
Wilms Tumour © Norbert Graf
Bilateral Wilms Tumor
Wilms Tumour © Norbert Graf
Nephroblastomatosis
Wilms Tumour © Norbert Graf
Bilateral disease
Wilms Tumour © Norbert Graf
Bilateral disease
Metachronous bilateral Nephroblastoma
Nephroblastoma &
contralateral N‘osis
Synchronous bilateral
Nephroblastoma
Wilms Tumour © Norbert Graf
Renal sparing surgery
•Unilateral Wilms tumor
•Bilateral Wilms tumor
•Patients at risk
• for bilateral disease
• for renal failure
Wilms Tumour © Norbert Graf
Tumor volume change
> 12
Wilms Tumour © Norbert Graf
Histology and tumor volume
1783N =
stromal / epithelialall other
tum
ou
r v
olu
me
at d
iag
no
sis
[m
l]
1000
900
800
700
600
500
400
300
200
100
0
945N =
stromal / epithelialall other
tum
ou
r v
olu
me
re
du
ctio
n [m
l]
1000
900
800
700
600
500
400
300
200
100
0
at diagnosis reduction
Wilms Tumour © Norbert Graf
Surgery
L: CN 24 PN 60
R: CN 24 PN 59
BCN P&CN BPN UCN UPN
Wilms Tumour © Norbert Graf
Outcome
[YEARS]
Localised Stage V: 81% (76%)
Localised Stage V pre-treated for Nephroblastomatosis: 26% (p<0.001)
Stage V with metastasis: 47% (p<0.001)
Localised Stage V: 90% (76%)
Localised Stage V pre-treated for Nephroblastomatosis: 52% (p<0.001)
Stage V with metastasis: 58% (p<0.001)
Progression Free Survival Overall Survival
Wilms Tumour © Norbert Graf
Outcome
[YEARS]
Low/intermediate risk : 74% (67%)
High risk : 63% (63%) Log Rank ns
Low/intermediate risk : 88% (85%)
High risk : 72% (65%) Log Rank p=0.05
Progression Free Survival Overall Survival
Wilms Tumour © Norbert Graf
Outcome
Progression Free Survival Overall Survival
[YEARS]
I: 79%
III: 59% (46%) (p=0.012)
II: 74%
I: 90%
III: 76% (68%) (p=0.017)
II: 86% (78%)
Wilms Tumour © Norbert Graf
Outcome stage III
• 40 Patients with stage III
• 13 patients did relapse
• 11 local 1 combined 1 metastasis
• Out of 32 patients data are available regarding irradiation
• 11 patients did receive irradiation
• 2 with nephroblastomatosis
• 21 patients did not receive irradiation
• 7 with nephroblastomatosis
• Irradiated patients (5y PFS): 91% ± 9%
(1/11)
• Non-irradiated patients (5y PFS): 65% ± 11%
(8/21)
p=0,076
Wilms Tumour © Norbert Graf
Stage V – Cox Regression - PFS
Sig
Exp(B)
Lower
Upper
Age .195 1.122 .943 1.334
Metastasis .002 5.178 1.835 14.610
Pretreatment for NBL .000 8.032 2.641 24.424
Partial nephrectomy .017 4.344 1.294 14.585
Gender .609 .802 .343 1.871
Local stage (overall) .301
I + III vs II .196 2.139 .676 6.769
III vs I + II .203 1.831 .721 4.650
Histology (overall) .672
IR vs HR + LR .704 .741 .158 3.485
HR vs IR + LR .440 .496 .084 2.935
95% CI for Exp(B)
Wilms Tumour © Norbert Graf
Stage V – Cox Regression - OS
Sig
Exp(B)
Lower
Upper
Age .254 1.175 .891 1.549
Metastasis .026 5.685 1.234 26.180
Pretreatment for NBL .024 7.315 1.296 41.275
Partial nephrectomy .412 .509 .101 2.554
Gender .685 1.335 .331 5.386
Local stage (overall) .150
I + III vs II .096 4.625 .763 28.048
III vs I + II .065 5.168 .903 29.582
Histology (overall) .109
IR vs HR + LR .075 .171 .024 1.192
HR vs IR + LR .602 .594 .084 4.216
95% CI for Exp(B)
Wilms Tumour © Norbert Graf
Late effects
2 patients acute post operative renal failure
5 patients persistent chronic renal failure
2 patients persistent tubulopathy
1 patient bilateral complete nephrectomy
1 patient Cardiomyopathy
7 patients VOD
33 patients Toxicity related dose reductions
1 patient MDS
5 patients Treatment related deaths
(1 N‘osis, 4 WT St.V)
3 Infection, 2 Surgery
Wilms Tumour © Norbert Graf
Conclusions
• 50% Progression in patients with nephroblastomatosis, most
of them develop a (fatal) WT
• Non-metastasized and non-pre-treated bilateral WT have an
outcome comparable to unilateral diseases
• PN is possible in 55 % of patients on both sides, only ¼ of
kidneys have to be removed
• Independent risk factors:
• Metastasis and pre-treatment for bilateral nephroblastomatosis
• Local stage III and high risk histology have a negative impact on
overall survival
• Pre-Operative treatment should not be prolonged for more than 12
weeks
Wilms Tumour © Norbert Graf
Quality control percentage
Wilms Tumour © Norbert Graf
Acknowledgement
• Patients with kidney tumors and their parents
• Local physicians, nurses, psychosocial and
other team members treating patients with
kidney tumors
• Reference physicians and panel members
• Statisticians and data managers
• German Cancer Aid and further Sponsors
grant No.: 50-2709-Gr 2
Wilms Tumour © Norbert Graf
Wilms Tumour © Norbert Graf
Nephroblastomatosis
Progression Free Survival Overall Survival
[YEARS]
5y-PFS (n=27): 48,7% PD n=3 (2 PD to WT) P to WT n=10
5y-OS (n=27): 78,7% DOD n=5 TrD n=1 (Infection)
Wilms Tumour © Norbert Graf
Lessons to learn
• Factors contributing to decreased survival
• Understaging undertreatment
• Lymph nodes most critical
• Delay in local control
• Non-responders need earlier surgery
• Imaging response does not always correlate with
tumor response based on histology
• Increased incidence of anaplasia
Wilms Tumour © Norbert Graf
Treatment duration
Wilms Tumour © Norbert Graf
Nephroblastomatosis
[YEARS]
5y-PFS: n.s. Male (n=12) 60% Female (n=15) 46%
5y-OS: Log-Rank p=0.016 Male (n=12) 50% Female (n=15) 93%
Progression Free Survival Overall Survival
Wilms Tumour © Norbert Graf
AREN 0534 Objectives
• To improve 4-yr EFS for patients with BWT to
73%
• To prevent complete removal of at least one
kidney in at least 50% of patients with BWT
• To evaluate the efficacy of chemotherapy in
preserving renal units in children with DHPLNR
• To facilitate partial nephrectomy in lieu of
nephrectomy in 25% of children with unilateral
tumors with aniridia, BWS, hemihypertrophy
and other overgrowth syndromes by using
prenephrectomy 2 drug induction therapy
Wilms Tumour © Norbert Graf
Treatment (SIOP)
V V V V Act-D Act-D _____________________________________________
week 1 2 3 4
evaluation after each cycle decrease of
tumour volume
stable disease
sparing surgery possible
sparing surgery not possible
progressive disease
V V V V Act-D Act-D DOX DOX ___________________________________________________
week 1 2 3 4
surgery start with the less involved kidney
postoperative chemotherapy highest stage and histology at least stage II treatment
evaluation after each cycle
Wilms Tumour © Norbert Graf
Treatment (COG – AREN0534)
VAD for 6 weeks then evalute with CT/MRI
Bilateral PN feasible
Surgery at week 6
PN not feasible
> 50% reduction in both kidneys
Continue VAD for 6
more weeks
Surgery at week 12
< 50 % reduction in either kidney
Bilateral open
biopsies
Anaplasia
Change to anaplastic regimen
Necrotic tumor
PN or enucleation
Blastemal predominant
Change to regimen I,
reassess after 12 weeks
All other histologies
Continue VAD for 6
weeks
Wilms Tumour © Norbert Graf
Treatment (COG – AREN0534)
Surgical resection completed
Stage I, II CN
Stage I Intermediate risk tumors
EE4A
18 weeks
Stage I blastemal predominant
Stage I anaplasia
Stage III CN
DD4A
24 weeks
Stage II-IV
blastemal predominant
Regimen I
24 weeks
Stage II-IV
anaplasia
Regimen UH-1
30 weeks
Wilms Tumour © Norbert Graf
DHPLN Initial Treatment
EE4A chemotherapy x 6 weeks, then evaluate with MRI
Progression of disease during
therapy
PN feasible
Surgery
PN not feasible
Treat per bilateral Wilms
protocol
Good response > 50 %
reduction in both kidneys
Continue therapy for a
total of 18 weeks
Treatment (COG – AREN0534)
Serial imaging evaluation
every 3 moths after
completion of therapy
Wilms Tumour © Norbert Graf
Treatment (COG – AREN0534)
Initial treatment unilateral Wilms at High Risk for BWT
EE4A chemotherapy x 6 weeks, then evaluate with MRI
PN feasible
Surgery
PN not feasible
> 50% reduction
Continue VA for 6 more
weeks
PN feasible PN not feasible
< 50% reduction
Nephrectomy
Wilms Tumour © Norbert Graf
Bilateral renal tumors
All bilateral tumors from January 1989 – May 2005
138 patients from A, CH & D
None: Bilateral CCSK, RT, RCC SIOP 9/GPO - 25 patients SIOP 93-01/GPOH - 86 patients SIOP 2001/GPOH - 25 patients Median follow up: 6.2 y (min 0.8y – max 15.0y) Syndromes: 22 (16%)
Wilms Tumour © Norbert Graf
Age distribution
Median Age at diagnosis Nephroblastomatosis: with Progression to WT : 1.0y (WT: 3.3y) without Progression to WT : 1.1y Stage V Nephroblastoma : 2.2y p=0,001
[years]
nu
mb
er
Wilms Tumour © Norbert Graf
Gender
Nephroblastomatosis Nephroblastoma
Male Female
25% 60%
Exact Test: p=0,12
Male Female
Wilms Tumour © Norbert Graf
Nephroblastomatosis
Average pre-OP treatment duration: 64 weeks ( 4 - 216w) -Stage V preoperative treatment: 6
& Nephroblastomatosis treatment 5 & Wilms treatment + N‘osis treatment 1 & Watch and wait 0
-Radiologic diagnosis & Nephroblastomatosis treatment: 7
-Initial Biopsy/Surgery: 13 & Nephroblastomatosis treatment: 12 & Watch and Wait (after surgery): 1 -no treatment 1