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.: The Role of Preoperative Chemotherapy in the Management of Wilms Tumor - The SIOP

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


Preoperative Chemotherapy

bei Diagnose nach 4 Wochen VCR / ACT-D


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


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%


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%).


SIOP 2001 - Prognosis

SIOP-RTSG, Interim Report - Update April 2010


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


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


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


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


LOH (COG Daten)

Paul Grundy et al., JCO 2005

stage I & II

stage III & IV


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


Bilateral Wilms Tumor


Nephroblastomatosis


Bilateral disease


Bilateral disease

Metachronous bilateral Nephroblastoma

Nephroblastoma &

contralateral N‘osis

Synchronous bilateral

Nephroblastoma


Renal sparing surgery

•Unilateral Wilms tumor

•Bilateral Wilms tumor

•Patients at risk

• for bilateral disease

• for renal failure


Tumor volume change

> 12


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


Surgery

L: CN 24 PN 60

R: CN 24 PN 59

BCN P&CN BPN UCN UPN


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


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



Outcome


[YEARS]

I: 79%

III: 59% (46%) (p=0.012)

II: 74%

I: 90%

III: 76% (68%) (p=0.017)

II: 86% (78%)


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


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)


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)


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


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


Quality control percentage


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



Nephroblastomatosis


[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)


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


Treatment duration


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%



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


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


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



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


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


Serial imaging evaluation

every 3 moths after

completion of therapy



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


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%)


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


Gender

Nephroblastomatosis Nephroblastoma

Male Female

25% 60%

Exact Test: p=0,12

Male Female


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

Documents

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.: The Role of Preoperative Chemotherapy in the Management of Wilms Tumor - The SIOP