Copyright Prof. Dr. Graf, Homburg. Prognosis of Nephroblastoma since 1915 Copyright Prof. Dr. Graf,...

Copyright Prof. Dr. Graf, Homburg

1915 1925 1935 1945 1955 1965 1975 1985 19950

20

40

60

80

100

year survival comment

1915 10 % 25 % operative mortality1925 15 % 20 % operative mortality1935 30 % < 5 % operative mortality1945 45 % postoperative irradiation1965 80 % chemotherapy1980 90 % risked adapted treatment prospective randomised studies

Prognosis of Nephroblastoma since 1915


Malignancies in Children

Nephroblastoma 6,1%

CNS-Tumor 16,3%

Lymphoma 11,3%

Neuroblastoma 7,2%

Soft tissue sarcoma 6,9%

Leukemia 34,5% Bone tumor 5,1%

Germ cell tumor 3,7%

Histiocytosis 3,3%

Other 5,6%

Deutsches Kinderkrebsregister, 1992


10,910,3

9,28,5

87,9

7,57,5

7,27,27,27,2

7,16,8

6,76

4,63,83,8

3,22,8

2,5

USA [Black]Nigeria

SwedenUSA [White]

GermanyUganda

ItalyAustralia

BrazilPuerto Rico

CanadaEngland

ZimbabweIsrael [Jews]

HungaryKuwait [Non-Kuwaiti]

Israel [Non-Jews]Kuwait [Kuwaiti]

IndiaJapan

PhilipinesChina

0 2 4 6 8 10 12

Incidence of Nephroblastoma

Breslow N et al.: Epidemiology of Wilms Tumor. MPO 21:172-181, 1993

Age standardised ratio [per Million]


Tumor 56 %Pain 25 %Haematuria 18 %Fever 10 %Urinary tract infection 6 %Weight loss 5 %Constipation 6 %Enteritis 4 %Vomiting 6 %Other 19 %

0%

20%

40%

60%

80%

100%

symptomatic

other symptoms

U3 - U9 (no symptoms)

Symptoms in Wilms´ Tumor

Gutjahr P: Bundesweite Wilmstumor-Studie 1980 bis 1988. Dt Ärztebl 87:B2130-B2134, 1990


Ag

e d

ist r

i bu

t io

n o

f N

eph

r ob

last

om

a

Breslow N et al.: Epidemiology of Wilms Tumor. MPO 21:172-181,1993


right43,6%

left47,8%

bilateral8,0%

extrarenal0,6%

SIOP 93-01 / GPOH


Other malignancies : Neuroblastoma Adenocarcinoma of kidney Lymphoma Langerhans Cell Histiocytosis Teratoma

Benign diseases : Abscess of the kidney Fibroma of the kidney Haematoma Hydronephrosis Cystadenoma Ganglioneuroma Hamartoma

Differential Diagnosis


without87,6%

with12,4%

aniridia4,4%

HH13,3%

BWS2,2%UGM

33,3%

Drash4,4%

familiar4,4%

other37,8%

SIOP 93-01 / GPOH

Malformations and Syndromes


Frequency of congenital Anomalities

Anomalia NWTS [%] SIOP [%]

CNS 0.47 1.66 Eye (all) 1.21 2.17 only Aniridia 0.84 Cardiopulmonal 1.52 Gastrointestinal 0.68 Urogenital (all) 4.61 4.41 Cryptorchism 2.78 Hypospadia 1.78 Hair, skin, nails 1.78 Hemihypertrophia 2.47 3.13 Neurofibromatosis 0.10

Bürger D, Feickert HJ, Mildenberger H: Current status of nephroblastoma treatment. Monogr Paediatr 18:224-242, 1986


Wilms´ Tumor

Kidney Diaseases or Anomalities Nephroblastomatosis Denys-Drash-Syndrome Multicystic Kidneys Glomerular Diseases

HamartomaM. Recklinghausen

Growth Beckwith-Wiedemann-Syndrome Marfan-Syndrome Cerebral Gigantism Hemihypertrophia Klippel-Trenaunay-Syndrome

Sporadic Aniridia 11p-Deletion-Syndrome

Bone Anomalities Klippel-Feil-Syndrome Club-foot

Urogenital Anomalities Hypospadia Cryptorchism Pseudohermaphroditism Horseshoekidney Genital Malformations

Syndromes und congenital Anomalities in Association with Wilms´ Tumor


without86,5%

with13,5%

lung61,4%

liver11,4%

bone7,1%

brain1,4%

other18,6%

SIOP 93-01 / GPOH

Metastasis at diagnosis (isolated 60 %, multipel 40 %)


Nephroblastoma NeuroblastomaCopyright Prof. Dr. Graf, Homburg

AUG 15 min


Sonography


CT


MRI


Bilateral nephroblastoma


bef

ore

afte

r 4

wee

ks

US CT MRI

chem

oth

erap

y


Tumorvolume [Sonography]

initial after 4 weeks after 8 weeks0

100

200

300

400

500

600

700Tumorvolume [ml]

preoperative chemotherapy

75 %

median

25 %

stage I65,0%

stage II N-22,2%

stage II N+ & III12,8%

I62,0%

II N-25,1%

II N+ & III12,8%


SIOP NWTS

Philosophy preoperative chemotherapy primary surgery

Histology low / intermediate / high favorable / unfavorable

Staging II Lymphnode negativ II

II Lyphmnode pos., III III

Duration maximal 8.5 months maximal 6 months

Anthracyclines stage II and higher stage III and higher

40 % of patients 30 % der Patienten

Irradiation (local) never stage I CCSK also stage I

18 % der Patienten > 30 % of patients

Irradiation (lung) only if non CR all stage IV

SIOP - NWTS


tum

or v

olum

e

SIOP 9 and SIOP 93-01 / GPOH

N = 513 411 114mean = 435 226 200median = 364 149 113std = 344 291 223

2400

2000

1600

1200

800

400

0

preoperative chemotherapy primary surgery

at diagnosis at time of surgery

I55,4%

II27,7%

III16,9%

I44,7%

II17,5%

III37,7%

postoperative stage distribution



8547051N =

2000

1600

1200

800

400

0

7538227N =

1200

800

400

0

low risk intermediate risk high risk low risk intermediate risk high risk

Tu

mo

r v

olu

me

[m

l]

aft

er c

hem

oth

erap

y

at

dia

gn

osi

s

mean 313 ml 434 ml 457 ml

mean 166 ml 223 ml 423 ml

P < 0.001 p < 0.001 n.s.


SIOP 9 and SIOP 93-01 / GPOHT

um

or

volu

me

redu

ctio

n a

fter

pre

op

era

tive

ch

em

oth

era

py [m

l]

low risk intermediate risk high risk low risk intermediate risk high risk

mean 225 ml 215 ml 29 mlmedian 205 ml 152 ml 0 ml

7136625N =

3000

2000

1000

0

-1000

-2000

P < 0.001p < 0.001


Risk of preoperative chemotherapy withouthistological proven Wilms´ tumor.

Study n

wronglypreoperatively

treated(all)

wronglypreoperatively

treatedbenign tumors

n % n %

SIOP 6 1095 38 3.5 16 1.5

SIOP 9 511 28 5.5 8 1.6


Obstruction of the gut and ileus 6.9 %Severe bleeding 5.9 %Wound infection 3.0 %Vessel injury 1.4 %Hernia 0.8 %Gut infarction 0.6 %Obstruction V. cava inferior 0.5 %Spleen injury 0.5 %Gut injury 0.5 %Pneumothorax 0.4 %Chylous ascites 0.4 %

ML Ritchey et al.: Surgical Complications after Nephrectomy for Wilms´ Tumor. Surg Gynecol Obstet 175:507-514, 1992

Operative Complications


SIOP 93-01 / GPOH

unknown

I

II N-

II N+ / III

11,0%

49,0%

2,0%38,0%

unknown

I

II N-

II N+ / III

7,0%

58,0%

22,0%

13,0%

primary surgery primary chemotherapypostoperative local stage


Tumorrupture

no84,6%

yes15,4%

no97,0% yes

3,0%

without preoperative with preoperative chemotherapy chemotherapy

Ludwig R et al.: Präoperative Chemotherapie des Nephroblastoms. Vorläufige Ergebnisse der Therapiestudie SIOP-9/GPO. Klin Pädiatr 204:204-213, 1992


SIOP 1 SIOP 2 SIOP 5 SIOP 6 SIOP 90

20

40

60

80

100

irradiation

no irradiation

[%] of patients

Radiotherapy during SIOP-1, 2, 5, 6 and 9

Jereb B et al.: Radiotherapy in the SIOP (International Society of Pediatric Oncology) Nephroblastoma Studies: A Review. MPO 22:221-227, 1994Graf N et al.: The Role of Preoperative Chemotherapy in the Management of Wilms Tumor - The SIOP Studies. Urological Clinics of North America, in press


0

10

20

30

40

50

60stage I [%] II N- [%] II N+ & III [%]

rupture [%]

SIOP-1, 2, 5 and 6

Jereb B et al.: Radiotherapy in the SIOP (International Society of Pediatric Oncology) Nephroblastoma Studies: A Review. MPO 22:221-227, 1994

SIOP-1 SIOP-2 SIOP-5 SIOP-6 OP 20 Gy OP 20 Gy + ACT-D VCR + ACT-D


LOW RISK TUMOURS ("FAVOURABLE")

Cystic partially differentiated nephroblastomaNephroblastoma with fibroadenomatous-like structuresNephroblastoma of highly differentiated epithelial typeNephroblastoma - completely necroticMesoblastic nephroma

INTERMEDIATE RISK TUMOURS ("STANDARD")

Non-anaplastic nephroblastoma with its variantsNephroblastoma - necrotic but some features left (<5%)

HIGH RISK TUMOURS ("UNFAVOURABLE")

Nephroblastoma with anaplasiaClear cell sarcoma of the kidneyRhabdoid tumour of the kidney

OTHER TUMOURS

Cystic nephromaRenal cell carcinomaTransitional cell carcinomaNeuroepithelial tumours

renal neuroblastomarenal P.N.E.T.renal carcinoid

Miscellaneous sarcomasRenal lymphomaAngiomyolipomaAdenomasOther tumours and lesionsMetastases from other sites

ADDENDUM

Presence/absence of nephrogenic rests should be clearly stated

Sto

ckho

lm W

orki

ng C

lass

ifica

tion

of R

enal

Tum

ours

of C

hild

hood


Tumor staging


primary surgery, SIOP 1, 2, [n=110]

preoperative irradiation, SIOP 1, [n=73]

preoperative irradiation + AMD, SIOP 2, 5, [n=162]

preoperative chemotherapy SIOP 5, 6, 9, [n=1077]

0 20 40 60 80 100

%

stage I stage II N0 stage II N1 & III % tumor ruptures


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

05101520253035 0 5 10 15 20 25 30 35 40


stage I - III preoperative chemotherapy stage IV

tumornephrectomy +/- metastasectomy

risk

stage low intermediate high

except stage I anaplasia

CR : therapy according intermediate risk local stage, at least stage II

NON-CR: therapy according high risk

AV AVE

II N0 AVE

II N1 / III AVE + 15 (+15) Gy

I no AV R

CARBO / VP 16 IFO / EPI + 30 (+5) Gy

Treatment schedule of the study SIOP 93-01


SIOP 9 / SIOP 93-01

Factor Risk ratio 95 % CI p-value

High vs low, intermediate 2.652 1.546 4.549 0.0004

Volume after pre-operative CT>= 400 ml vs < 400 ml

1.929 1.198 3.105 0.0068

Stage I vs II N-, II N+, III 0.551 0.333 0.914 0.0209

multivariate analysis


6838231453191N =

IIIII N+II N-Iunknown

tum

ou

r vo

lum

e a

fte

r p

reo

pe

rative

CT

2000

1500

1000

500

0

SIOP 9 / SIOP 93-01Tumour volume and local stage


Chisq= 10.9 on 1 degrees of freedom, p= 0.000941

SIOP 9 / SIOP 93-01Survival according to treatment - correct / incorrect


SIOP 9 / SIOP 93-01


SIOP 9 / SIOP 93-01

months

4842363024181260

Su

rviv

al P

rob

ab

ility

1,0

,8

,6

,4

,2

0,0

602 543 489 457 419 383 345 294 245 I

315 270 231 211 195 171 149 128 100 II N-

49 43 42 41 35 33 31 29 23 II N+

114 99 80 68 57 52 43 40 30 III

stage Istage II N-stage II N+

stage III


SIOP 9 / SIOP 93-01


SIOP 9 / SIOP 93-01

0 6 12 18 24 30 36 42 48

months

0.0

0.2

0.4

0.6

0.8

1.0

Surv

iva

l P

rob

abili

ty

1193 996 842 762 673 596 520 454 371 inter (rest)

135 126 112 99 92 76 58 43 30 epithelial/stromal

83 62 51 46 39 34 31 24 17 blastemal

inter (rest)

epithelial/stromal

blastemal


SIOP 9 / SIOP 93-01

0 6 12 18 24 30 36 42 48

months

0.0

0.2

0.4

0.6

0.8

1.0

Surv

iva

l P

rob

ab

ility

47 46 40 38 30 26 20 19 16 low risk

815 735 641 594 533 477 424 377 313 inter (rest)

135 126 112 99 92 76 58 43 30 epithelial/stromal

83 62 51 46 39 34 31 24 17 blastemal

102 82 68 57 50 43 38 31 22 high risk

low risk

inter (rest)

epithelial/stromal

blastemalhigh risk


Outcome focal vs diffuse anaplasia

death [%] 2 y SUR [%] 4 y SUR [%]0

20

40

60

80

100

120

stage I stage II stage III stage IV

stage I stage II stage III stage IV

NWTS-3 and NWTS-4 randomised anaplastic nephroblastoma patients

focal diffus focal diffus focal diffus


SIOP 9 / SIOP 93-01

0 6 12 18 24 30 36 42 48

months

0.0

0.2

0.4

0.6

0.8

1.0

Su

rviv

al

Pro

ba

bili

ty

83 62 51 46 39 34 31 24 17 blastemal predom

31 27 24 22 21 20 18 12 6 focal anaplasia

56 41 32 24 19 14 12 11 9 diffuse anaplasia

blastemal predom

focal anaplasia

diffuse anaplasia


SIOP 9 / SIOP 93-01

months

4842363024181260

Su

rviv

al P

rba

bility

1,0

,8

,6

,4

,2

0,0

141 128 104 92 81 74 67 61 52 no volume reduction

778 712 628 569 458 443 396 330 256 volume reduction

volume reduction

no volume reduction


SIOP 9 / SIOP 93-01

months

4842363024181260

Su

rviv

al P

rob

ab

ility

1,0

,8

,6

,4

,2

0,0

809 754 659 598 545 487 424 357 282 < 400 ml

172 142 122 109 94 82 71 63 55 >= 400 ml

volume < 400 ml

volume >= 400ml

Tumor volume after preoperative CT


SIOP 9 / SIOP 93-01

months

4842363024181260

Su

rviv

al P

rob

ab

ility

1,0

,8

,6

,4

,2

0,0

682 569 492 449 402 352 306 259 200 < 400 ml

562 475 396 353 316 273 232 198 160 >= 400 ml

volume < 400 ml

volume >= 400ml

Tumor volume at diagnosis


SIOP 9 / SIOP 93-01

0 6 12 18 24 30 36 42 48

months

0.0

0.2

0.4

0.6

0.8

1.0

Su

rviv

al

Pro

ba

bili

ty

339 318 284 265 248 230 211 192 163 <500 ml

41 32 28 27 22 21 21 19 16 > 500 ml

<500 ml

> 500 ml

Mixed subtype, focal anaplasia


SIOP 9 / SIOP 93-01

number ofpatients

number ofevents

event freesurvival after

60 months

p-value

specimen weight< 250 g 561 49 0.87 0.0002

>= 250 g 499 83 0.79tumour volume reduction

yes 778 83 0.86 0.01no 141 25 0.80

tumour volume at diagnosis< 400 ml 682 68 0.86 0.04

>= 400 ml 562 78 0.82tumour volume after preoperative CT

< 400 ml 809 77 0.88 0.0001>= 400 ml 172 38 0.76


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Copyright Prof. Dr. Graf, Homburg. Prognosis of Nephroblastoma since 1915 Copyright Prof. Dr. Graf,...

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