Copyright Prof. Dr. Graf, Homburg. Prognosis of Nephroblastoma since 1915 Copyright Prof. Dr. Graf,...
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Transcript of 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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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]
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
right43,6%
left47,8%
bilateral8,0%
extrarenal0,6%
SIOP 93-01 / GPOH
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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 %)
Copyright Prof. Dr. Graf, Homburg
Nephroblastoma NeuroblastomaCopyright Prof. Dr. Graf, Homburg
AUG 15 min
Copyright Prof. Dr. Graf, Homburg
Sonography
Copyright Prof. Dr. Graf, Homburg
CT
Copyright Prof. Dr. Graf, Homburg
MRI
Copyright Prof. Dr. Graf, Homburg
Bilateral nephroblastoma
Copyright Prof. Dr. Graf, Homburg
bef
ore
afte
r 4
wee
ks
US CT MRI
chem
oth
erap
y
Copyright Prof. Dr. Graf, Homburg
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%
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
SIOP 9 and SIOP 93-01 / GPOH
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.
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
Tumor staging
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
preop. chemotherapy primary surgery
%
SIOP 9 and SIOP 93-01 / GPOH
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
Chisq= 10.9 on 1 degrees of freedom, p= 0.000941
SIOP 9 / SIOP 93-01Survival according to treatment - correct / incorrect
Copyright Prof. Dr. Graf, Homburg
SIOP 9 / SIOP 93-01
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
SIOP 9 / SIOP 93-01
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg
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
Copyright Prof. Dr. Graf, Homburg