childhood liver tumours the siopel experience...laparoscopic guided liver biopsies hepatoblastoma...
TRANSCRIPT
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Childhood Liver Tumours – The SIOPEL
experience
Giorgio Perilongo,
Clinica Pediatrica, Dipartimento A.I. Di
Pediatria di Padova
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On behalf of the International Childhood Liver Tumour Strategy
Group - SIOPEL
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Trial office:
Leicester UK
Statistical
office:
Berne,
Switzerland
Strategy Group
cohordinator
office: Gzdank,
Poland
WEB System
headquarter:
Bologna, Italy
* Project
leaders’
offices
*
* * *
*
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Trial office: Leicester, UK International tissue bank: Zurich, Switzerland Statistical office: Berne, Switzerland Strategy Group coordinator office: Padua, Italy WEB System headquarter: Bologna, Italy Project leaders’ offices
1
2 3 4 5
1
2
3
4
5
Y
Y
Y Y
Y
Y
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In 2007 there is not a uniformally
accepted standard of care for
childhood Hepatoblastoma. Thus,
different groups give different
answers to the same questions.
Status of the arte lecture on
Treatment of …Hepatoblastoma
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Which is the standard of care?…and more precisely
Why, which, when and how much Chemotherapy?
Status of the arte lecture on
Treatment of …Hepatoblastoma
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COG staging system
Surgical staging
Imaging for metastases
PRETEXT system (2005 revision)
Applicable to all paediatric primary liver tumours
Non-surgical staging
Imaging is crucial
Staging of Primary
Childhood Liver Tumours
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Stage I: gross total resection
Stage II: microscopic residual disease (includes tumour
rupture and tumour spill at time of surgery)
Stage III: gross residual tumour and/or positive nodes
Stage IV: distant metastases
COG Staging System
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4 2
3
fissure of the
ligamentum teres
LPV
LHV
1
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PRETEXT I left lateral or right
posterior section involved
PRETEXT II two adjoining sections
free of tumour
PRETEXT III one section free, or two non-
adjoining sections free
PRETEXT IV four sections involved
PRETEXT
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PRETEXT I
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PRETEXT II
section 1
(caudate)
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PRETEXT III
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PRETEXT IV
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C: involvement of segment 1
E: extrahepatic abdominal disease
F: multifocal liver tumour
H: tumour rupture at diagnosis
M: distant metastases
N: lymph node metastases
P: portal vein involvement
V: involvement of hepatic veins or IVC
PRETEXT:
additional criteria
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High risk
serum AFP < 100 μg/L
PRETEXT IV
E1, E1a, E2, E2a
H1
M1
N1, N2
P2, P2a
V3, V3a
SIOPEL Risk Stratification
in Hepatoblastoma
Standard risk
All other patients
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Extrahepatic disease
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Venous involvement
no involvement involvement
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Venous invasion
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Biopsy is usually required
• possible exception
–age 6 months to 3 years
–alfa-fetoprotein elevated
SIOPEL recommends tissue diagnosis
Various biopsy methods are available
Tumour biopsy
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Hepatoblastoma
Laparoscopic guided liver biopsies
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Laparoscopic guided liver biopsies
Hepatoblastoma
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Laparoscopic guided liver biopsies
Hepatoblastoma
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Laparoscopic guided liver biopsies
Hepatoblastoma
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Coaxial biopsy technique
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Coaxial biopsy technique
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Which is the standard of care?…and more precisely
Why, which, when and how much Chemotherapy?
The European (SIOPEL) point of view
Status of the arte lecture on
Treatment of …Hepatoblastoma
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Treatment results in the seventies
Combination chemotherapy in the treatment of children
with malignant hepatoma - A.E. Evans et al. Cancer 1982
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Treatment of hepatoblastoma
Treatment results of
modern multi-modality
treatment strategy !!
75% (95 CI 68-82%)
SIOPEL1 study
5-years Overall Survival
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Which is the standard of care?…and more precisely
Why, when, which, and how much Chemotherapy?
The European (SIOPEL) point of view
Status of the art lecture on
Treatment of …hepatoblastoma
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Pre-operative
chemotherapy Delayed surgery
Post-operative
chemotherapy
B
I
O
P
S
Y
The European way of treating HB - SIOPEL
Hepatoblastoma
Chemotherapy before
definitive surgery!!
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Pre-operative
chemotherapy
2 - 3 months
Post-operative
chemotherapy DELAYED
SURGERY
B
I
O
P
S
Y
2 months
SIOPEL TREATMENT STRATEGY
Hepatoblastoma - SIOPEL Experience
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Which is the standard of care?…and more precisely
Why, when, which and how much Chemotherapy?
The European (SIOPEL) point of view
Status of the art lecture on
Treatment of …hepatoblastoma
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Which is the standard of care?…and more precisely
Why, when, which and how much Chemotherapy?
It depents ! It depends by….
Status of the art lecture on
Treatment of …hepatoblastoma
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Standard risk-HB tumour confined to the liver,
involving at the most 3 hepatic
sectors (PRETEXT I-III),
SIOPEL – Patient stratification concepts
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High risk - HB tumour extending to all 4 sectors
(PRETEXT IV) and/or with intra-
abdominal and/or distant
extrahepatic (M) disease and/or
AFP >100 ng/ml
SIOPEL – Patient stratification concepts
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German Pediatric Liver-Tumour Study HB89 - 72 children
AFP at diagnosis - D. von Schweinitz - Int. J. Cancer 1997
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OS of 15 patients with low level of AFP
0 10 20 30 40 50 60 70 80 90 100 110 120
Time in months
100
90
80
70
60
50
40
30
20
10
0
Surv
ival pro
babili
ty (
%)
Overall survival of 15 patients with an hepatoblastoma and
AFP level < 100 ng/ml – SIOPEL 2 & 3
Thanks, Luarence!
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INT-0098
(CCG 8881;
POG 8945).
1989 - 1992
16 Undifferentiated small
cell (SCUD) HB among 111
completely resected HB
Median age 11 m
Surival rate 9/16
Recurrence rate 63%
Undifferentiated small cell (SCUD) HB
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Undifferentiated epithelial liver tumors
Small cell undifferentiated hepato-
blastoma ( SCUD; and variants )
Undifferentiated hepatoblastoma,
intermediate cell type ( ICUD )
Undifferentiated hepatoblastoma,
large cell type ( LCUD )
Undifferentiated hepatoblastoma
with PNET-like features
Stem cell disorders or offspring of
an immature cell lineage ?
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Standard risk-HB tumour confined to the liver,
involving at the most 3 hepatic
sectors (PRETEXT I-III),
SIOPEL – Patient stratification concepts
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B
I
O
P
S
Y
CDDP
DOXO
D
E S
L U
A R
Y G
E E
D R
Y
CDDP = Cisplatin 80 mg/m²/24 hours i.v. continuous infusion
Doxo = Doxorubicin 60 mg/m²/48 hours i.v. continuous infusion -
SIOPEL 1 - 1990-1994
1 21 42 63 1 21
CDDP
DOXO
CDDP
DOXO
CDDP
DOXO
CDDP
DOXO
CDDP
DOXO
Hepatoblastoma – SIOPEL experience
Standard of care for standard risk HB
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The European way of treating HB – SIOPEL
Which chemotherapy?
.
Hepatoblastoma
For standard risk HB – PLADO
(as of to-day)
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B
I
O
P
S
Y
CDDP
PLADO x 3
CDDP x 3
PLADO x 2
CDDP x 2
CDDP = cisplatin 80 mg/m²/24 hours i.v. continuous infusion
PLADO = cisplatin (as above), doxorubicin 60 mg/m²/48 hours i.v. c.i.
Standard Risk Hepatoblastoma
SIOPEL 3 – STUDY DESIGN
D
E
L
A
Y
E
D
S
U
R
G
E
R
Y
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0.0
0
.2
0.4
0
.6
0.8
1
.0
6 12 18 24 30 36 42 48
SIOPEL 2 pilot study -Treatment results -
5-year survival data by risk category
months Overall survival
Progression free survival
%
Standard risk
High risk
CDDP alone
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0.0
0.2
0.4
0.6
0.8
1.0
months
% s
urvi
ving
6 12 18 24 30 36 42 48 54 60
Event Free Survival, standard risk HB
SIOPEL 3 Preliminary treatment outcome data
Standard risk HB – All randomized patients
20 patients had an event
3-year EFS = 80% (95%CI ± 6%)
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0.0
0.2
0.4
0.6
0.8
1.0
months
% s
urvi
ving
6 12 18 24 30 36 42 48 54 60
Overall Survival, standard risk HB
SIOPEL 3 Preliminary treatment outcome data
Standard risk HB – All randomized patients
9 patients died, of whom two with HR-HB/ 1 SR-HB died from surgery, 1 from other causes
3-year OS = 95% (95%CI ± 5%)
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B
I
O
P
S
Y
CDDP CDDP CDDP
D
E S
L U
A R
Y G
E E
D R
Y
CDDP = Cisplatin 80 mg/m²/24 hours i.v. continuous infusion -
SIOPEL Experience possible standard of care
for “our” standard risk HB
CDDP CDDP CDDP
1 15 29 43 1 15
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B
I
O
P
S
Y
CDDP + STS x 4
CDDP x 2
CDDP + STS x 2
CDDP = cisplatin 80 mg/m²/6 hours i.v. continuous infusion
STS = 20 gr/m2 over 15 minutes infusion, starting 6 hour after the end of CDDP
SIOPEL 6 – STUDY DESIGN
D
E
L
A
Y
E
D
S
U
R
G
E
R
Y
CDDP x 4
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Sodium thiosulfate (STS) Properties
• Na2S2O3
• Water soluble
• Thiol compound
• Reducing agent
• Excreted by kidney
• Biological T1/2 18
min
• Antidote for cyanide
Relevant Effects
• Thiol-binding of electrophilic platinum
• Scavenging of reactive oxygen species
• May concentrate in cochlear endo- and perilymph
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High risk - HB tumour extending to all 4 sectors
(PRETEXT IV) and/or with intra-
abdominal and/or distant
extrahepatic (M) disease and/or
AFP >100 ng/ml
SIOPEL – Patient stratification concepts
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CDDP
D
E S
L U
A R
Y G
E E
D R
Y
CDDP = Cisplatin 80 mg/m²/24 hours i.v. continuous infusion
CARBO = Carboplatin 500 mg/m² -
Doxorubicin = 60 mg/m²/48 hours i.v. continuous infusion
SIOPEL High risk hepatoblastoma –
Standard of care
CARBO
DOXO
CARBO
DOXO
CDDP
CARBO
DOXO
CDDP CDDP
CARBO
DOXO
CARBO
DOXO
d 1 15 29 43 57 71 85 1 15 29
CDDP
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0.0
0.2
0.4
0.6
0.8
1.0
months
% e
ve
nt fr
ee
6 12 18 24 30 36 42 48 54 60 66 72 78 84
Event Free Survival, high risk HB SIOPEL 3
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0
.00
.20
.40
.60
.81
.0
months
% s
urv
ivin
g
6 12 18 24 30 36 42 48 54 60 66 72 78 84
Overall Survival, high risk HB
SIOPEL 3
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0
.00
.20
.40
.60
.81
.0
months
% e
ve
nt fr
ee
6 12 18 24 30 36 42 48 54 60 66 72 78 84
Event Free Survival, high risk HB: M0 vs M1
M1M0
SIOPEL 3
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0
.00
.20
.40
.60
.81
.0
months
% s
urv
ivin
g
6 12 18 24 30 36 42 48 54 60 66 72 78 84
Overall Survival, high risk HB: M0 vs M1
M1M0
SIOPEL 3
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SIOPEL 1 - HB and metastases
5-year EFS - 31 children
28% (95%CI 12-44%)
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POG 9345
1993 1995
for
unresectable or
metastatic HB
Hepatoblastoma
North American Experience
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Block A1
Block A2
Block A3
Block B
Block C
STOP
therapy
Phase II
trial
PD
PD
or
SD
PD
SURGERY
incl. OLT
SURGERY incl. OLT
unresectable
D 1 D 29 D 85 D 57
SIOPEL 4 – High risk HB
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Cisplatin
70 mg/m2/day
in 24 hour infusion
on days: 1,8,15,29,36,43
57 and 64
Doxorubicin
30 mg/m2/day x 2 days
in 6 hour infusion
to start on days:
8,36 and 64
Block A 1 Block A 2 Block A 3
SIOPEL 4 – High risk HB
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Which is the standard of care?…and more precisely
Why, which, when and how much Chemotherapy?
The North American point of view!!
Childhood Liver Tumours
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Which is the standard of care?…and more precisely
Why, when, which and how much Chemotherapy?
The North American point of view!!
Childhood Liver Tumours
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Primary
surgery Post-operative
chemotherapy
II look
surgery
The American Standard of care -
INTEGROUP HEPATOMA STUDY
Further
CT
Hepatoblastoma
Chemotherapy after
primary surgery
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Resect at diagnosis:
PRETEXT I
PRETEXT II
(unifocal tumors with
obvious >1cm margin)
USA/COG Surgical
Resection Guidelines
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Neoadjuvant Chemotherapy to
downstage
PRETEXT II (multifocal, < 1cm margin),
PRETEXT III
PRETEXT IV
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Still Potentially Unresectable
After First 2 cycles of
Neoadjuvant Chemotherapy?
PRETEXT III Multifocal
PRETEXT III +V PRETEXT III +P
PRETEXT IV
Referral to surgical center with transplant
capability, transplant vs. extreme liver resection
after 4th cycle of chemotherapy
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Which is the standard of care?…and more precisely
Why, when, which and how much Chemotherapy?
The North American point of view!!
Childhood Liver Tumours
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Hepatoblastoma
The North American Experience - short historical
background
CCG-823F (late ‘80s) - Single arm study - CDDP/DOXO
- 66% 3-years OS in unresectable HB
POG trial (late‘80s) - Single arm study -
CDDP/VCR/5-FU - 67% 4-years OS in unresectable
HB
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Hepatoblastoma
INT-0098 (CCG 8881; POG 8945). 1989 - 1992
CDDP/DOXO (reg. B) Vs CDDP/5-FU/VCR (reg.A)
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Hepatoblastoma
INT-0098 (CCG 8881; POG 8945). 1989 - 1992
CDDP/DOXO (reg. B) Vs CDDP/5-FU/VCR (reg.A)
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Hepatoblastoma - North American Experience
INT-0098 (CCG 8881; POG 8945). 1989 - 1992
Relevant conclusions
Treatment outcome was not significantly
different between regimen A and regimen B.
New treatment strategies are needed for the
majority of patients with advanced-stage
hepatoblastoma.
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Hepatoblastoma - North American Experience
INT-0098 (CCG 8881; POG 8945). 1989 - 1992
Relevant conclusions
Grade 3 or 4 toxicities were more common among
patients on regimen B than among patients on
regimen A. Two toxic deaths were reported for
regimen B patients, and both were attributable to
continuous infusion DOX-induced cardiomyopathy.
No toxic deaths were observed for regimen A.
CDDP/VCR/5-FU the Gold Standard
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Hepatoblastoma - North American Exp.
The North American Experience - Late ‘90s
CDDP/VCR-5-FU Vs CDDP/CARBO
Study prematurely closed for excess of failures in
the CDDP/CARBO arm
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Hepatoblastoma - North American Exp.
POG 9345
1993 1995
for
unresectable or
metastatic HB
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INT-0098
(CCG 8881;
POG 8945).
1989 - 1992
HB Completely
resected; purely fetal
histology pattern with
low mitotix index (< 2
per 10 higher power
field)
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All nine patients with stage I-FH disease
treated with low-dose bolus IV DOXO
were alive and free of disease at the
time of last contact –
Pure Fetal HB completely resected
represent a FH HB and actually may be
cured with surgery alone
INT-0098 (CCG 8881; POG 8945). 1989 - 1992
Relevant conclusions
Hepatoblastoma - North American Experience
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Which is the standard of care?…and more precisely
Why, when, which and how much Chemotherapy?
It depends! It depends by their three risk categories!
Childhood Liver Tumours
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COG Hepatoblastoma
Treatment Strategy
Low Risk= Diminish Toxicity
• resection at diagnosis, PRETEXT 1 and PRETEXT 2 with >1 cm radiographic margin
• Stage I, pure fetal histology, Surgical resection alone
• Stage I, 2 cycles adjuvant chemotherapy
Intermediate Risk= Increase Survival
• C5V vs. C5V-D
• Four cycles neoadjuvant
• Two cycles adjuvant
• Stage III Resection PRETEXT 2 <1cm PRETEXT 3
• Transplant Referral PRETEXT 3 multifocal, V,P or PRETEXT 4, PLUTO registry all transplants
High Risk=Identify New Agents • Stage IV
• Small Cell Undifferentiated
• AFP < 100 at diagnosis
• Irinotecan/Vincristine up-front window chemotherapy
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COG Hepatoblastoma
Treatment Strategy Low Risk= Diminish Toxicity
• resection at diagnosis, PRETEXT 1 and PRETEXT 2 with >1 cm radiographic margin
• Stage I, pure fetal histology, Surgical resection alone
• Stage I, 2 cycles adjuvant chemotherapy
Intermediate Risk= Increase Survival
• C5V vs. C5V-D
• Four cycles neoadjuvant
• Two cycles adjuvant
• Stage III Resection PRETEXT 2 <1cm PRETEXT 3
• Transplant Referral PRETEXT 3 multifocal, V,P or PRETEXT 4, PLUTO registry all transplants
High Risk=Identify New Agents • Stage IV
• Small Cell Undifferentiated
• AFP < 100 at diagnosis
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COG Hepatoblastoma
Treatment Strategy
Low Risk= Diminish Toxicity
• resection at diagnosis, PRETEXT 1 and PRETEXT 2 with >1 cm radiographic margin
• Stage I, pure fetal histology, Surgical resection alone
• Stage I, 2 cycles adjuvant chemotherapy
Intermediate Risk= Increase Survival • C5V vs. C5V-D
• Four cycles neoadjuvant
• Two cycles adjuvant
• Stage III Resection PRETEXT 2 <1cm PRETEXT 3
• Transplant Referral PRETEXT 3 multifocal, V,P or PRETEXT 4, PLUTO registry all transplants
High Risk=Identify New Agents • Stage IV
• Small Cell Undifferentiated
• AFP < 100 at diagnosis
• Irinotecan/Vincristine up-front window chemotherapy
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COG
S + 4 cycles “C5V”
“pure fetal” nothing!
SIOPEL
4 PLADO + S+ 2 PLADO
The Gold standard - PRETEXT I and II
COG
S + 2 cycles “C5V”
“pure fetal” nothing!
SIOPEL
4 CDDP + S + 2 CDDP
The present The future
C5V = Cisplatin, Vincristine, 5-Fluorouracile
S = surgery
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COG
4 “C5V”-S- 2 cycles “C5V”
SIOPEL
4 PLADO-S-2 PLADO
The Gold standard - PRETEXT III
COG
“C5V” Vs “C5v”- Doxo
SIOPEL
4 CDDP-S-2 CDDP
The present The future
C5V = Cisplatin, Vincristine, 5-Fluorouracile
S = surgery
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COG
4 “C5V”-S- 2 cycles “C5V”
& transplant
SIOPEL
CARBO/DOXO/CDDP -S- …
& transplant
The Gold standard - PRETEXT IV
COG
“C5V” Vs “C5v”- Doxo
& transplant
SIOPEL
Intensified CDDP-S-
& transplant
The present The future
C5V = Cisplatin, Vincristine, 5-Fluorouracile
S = surgery
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COG
4 “C5V”-S- 4/2 cycles “C5V”
SIOPEL
CARBO/DOXO/CDDP -S- …
The Gold standard – M+ Hepatoblastoma
COG
Epxerimental “window
approach” Ironotecan/V
SIOPEL
Intensified CDDP-S-
The present The future
C5V = Cisplatin, Vincristine, 5-Fluorouracile
S = surgery
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The early endoderm – liver pathway
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Cerebellar development & Medulloblastoma
Maturity is achieved
several months after
birth resulting in a
prolonged formative
period with an
increase vulnerability
to developmental
aberration and
neoplasia
Cerebellum the main
site of post-natal cell
proliferation within
the CNS
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WNT and SHH signalling pathways: regulators of wide range of
developmental events particularly in the cerebellar granule cells
PTCH binding
normally activates a
signalling pathways
that has a
pleyotropic roles in
development
Nature Review, Cancer June 2005
SHH signalling
regulates granule-
cell proliferation
during normal
cerebellum
development…SHH
expressed by the
Purkinje cells
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Molecular regulation of granule cell proliferation
Purkinje cells are established quite early in cerebellum
development
Mutation of the PTHC
gene results in a
constitutive activation
of this pathway, leading
to increase proliferation
of the granule-cell
precursors
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Medulloblastoma treatment – future
prospectives
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On behalf of the International Childhood Liver Tumour Strategy
Group - SIOPEL
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Hepatoblastoma – The SIOPEL experience