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Results of the SIOPEL 4 trial
Zsíros J,
Brock P, Brugieres L, Maibach R, Roebuck D,
Zimmermann A, Rangaswami A, Casanova
M, Pariente D, Sullivan M, Laithier V, Ronghe
M, Capra M, Otte J, Childs M, Fabre M,
Plaschkes J, Perilongo G, Czauderna P
ON BEHALF OF THE INTERNATIONAL
CHILDHOOD LIVER TUMOURS STRATEGY
GROUP (SIOPEL)
Treatment results in high risk HB
SIOPEL 2 HR SIOPEL 3 HR
Perilongo G et al 2009 Zsiros J et al 2010
Main objective SIOPEL 4
• To determine the efficacy and short
term toxicity of a new chemotherapy
regimen based on weekly cisplatin
(given in combination with
doxorubicin) in children with high risk
hepatoblastoma
Design
• Phase II clinical trial
• Histologically proven HB, high risk
• Primary end point:
–Remission status at the end of
treatment
• Calculated complete remission (CR)
rate previously: 60%
• Target rate: 80%
High risk criteria
• Tumor involving all four liver sectors (Pretext IV)
• Presence of distant metastases (M+)
• Abdominal extra-hepatic disease (E+)
• Major involvement of hepatic or portal veins (V+, P+)
• Alpha-fetoprotein (AFP) < 100 μg/L ornormal for age
• Tumor rupture at diagnosis
SIOPEL 4 trial treatment
C* C C
D
C C C
D
C C
D
CA CA CA
D D D
CA* CA*
D* D*
STOP
therapy
Phase
II trial
PD PD
or
SD
PD
SURGERYincl. OLT
SURGERYincl. OLT
unresectable
D 1 D 29 D 85D 57
Block A1 Block A2 Block A3
Block B
Block C
Cisplatin70 mg/m2/dayin 24 hour infusionon days: 1,8,15,29,36,4357 and 64
Doxorubicin30 mg/m2/day x 2 daysin 24 hour infusionor In 1 hour inf with Dexrazoxaneto start on days:8,36 and 57
Block A 1 Block A 2 Block A 3
Pre-operative chemotherapy
Patient accrual
• January 2005 – August 2009
Registered,
eligible
N = 69
Excluded
after central
review
N = 8
Included in
analysis
N = 61
Hepatocellular Carcinoma n=4
Transitory Liver Cell Tumor n=3
Rhabdoid Tumor of the Liver n=1
High risk criteria
Nr of patients
% of patients
Distant metastasis (M+) 39 64
All liver sectors involved (Pretext 4) 16 26
Major vascular involvement (V+ or P+) 24 39
Intra-abdominal extension (E+) 6 10
AFP < 100 μg/L 2 3
Tumor rupture 10 16
Response to chemotherapy
Response after cycles A1-3* (+B) Nr of patients
Complete response 0
Partial response* 58 (97 %)
Stable disease 0
Progressive disease 0
Not assessable 2
Total†: 60
* Response was assessed after 2 cycles in 2 patients† 1 pt had primary resection
Complete response: No evidence of disease and normal AFP
Partial response: > 1 log decrease in AFP + any tumour shrinkage
Surgical outcome
Nr (%) of patients
Partial hepatectomy 36 (60 %)
Liver transplantation 16 (27 %) ( 87 % )
Surgical death 2 ( 3 %)
Unresectable 1 ( 1,5 %)
No surgery (died, withdrawn) 4 ( 7 %)
Unknown 1 ( 1,5 %)
Total†: 60
† 1 pt had primary resection
End of treatment status
Nr (%) of patients
Alive, in complete remission 48 (79 %) 95% CI (69-88%)
Alive with evidence of disease 6 ( 9,8 %)
Died of disease (bleeding) 1 ( 1,6 %)
Died of toxicity 1 ( 1,6 %)
Died of surgery 2 ( 3,2 %)
Withdrawn 2 ( 3,2 %)
Unknown 1 ( 1,6 %)
Total: 61
CR: lack of evidence of residual disease and normal AFP
Follow-up, events
Events (nr of pts)
Died (nr of pts)
Died of disease (bleeding) 1 1
Died of toxicity 1 1
Died of surgery 2 2
Tumor progression (after treatm.) 5 4
Relapse 4 1
Total: 13 9
Median FU time: 23,5 months
Event free survival0.
00.
20.
40.
60.
81.
0
months
% e
vent
free
12 24 36 48
2 yrs: 80% 95% CI: 69%-92%
Overall survival0.
00.
20.
40.
60.
81.
0
months
% s
urvi
ving
12 24 36 48
2 yrs: 82% 95% CI: 71%-93%
Subgroups
Metastaticdisease
n=39
Pretext IV tumor n=16
SCUD histology
n=5
End of treatment
CR 29 (74 %) 12 (75%) 3 (60%)
Alive WED 6 1 2 ( 2 M+)
Died 3 1 0
Withdrawn 1 2 0
Relapse 0 2 0
EFS 2 yr 77 % 75% 60%
OS 2 yr 77 % 81 % 60 %
SCUD: Small Cell Undifferentiated Hepatoblatoma
SIOPEL results compared
SIOPEL 1 HR
SIOPEL 2 HR
SIOPEL 3 HR
SIOPEL 4HR
Response rate 78 % 76 % 77,5% 97 %
Compl. resection rate 58 % 66 % 69,0 % 87 %
EFS 3 yrs 45 % 47% 65% 80 %*
OS 3 yrs 57 % 52% 73% 82 %*
EFS Metastatic 28% 44 % 56% 77 %*
EFS Pretext 4 46% 61 % 64% 75 %*
* 2-yrs EFS and OS
Grade 3 + 4 toxicity
A1-A3 B C
% of patients
Neutropenia 77 - 83 92 89
Thrombocytopenia 57 - 63 83 74
Fever/Infection 6 - 9 17 9
Mucositis 5 - 8 8 0
Toxicity is graded according to the NCI CTCAE v.3.0
One child is died of infection in neutropenia
Ototoxicity
Maximal Brock grade Nr (%) of patients
0 (no toxicity) 25 (42 %)
1 (mild) 6 (10 %)
2 (moderate) 10 (17 %)
3 (marked) 11 (18%)
4 (severe) 2 ( 3%)
Unknown 6 (10%)
Total: 60 *
* One patient who received only one cycle is not included
Conclusions
• The SIOPEL 4 treatment regimen is feasible with acceptable toxicity
• This regimen is efficacious in achieving complete remission
• EFS and OS are promising
• Results are especially interesting for patients with metastatic disease or SCUD
SIOPEL plans
• To include dose intensive cisplatin in the treatment strategy of (very) high risk patients (M+, SCUD)
• To test the combination of dose intensive cisplatin and irinotecan
• To redefine the treatment stratification system (more than 2 treatment strategies?)
Australia
Belgium
Brazil
Chile
France
Ireland
Italy
Jordan
Malaysia
Netherlands
New Zeeland
Northern Ireland
Poland
Spain
Switzerland
United Kingdom
USA
Possible treatment stratification
• M+, AFP <100 μg/L, SCUD, rupture
High Risk
• Pretext IV, I-III unresectable, P+/V+/E+,
• M-, no other features
Medium Risk
• Pretext I-III, resectable
• no other features
Standard Risk
Dose intensive cisplatin based multi-agent chemotherapy incl. irinotecanand doxorubicin
Total cumulative doses
SIOPEL1 SIOPEL2
HR
SIOPEL3
HR
SIOPEL 4
Cisplatin 480 320 400 560
Doxorubicin 360 360 300 300/330
Carboplatin - 3000 2500 1500/1600
Results of other studies
EFS/PFS
INT-0098 M+Ortega, JCO 2000
25 % (5y)
POG 9345 M+ Katzenstein, JCO 2002
27 % (5y)
HB 94 M+Fuchs, Cancer 2002
21% (??)
JPLT-1 M+Matsunaga, Ped Surg Int 2003
39 % (3y)
CarboplatinAUC 10.6 mg/ml.minin 1hour infusionon days: 1,22
Doxorubicin25 mg/m2/day x 3 daysin 24 hour infusionor 1 h inf with Dexrazoxanto start on days:1,22
Block B
Cycle B
CarboplatinAUC 6.6 mg/ml.minin 1hour infusionon days: 1,22 and 43
Doxorubicin20 mg/m2/day x 2 daysin 24 hour infusionor 1 h inf with Dexrazoxanto start on days:1,22 and 43
Block C
Cycle C
Central review
• Pathology slides
– 74 % (45/61) reviewed
• HB confirmed
• HB subtype classified
• Radiology
– 62 % (38/61) reviewed
• Risk category confirmed
Patients characteristics
• M : F = 1,65
• Age (median): 19,4 months
0
5
10
15
20
25
30
35
0-3 mo 3-12 mo 1-3 yrs 3-6 yrs 6-12 yrs > 12 yrs
Nr. of patients
Chemotherapy received
Cycle Nr of patients % of patients
A1 61 100
A2 59 97
A3 57 93
B 12 20
C 37 61
Response definition
• Complete response:– No evidence of disease and AFP normal
• Partial response:– > 1 log decrease in AFP ± any tumour
shrinkage
• Stable disease:– No change in volume and < 1 log decrease
of AFP
• Progressive disease:– Unequivocal increase in tumour
diameter/volume or unequivocal increase in AFP