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