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The Royal Hospital for Sick Children Edinburgh

The Royal Hospital for Sick Children Edinburgh. SIOP-ASPHO-ESO teaching course Treatment of Hepatoblastoma - SIOPEL group. Why don’t you join us in this effort??!. Liver Tumours in Children. Hepatoblastoma (HBL)* Hepatocellular carcinoma (HCC)* Sarcomas NHL MGCT* Benign tumours**

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The Royal Hospital for Sick Children Edinburgh

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  1. The Royal Hospital for Sick Children Edinburgh

  2. SIOP-ASPHO-ESO teaching course Treatment of Hepatoblastoma - SIOPEL group Why don’t you join us in this effort??!

  3. Liver Tumours in Children • Hepatoblastoma (HBL)* • Hepatocellular carcinoma (HCC)* • Sarcomas • NHL • MGCT* • Benign tumours** * AFP raised ** AFP normal for age

  4. Hepatoblastoma • More boys than girls – 1.5:1 • Some tumours multifocal • Mean age 20 months, rare above 5 yrs • Over 95% sporadic, 2-3% predisposed (BWS, FAP) • Pancreatoblastoma is a similar tumour • 1 in 60,000 children so cooperationmandatory

  5. Hepatoblastoma • Prenatal diagnosis • Endocrine syndrome • Thrombocytosis in a ‘poorly’child • Non-accidental injury • ‘Second tumour’ (BWS)

  6. Hepatoblastoma • Essential Investigations • MRI/CT of liver • CXR plus CT of lungs • Renal, auditory, cardiac function • FBC and coagulation

  7. M: lung metastases M+ M+

  8. M: lung metastases M+ M?

  9. SIOP-ASPHO-ESO teaching course Treatment of Hepatoblastoma –INT experience The American way – INTERGROUP/COG HEPATOMA STUDIES Primary surgery 2nd look surgery Post-operative chemotherapy Further CT initially unresectable tumours

  10. SIOP-ASPHO-ESO teaching course Treatment of Hepatoblastoma - SIOPEL group The European way of treating HB - SIOPEL B I O P S Y Pre-operative chemotherapy Post-operative chemotherapy Delayed surgery

  11. freehand ultrasound guidance

  12. Laparoscopic guided liver biopsies Hepatoblastoma

  13. Hepatoblastoma – Histopathology points N American Approach – Laparotomy Pathology secure ‘R-O-W’ Approach ( SIOPEL) - Biopsy Recommended but not mandatory between 6-36 months Biopsy may be unrepresentative Chemotherapy distorts pathology Central review mandatory (Germany/Austria and Japan shifting to R-O-W view)

  14. Treatment results in the seventies Combination chemotherapy in the treatment of children with malignant hepatoma - A.E. Evans et al. Cancer 1982

  15. SIOP-ASPHO-ESO teaching course Treatment of Hepatoblastoma -SIOPEL experience D E S L U A R Y G E E D R Y SIOPEL 1 - 1990-1994 B I O P S Y CDDP DOXO CDDP DOXO CDDP DOXO CDDP DOXO CDDP DOXO CDDP DOXO 21 42 1 1 21 63 CDDP = Cisplatin 80 mg/m²/24 hours i.v. continuous infusion Doxo = Doxorubicin 60 mg/m²/48 hours i.v. continuous infusion -

  16. SIOP-ASPHO-ESO teaching course Treatment of Hepatoblastoma -SIOPEL experience SIOPEL1 study - 5-years Event-Free Survival 66% (95 CI 59-74%)

  17. SIOPEL1 study - Treatment results 12/128 patients underwent total hepatectomy and OTL 5 patients had lung metastases at diagnosis All cleared their lung with chemotherapy and... 4 are alive NED (r: 72-79 months) 1 died of tumour at autopsy HB in the lung

  18. SIOPEL1 study - Treatment results 12/128 patients underwent total hepatectomy and orthotopic liver transplant

  19. 2 7 8 4a 3 6 5 4b Couinaud

  20. 4 2,3 5,8 6,7 Hepatic veins

  21. SIOPEL - Pre-treatment extent of disease evaluation system (PRETEXT)

  22. PRETEXT:“extrahepatic” tumour • V IVC and/or all of the three major hepatic veins • P main portal vein and/or both the left and right portal veins • E biopsy-proven extrahepatic abdominal disease • M distant metastases

  23. V+

  24. SIOPEL1 study - Event-free survival probability according to PRETEXT at diagnosis -

  25. SIOPEL 1 - Pre-treatment prognostic factors Multivariate relationship with5-years PFS PRETEXT (I to IV), lung metastases, tumour focality and enlarged lymph nodes were entered into the model Significant factors - PRETEXT & lung metastases hazard ratio 1.63 95% CI 1.05 - 2.50 p= 0.002 & 0.02 respectively

  26. SIOPEL 1 - Pre-treatment prognostic factors Multivariate relationship with 5-years OS PRETEXT (I to IV) and lung metastases were entered into the model Significant factor - PRETEXT hazard ratio 2.11 95% CI 1.2-3.6 p= 0.005

  27. SIOPEL 2 study concept With the HB patients two risk groups Standard risk-HB tumour confined to the liver, involving at the most 3 hepatic sectors (PRETEXT I-III),

  28. SIOP-ASPHO-ESO teaching course Treatment of Hepatoblastoma – INT experience INT-0098 (CCG 8881; POG 8945).1989 - 1992 CDDP/DOXO (reg. B) Vs CDDP/5-FU/VCR (reg.A)

  29. SIOPEL 2 - STUDY DESIGN - STANDARD RISK HB D E S L U A R Y G E E D R Y 1994/1998 B I O P S Y CDDP CDDP CDDP CDDP CDDP CDDP 15 29 1 1 15 43 CDDP = Cisplatin 80 mg/m²/24 hours i.v. continuous infusion -

  30. 1,000,000 100,000 x x x x AFP Level x 10,000 x 1000 x Cisplatin expected rate of fall of AFP 100 10 1 22 29 5 12 19 26 2 9 16 23 Dec ’96 Jan ’97 Feb ’97 Group 3 HbI-KC 21 months SIOP 2002

  31. SIOPEL 2 - Treatment results Resection rate * 7 with total hepatectomy and orthotopic liver transplantation

  32. SIOPEL 2 -Treatment results - 3-year PFS SR-HB 91%± 7% HR-HB 48%± 13%

  33. SIOPEL 2 -Treatment results Three year PFS, 59 high risk pts with/without metastatic disease 1.0 0.8 Without metastases 0.6 % event free 0.4 With metastases 0.2 0.0 6 12 18 24 30 36 42 48 54 60 months

  34. SIOPEL 3 – STUDY DESIGN Standard Risk Hepatoblastoma D E L A Y E D S U R G E R Y PLADO x 3 PLADO x 2 B I O P S Y CDDP CDDP x 2 CDDP x 3 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.

  35. SIOPEL 2 Vs 3* - Treatment resultsStandard risk HB - Response rate * Preliminary and confidential data * *Not yet known 29%

  36. SIOPEL 3 Preliminary treatment outcome data Event-free survival SR- HB Vs HR-HB

  37. SIOPEL 3 Preliminary treatment outcome data Standard risk HB – All 164 randomized patients 2-year OS = 95% (95%CI ± 5%) 9 patients died, of whom two with HR-HB/ 1 SR-HB died from surgery, 1 from other causes

  38. Hepatoblastoma An Heretical Proposal……… • If one drug is as good (or nearly as good) as 2 …or 3 ….or 4…..! either HBL is unique or Much of child cancer Rx is too complicated…!?! Amman Sept 2005

  39. SIOP-ASPHO-ESO teaching course Treatment of Hepatoblastoma - SIOPEL group

  40. Statistical office: Berne, Switzerland Trial office: Leicester UK * * * Strategy Group cohordinator office: Padua,Italy * * WEB System headquarter: Bologna, Italy * Project leaders’ offices

  41. Special project – SIOPEL “in India” R.Kumar Mahrawa, J. Pritchard, J. Plaschkes SIOPEL 1 (closed) and late effect study group Group chairmen J.Pritchard, P. Brook, E. Shafford,A. Levin... Worldwide registry on pancreatoblastoma M Sullivan, P. Dall’Igna SIOPEL 2 (closed) Group chairmen- G. Perilongo, E. Shafford, L Brugieres… SIOPEL 5 – HCC family Group chairmen P. Czauderna, B. Morland, M . Casanova, A.Zimmermann... SIOPEL 3 a & b Study committee G. Perilongo, E. Shafford, L. Brugieres, G. MacKinlay, P. Czauderna, JB. Otte, … Phase II studies/new agent group Group chairmen B. Morland, J. Zsiros, L. Brugieres,... SIOPEL 4 – HR-HB Group chairmen J. Zsiros P. Brook, JB Otte As of September 2004

  42. Some of the SIOPEL Group UKCCSG Trial office, Leicester (UK) in cooperation with SIAK coordination centre, Berne (CH)

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