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Prof. Tezer Kutluk, MD PhD FAAP Hacettepe University Dept of Pediatric Oncology Ankara

Learning from the Pediatric Oncologists: Similarities and pecularities of HCC in pediatric patients. Prof. Tezer Kutluk, MD PhD FAAP Hacettepe University Dept of Pediatric Oncology Ankara. Cancer Statistics, 2018, IARC. Liver tumors 841080 new cases 781631 deaths. Incidence.

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Prof. Tezer Kutluk, MD PhD FAAP Hacettepe University Dept of Pediatric Oncology Ankara

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  1. Learning from the Pediatric Oncologists: Similarities and pecularities of HCC in pediatric patients Prof. Tezer Kutluk, MD PhD FAAP Hacettepe University Dept of Pediatric Oncology Ankara

  2. Cancer Statistics, 2018, IARC Liver tumors 841080 new cases 781631 deaths

  3. Incidence • Primer Liver Tumors: %0.2- %2 of all pediatric tumors • Incidence 1.6-2 / million (HCC 0.8-1.5 per million) • 70% of pediatric liver tumors are malignant

  4. Chang M-H, Chen C-J, Lai M-S, et al.N Eng J Med 1997;336:1855–9. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Qx: Do you know when Hep B vaccine became available & when was it included in routine vaccination program?

  5. Histopathology in Pediatric HCC Two broad categories: • HCC in the context of underlying liver disease • De novo HCC • conventional HCC, • FL-HCC, • HCC with elements of hepatoblastoma

  6. Risk factors for pediatric HCC • HBV, HCV, • autoimmune hepatitis, • glycogen storage disease I–IV, • Alagille syndrome, • Tyrosinemia, • Wilson disease, • Hemochromatosis, • Alpha-1 antitrypsin deficiency, • Transaldolase deficiency, • Gardner syndrome, • Familial adenomatous polyposis, • Others: Fanconi anemia, ataxia telangiectasia, primary sclerosing cholangitis, and familial progressive intrahepatic cholestasis.

  7. Cytogenetic aberrations in HCC

  8. Targeted therapies

  9. Türk Pediatrik Onkoloji Grubu (TPOG) / Türk Pediatrik Hematoloji Derneği (TPHD) Pediatrik Tümör Kayıtları, 2009-2017 T.Kutluk & A. Yesilipek, TPOG/TPHD adına

  10. Türk Pediatrik Onkoloji Grubu (TPOG) / Türk Pediatrik Hematoloji Derneği (TPHD) Pediatrik Tümör Kayıtları, 2009-2017 TÜMÖR ALT GRUPLARINA GÖRE DAĞILIM

  11. Türk Pediatrik Onkoloji Grubu (TPOG) / Türk Pediatrik Hematoloji Derneği (TPHD) Pediatrik Tümör Kayıtları, 2009-2017 FARKLI TÜMÖR GRUPLARINDA YAŞAM T.Kutluk & A. Yesilipek, TPOG/TPHD adına

  12. SIOPEL Standard risk tumors PRETEXT I, II, or III. high-risk tumors tumors involving all four hepatic sectors (PREVEXT IV), or any tumor with metastasis (m), ingrowth of the vena cava (v), ingrowth of the portal vein (p) or contiguous extrahepatic disease (e), tumors that fail to express AFP with AFP <100 at diagnosis.

  13. PRETEXT

  14. PRETEXT Preoperatif staging Preoperative CT & delayed surgery SIOPEL 1 Predictivity of 3 staging system • PRETEXT a mid-level “overstaging” • TNM & PRETEXT good prective value for survival P .0021 & P .0006 • CCSG/POG, low prective value for survival (P .516) PRETEXT advantages • Preoperative use • Predictive for Survival • “ reproducibility” • Evaluation of the treatment efficiency • Allows comparisons

  15. US COG HB (AHEP 0731) A risk-based stratification of treatment as follows: • low risk (Stage I/II lacking any unfavorable biologic feature); • intermediate risk (Stage III or Stage I/II with small cell undifferentiated histology); • high risk (Stage IV or Stage I/II/III with AFP <100 at diagnosis).

  16. Survival Pediatric HCC % 17-22 in SIOPEL & COG Studies

  17. Survival in pediatric HCC,SIOPEL 2 & SIOPEL 3 JCI 2016

  18. Hacettepe Experience in Pediatric Liver Tumors

  19. HÜ Onkoloji Enstitüsü Pediatrik Onkoloji Karaciğer Tümörleri • 1972-2011 • Primary liver tumors • HCC 91 cases • HBL 42 case

  20. Survival

  21. Survival

  22. SIOPEL-1, 1990-1994 Non-randomized Pretext staging system, implemented • pre-operative CT: Cisplatin/Doxorubicin (PLADO) regimen • Standart risk & High risk concept • Prognostic factors • Pretext stage • Lung metastasis

  23. SIOPEL-2, 1994-1998Standard risk: PLADOHigh risk : CDDP-Carboplation/DOXO

  24. SIOPEL-3, 1998 • Standard risk, randomised • A: cisplatin (80 mg/m2), doxorubicin (60 mg/m2) (PLADO) x 3 wk, 3 preop, 2 postop • B: cisplatin (80 mg/m2) x 2 wk, 3 prereop & 2 postop • High risk patients • carboplatin (500 mg/m2) & doxorubicin (60 mg/m2) cisplatin (80 mg/m2) , üç preop, iki postop

  25. SIOPEL-4, 2004High risk hepatoblastoma One of the below • 4 sector involvement - PRETEXT IV • Abdominal ekstrahepatic disease (V,P,E) • Metastasis presence (M+) • Alpha-fetoprotein (AFP) < 100 ng/ml • Tumor rupture at diagnosis

  26. SIOPEL-4, 2004

  27. HCC SIOPEL-1 • 62% PRETEXT III/IV • 31% metastaz • 39% vaskuler invazyon • 56% multifocal tumors • 17% 5 yıllık EFS • 28% 5 yıllık genel yaşam • Uzun survival tam rezeksiyon olanlarda mümkün SIOPEL-2 • 24% 5 yıllık genel yaşam SIOPEL-5 • Standard neoadjuvan PLADO + Thalidomide

  28. SIOPEL Guidlelines for the treatment of HBL • Standard risk patients are eligible for entry to the SIOPEL 6 study however, we recommend the following treatment strategy for patients not entered into a clinical trial • Standard Risk Tumours: These are localised tumours (Pretext 1, 2 or 3) with no additional adverse features (e.g. low AFP, vascular involvement (V3 or P2), extrahepatic spread, tumour rupture, metastatic disease). The recommendation is to follow the cisplatin monotherapy arm of the SIOPEL 3 study (Perilongo et al 2009 NEJM 361:1662). The standard treatment is 4 cycles of preoperative chemotherapy followed by surgical resection and 2 post operative cycles of therapy. • High risk tumours: These tumours are defined as any tumour not meeting the standard risk or very high risk criteria. The recommendation is to receive the dose intensive “superPLADO” arm of the SIOPEL 3 study (Zsiros et al 2010 J Clin Oncol 28:2584). Patients in this group are likely to have challenging surgical disease and we would recommend consultation at the time of diagnosis with a specialist liver surgery/transplant service.

  29. High risk tumors Very high risk tumours: These tumours are defined by the presence of metastatic disease (usually lung) or very low AFP (<100 ng/ml). Pulmonary lesions documented on the chest X-ray and/or lung CT scan will be considered to be unequivocal metastatic tumour deposits if there is one nodule larger than 10 mm or several nodules with at least one larger than 5 mm. In the other cases, the metastases will be considered as doubtful and a surgical biopsy of one of the nodules should be discussed if the general condition of the child permits it. Patients should be treated with the approach utilised in the SIOPEL4 protocol with dose-intensive weekly cisplatin/doxorubicin induction therapy. This is an experimental regimen with limited pilot data shortly to be published. Particular attention should be paid to the potential toxicity and supportive care needs of patients on this regimen. All patients with low AFP should have an initial biopsy. The loss of INI1 expression is suggestive of rhabdoid tumour (sometimes confused with small cell undifferentiated hepatoblastoma) and we would recommend such patients are treated with a rhabdoid-style chemotherapy approach. Note some low risk localised tumours with small volume disease may also have a low AFP.

  30. SIOPEL 6 Objectives • To assess the efficacy of STS to reduce Cisplatin ototoxicity • To monitor any potential impact of STS on response to Cisplatin and overall survival Study population • Children 1 month –18 years old with histologically confirmed newly diagnosed SR-HB • PRETEXT (PreTreatmentEXTent of disease) I, II or III • No vascular invasion, no extra-hepatic or metastatic disease • Serum AFP > 100 μg/L

  31. Current COG study on HCC

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