1. Highlights in the management of gastrointestinal cancer Roma, 21 Maggio, 2010 Treatment algorithm for hepatocellular carcinoma Franco Trevisani Semeiotica Medica Dipartimento di Medicina Clinica Alma Mater Studiorum - Università di Bologna

2. Strategy for staging and treatment assignment (BCLC) Bruix and Sherman, Hepatology 2005 C

3. Trapianto: - Chi trapiantare? - Resezione o trapianto HCC suscettibile di entrambi?

4. Bruix and Sherman, Hepatology 2005

5. Linee guida: rapidi cambiamenti delle evidenze. Chi trapiantare? Toso et al., Hepatology 2009 Scientific Registry of Transplant Recipients (USA) 2003-07: 6478 OLT % Milano-out Total tumor volume

6. Mazzaferro et al., Lancet Oncol 2009 1556 pts. from 36 centres (1122 Milano-out at pathology examination) 5-year overall-survival Chi trapiantare? Il sistema metro ticket 10 20 30 40 50 60 70 80 90 100 Size of the largest (mm)

7. Linee guida: rapidi cambiamenti delle evidenze. Criteri down-staging di Bologna Post-Tx (88 vs. 32 pts) Intention-to-treat (129 vs. 48 pts) Down-staging: - 5.1-6 cm - 3.1-5 cm Milano-in dopo down-staging - 4 cm ciascuno, somma Ø 12 cm - AFP <400 ng/mL Ravaioli et al., Am J Transplant 2008

8. Resezione: - Chi resecare? Bruix and Sherman, Hepatology 2005

9. Resection for HCC Only single? Only without PHT? Ishizawa et al., Gastro 2008

10. Resection for HCC The Bologna-Torino experience 466 resections

11. Resection for HCC The Bologna-Torino model 0 - 3.3% 0 – 2.5% 0 Mortalità Bilirubin Creatinine INR MELD

12. Percutaneous ablation: for whom? PEI is ineffective against: - satellites - microvascular invasion PEI-induced necrosis is not predictable Bruix and Sherman, Hepatology 2005

13. Percutaneous ablation: for whom? 59% Ethanol injection

14. HCC size and microsatellites 2 cm 0.5 cm

15. PEI and RF outcome: the results of 5 RCT AuthorTumor number x size Initial CR (%) Treatment failure (%) (§) 3-year survival (%) P value Lencioni, 2003 PEI (n. 50) RF (n. 52) 1 x 5 cm or 3 x 3 cm 92 98 34 8 73 81 NS Lin, 2004 PEI (n. 52) RF (n. 52) 1-3 x 3 cm 91 96 45 17 50 74 0.014 Shiina, 2005 PEI (n. 114) RF (n. 118) 1-3 x 3 cm 100 11 2 63 80 0.02 Lin, 2005 PEI (n. 62) RF (n. 62) 1-3 x 3 cm 89 97 42 16 51 74 0.031 Brunello, 2008 PEI (n. 69) RF (n. 70) 1-3 x 3 cm 66 96 64 34 57 59 NS (§): incomplete initial response and/or local recurrence

16. RF vs. PEI (meta-analisi di RCT) Cho et al., Hepatology 2009 Sopravvivenza a 3 anni RF PEI Odds ratio 0.48 (95%CI: 0.34-0-67)

17. RF results in Child-Pugh A patients with a single HCC 2 cm Livraghi et al., Hepatology 2008 Mortality 0 Major complications 1.8% (1 seeding case) Complete radiological necrosis - 1st course 86% - 2nd course 12% - Total 98% Sustained complete response 97% (median follow-up 31 mo) Treatment failure 3% 232 pts 218 pts 6 pts (2.6%) unfeasibility

18. Survival of patients with single HCC 2 cm treated by RF (218 patients) Livraghi et al., Hepatology 2008

19. Survival of patients with singleHCC <2 cm treated by ablation Analysis by surgical candidacy (100 vs 118) Livraghi et al., Hepatology 2008

20. Terapie ablative percutanee: Termoblazione o alcolizzazione?

21. Strategy for staging and treatment assignment (BCLC) Bruix and Sherman, Hepatology 2005 C

22. Dynamic imaging techniques: arterial phase TC MRI

23. Conventional TACE + Embolic agent = Gelatine sponge PVA Microspheres N-isobutilcyanoacrialate Gelatine sponge

24. TACE Pre- TACE Post-TACE Cortesia dott.ssa R. Golfieri

25. 1.Proper patient selection 2.Proper tumor selection 3.Proper technical procedure 4.Proper timing of treatments Tumor ProgressionTreatment-induced liver failure Potential factors determining the results of TACE Trevisani et al., J Clin Gastroenterol 2001

26. TACE for intermediate-advanced HCC Llovet, Hepatology 2002 Overall 2-year mortality OR (95% C.I.) - Embolization 0.59 (0.29-1.20) - Chemoembolization 0.42 (0.20-0.88 )

27. DC Bead (Biocompatibles, UK) sulphonate- modified compressible hydrogel PVA microspheres designed to release chemotherapy at a slow rate Designed to be loaded with Doxorubicin: recommended dose of 25 mg/ml (maximum 37.5 mg/ml) Bead sizes 100-300 µm, 300-500 µm, 500- 700 µm, 700-900 µm DRUG-ELUTING BEADS: DC Beads TM (DEB-TACE)

28. Lewis et al J. Vasc. Interv. Radiol. 2006; 17(8):1335 -43 CONVENTIONAL TACE DC Bead TACE DRUG-ELUTING BEADS: DC Beads TM (DEB-TACE)

29. Doxorubicin in the tumor: more and longer –Doxorubicin presence in the tumor peaks at 3 days and remains in the tumor for 14 days –4 times more Doxorubicin in the tumor compared to conventional TACE DRUG-ELUTING BEADS: DC Beads TM (DEB-TACE) Area under the curve DEB-TACE TACE

30. RCT with DC Beads vs. TACE (Precision V study) - 212 pz. arruolati: C-P A/B, ECOG 0/1, lobi 1/2, precedente tx. - Procedure bimestrali - End points: 1. risposta tumorale (criteri EASL) a 6 mesi 2. effetti avversi severi P=0.11 Lammer et al., J Cardiovasc Intervent Radiol 2010

31. RCT with DC Beads vs. TACE (Precision V study) Picco ALT P<0.001 FEVs P=0.018 EA doxo-dipendenti P=0.0001 Alopecia 1% v. 20% Lammer et al., J Cardiovasc Intervent Radiol 2010 - 212 pz. arruolati: C-P A/B, ECOG 0/1, lobi 1/2, precedente tx. - Procedure bimestrali - End points: 1. risposta tumorale (criteri EASL) a 6 mesi 2. effetti avversi severi

32. RCT with DC Beads vs. TACE (Precision-Italy) 117 pazienti arruolati

33. YTTRIUM-90 microspheres: 20-40 μm particles emitting β-radiation, delivered via the hepatic arterial route. Average penetration range in tissue: 2.5 mm (maximum 11 mm). TAR (adio) E 90 Y-Radioembolization

34. Hypovascular-infiltrative HCCs Very large HCCs ± Portal invasion ECOG 2 No extrahepatic spread Child-Pugh class A-B Bilirubin <2 mg (risk of further liver deterioration) >2 mg: TACE preferable!! PATIENT SELECTION for 90Y vs. TACE in intermediate-advanced HCC

35. 01/0602/06 05/06 08/06 Radiation segmentectomy TAR(adio)E 90 Y-Radioembolization Cortesia dott.ssa R. Golfieri

36. HCC: response (WHO modified-EASL) 1 month 17 pts 3 months 14 pts 6 months 7 pts 9 months 5 pts >12 months 4 pts CR8 (47%)6 (43%)5 (71%)2 (40%)2 (50%) PR6 (35%)4 (29%)1 (14.5%)-- SD3 (18%)2 (14%) DP in target lesions 00000 DP new lesions02 (14%) (1 retreat.) 1 (14.5%) (1 retreat.) 3 (60%)2 (50%) Deaths (liver failure) 0 1233 Mean dose: 1350 MBq (range: 740-2010) Mean follow-up: 9.6 months 17 pts (19 treatments) Cortesia dott.ssa R. Golfieri

37. Strategy for staging and treatment assignment (BCLC) Bruix and Sherman, Hepatology 2005 Sorafenib El-Seragh et al., Gastro 2008 Llovet et al. J Natl Cancer Inst 2008

38. Strategy for staging and treatment assignment (Japanese system) Kudo et al., Oncology 2007; 72 (suppl.1): 2-15 Jap Soc Hepatol Guidelines, Hepatol Res 2008 Sorafenib b: for C-P class B and Ø 2 cm c: within Milano criteraia TACE TARE

39. Resection vs. ablation: the results of 3 RCT AuthorTumor No. x size Child- Pugh SurvivalDF survival Complica tions Periop. mortality Huang, 2005 Resection (n. 38) PEI (n. 38) 1-2 3 cm Hepatitis 19 A/B: 28/0 A/B: 29/3 5-yrs 82% 46% 5-yrs 48% 45% 0000 Chen, 2006 Resection (n. 90) RF (n. 71) Single 5 cm 4-yrs 64% 68% 4-yrs 52% 46% 55% 4% 1% 0 Lu, 2006 (abstr.) Resection (n. 54) RF/microw. (n. 51) Milano-in 3-yrs 86% 87% 3-yrs 82% 51% 11% 8% Huang G-T et al., Ann Surg 2005 Chen M-S et al., Ann Surg 2006 Lu MD et al., Zhonghua Yi Xue Za Zhi 2006

42. Sorafenib treatment for advanced HCC Overall Survival in the SHARP and Asia-Pacific Trials Months from Randomization Survival Probability Sorafenib (n=299) Median: 10.7 months 95% CI: 9.4-13.3 Placebo (n=303) Median: 7.9 months 95% CI: 6.8-9.1 HR (S/P): 0.69 95% CI: 0.55-0.87 P=0.00058 0.25 0.50 0.75 1.00 0 0 48121620 SHARP 1 Sorafenib (n=150) Median: 6.5 months 95% CI: 5.6-7.6 Placebo (n=76) Median: 4.2 months 95% CI: 3.7-5.5 HR (S/P): 0.68 95% CI: 0.50-0.93 P=0.014 0.25 0.50 0.75 1.00 0 0 48121620 Asia-Pacific 2 Months from Randomization Survival Probability 1. Llovet JM, et al. N Engl J Med. 2008;359(4):378-390 2. Cheng AL, et al. Lancet Oncol. 2009;10:25-34

43. Recidiva HCC dopo terapie potenzialmente radicali Hasegawa et al., J Hepatol 2008 7185 pazienti, 2000-2003 Resezione, PEI o RFA (HCC: 3 cm x 3)

44. 8 weeks randomise Stratify: - prior curative tx - geographical region - CP status Sorafenib 400mg bid Placebo - RFS - TTR - OS - Biomarkers 1:1 Design: double-blind RCT Resection RFA PEI Significant OS benefit in phase III gives rationale to go into adjuvant setting Prospective, randomized, double-blind, placebo-controlled, company sponsored phase III study Primary endpoint: recurrence-free survival Patients: n=1100 (randomised) Global trial, significant number of patients from China Clinicaltrials.gov

45. Strategy for staging and treatment assignment (BCLC) Bruix and Sherman, Hepatology 2005 Sorafenib El-Seragh et al., Gastro 2008 Sorafenib

46. Strategy for staging and treatment assignment (Japanese system) Kudo et al., Oncology 2007; 72 (suppl.1): 2-15 Jap Soc Hepatol Guidelines, Hepatol Res 2008 Sorafenib b: for C-P class B and Ø 2 cm c: within Milano criteraia TACE TARE

47. Key pathways in carcinogenesis and molecularly targeted agents under devolopment in advanced HCC

48. Strategy for staging and treatment assignment (BCLC) Paz. 58 aa, HCC 4.5 cm, no invasione postale, N 0, M 0, senza comorbilità, Child-Pugh C. Bruix and Sherman, Hepatology 2005 Paz. 58 aa, HCC 4.5 cm, no invasione postale, N 0, M 0, senza comorbilità, Child-Pugh A, varici F1.

49. HCC size and microsatellites Kojiro et al, Semin Liver Dis 1999 Maeda et al, Hepatogastroenterology 2000 Okusaka et al., Cancer 2002 Sasaki et al., Cancer 2005 Livraghi, J Hepatol Pancreat Surg 2010 2 cm 0.5 cm 3 cm 2 cm Microvascular Satellites invasion 1.5 cm 0 0 1.6 - 2 cm 10% 3%

50. TACE e HCC

51. Worldwide HCC burden HCC ranks first among PLC: 75-90% 5 th most frequent tumor in men, 9 th in women 3 rd cause of death among cancers 1 st cause of mortality in cirrhotic patients Incidence (620.000) annual mortality (595.000) Ferlay et al. IARC CancerBase no. 5, 2004 Parking Bray, CA Cancer J Clin 2005 El Serag Rudolph, Gastroenterology 2007