Interventional Treatment for Hepatocellular Carcinoma

1. Interventional Treatment for Hepatocellular Carcinoma Sheng-Long Ye, MD, PhD Liver Cancer Institute Zhongshan Hospital Fudan University Shanghai, China

2. China—High Incidence of Liver Cancer

3. New Cases of Liver Cancer (2008) x103 748 6 402 48.2%

4. Deaths of Liver Cancer (2008) x103 694 3 372 6 48.4%

5. The Second Cancer Killer in China PLC Mortality (per 105 people)

6. Problem in HCC Severe cirrhosis Intrahepatic spread and distant metastasis Lowresectability High postoperative recurrence

7. Vascular Invasion Number Tumor size HCC Treatment Algorithm HCC ECOG PS 0~2 PS 3~4 Liver Function Child-Pugh A/B Child-Pugh C Metastasis No Yes Yes No 2~3 Single ≥4 ≤3cm ＞3cm ≤5cm ＞5cm • Resection • Ablation (≤3cm) • Transplant • Resection • TACE • +Ablation • Transplant (UCSF) • TACE • Resection • +ablation • TACE • Radiotherapy • Molecular targeted • Systemic chemotherapy • Supportive care • Transplant (UCSF) • TACE • Resection • Radiotherapy • Targeted • Systemic chemotherapy Optimal treatment • Supportive care

8. Non-surgical Treatment • Interventional treatment – TACE, Intratumor injection, RFA, MWCT, Laser, HIFU, Cryotherapy • Radiotherapy • Chemotherapy • Biotherapy • Molecular targeted therapy • Traditional Chinese medicine

9. Interventional Treatment is a main modality for HCC TIPS, stent in IVC, biliary tract, portal vein…… 1994 Ohnishi PAI 1992 Masters Laser 1995 Murakami Microwave 1993 Rossi RFA 1986 Livraghi PEI 1986 Onik Cryoablation 1976 Goldstein TAE 1979 Nakakuma Lipiodol TACE

10. Normal PV Classic Normal HA Abnormal HA Arterial supply Portal supply RN low-DN high-DN EHCC wd-HCC md/pd-HCC Key Pathologic Features of HNS: Vascular Supply Significant overlap Loss of visualization of portal tracts and development of new arterial vessels

12. Arterial Embolization for HCCMeta-analysis of 6 RCTs (2-Yr Survival) Author, Journal Yr Patients, n Lin, Gastroenterology 1988 63 GETCH, NEJM 1995 96 Bruix, Hepatology 1998 80 Pelletier, J Hepatol 1998 73 Lo, Hepatology 2002 79 Llovet, Lancet 2002 112 Overall 503 Random Effects Model, OR (95% CI) 0.01 0.1 0.5 1 2 10 100 Z = -2.3 P = .017 Median survival: ~ 20 mos Favors Treatment Favors Control Llovet JM, et al. Hepatology. 2003;37:429-442.

13. HCC ECOG PS 0~2 PS 3~4 Liver Function Child-Pugh A/B Child-Pugh C Metastasis No Yes Invasion No Yes Tumor Number One 2~3 ≥4 < 5cm ≥5m Tumor Size ≤3cm ＞3cm ·TACE ·Resection ·Radiotherapy ·Sorafenib ·Chemotherapy Treatment ·Resection ·TACE+RFA ·Transplant • ·TACE • ·Resection • ·+Ablation • Transplant ·TACE ·Radiotherapy ·Sorafenib ·Chemotherapy Application of TACEfor HCC

14. Improvement of TACE H.A.-P.V. combined embolization Super selective segmental chemoembolization TACE with temporary occlusion of H.V. Hot lipiodol embolization Segmental ethanol-lipiodol infusion Stent in P.V. with I125 intra-radiation Radioembolization (Y90 microsphere) Drug-Eluting Beadembolization

15. Personalization of TACE Super-selective embolization Prolongation of treatment interval Tumor down-staging resection Adjuvant TACE Thrombus in P.V. and I.V.C. Combination treatment Avoiding over-treatment !

16. Local Ablation therapy Imaging-guided targeting cancer location, resulting in direct coagulation, necrosis and killing of cancer tissues by physical and chemical approaches with minimal invasion Safe, minimal-invasion, simplified，repeatable Clinical departments involving in ablation therapy ---- Surgical, Medical, Interventional, Radiology, Radiotherapy, Ultrasonography…）

17. Local Ablation PEI, RFA, MWCT, Laser thermal therapy, HIFU, (Argon-Helium)-Cryotherapy. All tumors amenable to ablation (enough margin of normal tissues). Tumors in a location accessible for ablation. Tumors ≤ 3cm --- optimally treated with ablation . Tumor 3-5cm --- combination of embolization and ablation. Unresectable/inoperable lesions (＞5cm) -– arterial embolization approaches. Caution --- ablating lesions near major vessels, major bile ducts and other intra-abdominal organs.

18. Ablation area should include at least 5 cm of surrounding tissues for “safe margin” Ablation area needs to be extended for liver cancer with infiltrative type or metastatic type if the surrounding tissues and structure are available Personalization of treatment strategy is important for liver cancers near heart, diagram, stomach, intestine, gallbladder and other organs Blood-supply vessels of hypervascular cancer may be blocked before ablation Principles of Ablation therapy

19. Jiang XC RFA for Small HCC

20. Wang ZS Wang ZS RFA for Small HCC Mao YY

21. RFA- CEUS

22. Small HCC: RFAvs Surgery Recurrence% 1-y 2-y 3-y Resection 65 10.7 18.4 24.6 RFA 47 8.5 19.1 23.4 Survival% 1-y 2-y 3-y 4-y 5-y Resection 90 93.9 89.1 80.0 67.4 48.6 RFA 71 90.7 83.3 74.9 57.0 47.2

23. HCC(≤4cm): RFAvs Surgery Recurrence% 1-y 2-y 3-y Resection 84 8.3 20.2 32.1 RFA 84 11.9 27.4 41.7 Survival% 1-y 2-y 3-y Resection 84 96.0 87.6 74.8 RFA 84 93.1 83.2 67.6

24. Application of Ablation for HCC HCC ECOG PS 0~2 PS 3~4 Liver Function Child-Pugh A/B Child-Pugh C Metastasis No Yes Vessel Invasion No Yes Tumor Number One 2~3 ≥4 < 5cm ≥5m Tumor Size ≤3cm ＞3cm Treatment ·Resection ·Ablation ≤3cm ·Transplant ·Resection ·TACE+Ablation ·Transplant • ·TACE • ·Resection • ·+Ablation • Transplant

25. Combination of TACEand ablation prolongs survival of cancer patients with multiple nodules Wang, et al. Liver International 2010

26. Outcome of Non-Surgical PLC (1995-2009） 44.6% 44.7% 41.0% 37.7% 37.9% 32.8% 25.3% TACE PEI RF RF+TACE TACE+PEI RF+PEI RF+PEI+TACE

27. Evidence Levels in the Treatment of HCC according to the strength of study design and of end-points Treatments assessed Benefit Evidence level Surgical treatments Surgical resection Increased survival3iiA Adjuvant therapies Controversial 1A-D Liver transplantation Increased survival3iiA Neo-adjuvant therapies Treatment response 3Diii Loco-regional treatments Percutaneous treatments Increased survival3iiA Radiofrequency ablation Better local control 1iiD Chemoembolization Increased survival1iiA Lipiodolization Treatment response 3iiDiii Internal radiation (I131, Y90) Treatment response 3iiDiii Systemic treatments Sorafenib Increased survival 1iA Tamoxifen No survival benefit 1iA Systemic chemotherapy No survival benefit 1iiA Immunotherapy No survival benefit 1iiA Llovet & Bruix: J Hepatol, 2008; 48: S20-S37

28. New Building for Liver Cancer Center 5-Year Plan