1. High-Intensity Focused Ultrasound for Hepatocellular Carcinoma Joint Hospital Surgical Grand Round Queen Mary Hospital 19/10/2013

2. How HIFU works Indications / Contraindications Complications Current results BACKGROUND

3. Hepatocellular carcinoma Most common primary liver cancer Only 15% resectable disease on presentation – Inadequate liver function – Multifocality Local ablative therapies for unresectable disease

4. Local ablative therapy Radiofrequency ablation Ethanol injection Microwave ablation High-intensity focused ultrasound

5. HOW HIFU WORKS Indications / Contraindications Complications Current results Background

6. High-Intensity Focused Ultrasound Focused ultrasound energy (0.8MHz) from distant transducer Hyperthermia Coagulative necrosis Intact tissues in between

7. Animal studies in 1940s Intended for treatment of Parkinson disease

8. Current clinical applications 1990s: Transrectal HIFU for prostate cancer 2000s: MRI guided HIFU for uterine fibroid Under investigation: Pancreatic tumour, bone tumours etc.

9. Ultrasound guided HIFU system

10. Water tank Therapeutic ultrasound transducer Diagnostic ultrasound probe

11. Procedure General anaesthesia – Immobilization – Interval cessation of ventilation Prone / right lateral position

12. Procedure Planning with diagnostic ultrasound Slice-by-slice ablation from deep to superficial region

13. Grayscale change Before ablationAfter ablation

14. Advantages / disadvantages Advantages – No internal bleeding – No needle tract seeding – Less liver derangement Disadvantages – Needs general anaesthesia – Lengthened procedure

15. INDICATIONS / CONTRAINDICATIONS Complications Current results Background How HIFU works

16. Indications Small tumour – Less than 3cm: ablation rate >85% Centrally located / liver dome tumour Adjacent to major bile duct / veins Child’s C liver function Gross ascites Cheung TT et al. HPB 2013

17. Liver dome tumour

19. Tumour adjacent to major vein

21. Indications Small tumour – Less than 3cm: ablation rate >85% Centrally located / liver dome tumour Adjacent to major bile duct / veins Child’s C liver function Gross ascites

23. Contraindications Not fit for general anaesthesia Cannot assume treatment position Very poor liver function Lesion not visualized by USG Overlying hollow viscus Deep tumour Tumour close to overlying rib

24. Deep tumour

25. Tumour close to rib Pre-ablationPost-ablation

26. COMPLICATIONS Current results Background How HIFU works Indications / Contraindications

27. Complications (10-20%) Skin burn Bruising Pneumothorax Incomplete ablation (10% for small tumours)

28. CURRENT RESULTS Background How HIFU works Indications / Contraindications Complications

29. Unresectable HCC (n=49) – Child’s A (n=41) and B (n=8) cirrhosis – Median size 2.2cm (0.9-8cm) Ng KK et al. Annals of Surgery 2011

30. Unresectable HCC Ablation rate 79.5% (n=39) Risk factor: median tumour size (2.3cm vs. 3.8cm; p=0.03) Ng KK et al. Annals of Surgery 2011

31. SMALL HCC HIFU v.s. RFA

32. Small (<3cm) unresectable HCC (n=106) – Percutaneous RFA if feasible (n=59) – HIFU (n=47) if Technically difficult percutaneous RFA – Liver dome tumour – Ascites Child’s B cirrhosis Cheung TT et al. HPB 2013

33. HIFU vs. RFA HIFU (n=47)RFA (n=59)p Child-Pugh class0.001 A31 (66%)54 (91%) B16 (34%)5 (9%) Tumour size (cm)1.5 (0.8-2.7)1.9 (1.0-2.8)0.006 Complete ablation41 (87.2%)56 (94.9%)0.290 Complication rates21%9%0.060 Skin burn (n=2)Pleural effusion (n=2) Pneumothorax (n=2)Liver abscess (n=1) Chest wall oedema (n=1) Major complications6.4%6.8%>0.05 Hospital stay (day)460.028 Cheung TT et al. HPB 2013

34. Survival 34% 26% 81% 80% Cheung TT et al. HPB 2013

35. TUMOURS CLOSE TO PEDICLES

36. Liver tumours (n=30) and pancreatic tumours (n=6) Tumour <1cm from – IVC / hepatic /portal veins (n=27) – Bile ducts (n=4) 1 portal vein thrombosis (Pancreatic cancer) No bile duct injury Franco O et al. AJR 2013; 195

37. HCC (n=39) with close proximity to major veins No venous thrombosis / bile duct injury Zhang L et al. Eur Radiol 2008

38. LOCALLY ADVANCED HCC Special condition

39. Locally advanced (4-14cm, mean 10.5cm) HCC (n=50) – Randomized controlled trial – TACE + HIFU (n=24) – TACE only (n=26) Wu F et al. Radiology 2005

40. TACE + HIFU vs. TACE TACE + HIFU(n=24)TACE (n=26)p Child-Pugh class>0.05 A24 (100%)24 (92%) B0 (0%)2 (8%) Tumour size (cm)10.0311.26>0.05 Course of treatment1.21.5 Median reduction in tumour size at 6 month 52.9%10.0%<0.01 Median survival (month)11.34.00.004 Wu F et al. Radiology 2005

41. Survival TACE only TACE + HIFU Wu F et al. Radiology 2005

42. Locally advanced HCC Combined HIFU / TACE is a promising approach On-going trial in QMH Wu F et al. Radiology 2005

43. BRIDGING TO TRANSPLANT Special condition

44. Retrospective study Transplant candidates for HCC (n=49) – Bridging HIFU (n=5) – Bridging TACE (n=29) – No bridging therapy (n=15) Non-transplant candidates with HIFU (n=5) Cheung TT et al. WJG 2013

45. Bridging to transplant HIFU(n=10)TACE (n=29)p Child-Pugh class0.267 A3 (30%)17 (58.6%) B6 (60%)12 (41.4%) C1 (10%)0 (0%) Tumour size (cm)2.6 (1.2-4.0)2.0(0.8-4.3)0.960 Number of tumour1 (1-2)1 (1-3)0.172 Complete response9 (90%)1 (3%)0.00 Partial response1 (10%)14 (48%)0.00 Progressive disease014 (48%)0.00 Cheung TT et al. WJG 2013

46. Bridging to transplant 3 patients in HIFU group received liver transplant Pathology – Complete necrosis (n=2) – 90% necrosis (n=1) Cheung TT et al. WJG 2013

47. Liver transplant candidate Effective bridging therapy to liver transplant Cheung TT et al. WJG 2013

48. Summary Current applications – Ablative therapy for small unresectable HCC Child’s C liver function Tumour close to major pedicle – Combined with TACE for large HCC – Bridging therapy to liver transplantation Under investigation More clinical studies warranted