Dr CF LAU United Christian Hospital JHSGR 23 Oct 2010

1. TACE plus PVE for HCC with insufficient future liver remnant:is the effect beneficial or detrimental? Dr CF LAU United Christian Hospital JHSGR 23 Oct 2010

3. Curative treatment options? • Liver transplantation • Ablative therapy • Extensive liver resection

4. Extensive liver resection • often results in >70% of the functioning liver parenchyma being removed • leads to an abrupt increase in the portal venous pressure, which may damage the residue liver

5. Extensive liver resection • In addition, most HCC patients have impaired liver function reserve because of hepatitis B and/or C virus-associated or alcoholic liver fibrosis/ cirrhosis • Can cause significant postoperative morbidity and liver failure

6. Any solution?

7. Portal Vein Embolization

8. Portal vein embolization • 1920 • Rous and Larimore demonstrated the ligation of a major branch of rabbit portal vein resulted in atrophy of the ipsilateral hepatic lobe and hypertrophy of the contralateral lobe • 1975 • Honjo tried portal vein ligation in liver cancer patients not fit for liver resection, aiming at suppressing tumour growth. This resulted in marked atrophy of the liver lobe with portal vein ligated including the tumour, and also hyperplasia of the non-ligated lobe

9. Portal vein embolization • 1982 • Makuuchi applied PVE on patients with bile duct carcinoma receiving extended lobectomy • 1986 • Kinoshita applied PVE on patients with HCC

10. Effects of PVE • Portal pressure • No change in total portal venous flow because the liver does not have intrinsic ability to modulate portal flow • Transient elevation in portal flow and pressure in non-embolized liver, and returns to baseline in 2-3 weeks

11. Effects of PVE • Volumetric change after PVE • Regeneration rate in non-cirrhotic liver • 12cm3/day at 2 weeks • 11cm3/day at 4 weeks • 6cm3/day at 32 days • For cirrhotic liver • 9cm3/day at 2 weeks • Affected by other factors such as diabetes, obstructive jaundice, active hepatitis, and the embolization material used

12. Indications for PVE • Major hepatic resection (> 3 segments) • Future liver remnant (FLR) <30% in patients with normal liver function (no jaundice, ICGR15 <15%); or <40% in patients with compromised liver function

13. Some issues to consider… • The underlying liver disease in the majority of patients may impair the capacity for liver remnant hypertrophy after PVE • Cessation of portal flow may induce a compensatory increase in the arterial blood flow in the embolized segments and result in the rapid growth of the tumours • most HCCs are supplied mainly by arterial blood flow • Arterioportal shunts, which are frequently found in cirrhotic livers and HCC tumours, may attenuate the effects of PVE

14. PVE + TACE • TACE is given with PVE before major liver resections, aiming at: • Enhancing the process of hypertrophy of the FLR segments after PVE • Preventing tumour progression during the interval between PVE and liver resection • Strengthening the effect of PVE by embolizing any arterioportal shunts

15. Adverse effect ? • Double occlusion of the arterial and portal venous systems may cause infarction of noncancerous liver paranchyma

16. Questions in mind… • Beneficial? • Does it enhance the hypertrophy of liver remnant? • Is tumour growth suppressed? • Detrimental? • Does it affect the liver function? • Does it cause significant necrosis of liver parenchyma? • What is the mortality?

17. Sequential preoperative arterial and portal venous embolizations in patients with hepatocellular carcinoma • Aoki et al. Arch Surg 2004; 139: 766-774 • University of Tokyo • 1 Oct 1994 - 31 Dec 2002 • 16 patients underwent hepatectomy out of 17 patients who had TACE + PVE • Sequential TACE and PVE for HCC: The University of Tokyo Experience • Imamura et al. Seminars in Interventional Radiology 2008; 25(2): 146-154 • University of Tokyo • 1995-2007 • 44 patients underwent hepatectomy as scheduled, 2 underwent downscaled hepatectomy, and 1 did not had any operation

18. Sequential arterial and portal vein embolizations before right hepatectomy in patients with cirrhosis and hepatocellular carcinoma • Ogata et al. BJS 2006; 93: 1091-98 • Hospital Beaujon, France • Nov 1998 - Oct 2004 • 18 patients had TACE + PVE before hepatectomy, 18 patients had PVE only

19. Does TACE enhance the effect of PVE in inducing hypertrophy of non-resected segments?

20. Ogata’s study

21. Ogata’s study • 12 of the 18 patients in the TACE + PVE group had an increase of >10%, while there was only 5 of the 18 patients in the PVE group (P=0.044)

22. Is tumour growth suppressed?

23. Imamura’s study • Tumour growth was at least suppressed by the preceding TACE

24. Aoki’s study Tumour Volume AFP DCP

25. Effect on liver function

26. The changes in liver function tests were transient Imamura’s study AST Bilirubin Prothrombin Time

27. Aoki’s study TACE PVE AST PVE ALT Bilirubin

28. Ogata’s study AST ALT Prothrombin Time Bilirubin

29. Examination of specimen

30. Imamura: • Necrosis of the non-cancerous liver parenchyma was minimal in most cases, whereas that of the HCC tumours was marked • Aoki: • Extent of the necrosis of the non-cancerous liver parenchyma was minimal in 14 patients, although segmental infarction was found in the resected right liver in 2 patients • Ogata: • Complete necrosis of the tumour induced by TACE + PVE occurred in 15 of 18 patients, compared with 1 of 18 patients after PVE alone (P<0.001)

31. Mortality

32. Imamura, Aoki: • No operative mortality • Ogata: • incidence of post-op liver failure and mortality were similar

33. Conclusion

34. Conclusion • TACE + PVE is a safe procedure which enables extensive liver resection in patients with HCC and inadequate future liver remnant volumes • Tumour growth is at least suppressed during the period of TACE + PVE • TACE enhances the ability of PVE to induce hypertrophy on the non-embolized liver segments

35. Conclusion • This double occlusion treatment affect the liver function only transiently • Extent of infarction of non-cancerous liver remnant is usually minimal

36. Conclusion • In view of limited amount of studies available, and limited sample size in each study, further investigation is needed

37. Thank you

39. Supplementary Slides

40. Portal vein embolization • 1920 • Rous and Larimore demonstrated the ligation of a major branch of rabbit portal vein resulted in atrophy of the ipsilateral hepatic lobe and hypertrophy of the contralateral lobe • Rous P, Larimore LD. Relation of the portal blood to liver maintenance. A demonstration of liver atrophy conditional on compensation. J Exp Med 1920; 31: 609-32 • 1975 • Honjo tried portal vein ligation in liver cancer patients not fit for liver resection, aiming at suppressing tumour growth. This resulted in marked atrophy of the liver lobe with portal vein ligated including the tumour, and also hyperplasia of the non-ligated lobe • Honjo I, Suzuki T, Ozawa K, Takasan H, Kitamura O. Ligation of a branch of the portal vein for carcinoma of the liver. Am J Surg 1975; 130: 296-302

41. Portal vein embolization • 1982 • Makuuchi applied PVE on patients with bile duct carcinoma receiving extended lobectomy 1975 • Makuuchi M, Takayasu K, Takuma T. Preoperative transcatheter embolization of the portal venous branch for patients receiving extended lobectomy due to the bile duct carcinoma. J Jpn Surg Assoc 1984; 45: 1558-1564 • 1986 • Kinoshita applied PVE on patients with HCC • Kinoshita H, Sakai K, Hirohashi K. Preoperative portal vein embolization for hepatocellular carcinoma. World J Surg 1986; 10: 803-8

42. Effects of PVE • Volumetric change after PVE • Regeneration rate in non-cirrhotic liver [1,2] • 12cm3/day at 2 weeks • 11cm3/day at 4 weeks • 6cm3/day at 32 days • For cirrhotic liver [1-3] • 9cm3/day at 2 weeks • (1) Lee KC et al. Extension of surgical indications for hepatocellular carcinoma by portal vein embolization. World J Surg 1993; 17: 109-15 • (2) Nagino M et al. Changes in hepatic volume in biliary tract cancer patients after right portal vein embolization. Hepatology 1995; 21: 434-9 • (3) T de Baere. Preoperative portal vein embolization for extension of hepatectomy indications. Hepatology 1996; 24: 1386-91

43. Tumour growth - Aoki • The tumour volume tended to decrease after PVE, although the difference did not reach statistical significance. • Serum AFP levels between the TACE and PVE procedures and between the PVE and the hepatectomy procedures were significantly lower than the AFP levels before TACE (P=0.001 and 0.003 respectively) • Plasma DCP level between the TACE and PVE procedures decreased significantly (P=0.002), whereas the DCP level between the PVE and the hepatectomy procedures showed a decrease of borderline significance (P=0.02)

44. Liver Fx Test - Aoki • All 3 variables increased significantly within 3 days after TACE and returned to their baseline values after 1 week • The AST and ALT values increased within 3 days after the PVE but returned to their pre-PVE values after 2 weeks. After PVE, bilirubin values remained stable.

45. LFT - Ogata • After PVE, minimum prothrombin time and peak serum total bilirubin were similar in the two groups • Peak levels of AST and ALT were significantly higher in the TACE + PVE group • P=0.026 and 0.031 respectively) • Before surgery, LFT results were comparable to those before PVE in both groups

50. UCH experience