1. Stefan Breitenstein Department of Visceral and Transplantation Surgery University Hospital Zurich SASL Tag der Leber 2012 KSSG, 30. August 2012 Lebertransplantation bei HCC

2. Male patient 24 y Family, 2 children Hep B Cirrhosis with HCC AFP 220 MELD 8 Listed for Liver TPL Case 1 Radiology, MRI:

3. Male patient 24 y Family, 2 children Hep B Cirrhosis with HCC AFP 220 MELD 8 Listed for Liver TPL Case 1 1.Escape from the list, no transplantation 2.Transplantation 3.Bridging (TACE, RF,…) and Transplantation Question: What to do?

4. Case 2 Male patient 59 y Family, 2 children Hep C Cirrhosis with HCC AFP 14 MELD 25 Radiology, MRI 1.No transplantation, ablative treatment (TACT, RF, …) 2.Transplantation 3.Bridging (TACE, RF, resection) and Transplantation 4.other Question: What to do?

5. Dutkowski, Clavien, Gastroenterology, 2010 Survival after Liver TPL in Europe

6. Dutkowski, Clavien, Gastroenterology, 2010 Survival after Liver TPL in Europe 5 yr survival: > 70%

7. HCC: Therapeutic Options Radiofrequency / Microwave Ablation Resection ? Cryo-Surgery Chemoembolization Transplantation Chemo-, Immunotherapy Radioembolization

8. Zurich, Switzerland 2-4 December 2010 Recommendations for Liver Transplantation for HCC: an International Consensus Conference Report

9. To establish the State of the Art regarding indications for OLT in patients with HCC To provide internationally accepted statements & guidelines Aim

10. Endorsing Societies European HepatoPancreatoBiliary Association American Association for the Study of Liver Disease American Society of Transplant Surgeons European Association for the Study of the Liver European Liver and Intestine Transplant Association International HepatoPancreatoBiliary Association International Liver Cancer Association International Liver Transplantation Society Liver and Gastrointestinal Disease Foundation The Transplantation Society

11. Methods Organizing Committee Danish Model Working Groups of Experts Jury Finest available knowledge WELL IN ADVANCE Recommendations Preparatory Meetings Boston Oct 2009 Vienna Apr 2010 Boston Oct 2010

12. ESSENTIAL RULE The members of the Jury draw the recommendations NOT the experts Methods

13. Level of Evidence Oxford Centre for Evidence-based Medicine

14. Strength of recommendations GRADE System Grading of Recommendations Assessment, Development and Evaluation BMJ 2008; 337: 327-30

15. Publication Lancet Oncol. 2012 Jan;13(1)

16. Liver TPL for HCC: Rational Multifocal diseases Best oncologic resection Treatment of cirrhosis Restores normal hepatic function

17. Liver TPL for HCC: History Indications in the 80s/ 90s Easier Assumption of cure No other options

18. AuthorsyearsMortality3yr Survival Ringe198934%20% Iwatsuki199115%52% O ’Grady198831%32% Bismuth19935%49% Liver TPL for HCC: History

19. MILAN Criteria Liver TPL für HCC: Single tumor < 5 cm Two-three tumors < 3 cm No vascular invasion Mazzaferro et al., N Engl J Med 1996

20. MILAN Criteria

21. MILAN Criteria: Outcome AuthorsyearsMortality3yr Survival Ringe198934%20% Iwatsuki199115%52% O ’Grady198831%32% Bismuth19935%49% Mazzaferro19966%83% Figueras1997-75% Llovet199813%74% Bismuth19993%68% Herrero2001-76% Hemming200115%63% Beaujon200110%73% Ravaioli2004-82% Milan Criteria

22. Extended Criteria: UCSF Criteria:Solitary Tumor < 6.5 cm < 3 nodules with largest lesion < 4.5 cm Yao et al, Am J Transplantation 2007. Validation of University of California, San Francisco (UCSF) criteria. n = 168 patients with liver transplantation 38 patients exceeding Milan but meeting UCSF criteria

23. Extended Criteria: UCSF Criteria:Solitary Tumor < 6.5 cm < 3 nodules with largest lesion < 4.5 cm Yao et al, Am J Transplantation 2007. Validation of University of California, San Francisco (UCSF) criteria. 5-year recurrence-free probability UCSF 93% Milan 90%

24. Extended Criteria: 5 – 5 rule Sugawara et al, Dig Dis2007. Tokyo, Japan. Criteria:- less than 5 nodules - maximum diameter 5 cm 3-yr recurrence-free survival 5-5 rule 94% Exceeding 5-5 50%

25. Challenge of Milan Criteria

26. Yao F et al, Am J Transpl, 2008

27. What are the criteria for OLT? LT within the Milan criteria (1 tumor 70% 5-yr survival UCSF criteria (1 tumor ≤ 6.5cm, ≤ 3 with the largest ≤ 4.5 cm and total tumour Ø ≤ 8 cm) : same outcome in retrospective studies

28. What are the criteria for OLT? Recommendation Level of evidence Strength 1.The Milan Criteria are currently the benchmark, and the basis for comparison with other suggested criteria. 2bStrong 2.A modest expansion of the number of potential candidates may be considered on the basis of several studies showing comparable survival for patients outside the Milan criteria. 3bWeak 3.Patients with worse prognosis may be considered for OLT outside the Milan criteria if the dynamics of the waiting list allow it without undue prejudice to other recipients with a better prognosis. ØWeak

29. Negative risk factors of survival for HCC Multifocal tumor Size of tumor Poor differentiation Lympho/ vascular invasion AFP > 400 – 1000 ng/ml

30. Allocation for Liver TPL Model for End-stage Liver Diseases: MELD Score 2002 «United Network for Organ Sharing» (UNOS): To grade patients on the waiting list according to the severity of liver disease Serum Creatinine (mg/dl) Bilirubin (mg/dl) INR Score 6 - 40 Wiesner R et al., Gastroenterology, 2003 Kamath PS et al, Hepatology 2001 10 x (0.957 (Serum Crea) + 0.378 (Bilirubin) + 1.12 (INR) + 0.643)

31. Allocation for Liver TPL Model for End-stage Liver Diseases: MELD Score Highly predictive of the risk of dying from liver disease for patients on the waiting list Switzerland: Allocation according to MELD since 2007

32. Allocation: Problem HCC - MELD Patients with HCC often have low MELD score Long waiting time for Liver TPL Extra points T1(< 2 cm) +0 pts 33% OLT without HCC ! T2 (2-5 cm) 22 pts T3 – T4: +0 pts negative prognostic UNOSEurotx Minimum 22 Upgrade 10% MELD equivalent (3 months) Swisstx MEDIAN of the MELD score of all liver-patients of the month before: 14 1pt in addition every month on the waiting list

33. Allocation: Problem HCC - MELD Tumor progression Tumor growth Risk of Drop-out (2-4% / mt) Loss of benefit of TPL Transplantation TPL Decision Vascular invasion CH: waiting time: 7 - 9 months for HCC patients

34. Allocation: Problem HCC - MELD Contrast imaging every 3 mt (MRI) Consequences of long waiting time: 1. Monitoring - Trans-Arterial-Chemoembolization (TACE) - Percutaneous treatment (RFA) - Resection 2. Bridging

35. Trans-Arterial-Chemoembolisation as Bridge

36. AUTHORYEARnConclusions Maddala 200454 No survival advantage after LT Perez 200546 No survival advantage after LT Decaens 2005200 No survival advantage after LT Yao 2005168 Survival advantage for T2/T3 Porret 200664 No survival advantage after LT Kim et al., JACS, 2007 Only retrospective studies!

37. Trans-Arterial-Chemoembolisation as Bridge Improvement of long-term survival: unclear No increase of post-operative complications Insufficient evidence about TACE benefits Impact of hyperselective TACE ? Lesurtel et al, Am. J. Transplant. 2006

38. Radiofrequency Ablation as Bridge No randomized studies Controversial results Morbidity 2,2%, mortality 0,3% Good option for Child A-B patients with expected waiting time >6 months Kim et al, JACS, 2007 Lau et al, Ann Surg 2009

39. Resection as Bridge Salvage OLT Without recurrence With recurrence

40. Resection as Bridge Belghiti J et al., Ann Surg 2003; 238: 885-893 Primary OLT Secondary OLT after liver resection n = 70n = 18 Morbidity Mortality 36 (51%) 4 (6%) 10 (56%) 1 (6%) (Within Milan)

41. Resection as Bridge “OLT after liver resection is associated with an increased risk of recurrence and poorer outcome than primary OLT“ 1.0 0.8 0.6 0.4 0.2 0 012345012345 Years Disease-free survival Primary LT (n=195) LT after resection (n=17) 29% 64% 58% p=0.003 Adam R et al. Ann Surg,2003

42. Resection as Bridge 61 Resection of HCC within the Milan criteria Mean follow-up 4.3 years Recurrence present 31 (51%) Salvage LT possible: 24 out of 31 (77%) Cherqui D et al., Ann Surg 2009 5-year survival: 85%

43. Is treatment of HCC on the waiting list necessary? RecommendationLevel of evidenc e Strengt h 1.Based on current absence of evidence, no recommendation can be made on bridging therapy in patients with UNOS T1 (<2cm) HCC. ØNone 2.In patients with UNOS T2 HCC (1 nodule 2-5cm or ≤3 nodules each ≤3cm) and a likely waiting time longer than 6 months, loco-regional treatment may be appropriate. 4Weak 3.No recommendation can be made for preferring any type of loco-regional therapy over others. ØNone

44. Does a patient qualify for OLT after downstaging? Recommendation Level of evidence Strength 1.Transplantation may be considered after successful downstaging. 5Weak 2.Criteria for successful downstaging should include tumor size and number of viable tumors. AFP may add additional information. 4 Strong/ Weak 3.LT after successful downstaging should achieve a 5yr survival comparable to that of HCC patients who meet the criteria for LT without requiring downstaging. 5Strong 4.Based on existing evidence, no recommendation can be made for preferring a specific locoregional treatment for downstaging over others. ØNone

45. Contraindications for Liver TPL Cirrhosis, HCC: Tumor specific factors Age > 60 – 70 Protal vein occlusion Hypertension A. pulmonalis

46. Liver TPL: Current problem Shortage of organs Increase of donor rates Living Related Liver Transplantation Split Liver Transplantation Extend donor criteria (marginal organs)

47. Living Related Liver Transplantation

48. Donor

49. Living Related Liver Transplantation

50. RecepientDonor

51. Living Related Liver Transplantation Advantages Shorten waiting time < 2 - 4 weeks High quality graft > 95 % 1yr survival Positive impact on pool of organs

52. Living Related Liver Transplantation Disadvantages Donor Mortality : 0,2% Donor Morbidity: 16% Technically more demanding

53. Living Related Liver Transplantation Clavien et al., J Hep, 2009

54. V A What is the role of adjuvant therapy after LT for HCC? Recommendation Level of evidence Strength 1.The current evidence does not justify the routine use of adjuvant anti- tumour therapy after LT for HCC outside of a controlled clinical trial. NAWeak

55. Conclusions Milan criteria is the standard to select cirrhotic patients with HCC for liver TPL Survival after Liver TPL (HCC and other patients): 85% 1y, >70% 5y Allocation of Donor organs base on MELD score of recepients Resection/ Ablation and Transplantation should be associated rather than opposed Living related liver transplantation is one option to reduce shortage of organs

56. Male patient 24 y Family, 2 children Hep B Cirrhosis with HCC AFP 220 MELD 8 Listed for Liver TPL Case 1 Radiology, MRI:

57. Case 1 2y Follow up: uneventful

58. Case 2 Male patient 59 y Family, 2 children Hep c Cirrhosis with HCC AFP 14 MELD 25 Radiology, MRI

59. Case 2 Tumor recurrence after 6 mt Death after 8 mt