Epatocarcinoma: trapianto o resezione? A chi e perche? - Gastrolearning®

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Gastrolearning XVII lezione
Epatocarcinoma: trapianto o resezione? A chi e perche? - Prof. U. Cillo (Università di Padova).

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  • 1. Progetto GASTROLEARNINGwww.gastrolearning.itChirurgia Epatobiliare eCentro Trapianto di FegatoAzienda Università degli Studi di Padovacillo@unipd.itProf. Umberto Cillo, MD, FEBSPadova, 03 Giugno 2013EPATOCARCINOMA:TRAPIANTO O RESEZIONE?a chi e perchè
  • 2. HCCResection vs TransplantationResectionAblationTransplantationTACE Sorafenib
  • 3. Haynes RB, et al. BMJ 2002; 324: 1350An updated modelfor EBMclinical decisionsLimits of a specific therapy
  • 4. Flather M, et al. Clin Trials 2006; 3: 508-512RCT are not useful to measure the effectivenessof complex – multifaceted therapies like organ transplantationResearch evidence &treatment decision for HCC patients
  • 5. Variation in choice of therapy by nonclinical factors,after adjustment for clinical factorsNathan et al, Ann Surg Oncol. 2013 Feb;20(2):448-56
  • 6. TRANSPLANTATION- Indicated within Milan criteria- LDLT is an alternative if wating time >6 month- LDLT is a suitable setting for extended indicationsRESECTION-“Single tumors (no size limit), normal bilirubin with eitherHPVG<10mmHg or PLT<100.000- In multiple tumors within Milan criteria (not trasplantable)resection has to be considered (and validated)
  • 7. HCCResection vs TransplantationLIVERRESECTION
  • 8. AASLD 2005, 2010; EASL 2012 recommendationsAASLD 2005 = AASLD 2010= EASL 2012Treatment decision for HCC patients
  • 9. Lim et al, British Journal of Surgery 2012; 99: 1622–1629152 studies reviewedMedian 5-year overall survival rate: 67% (range 27-81)Median disease-free survival rate: 37% (range 21 – 57)Operative mortality rate 0.7% (range 0-5)Surgical resection offers good OSfor patients with HCCwithin the Milan criteriaand with good liver functionOutcomes have tended toimprove in more recent years
  • 10. Liver resection&LARGE HCCHCCResection vs Transplantation
  • 11. AUTHOR, YEAR N° OF PATIENTS 5-year survivalKelvin, 2005 380 39%Pawlik, 2005 300 (tumor > 10 cm) 27%Cillo, 2007 48 35%Minagawa, 20072312 (5-10 cm)843 (> 10 cm)43%38%Shah, 2007 24 (>10 cm) 54%Young, 2007 42 (> 10 cm) 45%Cho, 2007 62 (5-10 cm) 52%Wang, 2008 243 50%Torzilli, 2008 24 80% (3-year)Choi GH, 2009 50 (> 10 cm) 40%Yang LY, 2009 260 38%Delis SG, 2009 66 (> 5 cm) 32%Schiffman SC, 2010* 78 (> 5 cm) 20%Single tumor > 5 cmis an INDICATION to resectionif technically feasibleLiver resection for HCCExtension of resection (Size)
  • 12. “Single tumors > 5 cm are still considered for surgical resection as firstoption, because if modern MRI is applied in pre-operative staging, thefact that solitary large tumors remain single and with nomacrovascular involvement – which might be common in HBV-relatedHCC – reflects a more benign biological behavior”Early HCC (= BCLC stage A)• Single tumor >2 cm• 3 nodules <3 cm of diameter• ECOG-0• Child–Pugh class A or B
  • 13. Andreou et al, J Gastrointest Surg (2013) 17:66–771115 patients/539  Major hepatectomyMedian tumor size was 10 cm (range: 1–27 cm)22% bilateral lesionsThe TNM-Stage distribution:29% Stage I31%Stage II38 % Stage III2 % Stage IV35% Chronic Liver disease60% Microvascular invasion90-day p.o. mortality rate was 4%Median follow-up: 63 months5-year OS 40 %Patients treated with right hepatectomy (n=332) and those requiring extendedhepatectomy (n=207) had similar 90-day postoperative mortality rates(4 % and 4 %, respectively, p=0.976) and 5-year overall survival rates(42 % and 36 %, respectively, p=0.523)
  • 14. Andreou et al, J Gastrointest Surg (2013) 17:66–77Postoperative mortality and OS ratesafter major hepatectomyimproved over timeFactors associated with worse survival atmultivariate analysis:-AFP level >1,000 ng/mL-Tumor size >5 cm-Presence of major vascular invasion-Presence of extrahepatic metastases-Positive surgical margins-Earlier time periodExpansion of surgical indications to include major hepatectomyis justified by the significant improvement in outcomesover the past three decades
  • 15. LiverfunctionTumorextensionLocationExtensionof hepatectomyfor oncolgicalradicalityHCC: ResectabilityFunctionalreserve
  • 16. Liver resection&Portal HypertenisonHCCResection vs Transplantation
  • 17. Bruix et al, Gastroenterology 1996 Oct;111(4):1018-22.Bruix et al, Gastroenterology 1996 Oct;111(4):1018-22.29 HCC (all except one < 5 cm)CPT-AAt multivariate analysisonly HVPG was significant(P = 0.0001; OR 1.90; 95% CI 1.12-3.22).Preoperative HVPG of decompensated patient washigher (13.9±2.4 vs. 7.4±3.5 mmHg respectively)P < 0.001
  • 18. Ishizawa T, et al. Gastroenterology 2008; 134: 1908PH is not an absolute contraindicationto liver resectionNeed for RCT versus ablation136 PTH patients vs. 250 no PTH undergoing to resectionCPT-A patients 5-yr survival• PTH 56%• No PTH 71%Liver resection for HCCClinically Relevant Portal Hypertension
  • 19. No CRPH, Normal bilirubinCRPH and/or abnormal bilirubinGis`ele N’Kontchou, et al. Hepatology 2009; 505-year survival & prognosis factorsin 235 consecutive cirrhotic patients• CPT-A: 205• CPT-B: 30who received RFA as first-line treatmentfor up to three HCC<5 cm307 tumorsmean diameter: 29 mm53 multinodular formsLiver resection for HCCClinically Relevant Portal Hypertension
  • 20. 241 cirrhotic patients with HCC89 patients: with portal hypertension (PH)152 patients without portal hypertension (NPH)Preoperative mean MELD:PH  9.5 ± 7.8NPH  8.4 ± 1.3; P 0.001After one-to-one matching:PH (n=78) and NPH (n=78) had the same preoperative characteristics and showed thesame intraoperative course, postoperative occurrence of liver failure, morbidity, length of in-hospital stay and survival rates (P =ns in all cases).The only predictors of postoperative liver failurewere MELD score (P 0.001) and extent of hepatectomy (P 0.005)Cucchetti et al, Ann Surg 2009;250: 922–928Overall survival curves of resected patientswith and without PH (P =0.453)Faced with the same MELD scoreand extent of hepatectomypresence of PH should not be consideredas a contraindicationfor hepatic resection in cirrhotic patients
  • 21. Liver resection&Hepatic FunctionHCCResection vs Transplantation
  • 22. Cucchetti et al, Liver Transplantation 12:966-971, 2006Role of MELD score in predeictingp.o. liver failure and morbidityafter hepatectomy for HCC in cirrhotics154 HCC-resected cirrhotic patients11 (7.1%) p.o. liver failure (death or LT)46 (29.9%) developed ≥ 1 po complicationAt ROC analysis:• MELD ≥ 11 High risk for p.o. liver failure• MELD ≥ 9 Major risk for p.o. complicationsMELD andp.o. liver failure(AUC 0.9295% CI 0.87-0.96)MELD andp.o. complicationafter hepaticresectionin cirrhotics(AUC 0.85,95% CI 0.78-0.89).MELD score should be usedto select the best candidatesfor hepatectomy
  • 23. Selection of HCC patients for resection is based onplanned extension of hepatectomy and liver functional reserveCescon M, et al. Arch Surg 2009http://www.webaisf.org/Liver resection for HCC in cirrhosis
  • 24. Liver resection&MultifocalityHCCResection vs Transplantation
  • 25. 126 Multiple HCC vs308 single HCC undergoing to resectionChild A patients 5-yr survival•Multiple 58%•Single 68%Ishizawa T, et al. Gastroenterology 2008; 134: 1908Multiple tumorsare not a contraindicationto liver resection
  • 26. Lin CT et al. World J Surg 2010; 34: 2155Hepatic resection combinedwith intraoperative local ablation therapyis effective for multinodular HCCs
  • 27. AUTHOR, YEAR N° OF PATIENTS SurvivalKumada K, 1990 13 Median: 12monthsWu CC, 2000 112 5yr: 28%Minagawa M, 2001 18 5yr: 42%Pawlik TM, 2005 1025yr: 10%Median: 11monthsLe Treut YP, 2006 265yr: 13%Median: 9 monthsIkai I, 2006 783yr: 22%Median: 9 monthsChen XP, 2006 286 5yr: 18%Minagawa M, 2007 1517 5yr: 20-40%Liang LJ, 2008 86 Median=11monthsInoue Y, 2009 49 5yr: 40%Kondo K, 2009 48 5yr: 30%Ban D, 2009 45 5 yr: 21%Several papers on resection of BCLC C tumorsTumor ThrombectomyIn selected cases with tumor thrombus (child A,PST=0, no main trunc) surgery is an INDICATION(sorafenib as only alternative)
  • 28. Shi J, et al. Ann Surg Oncol 2010; 17: 2073Several papers on resection of BCLC C tumors
  • 29. Peng ZW, et al. Cancer 2012;118:4725-36Type I Type IType II Type II
  • 30. The impact of multinodularity on HCC outcomes.Patients with multiple neoplasms at the time of surgeryhad a lesser overall survival rate and greater recurrence rateChang WT, et al. Surgery 2012;152:809-20
  • 31. Wang et al, Digestive and Liver Disease 45 (2013) 510– 515SR- Median survival: 11 monthsSupportive-care- Median survival : 3.9 months (HR, 0.45; 95% CI, p < 0.001)Patients who underwent surgical resection had the longest survivalcompared to patients undergoing other treatments (33.4 months versus 8.1 months, p < 0.001).
  • 32. 2046 consecutive patients resected for HCC(10 centers)• BCLC-0/A: 1012 patients (50%)• BCLC-B: 737 patients (36%)• BCLC-C: 297 patients (14%)Overall Survival (P = 0.000)BCLC 0/A(50%; 1012)BCLC B(36%; 737)BCLC C(14%; 297)1 year 95% 88% 76%3 years 80% 71% 49%5 years 61% 57% 38%BCLC 0-ABCLC BBCLC CTorzilli et al, Ann Surg 2013;257: 929–937
  • 33. 2046 consecutive patients resected for HCC(10 centers)• BCLC-0/A: 1012 patients (50%)• BCLC-B: 737 patients (36%)• BCLC-C: 297 patients (14%)BCLC 0-ABCLC BBCLC CDisease Free Survival (P = 0.000)BCLC 0/A(50%; 1012)BCLC B(36%; 737)BCLC C(14%; 297)1 year 77% 63% 46%3 years 41% 38% 28%5 years 21% 27% 18%Resection is in current practice widely appliedamong patients with multinodular, large, and macrovascular invasive HCCwith acceptable short- and long-term resultsand justifying an updateof the EASL/AASLD therapeutic guidelines in this senseTorzilli et al, Ann Surg 2013;257: 929–937
  • 34. HCC staging and treatment algorithmJSH guidelines 2011Kudo et al., JSH Practice Guidelines,Dig Dis 2011; 29: 3339HCC
  • 35. HCCResection vs TransplantationLAPAROSCOPICLIVERRESECTION
  • 36. Bruix J, Sherman. Hepatology 2010Laparoscopy and HCC:high potential, poor evidenceLaparoscopic approach is an orphan procedureLaparoscopic approach is an orphan procedureAsian Oncology Summit 2009No reccomendations on laparoscopyPoon D, et al. Lancet Oncol 2009AASLD 2010No reccomendations on laparoscopyBruix J, et al. Hepatology 2010Rahbari NN, et al. Ann Surg 2011US National Conference 2010No reccomendations on laparoscopyPomfret EA, et al. Liver Transplant 2010Systematic Review 2011No reccomendations on laparoscopyHCC Consensus Gruop 2012No reccomendations on laparoscopy
  • 37. Laparoscopy and HCC:high potential, poor evidence
  • 38. 1. Same oncological radicality?1. Lower surgical stress(decompensated cirrhosis)1. Potential for redo and salvagesurgery (Open resection, OLTx)1. Multimodal therapyVLSResectionAblationStadiationPotentialforredoLaparoscopic ApproachMultimodal TreatmentLaparoscopic approach advantages:RESECTION
  • 39. 3 European centers Between 1998 and 2008163 LLR for HCCMedian surgical duration: 180 minutesMedian operative blood loss: was 250 mL9.8% patients received blood transfusion9.2% Conversion to open surgeryMedian tumor size: 3.6 cmMedian surgical margin: 12 mmLiver-specific complications: 11.6%General complications: 10.4%Hospital stay: 7 daysOverallSurvivalRecurrenceFree Survival1 yr 92.6% 77.5%3 ys 68.7% 47.1%5 ys 64.9% 32.2%Overall SurvivalDisease FreeSurvivalDagher et al, J Am Coll Surg 2010;211:16–23
  • 40. Levels of evidence 2b - 4MARGINS+RECURRENCEP>0.05P>0.05Same oncological radicalityLi N et al, Hepatology Research 2012; 42: 51–59
  • 41. MORBIDITYHOSPITALSTAYP<0.01P<0.01Li N et al, Hepatology Research 2012; 42: 51–59Levels of evidence 2b - 4 Lower Morbidity and Hospital Stay
  • 42. Liver Resection:Laparoscopic Surgery• 10 non-randomized controlled studies that reported 494 patients• 213 underwent laparoscopic liver resection (LLR)• 281 underwent open liver resection (OLR)
  • 43. Blood transfusion requirement:Patients in LLR had a lower rate of blood transfusion requirement(five trials reported this data, OR: 0.39, 95% CI: 0.18 to 0.86)
  • 44. LLR for HCC is superior to the OLR in terms of its perioperative resultsand does not compromise the oncological outcomes
  • 45. Yoon et al, Surg Endosc (2012) 26:3133–3140
  • 46. Belli G et al, Surg Endosc (2009) 23:1807–1811Recurrence of cancer and the need for several surgical treatments are the Achilles’ heel of HCCtreatment15 patients submitted to laparoscopic reintervention(hepatic resection or radiofrequency ablation)for a recurrence of HCC after a previous OLR o LLROverall postoperative mortality : 0%Overall postoperative morbidity : 26.65No patients had a severe postoperative complication.1/15 moderate ascites1/15 atelectasis requiring physiotherapy1/15 pneumonia, which was treated with antibiotics.OLR:More intra-abdominal adhesionsLonger operative timeLaparoscopic redo surgeryfor recurrent HCC in cirrhotic patientsis a safe and feasible procedure
  • 47. Belli G et al, Surg Endosc (2009) 23:1807–1811
  • 48. Laurent et al, J Hepatobiliary Pancreat Surg (2009) 16:310–31424 LT:12 following prior LLR12 following prior OLR19/24 Salvage LT5/24 Neoadjuvant procedure (bridge resection)
  • 49. Laurent et al, J Hepatobiliary Pancreat Surg (2009) 16:310–314Initial LLR facilitates subsequent LTcompared with OLRMedian duration of hepatectomy• LLR: 2.5 hours• OLR: 4.5 hoursMedian duration of LT:• LLR: 6.2 hours• OLR: 8.3 hoursReduced operative timeReduced blood lossReduced transfusion requirements
  • 50. Cillo U. unpublished dataLaparoscopic Liver Resection:Padova ExperienceFrom March 2004 to October 2012Total hepatic resection 1113Total VLS hepatic resection 129 (11.5%)converted to “open” 27 (20.9%)VLS hepatic resection for HCC 87 (67.4%)Hepatobiliary Surgery and Liver Transplant UnitUniversity of PadovaChief: Prof. Umberto CILLO
  • 51. Main indicationsMalignantHCCcolo-rectal metsnon colo-rectal metsCCA104 (80.6%)87 (83.7%)7 (6.7%)5 (4.8%)5 (4.8%)BenignAngiomaAdenomaFNC25 (19.4%)10 (40%)8 (32%)7 (28%)Hepatobiliary Surgery and Liver Transplant UnitUniversity of PadovaChief: Prof. Umberto CILLOLaparoscopic Liver Resection:Padova ExperienceCillo U. unpublished data
  • 52. Surgical ProceduresLeft Hepatectomy 7 (5.4%)Left Lobectomy 24 (18.6%)SegmentectomyS1S2S3S4S5S6S7S898 (76%)1 (1%)19 (19.3%)24 (24.5%)10 (10.2%)8 (8.2%)30 (30.6%)2 (2%)4 (4.1%)Laparoscopic Liver Resection:Padova ExperienceHepatobiliary Surgery and Liver Transplant UnitUniversity of PadovaChief: Prof. Umberto CILLOCillo U. unpublished data
  • 53. ComplicationsHepatobiliary Surgery and Liver Transplant UnitUniversity of Padova(Prof. Umberto CILLO)Ascites 2 42 (32.6%)Fever 2 35 (27.1%)Hemoperitoneum 3-b 4 (3.1%)Pleural effusion 2 4 (3.1%)Biliary leak 2 3 (2.3%)Intestinal perforation 3-b 2 (1.6%)Wound infection 2 2 (1.6%)BPCO 2 1 (0.8%)Laparoscopic Liver Resection:Padova ExperienceCillo U. unpublished data
  • 54. Courtesy by Luca AldrighettiLaparoscopic Approach1677 CASES
  • 55. Evolution in liver surgeryHCCResection vs TransplantationHow to recognize a high specialty center?- Preoperative planning- I.O. US- I.O. Technique- VLS approach available/ablation- P.O. fast track- High resection numbers- LT availability
  • 56. Improvement in Surgicaloutcome reflects…….evolution in anatomical knowledgeEtruscan LiverI-II century BCCouinaud’s liver segmentationXX century AC - 1957Virtual liverXXI century ACJin et al, Liver Transplantation 14:1180-1184, 2008
  • 57. Improvement in Surgicaloutcome reflects…….evolution in anatomical knowledgeEtruscan LiverI-II century BCCouinaud’s liver segmentationXX century AC - 1957Virtual liverXXI century ACJin et al, Liver Transplantation 14:1180-1184, 2008Jin et al, Liver Transplantation 14:1180-1184, 2008
  • 58. Provides essential information about:- tumor extension- vessel involvement- choice of resection plane- total liver remnant volumeImprovement in Surgicaloutcome reflects…….evolution in surgical planning
  • 59. Evolution in surgical planningU. CilloCasistica personale
  • 60. Evolution in surgical planningU. CilloCasistica personale
  • 61. Technical evolution:Intra-operative Ultrasound
  • 62. Technical evolutionIntraoperativeUltrasound (IOUS)&Contrast EnhancedUltrasound (CEUS)
  • 63. Technical evolution:Intra-operative UltrasoundU. CilloCasistica personale
  • 64. Improvement in Surgicaloutcome reflects…….evolution in surgical technologyCUSA:Cavitron UltrasonicSurgical Aspirator
  • 65. Technical evolution:CUSA dissectionU. CilloCasistica personale
  • 66. Three majorLiver Resection Schools
  • 67. Prospective - 161 patients•61 study group: underwent ERAS-protocol•100 control group: underwent traditional protocolERAS-group56/61 patients (92%) tolerated fluids within 4 hand a normal diet on day 1 after surgeryMedian hospital stay (including readmissions,)ERAS-group: 6.0 daysControl-group: 8.0 days (P < 0·001)Rates of readmissionERAS-group: 13%Control-group: 10% (P = NS)Morbidity and MortalityERAS-group: 41% and 0%Control-group: 31% and 2.0% (P = NS)The ERAS fast-track protocol is safe and effectivefor patients undergoing liver resection.Van Dam et al, British Journal of Surgery 2008; 95: 969–975
  • 68. Fattori di rischio per unadegenza complicataTotale pazienti N= 341VariabileChi-quadratoOddsratioIntervallo diconfidenza al95%pChild-Pugh B-C 4,18 2,74 1,08 7,66 0,0409Ipertensione clinicamentesignificativa6,91 2,47 1,27 4,94 0,0086BCLC B-C-D 0,32 1,21 0,63 2,34 0,5702Margini positivi 0,72 1,45 0,62 3,51 0,3971Satellitosi 1,75 3,00 0,62 3,51 0,1859Res ep magg> 2S 0,80 2,08 0,49 14,35 0,3704Durata intervento >200 min 8,87 2,64 1,40 5,05 0,0029Perdite intraop/100 3,97 1,87 1,01 3,47 0,0464RISULTATI 3
  • 69. Glasgow et al, Arch Surg 1999; 134: 30-35 Yasunaga- Hepatology Research 2012; 42: 1073–1080Improvement in Surgicaloutcome reflects...Centre Volume
  • 70. HCCResection vs TransplantationLIVERTRANSPLANTATION
  • 71. The Milan Criteria paradigm:DFS orientedSingle nodule < 5cm2 or 3 nodules < 3cmNo macroscopic vascular invasionNo metastasesMazzaferro V, et al. NEJM 1996; 334: 693
  • 72. • The Milan criteria paradigm:Sustainable?The Milan Criteria paradigm:DFS oriented
  • 73. PatientPatient Organ•8447 due to benign chronic liver disease•9725 deaths due to liver cancer •1041 Liver transplants• 6% of total deathshttp://www.istat.it/dati/dataset/20100129_00/Liver related deaths in Italy for 2007http://www.trapianti.salute.gov.it/cnt/The central axiom of LT:disparity demand/resourcesAvailable resources may potantially satisfy6% of whole demand and 20% of transplantable patients
  • 74. • The Milan criteria paradigm:Sustainable?Accurate?The Milan Criteria paradigm:DFS oriented
  • 75. FONTE DATI: Dati Reports CIRFONTE DATI: Dati Reports CIRRESOURCES: Fixed pool of donor organs
  • 76. Altekruse SF, et al. Hepatology 2011Among 21,390 HCC cases diagnosed examined during 1998-2008 there were 4,727(22%) with reported first course invasive liver surgery, local tumor destruction, or both.Incidence ratesof localized stage HCCincreased fasterthan rates of regionaland distant stage HCCcombined(8% versus 4% per year)Rising incidence of early-HCCIncreasing proportion of LT for HCCReason 2: EpidemiologicRESOURCES:Competition between different disease
  • 77. The Milan Criteria paradigm(YES or NO philosophy): DFS orientedSingle nodule < 5cm, 2 or 3nodules < 3cm, no macroscopicvascular invasion, no metastasesMazzaferro V, et al. NEJM1996; 334: 6935-yrsurvivalMultipleHCC>1cmMazzaferro. Lancet Oncol 2009Indivualized survival predictionThe Metroticket modelVascular invasionMinimum5-yrpost-LT survivalthreshold: 50%OLTxMilancriteriaUp-to-7criteriaMC are not accurate predictors ofpost-LT outcome (UTILITY)The dichotomous Milan criteria
  • 78. • Total tumor volume > 115 cm3as significant predictor of post-LT recurrence• 115 cm3= 1 nodule < 6cm, 3 < 4.2 cm, but it is not influenced by nodules < 1-2 cm• Radiologic TTV staging is more accurate than Milan and UCSF onesToso C, et al. Liver Transpl 2008; 14: 1107MC are not accurate predictors ofpost-LT outcome (UTILITY)
  • 79. Progression of Alphafetoprotein Before Liver Transplantationfor HCC in Cirrhotic Patients: A Critical FactorProgression group (26)No progression group (127)Vibert A, et al. Am J Transpl 2010; 10: 129ROLE OF DINAMIC CHANGES IN TUMOR BIOLOGYMC are not accurate predictors ofpost-LT outcome (UTILITY)
  • 80. 18F-FDG Uptake is the bestpredictor of microscopicvascular invasionKornberg A, et al. Liver Transpl 2012. In press91 patients underwent LT for HCC after PET evaluation.Patients with 18F-FDG non-avid HCC beyond the Milan criteria on clinicalstaging may achieve excellent recurrence-free long-term survival after LT.MC are not accurate predictors ofpost-LT outcome (UTILITY)
  • 81. Overall survival Disease-free survivalCillo U et al. Ann Surg 2004;239:150–159;DuBay D et al. Ann Surg. 2011;253:166–72Pre-transplant tumor biopsyPredictors of biologicaggressiveness
  • 82. Barry CT et al. Am J Transplant 2012:428–37Micro RNA Expression Profiles as Adjunctive Data to Assess the Risk of HepatocellularCarcinoma Recurrence After Liver Transplantation: a microarray study on 64 LT patientsPredictors of biologicaggressiveness
  • 83. • The Milan criteria paradigm:Sustainable?Accurate?Fair?The Milan Criteria paradigm:DFS oriented
  • 84. UrgencyUtilityOutcomewithout LTUrgencyUtilityOutcomewith OLTxUrgency UtilityNon HCC Pts (Cirrhosis)(no superior MELD limit)HCC PATIENTS(5yr surv > 70%)EquityMELD – HCC inequity
  • 85. NEEDUtilityOutcomewithout LTOutcomewith OLTxMC are not accurate predictors ofoutcome without LT (URGENCY)Available alternativetherapies??
  • 86. • 20% transplanted HCC are T1• 50% transplanted T1-T2 HCC haveMELD < 11Diffuse use of LT in pts with therapeuticalternatives (resection/ablation)Angelico M, Cillo U, et al. DLD 2011.
  • 87. OTHER EXCEPTIONSOrganized in WL according to joint clinical evaluation expressed in the weaklymultidisciplinary meeting.Modified RECIST criteriaEXCLUSION CRITERIA• Gross vascular invasionor metastases (T4b and /orN1, M1)• Poorly differentiated HCC atbiopsySECOND CRITERION = STAGEI. T1 1 nodule ≤ 1.9 cmII. T2 1 nodule 2-5 cm; 2-3 nodules all ≤ 3 cmIII. T3 1 nodule > 5 cm; 2-3 nodules 1 > 3 cmIV. T4a ≥ 4 nodules, any size;T4b any T with gross vascular invasionN1, M1 MetastasesTHIRD CRITERION = TIMEWaiting list time with HCCFIRST CRITERION = RESPONSE TO THERAPYI. Stable / Progression* = 6II. Untreatable (location, severity of cirrhosis)= 5III. Partial** = 4IV. Recurrent new tumor (> 6 mo last therapy) awaiting therapy = 3V. New tumor awaiting therapy= 2VI. Complete (total tumor necrosis)= 1* > 50% pre therapy vital tumor; ↑ n° nodules; ↓ AFP < 50% pre therapy level (if >200ng/ml)** < 50% pre therapy vital tumor; ↓ AFP > 50% pre therapy level (if > 200ng/ml)Priority in waiting list givenaccording to response to therapyCillo U, et al. Am J Transpl 2007
  • 88. Cox regression model for the progressionoutside the Milan criteria or death.De Giorgio M, et al. Liver Transplant 2010HCC persistence or recurrence after bridgingtherapy helps predicting transplant list dropout andgenerate a more equitable exception policy.HCC persistence or recurrence after bridgingtherapy helps predicting transplant list dropout andgenerate a more equitable exception policy.Response to therapy as prioritycriterionLevel of evidence 2b; Grade of reccomendation = BLevel of evidence 2b; Grade of reccomendation = B
  • 89. Freeman R, et al. Am J Transpl 2006; 6: 1416Multivariable analysis withcompeting risks showed thatMELD score and AFP, were mostinfluential in predicting dropout forHCC patients.Washburn K, et al. Am J Transpl 2010; 10: 1652Cox Model Competing risk ModelMC are not accurate predictors ofoutcome without LT (URGENCY)
  • 90. Il paziente con epatocarcinoma T1 e MELD minore di 15 nondeve essere inserito in lista per trapianto tranne che in benmotivate eccezioni (E2R1).STATEMENT 5.d12,5%12,5%75,0%D’accordoParzialmente d’accordoDisaccordo4,7%9,3%86,0%PARTECIPANTIGIURIATurin 18 October 2012
  • 91. • The Milan criteria paradigm:Sustainable?Accurate?Fair?Need for a Paradigm Shift ?The Milan Criteria paradigm:DFS oriented
  • 92. Paradigm shift?“We can’t solve problemsby using the same kind of thinkingwe used when we created them” Albert Einstein (1879-1955)Need for changesin allocationprinciples and LTendpoints
  • 93. Merion RM, et al. Transpl Int 2011; 25: 965The benefit of LT is better appreciated in terms of gain of LE(linked to recipient age and alternative treatment) than in terms of survivalBenefit and liver transplantation
  • 94. Man, 40 years old, HBV with 2 HCC nodules, the largestnodule 6 cm in size , Child B (MILAN OUT, UCSF OUT)Clinical scenario 1OLT (5 yr surv.=60%) LE=10 yrs (LDLT?)TACE (5 yr surv. = 10%) LE = 2 yrsGain in LE = 8 yrsyrs1 2 3 4 51 3 5 6 8%yrs2 4 7 9OLT (5 yr surv.=70%) LE=14 yrsResection (5 yr surv.=60%) LE = 10 yrsMan, 65 years old, HCV, with 1 HCC nodule (4 cm in size), Child AClinical scenario 2Gain in LE = 4 yrs/ 8 yrsTACE (5 yr surv. = 10%) LE = 2 yrsBalancing allocation principles:the transplant benefitThe benefit of LT is better appreciated in terms of gain of LE(linked to recipient age and alternative treatment) than in terms of survivalINDIVIDUAL BENEFIT
  • 95. 3-year (%) 5-year(%)Post-transplantation survival 79.1 70.3Post-surgical resection survival, median (range) 73 (62 to 92) 59 (51 to 80)Post-RFA survival, median (range) 69 (50 to 95) 51 (37 to 65)Survival benefit of transplantation over surgical resection,median (range) 6 (-13 to 17) 11 (-10 to 19)Survival benefit of transplantation over RFA, median(range) 10 (-16 to 29) 19 (5 to 33)3-year (%) 5-year(%)Post-transplantation survival 79.1 70.3Post-surgical resection survival, median (range) 73 (62 to 92) 59 (51 to 80)Post-RFA survival, median (range) 69 (50 to 95) 51 (37 to 65)Survival benefit of transplantation over surgical resection,median (range) 6 (-13 to 17) 11 (-10 to 19)Survival benefit of transplantation over RFA, median(range) 10 (-16 to 29) 19 (5 to 33)Ioannou G, et al. Am J Transpl 2012Liver transplantation in patients with stage II HCC and Child Acirrhosis results in a low survival benefitand may not constitute optimal use of scarce liver donor organsTransplant benefit in early HCC
  • 96. Fast track — ArticlesDOI:10.1016/S1470-2045(11)70144-9www.thelancet.com/oncologySubmitted April 19, 2011 Published Online June 17, 2011
  • 97. Unadjusted model Adjusted model11.217.724.934.611.213.517.428.5BCLC predicts the Transplant Benefit5-year transplant benefit modelMonte Carlo simulation: we obtained a list of1000 outcomes for each BCLC stageVitale A, et al. Lancet Oncol 2011
  • 98. PROPOSAL FOR GUIDELINES IMPROVEMENT 1.Milan InYes NoLiver Transplantation(CLT/LDLT)
  • 99. Tumor Liver function AlternativetherapyavailableDownstaging Bridging Priority Post-LTAASLD Milan § § - After 6mo - NoevidenceEASL Milan* § Resection No evidence After 6mo - -ESMO Milan § Resection - After mo - -Asian Milan Child CChild AB ifrecurrent HCCResection/ablation- - - -Japan Milan Child CChild AB ifrecurrent HCCResection/ablation- - - -AISF Milan** § § Yes After 6mo Responseto therapySizeAFPmTOR* Up-to-7 criteria should be validated prospectively**possibility to use expanded criteria in selected centers with well estabilished protocols§ Impaired liver function and alternative therapy only suggested in the comments/algorithm, no in reccomendationsSUMMARY OF AVAILABLE GUIDELINES FOR HCC LT
  • 100. Need for a Paradigm shift?Study period: 1998-2006Study group: 4482 HCC patients with HCC on the US - WLResults: 65% underwent LT, and 18% were dropouts.5-year intent-to-treat survival = 50%Pelletier SJ, et al. Liver Transpl 2009; 15: 85950%70%Ioannou, et al. Gastroenterology2008; 134: 1342
  • 101. Rahbari NN, et al. Ann Surg 2011Resection might compete with CLTxas first line therapy
  • 102. 0,00,10,20,30,40,50,60,70,80,91,0Survival0 12 24 36 48 60monthsBCLC 0, A1BCLC 0, A1 (85)BCLC A2, A3, A4 (152)BCLC B, C, D (104)Hazard ratio 95% ConfidenceintervalBCLC A2-A3- A4vs 0- A11,192515 0,786156 1,845475BCLC B-C-D vs A2,A3, A4 1,852244 1,300711 2,637639Need for a Paradigm shift?Intention to treat survivalHCC liver resection atPadua University-Period: 2000-2010- 342 patients with cirrhosisunderwent resection for HCC
  • 103. Koniaris LG, et al. Ann Surg 2011413 patients with HCC underwent:- Surgical resection (n = 106)- Transplantation (n = 270)or- Listed without receivingtransplantation (n = 37)Among known HCC patientswith preserved liver functionresection was associatedwith superior patient survivalversus transplantationNeed for a Paradigm shift?Intention to treat survival
  • 104. LT, ITT survivalLR for HCC with PHT5 yr surv = 56%LR for multiple HCC5 yr surv = 58%RF for unresectable HCC5 yr surv = 50%Laparoscopic RFfor HCCunsuitable for resectionor ablation5 yr surv = 40%Alternative therapies andBenefit for BCLC A2, A3, A4Livraghi T, Hepatology 2009 Cillo U, Plos One 2013Pelletier SJ, Liver Transpl 2009 Ishizawa T, et al. Gastroenterology 2008
  • 105. Milan InYes NoLiver Transplantation(CLT/LDLT)Consider ResectionConsider AblationConsider Liver TransplantConsider ResectionConsider AblationConsider Liver TransplantMultidiscipl.Setting onlyPROPOSAL FOR GUIDELINES IMPROVEMENT 2.
  • 106. Fuks et al, Hepatology 2012;55:132-140LT as second line therapy after resection
  • 107. Liver Transpl 2012LT as second line therapy after resection
  • 108. • 24 patients had undergone LT (21 for HCCrecurrence and three for liver failure).• No HCC recurrence occurred after LT.• The probability rates for 5-year overall andtumor-free survival were 74% and 69%,respectively.• Conclusions: First line RFA followed bysalvage LT allows survival figures that are atleast as good as a first-line LT, while limitingthe number of graftsRF ablation and salvage LTN’Kontchou G, et al. J Hepatol 2012LT as second line therapyafter ablation
  • 109. Milan InYes NoLiver Transplantation(CLT/LDLT)Consider ResectionConsider AblationConsider Liver TransplantConsider ResectionConsider AblationConsider Liver TransplantMultidiscipl.Setting only*Due to high benefitconsider downstagingin “early B”Due to high benefitconsider downstagingin “early B”PROPOSAL FOR GUIDELINES IMPROVEMENT 3.*including Tx specialists and considering organ availability CLT/LDLT
  • 110. STATEMENT 2.c HCC0,0%6,3%93,8%PARTECIPANTIGIURIAD’accordoParzialmente d’accordoDisaccordo0,0%12,5%87,5%Turin 18 October 2012
  • 111. Authors n Selection criteria Rec Survival* 4-yr survivalMazzaferro, NEJM 1996 48 Single < 5cm 8% 74%*3 nodules < 3cmBismuth, Semin Liver Dis 1999 45 Single< 3cm 11% 74%3 nodules < 3cmJonas, Hepatology 2001 120 Single< 5cm 16% 71%3 nodules < 3cmYao, Hepatology 2001 70 Single<6.5cm 11% 75%3 nodules < 4.5 cmTotal diameter<8cmCillo, Ann Surg 2004 48 G1-G2, no macrov.Inv. (38% Milan out) 6% 73%5-yrsurvivalMultipleHCC>1cmMazzaferro. Lancet Oncol 2009Indivualized survival predictionThe Metroticket modelVascular invasionMinimum5-yrpost-LT survivalthreshold: 50%In the Italian proposal there is no discrimination for HCC patients (futile LT = <50%5yr PT survival)= no absolute limits in size and number of nodulesTransplant benefit in intermediate HCC
  • 112. STATEMENT 3. Obiettivo: Minima soglia di sopravvivenza(Minima utilità)La soglia ad oggi accettabile di sopravvivenza stimata dopotrapianto è pari a 50% a 5 anni indipendentementedall’indicazione al trapianto di fegato (E3R2)0,0%6,7%93,3%PARTECIPANTIGIURIAD’accordoParzialmente d’accordoDisaccordo6,4%0,0%93,6%Turin 18 October 2012
  • 113. Criteria to establish a reliable selection policy:1.Defined entry criteria• Size/number or total tumour volume ofHCC• Biological/pathological and molecularmarkers1.Defined end-points of successful downstaging• Radiological• Degree of necrosis• Decrease in size• Biological: alpha-fetoprotein (AFP)1.Defined time between downstaging and listingfor LTToso C et al, J. Of Hepatology, 2010 vol.52; 930-936
  • 114. Successful downstaging ofHCC to within the Milancriteria is feasible in aproportionof patients. Absolute anddisease-free survival ratesin patients transplantedfollowing downstaging arecomparable to those inpatients within the Milancriteria.Systematic review of downstaging HCCbefore LT in patients outside the Milan crit.Downstaging for HCC beyond MCA. N. Gordon-Weeks, et al. Br J Surg 2011
  • 115. Ravaioli et al, American Journal of Transplantation 2008; 8: 2547–2557
  • 116. Ravaioli et al, American Journal of Transplantation 2008; 8: 2547–2557
  • 117. From 2003 to 2006177 HCC patients outside conventional criteria:• single HCC 5–6 cm• 2 HCCs ≤ 5 cm• < 6 HCCs ≤ 4 cm (sum diameter ≤ 12 cm)Within Milan criteria after down-stagingTransplantation rate:68% Milan-in HCC patients67% Downstaged HCC patients1 Year Disease Free Survival80% in Milan-in HCC patients78% in Downstaged HCC patients3 Years Disease Free Survival71% in Milan-in HCC patients71% in Downstaged HCC patientsActuarial intention-to-treat survival62.8% in Milan-in HCC patients56.3% in Downstaged HCC patientsRavaioli et al, American Journal of Transplantation 2008; 8: 2547–2557Patient survival after liver transplantation;CC: conventional criteria, BCDS: downstaged patientsIntention-to-treatsurvivalP=NS
  • 118. L’HCC oltre T2 dovrebbe essere rivalutato per indicazione epriorità al trapianto considerando le strategie di downstagingnell’ambito di protocolli dichiarati (E2 R2).STATEMENT 5.f0,0%6,7%93,3%D’accordoParzialmente d’accordoDisaccordo0,0%4,3%95,7%PARTECIPANTIGIURIATurin 18 October 2012
  • 119. c-KITSCFCellmembraneIGF1IGF2RASRAFAktPTENIGFBP3PROLIFERATIONCELL SURVIVALSorafenibGefitinibErlotinibERKPROTEINTRANSLATIONCetuximabMdm2 FKHR BADSunitinibSorafenibBevacizumabTargeted therapiesin phase II or III inHCCEverolimusRapamycinTargeted therapiesunder preclinicalevalutionAEE788mTORPI3KXL-765LapatinibHer2/neuMEKIGFRXL-228EGFEGFRVEGFVEGFRPDGFPDGFRMolecular targeted therapies and HCC
  • 120. “The central focus must beon increasing value for patients— the health outcomes achieved per dollar spent.Good outcomes that are achieved efficiently are the goal,not the false “savings” from cost shiftingnd restricted services”.From a “COST SHIFTING” systemToa “VALUE – BASED SYSTEM”From a “COST SHIFTING” systemToa “VALUE – BASED SYSTEM”A Strategy for Health Care Reform- Toward a Value-Based SystemPorter ME. N Engl J Med 2009; 361: 109-112
  • 121. P4P“Pay For Performance”The health caresystem tends to pay for quantity ofservices not quality. Experts haverecommended that hospitals anddoctors be paid based on deliveringhighquality care, or what is called "pay forperformance." The President’sBudget will link a portion of Medicarepayments for acute in-patient hospitalservices to hospitals’ performance onspecific quality measures. Thisprogram will improve the quality ofcare delivered to Medicarebeneficiaries,and the higher quality will save over$12 billion over 10 years.http://www.whitehouse.gov/omb/fy2010_key_healthcare/
  • 122. HCC: Resection vs. TransplantationSummary of surgical therapiesTumor/PatientCharacteristicsConsider 2° line TherapySingle HCC• > 2 cm any size• CPT-A-BRESECTION(OLTx-LDLT?)OLTxMultiple HCC•Portal Hypertension•HyperbilirubinemiaOLTx (LDLT)RESECTIONABLATIONBCLC-BDOWNSTAGING(RESECTION/ABLATION/TACE)and OLTxBCLC-CType 1-2RESECTIONBCLC-D • Milan in OLTx -
  • 123. • M ultidisciplinarietà• A lta specialità• N umerosità di casi assistiti• T rapianto• R ete gestionale• A llocazione equa delle risorse (con rispetto dellegerarchie terapeutiche: trattamenti potenzialmente radicali>altro)TERAPIA CHIRURGICADELL’HCC 2012
  • 124. Liang W et al, Liver Transplantation 2012, in pressMeta-analysisRecurrence Rate
  • 125. DonorharmRecipientTx benefitWaiting Listbenefit/harmThe Ethical Dimensions of Equipoise in LDLTLee HS. Dig Dis 2007; 25: 296 Miller C. Transpl Rev 2008; 22: 206RECIPIENT TX BENEFIT > (DONOR HARM + WL HARM)LDLTRecipientTx benefitCadaveric LTWaiting Listbenefit/harm
  • 126. Bhangui P, et al. Hepatology 2011; 53: 1579Recipient benefitLDLT for patients more in need(high transplant benefit)Cohort study on 183 consecutive HCC patients undergoing LDLT (36) orDDLT (147): INTENTION TO TREAT ANALYSISLDLT had a trend for lower post-LT outcome (selectionbias)but a lower dropout rates than DLDT (0% vs. 18%)HCCPATIENTS
  • 127. Within MC Beyond MCMizuno S, et al. Transplantation 2010; 89: 650Prospective comparison of the survival rates between HCC patients whounderwent LDLT (n=29) and those who did not undergo LDLT (n=27).*Period necessary todevelop macrovascularinvasion or metastases*Period necessary todevelop macrovascularinvasion or metastases*Recipient benefitLDLT for patients more in need(high transplant benefit) HCCPATIENTS
  • 128. Liang W et al, Liver Transplantation 2012, in pressLDLT represents an acceptable optionwhen compared to DDLT for HCC patientsespecially those within Milan criteriaComparative studies of LDLT vs. DDLT for HCC7 studies (1310 participants)Patient survival: COMPARABLE•1-year: OR = 1.03 (95% CI = 0.62-1.73)•3-years: OR = 1.07 (95% CI = 0.77-1.48)•5-years: OR = 0.64, (95% CI = 0.33-1.24)Recurrence-free survival: COMPARABLE•1-year: OR = 0.86 (95% CI = 0.54-1.38)•3-years: OR = 1.04 (95% CI = 0.69-1.58)•5-years: OR = 1.11 (95% CI = 0.70-1.77)Recurrence-rates: NO SIGNIFICANT DIFFERENCES•1-year: OR = 1.55, (95% CI 0.36-6.58)•3-years: OR = 2.57 (95% CI 0.53-12.41)•5-years: OR = 1.21, 95% CI 0.44-3.32).Subgroup analysis: similar outcomesfor patients with HCC meeting Milan criteria
  • 129. Meta-analysisPatient survivalLiang W et al, Liver Transplantation 2012, in press
  • 130. Liang W et al, Liver Transplantation 2012, in pressMeta-analysisRecurrence freesurvival
  • 131. Grant et al, Liver Transplantation, Vol 17, No 10, Suppl 2 (October), 2011: pp S133-S138Theoretical reasons for the potential higherrates of HCC recurrence after LDLT:•Stimulation of residual cancer cells by GF inthe regenerating liver•Relatively brief waiting time for LDLT (LT forpatients whit aggressive or rapidly progressiveHCC•More limited oncological clearance with theIVC–sparing technique•Presence of programmatic biases:Centers unknowingly offer LDLT to patientswith a higher risk of HCC recurrence.Is it ehical to offer a potentially riskyprocedures to a potentialLow transplant benefit population?In selected conditions yesbut still waiting for evidences
  • 132. Anti-IL-2RαMMFAZASIR-EVRTACCsAmAbspAbsSTERHalloran et al, NEJM 2004; 351: 2715Molecular targets of IS
  • 133. mTORi-based IS may be associatedwith increased survival afterliver transplant for HCCMultivariate analysis of a registry population of adult liver transplant recipientsResults corrected for MELD, year of transplant, primary liver disease (non HCC),age at transplant and, when applicable, TTV, AFP and pre-transplant HCC treatmentToso C et al.Hepatology 2010;51:1237–43
  • 134. Possible mechanisms:1. Inhibit mTOR which is the downstreameffector of PI3k/Akt pathway, which canserve as an oncogenic event whenoveractive1. Delay cancer progression by anti-angiogenesis1. Disregulate the oxygen supply to cancercellsAnti-neoplastic effectsof mTORiGuba M et al. Nat Med 2002;8:128–35;Lang SA et al. Int J Cancer 2007;120:1803–10;Lang SA et al. Hepatology 2009;49:523–32;Cohen A, Hall MN. Cell 2009;136:399–400;Nicklin P et al. Cell 2009;136:521–34;Rao RR et al. Immunity 2010;32:67–78;Koehl GE et al. Transplant Rev 2005;19:20–31
  • 135. mTOR has been implicatedin cancer progression in HCC40–50% of patients with HCC demonstrate mTOR activationmTOR activation (indicated by pRPS6 staining)associated with recurrence in surgically resected patientsTrieber G. Expert Rev Anticancer Ther 2009;9:247–61;Villanueva A et al. Gastroenterology 2008;135:1972–83
  • 136. mTORi mediated growth inhibitionof HCC cells: preclinical dataTumour volume and mice survival in xenografts treated with EGFRi and everolimusVillanueva A et al. Gastroenterology 2008;135:1972–83;Schumacher G et al. World J Gastroenterol 2005;11:1420–5
  • 137. Menon et al, Aliment Pharmacol Ther 2013; 37: 411–419Recurrence rateSRL group (4.9–12.9%) < CNIs (17.3–38.7%)RFS SIR RFS CNI93–96% 1 year 70–78%82–86% 3 years 64–65%79–80% 5-years 54–60%OS SIR OS CNI94–95% 1 year 79–83%85% 3 years 66%80% 5-years 59–62%In the Sirolimus-group:1. Lower recurrence (OR = 0.30, 95% CI = 0.16–0.55, P < 0.001)1. Lower recurrence-related mortality (OR = 0.29, 95% CI = 0.12–0.70, P = 0.005)1. Lower overall mortality (OR = 0.35, 95% CI = 0.20–0.61, P < 0.001)