Ablazione chirurgica e trapianto

Transcription

1 Unità di Chirurgia Epatobiliare e Trapianto Epatico Azienda Università di Padova Personalizzazione dell indicazione terapeutica Ablazione chirurgica e trapianto Prof. Umberto Cillo cillo@unipd.it

2 Umberto Cillo Unitàdi Chirurgia Epatobiliare e Trapianto di Fegato Università di Padova Il sottoscritto dichiara di aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione con: Novartis e Astellas Italia Spa e che la presentazione NON contiene discussione di farmaci in studio o ad uso off-label

3 INDIVIDUAL DECISION MAKING PROCESS FOR SURGICAL APPROACH TO HCC PATIENTS Guidelines are detached from clinical reality Individual prognosis as tool in therapy decision making Therapeutic hierarchy: the terapeutic benefit Multidisciplinarity to identify the best terapeutic benefit in complex systems

4 Guidelines are detached from clinical reality 1034 (50%) patients undergoing liver resection in this series were found to be at a stage in which the EASL/AASLD recommendations would consider them unsuitable for hepatectomy (Ann of Surgery 2013). More than 800 patients underwent laparoscopic liver resection in Italy in the last 5 yrs (not included in EASL guidelines) An increasing number of centers routinely adopt VLS ablation (not included in EASL gudelines) Increasing number of Centers worldwide include T3 HCC patients in transplant lists

5 Guidelines and yes/no algorithm in decision making processes in HCC AASLD, EASL, ESMO 2012 GUIDELINES

6 Caso clinico Stadiazione TUMORE: HCC singolo, diametro 2 cm. FUNZIONE EPATICA: Cirrosi ben compensata, Child A, Ipertensione portale clinicamente significativa II CONDIZIONI GENERALI DEL PAZIENTE: buone condizioni generali (PST=0). 69 anni. Coledoco litiasi recidivante

7 Caso clinico Morfologia Fase arteriosa Fase tardiva

8 Caso clinico: scelta terapeutica AASLD, EASL, ESMO GUIDELINES

9 Caso clinico: scelta terapeutica AASLD, EASL, ESMO GUIDELINES

10 Caso clinico: scelta terapeutica AASLD, EASL, ESMO GUIDELINES

11 Caso clinico: scelta terapeutica Sede/ Tecnica AASLD, EASL, ESMO GUIDELINES

12 Caso clinico: scelta terapeutica Sede/ Tecnica Sede/ Tecnica AASLD, EASL, ESMO GUIDELINES

13 INDIVIDUAL DECISION MAKING PROCESS FOR SURGICAL APPROACH TO HCC PATIENTS Guidelines are detached from clinical reality Individual prognosis as key tool in therapy decision making Therapeutic hierarchy: the terapeutic benefit Multidisciplinarity to identify the best terapeutic benefit in complex systems

14 Balancing the weight of different prognosticators EASL 2000 EASL 2011 There are 4 main factors affecting HCC prognosis Tumour burden Liver function Health status Treatment intervention There are 3 main factors affecting HCC prognosis Tumour burden Liver function Health status Patient ECOG PS Therapy CURE Child- Pugh BCLC 4 CUPI 5 GRETCH 6 Okuda 7 CLIP 8 JIS 9 TNM 1)Tumour burden 2)Liver function 3)Health status 4)Treatment intervention 5)Treatment availability 6)Potential for 2 nd 3 rd line Liver Tumor

15 HCC: Resectability Liver function Tumor extension Location Functional reserve Extension of hepatectomy for oncolgical radicality

16 Technical feasibility for surgery Selection of HCC patients for resection is based on planned extension of hepatectomy and liver functional reserve Cescon M, et al. Arch Surg

17 Prognostic staging of HCC RESECTION Overall survival of the 152 patients subdivided according to the absence (continuous line) or presence (dashed line) of clinically significant portal hypertension. Giannini EG, et al. Liver Int 2013 Cucchetti et al, Ann Surg 2009;250:

18 126 Multiple HCC vs 308 single HCC undergoing to resection Child A patients 5-yr survival Multiple 58% Single 68% Multiple tumors are not a contraindication to liver resection Ishizawa T, et al. Gastroenterology 2008; 134: 1908

19 The T category of LCSGJ is determined on the basis of the number, size, and vascular or bile duct invasion. All multiple tu- mors, including multicentric tumors and intrahepatic metastatic tumors, are equally counted. Number of liver nodules Maximum diameter of liver nodules Location of portal invasion Kaplan-Meier survival analysis (solid line) with 95% confidence interval (dotted line) for patients in the curative-hepatectomy- N0M0 cohort stratified according to the num- ber of liver nodules (a), the maximum diame- ter of liver nodules (b), and the location of portal invasion (c). The number, median sur- vival time (95% CI), and 5-year survival rate of patients are described in Table 4 Minagawa et al, Annals of Surgery Volume 245, Number 6, June 2007

20 Minagawa et al, Annals of Surgery Volume 245, Number 6, June 2007

21 Minagawa et al, Annals of Surgery Volume 245, Number 6, June 2007

22 Kaplan-Meier survival analysis (solid line) with 95% confidence interval (dotted line) for patients in the curative-hepatectomy- N0M0 cohort Minagawa et al, Annals of Surgery Volume 245, Number 6, June 2007

23 Tumor Thrombectomy Several papers on resection of BCLC C tumors AUTHOR, YEAR N OF PATIENTS Survival Kumada K, Median: 12months Wu CC, yr: 28% Minagawa M, yr: 42% Pawlik TM, yr: 10% Median: 11months In selected cases with tumor thrombus 5yr: (child 13% A, Le Treut YP, PST=0, no main trunc) surgery is an Median: INDICATION 9 months Ikai I, 2006 (sorafenib as only 78 alternative) 3yr: 22% Median: 9 months Chen XP, yr: 18% Minagawa M, yr: 20-40% Liang LJ, Median=11months Inoue Y, yr: 40% Kondo K, yr: 30% Ban D, yr: 21%

24 Technical feasibility for surgery RESECTION SCORE : MULTIVARIATE LOGISTIC REGRESSION PRIMARY ENDPOINT: Irreversible postoperative liver failure (IPLF = death or LT due to liver decompensation within 6 months) Term Estimate Prob>ChiSq Odds Ratio Odds Lower Odds Upper Na+ 0, ,9515 1, , , CHILD CLASS B 0, ,1082 2, , , CRPH 0, ,6041 1, , , Other vs anterior 1, ,0116 3, , , MELD 9-10 vs MELD < 9 2, ,0024 8, , , MELD >10 vs MELD , ,4723 1, , , AFP vs <100 0, ,0710 2, , , AFP >1000 vs , ,1197 2, , , TUMOR VARIABLE 1, ,0139 3, , , TUMOR VARIABLE = largest diameter (cm) + nodule number index* (1 for single, 2 for 2-3 nodules, 5 for > 3 nodules) CRPH = clinically relevant portal hypertension *Nodule number index is thought to overcome problems of preoperative imaging in staging coorectly number of nodules

25 Technical feasibility for surgery PRIMARY ENDPOINT: Irreversible postoperative liver failure (IPLF = death or LT due to liver decompensation within 6 months) A resection score > 5 means high risk of IPLF (> 10%) RESECTION SCORE (derived from estimate x 1,5) IPLF risk 0,7 0,6 0,5 0,4 0,3 0,2 0, RESECTION SCORE LOCATION AFP TUMOR VARIABLE > 7 Anterior Other >1000 No Yes MELD < >

26 Technical feasibility for surgery PRIMARY ENDPOINT: Irreversible postoperative liver failure (IPLF = death or LT due to liver decompensation within 6 months) True Positive Sensitivity 1,00 0,90 0,80 0,70 0,60 0,50 0,40 0,30 0,20 0,10 0,00 0,00 0,20 0,40 0,60 0,80 1,00 1-Specificity False Positive Area Under Curve =

27 Technical feasibility for surgery Resection Score : Impact of Long Term survival Survival 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 BCLC A patients (n=280) P= Months Survival 1,0 0,9 0,8 0,7 0,6 0,5 0,4 BCLC B-C patients (n=119) 0,3 0,2 P= ,1 0, Months Resection score 5 (n=218) Median survival = 67 months Resection score 5 (n=82) Median survival = 42 months Resection score > 5 (n=62) Median survival = 34 months Resection score > 5 (n=37) Median survival = 10 months

28 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-A BCLC B BCLC C 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%

29 2046 consecutive patients resected for HCC (10 centers) BCLC-0/A: 1012 patients Resection (50%) is in current practice widely applied BCLC-B: 737 among patients patients (36%) with multinodular, large, and macrovascular invasive HCC BCLC-C: 297 patients (14%) with acceptable short- and long-term results and justifying an update of the EASL/AASLD therapeutic guidelines in this sense BCLC 0-A BCLC B BCLC C Disease 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%

30 The impact of multinodularity on HCC outcomes. Patients with multiple neoplasms at the time of surgery had a lesser overall survival rate and greater recurrence rate Chang WT, et al. Surgery 2012;152:809-20

31 SR- Median survival: 11 months Supportive-care- Median survival : 3.9 months (HR, 0.45; 95% CI, p < 0.001) Patients who underwent surgical resection had the longest survival compared to patients undergoing other treatments (33.4 months versus 8.1 months, p < 0.001). Wang et al, Digestive and Liver Disease 45 (2013)

32 Individual prognosis in transplantation by MELD: In cirrhosis, preolt death prediction and benefit Schaubel DE. Am J Transpl 2009; 9: 970

33 The Milan Criteria paradigm: a de-personalized approach - DICOTOMIC STRATIFICATION: YES/NO - NO PREDICTION ON DROPOUT RISK (ITT surv) - NO EVALUATION OF NEED (URGENCY) - NO CONSIDERATION OF ALTERNATIVE THERAPY (BENEFIT) Mazzaferro V, et al. NEJM 1996; 334: 693

34 MC are not accurate predictors of post-lt outcome (UTILITY) The dichotomous Milan criteria The The Milan Metroticket Criteria model paradigm (YES or NO philosophy): DFS oriented Indivualized survival prediction 0.8 Multiple HCC > 1 cm N. Noduli Minimum 5-yr post-lt survival threshold: 50% 0.75 Up-to-7 criteria 0.70 OLTx Milan criteria Vascular invasion Dimensioni mm 0.40 Single nodule < 5cm, 20.6 or 3 nodules < 3cm, no macroscopic 0.5 vascular invasion, no metastases Mazzaferro V, et al. NEJM ; 334: Mazzaferro. Lancet Oncol yr survival

35 Benefit and liver transplantation The benefit of LT is better appreciated in terms of gain of LE (linked to recipient age and alternative treatment) than in terms of survival Merion RM, et al. Transpl Int 2011; 25: 965

36 Prognostic staging of HCC TRANSPLANTATION 5-year transplant benefit model Monte Carlo simulation: we obtained a list of 1000 outcomes for each BCLC stage Adjusted model 28.5 LT AS FIRST LINE THERAPY FOR CHILD C HCC PATIENTS Vitale A, et al. Lancet Oncol 2011

37 Balancing allocation principles: the transplant benefit INDIVIDUAL BENEFIT The benefit of LT is better appreciated in terms of gain of LE (linked to recipient age and alternative treatment) than in terms of survival Clinical scenario 2 Clinical scenario 1 % Man, Man, years years old, old, HCV, HBV with with 2 1 HCC HCC nodules, nodule the (4 largest cm in size), Child A nodule 6 cm in size, Child B (MILAN OUT, UCSF OUT) OLT (5 OLT yr surv.=60%) (5 yr surv.=70%) LE=10 yrs LE=14 (LDLT?) yrs Resection (5 yr surv.=60%) LE = 10 yrs TACE (5 yr surv. = 10%) LE = 2 yrs TACE (5 yr surv. = 10%) LE = 2 yrs Gain in Gain LE = 8 in yrs LE = 4 yrs/ 8 yrs yrs yrs

38 Availability of surgical therapies LT as second line therapy in HCC with well compensated cirrhosis DOWNSTAGING Gordon Yao Weeks FY, et AN, al. Hepatology et al. Br J Surg 2008; 2011; 48: : 1201

39 PROPOSAL FOR GUIDELINES IMPROVEMENT 1. Milan In Yes No Liver Transplantation (CLT/LDLT)

40 Prognostic staging of HCC TRANSPLANTATION Bolondi, et al. Semin Liver Dis 2012;32:

41 PROPOSAL FOR GUIDELINES IMPROVEMENT 3. Milan In Due to high benefit consider downstaging in early B Yes No Liver Transplantation (CLT/LDLT) Consider Resection Consider Ablation Consider Liver Transplant Multidiscipl. Setting only* *including Tx specialists and considering organ availability CLT/LDLT

42 INDIVIDUAL DECISION MAKING PROCESS FOR SURGICAL APPROACH TO HCC PATIENTS Guidelines are detached from clinical reality Individual prognosis as key tool in therapy decision making Therapeutic hierarchy: the therapeutic benefit Multidisciplinarity to identify the best terapeutic benefit in complex systems

43 Alternative therapies and Benefit for BCLC A2, A3, A4 LT, ITT survival LR for HCC with PHT 5 yr surv = 56% LR for multiple HCC 5 yr surv = 58% Pelletier SJ, Liver Transpl 2009 Ishizawa T, et al. Gastroenterology 2008 Laparoscopic RF for HCC unsuitable for resection or ablation 5 yr surv = 40% RF for unresectable HCC 5 yr surv = 50% Livraghi T, Hepatology 2009 Cillo U, Plos One 2013

44 The Ethical Dimensions of Equipoise in LDLT LDLT Recipient Tx benefit Cadaveric LT Recipient Tx benefit Donor harm Waiting List benefit/harm Waiting List benefit/harm RECIPIENT TX BENEFIT > (DONOR HARM + WL HARM) Lee HS. Dig Dis 2007; 25: 296 Miller C. Transpl Rev 2008; 22: 206

45 Scoring systems according to life - expectancy stages The 4 EASL-AASLD variables (tumor, liver function, PST, specific therapy) are combined to give an estimation of life expectancy >8.6 yrs Very early yrs Early yrs Intermediate yrs Advanced Resection /ablation? (T1, CTP A, PST 0) Resection (T1-2, CTP A, PST 0) Resection (T3, CTP A-B, PST 0-1) Resection (T4, CTP A-B, PST 0-1) Ablation (T1, CTP A, PST 0) Ablation+TACE (T2, CTP A, PST 0) Ablation (T2, CTP A-B, PST 0) Ablation (T3, CTP A-B, PST 0) LT (T1-2, all CTP/PST) LT (T2, all CTP/PST) LT, TACE (T3, T4a, CTP A, PST 0) TACE (T2-3, CTP A-B, PST 1) <4.6 yrs End-stage TACE (T4a, CTP A-B, PST 1) Sorafenib LT (BCLC-D) BSC (T4a, CTP A-B, PST 1-2) (BCLC C-D)

46 Availability of surgical therapies Availability of LT at hospital increases its use for HCC patients Nathan H, et al. Ann Surg Oncol 2013

47 Unadjusted survival benefit of liver resection 4713 HCC patients from Italy and Taiwan. Period Exclusion criteria: LT and child C R LR R BSC LR BCLC 0 (n=387) p= BCLC A (n=1570) p< BSC R R BCLC B (n=812) p< BSC LR BCLC C (n=1941) p< LR BSC R = resection LR = non surgical loco-regional therapies BSC = systemic therapy or best supportive care

48 Model BCLC stage Therapy HR (95% CI) P value Covariates Unadjusted 0 R=72 A R=614 B R=209 C R=444 + Patient 0 R=72 + Patient +Liver function +Patient +Liver function +Tumor Adjusted survival benefit of liver resection A R=614 B R=209 C R=444 0 R=72 A R=614 B R=209 C R=444 0 R=72 A R=614 B R=209 C R=444 LR = 286 BSC = 29 LR = 852 BSC = 104 LR = 467 BSC = 138 LR = 801 BSC = 696 LR = 286 BSC = 29 LR = 852 BSC = 104 LR = 467 BSC = 138 LR = 801 BSC = 696 LR = 286 BSC = 29 LR = 852 BSC = 104 LR = 467 BSC = 138 LR = 801 BSC = 696 LR = 286 BSC = 29 LR = 852 BSC = 104 LR = 467 BSC = 138 LR = 801 BSC = ( ) 0.27 ( ) 0.64 ( ) 0.33 ( ) 0.71 ( ) 0.25 ( ) 0.62 ( ) 0.22 ( ) 0.70 ( ) 0.38 ( ) 0.68 ( ) 0.47 ( ) 0.69 ( ) 0.31 ( ) 0.63 ( ) 0.24 ( ) 0.78 ( ) 0.50 ( ) 0.75 ( ) 0.57 ( ) 0.66 ( ) 0.30 ( ) 0.67 ( ) 0.26 ( ) 0.67 ( ) 0.51 ( ) 0.69 ( ) 0.53 ( ) 0.63 ( ) 0.31 ( ) 0.54 ( ) 0.29 ( ) < < < < < < < < < < < < < < < < Age Nationality Age Nationality Child class CRPH Age Nationality Child class CRPH AFP N of nodules Diameter R = resection LR = non surgical loco-regional therapies BSC = systemic therapy or best supportive care

49 Therapeutic hierarchy Treatment related prognosis Patient (Tumor stage, liver function, general conditions) Scoring system according to life expectancy-stages Treatment specific prognostic scores LT Resection Ablation TACE New therapies (Sorafenib) BSC Life expectancy Life expectancy Life expectancy Life expectancy Life expectancy Life expectancy Choose the best feasible treatment

50 INDIVIDUAL DECISION MAKING PROCESS FOR SURGICAL APPROACH TO HCC PATIENTS Guidelines are detached from clinical reality Individual prognosis as key tool in therapy decision making Therapeutic hierarchy: the terapeutic benefit Expert multidisciplinarity to identify the best terapeutic benefit in complex systems

51 Levels of evidence 2b - 4 N pz Morbidity (%) Mortality (%) Survival 1yr (%) RF Cillo, (2013) Karabulut, Simo, Asahina, Santambrogio, 2009 Technical feasibility for surgery Eisele, Ballem, MW Hsieh, Seki, Kawamoto, Simo, Survival - 3yr (%) In non-resectable Buell, cases 13 where RFTA 2.1 is not feasible (due to insufficient Berber, 2007US visibility or proximity 1.83 to hollow 86 organs 43 or coagulopathy), video-laparoscopic RFTA, performed in expert centres should be considered (5-D) AISF position paper. DLD 2013.

52 Technical feasibility for surgery Period patients LAPAROSCOPIC ABLATION for HCC pts unsuitable for resection or percutaneous ablation PATIENTS CHARACTERISTICS Age (years) 62 (34-84) Males 143 (85%) HCV 72 (43%) Clinically relevant portal hypertension 121 (72%) Child-Pugh B 57 (34%) MELD 10 (6-21) New-onset HCC 103 (61%) α-fetoprotein (µg/l) α-fetoprotein > 400 µg/l 23 ( ) 17 (10%) Diameter of the largest nodule (mm) 25 (10-68) Number 1 85 (50%) (36%) >3 23 (14%) BCLC 0 6 (3%) A1 17 (10%) A2 7 (4%) A3 45 (27%) A4 37 (22%) B 57 (34%) Ablation procedure tot. 169 RF 103 (61%) Alcohol 58 (34%) MW 8 (5%) Transplantation as 2 nd line therapy 33 (20%) Cillo U. PLOS One 2013

53 Technical feasibility for surgery LAPAROSCOPIC ABLATION for HCC pts unsuitable for resection or percutaneous ablation periop. Mortality 0% p.o. complications 24% median hospital stay 3 days BCLC A BCLC (p =0,0822) BCLC B Transplant (33) No transplant (136) OLTx (p =0,0001) Cillo U. PLOS One 2013

54 Technical feasibility for surgery MW LAPAROSCOPIC ABLATION NO-MATCHED MATCHED (propensity score) Cillo U et al. EJSO submitted

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61 Alternative therapies general perspective AASLD, EASL, ESMO GUIDELINES AISF expert panel points out that BCLC treatment allocation should be considered as a general frame indicating the most beneficial treatment option for most patients included in each stage of the disease according to available trials. The definitive therapeutic choice should be personalised at the individual level, taking into account several clinical variables and regional organisational settings that may lead to combined/sequential treatments (5-D). DLD 2013 Key role of multidisciplinar clinical judgment