16 th AISF Pre-Meeting Roma, 19 Febbraio 2014

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1 16 th AISF Pre-Meeting Roma, 19 Febbraio 2014 Session II Clinical Management of patients while in waiting list Treatment and down-staging procedures for HCC Prof. Umberto Cillo MD, FEBS Chirurgia Epatobiliare e Centro Trapianto di Fegato Azienda Ospedaliera Policlinico Padova cillo@unipd.it

2 Turin October 2012 Palermo June 2013 AISF-SITO STATEMENT 1. Best utility Indicator (ENDPOINT) Five year ITT patient survival has to be preferred to absolute survival for all ESLD patients with or without HCC, since ITT analysis is able to capture the entire therapeutic process that includes liver transplantation (E2 R1)

3 Rationale for treating patients in the waiting list: BRIDGING DROPOUT RISK ranging from 15 to 30% at 1 year from listing Yao, Hepatol. 2001, 33: 1394, Llovet, Hepatol:1999, 30:1434, Washburn; Am J Tr, 2010, 10: 1643, Freeman, Am J Tr 2008, 8:958 Rene Cuore Fegato DROPOUT RISK in the Nitp Area: Courtesy of Tullia De Feo, NITp (<15%) Pancreas Polmone Intestino 2 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Trapiantati (cad+viv) Usciti Deceduti Ancora in lista

4 Turin October 2012 Palermo June 2013 AISF-SITO STATEMENT 7a. Benefit as indicator (ENDPOINT) 5-year transplant benefit is the best indicator available to maximize the life saving efficiency of procured livers (E2, R2)..

5 Rationale for reducing the tumor bulk before listing: DOWNSTAGING (p=0.2 Gain in life expectancy with transplant (months) Vitale A, et al. Lancet Oncol 2011

6 PROPOSAL FOR GUIDELINES IMPROVEMENT 2 Milan In Due tohigh benefit consider downstaging in early B Yes No Liver Transplantation (CLT/LDLT) *including Tx specialists and considering organ availability CLT/LDLT

7 HCC & Tumor Bulk DOWNSTAGING the aim or the result of a treatment that intends to facilitate make possible a surgical procedure otherwise too risky or unfeasible NEO-ADJUVANT TREATMENTS to improve long-term results The aims are to limit complications during waiting-time given to patients in whom the procedure can be done primarily Toso C et al, J. Of Hepatology, 2010 vol.52;

8 AIMS of treating patients before transplant (Downstaging and/or Bridging) 1. Giving a potentially radical chance of therapy to those with poor therapeutic alternatives(downstaging) 2. Controlling HCC progression (Downstaging/ Bridging) 3. Selecting patients with favourable biology(through time and/or therapeutic pressure (Downstaging/ Bridging) 4. Helping balance in prioritization

9 AIMS of treating patients before transplant (Downstaging and/or Bridging) 1. Giving a potentially radical chance of therapy to those with poor therapeutic alternatives(downstaging) 2. Controlling HCC progression (Downstaging/ Bridging) 1. Selectingpatientswith favourablebiology(throughtime and/or therapeuticpressure (Downstaging/ Bridging) 1. Helping balance in prioritization

10 Criteria to establish a reliable selection policy: 1.Defined entry criteria Size/number or total tumour volume of HCC Biological/pathological and molecular markers 1.Defined end-points of successful downstaging Radiological Degree of necrosis Decrease in size Biological: alpha-fetoprotein (AFP) 1.Defined time between downstaging and listing for LT Toso C et al, J. Of Hepatology, 2010 vol.52;

11 Successful downstaging of Milan-in HCC is feasible in a proportion of patients OS and DFS in patients transplanted following downstaging are comparable to those in patients Milan-in A. N. Gordon-Weeks, et al. Br J Surg 2011

12 Summary of the intention-to-treat outcome of 61 patients undergoing down-staging of HCC Prospective study January 2002 January patients exceeding T2 Eligibility criteria: One lesion>5 cm and up to 8 cm Two to three lesions with at least one lesion>3 cm and not exceeding 5 cm, with total tumor diameter up to 8 cm Four to five lesions with none >3 cm, with total tumor diameter up to 8 cm. Minimum observation period: 3 months after down-staging before OLT 57.4% received OLT (2 LDLT) LOW CORRELATION RADIOLOGY/EXPLANT (<60%) Yao F.Y. et al. Hepatology, Vol. 48, No. 3, 2008

13 No HCC recurrence after 25 months (median) DS-date The Kaplan-Meier intention-to-treat survival: 1-year after down-staging: 87.5% 4-year after down-staging: 69.3% The Kaplan-Meier probabilities of treatment failure (including death without OLT or dropout ) 32% at 2 years and beyond LT-date The only factor predicting treatment failure was pre-treatment alpha-fetoprotein >1,000 ng/ml HR 7.75 ( ) P < The Kaplan-Meier post-transplantation survival rates: (of downstaged patients) 1-year after OLTx: 96.2% 4-year after OLTx: 92.1% Yao F.Y. et al. Hepatology, Vol. 48, No. 3, 2008

14 Ravaioli et al, American Journal of Transplantation 2008; 8:

15 From 2003 to HCC patients, 48 outside CC: Median FU 24 mo Patient survival after liver transplantation; CC: conventional criteria, BCDS: downstaged patients single HCC 5 6 cm 2 HCCs 5 cm < 6 HCCs 4 cm (sum diameter 12 cm) Within Milan criteria after down-staging, 3 mo STABLE DISEASE, Alfa FP<400 Transplantation rate: 68% Milan-in HCC patients 67% Downstaged HCC patients 1 Year Disease Free Survival 80% in Milan-in HCC patients 78% in Downstaged HCC patients 3 Years Disease Free Survival 71% in Milan-in HCC patients 71% in Downstaged HCC patients Intention-to-treat survival P=NS Actuarial intention-to-treat survival 62.8% in Milan-in HCC patients 56.3% in Downstaged HCC patients Ravaioli et al, American Journal of Transplantation 2008; 8:

16 27% tumor progression vs 11% CC 50% UNDERSTAGE vs 26% CC Recurr 18.8% AFP<30: 6.7% Ravaioli et al, American Journal of Transplantation 2008; 8:

17 July 2001 January patients 58 initially Milan-out Milan-in and Milan-out group showed similar tumor characteristics Downstaged Milan-out group had better tumor histopathologic grading (P=0.027) Successful downstaging therapies can provide a comparable post-lt overall and tumor-free survival Better tumor grading in DST patients Overall Survival (P=0.540) Milan-in 1-yr: 91.4% 1-yr: 92% 3-yr: 82.8% 3-yr: 85.7% 5-yr: 70.7% 5-yr: 74.1% (median post-lt follow-up 35 months) Tumor-free survival not statistically significant (P=0.667) Lei et al, J Gastrointest Surg (2013) 17:

18 HCC-patients initially exceeding MC TACL for tumour downstaging 160 (41.5%): successful downstaging into MC 20% drop-out 21% LT (76) Estimated dropout rates: 1-yr: 46.7% 2-yr: 70.2% 5-yr: 87.2% Overall post-lt survival rates: 1-yr: 89.2% 2-yr: 70.3% 5-yr: 54.6% Patients with a maximum tumour size <7 cm who achieve complete necrosis together with AFP levels <100 ng ml at LT may be the best candidates for LT following downstaging using TACL (87%DFS 6 yrs) Recurrence-free survival: 1-yr: 74.7% 2-yr: 71.8% 5-yr: 66.3% Jang et al, Aliment Pharmacol Ther 2010, 31,

19 XXL-Trial Clinicaltrials.gov - NCT

20 Absolute Downstaging unrelated to TX entry criteria DOWN-STAGING BASED BOTH ON MORPHOLOGICAL CRITERIA BIOLOGICAL CRITERIA Absolute because downstaging has not specific entry criteria and morphological endpoints but simply aims to disease control (=no progression) and selection of good biology cases

21 Absolute Downstaging : no progression Lencioni R, et al. Sem in Liver Dis 2010; 30: 52

22 LT if response > 30% to TACE Even if out of Milan Sustained response to TACE is a better selection criterion than size and n of nodules (MC no impact) 39 pts with uneventful course of TACE (2 recurrences) 11 pts with tumor progression after TACE (5 recurrences) Milan IN/OUT not impacting recurrence Otto G et al. Liver Transpl 2006; 12; 1260

23 To investigate a-fp as a predictor of outcome of LT HCC-listed patients (TTV>115=0.5%) -Local pre-transplant HCC treatment: 41% of patients on the WL. -8.2% AlfaFP> 400 Patients with afp levels >400 ng/ml at the time of listing who were downstaged to AFP 400 ng/ml (DS-HCC) has better intent-to-treat survival than patients failing to reduce AFP to 400 Intention-to-treat 3-years survival DS-HCC: 81% p <0.001 Not DS-HCC: 48% Dropout risk factors AFP listing AFP TX AFP velocity p=0.001 TTV velocity p=0.015 afp downstaging associated with good survivals whatever the level of the original afp (even>1000 ng/ml) Only the last pre-transplant afp independently predicted survival (p 0.001) Merani et al, Journal of Hepatology 2011 vol

24 Predictors of biologic aggressiveness: α-fp Combination of HCC burden and AFP levels to stratify prognosis LT between in the US HCC + MELD exception points: HCC no exception points: 3196 Milan-out + AFP 15 ng/ml AHR=0.97 Milan-in + AFP > 66 ng/ml AHR=1.93 The absolute serum AFP level and its changes strongly predict post-transplant survival independently of the tumor burden Berry et al, Liver Transplantation 19: , 2013

25 Intention to treat survival: whole group yr 3yr 5yr List entry 451 HCC pts 87% 70% 63% 279 LT (77 BCLC B) Median survival 99 months ( ) University of Padova

26 Intention to treat survival: role of BCLC staging BCLC at listing 0 (n=95) Dropouts 14% BCLC at LT 0 (n=54) D vs. other, p=0.01 A (n=168) 18% A (n=101) B (n=103) D (n=76) 13% 21% B (n=77) D (n=46) Log Rank, P=0.06 Log Rank, P=0.61 Log Rank, P=0.67 University of Padova

27 Intention to treat TRANSPLANT BENEFIT: role of BCLC staging Comparison with matched patients from ITA.LI.CA database BCLC 0 BCLC A LT (n=95) Non-LT (n=211) LT (n=168) Non-LT (n=456) P= P< University of Padova

28 Intention to treat TRANSPLANT BENEFIT: role of BCLC staging Comparison with matched patients from ITA.LI.CA database BCLC B LT (n=105) Non-LT (n=291) BCLC D LT (n=76) Non-LT (n=82) P< P< University of Padova

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30 AIMS of treating patients before transplant (Downstaging and/or Bridging) 1. Giving a potentially radical chance of therapy to those with poor therapeutic alternatives(downstaging) 2. Controlling HCC progression(bridging) 3. Selecting patients with favourable biology(throughtime and/or therapeuticpressure (Downstaging/ Bridging) 1. Helping balance in prioritization

31 Evidences on bridging: No differences with untreated patients Study/Yr/Npts Treatme nt Majno pts Retrospective Study/Yr/N Porrett pts pts Retrospective Treat ment Radiol Resp. Radiol Resp. Dropout % Dropout % Waiting time Waiting time % Transplante d % Transpla nted ITT surv Post OLT surv TACE 56% NA NA NA NA 55-57% vs 62-59% p=ns TACE, PEI TARE, RFA, CR 20% NA 6.6 months (mean) ITT surv Post OLT surv NA NA 84 vs. 91% 3 ys p=ns DFS p= NS DFS p=ns Decaens pts Retrospective TACE PR> 80% In 30% cases NA 4.2 months NA NA 59.4% vs. 59.3% 5 ys p=ns Pelletier pts Retrospective - ITT TACE, RFA NA 18% 138 days (1-2655) 65% 51% 5 ys No difference between treatedand untreated NA Bias related to short list waiting times

32 Evidences on bridging: IMPACT on long term results Study/Yr/Npts Treatm. Rx Resp. Dropout % Wait. time % OLTx ITT surv Post OLT surv DFS Millonig pts Retrospective Graziedei pts Prospective Fisher pts Prospective Otto pts Prospective Tsochatzis pts Prospective Cucchetti retrosp TACE NA 8.6% 9 months (1.2-34) TACE CR: 29.2% PR: 66.7% SD/PD: 4.1% TACE TACI RFA PEI 0% days NA 12.19% months TACE PR: 54.8% 17.6% 218 (22-756)days TACE RESECT ABLAT TACE NA Histo: CR: 33% PR: 54% SD/PD: 19% 60.3% ifpot radical ther 91.4% CR:87.5% PR: 66.2% SD/PD 19.3% 5 yrs 85.4% 94% 5 ys 85% 79% (32 months) NA NA 45% At multivariate Bridging favouringitt, DFS HR>5 Bridge 18% 1 yr No Bridge CR: 85.1% PR: 63.9 SD/PD: 51.4% 5yrs 93% 5 ys 92.9% 4 ys NA NA 95.24% 4 ys 52% NA 74.4% 95% PR, CR 35.4% PD 5 ys NA NA

33 From 2002 to HCC patients 176 Milan-in 49 R4 T3 criteria HCCs in R4T3 criteria less favorable biological features Higher median afp (21.9 vs. 8.5 ng/ml, p = 0.01) Larger tumor size Larger tumor number Higher incidence of microvascular invasion (22% vs. 5%, p = 0.002) Milan in R4T3 p 5-y Survival 79% 69% 0.03 Rec. Rate 5% 13% 0.05 Pre-transplant LRT did not affect post-transplant outcomes in Milan-in but did result in lower 3-yr HCC recurrence (7% vs. 75%, p < 0.001) and better 3-yr survival (p = 0.02) in patients meeting R4T3 criteria Tumor biology and pre-lt LRT are important factors that determine the post-lt outcomes in patients with HCC who meet R4T3 criteria Kim et al, Clin Transplant 2013: 27:

34 Evidences on bridging: Best bridge Therapy? Ablation Study/Yr/Npt s Treatm ent Pathology Resp. Dro pou t% Waiting time % Transplanted ITT surv Post OLT surv DFS Mazzaferro pts Prospective RFA 70% CR: 55% (63% in <= 3 cm) 0% NA 100% NA 83% 3 ys NA Pompili pts Retrospective RFA, PEI <3cm CR: 53%% PR>50% 25% PR<50% 12% No necr: 9.4% NA 9.5 months 100% NA 85.4% 3 ys NA >3cm CR14.3% PR 78.4% No necr7% Lu nodules Retrospective RFA 47% perivascular 88% non perivascula Overall 74%r NA NA 100% NA NA NA

35 Evidences on bridging: Best bridge Therapy? Ablation Huo et al, Clin Transplant 2008: 22:

36 Bridging treatments: when? Clavien et a, Lancet Oncoloy 2012; 13: e11-22

37 AIMS of treating patients before transplant (Downstaging and/or Bridging) 1. Giving a potentially radical chance of therapy to those with poor therapeutic alternatives(downstaging) 2. Controlling HCC progression(downstaging/ Bridging) 3. Selecting patients with favourable biology(through time and/or therapeutic pressure (Downstaging/ Bridging) 1. Helping balance in prioritization

38 BRIDGING and PROGNOSIS 136 HCC-patients with >= 2 pre-lt TACE 46 Milan-out Tumour recurrence: 15% Recurrence-Free Survival (5 years) Milan-in or down-staged to whitin MC: 88% Milan-out: 55% 5-year absence of recurrence was better predicted by the criterion Progressive Disease according to RECIST (p <0.0001) If progression was defined as any progression predictability of recurrence was 0.86 Otto et al, Journal of Hepatology 2013 vol. 59;

39 BRIDGING and PROGNOSIS 136 HCC-patients with >= 2 pre-lt TACE 46 Milan-out Tumour recurrence: 15% Recurrence-Free Survival (5 years) Milan-in or down-staged to whitin MC: 88% Milan-out: 55% 5-year absence of recurrence was better predicted by the criterion Progressive Disease according to RECIST (p <0.0001) If progression was defined as any progression predictability of recurrence was 0.86 Characteristics of tumour response to TACE are reliably recognized and allow identification of suitable patients for transplantation Otto et al, Journal of Hepatology 2013 vol. 59;

40 BRIDGING and PROGNOSIS To evaluate the impact of postinterventional tumor necrosis on recurrence-free long-term survival after LT in patients with HCC according to MC 93 HCC-candidates 36 Milan-out 59 bridged by TACE or RFA Post-interventional tumor necrosis (explant pathology) was correlated with outcome post-lt 5 yr DFS: IBT: 78% Non IBT: 68% (P = 0.25) Outcome according response to IBT (necrosis >=50%) IBT-responder: 96% (P <0.001) IBT non responder: 21% 5-yr DFS: Milan-out + extended response to IBT: 80% Milan-out no response to IBT: 0% (P <0.001) Kornberg et al, January 2013 Volume 8 Issue 1 e53960

41 BRIDGING and PROGNOSIS Response to preoperative chemoembolization may predict long-term outcome after LT Intention-to-treat analysis of embolization group (n =116) Millonig et al Liver Transpl 13: , 2007

42 BRIDGING and PROGNOSIS 118 HCC patients to OLTx January 2000 December 2007 Group A: After PD after aggressive LRT Progression HCC treatment before LT Group Imaging B: CR after progression LRT while on the waiting list Group Is a C: strong PR afterpredictor LRT of high HCC recurrence rate Group D: also SD after in patients LRT who met the Milan criteria Progression Group A Group BCD p 3-y OS 65.5% 84.8% 5-y OS 48.9% 74.6% 3-y DFS 74% 95.7% 5-y DFS 74% 93% Progression PD was the only independent risk factor according to Cox regression (p=0.014; OR 4.4) De Carlis et al, J Clin Gastroenterol 2012;46:78 86

43 AIMS of treating patients before transplant (Downstaging and/or Bridging) 1. Giving a potentially radical chance of therapy to those with poor therapeutic alternatives(downstaging) 2. Controlling HCC progression(downstaging/ Bridging) 3. Selectingpatientswith favourablebiology(throughtime and/or therapeutic pressure (Downstaging/ Bridging) 4. Whohasto be prioritized?

44 398 consecutive T2-HCC listed for LT (MELD exception) Probabilities of dropout: 6 months: 9.4% 12 months: 19.6% Median time from listing to LT: 8.8 months Median time from listing to dropout: 7.2 months A subgroup (19.9%): 1 tumor of 2 to 3 cm CR after the first LRT afp level < =20 ng/ml after the first LRT) Dropout probabilities: 1-year: 1.3% vs. 21.6% 2-years: 1.6% vs 26.5% (P = 0.004) Mentha et al, Liver Transpl 19: , 2013.

45 315 HCC-patients listed for LT Median follow-up: 24 months 50% CR 10% Recurrence Response to bridge therapy significantly affected: Recurrence rate (P=0.017) Overall ITT survival rate (P=0.001) Dropout rates: 3 months: 3.5% 6 months: 6.5% 12 months: 19.9% Response to therapy is a potentially effective tool for prioritizing HCC patients for LT as well as select cases with different risks of tumor recurrence after transplantation Significantly affected by: 1. MELD score (P=0.032) 2. Tumor stage at diagnosis (P=0.041) 3. Response to bridge therapy (P < 0.001) Dropout rates by T stratification and response to bridge therapy: T2 patients with PR or SD/PD T3-T4a patients succesfully down-staged (P=0.037) T2 patients with CR (P=0.964) T1 patients Cucchetti et al, Liver Transpl 17: , 2011

46 All regions Excluding regions 4 and 5 Bittermann et al, American Journal of Transplantation 2014; 14: 79 87

47 It is not only appropriate to consider transplantation for patients withhcc beyond MC but may also be suitable to prioritize certain candidates because of their higher risk of waitlist mortality Bittermann et al, American Journal of Transplantation 2014; 14: 79 87

48 Response to therapy as priority criterion FIRST CRITERION = RESPONSE TO THERAPY I. Stable / Progression* = 6 II. Untreatable (location, severity of cirrhosis) = 5 III. Partial** = 4 IV. Recurrent new tumor (> 6 mo last therapy) awaiting therapy = 3 V. New tumor awaiting therapy = 2 VI. 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) EXCLUSION CRITERIA SECOND CRITERION = STAGE I. T1 1 nodule 1.9 cm II. T2 1 nodule 2-5 cm; 2-3 nodules all 3 cm III. T3 1 nodule > 5 cm; 2-3 nodules 1 > 3 cm IV. T4a 4 nodules, any size; T4b any T with gross vascular invasion N1, M1 Metastases THIRD CRITERION = TIME Waiting list with HCC Gross vascular invasion or metastases (T4b and /or N1, M1) Poorly differentiated HCC at biopsy Cillo U, et al. Am J Transplant 2007; 7: 972 Vitale A, et al. Ann Surg Oncol 2010.

49 Response to therapy as priority criterion Level of evidence 2b; Grade of reccomendation = B Cox regression model for the progression outside the Milan criteria or death. HCC persistence or recurrence after bridging therapy helps predicting transplant list dropout and generate a more equitable exception policy. De Giorgio M, et al. Liver Transplant 2010.

50 Conclusion 1: role of DST / BRIDGING in LT for HCC Still an open issue due to evidence weekness for : 1) Arbitrary and disomogeneous START/ENDPOINT of DST 2) Small choort studies 3) Short F.U. 4) High degree of discrepancy between radiology and explant Pathology 5) Lack of comparison among treatments Expert opinionists favourable to clinical adoption for: 1) Rationale of relevant transplant benefit and controlling dropout 2) Downstaging therapies overlapping with palliation 3) Relevant potential in prognositcal stratification of patients Features for proposals: 1) START from 50% 5yrs expected survival 2) Stratification with biopsy morphology and AlfaFP 3) Morphologic and biologic response 4) Long termf.u

51 Conclusion 2 From a static to a dynamic concept Anubi e il peso dell anima Il libro dei morti 1300 a.c. Dinamismo di un corpo umano n 1 Umberto Boccioni, 1913, Galleria d'arte Moderna, Milano

52 Conclusion 3 With new IFN free antiviral protocols: A few free seats for HCC at high benefit from OLTx?