Dalle linee guida dell'epatocarcinoma alla pratica clinica - Gastrolearning®
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Dalle linee guida dell'epatocarcinoma alla pratica clinica - Gastrolearning®

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Gastrolearning XVI lezione

Gastrolearning XVI lezione
Dalle linee guida dell'epatocarcinoma alla pratica clinica - Prof. F. Trevisani (Università di Bologna).

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  • Sappiamo con certezza che, nelle aree non colpite da una iperendemia da HBV, almeno l’80%. Se poi consideriamo le cause più comune di CLD e HCC nel mondo occidentale (C ed alcool), raggiungiamo prevalenze prossime al 100%.
  • Alllora si può pensare di accoppiare, come viene accettato dalle attuali linee guida, di accoppiare i due test di sorveglianza. Vediamo vantaggi e svantaggi di questa strategia analizzando i risultati di uno studio prospettico su un grande campione di soggetti con infezione cronica da HBV: accoppiandoli si ottiene un aumento della sensibilità dell’8%, ma a prezzo di un raddoppiamento dei risultati falsi positivi ed un dimezzmento del PPP.
  • La ripercussione economica è pesantissima, aumentando il costo di ogni HCC diagnosticato dell’84% rispetto all’uso della sola US.
  • Rispetto alle AASLD Practice Guidelines 2010 (1), l’algoritmo proposto: 1) contempla anche la CEUS fra le tecniche di diagnosi per immagini utilizzabili ai fini diagnostici 2) predilige la sorveglianza trimestrale (invece che lasciare spazio a un programma semestrale o trimestrale, a scelta del clinico) per i primi 12 mesi, nel caso di nodulo < 1cm o nodulo atipico.
  • Lo schema di trattamento BCLC propone differenti opzioni terapeutiche in base allo stadio del tumore. I pazienti in stadio 0 (HCC molto precoce) sono candidati ideali alla resezione. I pazienti in stadio A presentano tumori in stadio precoce asintomatici e sono idonei a trattamenti radicali (resezione, trapianto, trattamenti percutanei, quali alcolizzazione o radiofrequenza). Lo stadio B (HCC intermedio) include pazienti con HCC multinodulare asintomatico che possono trarre beneficio dalla chemioembolizzazione. Nello stadio C (HCC avanzato) sono inclusi pazienti con tumori sintomatici e/o con invasione vascolare/disseminazione extraepatica. Questa categoria di pazienti è idonea al trattamento con sorafenib. I pazienti appartenenti allo stadio D presentano una prognosi molto sfavorevole, per loro si suggerisce un trattamento sintomatico. Llovet JM et al. J Gastroenterol 2005; 40: 225-235; Llovet JM et al. J Natl Cancer Inst 2008;100: 698 – 711
  • This slide presents preliminary OS by concomitant TACE use from the start of sorafenib therapy Preliminary median OS from the start of sorafenib therapy was longer for patients who received concomitant TACE Median OS was 13.1 months and 8.5 months, respectively, in patients who did and did not receive TACE concomitantly with sorafenib In this second interim analysis, outcomes data must be considered preliminary. Final analyses are planned in the future, in fully mature data

Dalle linee guida dell'epatocarcinoma alla pratica clinica - Gastrolearning® Dalle linee guida dell'epatocarcinoma alla pratica clinica - Gastrolearning® Presentation Transcript

  • Corso“Gastrolearning”Bologna, 20 Maggio 2013Linee guida AISFFranco TrevisaniSemeiotica MedicaDipartimento di Scienze Mediche e ChirurgicheAlma Mater Studiorum - Università di Bologna
  • 20122010
  • Adjuvant therapy after resectionOLT-extendedNeoadjuvant therapy in waiting listLDLTDownstagingInternal radiation Y90ResectionLevels ofevidence(NCI)Grade of recommendation(GRADE)1232 (weak) 1 (strong)RF (<5 cm),RF/PEI (<2 cm)ChemoembolizationExternal/palliative radiotherapySorafenibAC BAC BOLT-MilanEASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. Journal of Hepatology 2012 vol. 56 j 908–943Levels of evidence and grade of raccomandation
  • Sorveglianza del paziente arischio di HCC
  • Surveillance for HCC: the RCTZhang BH, et al. J Cancer Res Clin Oncol. 2004;130:417-2218,816 patients with HBsAg+ chronic hepatitis9,373AFP + US (semi-annual)9,443No surveillance86 67HCC83/100,000 131/100,000HCC mortalityHCC mortality rate ratio:0.63 (95% CI 0.41–0.98)- Compliance 58%- LT not availableAFP = alpha-fetoprotein;RCT = randomized controlled trial; US = ultrasonography.
  • 205 cirrhotic patients (Child–Pugh A/B)Decision aidpaperSurveillance for HCC in cirrhosis: unfeasibility ofRCT when informed consent is givenPoustchi H, et al. Hepatology ,2010; 54: 1998–2004 [Epub ahead of print 2011 July 28]181chosesurveillance21continued theirusual care2wereundecided6 mo. US + 3 mo. AFPvsno surveillance204 pts. (99.5%)declined randomizationThis topic can be onlyaddressed with carefullyconducted cohort studies
  • Surveillance for HCC in cirrhosis:survival in cohort studiesDe Masi S, et al. Dig Liver Dis. 2005;37:260-8.Cirrhosis 3-year survival rateKemp, 2005AustraliaHCV, HBV,alcoholRetrospective US 6–12 m 41 55 38% 19% 329 days(median)Toyoda, 2006JapanHCV, HBV Retrospective US + AFP +DCP1,050 591 36% 19%Stravitz, 2008USAHCV, acohol Retrospective US (others)12 m172 107 40% 13% 916 days(median)Kuo, 2010TaiwanHBV, HCV Retrospective US ≤12 m 318 1118 59% 29%Kemp W, et al., J Gastroenterol Hepatol. 2005;20:873-8. Toyoda H, et al., Clin Gastroenterol Hepatol. 2006;4:1170–6. Stravitz RT, et al., AmJ Med. 2008 Feb;121:119-26. Kuo Y-H, et al., Eur J Cancer 2010; 46:744-51
  • Surveillance for HCC in cirrhosis:survival in cohort studiesDe Masi S, et al. Dig Liver Dis. 2005;37:260-8.Lead time
  • Surveillance for HCC
  • Pazienti candidati alla sorveglianzaAISF position paper, Digest Liver Dis, 2013
  • Subject to PATH Program DisclaimerEffect of surveillance on survival(adjusted for the “lead time”) in cirrhosisChild–Pugh CChild–Pugh BTrevisani F et al., for ITA.LI.CA. Am J Gastroenterol 2002;97:734-44Trevisani F et al., for ITA.LI.CA. Am J Gastroenterol 2007;102:2448-57SurveillanceNo surveillanceLead timeChild–Pugh A
  • Pazienti candidati alla sorveglianzaAISF position paper, Digest Liver Dis, 2013
  • Baseline HBV-DNA level andrisk of HCC in chronic hepatitis BChen et al., JAMA 2006<10˙000 c/mL1˙000˙000 c/mL>1˙000˙000 c/mL100˙000 c/mLAt entry:- HBeAg neg.- Normal ALT- No cirrhosisHBV-DNA (c/mL) Annual incidence of HCC (%)<10,000 0.1110,000-99,9999 0.29100,0000-999,9999 0.96≥1 Million 1.15
  • Yang HI, et al. Lancet Oncol. 2011;12:568-74.Risk estimation for hepatocellular carcinoma inchronic hepatitis B (REACH-B):development and validation of a predictive score12 months6 months
  • Pazienti candidati alla sorveglianzaAISF position paper, Digest Liver Dis, 2013
  • HCC risk in non-cirrhotic HCV+ patientsLok AS, et al. Gastroenterology. 2009;136:138-48.0.8% / year1.4% / year
  • HCC risk in non-cirrhotic populationsMasuzaki R, et al. Hepatology, 2009:49:1793-4Liver stiffness (kPa) Hazard ratioAnnual incidenceof HCC (%)≤ 10 1 0.110.1–15 16.7 2.915.1–20 20.9 5.020.1–25 25.6 8.3> 25 45.5 14.4Prospective study with elastography (FibroScan®)866 patients anti-HCV+Cirrhosis: 13–17 kPaStarting pointforsurveillance?
  • Pazienti candidati alla sorveglianza
  • Rischio HCC in pazienti divenuti non viremiciHBVHCVAghemo et al., J Hepatol 2012;57:1326-35
  • Surveillance for HCC: how?The popularity of US relies on the absence of risk, non-invasiveness,easy accessibility, and relatively moderate costBruix J, Sherman M. Hepatology. 2011;53:1020-2Raccomadazioni AISF 2012; www.webaisf.orgEASL-EORTTC guidelines. J Hepatol 2012; 56; 908–943Surveillance with US should be performed by an experiencedoperator (evidence 5, strengh D).
  • Pooled sensitivity of ultrasoundultrasound forearly stageearly stage HCCHCCSurveillance for HCC: how?Singal A, et al. Aliment Pharmacol Ther 2009;30:37-47
  • Pooled sensitivity of ultrasoundultrasound forearly stage HCCearly stage HCCPooled sensitivity of ultrasound + AFPultrasound + AFP forearly stage HCCearly stage HCCSensitivity: + 6%Surveillance for HCC: is US plus AFP better?Singal A, et al. Aliment Pharmacol Ther 2009;30:37-47
  • Sensitiv. False + PPV• US 84% 2.9% 6.6%• US + AFP 92% 7.5% 3.0%• AFP 69% 5.0% 3.3%Semi-annual surveillance of 9,373 patientswith HBsAg+ or with chronic hepatitis+ 8%Zhang B, Yang B. J Med Screen 1999;6:108-10PPV = positive predictivevalue.Alpha-fetoprotein as surveillance test
  • Cost for each smallHCC detected(USA $)• US 1,980• US + AFP 3,640 (+84%)• AFP 3,030 (+53%)Alpha-fetoprotein as surveillance testSemi-annual surveillance of 9,373 patientswith HBsAg+ or with chronic hepatitisZhang B, Yang B. J Med Screen 1999;6:108-10
  • Sensitivity of US-based surveillancefor early HCCearly HCC by interval (6 vs 12 months)Meta-regressionSingal A, et al. Aliment Pharmacol Ther 2009;30:37-47
  • Distribution of HCC staging according to thesurveillance interval (6 vs 12 months)Retrospective study on 634 patients withChild–Pugh class A/B cirrhosisHCC (number and ∅)6 months(497 patients)12 months(137 patients)Single ≤ 2 cm (very early) 120 (24%) 7 (5%)Single 2.1–3 cm (early) 94 (19%) 22 (16%)Single 3.1–5 cm (early) 61 (13%) 30 (22%)2–3 x ≤ 3 cm (early) 73 (15%) 20 (15%)Milan out 149 (30.0%) 58 (42%)p < 0.001STAGEMIGRATIONSanti V et al., for ITA.LI.CA, J Hepatol 2010;53:291-7
  • Survival according to thesurveillance interval (6 vs 12 months)Corrected (for the lead time) survivalSensitivity analysis: semi-annual is superior to annual program in patients witha tumor volume doubling time ≤ 147 daysObserved survivalSanti V et al., for ITA.LI.CA, J Hepatol 2010;53:291-7Retrospective study on 634 patients withChild–Pugh class A/B cirrhosis
  • Politica di richiamo(diagnosi)
  • * OneOne imaging technique only in centers of excellence with high-end radiological equipmentin centers of excellence with high-end radiological equipment.** HCC radiological hallmark: arterial hypervascularity and venous/late phase washoutMass/nodule on US< 1 cm 1-2 cm > 2 cm4-phase CT or DynamicContrast enhanced MRI4-phase CT/DynamicContrast enhanced MRIRepeat US at 4 moGrowing/ChangingCharacterStable1 or 2 positive techniques*:HCC radiological Hallmarks**1 positive technique:HCC radiological Hallmarks**Yes NoHCC BiopsyInvestigateaccording to sizeInconclusiveYes NoHCC BiopsyEASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2012; 56; 908–943Diagnostic recall policy?
  • Algoritmo diagnostico raccomandazioni AISFNuovo nodulo in cirrosiAumento (Ø > 1 cm)NO SìEcografia/3 mesiØ < 1 cmAumento (Ø > 1 cm)Ecografia/3 mesi(per 12 mesi)NOEcografia/6 mesiSìHCCNon diagnosticaØ > 1 cmAspetto atipicoAltra metodicacontrastograficaAspetto tipico(wash-in e wash-out)NO SìAspetto tipicoBiopsiaTC, RM, CEUSAltra diagnosiAISF position paper, Digest Liver Dis, 2013
  • Efficacy vs effectiveness of surveillanceEfficacy (mortality reduction) H R 3-year- ITA.LI.CA (Am J Gastroenterol, 2002) 41% -- Kemp et al. (J Gastroent Hepatol,2005) 76% 100%- Bolondi et al. (Gut, 2001) - 42%- Toyoda et al. (Clin Gastroenterol Heptol, 2008) - 89%- Kuo et al. (Eur J Cancer, 2010) - 103%Determinants of Effectiveness- Doctor recommendation 80%- Patient acceptance 90%- Patient adherence 80%- Proper recall policy 80%- Timely available diagnostic and therapeutic options 80%Effectiveness:40% x 0.8 x 0.9 x 0.8 x 0.8 x 0.8 = 15%80% x 0.8 x 0.9 x 0.8 x 0.8 x 0.8 = 29%
  • Stadiazione e prognosi
  • Portal pressure/bilirubinHCCPEI/RFA SorafenibStage 0PST 0, Child–Pugh AVery early stage (0)1 HCC < 2 cmCarcinoma in situEarly stage (A)1 HCC or 3 nodules< 3 cm, PST 0End stage (D)Liver transplantation TACEResectionCurative treatments (30%)5-year survival (40–70%)Target: 20%OS: 20 mo (45-14)Associated diseasesYesNo3 nodules ≤ 3 cmIncreasedNormal1 HCCStage DPST > 2, Child–Pugh CIntermediate stage (B)Multinodular,PST 0Advanced stage (C)Portal invasion,N1, M1, PST 1–2Stage A–CPST 0–2, Child–Pugh A–BEASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. Journal of Hepatology 2012 vol. 56 j 908–943Target: 40%OS: 11 mo (6-14)Best supportivecareTarget: 10%OS: <3 moUpdated BCLC staging system andtreatment strategyPST 0-1
  • PERFORMANCE STATUS(Eastern Cooperative Oncology Group)Grade ECOG0 Fully active, able to carry on all pre-disease performance withoutrestriction1 Restricted in physically strenuous activity but ambulatory and able tocarry out work of a light or sedentary nature, e.g., light house work,office work2 Ambulatory and capable of all selfcare but unable to carry out anywork activities. Up and about more than 50% of waking hours3 Capable of only limited selfcare, confined to bed or chair more than50% of waking hours4 Completely disabled. Cannot carry on any selfcare. Totally confinedto bed or chair5 DeadOken, et al., Am J Clin Oncol 5:649-655, 1982
  • Terapia
  • Portal pressure/bilirubinHCCPEI/RFA SorafenibStage 0PST 0, Child–Pugh AVery early stage (0)1 HCC < 2 cmCarcinoma in situEarly stage (A)1 HCC or 3 nodules< 3 cm, PST 0End stage (D)Liver transplantation TACEResectionResectionCurative treatments (30%)5-year survival (40–70%)Target: 20%OS: 20 mo (45-14)Associated diseasesYesNo3 nodules ≤ 3 cmIncreasedNormal1 HCCStage DPST > 2, Child–Pugh CIntermediate stage (B)Multinodular,PST 0Advanced stage (C)Portal invasion,N1, M1, PST 1–2Stage A–CPST 0–2, Child–Pugh A–BEASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. Journal of Hepatology 2012 vol. 56 j 908–943Target: 40%OS: 11 mo (6-14)Best supportivecareTarget: 10%OS: <3 moUpdated BCLC staging system andtreatment strategyPST 0-1
  • Resection for HCCOnly single? Only without PHTIshizawa et al., Gastro 2008CPA = Child Pugh Class ACPB = Child Pugh Class BPHT = Portal Hypertension
  • Resection for HCCThe Bologna experienceP=0.008241 pts.156 pts.
  • BCLC-AASLD-EASL Staging Systemand Treatment ScheduleAssume i fattori prognostici negativi come“controindicazioni” a un trattamento
  • MELD score9 - 10Serum sodium levelCirrhotic patient eligible forliver resection≥ 140 mEq/L < 140 mEq/LSegmentectomy orbisegmentectomySegmentectomyor limitedresectionMajorhepatectomy (upto 4 segments)Risk ofIPLF>15% inall types ofhepatectomy>10<9Algoritmo per candidare alla resezioneepatica il paziente con HCC0 - 3.3% 0 – 2.5%0MortalitàAISF position paper, Digest Liver Dis, 2013
  • Algoritmo per candidare alla resezioneepatica il paziente con HCCAscites, Bilirubin, Indocianine green retention rate at 15 minImamura H et al, J Hepatobiliary Pancreat Surg. 2005:16-22ABI
  • ResectionAblationIs there a winner?
  • RF results in Child-Pugh A patientswith a single HCC ≤2 cmLivraghi et al., Hepatology 2008Mortality 0Major complications 1.8%(1 seeding case)Complete radiological necrosis- 1st course 86%- 2nd course 12%- Total 98%Sustained complete response 97%(median follow-up 31 mo)Treatment failure 3%232 pts218 pts6 pts(2.6%)unfeasibility
  • Survival of patients with single HCC <2 cmtreated by ablationAnalysis by surgical candidacy (100 vs 118)Livraghi et al., Hepatology 2008
  • Results of RF and resection in patients withvery early HCC (single <2 cm)Propensity analysis (resection 52 vs RF 91→52)Wang JH et al., J Hepatol 2011 [Epub haed of print]One-to-one near-neighbor matching for:sex, age, HBsAg, anti-HCV, platelet, Child-Pugh, AFP, ALT, BMI, hypertension, diabetes.• Negligible mortality• Lower liver mutilation• Lower costs• Shorter hospital stay• Easy repeatibility
  • Cho YK et al., Hepatology 2010; 51: 1284-90In compensated cirrhosis, first-line RF (followed by resection if failure)is better than resection (followed by RF for recurrence)if:>>>><
  • Cho YK et al., Hepatology 2010; 51:1284-90Two-way sensitivity analysis:HR mortality vs. local recurrence for overall mortalityHResectionRF (± HR)2.5% increase in local recurrence = 1% increase in periop. Mortality
  • Tumor size and first-line treatment≤ 2 cm2.1- 3 cm> 3 cmRFAResectionAISF position paper, Digest Liver Dis, 2013
  • Portal pressure/bilirubinHCCPEI/RFA SorafenibStage 0PST 0, Child–Pugh AVery early stage (0)1 HCC < 2 cmCarcinoma in situEarly stage (A)1 HCC or 3 nodules< 3 cm, PST 0End stage (D)Liver transplantation TACEResectionCurative treatments (30%)5-year survival (40–70%)Target: 20%OS: 20 mo (45-14)Associated diseasesYesNo3 nodules ≤ 3 cmIncreasedNormal1 HCCStage DPST > 2, Child–Pugh CIntermediate stage (B)Multinodular,PST 0Advanced stage (C)Portal invasion,N1, M1, PST 1–2Stage A–CPST 0–2, Child–Pugh A–BEASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. Journal of Hepatology 2012 vol. 56 j 908–943Target: 40%OS: 11 mo (6-14)Best supportivecareTarget: 10%OS: <3 moUpdated BCLC staging system andtreatment strategyPST 0-1
  • Mazzaferro et al., Lancet Oncol 20091556 pts. from 36 centres (1122 Milano-out at pathology examination)5-year overall-survivalLinee guida: rapidi cambiamenti delle evidenze.Chi trapiantare?1 5 1510 8520 25 30 35 504540 55 60 65 7570 80Size of the largest tumor (mm)
  • Linee guida: rapidi cambiamenti delle evidenze.Criteri down-staging di BolognaDown-staging:- 5.1-6 cm- 3.1-5 cm “Milano-in” dopo down-staging- ≤4 cm ciascuno, somma Ø ≤12 cm0204060801000 12 24 36Actuarialsurvival(%)Milano-in Down-stagingPost-Tx (88 vs. 32 pts)0204060801000 12 24 36Actuarialsurvival(%) Milano-in Down-stagingIntention-to-treat (129 vs. 48 pts)Ravaioli et al., Am J Transplant 2008
  • Linee guida: rapidi cambiamenti delle evidenze.Criteri down-staging UCSFDown-staging:- ≤ 8 cm- ≤ 5 cm ciascuno, somma Ø ≤ 8 cm- ≤ 3 cm ciascuno, somma Ø ≤12 cmYao et al., Hepatology 2008Inizio down-staging
  • Multimodal treatment of HCCOLT and neoadjuvant theraphy: the down-stagingClavien et al., Lancet Oncol 2012; 13: 11-22
  • Multimodal treatment of HCCOLT and neoadjuvant theraphyAISF position paper, Digest Liver Dis, 2013
  • Portal pressure/bilirubinHCCPEI/RFA SorafenibStage 0PST 0, Child–Pugh AVery early stage (0)1 HCC < 2 cmCarcinoma in situEarly stage (A)1 HCC or 3 nodules< 3 cm, PST 0End stage (D)Liver transplantation TACEResectionCurative treatments (30%)5-year survival (40–70%)Target: 20%OS: 20 mo (45-14)Associated diseasesYesNo3 nodules ≤ 3 cmIncreasedNormal1 HCCStage DPST > 2, Child–Pugh CIntermediate stage (B)Multinodular,PST 0Advanced stage (C)Portal invasion,N1, M1, PST 1–2Stage A–CPST 0–2, Child–Pugh A–BEASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. Journal of Hepatology 2012 vol. 56 j 908–943Target: 40%OS: 11 mo (6-14)Best supportivecareTarget: 10%OS: <3 moUpdated BCLC staging system andtreatment strategyPST 0-1
  • HCC in stadio intermedioPaz. 58 aa, Child-Pugh A, MELD 9, PS 0, non invasione portale, N 0, M 0,non comorbilità, varici F1.6 cmTACE (sempre?)3.5cm
  • Trattamento HCC in stadio BCLC intermedioLin et al., W J Surg 2010Overall survivals adjusted for serum albumin (independent factor)in Hepatic Resection (n. 93) and TACE (n. 73) pts.Child-Pugh A
  • Trattamento HCC in stadio BCLC intermedioVitale et al., Transplant Proc 2009Surgical options:LT, resection, laparoscopic ablation(124 pts.)(91 pts.)
  • Trattamento HCC in stadio BCLC intermedioWang et al., Eur J Cancer 2008ResectionTAE
  • Resection for HCC: an international study from referral centersResection for HCC: an international study from referral centers(Asia, Europe, America)(Asia, Europe, America)Trattamento HCC in stadio BCLC intermedioTorzilli G et al., Ann Surg 2013 257; 929-37
  • RecommendationContraindications andspecificationsBCLC stage B pts not eligible for surgery or ablation (1a-A).Best candidates are asymptomatic (PS 0) Child-Pugh class A pts (1b-A);Child-Pugh score of B7 or PS 1 can be considered (5-D)Jaundice, untreatableascites, portal or mainbranch thrombosis,hepatofugal portal flow, andHCC >10 cmTACE can be utilized in pts with early stage HCC if surgical or ablativetechniques are not applicable (technical reasons and/or comorbidities)TACE should be performed with a selective or super-selective (segmentalor sub-segmental) technique to optimize risk/benefit ratio and increaselikelihood of complete response (2b-B)For bi-lobar HCCs nottreatable with a super-selective approach, treatinga single lobe per sessionshould be considered (5-D)Peripheral, segmental or intra-tumoral thrombosis is not an absolutecontraindication to TACE, and should be used in association with a systemictreatment (5-D)Should be considered inthe frame of controlledclinical studiesIn absence of radiologic evidence of disease persistence (completeresponse), TACE should not be repeated, due to its risks, costs and impacton the pt’s quality of life. TACE should be repeated “on demand” (5-D)2012 AISF recommendations forTACE in HCCAISF position paper, Digest Liver Dis, 2013
  • HCC in stadio intermedioPaz. 58 aa, Child-Pugh A, MELD 9, PS 0, non invasione portale, N 0, M 0,non comorbilità, varici F1.TACE (sempre?)
  • Intermediate-stage HCCITA.LI.CA database 2008The “real word” treatment in… ITA.LI.CA324 intermediate (BCLC C) HCC pts.124 TACE(38%)18 TACE + PEI(5.5%)85 curativetreatments(26.5%)68 BSC(30%)3-year survival: 32%val:- Ablation 62 months (I.C. 43-82)- Surgery 42 months (I.C. 29-55)- TACE 37 months (I.C. 30-43)- BSC 27 months (I.C. 17-36)(p<0,001)Child AChild BElderly
  • Quale trattamento per HCC intermedio?SorafenibChemoembolizationPEI/RFALivertransplantation(CLT/LDLT)ResectionCurative treatmentsHCCStage A–COkuda 1–2, PS 0–2, Child-Pugh A–BStage 0PS 0, Child-Pugh AStage DPS >2, Child-Pugh CVery early stage(0)Single <2 cmcarcinoma in situEarly stage(A)1–3 nodules <3 cm, PS0Intermediate stage(B)Multinodular,PS 0Advanced stage(C)Portal invasion,N1, M1, PS 1–2End stage(D)Single 3 nodules ≤3 cmPortal pressure/bilirubinIncreased Associated diseasesNormal No YesRandomized controlled trialsSymptomatictreatment
  • Criteri radiologici di valutazionedella risposta al trattamento
  • 1979 1992 2000 2001 2009 20102008WHOHandbook forreporting results ofcancer treatment1mWHOModified WHOcriteria2,3RECISTResponseEvaluation Criteria InSolid Tumors4EASL criteriaConclusions from theBarcelona 2000 EASLconference5RECIST 1.1Revised RECISTguidelines8mRECIST for HCCProposed modifications toRECIST 1.1 for assessingresponse in HCC6,7EASL, European Association for the Study of the Liver; HCC, hepatocellular carcinoma; RECIST, Response Evaluation Criteria In Solid Tumors;WHO, World Health Organisation.1. WHO 1979. Available at: http://whqlibdoc.who.int/offset/WHO_OFFSET_48.pdf; 2. Green S, et al. Invest New Drugs 1992;10:239-53; 3. P. TherasseAnn Oncol (2002) 13(suppl 4): 127-129 ; 4. Therasse P, et al. J Natl Cancer Inst 2000;92:205-16; 5. Bruix J, et al. J Hepatol 2001;35:421-30; 6. Llovet JM, et al.J Natl Cancer Inst 2008;100:698-791; 7. Lencioni R, et al. Semin Liver Dis 2010;30:52-60; 8. Eisenhauer EA, et al. Eur J Cancer 2009;45:228-47; 9. EASL-EORTC Guidelines. J Hepatology 2012;56:908-43Guidelines for evaluating response to treatmentin solid tumours have evolvedmRECISTEASL-EORTCHCC guideline92012
  • Conventional RECIST:longest overall tumor diametermRECIST:longest viable tumor diameterLencioni R, Llovet JM. Semin Liver Dis. 2010;30:52–60.
  • RECIST vs mRECIST criteriaDr. Golfieri(Bologna, Italy)has proposed agraphicalrepresentation ofthe change intumour dynamicfor RECIST vsmRECIST
  • TACE: concordance between EASLand mRECIST responsesGillmore R, et al. J Hepatol 2011;55:1309–16;Overall response (CR +PR), assessed at a median of 64 daysafter TACE, was:- almost identical using EASL and mRECIST- much better than that calculated with RECIST•EASL: 58%•mRECIST: 57%•RECIST 1.1: 7%
  • TACE: prognostic power of the response according tothe criteria utilizedEASL1RECIST1mRECIST1Survival similar with EASL and mRECIST, and better in pts. with an overall response,assessed at an early time point (median 64 days)1:Responder Non-responders P•EASL: 22.0 months 12.7 months 0.019•mRECIST: 20.7 months 13.3 months 0.009•RECIST 1.1: 12.4 months 16.8 months n.s1. Shim et al. Radiology 2012;262(2):708-18; 2. Llovet JM, Ducreux M, et al. J Hepatol. 2012;56:908-943
  • TACE: concordance between EASL and mRECISTresponsesRetrospective analysis: 332 patients in Korea treated with TACE1– CP-A liver function and BCLC-B disease prior to treatment•Excellent agreement between EASL and mRECIST– κ value of 0.94 (95% CI: 0.91-0.97)•Poor correlation between WHO and RECIST vs enhancement criteria– κ value of <0.20 for both comparisonsEASLRECIST mRECIST1. Shim et al. Radiology 2012;262(2):708-18; 2. Llovet JM, Ducreux M, et al. J Hepatol. 2012;56:908-943WHOOS according to:EASL-EORTC and AISF guidelines recommend mRECISTcriteria for assessment of response in HCC2
  • http://www.webaisf.org/
  • RECIST vs. mRECIST with SorafenibEdeline J et al., Cancer 2011;118:147–56Before AfterrafenibRECISTmRECIST
  • Quando continuare e quandofermarsi con la TACE?Proposta di un algoritmo AISF«razionale»
  • * percorso valido per ogni seduta di TACE; ** :i caso di cTACE è preferibile RM, in quanto alla TC l’accumulo di lipidol può “mascherare un’attività residua di malattia*** risposta al trattamento definita secondo i criteri RECIST modificati [CR: risposta completa; PR: risposta parziale; SD: malattia stabile (si intende nessunamodificazione favorevole della lesione trattata); DP: progressione di malattia.HCC CANDIDATO A TACEHCC CANDIDATO A TACE- No trombosi portale (ammessa trombosi di ramo segmentario)- No malattia extraepatica- Classe di Child Pugh A o B7Deterioramento epatico,complicazioni maggiori *CR ***RM o TCtrimestraleRecidiva di malattia ***PR ***RisoluzioneNoPalliazioneSìProgressione di malattia(DP) o non risposta altrattamento (SD) ***NuovalesioneCrescita lesionitrattate o SD***ConsideraSORAFENIBConsidera nuovo trattamento(cTACE o DEB-TACE)Trattamento cTACE o DEB-TACERM o TC **(dopo 1 mese)Trattamento cTACE o DEB-TACERM o TC **(dopo 1 mese)AISF position paper, Digest Liver Dis, 2013
  • Trattamenti combinati/sequenziali
  • Per-nodule response rate to the1stTACE: the role of tumour size• Retrospective cohort study: 271 patients eligible to TACE with 635 treated nodules• cTACE* performed ‘on demand’ upon demonstration of viable tumour (non-CR)• Tumour assessment according to mRECIST (after 1 month and then every 3–4 months)• Mean follow-up: 12 months (range 1-51)CR, complete response; PR, partial response;; TACE, transarterial chemoembolization*cTACE was 50 mg doxorubicin + Spongel; superselective technique where possibleGolfieri R et al., JVIR2013Tumor diameter ≤2 cm (N=386) 2.1-5 cm (N=211) >5 cm (N=36)N. nodes % N. nodes % N. nodes %Tumour responseCR 263 68 134 64 9 25PR 123 32 77 36 27 75Local RecurrenceRate52 20 36 27 6 57Only 25% of large (>5 cm) nodules achieve CR and, in these nodules,local relapse is very frequent.
  • Trattamenti locoregionali combinatiMarelli L et al., Cancer Treatment Rev 2006; 32:594-606OR = 0.53 (95% CI = 0.29-0.99)
  • Trattamenti locoregionali combinatiWang W et al., Liver International 2010; 30: 741-749Sopravvivenza a:- 1 anno: 512 paz. → OR = 3.26 (95% CI = 1.23-8.69)- 2 anni: 437 paz. → OR = 4.53 (95% CI = 2.62-7.82)- 3 anni: 425 paz. → OR = 3.50 (95% CI = 1.75-7.02)Confronto N. trials:•TACE + PEI vs. TACE 4•TACE + RF vs. RF 2•TACE + PEI vs. PEI 1•TACE + RF vs. TACE 1•TACE + PEI vs. TACE o PEI 1•TACE + RF vs. TACE o RF 1Recurrence rate
  • Preliminary OS from start of sorafenib therapy in patients who did and did notreceive concomitant TACECI, confidence interval; OS, overall survival ASCO GI 2012
  • Trattamenti locoregionali combinatiAISF position paper, Digest Liver Dis, 2013
  • SorafenibTarget: 40%OS: 11 mo (6-14)Portal pressure/bilirubinHCCPEI/RFAStage 0PST 0, Child–Pugh AVery early stage (0)1 HCC < 2 cmCarcinoma in situEarly stage (A)1 HCC or 3 nodules< 3 cm, PST 0End stage (D)Liver transplantation TACEResectionCurative treatments (30%)5-year survival (40–70%)Target: 20%OS: 20 mo (45-14)Associated diseasesYesNo3 nodules ≤ 3 cmIncreasedNormal1 HCCStage DPST > 2, Child–Pugh CIntermediate stage (B)Multinodular,PST 0Advanced stage (C)Portal invasion,N1, M1, PST 1–2Stage A–CPST 0–2, Child–Pugh A–BEASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. Journal of Hepatology 2012 vol. 56 j 908–943Best supportivecareTarget: 10%OS: <3 moUpdated BCLC staging system andtreatment strategyPST 0-1
  • Sorafenib increased overall survival indifferent patient populations1.000.750.500.250 4 6 8 10 12 14 1620.0018SurvivalprobabilityMonthsSorafenib (n = 150)Median OS: 6.5 months(95% CI: 5.6–7.6)Placebo (n = 76)Median OS: 4.2 months(95% CI: 3.7–5.5)1.000.750.500.250 4 8 12 220.002 6 10 14 16 18 20HR = 0.68Asia–Pacific 21. Llovet JM, et al. N Engl J Med. 2008;359:378-90.2. Cheng A-L, et al. Lancet Oncol. 2009;10:25-34.SurvivalprobabilityMonthsSorafenib (n = 299)Median OS: 10.7 months(95% CI: 40.9–57.9)HR = 0.69SHARP 1Placebo (n = 303)Median OS: 7.9 months(95% CI: 29.4–39.4)Sorafenib prolongs OS by 44% Sorafenib prolongs OS by 47%
  • Sorafenib dose and overall survival in clinical practiceSOFIA studyGIDEON study
  • • Systemic chemotherapy with conventional agents, octreotide, interferon,tamoxifen, and anti-androgenic drugs has no role in HCC treatment (1b-A).****• Full dose sorafenib is the recommended treatment for HCC patients withpreserved liver function who are not amenable to surgery and loco-regional treatments or in whom TACE failed, according to the ItalianNational Health Service rules (1b-A).In patients intolerant to full dose sorafenib, the tolerance to a reduced dose(400 mg/day) is to be pursued before definitively suspending thetreatment (2b-B).****• HCC patients who cannot receive any effective treatment for HCC mustreceive symptomatic treatment for pain management, and nutritional andpsychological support (5-D).Terapia sistemica dell’HCC:raccomandazioni AISFAISF position paper, Digest Liver Dis, 2013
  • Terapia antivirale:raccomandazioni AISF• All HBV-DNA positive patients should receive antiviraltherapy with nucleos(t)ide analogues at the time of and afterHCC treatment (2b-B).• HCV-RNA positive patients with preserved liver function(Child-Pugh class ≤8) whose HCC has been treated withcurative intent should be considered potential candidates toantiviral therapy (2b-B).• The AISF position on the usage of antiviral drugs is reported in greaterdetailed elsewhereAISF position paper, Digest Liver Dis, 2013
  • Fine(finalmente!)