TRANSPLANTATION HEPATIQUE POUR CARCINOME HEPATOCELLULAIRE

TRANSPLANTATION HEPATIQUE POUR CARCINOME HEPATOCELLULAIRE Professeur Didier SAMUEL Centre Hepatobiliaire, INSERM Unit 785 Hopital Paul Brousse, Université Paris Sud

Guidelines de Prise en Charge du CHC Llovet, Bruix Lancet 2009 C.H.B

INTRODUCTION Indications validated for LT for HCC: Milan criteria: 1 single nodule < 5 cm 3 Nodules < 3cm No vascular invasion Indications to be validated: UCSF Criteria One single nodule < 6.5 cm Three Nodules with a Tumor mass < 8.5 cm No vascular invasion

Indication CHC Sur les Listes d Attente en France 2007-2008 60 50 40 30 20 10 48 40 40 41 42 44 44 28 28 28 30 30 31 34 35 35 36 37 37 37 part des CHC 0 BO5FA LY3FD ST2FA PP7FA CF3FA PC7FA NI4FR BE2FA TO5FR CA6FA GR3FA MO5FA MA4FC PJ7FA LY3FP LI1FA PH7FA PI7FA PD7FA RE6FA équipes de greffe * Sauf SU et pédiatrie

Impact des Critères d Allocation des Greffons pour CHC aux USA Ioannou Gastro 08

SURVIE A 5 ANS APRES TH SELON LES CRITERES MILAN, UCSF, > UCSF CRITERIA Yao AJT 08

Survie après TH pour CHC selon le nombre et la Taille des Nodules Not taking into account microinvasion Without Vascular microinvasion With Vascular microinvasion Mazzaferro Lancet Oncology 2009 C.H.B

Survie après TH pour CHC selon le nombre et la Taille des Nodules 7 criteria: 7 = sum of the size of largest nodule (cm) + number of nodules Mazzaferro Lancet Oncology 2009 C.H.B

AFP, DCP and L3 AFP as Biomarkers in early HCC Afp Cut-off 10.9 ng/ml remains the best biomarker Marrero Gastro 09

Specificity and Sensitivity of AFP in early Viral and non-viral HCC Marrero Gastro 09

Impact de l AFP et du Score de Meld sur la Survie Post-TH Ioannou Gastro 08

Augmentation de l AFP > 15 ng/ml/mois et Récidive du CHC Post-TH Vibert AJT 2010

Augmentation de l AFP > 15 ng/ml/mois et Survie Sans Récidive Vibert AJT 2010

Accès à la Transplantation pour CHC en France 2007-2008 médian waiting time No HCC : 2.7 months HCC : 5.4 months P<0.0001 * Sauf SU et pédiatrie

SORTIE DE LISTE D ATTENTE ( DROP OUT) Risk Increased with time Depends of the size and number of nodules at listing When to drop out?: Increased HCC out of Milan criteria or UCSF criteria? Vascular invasion? Interval of surveillance on the waiting list? Treatment of HCC to avoid drop out?

Taux de Sortie de Liste Chez les Patients avec CHC Majno J Hepatol 2005

Strategies à Geneve chez les Patients avec CHC en attente de TH Majno J Hepatol 2005

STRATEGIES Depends of the waiting time Main possibilities: Percutaneous treatment : Radiofrequency Transarterial chemoembolisation Surgical Resection Targeted Therapies?

Probability de Survie dans le CHC En Intention de Traiter Survival After LT Survival After Registration on the waiting list LT Lu Hepatology 2005

Yao Hepatology 2005 Downstaging pour CHC avant TH

Survie et Echec chez les Patients avec CHC Après Tentative de Downstaging Yao Hepatology 2005

Récidive après Traitement Percutané pour CHC Lin SM Gut 2005; 54: 1151-1156

Résultats de la Radiofréquence pour CHC Mazzafero Ann Surg 2006

Probabilité de Persistance Tumorale à la TH selon le Délai d Attente après Radiofréquence pour CHC Mazzafero Ann Surg 2004

Resultats de la Radiofrequence pour CHC Lu Hepatology 2005

Facteurs de Récidive après Radiofréquence pour CHC Kim YS EJR 2006

Facteurs de Récidive après Radiofréquence pour CHC Kim YS EJR 2006

CHIMIOEMBOLISATION ARTERIELLE LIPIODOLEE Survival: chemoembolisation vs control 100 Survival rate (%) 80 60 40 20 Control (n=35) Chemoembolization (n=40) p<0.009 Patients at risk 0 0 12 24 36 48 60 months Chemoembolization 40 29 14 4 2 Control 35 19 7 3 0 Llovet JM et al. Lancet, 2002. C.H.B

Impact du Downstaging Post-Chimioembolisation avant TH Majno Ann Surg 1997

Downstaging avant Transplantation Yao Hepatology 2005

Yao AJT 2008 Downstaging avant Transplantation

Impact du Downstaging pour CHC Yao Liver Transplant 2005

Benefice de la CE selon la Durée du Temps d attente de la TH TACE Benefit -Porrett post-meld (54d) -Oldhafer (118d) -Decaens (128d) -Roayaie (142d) +Graziadei (178d) +Yao (180d) +Maddala (211d) +Fisher (277d) -Hayashi (343d) -Porrett pre-meld (574d) Time Aloia T, Adam R, Samuel D, J Gastro Intest Surg 2007 C.H.B

Disease Free Survival in HCC According to TACE Decaens Liver Transplant 2005

Absence de récidive Post-TH selon la Progression sous CE Otto Liver Transplant 2005

Survie Après TH en Fonction de la Réponse à La CE Pre-TH Transplanted Patients After Dowstaging All Patients No Response to TACE Otto Liver Transplant 2007

Survie sans récidive à 5 ans après TH selon la Nécrose post-ce D un Nodule< 5cm Dharancy Liver Transplant 2007

TH d Emblée Vs TH de sauvetage pour CHC sur Cirrhose Belghiti Ann Surg 2003 C.H.B

TH d Emblée Vs TH de sauvetage pour CHC sur Cirrhose Overall survival Disease-Free Survival Adam, Ann Surg 2003; 238: 508-519 C.H.B

TH d Emblée Vs TH de sauvetage pour CHC sur Cirrhose Hwang Liver Transplant 2007

TH d Emblée Vs TH de sauvetage pour CHC sur Cirrhose Hwang Liver Transplant 2007

Résection Hépatique Avant TH Good results in CPT A patients with one small HCC nodule Risk of recurrence depends from: The margin of resection The histological criteria of HCC The control of the cause ( HCV, HBV, alcool) Transplantability in case of recurrence Variable Not 100%( 50%?) Requires a cautious follow-up

RELATIONSHIP BETWEEN HBV DNA LEVEL AND HCC IN TAIWAN Chien-Jen Jama 2006; 295: 65-73

Progression of Disease on Lamivudine in Chronic Hepatitis B and HBV Cirrhosis Yun-Fan-Liaw NEJM 2004; 351: 1521-1531

PREVENTION OF HCC WITH IFN IN HCV + PATIENTS Heathcote Gastroenterology 2004; 127: S294-S302

PREVENTION OF HCC AND LIVER DECOMPENSATION WITH IFN IN HCV + PATIENTS Shiratori Ann Int Med 2005; 142: 105-114

Evaluation de l Explant Hépatique 20-30% under, over estimation of size and number of nodules Milan and UCSF criteria based on explant analysis Differenciation: Edmonson Grade Number and size of nodules Presence of capsule Satellite nodules Percentage of necrosis Micro or macro Vascular invasion Gene signature, Fractionnal allelic imbalance Final classification C.H.B

Resultats de Radiofréquence pour CHC Analyse de l Explant Complete Response Partial Response Cn coagulative Necrosis, T tumor, TS Satellite Tumor Mazzafero Ann Surg 2004

Provided by C Guettier Invasion Microvasculair

Provided by C Guettier Tumeur Résiduelle après CE

Edmonson Histologic Grade I II Provided by C Guettier III IV

A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells Lee Nature Med 2006

Prediction of HCC Recurrence After Surgery Liver Gene Signature of the Adjacent Liver Tissue Yoshida NEJM 2008 C.H.B

Fractional Allelic Imbalance (FAI) as a Marker of HCC Recurrence in Patients Beyond the Milan Criteria Schwartz J Hepatol 2008 C.H.B

MONITORING AFTER LIVER TRANSPLANTATION CT Scan abomen + thorax every 3-4 months Alternance with US AFP level if elevated prior to LT Duration unknown» Some cases of late recurrence afer 5 years. C.H.B

MODULATION OF IMMUNOSUPPRESSION IS has been associated with progression of tumoral cells Strategy to decrease IS is logical, but efficacy not proven Deleterious role of some drugs: calcineurin inhibitors? Beneficial role of mtor inhibitors: Sirolimus, Everolimus? Slver Study (ongoing) RCT of introduction of Sirolimus at month 1 in patients transplanted for HCC C.H.B

5 FU+Doxorubicin+Cisplatin (Olthoff Ann Surg 1995, Shimoda Liver Transplant 2004) Doxorubicin (Stone Gastro 1993) Doxorubicin in patients with large tumors (Royaie Ann Surg 2002) Doxorubicin (RCT 19 patients) ( Soderdahl Transplant Int 2006) Few RCT No proof of efficacy Morbidity: CHEMOTHERAPY POST-LT Controversial results» Liver toxicity» Leucopenia, Thrombocytopenia» Pneumocystosis, CMV infection, Pneumonia C.H.B

CHEMOTHERAPY POST-LT Options: Treat all patients: probably not acceptable» Low risk of recurrence in Patients with Milan Criteria» Reserved to patients outside Milan Criteria?» Reserved to patients with high risk of recurrence: Vascular invasion, poor differentation, Satellite nodules.. RCT needed C.H.B

CHEMOTHERAPY POST-LT Which drug? Doxubicin, Toxic No proof of efficacy» Combination Gemcitabine,oxaliplatine ( Gemox)» New targeted therapies: Sorafenib.» Need to be evaluated: Survival Ratio Benefit/risk: When to start? duration? C.H.B

INTERACTION WITH HCV HCV recurrence constant HCC has been associated with poorer survival Role of antiviral therapy with IFN on HCC recurrence unknown Increased progression of HCV related fibrosis due to post-transplant chemotherapy? Differential diagnosis beween de novo HCC on HCV cirrhosis on the graft and recurrent HCC C.H.B

HCC AND HBV RECURRENCE POST-LT Univariate analysis of risk of HBV recurrence HCC Recurrence Cumulative Corticosteroid doses Post-LT Chemotherapy Multivariate analysis of risk of HBV recurrence Cumulative corticosteroid doses Post-LT chemotherapy HJ Yi Liver Transplant 2007; 13: 451-458 C.H.B

HBV Recurrence In Patients with and without HCC Paul Brousse 1995-2005 Faria Gastroenterology 2008

HBV Recurrence In Relation with Presence of HCC Within or Without Milan criteria Paul Brousse 1995-2005 Faria Gastroenterology 2008

HBV Recurrence In Relation with HCC Recurrence Paul Brousse 1995-2005 Faria Gastroenterolgy 2008

CONCLUSION 1 nodule HCC < 3 cm on Child A cirrhosis If Cause of cirrhosis controlled No LT first line if complete response to resection, RF LT if recurrence or partial response But transplantability when recurrence to be evaluated Within Milan Criteria 1 nodule HCC > 3cm ou 2-3 nodules LT first line

CONCLUSION Patients Within UCSF ou up to seven criteria 30-40% of current indications of LT LT But Evaluation of results Patients outside these criteria High risk of recurrence LT probably not indicated

STRATEGIES BEFORE LT No treatment before LT: Interesting in case of unique nodule with short waiting time Only possibilty in Child C cirrhosis Risk of transplanting aggressive tumor Treatment before LT: Able to stabilize the tumoral evolution for transient period Possibility of downstaging Selection of tumor with low progression rates Beneficial in case of intermediate waiting time and in case of full necrosis or downstaging Type and strategy still to be defined