Liver Transplantation for HCC, CCA, CRLM
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1 Liver Transplantation for HCC, CCA, CRLM Robert J. Porte Professor of Surgery HPB Surgery and Liver Transplantation University Medical Center Groningen Groningen, The Netherlands
2 Liver Transplantation for Malignant Tumors Hepatocellular Carcinoma Cholangiocarcinoma Colorectal liver metastases
3 Liver Transplantation in The Netherlands transplants / year 100 Adults 20 Children International collaboration and sharing via Eurotransplant Leiden Rotterdam Groningen
4 Survival After Liver Transplantation UMCG % year survival 70-80% Years
5 Indications for Liver Transplantation in Europe (n=79,044) 13% for cancer European Liver Transplant Registry
6 Indications for Liver Transplantation Hepato-Biliary Cancers in Europe Metastases 8% Biliary tract cancer 6% HCC 72% Peripheral Cholangioca 5% Others 9%
7 Why Only 13% of Liver Transplantations for Malignancy? There is donor organ shortage We have to deal with the gap between supply and demand and to ensure: Avoidance of death on the waiting list Optimization of outcome and avoidance of futility
8 The Gap Between Donor Liver Supply and Demand
9 Evolution of Indications for Malignancies in Europe ELTR 12/ % 80% 60% 40% 20% 0% Hepatocellular carcinoma : 5622 Cholangiocellular carcinoma : 269 Carcinoma biliary : 256 Metastases : 443 Others : 480
10 Liver Transplantation for Malignant Tumors Hepatocellular Carcinoma Cholangiocarcinoma Colorectal liver metastases
11 Hepatocellular Carcinoma - Epidemiology - Malignant tumor arising from hepatocytes, Most frequent primary hepatic cancer worldwide Third leading cause of cancer mortality worldwide 0.5 to 1 million cases / year worldwide Wide geographic variability Male : Female = 4 : 1
12 Hepatocellular Carcinoma - Etiology - Clear relationship between HCC and cirrhosis 80-90% of all HCC originates in cirrhotic livers Annual risk of developing HCC in cirrhosis: 1-6% All types of cirrhosis are at increased risk
13 Hepatocellular Carcinoma - Treatment Modalities - With curative intent: Partial liver resection Liver transplantation Local ablative therapy radio frequency or microwave ablation (RFA/MWA) Palliative: Sorafinib (tyrosine kinase inhibitor) Transarterial chemoembolization (TACE) Yttrium-90 radioembolization (microspheres)
14 Hepatocellular Carcinoma - Indications for Liver Transplantation - The Milano or Mazzaferro Criteria: Cirrhosis 1 HCC < 5 cm, or 3 HCCs < 3cm Mazzaferro et al. New Engl J Med 1996; 334: Survival after liver transplantation for HCC within these criteria is similar to that for other indications: 70-80% survival at 5-years
15 The Milan Criteria (based on tumor size) are not relevant for HCC in otherwise normal livers Relevant factors: - No macrovascular invasion - No lymph node metastases - > 12 months after primary resection
16 Published Online November 2011
17 Liver Transplantation for Malignant Tumors Hepatocellular Carcinoma Cholangiocarcinoma Colorectal liver metastases
18 Cholangiocarcinoma Incidence 1 per 100,000 / yr In US: ± 3000 new cases / yr Predisposing factors: PSC / ulcerative colitis Inflammation Intrahepatic stone disease Liver flukes ± 10% 60-70% 20-30% Generally divided in: Intrahepatic Perihilar Distal
19 Liver Transplantation versus Resection for Cholangiocarcinoma Resection not possible: Anatomical situation Vascular encasement Bilateral intrahepatic extension Concomitant liver pathology Fibrosis, cirrhosis (PSC) Portal hypertension Potential advantages of transplantation: Most radical resection / full hepatectomy Lower risk of postoperative liver failure No small remnant liver volume No remnant diseased liver tissue (e.g. PSC)
20 Overall Results of Liver Transplantation For Cholangiocarcinoma (ELTR) Low overall 5-year survival: 10-30% High tumor recurrence rate However: Majority had advanced disease: stage III or IV tumors No (neo)adjuvant treatment In the mean time: Better imaging techniques (better selection possible) Lower perioperative mortality More specific immunosuppressive medication Neo-adjuvant chemoradiation protocols
21 Mayo Clinic Protocol Entry Criteria Perihilar cholangiocarcinoma Brush cytology or endoscopic biopsy, or CA19-9 > 100 ng/ml + malignant stricture, without cholangitis Unresectable tumor Tumor diameter 3 cm No intra- or extrahepatic metastases (Stage I or II) CT scan and MRI EUS-guided FNA of regional lymph nodes No prior abdominal radiation therapy No transperitoneal or transgastric biopsy of the primary tumor No prior attempt at resection with violation of the bile ducts
22 Neo-Adjuvant Treatment Protocol External beam radiation therapy 5-Fluorouracil Brachytherapy with Iridium 192 Exploratory laparotomy (20-25% drop out) Capecitabine
23 Survival and Recurrence Following Transplantation for CCA at Mayo Clinic > 1500 patients referred 148 have begun neoadjuvant therapy at Mayo Clinic since 1993 (65% had PSC) 90 had favorable findings at staging laparotomy and underwent transplantation Overall recurrence rate: 17% 5-year survival for all patients that began neoadjuvant therapy: 55% 5-year survival after Tx: 71% 5-year disease free survival: 60% Heimbach, et al. Transplant 2006 Gores, et al. J Hepatol 2007 Rosen, et al. HPB 2008
24 Other Important Unanswered Questions What is more important? Better preoperative staging and selection of only stage I and II? Or neoadjuvant therapy? Nordic experience, without neoadjuvant Rx Spanish multicenter experience without neoadjuvant chemo- or radiotherapy 5 year survival for stage I and II: 47% 5 year survival for stage III and IV: 15% Robles, et al. Ann Surg 2004 Brandsaeter, et al. J Hepatol 2004
25 Liver Transplantation for Cholangiocarcinoma in the Netherlands Accepted indication since 2011 Very strict screening protocol Only stage II or lower Screening according to Mayo Clinic protocol No neo-adjuvant chemo-radiation therapy
26 Liver Transplantation for Malignant Tumors Hepatocellular Carcinoma Cholangiocarcinoma Colorectal liver metastases
27 Liver Transplantation for Colorectal Liver Metastases Currently considered an absolute contraindication ELTR: 55 patients transplanted for CRLM Vienna experience: 24 patients ( ) 5-year survival: 18% Muhlbacher, et al. Transplant Proc 1991; 23: 1567
28 2010 Major advances have been made in the fields of oncological treatment and transplantation since the mid 1990 s. Better chemotherapeutic strategies Better imaging and staging Genetic detection of lymph node micrometastases (Kras, p53)
29 Liver Transplantation for HCC, CCA and CRLM Conclusions Balance between organ demand and supply We have to avoid futility (5-year survival <50%) HCC and CCA are accepted indications for liver transplantation in the Netherlands HCC in cirrhotic liver: within Milan criteria HCC in normal liver: no macrovascular invasion no lymph node metastases or > 12 months after primary resection CCA: Stage II or less (lymph node negative) CRLM: not an indication for transplantation because of low survival rates
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