Liver Transplantation for Hilar Cholangiocarcinoma Mary Douglas, RN, MSN,CCTC Clinical Transplant Coordinator University of Wisconsin- Madison

Case Study 44 yo male with PSC/ UC. Dx with UC age 37, PSC at age 42 ERCP 5 years after diagnosis revealed adenocarcinoma via brushings FISH positive for polysomy Presented with weight loss, obstructive jaundice and abdominal discomfort

Diagnosis of Cholangiocarcinoma CCA is slow growing tumor that invades adjacent neural, lymphatic and hepatic tissue. Intertwining with bile ducts. Brushings are 50% accurate, now use FISH ( fluorescence in situ hybridization) Median survival of unresectable disease with only XRT is 9-12 months. With surgical resection, median survival is months with 5 year survival at 5-20%

Liver Transplantation 1980’s Liver txp was used for unresectable tumor, only 10-20% survived >5years. CCA –contraindication for oltx

Mayo Protocol 1993 Diagnosis of CCA established- –Biopsy( transluminal) positive for cancer –Positive or suspicious cytology on brush cytology –Stricture, and FISH polysomy –Mass lesion on cross-sectional imaging –Malignant-appearing stricture and CA19- 9>100 or FISH polysomy

Indeterminate Diagnostic Criteria FISH trisomy ( 7 or 3) Dysplasia DIA>1.8 in isolation(FISH neg,cyt neg) FISH polysomy in absence of malignant- appearing stricture Malignant-appearing stricture in absence of mass lesion, positive cytology, biopsy, elevated CA19-9 or FISH polysomy

Prior to protocol EUS guided regional lymph node aspiration routinely before beginning neoadjuvant therapy. The identification of lymph node metastases obviated the need for exploratory laparotomy and disqualified the patients from subsequent liver transplantation With the introduction of EUS in 2002, the percentage of patients with a positive staging laparotomy has decreased from 30 to 15%.

Mayo Protocol Neoadjuvant Therapy Neoadjuvant therapy ( cGy) is administered by external beam radiation in 30 fractions Followed by transcatheter radiation ( cGy) with iridium-192 wires( brachytherapy) These wires placed by ERCP or PTC Infusional 5-FU is given during XRT, followed by oral capecitabine after the radiation therapy until the day of oltx.

Protocol Staging laparotomy is preformed upon completion of neoadjuvant radiotherapy. Usually within 2-3 weeks after brachy therapy. This involves complete abdominal exploration with biopsy of any lymph nodes/nodules suspicious for tumor, examination of tumor, and routine biopsy of regional lymph nodes. At least one lymph node must be taken. (laparoscopic?) If negative staging operation, then eligible for listing for OLTX MELD exception=22 in Region 7. 10% MELD upgrade every 3 months if not transplanted

Liver Transplantation If LRD, do staging operation 1-2 days prior If CAD, stage, waitlist, MELD exception During oltx, if there is microscopic tumor involvement, a pancreaticoduodenectomy is also preformed Unique complications with LRD vs. CAD with vessels due to XRT exposure.

Outcomes :167 patients 12 deaths,2 txp elsewhere,10 received neoadjuvant rx. 143 had irradiation and 5FU and staging 27 were positive (19%), 2 waitlist, 1 death, 2 txp elsewhere 111 transplants, 75 CAD,35 LRD,1 domino

Outcomes 1 -,3-, and 5-year patient survivals after the start of therapy(167) are 84%, 64% and 56%. 1-,3-,and 5-year patient survivals after liver transplantaion ( N=111)are 96%, 83%, and 72%. No difference in survival regarding LRD vs.CAD There have been 15 recurrences in 111 oltx (14%), occurring at a mean of 25 months after oltx (range: 7-64 months).

Organ Allocation To get MELD exception: Transplant center submit formal patient care protocols to UNOS Liver /Intestinal Committee Candidates satisfy accepted diagnostic criteria for CCA and be considered un-resectable on basis of technical considerations or underlying liver disease (PSC) tumor mass <3cm diameter on imaging imaging studies to r/o mets negative exploratory lap primary tumor cannot be biopsed

Further investigations OLTX is superior in outcomes to resection Should this therapy be applied to other patients without liver disease ( PSC)? Neoadjuvant therapy with XRT can damage bile ducts, which precludes biliary reconstruction after resection.

Summary Role of oltx in setting of CCA has undergone radical changes in past 20 years. With rigorous patient selection,neoadjuvant XRT, operative staging and oltx, the protocol has achieved a 72% survival at 5 years. We need to continue to work on advances in XRT, chemo agents, protocol development Future role of this therapy for patients with resectable tumors, but outcomes not as positive as in liver transplantation.

Patient Case Study Patient went thru this protocol, exploratory lap was negative. MELD=22 Got exception to 25 after 3 months Transplanted 4 months after getting to list CA19-9=125. Age<45 Out 3 years to date. No recurrence

Bibliography: Gores GJ. Cholangiocarcinoma: current concepts and insights. Hepatology 2003; 37: De Vreede I, Steers JL, Burch PA, Rosen CB, Gunderson LL, Haddock MG, et al. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl 2000; 6: Sudan D, DeRoover A, Chinnakotla S, Fos I, ShawB, Jr, McCashland T, et al. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transplant 2002;2: Burak K, Angula P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol 2004; 99: Brandsaeter B, Isoniemi H, Broome U, Olausson M, Backman L, Hansen B, et al. Liver transplantation for primary sclerosing cholangitis; predictors and consequences of hepatobiliry malignancy. J Hepatol 2004; 40: Heimbach J, Haddock M, Alberts S, Nyberg S, Ishitani M, Rosen C, Gores G. Transplantation for Hilar Cholangiocarcinoma. Liver Transplantation 2004; 10:S65-S68. Rea, DJ.,et.al,Liver Transplantation with Neoadjuvant Chemoradiation is More Effective than Resection for Hilar Cholangiocarcinoma. Annals of Surgery:242;3,Sept 2005 Lazaridis KN, Gores GJ. Semin Liver Dis.2006 Feb:26(1):42-51 Heimbach, JK, et.al.,Transplantation 2006 Dec 27:82(12):1703-7

Bibliography Rosen, CD, Heimbach, JK, Gores, GJ Surgery for cholangiocarcinoma: the role of liver transplantation. HPB 2008 June 1: 10(3): Rea, DJ, Rosen,CB,Nagorney,DM, Heimbach, JK, Gores, GJ Transplantation for Cholangiocarcinoma: When and for Whom? Surg Oncol Clin NAM 18(2009) Heimback,JK, Gores, GJ, Haddock,MG, Alberts,SR,Pedersen, R, Kremers, W, Nyberg,Sl, Ishitani, MB, Rosen, CB. Predictors of Disease Recurrence Following Neoadjuvant Chemoradiotherapy and Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma