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 11-38 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 (4000-4500 cGy) is administered by external beam radiation in 30 fractions

• Followed by transcatheter radiation (2000-3000cGy) 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

• 1993-2008:167 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: 961-969.

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: 309-316.

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: 774-779.

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: 523-526.

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: 815-822

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): 186-189.

• Rea, DJ, Rosen,CB,Nagorney,DM, Heimbach, JK, Gores, GJ Transplantation for Cholangiocarcinoma: When and for Whom? Surg Oncol Clin NAM 18(2009)325-337.

• 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