Liv iver T Trans anspl plan antat ation Op Option ions f for or Chola langioca carci cinoma ma Keri E E. Lunsford, M MD, Ph , PhD, FACS Assistant Professor of Surgery Director of Transplantation Research Division of Transplant and Hepatobiliary Surgery Center for Immunity and Inflammation Rutgers / New Jersey Medical School
Perihilar and Intrahepatic Cholangiocarcinoma • Prognosis grim if unresectable – Expected survival 6-12 months • Only ~40% resectable at Dx – 2/3’s resected pts recur • Challenges with resection – Infiltration beyond radiographic tumor extent – Location near critical structures • Liver transplantation offers an alternative to resection in select patients – Achieves tumor-free margins – Treats parenchymal invasion – Removes underlying tumor
Historic outcomes for transplant for cholangiocarcinoma compared to other liver cancers Thelen 2011 J HPB Surg
Mayo Clinic Protocol for Liver Transplant for Perihilar CCA External Beam Radiation Ma Mayo C Clin inic Selection Crit iteria ia • (4500 cGy in 30 Fractions) + – Early stage hilar CCA 5FU – Diagnostic criteria: Intrabiliary Brachytherapy • Malignant appearing stricture or mass with one of the following: (2000-3000 cGy) + – Malignant cells by biopsy or cytology 5FU – Positive aneuploidy – CA19-9 >100 Exploratory Laparoscopy – Unresectable disease due to liver disease or mass location - Rule out peritoneal mets – If mass present must be <3cm -Perihilar LN biopsy – No LN metastases – Biliary sepsis controlled Oral capecitabine – No intrahepatic CCA – No prior transperitoneal biopsy or prior surgical resection Liver Transplantation Panjana 2012 Liver Transplantation
Transplantable Hilar CCA by Mayo Criteria Zamora-Valdes 2018 Gastroentero Clin N Am
Mayo Clinic Protocol for Liver Transplant for Perihilar CCA Survival following phCCA Treatment • Outcomes for Mayo Clinic Protocol – Recurrence rates • 13% for OLT • 27% for Resection – Improved survival over resection – 42% had no residual disease on explant (complete pathologic response) – Predictors of recurrence • Lack of pathologic response on explant • Pre-transplant portal vein encasement Rea 2005 Ann Surg
Multicenter Evaluation of Mayo Clinic Protocol for Transplantation in Perihilar CCA • 12 center consortium 287 patients • • Outcomes: – Within Mayo– 69% 5yr RFS – Outside Mayo -32% 5yr RFS Murad et al. Gastroenterol 2012.
Liver Transplantation for De Novo versus PSC Associated Perihilar Cholangiocarcinoma • PSC A Associ ciated d phCCA hCCA • De N Novo phCCA hCCA – Lifetime incidence of – More likely resectable CCA 6.8-13% – Older age (64±10 yrs) – Younger age (47±9 yrs) – Larger tumors at – Earlier stage at diagnosis diagnosis, more likely – Mayo 5-year survival multifocal after liver transplant – Pathologic confirmation 56% (n=68) often absent – Outcomes more – Mayo 5-year survival comparable to R0 after liver transplant resection 77% (n=113) Zamora-Valdes 2018 Gastroentero Clin N Am
Liver Transplantation for Cholangiocarcinoma • Currently accepted as indication for liver transplantation for perihi hila lar C CCA meeting Mayo criteria per UNOS/OPTN guidelines • Must have institutional protocol in place • Patients receive MELD exception for waitlist prioritization HOWEV EVER ER • Per ILCA guidelines 2014: – Liver transplantation is not r t recom ommended for Intrahepatic cholangiocarcinoma or Hepatocholangiocarcinoma because results are well below those published for standard indications
Liver Transplant for Intrahepatic Cholangiocarcinoma • International multicenter retrospective study – 17 multinational center participation – All tumors incidental or misdiagnosed preTx as HCC in cirrhotic pts – Most patients received preTx LRT – Excluded patients receiving neoadjuvant therapy – Two groups • “Very Early” iCCA: Single tumor < 2cm • “Advanced” iCCA: Single tumor > 2cm or Multiple tumors Sapisochin 2016 Liver Transplantation
Liver Transplantation for Intrahepatic CCA Tumor Recurrence Overall Survival Liver Transplantation reasonable for patients with “very early” iCCA <2 cm Sapisochin 2016 Liver Transplantation
Risk Stratification for Disease Recurrence Following Liver Transplant for Cholangiocarcinoma Hong 2011 JACS • Retrospective Evaluation of 43 pt undergoing liver transplant for cholangiocarcinoma • 26 iCCA and 14 phCCA • Intrahepatic location and pretransplant neoadjuvant therapy associated with improved outcomes
Prospective Evaluation of Liver Transplant for Intrahepatic Cholangiocarcionma • Prolonged disease stability/response to chemotherapy may be used to select for biologically favorable intrahepatic cholangiocarcinoma for liver transplant – Stable disease > 6 months – Continued neoadjuvant therapy until transplant
The Methodist-MD Anderson Protocol for Liver Transplant in Intrahepatic CCA • Tumor Characteristics • Biopsy proven CCA • Intrahepatic location • Not amenable to surgical therapy • No evidence of extrahepatic disease • Prior resection allowed if >6 months from listing and all other criteria met • Diagnostic Criteria • Triple phase CT of the Chest/Abd/Pelvis • MRI bone scan • FDG-PET • EUS guided biopsy of enlarged nodes Lunsford 2018 Lancet Gasto and Hep
The Methodist-MD Anderson Protocol for Liver Transplant in Intrahepatic Cholangiocarcinoma Neoadjuvant Chemotherapy • First line platinum-based therapy + gemcitabine • Second-line chemotherapy for progression or intolerance • Addition of targeted biologics on case-by-case basis Disease stability for at least 6 months on given regimen • Repeat Imaging every 3 months • Radiographically stable or regressing disease • No extrahepatic disease • Post-transplant adjuvant therapy for 4-6 months depending on explant pathology
The Methodist MD-Anderson Experience for Liver Transplant in Intrahepatic Cholangiocarcinoma N=14 Excluded due to Extrahepatic Disease N=5 Down-Staged or Resected N=1 N=41 N=11 Medically Unacceptable Referred for Evaluation Transplanted Candidate N=2 N=2 Currently Undergoing Further Down-Staged to Evaluation Resection N=2 N=19 Aborted at Exploration Listed for Liver Transplant Due to Adhesive Disease N=3 Actively Awaiting Transplant N=1 Delisted Due to Disease Updated from Lunsford KE et al 2018 Lancet Gastro Hep Progression
Radiographic Tumor Characteristics for Patients Transplanted for iCCA Lunsford 2018 Lancet Gasto and Hep
Intention to Treat Analysis of Patients Listed for Locally Advanced iCCA N=17 Listed for Liver Transplant N=11 N=6 Transplanted Delisted N=2 Further Down- Staged to Resection N=2 Aborted at Transplant N=2 Delisted due to disease progression
Survival Following Liver Transplantation for Intrahepatic Cholangiocarcinoma Updated from Lunsford KE et al 2018 Lancet Gastro Hep
Explant Pathologic Tumor Characteristics for Patients Transplanted for iCCA Characteristics Median 1 2 3 4 5 6 7 8 9 10 11 Explant II II II IIIA I II IIIB II II 0 II Stage (TMN) II T2N0 T2N0* T2N0* T3N0 T1bN0 T2N0 T4N1* T2N0 T2N0 T0N0 § T1aN0 T2N0 # of lesions 3 8 6 10 1 1 10 1 1 3 0 1 Max size (cm) 6.5 4.2 9.0 3.5 5.2 6.5 10.5 8 8.5 2.0 0 3.6 18·7 13·0 15·3 5·2 6·5 20·0 8 8.5 5.3 0 3.6 Total Diameter (cm) 8.5 Bilobar Bilobar Bilobar Left Left Bilobar Bilobar Bilobar Bilobar N/A Right Location N/A Differentiation Poor Well Poor Mod Mod Poor Mod Poor Mod N/A Mod Lymphatic Invasion No Yes No Yes No No No Yes Yes No No No Perineural Invasion No No No No Yes No No Yes Yes No No No Yes No Yes No No No Yes Yes No No No Microvasc Invasion No No No No Yes No No Yes No No No No Positive Margins No Percent Necrosis 0% 0% 95% 0% 0% 0% 90% 0% 0% 0% 100% 20% *Retrospective evidence of extrahepatic disease prior to transplant § Complete pathologic response (no viable tumor) on explant
NGS Mutation Analysis of Recipients Pt Genetic Mutation 1 Not Done (KRAS wt) 2 BLM, FANCF, FGFR2, KDR, MITF, MS6H6, NFKB1A, PDK1, PRKAR1A, SMARCA4, SPTA1 3 BAP1, FGFR2, MYC, MYST3 4 IDH1, KRAS 5 FGFR3, FRS2, MDM2, PTEN, SMAD4, SPTA1 6 BRAF 7 BRCA1, FGFR2 1 , FGFR3 1 , RAF1 1 , MYC, ARID1A 1 , CCND3 1 , NOTCH1 1 , SMAD4 1 , TP53, VEGFA 1 8 IDH1, BRAF 9 ARID1A 1 , EGFR, MYC, TP53, SOX2 2 , NBN 2 , LATS2 2 10 AKT1, BAP1, CHK2, FANCA, IDH1, IL6ST, LATS2, MLL, MSH2, PBRM1, ROS1, STAG2 11 BAP1, GNAS, IRF2, NF1, PIK3CA, SMARCA4 1 Present in pretransplant biopsy but not explant, 2 Present in explant but not pretransplant biopsy Denotes targeted therapy
Conclusions: Liver Transplant for Intrahepatic Cholangiocarcinoma • Despite large tumor burden, patients with advanced iCCA demonstrating long-term disease stability with neoadjuvant therapy demonstrate excellent OS and acceptable RFS • Results under this protocol exceed those previously reported for either liver resection, chemotherapy, or liver transplant in the absence of neoadjuvant therapy for iCCA • Tumor biology is likely critical for proper patient selection for transplantation in this population • Based on this pilot study, a multicenter clinical trial is underway to evaluate liver transplant as a treatment for advanced iCCA
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