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Liv iver T Trans anspl plan antat ation Op Option ions f for

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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

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Mayo C Clin inic Selection Crit iteria ia – Early stage hilar CCA – Diagnostic criteria:

• Malignant appearing stricture or mass with one of the following:

– Malignant cells by biopsy or cytology – Positive aneuploidy – CA19-9 >100

– Unresectable disease due to liver disease or mass location – If mass present must be <3cm – No LN metastases – Biliary sepsis controlled – No intrahepatic CCA – No prior transperitoneal biopsy or prior surgical resection

External Beam Radiation (4500 cGy in 30 Fractions) + 5FU Intrabiliary Brachytherapy (2000-3000 cGy) + 5FU Exploratory Laparoscopy

• Rule out peritoneal mets
• Perihilar LN biopsy

Oral capecitabine 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

• 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

Survival following phCCA Treatment

Rea 2005 Ann Surg

Murad et al. Gastroenterol 2012.

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

• PSC A

Associ ciated d phCCA hCCA

– Lifetime incidence of CCA 6.8-13% – Younger age (47±9 yrs) – Earlier stage at diagnosis, more likely multifocal – Pathologic confirmation

• ften absent

– Mayo 5-year survival after liver transplant 77% (n=113)

• De N

Novo phCCA hCCA

– More likely resectable – Older age (64±10 yrs) – Larger tumors at diagnosis – Mayo 5-year survival after liver transplant 56% (n=68) – Outcomes more comparable to R0 resection

Liver Transplantation for De Novo versus PSC Associated Perihilar Cholangiocarcinoma

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

• mmended 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 Sapisochin 2016 Liver Transplantation Liver Transplantation reasonable for patients with “very early” iCCA <2 cm

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

Updated from Lunsford KE et al 2018 Lancet Gastro Hep

N=41 Referred for Evaluation N=14 Excluded due to Extrahepatic Disease N=5 Down-Staged or Resected N=1 Medically Unacceptable Candidate N=2 Currently Undergoing Evaluation N=19 Listed for Liver Transplant N=11 Transplanted N=2 Further Down-Staged to Resection N=2 Aborted at Exploration Due to Adhesive Disease N=3 Actively Awaiting Transplant N=1 Delisted Due to Disease 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 Transplanted N=6 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 Stage (TMN) II T2N0

II T2N0 II T2N0* II T2N0* IIIA T3N0 I T1bN0 II T2N0 IIIB T4N1* II T2N0 II T2N0 T0N0§ II T1aN0

# of lesions 3

8 6 10 1 1 10 1 1 3 1

Max size (cm) 6.5

4.2 9.0 3.5 5.2 6.5 10.5 8 8.5 2.0 3.6

Total Diameter (cm) 8.5

18·7 13·0 15·3 5·2 6·5 20·0 8 8.5 5.3 3.6

Location N/A

Bilobar Bilobar Bilobar Left Left Bilobar Bilobar Bilobar Bilobar N/A Right

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

Microvasc Invasion No

Yes No Yes No No No Yes Yes No No No

Positive Margins No

No No No Yes No No Yes No No No 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, FGFR21, FGFR31, RAF11, MYC, ARID1A1, CCND31, NOTCH11, SMAD41, TP53, VEGFA1 8 IDH1, BRAF 9 ARID1A1, EGFR, MYC, TP53, SOX22, NBN2, LATS22 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

Liver Transplantation for Cholangiocarcinoma

• Under appropriate protocols, liver transplant can achieve excellent

result for unresectable CCA

– Currently accepted therapy for small perihilar CCA – Recent multinational study suggest excellent outcomes for small (<2cm) intrahepatic CCA

• Preliminary prospective data suggests liver transplant also reasonable

for large iCCA treated with neoadjuvant chemotherapy

– Need to reconsider as indication for transplantation – Need to better define “favorable” biology – Careful attention to indolent metastatic disease prior to OLT

Metho hodist- MD Anderson J Joint C Cholan langiocar arcinom

• ma

a Collab llabor

• rat

ative C Committee Thomas A. Aloia, MD Maen Abdelrahim, MD, PhD

• A. Osama Gaber, MD, PhD
• R. Mark Ghobrial, MD, PhD

Ed Graviss, PhD, MPH Nakul Gupta, MD Kirk Heyne, MD Mark Hobeika, MD Milind Javle, MD Keri E. Lunsford, MD, PhD Robert McFadden, MD Constance M. Mobley, MD, PhD Howard P. Monsour, MD Duc Nguyen, MD, PhD Ashish Saharia, MD Rashna T. Schroff, MD David W. Victor, MD Jean-Nicholas Vauthey, MD Reham Abdel-Wahab, MD, PhD

Ack cknowledgements

Multicenter Trial for Liver Transplant in Intrahepatic Cholangiocarcinoma Institutions: