Resection or Transplantation for Perihilar Cholangiocarcinoma:

1. Yes Resection or Transplantation for PerihilarCholangiocarcinoma: Julie Heimbach, MD Professor of Surgery Chair, Division of Transplantation Surgery Mayo Clinic

2. Intrahepatic (5-10%) (50-60%) (20-30%) • Diagnosis challenging • Surgical resection mainstay • Prognosis remains poor

3. Incidence of cholangiocarcinoma • Second most common primary liver tumor • Incidence of intrahepatic CCA is rising, while perihilar and distal CCA is generally stable. Issues with classification (location) and increased accuracy of diagnosis may be contributing to these shifts. • Range 0.5–2.0 per 100,000 in western countries (PSC is primary risk: 6-11% at 10 years), and much higher in eastern counties (Liver fluke)

4. Diagnosis of peri-hilar cholangiocarcinoma • Imaging with CT (vascular involvement) and MRI/MRCP (ductal involvement). MR superior to CT • EUS: good for detection of nodal disease, avoid biopsy of primary tumor for those being considered for curative therapy • ERCP: malignant appearing stricture, brushing, endoscopic biopsy • Elevated Ca 19-9 (in absence of cholangitis-- may be normal– Lewis antigen negative) • Differentiate from IgG4 cholangiopathy

5. Resection for Perihilar CCA • Poses technical challenges to resection (R0 resection possible 70-80% of attempted resection) • Margins of resection • Ducts • Liver • Vessels • Tumor size/site limits accurate staging by imaging • Outcomes following resection depend on complete resection (R0), node status, tumor grade, presence of vascular invasion.

6. Hilar Cholangiocarcinoma: Survival after Resection

7. Perihilar Cholangiocarcinoma:Current State of Surgical TreatmentOverall Survival by Stage (%)100 80 60 40 20 0 100% N=8 84.8% N=56 59.0% N=421 45.7% N=144 37.7% N=84 25.4% N=468 10.8% N=171 — Stage 0 (TisN0M0) —Stage I (T1N0M0) —Stage II (T2N0M0) —Stage IIIA (T3N0M0) — Stage IIIB (T4N0M0) — Stage IIIC (TanyN1M0) — Stage IV (N2/M1) P=0.948 P=0.006 P=0.003 P=0.056 P=0.142 0<0.001 0 1 2 3 4 5 (Years after surgery) AJCC Cancer Staging Manual, 8th Edition, 2017

8. Recurrence after curative-intent resection of perihilarcholangiocarcinoma: analysis of a large cohort with a close postoperative follow-up approach: Komayaet Surgery 2018:213;732-38 • N=401 patients. More than 50% of patients experience recurrence, even after R0 resection. Median survival 3.9 years, with 43% survival at 5 years.

9. HPB 2015;17(8):691-9 • Minimum diagnostic/staging work up requires Ca 19-9 + cross-sectional imaging • Pathological confirmation not required before proceeding to resection/transplant • Resection involves removal of intra/extrahepatic bile duct plus ipsilateral resection of involved liver • Portal vein embolization is safe/effective for increasing FLR • Selected patients with unresectable CCA should be considered for neoadjuvant chemo-radiotherapy plus liver transplantation

10. PerihilarCholangiocarcinoma:Current Surgical Management Mayo Clinic Suspected HC CT, MRI/MRC* ERC Diagnostics/Stenting HC+/probable HC - Assess Resectability T – Ductal extent, PV, HA N – Regional (EUS) Distant (PET) M – CT Repeat ERC Diagnostics q 3 months Resectable locally +/- LN Unresectable locally - LN (EUS) Unresectable distant Volumetry+/- PVE Transplant Evaluation Neoadjuvant Protocol Staging Laparoscopy Transplantation Metal stenting Palliative therapy Clinical trials Staging lap, Resection

11. Neoadjuvant radiation and chemotherapy External beam radiotherapy (4500), with 5-FU Brachytherapy with protracted capecitabine Staging laparoscopy to rule-out metastases or local extension precluding complete resection of tumor Liver Transplantation Selected patients with unresectable hilar cholangiocarcinoma: Mayo Clinic (1993)

12. PerihilarCCA: Diagnosis and Eligibility • Malignant appearing stricture and at least one of the following: • Malignant cytology or histology • CA-19.9 > 130 U/mL without cholangitis • Polysomy on FISH • Cancer located primarily above the cystic duct • Unresectable cancer (de novo CCA) or cancer arising in setting of PSC

13. Exclusion Criteria • Prior attempted resection with violation of tumor plane, or trans-peritoneal biopsy • Presence of mass lesion >3 cm radial margin (longitudinal margin not a contraindication) • Intrahepatic or extra-hepatic metastases, prior abdominal radiationthat would preclude additional radiation, or other medical contraindication to surgery/transplant.

14. CholangiocarcinomaTreatment Protocol Results (1993- 2018) 349 patients 45 deaths / disease progression Radiation + chemo 6transplant elsewhere 21 awaiting staging 277 staging operation 56 (20%) positive 2awaiting transplantation 3 transplant elsewhere 5 progression/death 211 liver transplantation 134 deceased donor 78 living donor 1 domino donor

15. 10 year Patient Survival After Start of Therapy- “intention to treat”1993 – 2018n=349 80 + 2% % 74 51 + 3% 46 + 3% Years after registration

16. 10 year Patient Survival After Transplantation1993 – 2018n=211 91 + 2% 70 69 + 3% 62 +4% % Years after registration August 18, 2018

17. Patient Survival After Transplantation1993 – 2018 92 +2% 76 +4% 70 +4% 90 +4% 50 21 % 58 + 6% 49 + 7% p = 0.02 log-rank p = 0.02 Wilcoxon Years after registration August 18, 2018

18. Multivariate Predictors of Recurrence after LT (N=25) At presentation Darwish-Murad et al, Hepatology 2012 From time of transplant

19. Explanted Liver After Neoadjuvant Therapy

20. Medical problems • DVT and PE • Duodenal ulceration – perforation, bleeding, anorexia • Cholangitis, Cholecystitis, gall bladder perforation • recurrence Technical problems • Early hepatic artery thrombosis • Caudate involvement • Biliary Wall stents • Common bile duct involvement • Late vascular strictures

21. Multi-center Recurrence-free survival post-LT (N=214, 12 centers) Gastroenterology 2012 143:88-98

22. Multi-center survival post-OLT (N=214). Gastroenterology 2012 143:88-98 • Standard criteria: • Mass size ≤ 3 cm • No metastases at OLT • No previous malignancy (≤ 5 yr) • No transperitoneal tumor biopsy

23. Prognostic significance of histologic response to neoadjuvant therapy Lerhke et al Am J Surg Path 2016 • N=153 explanted livers, 1993-2013 • 5 year survival 69% • Extent of residual tumor strongly predicted 5 year survival (p=0.009) • After adjusting for age, stage and presence of PSC, residual tumor still strongly predictive of outcome (p< 0.0001) • PSC had higher survival (78% versus 54%) however, when adjusted for age and residual tumor, differences not significant. 71% PSC patients had CR, vs 31% non-PSC

24. Prognostic significance of histologic response to neoadjuvant therapy Lerhke et al Am J Surg Path 2016

25. Neoadjuvant chemoradiotherapy followed by liver transplantation for unresectable cholangiocarcinomaHPB Duignan et al 2014 • 20 patients treated with neoadjuvant therapy and LT (4 died post-op) • 61% 4 year survival for those who left hospital • Conclude short-term morbidity and mortality is high but long term survival outcome are good

26. Strict Selection Alone of Patients Undergoing Liver Transplantation for Hilar Cholangiocarcinoma Is Associated with Improved Survival. Plos1 2016 Mantel et al • Outcomes 1990-2010 transplanted in Europe (ELTR) • Selection of 28 (19%) patients out of 249 with LT for hilar CCA group A • 46% recurrence at 5 years in group A • Overall survival was 32% for whole cohort

27. Is Liver Transplantation Appropriate for Patients with Potentially Resectable De Novo Hilar Cholangiocarcinoma? Croome et al JACS 2016 • N=99 resection vs 54 unresectable CCA undergoing LT • If comparing R0, node negative patients, no difference in survival • Comparing type IV, LT outcomes are improved versus resection (p=0.039) • For borderline resectable patients, the decision to proceed to resection or transplant may favor TX.

28. Ethun et al., Annals of Surgery 2017 • 10 US centers, 2000-2015, perihilar CCA undergoing resection versus TX • N=304 patients (234 resection, 70 TX) • 3 year survival 72% vs 33% • 5 year survival 64% vs 18% • Resection for hilar CCA that meets transplant criteria (tumor <3 cm, node negative disease) is associated with worse survival. Prospective trials are justified.

29. Marginally Resectable Hilar CholangiocarcinomaImportant considerations • Resection is not safe after high dose neoadjuvant therapy • Attempted resection compromises outcome of neoadjuvant therapy and liver transplantation • Cross-over from one modality to the other is not possible (if in doubt for RO: transplant, if suspect nodes: resect)

30. Summary • Surgical therapy is standard of care for resectable patients • Combined neoadjuvant therapy plus LT achieves favorable results for unresectable patients • Need better diagnostic tools to identify disease earlier (PSC) • Need better neoadjuvant therapy in the transplant setting, maybe in resection setting • ? role for adjuvant therapy (targeted)

31. Questions? Heimbach.julie@mayo.edu