Surgical Approaches to CCA, Part 3: Liver Transplant

Maria Majella Doyle, MD, MBA

Historically, liver transplantation in patients with cholangiocarcinoma (CCA) was considered a contraindication at most US medical centers; however, with recent advances, the United Network for Organ Sharing (UNOS) liver intestine committee now recognizes that transplantation is indicated in hilar CCA when performed under institutional protocols with neoadjuvant chemoradiation. Maria Majella Doyle, MD, MBA, of Washington University School of Medicine and Mid America Transplant Services, discussed liver transplant in her presentation, detailing protocols and efficacy results from the Mayo Clinic and other centers in hilar CCA and beyond.

From the early 1990s, the Mayo Clinic has been the leader in transplantation for hilar CCA, with many other centers following their lead. The Mayo Clinic protocol for transplant in patients with unresectable hilar CCA includes neoadjuvant radiation and chemotherapy with brachytherapy; next, a staging operation is used to rule out metastases, and then the liver transplant is performed. Early results from the Mayo Clinic demonstrated that in 56 patients considered for transplant, there was an 82% 5-year survival rate.¹ Most patients had primary sclerosing cholangitis (PSC), and this group demonstrated an 80% 5-year survival compared with 64% in patients without PSC.^1-3 Long-term outcomes from the Mayo Clinic data also supported these findings with 10-year survival rates after transplant of 62%.³

Other clinics have also shown promising results with transplantation in hilar CCA. A study of 12 centers with 287 patients demonstrated a 5-year recurrence-free survival (RFS) of 65% and a 10-year RFS of 59% in patients who underwent transplantation and received neoadjuvant therapy.⁴ Patients within the UNOS Model for End-Stage Liver Disease (MELD) criteria exception had better outcomes, with a 5-year RFS rate of 72% versus 40% in patients outside the UNOS criteria for MELD exception. In addition, patients with smaller tumors (<3 cm) had better outcomes than those with tumors >3 cm, with 69% and 32% 5-year RFS, respectively.⁴ Data from Washington University also demonstrated encouraging results, with a 50% 5-year survival with transplant in patients with hilar CCA who otherwise had no other surgical treatment option.⁵

Dr. Doyle also discussed the consideration of upfront transplantation in patients with resectable hilar CCA. Researchers looked at Mayo Clinic data from 1993 to 2013 in 99 patients with Bismuth-Corlette type III undergoing resection and 54 patients with Bismuth-Corlette type IV undergoing transplantation to compare survival rates. A significant difference in survival was found in patients who underwent transplantation; however, when matched for age, lymph node metastases, and tumor size, no survival difference was seen.⁶ After a postoperative pathologic review, hilar CCAs after resection were reclassified as Bismuth-Corlette type IV based on the necessity of multiple biliary anastomoses, and those patients were found to have a better survival after transplantation compared with resection.⁶ In addition, researchers looking at retrospective data from 10 centers from 2000 to 2015 using the US Extrahepatic Biliary Malignancy Consortium found that transplantation in patients with hilar CCA was significantly better than resection in terms of progression-free survival and overall survival, especially in patients with tumors <3 cm.⁷

In patients with intrahepatic CCA (iCCA), surgical resection, when possible, is the gold standard; however, many patients are not surgical candidates and may die from intrahepatic tumor-related liver failure. International Liver Cancer Association guidelines do not recommend transplant for iCCA and note it should only be offered under a treatment protocol or clinical trial.⁸ A multicenter trial investigated transplantation in patients with very early iCCA and found that the cumulative risk of recurrence was much lower compared with more advanced disease; 5-year cumulative risk of recurrence was 18% in early iCCA versus 61% in patients with advanced CCA, and 5-year actuarial survival rates were 65% in early iCCA versus 45% in those with advanced disease (P = .02).⁹ A study of transplantation outside of those with early iCCA using an institutional protocol in 6 patients with locally advanced, unresectable iCCA found a 1-year overall survival rate of 100%, and the 3-year overall survival was 83%.¹⁰ Updated results using this protocol continued to show favorable outcomes in 18 patients who had undergone transplantation, with a 57% 5-year overall survival and 52% 3-year RFS after transplant.¹¹

Dr. Doyle also discussed technical advances using normothermic machine perfusion (NMP) that assesses the viability of the liver after it has been removed from the donor to allow patients outside of standard criteria to receive transplantation. The Washington University RESTORE protocol for patients with unresectable iCCA who have low MELD scores and are poor candidates for transplant takes donor livers that would traditionally not be used, assesses their viability with NMP, and then transplants viable livers into patients who would otherwise not be transplant candidates.

References

1. Gores GJ, Nagorney DM, Rosen CB. Cholangiocarcinoma: is transplantation an option? For whom? J Hepatol. 2007;47(4):455-459.
2. Rosen CB, Heimbach JK, Gores JG. Liver transplantation for cholangiocarcinoma. Transpl Int. 2010;23(7):692-697.
3. Tan EK, Taner T, Heimbach JK, et al. Liver transplantation for peri-hilar cholangiocarcinoma. J Gastrointest Surg. 2020;24(11):2679-2685.
4. Murad SW, Kim WR, Harnois DM, et al. Efficacy of neoadjuvant chemoradiation followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology. 2012;143(1):88-98e3.
5. Ahmed O, Vachharajani N, Chang S-H, et al. Single-center experience of liver transplantation for perihilar cholangiocarcinoma. HPB (Oxford). 2022;24(4):461-469.
6. Croome K, Rosen CB, Heimbach JK, Nagorney DM. Is liver transplantation appropriate for patients with potentially resectable de novo hilar cholangiocarcinoma? J Am Coll Surg. 2015;221(1):130-139.
7. Ethun CG, Lopez-Aguiar AG, Anderson DJ, et al. Transplantation versus resection for hilar cholangiocarcinoma: an argument for shifting treatment paradigms for resectable disease. Ann Surg. 2018;267(5):797-805.
8. Bridgewater J, Galle P, Khan SA, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014;60(6):1268-1289.
9. Sapisochin G, Facciuto M, Rubbia-Brandt L, et al. Liver transplantation for “very early” intrahepatic cholangiocarcinoma: international retrospective study supporting a prospective assessment. Hepatology. 2016;64(4):1178-1188.
10. Lunsford KE, Javel M, Heyne K, et al. Liver transplantation for locally advanced intrahepatic cholangiocarcinoma treated with neoadjuvant therapy: a prospective case-series. Lancet Gastroenterol Hepatol. 2018;3(5):337-348.
11. McMillan RR, Javle M, Kodali S, et al. Survival following liver transplantation for locally advanced, unresectable intrahepatic cholangiocarcinoma. Am J Transplant. 2022;22(3):823-832.