Research Advocates 4.30

Liver Transplantation in Cholangiocarcinoma

"In 2010, they said no transplant"

Trudy Wu, MDUCLA Department of Radiation Oncology

wow

Liver/CCA is projected to become the 3rd leading cause of cancer-related death

Rahib L, et al. Estimated Projection of US Cancer Incidence and Death to 2040. JAMA Netw Open. 2021

Cholangiocarcinoma (CCA)

• Malignancy originating from the epithelium of the bile ducts
• Risk Factors: primary sclerosing cholangitis (PSC), hepatolithiasis, choledochal cysts, and liver fluke infection
• Anatomic location informs prognostication and treatment options
• ~30% cases are resectable at diagnosis

NCCN Guidelines

Extrahepatic CCA

Intrahepatic CCA

wo

The addition of immunotherapy in Advanced and Metastatic CCA

2022

TOPAZ-1

2023

KEYNOTE-966

NCCN Guidelines

OLT referral for unresectable extrahepatic CCA

The Role of Orthotopic Liver Transplant (OLT) in CCA

wow

The History of OLT for CCA

1963

Second successful OLT indicated for cancer was performed for iCCA

1980s

High rates of relapse and poor OS after OLT alone

1987

University of Nebraska treats first patient with neoadjuvant therapy

1993

Mayo Clinic treats first patient with neoadjuvant therapy

2021

Cambridge Meta-analysis

Gemcitabine/cisplatin5-FU/capecitabine

40-50 Gy in 5 fx

Unresectable hilar or intrahepatic CCA

OLT Protocol at UCLA

OLT

Chemo

SBRT

2012-2019

Dropout Patients

Wu TC, et al. A Single Center Experience Using SBRT on Orthotopic Liver Transplant Protocol for Unresectable Cholangiocarcinoma. HPB. 2024

Transplant

OLT protocol

Patients treated per protocol at UCLA

Wu TC, et al. HPB. 2024

OLT patients 1-year OS 100% 3-year OS 75%

Median RFS 49.9 weeks (range 35.9-127.7)

• 3 local, 1 distant, 1 local and distant

Median OS of 3.8 years (range 2.6-5.5)

Recurrent disease

Residual tumor

Pathologic complete response

Median wait time 61.4 weeks (range 26.6-97.6)

Transplant

Wu TC, et al. HPB. 2024

2012-2019

Dropout Patients

Transplant

OLT protocol

Patients treated per protocol at UCLA

Wu TC, et al. HPB. 2024

Dropout patients 1-year OS 76% 3-year OS 9%

• 3 sepsis from cholangitis, 1 liver failure

Death from other causes

• 10 local, 3 distant

Disease Progression

Dropout Patients

Median time from SBRT to progression 36.1 weeks (range 3.7-81.4)

Wu TC, et al. HPB. 2024

Overall Survival

Overall Survival

Overall Survival is better after OLT

Wu TC, et al. HPB. 2024

Recurrence-free Survival

Overall Survival

Progression-Free Survival

Overall Survival

Recurrence-free Survival

Overall Survival

A trend towards better RFS and OS after pCR

Is pCR a reliable surrogate marker for RFS and OS after OLT?

pCR associated with improved OS across sites

NSCLC

Mouillet et al. Combined Analysis of 2 IFCT Randomized Trials. JTO. 2012.

Breast

Cortazar et al. CTNeoBC Pooled Analysis. The Lancet. 2014.

Rectal

Maas et al. Pooled Analysis. Lancet Oncol. 2010.

Over half of explants achieved a pCR at Mayo

1. Complete/near-complete ≤1% ERT2. Marked >1 to <10% ERT3. Moderate 10 to <30% ERT4. Minimal >30% ERT

• Retrospective review of 152 explants
• 63.8% cases associated with PSC
• Extent of residual tumor (ERT) categorized as

Lehrke H, et al. The American Journal of Surgical Pathology. 2016.

57%

of explants achieved a complete/near-complete response

Extent of residual tumor

9%

57%

18%

16%

Cambridge, et al. Meta-analysis and Meta-regression of Survival After Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma. Annals of Surgery. 2021.

Heterogenous NAT regimens in practice

Is there robust, multi-center data to support the prognostic impact of a pCR in CCA?

Do specific OLT protocols result in higher pCR rates?

Wu TC et al. A Systematic Review and Meta-analysis of Pathologic Complete Response Rates for Patients with Unresectable Cholangiocarcinoma treated on Orthotopic Liver Transplant Protocols. Journal of Surgical Oncology, 2023.

pCR rates range widely

Wu TC et al. Journal of Surgical Oncology, 2023.

Pooled pCR rate among all protocols is 32%

Highest pCR rates achieved with Mayo protocol

Pooled pCR rates

pCR rate highest with the Mayo Protocol (46%) Limited by few institutional studies Pooled pCR rate is 32%

Is there robust, multi-center data to support the prognostic impact of a pCR in CCA?

Do specific OLT protocols result in higher pCR rates?

Wu TC et al. Journal of Surgical Oncology, 2023.

Pooled Overall Survival

• 1-year: 91%
• 3-year: 72%
• 5-year: 61%

No association between pCR and survival in the meta-regression

In our meta-analysis, pCR was not associated with better OS

pCR rate highest with the Mayo Protocol Limited by few institutional studies Pooled pCR rate is 32%

Is there robust, multi-center data to support the prognostic impact of a pCR in CCA?

Do specific OLT protocols result in higher pCR rates?

Wu TC et al. Journal of Surgical Oncology, 2023.

Wu TC et al. In press, Journal of Surgical Oncology02.

Conclusions

• The pooled incidence of achieving a pCR after NAT and OLT for CCA is 32%
• Institutions utilizing the Mayo protocol achieved highest rates of pCR (46%)
• pCR was not associated with OS
• Limitations: small patient cohorts, absence of individual level patient data, protocol heterogenity

Some food for thought...

• Collaborate across transplant centers to prospectively study OLT for CCA
• Leverage modern RT techniques and systemic therapies to improve reduce dropout rates
• UCLA's pCR rate (44%) is higher than the other SBRT studies

Additional studies utilizing modern local and systemic treatment techniques are needed to better compare protocols and evaluate the prognostic significance of pCR

How do we know?

• Prospective, single-arm phase I trial at UCLA from 2015-2017
• Median prescription: 54 Gy in 3 fx
• 1-year LC: 94.7%, 2-year LC: 79.6%

• Comparable to LC with CTgRT
• BED ≥ 100 Gy10 and single treated lesion associated with improved LC
• No acute Grade ≥ 3 toxicities

MRgRT is a viable and safe option in the delivery of SBRT to liver tumors resulting in high rates of LC and very favorable toxicity profiles

van Dams R*, Wu TC*, et al. Ablative radiotherapy for liver tumors using stereotactic MRI-guidance: A prospective phase I trial. Radiother Oncol. 2022

MR-guided SBRT to the liver is safe and effective

NCCN Guidelines

Extrahepatic CCA

Intrahepatic CCA

wo

The Field Cancerization Effect of CCA

Intrahepatic CCA

Hu LS, et al. Recurrence Patterns and Timing Courses Following Curative-Intent Resection for Intrahepatic Cholangiocarcinoma. Ann Surg Oncol. 2019

After surgical resection,

• 50-70% of patients relapse
• 5-year OS is 20-35%

Most patients die from tumor-related liver failure

The challenge is within the liver itself, which can result in significant morbidity (recurrent cholangitis, hyperbilirubinemia, liver failure)

Intrahepatic Cholangiocarcinoma behaves as an infiltrative, multifocal disease.

Wei T et al. Classification of Intrahepatic Cholangiocarcinoma into Perihilar Versus Peripheral Subtype. Ann Surg Oncol. 2023

198819881997199720002004

Pichlmayr R. Is there a place for liver grafting for malignancy? Transplant Proc. O'Grady JG, et al. Liver transplantation for malignant disease. Results in 93 consecutive patients. Ann Surg. Pichlmayr R, et al. Indications and Role of Liver Transplantation for Malignant Tumors, The Oncologist. Casavilla FA, et al. Hepatic resection and transplantation for peripheral cholangiocarcinoma. Journal of the American College of Surgeons. Meyer C, et al. Liver transplantation for cholangiocarcinoma: Results in 207 patients. Transplantation. Robles R, et al. Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma. Ann Surg.

The historical exclusion of OLT for iCCA

20142016 2018 2022

Sapisochin G, et al. "Very early" intrahepatic cholangiocarcinoma in cirrhotic patients: should liver transplantation be reconsidered in these patients? Am J Transplant. Sapisochin G, et al. Liver transplantation for "very early" intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment. Hepatology. Lunsford KE, et al. Liver transplantation for locally advanced intrahepatic cholangiocarcinoma treated with neoadjuvant therapy: a prospective case-series. Lancet Gastroenterol Hepatol. Ito T, et al. A 3-Decade, Single-Center Experience of Liver Transplantation for Cholangiocarcinoma: Impact of Era, Tumor Size, Location, and Neoadjuvant Therapy. Liver Transpl.

OLT reconsidered for iCCA

Sapisochin, G et al. Liver Transplantation for Intrahepatic Cholangiocarcinoma: Ready for Prime Time?. Hepatology. 2022

A Glimpse into the Future

Maximizing patient pathways to OLT

Drop out rates

Impact on... Graft rejection?Toxicity?RFS?

PLUS immune checkpoint inhibitors

Unresectable hilar or intrahepatic CCA

On-table Adaptation Dose Escalation

OLT

Chemo

SBRT

Maximizing patient pathways to OLT through patient advocacy and education

Liver/CCA is projected to become the 3rd leading cause of cancer-related death

Rahib L, et al. Estimated Projection of US Cancer Incidence and Death to 2040. JAMA Netw Open. 2021

KEYNOTE-966

Kelley RK et al. The Lancet. 2023

Sapisochin, G, et al. Hepatology. 2016.

"Very Early" CCA (≤2 cm) achieve promising outcomes after OLT

Large international multicenter study reveals 5-year OS of 65% for "very early" tumors without NAT

Cambridge WA et al. Annals of Surgery. 2021

Cambridge et al. Meta-analysis

• Total: 20 studies, 428 patients
• 11 studies (272 patients) reported use of neoadjuvant protocols
• 3 studies treated per Mayo protocol (203 patients)
• Pooled 5-year OS with NAT 65% (vs. 31% without NAT)
• Other protocols
• 55-75 Gy BID + capecitabine
• SBRT 50-60 Gy in 3-5 fx + capecitabine
• Brachytherapy alone
• Brachytherapy + EBRT 45-55 Gy QD

Got an idea?

Use this space to add awesome interactivity. Include text, images, videos, tables, PDFs... even interactive questions!Premium tip: Get information on how your audience interacts with your creation:

• Visit the Analytics settings;
• Activate user tracking;
• Let the communication flow!

Two FDA-approved immune checkpoint inhibitors for advanced/metastatic CCA!

Sudan et al. Am J Transplant. 2002

University of Nebraska Protocol

• 17 patients with peri-hilar CCA
• Neoadjuvant Protocol
• 60 Gy brachytherapy delivered through percutaneous transhepatic catheters
• 5-FU until OLT
• Exploratory laparotomy before OLT
• 35% drop out rate
• 65% (n=11) made it to OLT
• 5 patients were free of any tumor recurrence, 2.8–14.5 years after OLT

Wu TC et al. Identifying predictors of on-table adaptation for pancreas stereotactic body radiotherapy (SBRT). Clin Transl Radiat Oncol. 2023

>40 Gy in MRI-guided pancreas SBRT associated with increased use of on-table adaptation

Heimbach et al. Liver Transpl. 2004

Mayo Clinic Rochester Protocol

• 56 patients with peri-hilar CCA
• Neoadjuvant Protocol
• EBRT 45 Gy in 1.5 Gy fx (BID) with bolus 5-FU, followed by brachytherapy (20-30 Gy)
• Exploratory Laparotomy
• 5-FU until OLT

• 39% drop out rate
• 50% (n=28) made it to OLT
• 4 developed recurrent disease after OLT
• 1-year OS 88%, 5-year OS 82%

Got an idea?

Use this space to add awesome interactivity. Include text, images, videos, tables, PDFs... even interactive questions!Premium tip: Get information on how your audience interacts with your creation:

• Visit the Analytics settings;
• Activate user tracking;
• Let the communication flow!

TOPAZ-1

Oh, DY et al. NEJM Evid. 2022

Lunsford KE, et al. Lancet Gastroenterol Hepatol. 2018.

Long-term survival achieved in patients with iCCA!

5-year OS rates of 83.3%!

OLT without NAT for CCA

Castaldo et al. HPB. 2007