Research Advocates 4.30
Trudy Wu
Created on April 29, 2024
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Transcript
Liver Transplantation in Cholangiocarcinoma
"In 2010, they said no transplant"
Trudy Wu, MDUCLA Department of Radiation Oncology
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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
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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
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%
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
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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
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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%
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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%!