Liver transplant is an effective therapy for patients with primary liver cancer, and outcomes after transplantation are often superior to surgical resection. But the pool of potential patients is increasing, as transplantation is now emerging as an attractive option for select patients with nonresectable colorectal cancer (CRC) liver metastases, as well as those with intrahepatic cholangiocarcinoma (CCA).
Experts in the field highlighted some of the current challenges and opportunities in transplant oncology during a special session at the 2023 Gastrointestinal Cancers Symposium.
Transplant Is Here to Stay
To date, the only curative or potentially curative therapy for patients with CRC liver metastases and intrahepatic CCA has been the combination of systemic therapies and R0 resection, commented Gonzalo Sapisochin, MD, assistant professor, Division of General Surgery, Department of Surgery, University of Toronto, Ontario, Canada.
The new idea is that for patients with unresectable disease, total hepatectomy followed by a liver transplant may be a promising strategy, he said. “This is a very hot topic in transplant oncology.”
He noted that liver transplantation is already established as the best treatment option for patients with primary hepatocellular carcinoma, which has become the main indication for liver transplantation at many centers.
For patients with CRC metastases and intrahepatic CCA, liver transplantation may help cure some patients by extending the conventional margins of surgical oncology, he suggested. “This is basically going to work in patients who have exclusive liver-restricted disease and not in those with metastatic disease,” he said. “The efficacy is going to be seen by objective and sustained response to some sort of neoadjuvant therapy.”
However, Sapisochin emphasized liver transplantation is not an option for every patient. “We’re going to have to have clear inclusion and exclusion criteria that need to be defined a priori,” he said.
Intrahepatic CCA has historically been considered a contraindication for liver transplantation. Surgical resection is the preferred first-line treatment and the only one that is potentially curative, he explained. However, most patients are not candidates for surgery, and even if they do have a resection, many of these patients will experience a recurrence, usually in the liver.
There are some studies that support transplantation in this patient population, including one by Sapisochin and colleagues. That study looked at patients who were transplanted under the assumption that they had hepatocellular carcinoma but were found to actually have intrahepatic CCA. The recurrence rate at 5 years was 18%, and 5-year survival was 65%.
“We were able to show that those patients with small tumors actually can do very well after transplant, with survivals over 70% to 80%, which in this population is a very good outcome,” he said.
Transplant for CRC Metastases
Unresectable liver metastases from colorectal cancer can also be challenging to treat, Sapisochin commented. Surgical resection is the only potential cure with a combination of systemic chemotherapy, but only a minority of patients are candidates for surgery.
Data supporting transplantation for CRC metastases have been emerging. One trial was conducted by researchers in Oslo, Norway, who developed the Oslo score for risk stratification. “Those with risk factors had worse outcomes, and obviously, having a large tumor diameter, a high CEA [carcinoembryonic antigen], progressing on chemotherapy, or a short interval between the primary resection and the transplant were risk factors for recurrence,” said Sapisochin.
The 10-year survival among patients with a low Oslo score was 50%. “So we’re talking about patients who had no resection possibility and received a transplant after systemic chemotherapy, and they had a 10-year survival of 50%,” he emphasized.
However, Sapisochin acknowledged that the biggest problem transplant surgeons face is that there are not enough donor organs.
One solution is living donor liver transplantation. “Given that this is an unlimited source, you can utilize this as extended criteria and it adds another graft to the system,” he explained, adding that at his institution, they have been doing this for quite a while.
“We have a protocol for living donor liver transplantations for patients with colorectal liver metastasis,” said Sapisochin. “We’ve done seven cases so far with pretty good outcomes. One patient, unfortunately, passed away 14 months after transplant with lung metastases, but the rest are alive with no recurrence.”
More Available Organs?
Rafik Mark Ghobrial, MD, PhD, director, J.C. Walter Jr. Transplant Center and professor of surgery, Houston Methodist Hospital, Texas, commented that 5 years ago, he was very cautious about liver transplantation for intrahepatic CCA.
He pointed out that although transplantation for hepatocellular cancer was being done in the 1990s, the results were so poor that a moratorium was placed on the practice. “But now liver transplantation has become the definitive therapy for hepatocellular cancer, and intrahepatic cholangiocarcinoma is going the same way,” he said.
Ghobrial reiterated that one of the issues in transplantation for oncology patients is the limited supply of available organs, but he believes the landscape for liver transplantation has changed, resulting in more available organs. One factor is that hepatitis C has become curable with the advent of new therapies, and hence, the need for transplantation for patients with this disease has plummeted.
“I’ve done about maybe 800 transplants in the last 5 years. I’ve only transplanted two patients with hepatitis C,” said Ghobrial. “Now we are doing more transplants for alcoholic liver disease and cancer.”
Improvements in technology are also allowing for more livers to become useable, he pointed out. One example is normothermic machine perfusion, which has entered the clinical arena in the last decade. The technique has shown promising results in improving the quality of marginal organs and increasing the pool of liver grafts.
Another factor that has increased the number of livers available for transplantation is the move to accept organs from circulatory death donors, as well as donations after brain death. “Our transplantation was about 4% of donors after cardiac death, but today this has gone up to almost 16% or 20% of the livers,” he said. “And in some centers, this has gone up to about 50%.”
“Liver transplantation for intrahepatic cholangiocarcinoma and colorectal cancer metastases has come of age for selected patients,” Ghobrial declared.
More Caution Needed
However, another expert urged some caution, warning that live donation carries risk. Yuman Fong, MD, of the City of Hope Medical Center, Duarte, California, told Medscape Medical News that around “1 in 600 live donors die from donation. That is a healthy person dying. This is not a small issue.”
He also pointed out that if the criteria for transplant is greatly liberalized, the 5-year survival will not be as high as demonstrated in clinical trials.
Writing about the issue in a recent editorial, Fong pointed out that cadaveric livers for transplant remain a finite resource and that more than 1000 patients still die every year on the waiting list for a transplant.
A more reasonable approach would be to advocate for this type of program in regions of the world where cadaveric livers are more plentiful or centers with established living donor transplant programs.
“For us to develop this resource and safeguard patients, family organ donors, and resources, we need to develop what are the best inclusion criteria,” Fong said. “We have to optimize use of all cadaveric organs and determine if we are willing to transplant borderline organs.”
Ethics of Transplanting
Weighing in on the issue, ethicist Art Caplan, PhD, professor of bioethics at New York University Grossman School of Medicine in New York City, noted this is an interesting development in the field of liver transplantation. “There have been attempts in the past, and many did not end well, such as with Steve Jobs,” he said. “But transplantation is always pushing to expand eligibility, and there has also been much success with that.”
However, Caplan emphasized the new data are innovative and experimental, which may control how many centers will be able to perform liver transplants in these cancer patient populations. “It has to be data-driven as we are dealing with an exceedingly scarce source,” he said. “We know that people can do well, but it adds more stress to the supply of organs, and some patients may not do as well.”
He also emphasized that live donation is not a panacea. “Liver donation from a live donor is not the same as live donation for a kidney,” said Caplan. “It is much riskier and not that common. So not quite the same.”
The bottom line is that livers for transplantation are a scarce resource and transplant may work well in some cancer patients but not others, Caplan emphasized. “Morally, we want to save lives, but not by adding in people who may not do well. And if programs try to stretch the criteria, some may try transplants with more marginal organs.”
Sapisochin has disclosed relationships with Bayer, Roche, Novartis, Integra, AstraZeneca, Chiesi, Evidera, and Stryker. Ghobrial has reported no relevant financial relationships. Fong has reported being a scientific consultant for Medtronic and Johnson & Johnson and receiving royalties from Merck and Imugene. Caplan writes a regular column on ethics for Medscape.
Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.
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