Benjamin L. Schlechter, MD

This transcript has been edited for clarity.
 

Benjamin L. Schlechter, MD: Today we’re discussing liver transplant for metastatic colorectal cancer with our guest, Dr. Martin Dib. Dr. Dib is the director of the Hepatobiliary Surgery and Living Donor Program at Beth Israel Deaconess Medical Center here in Boston, and a Harvard Medical School faculty member.

He was previously at the Pontificia Universidad Católica de Chile, a leading international institution investigating the role of liver transplant in colorectal cancer, among other diseases. Dr. Dib, before we move to our discussion, I’d like to hear a bit about your pathway to becoming a transplant surgeon. How did you end up working on colorectal cancer and liver transplants in this field?

Martin J. Dib, MD: Thank you so much, Dr. Schlechter. I am originally from Chile. I had an opportunity to come to Beth Israel Deaconess Medical Center after medical school and I did liver regeneration research at the transplant center. After that, I was lucky enough to match as a general surgery resident at Beth Israel Deaconess.

This is my alma mater and I was able to graduate as a surgeon here. You and I had some paths together. After graduating from Harvard as a surgeon, I was trained in liver transplant, abdominal transplant, surgical oncology, and hepatobiliary surgery at the University of Toronto.

I have been developing this passion for being able to transplant cancer patients and use organ transplant techniques to be able to do complex resections for cancer.

Dr. Schlechter: Let’s talk about the topic for today, which is liver transplant and colorectal cancer. I’ll be honest — this is not a very familiar topic for a lot of oncologists. There are a lot of details that I think are new to us as oncologists. We need to expand this conversation to get access to patients for this.

First and foremost, can you talk about some of the parameters for a resectable liver metastasis vs unresectable disease that would be an indication for a liver transplant?

Dr. Dib: I think this is a very interesting topic because liver transplantation for cancer is not new. Liver transplantation started in the 1960s when people started doing liver transplants for advanced liver tumors. The problem is that they were selecting patients who had very advanced — and poor tumor biology — tumors. The outcomes were not good.

It was only in 1996 when the Milan criteria started. Mazzaferro and colleagues, using strict patient selection, were able to do liver transplant for selected hepatocellular carcinoma patients. Having those excellent outcomes in selecting patients opened the field for what we now call transplant oncology, which is using selection criteria and using other methods to be able to select which patients will do well after transplantation, even with immunosuppression.

Liver transplantation for colorectal metastasis was used at the very beginning of the era of liver transplantation, but with very poor outcomes. It was abandoned because of the outcomes. It is exciting to see that after 20 years of not doing it, there was a group in Norway that started again. They are doing liver transplants for colorectal metastases (mets), but with very selected patients.

In Norway, they had a very unusual setting where they had more liver donors than patients on the list waiting for liver transplant. So they can’t share these livers and we’re all jealous, right? Every single country in the West struggles because we don’t have enough livers for the rest of the list. And they had a lot of livers to be able to transplant people.

They decided to transplant some selected patients with colorectal mets that were unresectable. And the surprise was that they found that they were able to get a 60% survival at 5 years. And so that was new. After that, in Norway, they started showing this data to other centers in the world. It wasn’t until this year that we could see not only the long-term data and long-term outcomes of using liver transplantation for unresectable colorectal mets, but also we’re now having data from a prospective clinical trial from France.

It was three countries in the prospective clinical trial: France, Belgium, and Italy. We now see that we have a little stronger data to support the use of liver transplants for unresectable colorectal mets.

Dr. Schlechter: That’s the TRANSMET study you’re referencing that was presented at ASCO in the late-breaking abstract session in 2024, and then more recently in The Lancet’s eClinicalMedicine. Both of those papers were led by René Adam. That was a cool presentation to sit through. I was in the room, and I was taking a ton of notes and there was a lot of info that came out of that.

First of all, it showed that patients who had received chemotherapy and were responding could then go on to liver transplant in that population. Impressively, 81% of the patients who were randomized to transplant received it. Frankly, that’s a big number, especially compared with the West, as you said, and in particular the US and here in New England where livers are a very precious commodity.

And even accounting for that, if you look at the intention-to-treat analysis, the 5-year overall survival in that population was 57% compared with 13% with chemotherapy. And that feels like a real number for chemotherapy. If you look at the per-protocol analysis, frankly, the numbers are higher.

It’s always a challenging assessment. What was also interesting to me was the pattern of recurrence, which in general was that recurrences were extrahepatic. So not only were patients rendered disease-free, but in general, the liver remained disease-free and only 3% of patients had liver-only recurrence and 11% had widespread metastatic disease.

The biggest group was lung metastases, at about 40%. Ultimately, they reported a progression-free survival of 17. 4 months for transplant compared with 6. 4 months with chemotherapy. On every parameter, it looks like liver transplant wins for these people. Help me out. Who are these people? How do we find these people?

What are the inclusions and exclusions for this population?

Dr. Dib: I think that’s very important. This is not a therapy that will be for every patient. These are selected patients who have liver-only unresectable colorectal mets. These are patients that don’t have any extrahepatic disease and that either the primary has been taken out already or that they have the primary present, but the plan is to take the primary and then do a liver transplantation after 3 months, hopefully after 6 months, of removing the primary.

These are patients who meet all the criteria that we have seen in terms of the best outcomes — patients that have Oslo scores of less than three. The Oslo trial, which included the SECA (Secondary Cancer)-I and SECA-II trials, basically showed that patients with a maximal tumor diameter of less than 5.5 with a pretransplant CEA (carcinoembryonic antigen) of less than 80 that do not have progression on chemotherapy, among other variables, do better. But the concept is that this is a therapy that will apply only to selected patients. That way we can continue to have adequate overall survival post-transplant that would be comparable to other diseases that we do liver transplants for.

Dr. Schlechter: Were there other biomarkers, any mutations that were included or excluded?

Dr. Dib: Yes. If you look at SECA-I, SECA-II trial outcomes, and also TRANSMET, they all say patients with BRAF mutations shouldn’t be transplanted. There are other parameters, including, for example, the site of the primary tumor. Patients with a left-sided colon primary tumor do much better than patients who have a right-sided primary tumor.

That’s not a complete contraindication, but if you look at the most updated inclusion criteria of programs, like the ones that the one that we have here at Beth Israel Deaconess and many others, the inclusion criteria protocols include patients who have only hepatic disease.

So, if there are no extrahepatic mets, the resection of the primary has been done or will be done after a multidisciplinary discussion. We want to make sure they have the absence of BRAF mutation, and that they don’t have disease progression while on chemotherapy. So hopefully we have data from enough months to be able to make sure that there’s no intrahepatic or extrahepatic progression while on chemotherapy.

And that’s including CEA and also looking at the imaging.

Dr. Schlechter: When you’re seeing a patient, how much chemo do you think they should have? What’s a good run chemotherapy-wise for these patients? Let’s say, before I refer a patient to you, how much chemo should they have? And then what should I do? Do I get a PET scan? Do I get MRI? What’s the right scanning I should do to prove there’s no extrahepatic disease before sending a patient in for consideration?

Dr. Dib: First, we need to confirm unresectability. Referring patients early is always a good measure to make sure that we’re all in agreement that it’s an unresectable patient. Having a PET scan from the very beginning is helpful because it shows the disease before doing chemotherapy.

In terms of the lines of chemotherapy, ideally in the TRANSMET trial, for example, the idea was to show tumor control for at least 3 months, with less than three lines of chemotherapy. Some patients will do that with FOLFIRI. It depends on the case.

I think some of those evaluations will need a multidisciplinary discussion. In our case, we are connected to the Norway team. We frequently talk with the Oslo team and an international community of transplant centers to get opinions on particular cases.

But I think referring patients early is a good measure. If we don’t think that they qualify, we will let the team know. We’re strictly looking at patients who have unresectable liver mets that don’t have extrahepatic disease. The idea is to do a primary tumor resection, and then get to transplantation, hopefully after 6 months. In some cases that have some concerns in terms of tumor biology, we may even extend the time from diagnosis to transplant to over 1.5 years.

Dr. Schlechter: Excellent. And what’s the experience like for these patients? In training as a resident many years ago, I saw patients with cirrhosis who went on to have a liver transplant, and that was sort of trading one disease for another. What is the posttransplant, or the remission, experience of a liver transplant for colorectal cancer like for the patient?

Dr. Dib: That’s a very important point. I think that transplantation has gotten better and better, as has chemotherapy systemic therapy. The liver transplantation experience from 20 years ago has improved dramatically. I think the quality of life of liver transplant patients after transplantation has increased quite a bit.

At Beth Israel Deaconess, we have a liver transplant program that is doing over a 100 livers a year. And when you have a high-volume center, usually the experience gets better. The time in the hospital post-transplant decreases.

In general, when we’re doing liver transplants, patients are getting extubated in the OR 30% of the time. The vast majority of patients are going home within 1 or 2 weeks. They need to have immunosuppression for the rest of their lives. We have a very good program of transplant coordinators that will help the family and the patient to live with immunosuppression and live with a transplanted organ.

But I would say that we have many, many patients, especially these patients who are not patients with cirrhosis. Their health is not as deteriorated as patients who have low MELD (model for end-stage liver disease) scores. They don’t have liver disease. They have cancer. So usually patients like that, many of them can go back to work and live a quality of life that is fairly reasonable.

Dr. Schlechter: That’s good to hear. When we hear statements like liver transplant for colon cancer, a lot of us have this picture of a much sicker population, but it’s interesting and true that the colorectal cancer population as a candidate for liver transplant is a much healthier population than the population with cirrhosis.

Let’s talk about organs and donors. Largely in the TRANSMET study, for example, that was cadaveric donors. Those were not living donors and you’ve done a lot of work on living donors. If the answer in the United States, because of limited access to organs, is going to be living donors, who are those donors?

What is that like? How do you identify them?

Dr. Dib: There’s a lot of advantages to using living donors for these patients. In any type of patient that needs a liver transplant, cadaveric donors or deceased donors is the same concept. There are two types of deceased donors: the brain-dead donors and donors after cardiac death. Those are hard to come by.

We still have 15%-20% mortality on the waiting list in the United States. We’re already still struggling to get enough donors to transplant the patients that are on the list. Now, if you add a new indication, which is unresectable colorectal mets, we need to make sure that the outcomes are equivalent to the patients who are going to be transplanted for other reasons.

Right now, for example, the 5-year overall survival of a patient with cirrhosis, or a patient with hepatocellular carcinoma, is over 80% 5-year survival. In the SECA trials and TRANSMET trial, if we do a good selection, I think we can get to 70% 5-year survival. But until we have more data, I think it’s a cautious measure to, as a field, try to use living donors and not compete with the rest of the list of patients who are already dying on the list for liver transplants.

Once we get more data, it’s going to be something that, in the transplant community, we may be able to use deceased donors. Especially deceased donors with maybe extended criteria that are not going to be used for other patients. We can do living-unrelated or living-related donations. Family members or also friends or neighbors or part of the community, even altruistic donors, can donate to a potential recipient. And that enables us to not only time the transplant in an adequate manner, because we’re able to transplant the patient early, but also time it so we can give the number of chemotherapy cycles that we want to give.

That’s a huge advantage. You don’t compete for a liver with the cadaveric waiting list of patients that are waiting for other reasons, and you can select the tumor biology very well because you know exactly when the surgery is going to be. For instance, we can say, okay, this patient has KRAS mutation, left-sided colon cancer, and has been having good tumor biology with no progression. We will wait 6 months from the primary tumor to the transplant, which is going to be 1 year from diagnosis to transplant. And we can see during that time whether they continue to have good tumor biology.

But if you have a deceased donor liver transplant, sometimes you can’t time that well and schedule it. It becomes a bit more tricky in terms of patient selection and making sure that we do this for the people who are going to benefit.

Dr. Schlechter: And how does donor matching work? Is it HLA (human leukocyte antigen) matched or ABO-matched? Who can donate when you say a living-related? For example, when we think about bone marrow transplantation, which we’re all familiar with in the oncology population, it’s an incredibly complex match process. Is this the same challenge?

Dr. Dib: No, it’s a little bit simpler. Living donors for liver transplants need to be between the ages of 18 and 60. They need to be relatively healthy, relatively fit, with a BMI hopefully less than 30, definitely less than 35. The compatibility is ABO compatibility. So, if they’re ABO-compatible, relatively young, relatively healthy, they would be a potential donor and we will go ahead and do a CT scan.

If the CT scan shows that they have a good, adequate anatomy, more than 90% of those will be good donors. I would say that out of 100 people who want to be donors, 25 of them will be adequate. One out of four people who want to save their family member and want to have this operation are able to donate half of their liver to their family member or loved one.

Dr. Schlechter: Excellent. And it’s helpful to know that the matching process is simpler. During his discussion, René Adam unequivocally stated that liver transplants are a new standard of care for colorectal cancer. And I guess my question is, do you agree with this statement? How do we balance the demand for living donors and the demand for deceased donors? Especially in a time of increasing fatty liver disease and obesity, other indications for liver transplant, causes of cirrhosis, and also in an era of young-onset colorectal cancer. Patients are younger. Is this a new standard of care? Do you agree with that statement?

Dr. Dib: I do agree with that statement. I think it’s important to understand that not all patients with colorectal mets are the same. Of the number of patients in the United States who have colorectal cancer, let’s say 50% of them will have liver metastasis. Only 15%-20% of them will have liver-only metastasis.

This is only for patients who have liver-only metastasis without extrahepatic disease. And only maybe 15%-20% of them will meet all the criteria to be able to undergo liver transplantation. I think it’s for a very selective subset of patients who have very good tumor biology, generally young patients who don’t have any other alternative to having even a complex liver resection and are not able to get R0 resection. That is when we could think about doing liver transplantation.

It’s one more of the skills that we can have. It doesn’t mean that it will be the only skill, or the best skill, for all of the patients.

Dr. Schlechter: When a patient volunteers to be a living donor for a loved one or a family member, and they go through all the screening and they’re found to be a candidate, what is the surgical experience for that patient?

How long are they in the hospital? What sort of operation is that?

Dr. Dib: Living donors are very special patients. These are patients who do not need an operation. And the only reason they’re doing this is to save the life of their loved one. Donor safety is our priority number one, two, three, and four. The donor operation needs to be perfect.

And so we take good care of, first of all, selecting the living donors, making sure that they’re young and they don’t have any big contraindications. We also ensure that they are well informed of the process. The living donor surgery that we’re now doing is laparoscopic and minimally invasive. Here at Beth Israel Deaconess, we have done it laparoscopically with very good results.

I think that experience before and after the surgery gets so much better because of the better recovery. They’re able to go home, in general, within 4 or 5 days, and they get on with their normal life within 6-8 weeks. I think it’s important for them to know all the processes and the actual risks and benefits for the recipient.

Among those risks, I think it’s important for them to understand that this is a complex operation. Even if we do it laparoscopically or robotically, so that the scar is less, inside we’re still taking out half of the liver. That is a surgery that needs to be undertaken very meticulously, with a focus on minimizing any bleeding.

It’s a surgery that takes a long time. It takes about 6 hours. We do our best to try to minimize any risks.

Dr. Schlechter: Excellent. Thanks for that. Today we had Dr. Martin Dib joining us to discuss liver transplant for metastatic colorectal cancer. We discussed the various important criteria. We discussed that early referral to multidisciplinary centers that manage these is important to help get patients set up.

We discussed the fact that there are certain inclusion and exclusion criteria to consider. Obviously, unresectable disease is a critical determination that should be made by a liver surgeon. The absence of extrahepatic disease is important in staging with PET or other imaging. We discussed certain other biological exclusions.

There’s a relative contraindication of right-sided vs left-sided cancers, but right-sided cancers can be transplanted. We discussed that an elevated CEA greater than 80 is a contraindication, as are mutations in BRAF. We reviewed data from both the TRANSMET trial recently published in The Lancet and presented at ASCO in 2024, as well as the older Oslo criteria and Oslo trials and SECA trials.

And finally, we heard that donors can now come as living donors, a laparoscopic robotic surgery with a better safety profile, and greater access to organs that are ABO matched and not HLA matched because of the nature of the biology. Thank you again for joining us.


 

Benjamin L. Schlechter, MD, is senior physician, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts. He has disclosed no relevant financial relationships. Martin J. Dib, MD, is member of the faculty, Department of Surgery, Harvard Medical School; director of Hepatobiliary Surgery, Division of Transplantation, Beth Israel Deaconess Medical Center, Boston. He has disclosed no relevant financial relationships.

A version of this transcript appeared on Medscape.com.

This transcript has been edited for clarity.
 

Benjamin L. Schlechter, MD: Today we’re discussing liver transplant for metastatic colorectal cancer with our guest, Dr. Martin Dib. Dr. Dib is the director of the Hepatobiliary Surgery and Living Donor Program at Beth Israel Deaconess Medical Center here in Boston, and a Harvard Medical School faculty member.

He was previously at the Pontificia Universidad Católica de Chile, a leading international institution investigating the role of liver transplant in colorectal cancer, among other diseases. Dr. Dib, before we move to our discussion, I’d like to hear a bit about your pathway to becoming a transplant surgeon. How did you end up working on colorectal cancer and liver transplants in this field?

Martin J. Dib, MD: Thank you so much, Dr. Schlechter. I am originally from Chile. I had an opportunity to come to Beth Israel Deaconess Medical Center after medical school and I did liver regeneration research at the transplant center. After that, I was lucky enough to match as a general surgery resident at Beth Israel Deaconess.

This is my alma mater and I was able to graduate as a surgeon here. You and I had some paths together. After graduating from Harvard as a surgeon, I was trained in liver transplant, abdominal transplant, surgical oncology, and hepatobiliary surgery at the University of Toronto.

I have been developing this passion for being able to transplant cancer patients and use organ transplant techniques to be able to do complex resections for cancer.

Dr. Schlechter: Let’s talk about the topic for today, which is liver transplant and colorectal cancer. I’ll be honest — this is not a very familiar topic for a lot of oncologists. There are a lot of details that I think are new to us as oncologists. We need to expand this conversation to get access to patients for this.

First and foremost, can you talk about some of the parameters for a resectable liver metastasis vs unresectable disease that would be an indication for a liver transplant?

Dr. Dib: I think this is a very interesting topic because liver transplantation for cancer is not new. Liver transplantation started in the 1960s when people started doing liver transplants for advanced liver tumors. The problem is that they were selecting patients who had very advanced — and poor tumor biology — tumors. The outcomes were not good.

It was only in 1996 when the Milan criteria started. Mazzaferro and colleagues, using strict patient selection, were able to do liver transplant for selected hepatocellular carcinoma patients. Having those excellent outcomes in selecting patients opened the field for what we now call transplant oncology, which is using selection criteria and using other methods to be able to select which patients will do well after transplantation, even with immunosuppression.

Liver transplantation for colorectal metastasis was used at the very beginning of the era of liver transplantation, but with very poor outcomes. It was abandoned because of the outcomes. It is exciting to see that after 20 years of not doing it, there was a group in Norway that started again. They are doing liver transplants for colorectal metastases (mets), but with very selected patients.

In Norway, they had a very unusual setting where they had more liver donors than patients on the list waiting for liver transplant. So they can’t share these livers and we’re all jealous, right? Every single country in the West struggles because we don’t have enough livers for the rest of the list. And they had a lot of livers to be able to transplant people.

They decided to transplant some selected patients with colorectal mets that were unresectable. And the surprise was that they found that they were able to get a 60% survival at 5 years. And so that was new. After that, in Norway, they started showing this data to other centers in the world. It wasn’t until this year that we could see not only the long-term data and long-term outcomes of using liver transplantation for unresectable colorectal mets, but also we’re now having data from a prospective clinical trial from France.

It was three countries in the prospective clinical trial: France, Belgium, and Italy. We now see that we have a little stronger data to support the use of liver transplants for unresectable colorectal mets.

Dr. Schlechter: That’s the TRANSMET study you’re referencing that was presented at ASCO in the late-breaking abstract session in 2024, and then more recently in The Lancet’s eClinicalMedicine. Both of those papers were led by René Adam. That was a cool presentation to sit through. I was in the room, and I was taking a ton of notes and there was a lot of info that came out of that.

First of all, it showed that patients who had received chemotherapy and were responding could then go on to liver transplant in that population. Impressively, 81% of the patients who were randomized to transplant received it. Frankly, that’s a big number, especially compared with the West, as you said, and in particular the US and here in New England where livers are a very precious commodity.

And even accounting for that, if you look at the intention-to-treat analysis, the 5-year overall survival in that population was 57% compared with 13% with chemotherapy. And that feels like a real number for chemotherapy. If you look at the per-protocol analysis, frankly, the numbers are higher.

It’s always a challenging assessment. What was also interesting to me was the pattern of recurrence, which in general was that recurrences were extrahepatic. So not only were patients rendered disease-free, but in general, the liver remained disease-free and only 3% of patients had liver-only recurrence and 11% had widespread metastatic disease.

The biggest group was lung metastases, at about 40%. Ultimately, they reported a progression-free survival of 17. 4 months for transplant compared with 6. 4 months with chemotherapy. On every parameter, it looks like liver transplant wins for these people. Help me out. Who are these people? How do we find these people?

What are the inclusions and exclusions for this population?

Dr. Dib: I think that’s very important. This is not a therapy that will be for every patient. These are selected patients who have liver-only unresectable colorectal mets. These are patients that don’t have any extrahepatic disease and that either the primary has been taken out already or that they have the primary present, but the plan is to take the primary and then do a liver transplantation after 3 months, hopefully after 6 months, of removing the primary.

These are patients who meet all the criteria that we have seen in terms of the best outcomes — patients that have Oslo scores of less than three. The Oslo trial, which included the SECA (Secondary Cancer)-I and SECA-II trials, basically showed that patients with a maximal tumor diameter of less than 5.5 with a pretransplant CEA (carcinoembryonic antigen) of less than 80 that do not have progression on chemotherapy, among other variables, do better. But the concept is that this is a therapy that will apply only to selected patients. That way we can continue to have adequate overall survival post-transplant that would be comparable to other diseases that we do liver transplants for.

Dr. Schlechter: Were there other biomarkers, any mutations that were included or excluded?

Dr. Dib: Yes. If you look at SECA-I, SECA-II trial outcomes, and also TRANSMET, they all say patients with BRAF mutations shouldn’t be transplanted. There are other parameters, including, for example, the site of the primary tumor. Patients with a left-sided colon primary tumor do much better than patients who have a right-sided primary tumor.

That’s not a complete contraindication, but if you look at the most updated inclusion criteria of programs, like the ones that the one that we have here at Beth Israel Deaconess and many others, the inclusion criteria protocols include patients who have only hepatic disease.

So, if there are no extrahepatic mets, the resection of the primary has been done or will be done after a multidisciplinary discussion. We want to make sure they have the absence of BRAF mutation, and that they don’t have disease progression while on chemotherapy. So hopefully we have data from enough months to be able to make sure that there’s no intrahepatic or extrahepatic progression while on chemotherapy.

And that’s including CEA and also looking at the imaging.

Dr. Schlechter: When you’re seeing a patient, how much chemo do you think they should have? What’s a good run chemotherapy-wise for these patients? Let’s say, before I refer a patient to you, how much chemo should they have? And then what should I do? Do I get a PET scan? Do I get MRI? What’s the right scanning I should do to prove there’s no extrahepatic disease before sending a patient in for consideration?

Dr. Dib: First, we need to confirm unresectability. Referring patients early is always a good measure to make sure that we’re all in agreement that it’s an unresectable patient. Having a PET scan from the very beginning is helpful because it shows the disease before doing chemotherapy.

In terms of the lines of chemotherapy, ideally in the TRANSMET trial, for example, the idea was to show tumor control for at least 3 months, with less than three lines of chemotherapy. Some patients will do that with FOLFIRI. It depends on the case.

I think some of those evaluations will need a multidisciplinary discussion. In our case, we are connected to the Norway team. We frequently talk with the Oslo team and an international community of transplant centers to get opinions on particular cases.

But I think referring patients early is a good measure. If we don’t think that they qualify, we will let the team know. We’re strictly looking at patients who have unresectable liver mets that don’t have extrahepatic disease. The idea is to do a primary tumor resection, and then get to transplantation, hopefully after 6 months. In some cases that have some concerns in terms of tumor biology, we may even extend the time from diagnosis to transplant to over 1.5 years.

Dr. Schlechter: Excellent. And what’s the experience like for these patients? In training as a resident many years ago, I saw patients with cirrhosis who went on to have a liver transplant, and that was sort of trading one disease for another. What is the posttransplant, or the remission, experience of a liver transplant for colorectal cancer like for the patient?

Dr. Dib: That’s a very important point. I think that transplantation has gotten better and better, as has chemotherapy systemic therapy. The liver transplantation experience from 20 years ago has improved dramatically. I think the quality of life of liver transplant patients after transplantation has increased quite a bit.

At Beth Israel Deaconess, we have a liver transplant program that is doing over a 100 livers a year. And when you have a high-volume center, usually the experience gets better. The time in the hospital post-transplant decreases.

In general, when we’re doing liver transplants, patients are getting extubated in the OR 30% of the time. The vast majority of patients are going home within 1 or 2 weeks. They need to have immunosuppression for the rest of their lives. We have a very good program of transplant coordinators that will help the family and the patient to live with immunosuppression and live with a transplanted organ.

But I would say that we have many, many patients, especially these patients who are not patients with cirrhosis. Their health is not as deteriorated as patients who have low MELD (model for end-stage liver disease) scores. They don’t have liver disease. They have cancer. So usually patients like that, many of them can go back to work and live a quality of life that is fairly reasonable.

Dr. Schlechter: That’s good to hear. When we hear statements like liver transplant for colon cancer, a lot of us have this picture of a much sicker population, but it’s interesting and true that the colorectal cancer population as a candidate for liver transplant is a much healthier population than the population with cirrhosis.

Let’s talk about organs and donors. Largely in the TRANSMET study, for example, that was cadaveric donors. Those were not living donors and you’ve done a lot of work on living donors. If the answer in the United States, because of limited access to organs, is going to be living donors, who are those donors?

What is that like? How do you identify them?

Dr. Dib: There’s a lot of advantages to using living donors for these patients. In any type of patient that needs a liver transplant, cadaveric donors or deceased donors is the same concept. There are two types of deceased donors: the brain-dead donors and donors after cardiac death. Those are hard to come by.

We still have 15%-20% mortality on the waiting list in the United States. We’re already still struggling to get enough donors to transplant the patients that are on the list. Now, if you add a new indication, which is unresectable colorectal mets, we need to make sure that the outcomes are equivalent to the patients who are going to be transplanted for other reasons.

Right now, for example, the 5-year overall survival of a patient with cirrhosis, or a patient with hepatocellular carcinoma, is over 80% 5-year survival. In the SECA trials and TRANSMET trial, if we do a good selection, I think we can get to 70% 5-year survival. But until we have more data, I think it’s a cautious measure to, as a field, try to use living donors and not compete with the rest of the list of patients who are already dying on the list for liver transplants.

Once we get more data, it’s going to be something that, in the transplant community, we may be able to use deceased donors. Especially deceased donors with maybe extended criteria that are not going to be used for other patients. We can do living-unrelated or living-related donations. Family members or also friends or neighbors or part of the community, even altruistic donors, can donate to a potential recipient. And that enables us to not only time the transplant in an adequate manner, because we’re able to transplant the patient early, but also time it so we can give the number of chemotherapy cycles that we want to give.

That’s a huge advantage. You don’t compete for a liver with the cadaveric waiting list of patients that are waiting for other reasons, and you can select the tumor biology very well because you know exactly when the surgery is going to be. For instance, we can say, okay, this patient has KRAS mutation, left-sided colon cancer, and has been having good tumor biology with no progression. We will wait 6 months from the primary tumor to the transplant, which is going to be 1 year from diagnosis to transplant. And we can see during that time whether they continue to have good tumor biology.

But if you have a deceased donor liver transplant, sometimes you can’t time that well and schedule it. It becomes a bit more tricky in terms of patient selection and making sure that we do this for the people who are going to benefit.

Dr. Schlechter: And how does donor matching work? Is it HLA (human leukocyte antigen) matched or ABO-matched? Who can donate when you say a living-related? For example, when we think about bone marrow transplantation, which we’re all familiar with in the oncology population, it’s an incredibly complex match process. Is this the same challenge?

Dr. Dib: No, it’s a little bit simpler. Living donors for liver transplants need to be between the ages of 18 and 60. They need to be relatively healthy, relatively fit, with a BMI hopefully less than 30, definitely less than 35. The compatibility is ABO compatibility. So, if they’re ABO-compatible, relatively young, relatively healthy, they would be a potential donor and we will go ahead and do a CT scan.

If the CT scan shows that they have a good, adequate anatomy, more than 90% of those will be good donors. I would say that out of 100 people who want to be donors, 25 of them will be adequate. One out of four people who want to save their family member and want to have this operation are able to donate half of their liver to their family member or loved one.

Dr. Schlechter: Excellent. And it’s helpful to know that the matching process is simpler. During his discussion, René Adam unequivocally stated that liver transplants are a new standard of care for colorectal cancer. And I guess my question is, do you agree with this statement? How do we balance the demand for living donors and the demand for deceased donors? Especially in a time of increasing fatty liver disease and obesity, other indications for liver transplant, causes of cirrhosis, and also in an era of young-onset colorectal cancer. Patients are younger. Is this a new standard of care? Do you agree with that statement?

Dr. Dib: I do agree with that statement. I think it’s important to understand that not all patients with colorectal mets are the same. Of the number of patients in the United States who have colorectal cancer, let’s say 50% of them will have liver metastasis. Only 15%-20% of them will have liver-only metastasis.

This is only for patients who have liver-only metastasis without extrahepatic disease. And only maybe 15%-20% of them will meet all the criteria to be able to undergo liver transplantation. I think it’s for a very selective subset of patients who have very good tumor biology, generally young patients who don’t have any other alternative to having even a complex liver resection and are not able to get R0 resection. That is when we could think about doing liver transplantation.

It’s one more of the skills that we can have. It doesn’t mean that it will be the only skill, or the best skill, for all of the patients.

Dr. Schlechter: When a patient volunteers to be a living donor for a loved one or a family member, and they go through all the screening and they’re found to be a candidate, what is the surgical experience for that patient?

How long are they in the hospital? What sort of operation is that?

Dr. Dib: Living donors are very special patients. These are patients who do not need an operation. And the only reason they’re doing this is to save the life of their loved one. Donor safety is our priority number one, two, three, and four. The donor operation needs to be perfect.

And so we take good care of, first of all, selecting the living donors, making sure that they’re young and they don’t have any big contraindications. We also ensure that they are well informed of the process. The living donor surgery that we’re now doing is laparoscopic and minimally invasive. Here at Beth Israel Deaconess, we have done it laparoscopically with very good results.

I think that experience before and after the surgery gets so much better because of the better recovery. They’re able to go home, in general, within 4 or 5 days, and they get on with their normal life within 6-8 weeks. I think it’s important for them to know all the processes and the actual risks and benefits for the recipient.

Among those risks, I think it’s important for them to understand that this is a complex operation. Even if we do it laparoscopically or robotically, so that the scar is less, inside we’re still taking out half of the liver. That is a surgery that needs to be undertaken very meticulously, with a focus on minimizing any bleeding.

It’s a surgery that takes a long time. It takes about 6 hours. We do our best to try to minimize any risks.

Dr. Schlechter: Excellent. Thanks for that. Today we had Dr. Martin Dib joining us to discuss liver transplant for metastatic colorectal cancer. We discussed the various important criteria. We discussed that early referral to multidisciplinary centers that manage these is important to help get patients set up.

We discussed the fact that there are certain inclusion and exclusion criteria to consider. Obviously, unresectable disease is a critical determination that should be made by a liver surgeon. The absence of extrahepatic disease is important in staging with PET or other imaging. We discussed certain other biological exclusions.

There’s a relative contraindication of right-sided vs left-sided cancers, but right-sided cancers can be transplanted. We discussed that an elevated CEA greater than 80 is a contraindication, as are mutations in BRAF. We reviewed data from both the TRANSMET trial recently published in The Lancet and presented at ASCO in 2024, as well as the older Oslo criteria and Oslo trials and SECA trials.

And finally, we heard that donors can now come as living donors, a laparoscopic robotic surgery with a better safety profile, and greater access to organs that are ABO matched and not HLA matched because of the nature of the biology. Thank you again for joining us.


 

Benjamin L. Schlechter, MD, is senior physician, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts. He has disclosed no relevant financial relationships. Martin J. Dib, MD, is member of the faculty, Department of Surgery, Harvard Medical School; director of Hepatobiliary Surgery, Division of Transplantation, Beth Israel Deaconess Medical Center, Boston. He has disclosed no relevant financial relationships.

A version of this transcript appeared on Medscape.com.

This transcript has been edited for clarity.
 

Benjamin L. Schlechter, MD: Today we’re discussing liver transplant for metastatic colorectal cancer with our guest, Dr. Martin Dib. Dr. Dib is the director of the Hepatobiliary Surgery and Living Donor Program at Beth Israel Deaconess Medical Center here in Boston, and a Harvard Medical School faculty member.

He was previously at the Pontificia Universidad Católica de Chile, a leading international institution investigating the role of liver transplant in colorectal cancer, among other diseases. Dr. Dib, before we move to our discussion, I’d like to hear a bit about your pathway to becoming a transplant surgeon. How did you end up working on colorectal cancer and liver transplants in this field?

Martin J. Dib, MD: Thank you so much, Dr. Schlechter. I am originally from Chile. I had an opportunity to come to Beth Israel Deaconess Medical Center after medical school and I did liver regeneration research at the transplant center. After that, I was lucky enough to match as a general surgery resident at Beth Israel Deaconess.

This is my alma mater and I was able to graduate as a surgeon here. You and I had some paths together. After graduating from Harvard as a surgeon, I was trained in liver transplant, abdominal transplant, surgical oncology, and hepatobiliary surgery at the University of Toronto.

I have been developing this passion for being able to transplant cancer patients and use organ transplant techniques to be able to do complex resections for cancer.

Dr. Schlechter: Let’s talk about the topic for today, which is liver transplant and colorectal cancer. I’ll be honest — this is not a very familiar topic for a lot of oncologists. There are a lot of details that I think are new to us as oncologists. We need to expand this conversation to get access to patients for this.

First and foremost, can you talk about some of the parameters for a resectable liver metastasis vs unresectable disease that would be an indication for a liver transplant?

Dr. Dib: I think this is a very interesting topic because liver transplantation for cancer is not new. Liver transplantation started in the 1960s when people started doing liver transplants for advanced liver tumors. The problem is that they were selecting patients who had very advanced — and poor tumor biology — tumors. The outcomes were not good.

It was only in 1996 when the Milan criteria started. Mazzaferro and colleagues, using strict patient selection, were able to do liver transplant for selected hepatocellular carcinoma patients. Having those excellent outcomes in selecting patients opened the field for what we now call transplant oncology, which is using selection criteria and using other methods to be able to select which patients will do well after transplantation, even with immunosuppression.

Liver transplantation for colorectal metastasis was used at the very beginning of the era of liver transplantation, but with very poor outcomes. It was abandoned because of the outcomes. It is exciting to see that after 20 years of not doing it, there was a group in Norway that started again. They are doing liver transplants for colorectal metastases (mets), but with very selected patients.

In Norway, they had a very unusual setting where they had more liver donors than patients on the list waiting for liver transplant. So they can’t share these livers and we’re all jealous, right? Every single country in the West struggles because we don’t have enough livers for the rest of the list. And they had a lot of livers to be able to transplant people.

They decided to transplant some selected patients with colorectal mets that were unresectable. And the surprise was that they found that they were able to get a 60% survival at 5 years. And so that was new. After that, in Norway, they started showing this data to other centers in the world. It wasn’t until this year that we could see not only the long-term data and long-term outcomes of using liver transplantation for unresectable colorectal mets, but also we’re now having data from a prospective clinical trial from France.

It was three countries in the prospective clinical trial: France, Belgium, and Italy. We now see that we have a little stronger data to support the use of liver transplants for unresectable colorectal mets.

Dr. Schlechter: That’s the TRANSMET study you’re referencing that was presented at ASCO in the late-breaking abstract session in 2024, and then more recently in The Lancet’s eClinicalMedicine. Both of those papers were led by René Adam. That was a cool presentation to sit through. I was in the room, and I was taking a ton of notes and there was a lot of info that came out of that.

First of all, it showed that patients who had received chemotherapy and were responding could then go on to liver transplant in that population. Impressively, 81% of the patients who were randomized to transplant received it. Frankly, that’s a big number, especially compared with the West, as you said, and in particular the US and here in New England where livers are a very precious commodity.

And even accounting for that, if you look at the intention-to-treat analysis, the 5-year overall survival in that population was 57% compared with 13% with chemotherapy. And that feels like a real number for chemotherapy. If you look at the per-protocol analysis, frankly, the numbers are higher.

It’s always a challenging assessment. What was also interesting to me was the pattern of recurrence, which in general was that recurrences were extrahepatic. So not only were patients rendered disease-free, but in general, the liver remained disease-free and only 3% of patients had liver-only recurrence and 11% had widespread metastatic disease.

The biggest group was lung metastases, at about 40%. Ultimately, they reported a progression-free survival of 17. 4 months for transplant compared with 6. 4 months with chemotherapy. On every parameter, it looks like liver transplant wins for these people. Help me out. Who are these people? How do we find these people?

What are the inclusions and exclusions for this population?

Dr. Dib: I think that’s very important. This is not a therapy that will be for every patient. These are selected patients who have liver-only unresectable colorectal mets. These are patients that don’t have any extrahepatic disease and that either the primary has been taken out already or that they have the primary present, but the plan is to take the primary and then do a liver transplantation after 3 months, hopefully after 6 months, of removing the primary.

These are patients who meet all the criteria that we have seen in terms of the best outcomes — patients that have Oslo scores of less than three. The Oslo trial, which included the SECA (Secondary Cancer)-I and SECA-II trials, basically showed that patients with a maximal tumor diameter of less than 5.5 with a pretransplant CEA (carcinoembryonic antigen) of less than 80 that do not have progression on chemotherapy, among other variables, do better. But the concept is that this is a therapy that will apply only to selected patients. That way we can continue to have adequate overall survival post-transplant that would be comparable to other diseases that we do liver transplants for.

Dr. Schlechter: Were there other biomarkers, any mutations that were included or excluded?

Dr. Dib: Yes. If you look at SECA-I, SECA-II trial outcomes, and also TRANSMET, they all say patients with BRAF mutations shouldn’t be transplanted. There are other parameters, including, for example, the site of the primary tumor. Patients with a left-sided colon primary tumor do much better than patients who have a right-sided primary tumor.

That’s not a complete contraindication, but if you look at the most updated inclusion criteria of programs, like the ones that the one that we have here at Beth Israel Deaconess and many others, the inclusion criteria protocols include patients who have only hepatic disease.

So, if there are no extrahepatic mets, the resection of the primary has been done or will be done after a multidisciplinary discussion. We want to make sure they have the absence of BRAF mutation, and that they don’t have disease progression while on chemotherapy. So hopefully we have data from enough months to be able to make sure that there’s no intrahepatic or extrahepatic progression while on chemotherapy.

And that’s including CEA and also looking at the imaging.

Dr. Schlechter: When you’re seeing a patient, how much chemo do you think they should have? What’s a good run chemotherapy-wise for these patients? Let’s say, before I refer a patient to you, how much chemo should they have? And then what should I do? Do I get a PET scan? Do I get MRI? What’s the right scanning I should do to prove there’s no extrahepatic disease before sending a patient in for consideration?

Dr. Dib: First, we need to confirm unresectability. Referring patients early is always a good measure to make sure that we’re all in agreement that it’s an unresectable patient. Having a PET scan from the very beginning is helpful because it shows the disease before doing chemotherapy.

In terms of the lines of chemotherapy, ideally in the TRANSMET trial, for example, the idea was to show tumor control for at least 3 months, with less than three lines of chemotherapy. Some patients will do that with FOLFIRI. It depends on the case.

I think some of those evaluations will need a multidisciplinary discussion. In our case, we are connected to the Norway team. We frequently talk with the Oslo team and an international community of transplant centers to get opinions on particular cases.

But I think referring patients early is a good measure. If we don’t think that they qualify, we will let the team know. We’re strictly looking at patients who have unresectable liver mets that don’t have extrahepatic disease. The idea is to do a primary tumor resection, and then get to transplantation, hopefully after 6 months. In some cases that have some concerns in terms of tumor biology, we may even extend the time from diagnosis to transplant to over 1.5 years.

Dr. Schlechter: Excellent. And what’s the experience like for these patients? In training as a resident many years ago, I saw patients with cirrhosis who went on to have a liver transplant, and that was sort of trading one disease for another. What is the posttransplant, or the remission, experience of a liver transplant for colorectal cancer like for the patient?

Dr. Dib: That’s a very important point. I think that transplantation has gotten better and better, as has chemotherapy systemic therapy. The liver transplantation experience from 20 years ago has improved dramatically. I think the quality of life of liver transplant patients after transplantation has increased quite a bit.

At Beth Israel Deaconess, we have a liver transplant program that is doing over a 100 livers a year. And when you have a high-volume center, usually the experience gets better. The time in the hospital post-transplant decreases.

In general, when we’re doing liver transplants, patients are getting extubated in the OR 30% of the time. The vast majority of patients are going home within 1 or 2 weeks. They need to have immunosuppression for the rest of their lives. We have a very good program of transplant coordinators that will help the family and the patient to live with immunosuppression and live with a transplanted organ.

But I would say that we have many, many patients, especially these patients who are not patients with cirrhosis. Their health is not as deteriorated as patients who have low MELD (model for end-stage liver disease) scores. They don’t have liver disease. They have cancer. So usually patients like that, many of them can go back to work and live a quality of life that is fairly reasonable.

Dr. Schlechter: That’s good to hear. When we hear statements like liver transplant for colon cancer, a lot of us have this picture of a much sicker population, but it’s interesting and true that the colorectal cancer population as a candidate for liver transplant is a much healthier population than the population with cirrhosis.

Let’s talk about organs and donors. Largely in the TRANSMET study, for example, that was cadaveric donors. Those were not living donors and you’ve done a lot of work on living donors. If the answer in the United States, because of limited access to organs, is going to be living donors, who are those donors?

What is that like? How do you identify them?

Dr. Dib: There’s a lot of advantages to using living donors for these patients. In any type of patient that needs a liver transplant, cadaveric donors or deceased donors is the same concept. There are two types of deceased donors: the brain-dead donors and donors after cardiac death. Those are hard to come by.

We still have 15%-20% mortality on the waiting list in the United States. We’re already still struggling to get enough donors to transplant the patients that are on the list. Now, if you add a new indication, which is unresectable colorectal mets, we need to make sure that the outcomes are equivalent to the patients who are going to be transplanted for other reasons.

Right now, for example, the 5-year overall survival of a patient with cirrhosis, or a patient with hepatocellular carcinoma, is over 80% 5-year survival. In the SECA trials and TRANSMET trial, if we do a good selection, I think we can get to 70% 5-year survival. But until we have more data, I think it’s a cautious measure to, as a field, try to use living donors and not compete with the rest of the list of patients who are already dying on the list for liver transplants.

Once we get more data, it’s going to be something that, in the transplant community, we may be able to use deceased donors. Especially deceased donors with maybe extended criteria that are not going to be used for other patients. We can do living-unrelated or living-related donations. Family members or also friends or neighbors or part of the community, even altruistic donors, can donate to a potential recipient. And that enables us to not only time the transplant in an adequate manner, because we’re able to transplant the patient early, but also time it so we can give the number of chemotherapy cycles that we want to give.

That’s a huge advantage. You don’t compete for a liver with the cadaveric waiting list of patients that are waiting for other reasons, and you can select the tumor biology very well because you know exactly when the surgery is going to be. For instance, we can say, okay, this patient has KRAS mutation, left-sided colon cancer, and has been having good tumor biology with no progression. We will wait 6 months from the primary tumor to the transplant, which is going to be 1 year from diagnosis to transplant. And we can see during that time whether they continue to have good tumor biology.

But if you have a deceased donor liver transplant, sometimes you can’t time that well and schedule it. It becomes a bit more tricky in terms of patient selection and making sure that we do this for the people who are going to benefit.

Dr. Schlechter: And how does donor matching work? Is it HLA (human leukocyte antigen) matched or ABO-matched? Who can donate when you say a living-related? For example, when we think about bone marrow transplantation, which we’re all familiar with in the oncology population, it’s an incredibly complex match process. Is this the same challenge?

Dr. Dib: No, it’s a little bit simpler. Living donors for liver transplants need to be between the ages of 18 and 60. They need to be relatively healthy, relatively fit, with a BMI hopefully less than 30, definitely less than 35. The compatibility is ABO compatibility. So, if they’re ABO-compatible, relatively young, relatively healthy, they would be a potential donor and we will go ahead and do a CT scan.

If the CT scan shows that they have a good, adequate anatomy, more than 90% of those will be good donors. I would say that out of 100 people who want to be donors, 25 of them will be adequate. One out of four people who want to save their family member and want to have this operation are able to donate half of their liver to their family member or loved one.

Dr. Schlechter: Excellent. And it’s helpful to know that the matching process is simpler. During his discussion, René Adam unequivocally stated that liver transplants are a new standard of care for colorectal cancer. And I guess my question is, do you agree with this statement? How do we balance the demand for living donors and the demand for deceased donors? Especially in a time of increasing fatty liver disease and obesity, other indications for liver transplant, causes of cirrhosis, and also in an era of young-onset colorectal cancer. Patients are younger. Is this a new standard of care? Do you agree with that statement?

Dr. Dib: I do agree with that statement. I think it’s important to understand that not all patients with colorectal mets are the same. Of the number of patients in the United States who have colorectal cancer, let’s say 50% of them will have liver metastasis. Only 15%-20% of them will have liver-only metastasis.

This is only for patients who have liver-only metastasis without extrahepatic disease. And only maybe 15%-20% of them will meet all the criteria to be able to undergo liver transplantation. I think it’s for a very selective subset of patients who have very good tumor biology, generally young patients who don’t have any other alternative to having even a complex liver resection and are not able to get R0 resection. That is when we could think about doing liver transplantation.

It’s one more of the skills that we can have. It doesn’t mean that it will be the only skill, or the best skill, for all of the patients.

Dr. Schlechter: When a patient volunteers to be a living donor for a loved one or a family member, and they go through all the screening and they’re found to be a candidate, what is the surgical experience for that patient?

How long are they in the hospital? What sort of operation is that?

Dr. Dib: Living donors are very special patients. These are patients who do not need an operation. And the only reason they’re doing this is to save the life of their loved one. Donor safety is our priority number one, two, three, and four. The donor operation needs to be perfect.

And so we take good care of, first of all, selecting the living donors, making sure that they’re young and they don’t have any big contraindications. We also ensure that they are well informed of the process. The living donor surgery that we’re now doing is laparoscopic and minimally invasive. Here at Beth Israel Deaconess, we have done it laparoscopically with very good results.

I think that experience before and after the surgery gets so much better because of the better recovery. They’re able to go home, in general, within 4 or 5 days, and they get on with their normal life within 6-8 weeks. I think it’s important for them to know all the processes and the actual risks and benefits for the recipient.

Among those risks, I think it’s important for them to understand that this is a complex operation. Even if we do it laparoscopically or robotically, so that the scar is less, inside we’re still taking out half of the liver. That is a surgery that needs to be undertaken very meticulously, with a focus on minimizing any bleeding.

It’s a surgery that takes a long time. It takes about 6 hours. We do our best to try to minimize any risks.

Dr. Schlechter: Excellent. Thanks for that. Today we had Dr. Martin Dib joining us to discuss liver transplant for metastatic colorectal cancer. We discussed the various important criteria. We discussed that early referral to multidisciplinary centers that manage these is important to help get patients set up.

We discussed the fact that there are certain inclusion and exclusion criteria to consider. Obviously, unresectable disease is a critical determination that should be made by a liver surgeon. The absence of extrahepatic disease is important in staging with PET or other imaging. We discussed certain other biological exclusions.

There’s a relative contraindication of right-sided vs left-sided cancers, but right-sided cancers can be transplanted. We discussed that an elevated CEA greater than 80 is a contraindication, as are mutations in BRAF. We reviewed data from both the TRANSMET trial recently published in The Lancet and presented at ASCO in 2024, as well as the older Oslo criteria and Oslo trials and SECA trials.

And finally, we heard that donors can now come as living donors, a laparoscopic robotic surgery with a better safety profile, and greater access to organs that are ABO matched and not HLA matched because of the nature of the biology. Thank you again for joining us.


 

Benjamin L. Schlechter, MD, is senior physician, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts. He has disclosed no relevant financial relationships. Martin J. Dib, MD, is member of the faculty, Department of Surgery, Harvard Medical School; director of Hepatobiliary Surgery, Division of Transplantation, Beth Israel Deaconess Medical Center, Boston. He has disclosed no relevant financial relationships.

A version of this transcript appeared on Medscape.com.