Paths to long-term survival with CRC liver mets: Dr. Hernandez-Alejandro (2023)

Betsy Post 0:00
We will go ahead and get started with this evening’s program. We are so excited to have all of you here watching live, and then for all of you that will be watching this recording, we’re very happy to make this available that way as well, because it’s all about educating patients and caregivers on the treatment options available. So just a couple of housekeeping items before I get into the introduction and turn it over to Dr. Hernandez. We will be taking questions at the end, so you can jot your questions down, or hold them till the end of his presentation, or you can put them in the chat – so please put them in the chat. You can chat to Julie. You can see Julie there, Julie Clauer, or you can send them to me. …Or you can send them to everyone. So there should be the chat feature. Please send the questions in the chat. Or you can write them down and hold them till the end. You don’t have to write them down if you have a better memory than I do, so if you think 20 minutes later, you’ll remember you can definitely do that as well. We have everyone muted just because we do want to make sure we have undivided attention for Dr. Hernandez and his presentation, but we will absolutely make time for Q and A at the end of the presentation. So I’m going to go ahead and share my screen with you, and hopefully you can see this okay. Don’t worry, it’s not “death by PowerPoint”. I’m just going to do a few slides with an introduction. So again, welcome everyone to our DocTalk this evening on “Exploring Paths to Long Term Survival With Colorectal Cancer, Liver Metastases”. Tonight’s presentation is going to be a focus for folks that have bilateral liver mets or extensive metastases. This is a little bit different than anything that we’ve offered previously with Dr. Hernandez. It really is focused on the community that has a lot of liver mets, so I just wanted to preface that up front, I think there is something for everyone here, whether you have a little or a lot, but we really wanted to impact patients and caregivers as they’re thinking about, “I’ve been told I’m inoperable, I can’t have a resection” – all of these things. “What are some different options, perhaps available to me? And how do I think about those options?” So again, we welcome everyone, but really we are trying to hear that this evening. So we’re really excited to have Dr. Hernandez with us. His resume is very extensive. I think a lot of you know him. He is active in COLONTOWN and so helpful to us. He comes to us from the University of Rochester Medical Center, where he’s the Chief of the Division of Transplantation. He has extensive training around the world, including in Canada and Japan. He has actually now over 130, not 110, (I need to update that) peer-reviewed publications in the area of liver transplantation and hepatobiliary surgery and he is on the editorial board of the Annals of Surgery. He is a pioneer in ‘donation: after cardiac death’ liver transplantation in Canada; the first to perform ALPPS in North America, and he did open the program on liver transplantation for colorectal cancer liver metastases in Rochester. He is well recognized as a team leader andinnovator and a mentor. If you know him, I know that does not surprise you at all, but my favorite thing about Dr. Hernandez is who he is as a person and what he does every day for patients and caregivers. So to us in COLONTOWN, he is, “Dr. H.”. We really appreciate and love you, Dr. Hernandez, thank you for everything that you do for our patients and our caregivers every day and for the impact that you make in their lives. We really appreciate you, and we’re really happy to have you here with us this evening. With that, I’m going to turn it over to you, and just remember to save your questions for the end. We will take those, put them in the chat or be prepared to answer live at the end. So thank you so much, and I will stop sharing and turn it over to you.

Dr. Roberto Hernandez-Alejandro 4:23
Thank you very much to all the members of COLONTOWN. Thank you very much, Julie and Betsy. Very nice introduction. It is a pleasure for me to be with all of you. I can see some familiar faces here, and I recognize also some other names. I think, before presenting, for some of you who don’t know who I am, I am very passionate about the field of of liver metastasis, since my early stages in my training. You know my title is in transplantation, and I use the hat of ‘transplanter’ but I want you to know that I do many liver resections. Perhaps, in my life, I have done more liver resections than liver transplants. Liver transplants are more complex. Liver resections are much more common. And the most common reason that we do liver resections is for liver metastasis. So I do a lot of liver metastasis resections and my presentation, I don’t want to be a bias on towards transplantation. I want to be fair with everything, and I don’t want to be moving things into the fields that I do, and before I decided to name the title of this presentation, I was thinking about, if I was a patient, if I would have one of my family members as a patient with colon cancer, what would I like to know and do, especially when the disease is advanced. And I try to be in your shoes on how stressful this could be, especially knowing all the options that are out there. And then you probably are scratching your head, where do I go? So with this, thank you again, for everybody that are opening the cameras and I’m looking forward to have questions. There are always great questions. And I am impressed with the participants, 64- that’s pretty great. So I’m going to share my screen. Let me know if this works. Can someone tell me if they can see me?

Betsy Post 7:03
Yes.

Dr. Roberto Hernandez-Alejandro 7:05
Perfect. Thank you, Betsy. All right, interrupt me if there’s a problem, Betsy and Julie. So this is titled “Exploring Paths to Long Term Survival With Colorectal Metastasis”, we have different options, on where we want to go, and I don’t think there’s a correct answer every time. There’s sometimes that there’s clear answers, but there’s a lot of times that there’s no clear answer. Seems to me that this group here, all of you know what’s happening with colon cancer, before the media. It’s impressive that years later, the media is putting in first page of Wall Street, and recently, I saw in CNN talking about a young population developing colon cancer. All of you guys know that this is happening since a long time ago. At least you, COLONTOWN, and the patients are making noise, and this is opening areas for research, and we need to work as a community on doing research and understand why colon cancer is happening more and is increasing in younger population. This graph represents what has been happening over the last few years. You can see here the year of birth in the bottom part, and this is a rate for 100,000. You don’t have to be epidemiologists to understand this graph, but you can see here from people that are 85 to around 50 years old that the rate of colon cancer, the detection, everything, is coming down. Why? Because we’re more aggressive. We have programs for doing colonoscopies. But the population from 45’s, 40’s, 30’s and 20s, we are not used to doing colonoscopies, and this is the area and the population where it’s increasing. Doesn’t mean that we shouldn’t be paying attention in this population, but this population requires a lot of work, and we need to do a lot of research to understand why, because this is a very silent disease, and many of the times when we diagnose the patients, which is 39-45 they have metastases and sometimes itgoes beyond the liver. Just to give some data, in 2021 there were in the US more than 150,000 new cases. And we know that half of the patients who have metastatic colon cancer will develop liver metastasis. So it’s not uncommon. Colon cancer is the third most common cancer in the world, after breast and prostate cancer is the most common cancer, and half of the stage IV population will develop liver metastasis. And I want to be very clear so far, until this moment, the only, and I will repeat it again, the only curative treatment is surgery. We haven’t been able to cure with other means at this moment. There’s no evidence. We help with other other treatments but the only thing that can potentially cure, not always, but many times, is surgery. So we need to try to focus and try to aim for: can we reach surgery? Sometimes there’s noway that we can reach surgery, so let’s go for other alternatives. But if we can reach surgery, how do we get there and how do we use the other alternatives as a bridge to surgery? This is very important, the concept of that. And the definition of cure that I want to be very clear about here, because a lot of you patients go to the oncologist or to the surgeon or to other specialists. When we say ‘cure’, it’s defined as five years, whether if you are in the field of oncology or transplant, we call it ‘cure’ at five years, if there’s no evidence of disease. There are some diseases that can come back after five years. Colon cancer, if we resect it, or we remove it, and it’s not coming back in five years, we call it cured. Still a little, little chance that it will come back, but probably not that much. However, there’s some data on follow up at 10 years or even more. So the goal of every patient that I personally think who has colorectal metastasis will be, I think they want to be cured. That’s the number one goal, or at least live longer with good quality of life, and also reduce the exposure to chemotherapy for as much time as possible. I think those are the goals when apatient has colorectal metastases, who is going to go for treatment. So how can we reach those goals?

Dr. Roberto Hernandez-Alejandro 11:48
Number one, you need a good medical and surgical team. That for me, is the most important part of this. You need a group or a liver surgeon, whether it’s in different fields, but a liver surgeon, you need a medical oncologist, you need a hepatologist – nowadays it’s a field that is working more on patients with colon cancer, the hepatologists are the liver specialists and they look at livers when they have fatty liver disease, other problems when the liver enzymes are going up. So it’s so important to involve them as well. Radiationoncologists, many of the times we need the interventional radiologists where, Y90 or TACE or other type of treatments, when we do portal vein embolization and those types of treatments, and we need to develop strategies to reach a surgical resection, as I mentioned a few minutes ago. Reaching resection, routine surgery will be the most important thing and the best potential outcome. And sometimes we have to be creative and innovative as professionals. If I’m a patient who has one or two liver metastases on the left side, I can tell you, you don’t have to be traveling and look for too many options. Probably close to you, there will be a person who will be able to do it, a good surgeon who’s going to be able to do a liver resection in the left side. They give you chemotherapy, and you have a good chance that probably to be cured, or if it has recurrence, to have follow up and to do something more. But when there are multiple spots – tumors, and you need someone to be creative and have strategies, then this is when you need this type of teams. When there are metastases in your lungs or in the adrenal glands, or when there is local recurrence, then we need to have a surgical team that is willing to push the envelope.

Dr. Roberto Hernandez-Alejandro 13:51
Resection of all the disease is something that is, …I call it ‘imperative’. We shouldn’t be doing a little resection here in the liver and then a little resection later on. Remember, liver metastasis, metastasize. What does that mean? If we have metastases in the liver, and we’re not treating those metastases, and we just leave them there. They’re going to send cancer cells to other places or to the other sites of the liver, and it’s going to come back. And I mean, with that living residual disease in colorectal metastasis shouldn’t be an option. This is what happens when we don’t have many options and we just give chemotherapy. And I think that this is complex and a difficult to understand, and a difficult pill to swallow. When we show this graph where we see that five year survival, it’s only 5 to 10% under chemotherapy, but it’s true, and this is what we’re facing. We want to be out of there. What happens when we use other types of treatment different than systemic chemotherapy? Many of you are aware about the hepatic artery infusion pump? Which I want to be very clear, I’m not against it. I think it has an impressive response. It’s great for patients who have advanced disease and perhaps for patients who are progressing. But this study here, it shows the group of hepatic artery infusion and those with systemic chemotherapy. So these two groups were patients who have unresectable liver disease, patients who we cannot go and resect them. And then they decided to go one went to systemic chemotherapy as a palliative treatment, and otherwise for the pump as a palliative treatment. And if you see, the dotted line is systemic and the solid line is hepatic artery infusion, and the survival at two years is practically the same. There was an increase of median survival of 24 months compared to 20 months in both of them. So definitely, there’s a little bit of benefit of hepatic artery infusion. But also we want to be very clear about what happened with with both of those things, and I’m going to make some comments about it.

Dr. Roberto Hernandez-Alejandro 16:11
I mentioned that ‘cure’ is defined at five years in the groups of transplantation and in the groups of cancer, but there’s some other groups that they really want to push and say, “Okay, let’s look at 10 years.”. So what happened when we resected the cancer? That means we removed it from the liver, the metastasis, the primary tumor, is removed. We resect it. What are my chances of being that patient and survive for 10 years or more? Well the chance is around 27%. So we know that a lot of patients during those 10 years, they will die from recurrence of the disease quite often. But remember, at five years, 5 or 10% when there’s only chemotherapy. So this is a huge benefit and a huge advantage to being able to go for resection, but the concept of resection is something that is very important, and that’s what I was mentioning about having a team that is willing to push the envelope. Many of you are familiarized with CT scans, hopefully not like this one, but well, there’s a lot of metastases. All those dark spots are metastases from colon cancer. So it’s difficult to be able to leave liver without cancer in this patient. So defining resectability many years ago, it was defined “arbitrary”. They said, if there’s less than four tumors, if we can leave good margins– that means that when we cut it, we stay far away from tumor, no evidence of disease outside the liver. And when the patient has a low clinical risk score– that is when there’s a single tumor or low CEA, which you know it’s a tumor marker, the nodes, etc, etc. — If I would be doing this in my life, I would be doing probably 10% of the surgeries that I do nowadays, only, or less than that. This has changed. And then in the early 2000s and later on, they started pushing the envelope and saying, let’s operate on patients, resect patients with more than four metastases. What happened to them? And this is a study that comes from Memorial Sloan Kettering center, almost 100 patients, and they started resecting and being more aggressive after receiving chemotherapy and resecting them, and it was an improvement of survival. So they were able to see, “alright, I think we can be more aggressive and push and operate on more liver metastases in the liver, not only four or less”. And this is a study that I want to show here, is what really changed in 2008 the management of colorectal liver metastases with chemotherapy. And I just want to let you know this journal, The Lancet, is very strong. It’s an extremely high impact factor. You publish there, you do very important research. And they analyzed 364 patients, all of them with less than four metastases. So a very simple study. And they said, “Okay, what happes if we give them chemo and then we operate on them compared to if we only operate on them without chemotherapy?”, and there was a 7% improvement of the disease-free survival. What does that mean? …That this patient, the recurrence, was later or more delayed compared to the patients who didn’t receive chemotherapy, showing a benefit of the chemotherapy. However, the chemotherapy didn’t have implications in the improval of overall survival, so the cancer came back later but at the end, patients survived at very similar rates. But there’s other benefits of the chemotherapy, which I think are more important which are learning thebehavior of the tumor, and it’s going to help us to decide what to do with the patients.

Dr. Roberto Hernandez-Alejandro 20:30
Now, let’s talk about what is one of the biggest problems that happen when we go and do resection, and what all the patients are afraid, is “oh, I’m going to have a recurrence”. So what happened with recurrence? In this study that is multi-institutional, many centers, more than 1600 patients: 947 patients had recurrence after resection. So they studied them, and they looked where the cancer came back. In 40%, only in the liver; in 20%, in the liver and outside the liver; and in 35% only outside the liver. So we know when it comes outside the liver in this population, the outcomes are not very good because the surgical treatment has to be different, especially those ones who are affected in several organs. But what happened with those ones who only came back in the liver? They went back for treatments, whether it was a resection or ablations or something that was going to remove them, and then when it came back again, there was 90%, so 372 patients that came back in the liver. So why am I showing you this road and this path? So there is a population of patients that we don’t know, but with time, we started learning that they only have liver disease, and these are the patients where we can even do much more and push the envelope and do big treatments, including liver transplantation in many of them. So what is this telling us? We need to identify clearly those patients that can be resected. But also we need to identify those ones who cannot be resected to be able to give alternatives, and maybe we can convert them to resection or other treatments. What other options do we have? Y90, microwave ablation, a lot of other centers they do RFA, or radio frequency ablation. The most common and advanced nowadays in the US is microwave ablation, external radiation and hepatic artery pump or other treatments that we’re seeing nowadays. So I was mentioning what is unresectable. In these slides, these slides that you can see, there’s a metastasis in this part. It’s the same one here, another one here. Well, maybe I can say, let’s go and do a big wedge here, and do a posterior right segmentectomy in this liver, and then hopefully the patient is cured. But perhaps other surgeons will think differently, they will say, “Oh, I will ablate this one here, and then I will do Y90, and then resect”. So which one is correct? Remember, surgery for most, if possible, will be the best. But of course, after chemotherapy to understand more the biology of the tumor in this patient, who has a lot of disease in the left side, and this is the same patient, a lot of disease in the right side, and you can see the amount of disease.

Dr. Roberto Hernandez-Alejandro 23:47
A lot of some colleagues that I know around the world, they will say, “No, this patient is unresectable”. Well, look at the segment 4 which has its own blood supply and own outflow. Maybe we can create growth there. Remember, the liver has regeneration. Maybe we can do a technique that makes thesegment to grow and have hypertrophy, and then we can go and do resection. What is that? It’s called ALPPS, right? And we were able to help this patient. This patient survived for seven and a half years and did very well. He was able to be with his grandchildren and enjoy life. The cancer came back later, but it was very different than surviving a few months or one year on. And this is what I was mentioning about in this paper, where a lot of surgeons from around the world – and I was invited to be part of these, from Switzerland, Norway, Brazil, United States, many other centers in Asia as well. We were asked and given tasks about, ‘would you resect these patients or not according to CT scans?”. And what it was, and this was more than 15 cases, and the conclusion was, there’s minimal agreement on therapeutic strategies. It’s inconsistent, and patients should consider going for second and third opinions. And this is very true. I think this paper shouldn’t go into a journal of medicine. This should go to magazines that people read. Because this is true, you need to be cautious on selecting your teams, because everything is going to be different, depending on where you go and wherever you feel comfortable, will be the best place to go.

Dr. Roberto Hernandez-Alejandro 25:39
What can we do nowadays when we see patients who have clearly unresectable disease, no place that we can do an ALPPS or a two-stage hepatectomy, what can we do with these patients? Well, this patient really received treatment here with us. Well, not necessarily with us, but long distance with us, under us, and impressively, the disease responded very well. And this is the same CT scans, but several months later, you can barely see those diseases. Patients get excited and say, “Well, my cancer is gone”. Wait a moment. No, it’s not gone. The cancer is going to be there the majority of time. And there’s evidence that it’s going to be there because it disappears in the CT scan or even in the MRI, it is still there at least 65-70% of the time the liver starts getting damaged. The cancer cell are there, and then they hide, and you cannot see them because the liver has already fatty disease in the liver, or some fibrosis, and we cannot see. The CT scan and the MRI are notmicroscopes. We can see around 3, 4, 5, 6, millimeters spots, but we cannot see microscopic spots, and they’re gonna come back. I think, with those patients, convert them with treatment and then we’ll check them.

Dr. Roberto Hernandez-Alejandro 27:19
Well, this is what happened: the recurrence it’s pretty high. It’s almost universal, and survival is around 30% for five years. And the majority of the patients, around 81-82% of them, will have cancer back by five years. It’s better than not having a resection, but definitely there’s an improval in the survival of these patients who are converted to resectable, but sometimes there could be other options. And, I have talked about this previously, but for the people who are new or that are new today, towards the right side, and we need to remove all the right side and the left side is small, we can do a portal vein embolization with interventional radiology or for patients who have several tumors, but we find there’s an area where we can resect these tumors, and after resecting these tumors, then we can embolize or, get the right portal vein, similar to the wall. We will wait several weeks until the left side of the liver where there’s no tumors, will grow. That’s called ‘hypertrophy’, or regeneration of the liver. And then we can go back to the operating room for a second operation, remove the right side of the liver and the patient is free of cancer. There’s also the ALPPS procedure, which is a very similar situation, but that thing is different, because in the first stage, we divide the liver and the liver will grow very quickly and very accelerated. I had the opportunity of being a pioneer on the ALPPS in North America having good outcomes. But unfortunately, the vast majority of the patients with the two stage hepatectomy with the ALPPS the vast majority of them will have recurrence, and this is disease-free survival. That means, how many of the patients are free of cancer at three years? 80%, the cancer has come back in this study of 459 patients. In these 65 patients, 80%, and in this group, 74% of the patients will have. This is from France, this is from MD Anderson, and this is a systematic review that means that …(extended internet connectivity interruption)…

Dr. Roberto Hernandez-Alejandro 29:49
…we have better chemotherapy, we know. We have better treatments, and if you compare different eras, so in the 2000’s and the late 1990’s, we have seen an increase in the survival of patients after resection. And I think, better surgeons we’re understanding more therapy. We were talking about recurrence. What happened when there is recurrence after resection? The line that is color yellow, it’s a line where it’s showing when the patients have liver disease only, and when they only have lung disease only, when it comes back in the lungs, these patients have a better survival. I’m talking here about resection. So patients who had colon cancer, liver metastases, they go for chemo, they are resected, the tumor is removed, the liver is doing well, and unfortunately, they have lung metastasis, if there’s only lung metastasis, they have better survival, compared to those ones who have liver recurrence. So liver recurrence, why it’s coming often the liver, those “ghost” metastases, those disappearing liver metastasis. I mentioned it a few minutes ago. They disappear. It doesn’t mean that they disappear. There has been, until a few years ago, evidence that radiologically, there’s nothing in the right side. They were metastasis in the right side, we give chemo. They disappear. We can only see the left side. We go and operate on the left side, and then in few months or one year, there they are on the right side. What does that mean? Are these recurrence or is this residual disease? Most likely residual disease. Studies show that around 83% of the patients clear on develop metastases is when we look at new CT scans or MRIs. Now, I will show you some data now with tissue, not necessarily with radiology. But what do we know, and I mentioned about the behavior of the tumor to understand how the tumors behave, and that’s the biology of the tumor, the size and the number of the tumors is important, the tumor markers, the level. Nowadays, a lot of people are asking, “What about Signatera or the new Guardant360?”. Our center is working on this and understanding more, it might be a good tool for decision making, before a decision of surgeries or transplantation, and to follow up with the patients. We call it liquid biopsies, or circulating tumor DNA. How much time has the patient had the disease? If the patient is stable and has one year, two years, probably we could be more aggressive to be able to do something. The fact that a patient is responding to chemotherapy, or to systemic chemotherapy, or to hepatic artery pump infusion, that is a good sign that the tumor is behaving and that justifies us to be aggressive. So all of these, the presence or not of lymph nodes, the evidence of extrahepatic disease, the genetics of the tumor, all of these are tools that for us as physicians who dedicate time for cancer patients, help us to decide what we can do for these patients.

Dr. Roberto Hernandez-Alejandro 33:41
And the next slide is just to show you, I know this is not a medical talk, but this is just to show you that the patients who have — the bigger the tumors, the more of the metastases, the outcome is going to be more complex. So you don’t have to really understand this. This is, I took it from a presentation that I gave to physicians and but what this slide is showing is the more tumor load, the worse the outcome. We need to help and find ideas on how to help these patients and what to do. The higher the CEA, the worse the outcome. And these are patients if we do liver resections with high CEA, with high tumor load, the presence of lymph nodes. We know that the outcome is going to be worse if there’s cancerous lymph nodes around the liver than if they are not cancerous lymph nodes around the liver. If a patient is progressing on their chemotherapy, that means that the tumors are growing, and then we go and resect, the outcome is worse than if the patient is responding to chemotherapy. The more mutations the patient has, if we compare it to the patients who have no mutations or only one mutation on the genetics, the more complex outcome the patient is going to have oncologically as well.

Dr. Roberto Hernandez-Alejandro 35:02
So let’s put together these cases’ time. Imagine that we have a 53 year old patient who has liver metastases from colon cancer, the primary is located in the right side. The patient has four liver metastases in the right side of the liver, and there’s no evidence of disease outside the liver, then what are we going to do? Okay, well, clearly we should give systemic chemotherapy. We will understand more about the biology of that tumor, maybe three months, and then we restage. We do a lot of CEA again. We do CT scans again, and the patient is responding. All right, let’s go to surgery. What are we going to do? Are we going to remove both of the tumors together, the liver and the colon? Well, we have to see if the patient is fit enough. We have a good team that communicates with colorectal surgeons and the liver surgeons. We can do simultaneous resection. What about if it’s a very big liver surgery and the tumor is located in the rectum, right? One very low, the other one, very high. Can we do that? And maybe the patient has a very high BMI? It’s a patient who has some obesity? Well, that’s going to be a more complex surgery. Should we do it all in one stage? Well, we have to decide and talk inthe tumor board. What are we going to do first? If the liver has more disease, then we go first for the liver, and then for the rectal tumor, the colon. Or sometimes we can do minimally invasive surgery, we can do the colon, and then we can do the liver with minimally invasive surgery, or we can combine.

Dr. Roberto Hernandez-Alejandro 36:45
So that is where the strategy of a team to develop what is the best for the patient comes in. What about if the patient is not responding? The same patient that I mentioned to you three months later, we do the CT scan and the tumors are growing. Now, I’m not going to tell the patient, “well, there’s nothing more to do”. No, that’s not an answer for me. Well, hepatic artery infusion could be a good option for these patients here. Why? What do we know about hepatic artery infusion? One of the good things is the conversion rate. It has a stronger conversion rate than the systemic chemotherapy, right? And we know that. I showed you at the beginning there’s no benefit to comparing both at the end, but in this situation, we know that systemic is not working. I totally justify going for surgery and getting the pump, and let’s see, hopefully this will work, and hopefully we can do something later. But you might ask yourself, so why not use the pump from the beginning? Well, to be honest, there’s some advantages, as I mentioned, and some disadvantages of the pump that I see. Let’s start with the advantages I mentioned, very good response and high rate of conversion, but you won’t necessarily have that with the systemic. The systemic can’t give you this as well. But the disadvantages, some of you know this, the travel arrangement, if you don’t live in a city or in a place where it has it financially, the pump has many times these functions. There’s an increased incidence of biliary and vascular complications. Some of the patients that maybe are here will be able to talk about it, some vascular complications that can happen aneurysms, bleeding or dysfunctions and biliary toxicity, which I really think is a little bit higher, perhaps, is underreported. But a lot of patients develop these biliary problems. It responds very well, and the tumors decrease. But you pay for these. And also here, I’ve seen some patients who have dislodgement, the pump flipped and needs to be reoperated on, and high risk of technical surgery complications could be happening.

Dr. Roberto Hernandez-Alejandro 39:04
Let’s move to the case 2 study. Imagine a 46 year old patient that we removed the primary. The CEA is in 42. The patient has a KRAS mutation, one of these mutations, but there’s no evidence of extrahepatic disease, and this patient has all these multiple tumors. What do we want to do? Systemic chemo, HAIP infusion? Do we go for resections? Do we do an ALPPS? Do we take the patient for transplant? So we can have many options for these patients. I don’t think there is one correct answer at this moment. We need to remember to understand how that tumor behaves. I will go for systemic chemotherapy. Let’s go for systemic chemotherapy, and the patient received FOLFOX and FOLFIRI. And look at these, a lot of calcifications, and those tumors got smaller. Now are we going to do resection and ablation? Are we going to give Y90? Remember, I mentioned to you the patient… — I will go back… look at the many lesions that this patient had. Now it’s here. For me, it will be very easy to say, “Oh, I do a resection, a wedge here, maybe ablation here, and a wedge here”. But I know that all of these are hiding, they are sleeping, and they’re going to come back. So those are the ghost metastases, and we know that there’s a high recurrence rate. Wait and see, hepatic artery pump infusion. What should we do? I think we need to talk and understand the patient, what they need, in my opinion, in this case that I created, resection, perhaps not ideal due to the high recurrence. Ablation, the same thing, higher recurrence, of course, it’ss not as invasive as a surgery, but it will have high recurrence. And I think the benefit is questionable. Y90 probably, maybe if the patient is not tolerating more chemotherapy, or maybe combined with chemo as a bridge for some bigger operation. Should we wait and see? I don’t think it’s ideal, if there’s no other treatment options, and the patient’s family are in agreement, maybe we can do it. The hepatic artery pump, I think is a good option if there are no other plans for a bigger operation, and if the patient doesn’t want to continue with systemic chemotherapy, such as FOLFIRI. So you can see that it also depends a lot on what the patient wants and where does the patient want to go? In my situation, I will continue. The patient is tolerating chemo that FOLFIRI is more tolerated. I will continue more time with the FOLFIRI and the low CEA had no evidence of progression. Well, guess what? That patient got transplanted and was successful. 1.5 years of chemotherapy, no evidence of disease, and a good quality of life. Some issues on bile duct structures, but the patient is out of chemotherapy and enjoying life.

Dr. Roberto Hernandez-Alejandro 42:13
And this is where it comes from, my field of transplantation, where all these data were coming from, from Norway, but not anymore. This data now, it’s coming from North America. This is the first paper that comes from North America. This is also one of the very high impact factor journals, JAMA surgery, where we published this showing the first 10 patients with living donor liver transplantation and unresectable liver metastases that fulfilled the criteria, showing very similar outcomes as the group of Norway. They have been doing this for more than 10 years. We just started doing this close to four years ago. And here is the United States. This is a study that also we recently participated, Dr Tommelyama. It’s here as well from our center, some of the groups from Stanford and Cleveland. And we published this together. 48 liver transplants at that moment, last year, around the end of the summer, went in the United States for liver transplants for colorectal metastasis. So it’s not only 10 or 15; – 48. So probably by this moment, there are 60 or probably more, and we were able to see that it has a pretty good outcome, similar to patients in Norway.

Dr. Roberto Hernandez-Alejandro 43:42
What is that? Imagine having an outcome that this population of patients with unresectable disease, where they have a five year survival of 5%, then, now in five years, they have a 60% survival. That is pretty impressive. Now, some of the patients got living donor. Some of the patients got a diseased organ. Disease organ means it’s coming from someone who was brain dead, someone who died in the ICU and the family decided to donate the organ. So how do those patients receive a diseased organ? The reason that they were able to receive an organ is because they have a sick liver, not only because of the cancer, because all the multiple treatments with chemotherapy, Y90, hepatic artery infusion, and this liver was burnt out liver, and the patient has liver dysfunction, and the patient received a liver transplant, and those are the ones who didn’t do very well, the outcome was more complex on these patients, unfortunately. So what I want to see here, and the message that is very important for those patients for transplant, transplant shouldn’t be the last option. Transplant should come early in the algorithm because the outcome would be much, much better if we transplant the patient in the early stages. If we wait for the patient to not have more options and to be a burnout liver, we may be able to do a transplant, but the outcomes might not be the best. Technically, they won’t be doing very well. So this is an important message. We receive patients who are at the end, and we help them. And if we can do it, we do it. But if it comes earlier, I tell you the story is completely different. This is my institution protocol that we have been modifying after we have been learning in the last four years. We go for something that is called the Oslo score, that was developed in Norway. But we also added more things here that makes us more strict to be sure that things go in the right direction.

Dr. Roberto Hernandez-Alejandro 45:57
One of our research fellows was working on this project, and we have 138 referrals, that was until, I think, January, patients that came to assess for being a transplant candidate. And from those patients, 53 were men. 46 were women. This is the location of the primary tumor, majority of the patients have the tumor in the left side or in the rectum, 20% of the states have been referring patients were situated here, and there were three patients that were international. The stars are centers that are in cities or states from where more patients have come to us. And from those evaluated, many of them drop out in the beginning, because I mentioned to you it is very strict, but there are still around 26 candidates, and we are monitoring them, hopefully they come into this field and are the ones who have liver transplantation. I have here 13, just a few days ago we did number 14. And this is what will happen, those ones who dropped out, many of them were disease progression. Many of them had other centers. But what I think is most important here is the referral was made an average of 10 months after the diagnosis. So again, the (internet connectivity dispruption) earlier the referral, the earlier we see them, we can come and work. Perhaps of those 112 patients, they will refer earlier, maybe, and this is speculation, but maybe around 15% of those patients maybe will have the chance of being transplanted. I might be wrong, and there’s no evidence of this, but that is my feeling just looking at the way that the disease progresses. I want to show you, and I hope you don’t mind, this is a real liver. This is a donor, and that’s what we do, and this is something that helps us. We use something that is called green indocyanine, where we have to divide the liver. The patient is going to donate the right side, and the left side of the liver will stay in the donor. And this is how we mark. (internet connectivity dispruption) And we know where we are going to be cutting with something that is called a hydro jet and you can see here we’re dividing –

Julie Clauer 48:59
Dr Hernandez, sorry, when the video was playing, it was hard to hear your voice. So do you mind just describing what was in the video again?

Dr. Roberto Hernandez-Alejandro 49:12
Can you hear me now?

Julie Clauer 49:14
Yes.

Dr. Roberto Hernandez-Alejandro 49:15
Okay, so you saw the liver getting green, right? And this is with a special lamp. We inject something that is called green indocyanine. We are blocking the right side, the artery and the vein, and this is helping us to decide where exactly we have to divide the liver. And I think it’s pretty impressive to see that, and it’s a lot of advanced technology that is helping us for doing the correct operation. Nowadays, these green indocyanine is also used to detect sometimes liver metastases. Some centers in Asia are using it and they inject it one week before doing the liver resections in these patients. But while if you were able to see the green, indocyanine part. I will skip that one. The next slide here, if you are still seeing me, is how we divide the liver, and I will play it and I will talk. But this is with a water jet. With water we divide the cancer cells. You can see in the right side here, it has already divided all the liver, and this is the left side that stays in the donor. I will play it and I will talk.

Dr. Roberto Hernandez-Alejandro 50:45
Okay, so that’s how we divide the liver, and we try to maintain like minimal blood loss in these patients, despite the fact that the liver is an organ that receives a lot of blood supply. In our experience doing living donor liver transplantation on these 14 patients, that is our survival: 80% survival at three years, and recurrence-free survival, only 90%. So this is, I would say, a little bit better than what is happening in Norway. But I think a lot of the patients, maybe some of them, will have recurrence at some moment. But the thing is, if it comes back and it comes back in the lungs, we can do a lot of other things.

Dr. Roberto Hernandez-Alejandro 51:24
What are the advantages of having living donor liver transplantation compared to other options? Well, there’s a risk to the donors, definitely, but we try to decrease as much as possible the risk in the donors, doing a very good selection of these patients; Problems of bile ducts or vascular complications, we have been fortunate that we haven’t had any biliary or vascular complications in all our donors. And the advantages is that we remove patients from the waiting list. We do this in patients with cirrhosis, right? That’s a very good way of helping patients on the waiting list, that we transplant the patients prior to the recipient becoming very sick, it’s elective and non emergency, and what I call here, minimal cold ischemia time, is that the liver stays in the ice for a short period of time. And probably a lot of benefits that we can talk about more in other moments. Do we transplant patients after the pump? What happened? They can have very good response, as you know. We use the same criteria as those patients who have systemic chemotherapy. However, patients need to understand that there’s a higher surgical challenge. The hepatic artery where they put the catheter of the pump gets very damaged, and the damage is because of the same chemotherapy that is going through that artery. And that artery cannot be used for putting back together. And the liver needs that artery to get oxygenated blood. So we need to come up with a strategy. And our expert here, Dr. Tomiyama, myself, and other surgeons that work together, like Dr. Piena, Dr. Nair, and all the team together, we find arteries that are behind the spleen that we will need to dissect and flip it over to the liver to be able to do this, or something that is called a conduit, that we use, coming from the artery to provide blood supply to the liver. So definitely, it’s a more complex operation. There are some patients, for some reason, that have less complications or less complexity of the operation, but there are other ones that have a higher complication rate.

Dr. Roberto Hernandez-Alejandro 53:44
This is a new study that I don’t think I have shown here, and this is pretty impressive, because this is a 10 years follow-up on the Norway patients. This is the first time that I’m showing a slide of Norway, right? Because now we have a lot of data from from the US, but we don’t have this data in the US yet, because this is our 10 years follow up from 60 patients of data, 10 year survival of 50%. These are patients who have unresectable liver metastases, stage four, who were going to have only palliative chemotherapy. They responded, they did a liver transplant, and at 10 years, 50% of them are alive. So this is pretty impressive, but this is only those ones who have an Oslo score of two, one or zero, which is strict, as I mentioned to you. I mentioned about pulmonary recurrence. When it comes in the lungs, we can treat these patients. We can resect it, and they do pretty well. When it comes in the liver, the outcome is not that good after transplantation. Just to mention about recurrence: Recurrence after resection is pretty high, that takes place in the liver, when in the liver after transplantation is pretty, pretty small, and the survival rate at five years, as I mentioned, 10 years, 50% at 10 years compared to 20% at 10 years on resection. I want to be very clear here: I’m not saying that instead of doing a resection, we should do a transplant. A patient who is resectable, we should do resection. A patient who is unresectable, which we hopefully, we can do a transplant, a patient who is unresectable and responded very well to chemotherapy, transplantation will have a huge benefit, in my opinion, on these patients. This study from our center, very recent study. We analyzed all the liver ‘explants’. That means what we removed, and those patients have a very good response, and we analyzed all the studies with the permission of the patients, and the analysis of the patients, and they signed the consent, and we analyzed how many metastases they had, and we compared to the CT scan or the MRI before the transplant, and they have —

Julie Clauer 56:17
Dr. Hernandez, I’m sorry this is such a good slide, can you put it on full screen, just because it’s so deep? It’s so detailed, I want to make sure people can see it. It’s such a good study. I’m so sorry.

Dr. Roberto Hernandez-Alejandro 56:27
All right. So these are the patients. They explant – that means that the liver, when it came out, went to pathology, and the pathologist sliced it and analyzed it centimeter by centimeter, and these are the amount of tumors that they found at the moment. The brown livers right? This one that is a partial liver is because this patient had a left hepatectomy, or these patients had a right hepatectomy. But they analyzed, and as you can see, the vast majority of the livers in pathology have more tumors than what the CT scan, which is the one in the middle the CT scan, or the MRI before the transplant. What is this telling us? That 64% of the time, we were able to find more disease of what we were able to see in the scans. I showed you that with radiology, but this is the first time that we have the entire liver that we’re able to prove it. So this is, I think, a very important information to give. And I think this is showing us why, when we do liver resection after a lot of liver metastases disappear, why we see a very high recurrence rate. I have to be fair, right? It’s not, “Okay. Let’s go for transplant, and you’re done”, and then you go and play in the park. Well, some of them can do that, but for some of them, life after transplantation, there could be some complications. You have to be on immunosuppression. It’s not like chemotherapy at all. It’s pretty well tolerated. Sometimes there could be some things, especially in the first year, that you have to be measuring and knowing the levels of your immunosuppression, but it’s pretty well tolerated and low side effects in the vast majority of the times. There can be some acute complications, such as vascular complications that probably in the artery that sometimes we need to put a stent or something like that, to to avoid the artery to close, because it’s very small vessels that we use. Unfortunately, biliary complications is more common.

Dr. Roberto Hernandez-Alejandro 58:38
What are those biliary complications? There could be leaks or strictures when we put together the donor and the recipient’s bile duct, sometimes we have to put those stents. And in some patients, we can remove it at one year, six months. And some of the patients require it for long term. And some of them, they require a metallic stent for life. Retransplantation could be an option for some patients. We have a patient that was transplanted and hasn’t had recurrence, but the liver developed some complications later on because of some biliary complications, and now the patient is listed for retransplantation. And also I put that with chemotherapy, the patients normally do not receive chemotherapy after transplant, but in case there’s recurrence, the patients can tolerate chemotherapy. And just to finalize here, I just want to show something that I know that one of the patients who came here with us, and I think it was in the group of COLONTOWN and decided to go to Germany, because this patient has some roots in Germany, went for a live donor liver transplantation with this concept that is called the ‘Rapid Concept’, and it’s using a live donor, but they use a small portion of liver instead of using the right side. They keep the right side with cancer but they wait for this growth in a few weeks, and then they come back when this left side is bigger, and remove it. And this is a new concept. There hasn’t been any center in the US or Canada doing this yet. I think it might happen at some moment. I think we have other options in North America. But this is a new concept that I just want you to know about the rapid surgery, which I think it’s a pretty impressive surgery, but perhaps is, there’s no need of doing it in that many patients. I want to leave this because this is for me, giving hope. This is hope for a lot of patients who are unresectable, or patients who perhaps have liver disease and lung disease and maybe disease in other places that are unresectable because there’s metastasis outside the liver. And I am not getting paid for it, nothing like that. I just wanted to, I asked them if they can share with me this short video. And I think some people have seen this. This is histotripsy. It’s an ultrasound that liquefies, destroys the tissue, creating dead cells. So imagine that we can use this. …I don’t think it’s going to run, so I apologize that it’s gonna… I have to do it this way.

Dr. Roberto Hernandez-Alejandro 56:29
Can you hear my voice?

Julie Clauer 1:01:50
Yes, yes.

Dr. Roberto Hernandez-Alejandro 59:56
Okay, so this is liquifying so it’s through an ultrasound with water, and it’s going to destroy the tumor in the liver, and it’s going to have an immediate reaction. So I’m really looking forward to doing this, and we don’t have to open the patient. This can be done from outside, but we need to anesthetize with general anesthesia, the patient in the operating room. General anesthesia, the patient gets intubated, so the patient is not moving. We rotate the patient, we put this machine and this area will go down to the abdomen of the patient, and there’s going to be a big bubble of water coming out here, like a balloon that incorporates to the skin of the patient. And we can assess the tumors in this ultrasound, and we can target the tumor and start decreasing it. Is this going to cure the patients? I’m not sure, but probably, and we need to develop more studies. The trials were done in the US and in Spain, in patients who were palliative the outcomes, it’s going to be helping all a lot of this, is going to be for trying to downsizing the tumor and to make the patient resectable, or to be able to bring those patients to transplant in different types of tumors, and a lot in colorectal liver metastases. And with that, I think I’m done.

Dr. Roberto Hernandez-Alejandro 1:00:38
Well, conclusions. Let’s let’s say, you need a good team. You need to feel comfortable with them. Chemotherapy is very important to understand the behavior of the tumor. There are different modalities that can be helped, and patients need to know about them. And also the field of liver transplantation in those patients with stage four advanced multiple metastases, they should know about that, and surgeons should be in their toolbox. Transplant shouldn’t be the last option. It’s not the last option. Liver transplantation in selected patients is providing great results, and it’s important to have a multidisciplinary team approach. We need to collect more data, and that’s what we’re doing here, and we are doing a lot of research in our institution and taking tissue and understanding more about the molecular phenomena that are happening in those tumors that hopefully we can help patients in the future. And with this, I would say thank you very much, and I will stop sharing.

Betsy Post 1:00:38
Great. Thank you. Julie, do you want to do some of the questions? I think just scroll to the top. Or do you want me to do them?

Julie Clauer 1:04:39
You’re so good at it. I’ll do it if you want me to, but you’re so good at doing it,

Betsy Post 1:04:45
I’ll start it off. So thank you so much. Thanks everyone for hanging in. We are going to go in order for some of the questions that were sent through chat. So the first question that I’m seeing is, you mentioned Fatty Liver. Is this a common thing to occur after you have liver surgery?

Dr. Roberto Hernandez-Alejandro 1:05:06
No, it’s not a common thing to have after surgery. Is not an uncommon thing to happen after receiving chemotherapy. Fatty Liver is very common nowadays, in the US, in a lot of us, we can develop fatty liver just because our the way that we eat and our sedentary lives can create that. But if we receive chemotherapy, that creates fatty liver as well. So it’s more common with chemo, not necessarily because of the surgery. The surgery itself do not create fatty liver.

Betsy Post 1:05:42
This one, I actually think you addressed but it’s on your thoughts on doing the hepatic pump with the goal of resection. But I think you addressed that a little bit later after that question came through.

Dr. Roberto Hernandez-Alejandro 1:05:54
I’ll just, to go quick, Betsy – is yes, pump, and surgery after pump. It’s a great thing that happens, and it has a very good response rate and conversion rate with the pump. Definitely. We know that there could be some hiding ghost metastases, in some of those patients. But it’s a risk that can happen, but it it makes it a little bit more complex, a bigger operation in the liver. Definitely, it’s a little bit more complex to do after the pump.

Betsy Post 1:06:32
So there was a paper that you showed from, I’m going to probably say this incorrectly, ‘brouquet’, ‘brocketts’, the 2011 paper where you showed the rate of disease-free survival, was there a rate of overall survival?

Dr. Roberto Hernandez-Alejandro 1:06:51
So what is the question?

Betsy Post 1:06:54
So she was saying that when you talked about that, or you referenced that particular paper, you showed the rate of disease-free survival. What was the rate of overall survival?

Dr. Roberto Hernandez-Alejandro 1:07:08
The one for brokette, let me see if it’s the one from Northern Europe, …I don’t know if which one is the one from Brockette, but what I can tell you is, disease-free survival after resection in patients who have response it’s disease-free survival. That means that patient, that won’t have disease at five years, right? It’s going to be around, generally, around 30% of the patients, depending on the amount of disease. So the majority of the patients, we know that they’re going to have recurrence of the disease after resection. Of course, as I mentioned, the more metastases we have and then going for resection, then the higher chances of having recurrence. So size matters for sure.

Betsy Post 1:08:10
Do we have data on outcomes for patients who get FOLFOX, then the hepatic pump, as compared to patients who get FOLFIRI and then the hepatic pump?

Dr. Roberto Hernandez-Alejandro 1:08:21
So, I’m not a medical oncologist, but I can tell you that the rate of response of FOLOFOX and FOLFIRI, is very similar. A lot of the time some of the initial studies, were done with FOLFOX. So that’s why they start with FOLFOX. The problem with FOLFOX is that many of you know that the side effects are neuropathy, and they can create problems with your fingers, with your toes, with your lips. So it’s not uncommon that the patient at six months does not tolerate so then they switch you to FOLFIRI. That is more tolerated than FOLFOX. So there’s no data which one of them will work best. I think both of them do have a very similar response rate, and normally when patients use a pump, they also receive systemic chemotherapy. So, many of them, they go on FUDR, which is the chemotherapy that is used in the pump, plus systemic chemotherapy, because, remember, the pump is only attacking the liver, but there is also systemic disease that the patients still need some chemotherapy for the systemic disease. We want those lymph nodes to be without cancer, so they need to attack from both sides.

Betsy Post 1:09:40
Do you think surgeons are on board with using CtDNA testing, and what actions could a patient take if there’s a positive ctDNA?

Dr. Roberto Hernandez-Alejandro 1:09:50
That’s a great question. A positive ctDNA, is something that is telling us there are circulating tumor cells. A lot of the times, the liver sheds DNA from the cancer, quite often, and we do CT scans and we cannot see it, and we do CT scans from head to toes, and we cannot see it, but later on, it’s going to come back. I think it’s difficult at this moment to justify if we resect the patient or we transplant the patient, and there’s no evidence of disease in the imaging, but the circulating tumor DNA is positive, it’s going up. It’s difficult to justify starting chemotherapy in that patient if we haven’t seen it, but I think collecting the data is going to be able to give us that answer in the future, because this is probably, I want to be cautious, probably better than having CEA measurements. A lot of the times the CEA is low and it never moves too much, and probably it’s more sensitive than circulating DNA. But we need to collect more of these data.

Betsy Post 1:11:00
Do you have an approximate percentage of people with colorectal cancer who will only develop a solitary liver met? I saw a video from a liver surgeon made a couple years ago, who said it was around 50%.

Dr. Roberto Hernandez-Alejandro 1:11:17
That only developed liver Mets?

Betsy Post 1:11:19
One liver met.

Dr. Roberto Hernandez-Alejandro 1:11:24
It happens. I don’t see that often, perhaps because my practice has turned into seeing patients with advanced and multiple liver metastases. One of our surgeons, Dr. Nair, just recently, did a robotic single resection of a met. And yeah, I think there are many of them, but I don’t know a percentage or a number that I could say. And though any patient who has one or five and they are resected, they need to have a close follow up, those patients, because recurrence can happen, and we need to have a close follow up.

Betsy Post 1:12:04
Is transplant an option if a stage four patient has recurrence in the liver after five years of being NED?

Dr. Roberto Hernandez-Alejandro 1:12:11
Definitely, the answer is yes, transplant could be an option for those patients who have recurrence of the disease, even after resection or after ablation, as long as we see that they fulfill the criteria that you know they are responding to any type of treatments, whether this is a local, regional therapy or surgery or ablation or chemotherapy. If they are responding and there’s no disease outside the liver, those patients could be candidates for transplantation.

Betsy Post 1:12:44
What are the common reasons that insurance companies deny coverage for a living-donor liver transplant?

Dr. Roberto Hernandez-Alejandro 1:12:51
I don’t think this is just for living-donor liver transplant. It’s for liver transplant because liver transplant for colorectal metastasis is not authorized or in the United States in insurance, and even if you live in a country where you know there’s a social system, like in Canada or in Norway or in France, you need to come with an idea on saying why you’re going to take a liver, like a cadaveric liver, and put it in a patient who is not normally on the waiting list. So you need to justify, very clearly that, – so here in the US, the insurance says, “Well, this is not an indication for liver transplantation”. And our team, what we have been doing, and we have turned to be, I would say, experts in this field, is fighting with insurance companies first in a polite and nice way, talking to them peer to peer and sending a lot of data and documentation. Initially, they were saying there’s no American data. Now we can provide that American data that I showed to you, and that helps us trying to get approval for these patients. And sometimes we need to use other medias, not necessarily the peer to peer. Sometimes, if it’s denied, denied, denied, sometimes, social media helps the patients a lot, and the insurance in the end, they accept. So far, we have been successful, but to do this, you need to have a team that is willing to move the needle.

Betsy Post 1:14:28
So many of us who come from rural areas have little support for determining a bridging strategy to get to transplant. Some of us might progress during this time when donors are being screened. How can we solve this problem and ensure people feel they have an appropriate bridging strategy?

Dr. Roberto Hernandez-Alejandro 1:14:50
Well, access to transplant… This is a big problem in the entire country, in the world, about access to healthcare systems, to different complex treatments. And this is not only for colorectal metastases. I think it’s also for other areas where I work in the field of complex liver surgery, complex cancer in the pancreas. You know, a lot of the patients, they are able to reach treatment because they have a better social media, they have a better/good insurance, or they live in a city that can provide different types of treatments, but not having access to these options, a lot of patients are in a disadvantage. I personally think that having places like on social media, like COLONTOWN, for example, or other groups that help support patients, and being able to provide this education exactly like what you’re doing today, it helps patients within the community, and you are the ones who have a voice and then spread it, and people who are able to reach out to you, and you can guide them and provide them the opportunities, right? It’s difficult, and hopefully it continues opening. And I think, making a voice, it’s so important to help different communities, people who have to live in small places, minorities that are disadvantaged, it’s really important to be able to provide this education.

Betsy Post 1:16:31
Definitely, I know we have at least one patient that’s kind of taking some of that on, so I can connect on that later with this person. Is there any comparative data comparing the hepatic pump versus Y90 therapy and converting nonresectable to resectable disease for surgical intervention?

Dr. Roberto Hernandez-Alejandro 1:16:55
I’m not aware that there’s a study comparing Y90 with the pump. I can tell you that I have a lot of experience with Y90 because as a transplanter, we do treatment of the most common primary tumor that is called HCC in liver. Nobody here, I think, is associated with the HCC. But this tumor is quite common, and we treat it very often in the US with Y90, and many of those patients later on go to transplant, and we see how they respond. Y90 works very well in HCC and in other cancers that is cholangiocarcinoma, it also is pretty helpful. But now using Y90 in liver metastases is not the norm. It’s not in very common use. We have used it very few times, but a lot of the patients that we see, some of them, they have been treated already with Y90. But those are the patients who’re going to go for liver transplant, the ones that I’m telling you that received some Y90, but comparing hepatic artery infusion with Y90, I’m not aware of any study comparing them. It’s a different strategy, and I think the indication is very different, because what the Y90 could be more located for a specific area of the liver, and the pump is more in an entire liver with a blood supply.

Betsy Post 1:18:28
Is liver transplant only available to patients that have cancer only in the liver?

Dr. Roberto Hernandez-Alejandro 1:18:37
To be very clear and orthodox, I have to say yes, but I have to tell you that, for example, we have a patient who had a lung metastasis, and that patient, they removed it, and the patient, one year later, after removal of the lung metastasis, came and said, “Can you transplant me?”, and there’s no evidence of recurrence in the lungs. And then the patient was a candidate because of liver, and we couldn’t find any other disease outside the liver. Am I going to say no? It was hard for us. We discussed it in our team, and we did a transplant, and the patient is doing well and there is no evidence of disease, I think more than two years now, or even two and a half, maybe a complex case, but the patient did very well. So I think there’s space for pushing the envelope in some specific patients. But to be very orthodox, if there’s disease outside the liver, it’s not in the best interest for the patient to have a liver transplant.

Betsy Post 1:19:46
When should a liver mets patient consider a second opinion or other opinions on their treatment?

Dr. Roberto Hernandez-Alejandro 1:19:58
That’s a tricky question. But I would say, if you go the first time and you feel very comfortable, and you know this person or this group or this team knows what they’re doing, and they’re giving you hope and opportunities to get treated and they’re looking for, ‘okay, this is the way that we’re going to get you to resection’. I would stay there. I wouldn’t move. If I feel that there’s something that I don’t feel very good, I will look for second, third opinions, fourth opinions. It’s not complex nowadays, especially, having virtual visits, the vast majority of the patients that my team says is with this disease are patients who we do telemedicine, right? We don’t ask the patient to be traveling to see us and spend thousands of dollars on a plane ticket and keeping them in the waiting room for a long time. They come here once, we’re going to treat them. But we manage the patient from a distance using telemedicine. So that is helpful, but if you don’t feel comfortable, or also if your disease is very complex, then probably you need to hear second, third opinions. And it doesn’t matter if you are with what you think is the best. A lot of the times, patients come with us for the first time. And if there’s complexity, I tell them, “Listen, go and talk to another one, the other person, other surgeon. And I want you, if you’re going to come to us, I want you to be sure that you are comfortable with us with the decision making”, so it’s important, it creates a better bonding with/ between the group, the surgeon and the patient and the family.

Betsy Post 1:21:51
Is a liver transplant preferable to multiple liver resections due to recurrences, or have liver resections as long as it is possible?

Dr. Roberto Hernandez-Alejandro 1:22:02
If I understand the question very well. So if you come, if your patient has a liver section, and then recurrence, and then resection, and then recurrence, is that something similar to having a liver transplant?

Betsy Post 1:22:15
So I think, I think he’s saying if you’re having multiple recurrences, should you then, be looking at transplant, or should I continue down this path of multiple liver resections?

Dr. Roberto Hernandez-Alejandro 1:22:29
Well, what I will be concerned with that patient that is having recurrence and recurrence and recurrence is that there’s going to be a moment that the recurrence is not going to be in the liver, it’s going to be outside the liver, and then that will change the plan and the strategy completely, and then transplantation is not going to be an option. Or also there’s going to be the moment that the tumors are going to mutate, and it’s going to change, and it’s not going to be responding to chemotherapy. So definitely the multiple recurrence, I think transplantation plays a very important role if we’re able to prove that there’s no disease outside. Hopefully that responds your question?

Betsy Post 1:23:19
Yes, that did. You were talking about the timing of transplantation and not to wait too long in people with liver-limited disease, when is a good time to start thinking about transplantation?

Dr. Roberto Hernandez-Alejandro 1:23:34
I think at any moment, you know, it’s March right now, and we recently saw a patient who was diagnosed with sigmoid cancer and multiple liver metastases, and the patient was going to the first session of chemotherapy. Before going to the first chemotherapy treatment the patient contacted us. I could say, “Well, there’s no problem. I can see the patient in six months”. No. Meeting with the patient, talking, meeting each other, connecting, creating a plan. I know it’s going to be a long term and probably the patient will drop off, hopefully not but guiding, talking to them and making connections with their oncology team from here, sometimes we connect with oncology teams from other centers. We talk to them, we explain what we’re doing. Some of them, they are aware of what we’re doing. Some of them, they are not aware about transplantation, for example, especially these complex cases. And sometimes we see patients that they were told that they were unresectable, and we say, “Wow, we think you’re resectable”. I can tell you a surgeon close to your place that maybe we’ll be able to do, or you want to come here, or something like that. So those things happen sometimes. So if the patient is in the early stages, we think it’s good to talk to the to the transplant team, they don’t have to wait for months or years ahead.

Betsy Post 1:25:12
Is there anything one can do to prevent developing fatty liver? You know, after having chemo or with chemo?

Dr. Roberto Hernandez-Alejandro 1:25:20
Not that I know, not that I know. I know that there was a study done in small animals about avoiding fatty liver with chemo, and I know that it was done with green tea. Green tea protected, but the amount of green tea that you will need to drink, you will need to be swimming in a big swimming pool and drinking all of it. So it was very high levels of green tea. That’s the only thing that I know that has help for decreasing fatty liver. But the amounts will have to be very high. And I think probably you will get intoxicated with green tea. Exercising, also watching the diet might be helpful, or at least decrease or delay the fatty liver, but the chemo will damage the liver.

Betsy Post 1:26:16
I’m going to mess this name up, just FYI. You can laugh at me, but it’s the new machine that you showed at the end that new technique. Are there any institutions that might be the first to jump on the histotripsy? See, I don’t know how to say it… technology!

Dr. Roberto Hernandez-Alejandro 1:26:33
Yeah, it’s called histo-trip-sy.

Betsy Post 1:26:36
See, that’s easy. I can say that now, okay.

Dr. Roberto Hernandez-Alejandro 1:26:39
I told them to change the name, because, but I cannot say names but there are two institutions, one, you know, which one that is, and the other one is not that far from here, that are pretty advanced, but these companies are working in many other places, trying to get these placed out there. So I think it’s going to take a couple of years to be out there strong in the market. But I think they’re going to start with, 3, 4, 5, centers, starting to do it, and hopefully by the end of this year or in the Fall, I’m looking forward to being able to use that here.

Betsy Post 1:27:32
You mentioned we don’t have too many questions left. You mentioned one of the patients you presented data on received remote care under your team? Can you clarify what that means, and how would one involve your team remotely from you? And he said, I’m seeing Dr. Kooby, and Dr. Mitel from Emory in Atlanta, whom you might know.

Dr. Roberto Hernandez-Alejandro 1:27:55
Yeah, well, what we do is, we invest a lot in the patient. We follow the patient pre-operatively, in the surgery, and sometimes the complexities that post op, and some patients clearly are concerned, especially because sometimes they want to have a very quick answer, right? We have been able to place a team of navigators that are helping all these patients. We have a coordinator on living-donor, one of the nurse practitioners helps us directly with patients with colorectal liver metastases. We need a nurse practitioner that was working with us that left, and we’re hiring a new one that is coming soon, so there’s a full team that follows these patients, and we’re going to put more resources in to follow these patients. What we do is we communicate with them and contact them, and then if it’s needed, if we there’s something surgically that is needed, we contact a liver surgeon or a hepatobiliary surgeon or a transplant surgeon in their place in Atlanta there, that’s the case that we do it. I know Dr. Kooby extremely well. We’re friends, we’re colleagues and a lot of other places that we know, and that’s what we’re trying to do, and connect with the patients pre-op as well, for the chemotherapy, and if it’s needed later on, to connect with the oncologist. That’s what we try to do as well.

Betsy Post 1:29:27
I can connect also with you, if you message me: the person that asked that question, so I can help you with that also. We just have a couple left. What are the chances of a stage three rectal cancer patient currently on FOLFOX to develop liver mets?

Dr. Roberto Hernandez-Alejandro 1:29:45
Wow, that’s a great question. So the patients who have a stage three, that’s a reason that they go for chemotherapy to decrease the chance of the patients to develop liver metastases. Those patients need to have follow up CT scans and CEA every six months, depending on the timing for the next five years, because we know that there can be some some recurrence rate. And I think it depends, also it’s not only stage three. There are different stage threes. There are A, B, and different depending on the amount of lymph nodes that were found in the rectal cancer. And it can go as high as 40% it can go as high as 60%, the chances of having liver metastases. The good thing is, the patient knows that there’s a risk, and there’s going to be a close follow up, and if they catch it earlier, then things can be done in an early stage. You don’t have to wait to have 10, 12, 15, metastases, and then, then there’s a complexity to this. So it’s terrible to have colon cancer, but you have, in earlier stages, you can be watching very closely for the metastasis and catch them in an early stage.

Betsy Post 1:31:24
And I think we just have one more: does the hepatic pump, those treatments cause significantly higher amounts of fatty liver?

Dr. Roberto Hernandez-Alejandro 1:31:34
Yes, but I think the fatty liver, it gets a little bit burnout. By burnout, what I mean, is it creates more fibrosis. Fibrosis creates scar tissue, and one of the problems of the pump is what I mentioned about the biliary damage. The liver produces bile, and it runs through little bile ducts, like a tree in the in the winter, right? No leaves. That’s exactly how a bile duct is inside of a liver. Those little branches and middle branches start getting damaged, and the bile cannot come down. And then this is when the patients start having the elevation of the bilirubin, or the liver enzymes elevated a little bit. So then they have to decrease the amount of FUDR, or they delay it, or they say, let’s stop it. And then it’s giving only systemic chemotherapy. So that’s the toxicity. It’s what happens. I’m not saying that this is bad, don’t use it. No, it has its benefits, it’s better to attack the cancer. But these are side effects that happen that creates, what’s called, fibrosis scar tissue. You saw those pictures that I put there with healthy livers from donors. If I would show you a liver after multiple treatments with the hepatic artery pump, you couldn’t recognize the liver. Of course, I will be putting the ones that we ended doing transplant because they got a lot of damage. There might be many that are not that damaged, but that could be created by too many treatments.

Betsy Post 1:33:09
I’m going to take this one last question. Is fatty liver irreversible? And what are the symptoms? Are there symptoms of it?

Dr. Roberto Hernandez-Alejandro 1:33:23
I think fatty liver is not irreversible. Fatty liver can be improved, especially when it’s not created by chemotherapy. And really, when we have a fatty liver with no chemotherapy, it can be changed in two, three months, in a patient who changed their habits of how they eat, how they work, how they do things in life that can be changed. Now, if it’s chemotherapy, that is creating the fatty liver? And if the chemotherapy is stopped, the patient will have improvement of the fatty liver and the liver definitely will. But I will be worried about,okay, if the patient had cancer and now stopped the chemotherapy, now what is the patient getting, right? So definitely, that will be a little bit of a concern. If the patient has fatty liver and went for resection, and there’s no evidence of recurrence, and it’s of chemotherapy, that liver is going to recover for sure.

Betsy Post 1:34:28
Do we have time for one more? There’s one more that just came in. I want to have to – it’s 9:35 – you’ve been so generous with your time, we’ll just take one more. Is the chance that the hepatic liver pump causes damage to the liver reduced for individuals who tolerated eight or 10 sessions of chemo FOLFOX without too much damage to the liver.

Dr. Roberto Hernandez-Alejandro 1:34:51
Oh, well, it would be difficult for me to answer that. And probably, you know the experts on maybe the Dr. Kemmeny in MSK, who is the person in the world who knows more about this will be able to answer that question. So I don’t feel I have the knowledge for you being able to answer that. I think there’s no association between if you tolerate a lot of FOLFOX, that means that you’re going to be able to tolerate a lot of FUDR in the pump. I don’t think it’s that. I think it must be something different, because the mechanism of action of FUDR in the pump is different than the systemic FOLFOX. It’s a different mechanism of action. So I don’t think they are associated. But don’t feel expert to answer this question.

Betsy Post 1:35:43
So I just want to thank you, Dr Hernandez, for all of your time, your amazing presentation, taking all of the questions, and, just being so generous with all of us, so thank you so much, and thanks everyone for attending. This was great, and we really appreciate it.

Dr. Roberto Hernandez-Alejandro 1:36:13
Well, yeah, thank you very much, Betsy. Thank you very much, Julie and everybody for being here. I think I probably prolonged too much my talk, sorry about that, and maybe was too much information. But I just wanted to be clear and showing that panorama about what is out there.

Betsy Post 1:36:23
Someone just said that three years ago this week, she was recovering from stage one ALPPS in Toronto. Her liver is clean to this day from that surgery.

Dr. Roberto Hernandez-Alejandro 1:37:02
I’m very happy about that.

Betsy Post 1:37:03
Yeah. I thought you’d like that. Lots of thank yous in the comments.

Dr. Roberto Hernandez-Alejandro 1:37:07
So thank you very much. And also I want to thank – because I wouldn’t be able to do this without the team – that the amazing team that I have surrounding myself, and the institution that is supporting me. So thank you everybody. I think there’s few members of my team that are in this talk, but well, thank you very much again.