Laura Kulik, MD (Host):Welcome. My name is Laura Kulik, and I am a transplant oncologist. And today, I am joined by four of my colleagues who make up the Northwestern Medicine Liver Transplant Oncology Team. We have Aparna Kalyan, who is our oncologist; Dr. Borja, a transplant surgeon; Dr. Lewandowski, interventional radiology; and Dr. Borhani, an abdominal radiologist. Today, we will be discussing the structure of the transplant oncology team, how this benefits our patients, leads to innovative procedures for our patients, and how we work and collaborate together. I'm going to start with Dr. Borja. And I'm going to ask you, can you describe what transplant oncology is, how it's evolved, and how we've been using it at Northwestern?

Daniel Borja, MD:So, transplant oncology is based on the principle that the best treatment for all patients with cancer is to remove the tumor with negative margins. As you know, sometimes that's not possible because we don't have enough liver, because we're very close to the vessels, because we cannot achieve that negative margin. But if we can replace the liver with a new liver, we can achieve that negative margin. Many years ago, the most typical tumors were considered an absolute contraindication for transplant. However, with the evolution of treatments, chemotherapy, with better diagnosis of systemic therapy, with better quality of CT scans, PET scans, MRIs, we can reevaluate and be more sure that the patient doesn't have any systemic disease and offer transplant. Really, transplant itself, the technical surgery has not evolved. But all the work that we do with people like you has evolved and allowed us now to transplant people that 20, 30 years ago were considered not candidates for transplant.

Host:Thank you. And Dr. Lewandowski, how have you seen the role of interventional radiology evolve over the years, and how would you compare it specifically at Northwestern to maybe some other centers in our approach in transplant oncology?

Robert Lewandowski, MD:Sure. I think we're lucky at Northwestern Medicine to have a big and strong interventional radiology program. With that, we're allowed the ability to sub-specialize. So, I joined in 2006, and I hate to say—or I should say I've been there for 20 years now. But I've really spent those 20 years building my practice in interventional oncology, which is unique, I think, which affords me the ability to not only learn the technical aspects of interventional oncology, but their clinical aspects as well, and learn how to translate these therapies among the rest of you, with Dr. Kalyan, with Dr. Borja, you know, trying to integrate with systemic therapies, trying to get patients to surgeries. So with transplant oncology, as Dr. Borja just said, the intent is to really be aggressive and get these patients to a curative intent therapy, moving beyond just hepatocellular carcinoma. So now, we're looking at colorectal cancer, looking at cholangiocarcinoma. I'm sure there'll be others. And really using all of our therapies that we have in a coordinated fashion to get these patients to those curative intent treatments.

Host:Great. And Dr. Kalyan, we have brought you over into the transplant world, and we used to go back and forth to oncology. How is this different now, the approach that we've taken where we're all housed in one area? You are part of the transplant team. What have you seen has been different using this approach?

Aparna Kalyan, MD:Well, thank you for taking me on in the transplant world. You know, historically, when we think about multidisciplinary clinic, which a lot of centers do, they tend to sort of run in parallel. So, patients are seen in different specialties, in different clinics, but they're sort of multidisciplinary. And I think what's really unique about what we do at Northwestern is that we're sort of all embedded together. And the nice thing from a patient perspective is that they're getting all of our opinions together at the one time. And the nice part is we're able to complete the treatment plan quite in advance, because we're seeing everybody at the same time. The longitudinal aspect of the clinic is also really nice. So, we start with a patient upfront. We come up with a treatment plan. And as it evolves, some of the plans that we have do change, right? So, patients who we might have thought upfront may not have necessarily been a transplant candidate, for example, might become transplant-eligible because of some of the treatments that we do. And I think that longitudinal aspect and sort of that arc that we see in the treatment plan is really nice. And I will say from an oncologist perspective, historically, it's always about what line of therapy it is going to be. Is it second line, third line? And we always think about it from a chemotherapy standpoint. And I think what this has allowed me to learn is that sometimes you can think outside the box, and having the tools that Dr. Lewandowski has, having Dr. Borja's input, really opens your mind into looking at how we can incorporate things like transplant at a time where you may not necessarily think about it. And the question really goes from saying, "We're going to keep a patient potentially on long-term chemo," to saying, "Not only can I take them off chemo, but maybe we can get them to a point where they don't really need chemotherapy altogether," and we're changing the natural history of the cancer.

Host:Great. And Dr. Borhani, as an abdominal radiologist, we get scans from all over, and these are radiologists who are reading various different parts of the body, and you specialize particularly in the liver. How do you think that that has such an impact on the decisions that we make here in this group?

Amir Borhani, MD:Well, thanks for having me, first of all. And so, I think it's important to have a diagnostic radiologist in the team, because a lot of these cases that we are seeing, everything is started with imaging. And there's some nuances in characterization of the liver lesions, because historically we thought that the vast majority of the lesions are HCC. But now, we're learning that there are different nuances or different subtypes. There are non-HCC malignancies in chronic liver disease. We've been using LI-RADS, which is a vastly adopted system for liver imaging, characterization of tumors. But as I mentioned, there are so many nuances of how to characterize a lesion, and that will impact the treatment decision: which lesion to biopsy, which one not, which one is approved for transplant. So, I feel that having a dedicated radiologist can bring some of that information to confirm. I think for transplant also, many times, we need a confirmation at MDC to confirm that this is a definite HCC or LI-RADS 5, or if it's not. Are there features for non-HCC malignancy that really guide the treatment? And, I think, another horizon is prognostication. Because technically, the amount of data that we have on our routine imaging studies, such as CT and MR, are a lot more than what you get on pathology slides. There are a lot of research and papers showing that there's very good correlation between imaging features and what they see on histopathology or immunophenotype of tumor and also prognosis. So, we try to also gather that information. So instead of saying this is HCC, we can also talk about that this is most likely an HCC with poor biology, probably poor prognosis. And in our experience, we have tried to use that information in making the decision. And then, I think the last aspect will be assessment of response to treatment. Historically, the majority of liver-directed therapy was ablation, and the assessment was easier because it's binary: yes or no. Do you see any enhancement after a treatment or not? But now that we're doing more of a radiation-based ablation, there are a lot more nuances to exactly assess and measure the treatment. And again, that's one area that having a dedicated liver radiologist besides other specialties can really come up to have an informed conversation about what's the next plan to do.

Aparna Kalyan, MD:Thank you.

Robert Lewandowski, MD:Can I just for a minute —I mean, Dr. Borhani is very humble. You know, I mean, he's been a tremendous addition to the team and really helped, and we're always looking to grow and build and add new specialties and different things. You know, as an interventional radiologist, my background is in radiology. And for many years, I filled that role in some capacity. But as I become more sub-specialized in what I do and as radiology becomes more and more complicated, having somebody like Amir as part of our group—he's indispensable, right? From the diagnosis to a lot of the other questions we get asked. You know, we sort of problem-solve a lot. A lot of people in our healthcare system or elsewhere get imaging with some findings that are just different. And, you know, what do we do with these? And we really utilize Amir's talents. And then, as you said, in the post-treatment realm, it can be very challenging. And as a practitioner doing these therapies, I sometimes feel I'd like somebody else that's not as invested as me to give us the response as well. So if I think it looks good, but I'm getting a report from an outside hospital that says it doesn't, we have Amir to be the adjudicator and help us make decisions. So, you know, thank you.

Amir Borhani, MD:Well, thank you for kind words. And also I can say that, like anything else, when you're subspecialized in one organ, you tend to learn more when you spend most of your time just looking at liver pathology and also spending time with people outside radiology. So, I'm learning the language of IR and hepatologists and transplant surgeons, oncologists. So, I think now we can understand what is relevant, what is not, what to look for, what to report. So, I think, as a team, we're really trying to get the best out of the imaging study and what is best for patient care.

Aparna Kalyan, MD:Can I just add one more to what Amir's saying, right? He is so humble. I think the other thing this has really allowed us is to identify gaps where we can fill in with clinical trials. That's a huge part of what we do, right? I think we cannot underscore how important that is. The ability of Amir to kind of read them, and for all of us to spend all this time and understand this biology allows us to really understand the disease so we can not only participate in trials, but really be the ones who are developing the trials. And I think we've got several trials that have started at Northwestern, and I think that goes to the strength of this clinic and program as a whole in being able to do this.

Host:Yeah, I 100% agree. Dan, can you talk a little bit where does living donor fit into this whole notion of transplant oncology? And what cancers is living donor more tailored towards, and why?

Daniel Borja, MD:Yes. So, at Northwestern, we offer both living donor and deceased donors for all the patients. It may be a little bit controversial, but there's no convincing evidence to say that living donor is superior to deceased donor or vice versa. However, having living donors offers a lot of advantages, like planning immunotherapy, number of cycles of chemotherapy, follow-up of patients. You guys were talking about the importance of having imaging and ruling out systemic disease. So when you have a living donor, you have the possibility to plan the treatment of patients months in advance. We routinely say, "We're going to give you this treatment the first month, and we're going to start chemotherapy. We're going to start with interventional radiology with liver-directed therapies." Then, we talk to our colleagues in medical oncology, Dr. Kalyan, and say, "This is the chemotherapy that we're going to offer," so we can plan it. Patients with cancer are used to having this type of treatment in which we can plan, and we can tell them, "This is what we're going to do over the first three to six months." We can downstage tumors. We can see tumors that initially look non-transplantable. But with these treatments, we wait, and we can offer transplant. Unfortunately, with the regulations, we're a little bit behind. Not everybody gets enough exception points to be a candidate for a deceased donor. There's a lot of people waiting for organs. So, every time that we have a living donor, we like to say that we bring an additional organ to the pool. We help someone else, and it provides advantages not just to the patient, but to the whole society, right? The last thing about living donors is people with cancer behave a little bit differently. I don't know why. It would be very interesting to study this. But I feel like while people are receiving their treatments, they tend to talk to more relatives, to more friends. And we receive more altruistic donors for people with cancer than probably other diagnoses. I think that there's some sympathy that patients with cancer have. And certainly, we see more and more altruistic donors that we have, because it seems that people feel more sympathy when they see someone with cancer.

Host:That's a good position to be in, to have people who want to reach out.

Daniel Borja, MD:Absolutely. If we plan the transplant, if we know the exact dates, we avoid a lot of stress in the family, like when we have to tell them, "We're going to call you in the middle of the night. We don't know when your transplant will be. We don't know when your last dose of chemotherapy will be. We don't know if we need another PET scan." Basically, if you have a living donor, we can plan the whole schedule for the next six to twelve months versus telling the patient, "Yeah, we'll wait for a deceased donor, and one day we'll call you." And if you receive chemotherapy, it doesn't matter. If you are not receiving chemotherapy, it doesn't matter. I think that it's similar to what we do in other hepatobiliary malignancies in which neoadjuvant therapy has demonstrated a lot of advantages.

Host:Bob, you've been here since 2006 and done a huge part of the Y-90 program, and Northwestern is really known for radioembolization, largely due to you. Can you talk a little bit about how you feel radioembolization, where you see its role, and how it compares to maybe some other local regional therapies?

Robert Lewandowski, MD:Yeah. I mean, obviously, this is a team effort throughout the system in terms of bringing radioembolization into the program, starting back in 2003. Northwestern has become known for radioembolization because we've done a lot of clinical trials. I've been very interested, and that's been supported by the multidisciplinary team. So, it's not just interventional radiology driving this program, which I think is super important to recognize. It really started as a palliative option for patients that were not candidates for surgery, not candidates for chemoembolization, other local regional therapies, not candidates for systemic therapies. And quite frankly, we really didn't have systemic therapies when this first started off. I mean, we learned early on that responses to it were good. And patients tolerated it quite well. This has evolved over a lot of time. And I think, you know, Daniel already mentioned it's gone more from a palliative therapy to a curative intent therapy. And Amir mentioned this as an ablative treatment too. So, it's a super versatile treatment option. It's well-tolerated by patients, and I think it integrates well with other therapies as we try to time systemic therapies and other types of therapies in getting patients to surgery. So, I think, why we use it so much now is we've studied it so well. But it's become very, very versatile. Having said that, you know, there are tools in our toolbox from percutaneous ablation-type therapies to other embolization therapies. So, we try to pick the appropriate therapy for the appropriate patient. But many times, that's radioembolization because of the different things that we can do with it. Again, having a big team like this and a really good team that's innovative, cutting-edge, and I think, as we've sort of demonstrated, we're all sub-specialized in this space now. We're always looking to be involved with new devices, new therapies, medicines, trying to do cutting-edge, innovative approaches to our patients in a very responsible way. So, you know, what it'll look like five, ten years from now, I'm not sure, but radioembolization really offers a lot for our patients now.

Host:And that brings up, you know, systemic therapy has really made an impact on transplant oncology. And you've been really interested in how do we integrate, when do we start using it. And you've put together some trials. And, you know, there are different systemic therapies, and which one to use on which patient is not always very clear. And to address some of that, you have designed some clinical trials. Can you talk a little bit about how those trials are being run?

Aparna Kalyan, MD:Yeah. So, I think, you know, the first thing is historically, you know, for HCC, for example, we didn't have a lot of options, right? We just had sorafenib and TKIs. And I think really, in the last two to three years with a lot of the immunotherapies coming through, it sort of really transformed the landscape of HCC. And to what Bob was saying earlier, I think we've come to understand that sequencing things or using things in parallel potentially is an advantage to some of these patients. So, using a combination of what Bob does with Y-90 and then adding in systemic therapy potentially might augment the response, and then maybe use that as a bridge to getting people who otherwise would not have been transplant candidates to transplant. And so, we have several clinical trials in different settings within HCC. So there's the patients who are trying to get downstaged or trying to see if we could get them potentially to some form of resection or some form of definitive therapy that way. And then, there are trials that are more for patients who have more advanced disease, but still trying to get the benefit of both the combination of what Bob can offer plus systemic therapy. And lastly, I think also looking at new drugs and newer combinations. And I think that's really where our strength has been putting together this whole team and identifying those patient populations. Now, I think the other big area that we've made strides in is colorectal cancer, right? Historically, colorectal cancer has been treated just with chemotherapy, and we've sort of always gone from one chemotherapy regimen to the next chemotherapy regimen. And I think particularly I would say, in the last year to 18 months, we've made huge strides in now being able to think about potentially liver transplant for colorectal cancer patients who have liver-limited metastatic disease. And some of this nuance of how we select patients has come from working with the transplant surgeons, but really for us to be able to sequence the treatments, and things like monitoring ways that we have, so using minimal residual disease with ctDNA as a form of monitoring when a patient could be considered for transplant. And a lot of this is not defined. And so, I think we are really at Northwestern trying to do this in a systematic fashion so we can lead the field in saying these are some of the parameters that we want to look for, which allows us to select patients better and increase the pool of patients who potentially might have just been on palliative therapy, but now could be considered as curative option therapies.

Host:Okay, great. Patients are always asking about PET scans. So, can you talk a little bit about when a PET is appropriate in the different transplant oncology cancers that we see, HCC, intrahepatic cholangiocarcinoma, and colon cancer, and how we use that modality to make decisions?

Amir Borhani, MD:Yeah. Maybe I'll step back first and talk about different modalities that we have for the evaluation of liver lesions. So historically, we had CT and then MRI. But we have a lot more options than that because there are different protocols, different types of contrast agents. And now, we are using contrast-enhanced ultrasound. And I think a lot of the decisions of which specific protocol to use or which patient to do targeted contrast-enhanced ultrasound is coming out of our discussion at MTC to do targeted assessment. So, another modality will be PET. Historically, PET is done with FDG, which is just looking for general metabolic activity of the tumor. And for HCC, only a third of them are FDG-avid compared to background liver. So historically, it hasn't been very useful for HCC. We've been using it for extrahepatic disease sometimes, but also you might have metastasis from HCC without FDG uptake. So, always, we've had this hesitation to use PET/CT for HCC. In some other cancers like cholangiocarcinoma or majority of colon cancers, by default, they are FDG-avid. So, it has been our go-to when it's needed, like for selection or for assessment of stage of disease. But I think there's a brighter future coming, because there's active research on new targets. And some of those targets are actually targeting fibrinogen and some other specific receptors for HCC. So, there is hope that down the road, we might have even more tools using PET with higher sensitivity and specificity for certain liver lesions such as HCC. Currently, we're using dotatate for neuroendocrine tumors, so that has very high specificity. So, we've been using that for that specific type of tumor. Again, for HCC, PET hasn't been the first line so far. But I'm hoping that in the next five to ten years, there will be a lot more options to use PET.

Host:That's exciting. We may have better ways to select patients for transplant based on their biological activity using some of these markers like PET and dotatate. Speaking of biological behaviors, people who have portal vein invasion from HCC have typically been thought that this is a death sentence. And we had started to use radioembolization and saw that there were some people that we could actually get to transplant with regression of the tumor, and then along came systemic therapy. And I think Northwestern, we were one of the first to really adopt that combination while the big clinical trials were starting to accrue and show data. What has been your experience and thoughts on combining radioembolization with systemic therapy, and how do you do it?

Robert Lewandowski, MD:Well, I mean, just in general upfront, thinking about a patient with vascular invasion, meaning typically invading the portal vein, not all patients are the same. And there are prognosticating scoring systems out there, the very simple one is to look at the extent of the vascular invasion, and those that have the vein invasion just up by the tumor do much better than if that tumor extension goes into the main portal vein or leaves the liver. So, we can really be more thoughtful about which patients we can be more aggressive in and which patients we should use combination therapies in, and then which patients we may ultimately get to surgery. That tends to be resection right now, although transplant is probably not off the table, and there are studies published, some from Italy and some other places, where they actually transplant these patients if they've had a complete and sustained response to therapy. So, that brings us back to how do we do that? How do we get these patients to have that complete and sustained response? And I think it goes back to we have a lot of experience with radioembolization. We're early adopters of that type of therapy that involved that palliative setting in some of these patients that had vascular invasion. We found that we can have responses and even complete responses with radioembolization. Well, move forward in the calendar, and now we have systemic therapies that are amazing in this space. The checkpoint inhibitions, combined systemic therapies really have become the standard of care for advanced stage disease, which is what you have when you have locally advanced therapy. So rather than transitioning all of these patients from local to systemic therapy, this is where the teamwork really comes into play. We are offering these patients both an aggressive local therapy done in a conscientious fashion so that these patients do go on to get their systemic therapy, so they're getting the benefits of both therapies. So, I think that it works really well, and it goes back to we take the patients who have good liver function, that have good performance status, that have limited disease. It tends to be unilobar type disease. The less disease, the better. But in a unilateral fashion, we can do this quite well. We try to do aggressive local therapy, and then we transition pretty quickly over to Dr. Kalyan and systemic therapy. With that, you know, we don't promise anything to these patients, but our eye is on getting a complete response and then having it sustained. And once we get that complete response, then they meet Dr. Borja, and we start talking about what the next steps are for these patients. And if we get there, it's a big win for everybody.

Aparna Kalyan, MD:And I think that's really where this multidisciplinary clinic really sort of shines. It's this longitudinal aspect of things, right? I think even if we don't necessarily talk about transplant or surgery when we first meet them, we talk about it more from a local therapy, systemic therapy. But as the disease evolves and as the treatment changes happen, we are then able to bring in this conversation to say, "Actually, I know we didn't talk about this before, but you've done so well. It might be reasonable to think about having perhaps a surgical input to kind of say—" And that's kind of a unique component, particularly in having all of us embedded in the clinic instead of being in silos. We're saying, "I'm going to reach out and see what they have to say." It's just so much an easier conversation to have.

Host:And I agree. I think one of the best things about our clinic is that no matter where the patient is starting, we offer to them that we are all here. We talk to them about what could be offered, that they know if things improve, that we have Dr. Borja. We have you see patients even after a resection because we know that a majority of those patients, unfortunately, are going to recur and what they may need down the line. So, I think that is one of the biggest strengths of our Northwestern multidisciplinary team, is the fact that we are so together all the time in seeing the patients. But I wanted to get back to, you know, we have some of these remarkable responses. And then, we start talking about transplant. But unfortunately, allocation does not always allow you to get an upgrade in order to get them to transplant. Northwestern has really been at the forefront in terms of using some of the pumps, as well as one of the first—I think the first in the United States—to do a procedure called RAPID. Could you talk a little bit about how that has afforded patients to get an organ?

Daniel Borja, MD:Absolutely. So, first, the RAPID is based on one of the properties of the liver: healthy liver to regenerate, right? We know that if you have a healthy liver, the liver has the ability to grow back. So, what we will do with RAPID is we take a little piece of liver that is typically 20 to 25 percent. We take the left lateral segment of the liver, which is not enough to keep any person with cancer alive. But we go to the operating room. We remove the left side of the liver. At the same time that we do the resection, we do a transplant. We transplant the left lateral segment or the left lobe of the liver. We wait for two weeks, we repeat imaging. And two weeks later, we remove the rest of the liver that has cancer. So with this, we increase the donor pool. We're able to use a small amount of liver, but it helps with the same-prognosis patients. It takes advantage of this characteristic of the liver, right? That's the first thing. So far in the United States, three patients have been transplanted with this technique. And we have done two of them—one with deceased donor, one with living donor. So at the end, what this technique is doing is it's increasing the donor pool. We don't have livers for everybody. And it also increases donor safety. Today, we're talking a little bit more about the recipients. But if we have to take the left lateral segment from a donor, it's still a big operation. But most donors recover faster. So, you are increasing the donor pool, but you are not increasing a lot of complications. So that's good for the donors, and that's good for the recipients. And finally, about the pumps, yes, organs that we used to say, "No, we cannot transplant because we don't have a recipient available now," because we don't think that we understand the characteristics of that liver. Now, we can place them on pumps. We can get biopsies. We can study the liver. We can study the characteristics of the liver while it's being perfused outside of the donor. These are all deceased donors. We can study the characteristics of the liver. If the liver looks good, we can transplant organs that five, ten years ago were considered non-transplantable.

Aparna Kalyan, MD:So when you talk about the RAPID technique, right? Do you do that primarily for HCC patients or colorectal patients?

Daniel Borja, MD:So, the main indication is colorectal. The patients that have been transplanted in the United States have been colorectal. I can say that this can be offered to people with neuroendocrine tumors. This can be offered to people with intrahepatic cholangiocarcinoma. This can be offered to HCC. There's a protocol in France in which they are starting to include people with cirrhosis and HCC. So, I think that in a few years, we'll see that RAPID is offered to any patient that is a candidate for transplant. Right now, it's a little easier for people that don't have a lot of liver disease and cirrhosis. That's why colorectal is taking the lead.

Host:And my last question will be to you, Aparna, as an oncologist, what would you say to some of the local oncologists based on the things that you have seen working in this transplant oncology group, like advice in terms of considering transplant?

Aparna Kalyan, MD:You know, I think the first thing I would say is we're happy to see patients, right? I think we're always happy to see patients and offer an opinion. This is not about patients at Northwestern or not Northwestern. We just want the best for the patient and be able to find techniques and opportunities that we can use for these patients. And I really try hard to tell patients when we see them to say, "You don't have to get systemic therapy with me. You can get the treatments closer to home," because this is about making it easier. And I think the goal of the clinic, and what a lot of us envision this clinic to be is the hub of where people come for an opinion. And whatever we're able to offer, if it's different—be it a clinical trial, be it opportunities like the RAPID protocol or surgical options—we want to be able to offer that. But it's not about keeping patients here. It's about keeping people informed of what we can do, but getting the treatment closer to home. So, the biggest takeaway I hope others would get is send patients if you're not sure. Because I think historically medical oncologists have a tendency to want to treat people with chemotherapy because we are not nuanced in the surgical or interventional radiology aspects of things. So, we think about it as lines of therapy. But that is evolving. And the only way to change that is if we can see some of these people at an earlier time in settings like this where we truly look at the surgery, the IR, the medical oncology together to then be able to say these are options that are available that may not be feasible otherwise.

Host:Well, with that, I'd like to thank my colleagues for this discussion. And I hope the audience can feel the energy and excitement we have as a group in this transplant oncology team. We're very excited to see patients in our clinic. If you'd like to refer a patient to Northwestern, please visit our website at breakthroughforphysicians.nm.org to connect with one of our providers. And thank you for joining us today.