The Latest Advancements in Y-90 Radioembolization and Practical Tips for Building a Y-90 Program

A Conversation With Ripal Gandhi, MD, FSIR

This podcast episode is part of the SIO Corner, a collaboration between IO Learning and the Society of Interventional Oncology. Today, we're pleased to welcome guest host Dr Elena Violari, interventional radiologist and member of the SIO's Publications Committee. Dr Violari is joined by Dr Ripal Gandhi, interventional radiologist at Miami Cardiac and Vascular Institute. Dr Gandhi discusses his experiences building a successful Y-90 program along with recent advancements in Y-90 radioembolization.

This podcast episode is also available on Spotify and Apple Podcasts!

AMI PELTIER: Welcome to IOL Radio, the podcast for IO Learning, a digital publication geared toward interventional oncologists and the news source for the symposium on clinical interventional oncology. This podcast episode is part of the SIO Corner, a collaboration between IO Learning and the Society of Interventional Oncology. Today, we're pleased to welcome guest host Dr Elena Violari, interventional radiologist and member of the SIO's Publications Committee. Dr. Violari is joined by Dr. Ripal Gandhi, interventional radiologist at Miami Cardiac and Vascular Institute. Dr. Gandhi will discuss his experiences building a successful Y-90 program along with recent advancements in Y-90 radioembolization.

Dr Elena Violari: Welcome, everyone. Thank you for joining us today. We're very excited to have Dr Ripal Gandhi, an interventional radiologist at Miami Cardiac and Vascular Institute. As a former MCVI fellow, I was fortunate to have worked and learned from you, Ripal, and I'm thankful for the opportunity to continue learning from your experience through this podcast today. Our main topic today would be to discuss how to build a successful Y-90 program, and we will also discuss a bit more about recent advances with Y-90. Ripal, welcome.

Dr Ripal Gandhi: Thanks. Elena. Pleasure to be here and thank you for the invitation.

Dr Elena Violari: My first question for you is what initially drew you into IR, and then more specifically, what made you be interested in international oncology?

Dr Ripal Gandhi: I initially started out as a surgical resident. I did my surgical internship at Cornell. I was actually a categorical surgical resident. At the time, I noticed that everything was going more and more minimally invasive, and I really wasn't exposed to a lot of interventional radiology as a medical student, and that really piqued my interest. I ultimately ended up changing fields because I really liked the minimally invasive nature of interventional radiology, and I really liked the gadgets, the tools, and the potential to really innovate. That's really what piqued my interest and which led me to this field.

Dr Elena Violari: That's a great story. I know from my personal experience at MCVI that you have a very busy interventional oncology practice with a robust Y-90 program. I was hoping you would talk to us a little bit more about the current state of your practice.

Dr Ripal Gandhi: Sure. We have a really comprehensive interventional oncology program here at Baptist, at Miami Cardiac and Vascular Institute at Miami Cancer Institute. We started building this practice pretty much when I came here, which was now almost 13 to 14 years ago. About 5 years ago, we built a half a billion dollar dedicated cancer institute on campus, and that has really further increased the growth of our practice, the number of patients that we're treating, and really treating the full range of patients with different oncologic conditions.

Dr Elena Violari: That's excellent. One of my questions is how did you manage to build such a strong IO practice and Y-90 program at a private practice, which for many years was predominantly known for endovascular aortic work and peripheral arterial disease?

Dr Ripal Gandhi: Well, I've always had an interest in cancer work, and actually before my residency, I spent a year at Sloan Kettering doing research on hepatic embolization and other cancer therapies. Then I had an interest in all aspects about interventional radiology, but I was driven a little bit more toward the cancer work. After my fellowship, I was fortunate to spend some time in Korea as well, spending some time at a busy center called Assan Medical Center, which had almost 3000 beds and really gave me even more exposure to cancer. When I came here to Miami, I wanted to really grow and develop the oncology practice. While they were doing some cancer work at the time here, there really wasn't a dedicated interventional oncology practice that really needed a lot of growth. The way we developed the practice here was initially going to a lot of tumor boards, developing relationships with our local oncologists, understanding the data, and slowly developing relationships, developing programs, and over time that really flourished into a very, very strong and robust interventional oncology practice in general, and especially a strong Y-90 program.

Dr Elena Violari: What were the main challenges you faced while building out the Y-90 program, and how did you overcome them?

Dr Ripal Gandhi: That's a great question. When I started, again, this was some time ago, 13-14 years ago. At the time, we didn't have the same clinical data for Y-90 that we have today. I think that was probably one of the major challenges. We had some data for HCC, we had some data for colorectal cancer and other metastatic diseases, but we didn't have strong, robust data. When sitting in a tumor board, I didn't have the same type of clinical data that I can quote today to support our treatments. That's probably the biggest challenge. The other challenges are challenges that we encounter anywhere—developing the right relationships, and the other challenge that we encountered was really understanding the role of Y-90 and other interventional minimally invasive therapies in the entire spectrum of oncologic treatments.

Dr Elena Violari: Yeah, that's a really important point. As physicians, I feel like we are primarily concerned about patient's welfare and doing what's best for the patient and the patient's outcomes. But sometimes hospitals, and especially private hospitals, they have to be concerned about the cost of procedures and the reimbursements. How did you get your hospital administration to buy into this new type of therapy and why would it be beneficial for them and of course for their patients?

Dr Ripal Gandhi: I think I was fortunate to be at a center which is really known for innovation in a lot of aspects of interventional radiology, and especially in the peripheral and aortic space. They were definitely used to innovation, so luckily I was fortunate there. Really, my focus has always been on the patient and doing the best care for the patient, and I really thought that Y-90, for example, was something that can really help our patients, had very few side effects, most patients went home the same day. Ultimately, we did an economic analysis and our COO said to me that this is one of the few Medicare procedures which is still profitable for the hospital. At the end of the day, it was a win-win. We were doing what I thought was best for the patients, and it was also economically very viable for the hospital.

Dr Elena Violari: For those younger interventional oncologists who want to build a Y-90 practice, can you walk us through how to do it successfully? I know this is a loaded question, and each institution probably has its own challenges, but for you, what are the general rules in building a successful Y-90 practice?

Dr Ripal Gandhi: I think there are several things that we have to look at. Number one, I don't think of a Y-90 practice alone. I think of interventional oncology practice, of which Y-90 is one of the components. But when we're looking at developing a practice, the things that I always tell our trainees when they go out are the three A's: available, affable, and able. The reality is probably the most important of the 3 you would think would be able, but probably the most important is being available. That's one of the very important things in whatever practice you're joining and whether you're building an IO practice or any other type of practice, you want to be available. I give my cell phone to everybody. I'm available 24-7. It doesn't matter if I'm on call or not, it doesn't matter if I'm traveling, I always answer my phone. That's extremely, extremely important.

Second is being affable. You might get calls for the most ridiculous things, but I always try to be friendly and affable. That is very, very important in developing relationships. Ultimately, you have to be able. You have to be able to have good outcomes. You want to make sure that you're not having a lot of complications, you want to make sure that you're providing good care to your patients. When you do those 3 things, you could be very successful in building a practice.

Dr Elena Violari: That's great advice, Ripal. What other collaborators do you think are necessary to make a Y-90 practice, for example, medical physicists, nuclear medicine department? Can you elaborate a little bit on that?

Dr Ripal Gandhi: Yeah, sure. Every institution has its own politics, and all politics are certainly local. Certainly at our center, nuclear medicine was very important and medical physicists have been absolutely critical. As we were getting more and more advanced in how we're doing our Y-90 and as we're doing voxel-based dosimetry, we trained one of our medical physicists who has really become an expert and really a big proponent of Y-90 as well. She does a lot of the volumes and dosimetry, and has become a real expert. We happen to use MIM software. I think that's been extremely helpful. But again, every institution is very, very dependent, and you want to really understand the different people at play and how you want to develop your program. Then ultimately, it's critical as you're growing the program to make it known in your tumor board and make sure that you're vocal in your tumor boards such that you can continue to grow the patient volume that you're seeing in your interventional oncology clinic.

Dr Elena Violari: What's the importance of seeing your patients in clinic before and after a Y-90 radioembolization procedure or any interventional oncology procedure?

Dr Ripal Gandhi: I think a clinic is very important. I was fortunate to join a practice which has a very robust clinic for many, many years, but what we didn't have was a specific interventional oncology clinic, which we developed. But I think with any of these procedures, the reality is as much as some of the referring physicians know about our procedures, they don't really understand a lot of the nuances. Only you can really explain to them what to expect before the procedure, during the procedure, after the procedure, type of potential side effects, potential toxicity, and what are the outcomes? One of the things that I noticed early on was you really have to explain to the patient, for metastatic disease, for example, that the results that you can best see are on a PET scan. If the patient got other types of imaging, often the tumors might be the same or minimally changed, and that's okay. With HCC for example, you might not expect to see a complete tumoral response on subsequent imaging. That doesn't mean that it's not working and you have to keep following these patients. If the patient got imaging very soon after the Y-90 for example, you're not going to necessarily see a result. These are things that are best managed by the interventional radiologist in the clinic.

Dr Elena Violari: I agree with you. I think it's very important that the person doing the procedure is involved with the entire process from beginning to end so that the patient receives the most appropriate treatment in the safest way. I feel like if we want to be respected as interventional oncologists, we have to be as accessible to our patients as our surgical and radiation oncolleagues colleagues. The reason I actually bring this up is because I feel that in smaller hospitals and practices, it can be a battle to set up an interventional radiology clinic because it does require additional ancillary staff, schedulers, nursing staff, clinic managers, and so forth, and some practices don't have the resources available. What are your thoughts on that? Do you think having a dedicated IR clinic is an absolute requirement to build a Y-90 program?

Dr Ripal Gandhi: That's a great question, Elena. I mean, I think it's very, very important, but I do understand the potential logistical challenges that maybe a smaller practice may have in developing such a clinic. I think early on what you can do, even if you don't have a purely dedicated clinic space, maybe you could see patients in your office or somewhere in a pre-procedural area and that can eventually develop into a clinic. The other thing I would definitely recommend is that you're billing for these consults. As we're moving forward, a lot of our procedural codes are decreasing in reimbursement, but in terms of consultation codes, ENM, follow-up afterwards, all of these are going to be increasing. I don't think that's the entire reason for doing it, but I think that's important in terms of what we discussed in being able to have longitudinal care of our patients.

Dr Elena Violari: I agree with you. That's great advice. I think you touched on this a little bit earlier, but besides having a dedicated clinic, I do remember as a fellow that you always emphasized the importance of attending the tumor boards in building a practice. Can you please tell us how tumor boards help build a practice?

Dr Ripal Gandhi: Look, I think tumor boards are absolutely critical. Anybody who knows me knows that I'm fanatical about attending our tumor board. It is very rare that I will miss a tumor board even though I'm on vacation. The nice thing right now is that we do have the option to attend virtually, at least at my own institution. I think the key thing about tumor boards is there's a dynamic there, and we have very strong medical oncologists, surgeons, radiation oncologists, and the reality is only you can really explain to the board where you have a potential role and in your absence sometimes you're out of sight and out of mind. It is absolutely critical to be there. It is absolutely critical to have a voice. Don't be afraid to speak up, because at the end of the day, this is where you're going to really generate a lot of your patient volume.

Dr Elena Violari: Exactly. How do you think an early career attending should be prepared for tumor boards?

Dr Ripal Gandhi: I think there's several different things you could look at it, but obviously you want to really, really understand the interventional oncology data. That should be very, very well known to you. When I was coming out of training, I thought my fellowship was fantastic. I trained at UCLA, I had a lot of great mentors, but did I know everything? Was I prepared for tumor boards? I don't know if you are prepared when you come out of training. I end up doing a lot of reading, and I went to a lot of different meetings to really understand our data. I also read data from other specialties as well. I want to understand the medical oncology data, I want to understand the surgical data, and I want to understand the radiation oncology data such that I can understand where I have a role, where there might be a potential synergistic role, and I want to understand the new developments in other specialties as well.

Dr Elena Violari: Exactly. Actually, some of the best advice I got regarding building an international oncology practice with a busy Y-90 program is that when you go to these tumor boards, you have to be very well rounded, not only regarding what IR can offer, but also be up to date with the medical oncology literature, the rad-onc literature, and the surgical oncology literature. How do you identify what the most important and impactful papers are within these other specialties, and how do you manage to keep up with it? There is so much to know, and how do you manage to identify the most important knowledge?

Dr Ripal Gandhi: That's a great question, Elana, and it's something that honestly I struggle to do. It's hard enough to keep up to date with our own literature, but to keep up with all the other literature is very challenging. I do glance through the important journals specifically in Journal of Clinical Oncology, the New England Journal of Medicine, JAMA Oncology, the Journal for Radiation Oncology, newsletters from some of the throwaway journals, which will have some of the major trials from other specialties. At the end of the day, I think it is very difficult and I think just going to a lot of meetings and trying to read as much as possible can be extremely beneficial. The other thing that I always tell our trainees regarding tumor boards is that I wish it was purely about data, but it is also about politics and relationships. Attending tumor boards is also about developing those relationships.

Dr Elena Violari: Finally, how do we get the word out? What's the best way to educate our medicine and surgery colleagues about the procedures we can offer in interventional oncology?

Dr Ripal Gandhi: I think a lot of that really comes down to different types of venues where you can get in front of them. Grand rounds can certainly be very valuable, but other things which I find to be as beneficial, if not more beneficial, are small “lunch and learn” type sessions. Conversations are important—you do a biopsy and you call your referring physician, then tell them about what you just did and mention a potential treatment you can offer. I think it always comes down to a lot of communication with other referring physicians.

Dr Elena Violari: Exactly. Well, thank you, Ripal. This was a great discussion on practice building for Y-90 and IO. Now, I want to shift gears a little bit and talk more about the specifics of Y-90 radioembolization. Y-90 for secondary hepatic malignancies is usually offered in patients who failed multiple lines of chemotherapy. Can you please update us a little bit on the current evidence for Y-90 for secondary hepatic malignancies?

Dr Ripal Gandhi: Secondary hepatic malignancy is obviously a big topic and includes a lot of diseases, so I'll focus on the example of colorectal cancer. We treat a decent number of colorectal cancer patients in our practice, so certainly if you look at the NCCN guidelines, Y-90 is recommended for patients with chemorefractory disease. We certainly have strong evidence to utilize it in the salvage setting, typically after 2 lines of systemic therapy. I tell our patients in that setting that we probably have a median overall survival of about a year plus or minus depending on the patient, which is significantly better than that of third line systemic therapy alone. We were talking about things like Lonsurf (Trifluridine/tipiracil) or regorafenib, which have minimal effectiveness and some toxicity, especially with regorafenib.

In terms of second-line therapy, the EPOCH trial was recently published, which showed that there was a 2-month improvement in hepatic progression-free survival. Unfortunately, the overall survival was unchanged, but the response rate was increased by about 13%. I think there is definitely a role in second-line treatment of colorectal cancer patients as well, especially when trying to downstage patients to resection, that improvement and response rate can be beneficial. In the first-line setting, on the basis of the SIRFLOX and FOXFIRE studies, there are some data that patients who had right-sided primaries had approximately 5-month improvement in overall survival. We'll consider that, in our patient population, especially for younger patients or for those patients that maybe we're trying to downstage for resection.

Dr Elena Violari: That leads me to the second question. The location of primary malignancy as well as tumor histopathology can affect the outcomes of radioembolization. What are some of the predictors or criteria that you use to select patients for radioembolization? Do you have different patient selection criteria based on each patient's primary tumor versus neuroendocrine and versus breast?

Dr Ripal Gandhi: That's a great question. We mentioned a little bit about tumor location, so we consider that, at least in the first-line setting, treatment of colorectal cancer, although we don't utilize it that often. In terms of tumor histopathology, let's talk about neuroendocrine tumor for example. These are patients that have a lot of treatment options available and now we have options such as peptide receptor radionuclide therapy (PRRT) and lutetium as well. How do we look at tumor grades, for example? At my institution, for example, in patients with low grade tumor, liver dominant metastatic disease from neuroendocrine tumor, we'll consider liver-directed therapy. We tend to use more bland embolization for those patients as there is some concern for liver toxicity in the long term because these patients tend to live for a longer period of time. However, if they have multifocal disease throughout the liver and it is not liver dominant, we tend to favor PRRT or lutetium in that setting once they have progressed on Sandostatin or Lanreotide.

On the other hand, if patients have intermediate or high-grade neuroendocrine tumors, we tend to favor liver-directed therapy with Y-90 in patients with liver dominant disease. That is just one example of how looking at the tumor grade influences how we treat the patient and which treatment we offer the patient.

Dr Elena Violari: In patients who are undergoing partial hepatectomy, interventional radiologists are often asked to assist in preoperative hypertrophy induction. One of the most commonly used methods to induce hypertrophy of future liver remnant is portal vein embolization; however, recent studies have shown that radioembolization can also induce hypertrophy of the contralateral lobe. In your practice, which method do you use and why?

Dr Ripal Gandhi: Well, we use both. I think there's pros and cons of both portal vein embolization and radioembolization. Let’s discuss some of the advantages of Y-90 over portal vein embolization, and then I'll explain when we use each method. The main potential benefit of Y-90 the tumor control during that time for hepatic hypertrophy. We commonly will utilize it when the tumor is actually abutting vessels or are very close to vessels, because you could get tumor shift away from the vessels to allow for an R-zero resection, and sometimes that is not possible, so it can be extremely beneficial. The other benefit of Y-90 is the “biological test of time approach,” because the downside of utilizing Y-90, at least in our experience, is that it takes a little bit longer for hypertrophy compared with portal vein embolization. The nice about that is that Y-90 does allow for the biological test of time. If the patient develops tumor progression during that time, they may not have benefited from a hepatectomy in the first place.

Finally, Y-90 can be utilized in patient with portal vein tumor thrombus as well. All those things are beneficial. On the other hand, for a patient that is purely resectable at the time of diagnosis but just needs a little bit more liver, we tend to favor, typically for metastatic disease, a portal vein embolization because hypertrophy is faster and the patient can have surgery faster. On the other hand, we tend to favor Y-90 for these patients where we want the biological test of time, where there's portal vein tumor thrombus, and especially when we are trying to cause a tumor shift away from the major blood vessels.

Dr Elena Violari: Can you briefly describe your method for dosimetry? What are your target doses for radiation lobectomy versus segmentectomy or if you combine the two sometimes in the same procedure?

Dr Ripal Gandhi: Sure. I have to make a differentiation between glass and resin radiomicrospheres. Let's start with glass. For radiation segmentectomy, on the basis of the LEGACY trial, we tend to use week 1 glass radiomicrospheres targeting at least 400 Gy to the tumor. For radiation lobectomy, there are multiple ways of doing it with glass radiomicrospheres. If you use single compartment dosimetry, we typically target about 150 Gy to the absorbed dose in the lobe, specifically typically for Child-Pugh A patients. If we're using multicompartmental dosimetry, on the basis of some data, especially from the DOSISPHERE trial, you want to have a minimum absorbed dose of at least 205 Gy and you want to have the actual dose to the normal tissue to be greater than 88 Gy to allow for maximal hypertrophy. Finally, you mentioned combining radiation segmentectomy or lobectomy, which can be done as well. I think it's been termed “boosted Y-90,” and that situation will give a radiation segmentectomy dose to the tumor of at least 400 Gy. Then, we'll give a second administration to the actual lobe of 100 Gy.

For resin Y-90, when we're doing a radiation lobectomy, we are targeting at least 70 Gy to the background liver, which results in significantly higher dose to the actual tumor. When we're doing radiation segmentectomy with resin, there is less data, but we will have more data with the ongoing DOORwaY-90 trial. Again, we also target greater than 70 Gy to the background liver, and we want to make sure that we get at least 150 Gy to the tumor. The new 4-day pre-calibration doses, which are now available, which have higher activity and fewer number of spheres, can be extremely valuable for radiation segmentectomy if you are utilizing resin radiomicrospheres.

Dr Elena Violari: That's great. Thank you so much for that detailed explanation. What are your thoughts on the combination of Y-90 radioembolization and a new checkpoint inhibitor immunotherapy for the treatment of either primary or secondary hepatic malignancies?

Dr Ripal Gandhi: Well, I think there is a lot of promise. Recently, there have been a couple of studies which have been done in the advanced stage HCC setting, specifically the IMbrave150 and HIMALAYA trials, which show the value of immune checkpoint inhibitors in patients with advanced HCC, although these studies were not done with locoregional therapy. The LAUNCH trial was recently published and specifically looked at the addition of transarterial chemoembolization (TACE) to lenvatinib in patients with advanced HCC, and there was an improvement in overall survival as well as improved progression-free survival and response rates. While we don't yet have a trial that specifically looks at Y-90 plus systemic therapy with immune checkpoint inhibitors, I think that the LAUNCH trial and the prior trials with immunotherapy and advanced Y-90 really support doing this trial. I think it's going to be a very beneficial, but we need the data to prove it.

Dr Elena Violari: Tell us a little bit more about your research trials.

Dr Ripal Gandhi: We are involved in the DOORwaY-90 trial, which is a Y-90 trial with resin radiomicrospheres, and we recently completed the RESIN Registry for Y-90. We are also involved in the EMERALD-1 and EMERALD-2 trials. EMERALD-1 looks at TACE in combination with durvalumab and bevacizumab in patients with HCC. EMERALD-2 looks at the same agents as adjuvant therapy in patients with HCC at risk of recurrence following curative treatments such as ablation. We also have a couple trials for pancreatic cancer. One is the TIGeR-PaC trial, which is a phase 3 randomized clinical trial that compares chemotherapy alone to intra-arterial administration of chemotherapy. That is promising and is currently underway. Then, we have 2 trials for irreversible electroporation, specifically looking at stage 3 pancreatic cancer as well. We are also looking into utilizing vascular robotics, which I think is going to be something that is going to be important in the future.

Dr Elena Violari: That is very exciting, and I am looking forward to follow-up on the results of these trials. Through the years, we have witnessed the evolution of radioembolization from a palliative treatment to a destination treatment or bridge to transplantation. What are your thoughts about the future of Y-90?

Dr Ripal Gandhi: Well, I think the future is bright. As you said, we have shown that there is better bridging to transplant than with TACE, at least in some studies. We can downstage to transplant, we can do radiation lobectomy as we discussed, which facilitates resection. We can do radiation segmentectomy, which has a 5-year survival of over 70% and could be potentially considered curative and an alternative to ablation. There have been some recent studies, specifically the TRACE trial, which was recently published in Radiology, which was a phase 2 randomized clinical trial that compared Y-90 with drug-eluting bead (DEB)-TACE and is the first randomized trial to show improvement in overall survival. In fact, survival rate was double, about 30 months vs 15 months with DEB-TACE, and there was improvement in time to progression as well. Again, these trials give us more data to support the utilization of Y-90.

The importance of personalized dosimetry is also very exciting. For example, the DOSISPHERE trial was a phase 2 randomized clinical trial that looked at large HCCs greater than 7 centimeters in size. I believe nearly two-thirds of the patients had portal vein tumor thrombus. This trial showed that when you utilize personalized dosimetry, you can improve the overall survival from 7 months to over 26 months. Finally, as we discussed before, I think the future is going to be combination therapy, and I think specifically looking at Y-90 in combination with immunotherapy is going to be very, very promising. I look forward to seeing the results and participating in such trials.

Dr Elena Violari: I agree with you, Ripal. The future is bright for interventional oncology, and this has been extremely helpful. I've learned a lot and it has been a pleasure speaking with you, as always. Thank you so much for spending your afternoon with us and sharing your knowledge and expertise.

Dr Ripal Gandhi: Thank you very much for the invitation, it was a pleasure.

Ami Peltier: That wraps up another episode of IOL Radio. To listen to more conversations with specialists at the forefront of interventional oncology, please visit our podcast page at IOLearning.com.