Y90 for CRC liver mets — What patients need to know
DocTalk
2024
Dr. Dayyani
Liver
Stage IV
Y90
In this DocTalk, Dr. Farshid Dayyani from UCI Chao Family Comprehensive Cancer Center discusses Y90 for liver mets. Recorded in August 2024.
Transcript
This is an automatically generated transcript.
Betsy Post 0:01
Good evening, everyone. We are going to go ahead and get started and kick off this evening’s program. Our DocTalk this evening is on Y-90 for metastatic colorectal cancer, “Liver, Mets and What Patients Need to Know”. I do want to say that everyone has been muted, you have been admitted on mute. We would ask kindly that you please remain on mute this evening for the duration of the program. We really want to be sure that we’re giving all of our attention to Dr. Dayyani and we want to make sure we don’t have any interruptions. So if you’ve never attended a DocTalk with me before, just keep in mind that we will have a live Q and A at the end of the presentation. So those questions please put in chat. So here in Zoom, there is a chat feature. You just click on chat, you can put your question there in the chat. We did submit quite a few questions to Dr. Dayyani in advance, so I think he’s ready for some of our FAQs. But as we go through this evening’s program, please do put those questions in the chat. We will have some live Q and A after the presentation, and please remain on mute. So with that, I am going to turn it over to Dr. Dayyani. I just want to thank you so much for being here to present to our COLONTOWN family of patients and caregivers. Dr. Dayyani joins us from the University of California Irvine. He is a medical oncologist with a wealth of experience in Y-90. He is specifically a GI oncologist. He works with a multidisciplinary team. He really is big on the patient selection, making sure that the right patients get routed for Y-90. So he’s going to educate us this evening all about this treatment. And Dr. Dayyani, I am so pleased to have you. You are our first ever Y-90 DocTalk. So we are very, very excited and honored to have you! With that, I’m going to turn it over to you. And thanks again for presenting for us.
Dr. Dayyani 2:00
Thank you. Thank you so much, it’s pleasure to be with you guys. I wish we were all in person, but then fewer people would be able to attend. Yeah, I’m a GI medical oncologist. I’m the Medical Director of the clinical trials unit, and I joined UC Irvine in 2016. I trained at MD Anderson Cancer Center in oncology, but really since joining UC Irvine Dr. Abi-Jaoudeh our Chief of Interventional Radiology, and I have been championing the radio embolization of Y-90 treatment protocol at UC Irvine for patients with liver disease, but especially colorectal cancer patients with liver metastatic disease. So it’s about 40-42 slides. It’s not too long. And don’t worry, I’m not going to stay too long on each slide. But I think the interesting part of it is maybe half of the slides are actual patient cases since 2017, obviously all deidentified, from my patient panels, just to show you the spectrum of patients eligible for Y-90 treatment in a multimodality setting. So I’m going to give you a brief overview of the biology of colorectal cancer. I think every speaker does that. We’re not going to dwell too long on that. Some treatment strategies for what we call liver-dominant disease, meaning the majority of the metastases are actually in the liver, confined to the liver. Then the rationale for SIR-spheres of Y-90 microspheres in radio embolization, or of liver metastases and then, as I said, we’ll go through the cases from the clinic, and then I’m happy to engage in a discussion with you guys. The numbers are improving. 154,000 new diagnoses in the US with cancers of the colon or rectum in the US. About 80% are presented stage 1,2,3, meaning the tumor might have maybe gone through the wall and lymph nodes, but not to other organs. So that’s stage 1,2,3. Those patients, as you know, undergo surgery with or without chemotherapy afterwards to mop it up, but unfortunately, half of those will have a recurrence. The cancer will come back despite the surgery and the chemotherapy, and we consider that another 20% present with stage four disease. That tells us about 40, 50% of these patients, at some point, will be diagnosed with stage four. And the liver is the most common site of tumor spreads from the colon due to the anatomic drainage of of the majority of the colon, so 70% of the patients with stage four, we have either liver-only or liver plus other sites of disease. So it’s a very important organ that we have to talk about because liver failure from the increasing liver burden from the tumors is the most common cause of patient demise. So as I said, this is the most common sight of disease. And the problem is the chemotherapy drugs we give, oxaliplatin, irinotecan, the staples of treatment of stage four disease, they can cause over time, also underlying liver damage. So what we’re dealing with here is now a tumor that preferentially goes to the liver, starts growing there, replacing normal liver, and at the same time, we’re trying to treat that tumor with chemotherapy drugs that further attack the liver function. And now that can lead to a perfect storm. So the idea is, kill as much tumor in the liver, and at the same time try to spare as much normal liver so the patient can a) be able to function longer, be able to access treatments longer, and hopefully not going to liver failure. So that’s the overarching concept of giving Y-90 into the liver in within this treatment spectrum of patients with liver disease try to kill tumor with a different mechanism of action, and at the same time try to spare some of the chemotherapy drugs and spare the normal liver. This is what happens at UC Irvine every Monday from 1 to 2pm local time. So that would be 4 to 6, 4 to 5pm Eastern, for example, we all come together. It’s actually hybrid. When I happen to be at the hospital, I go to the basement where the surgeons and the radiologists sit. But the important part is we have two to three liver surgeons. We have two to three radiation oncologists. We have maybe four GI-focused medical oncologists who treat patients with liver disease. Interventional Radiology is very important, two or three, and then radiologists, pathologists and trainees, residents, fellows, etc. They all come together, review all new cases for patients with colorectal liver metastases at these, and then the rest of the week we page each other, we text each other. I mean, these are becoming more obsolete, so it’s either email or or texting. So we have real time management of our patients, because the best outcome for the patients are achieved if everybody comes to the table and you bring in every single modality you have. Very few patients will be cured with one modality alone, certainly not chemotherapy alone. Surgery, I’ll show you, maybe 10, 15% but really, in order to bump that 17% five-year survival to 25, 30% we need to bring everybody to the table. You don’t need to memorize that. This just highlights that the best treatment for a patient with stage four colon or rectal cancer is to look holistically. You look at the patient: age, what are the comorbidities, how fit are they, what’s their preference, what’s their quality of life, how much toxicity can there tolerate? And that becomes very important when we think about Y-90 treatment. Which side of the colon is the tumor: on the right side, or we’re closer to the rectum, left or right? And then more and more – what are the molecular characteristics? So every single patient with a stage IV cancer should have comprehensive molecular testing and IHC testing at a minimum for mismatch repair proteins for colon cancer, RAS, RAF, BRAF, HER2, etc, etc, and we do both liquid biopsy and tissue testing, so we come as comprehensive as possible to the best treatment of our patients. So if you look at the guidelines and liver-specific treatment options for patients with colon cancer with liver metastases, about one in six patients might be candidates for upfront surgery. And even in those cases, as you might know, we tend to give some maybe two months of chemo upfront, make sure nothing new pops up, maybe shrink the tumors a little bit, present them to a tumor board, and then take them to surgery, remove or ablate the liver lesions and then clean it up with some more chemo. The problem is, 80% of those, the tumor will come back because there’s hidden tumors in the liver that we don’t see, and the chemo doesn’t get rid of them. But more importantly, eight out of 10, or 85% of the patients with that diagnosis, they have too much disease in the liver. They’re not really candidates for surgery. Even after chemotherapy, they might not be a candidate for surgery. And what do we do for those patients here? That’s what you see down here, there is what we call intra-arterial options, meaning the interventional radiologist takes a catheter and goes through the groin into the artery to the liver, and from there, injects these radioactive beats into the tumors. That’s called selective internal radioembolization, or Y-90, that actually has the highest category based on the NCCN guidelines for intra-arterial therapy to treat liver metastases. I’m sure most of you have heard of hepatic artery infusion. It has a category 2b, so a little bit lower level of evidence and recommendation based on NCCN. But importantly, if you think about quality of life, I hope you’ll find out within the next 30 minutes, that Y-90 is a single treatment to the right lobe. Four weeks later, a single treatment to the left lobe, and you’re done. Whereas hepatic arteries, you have a permanent catheter in your belly going into your liver, and you show up every two weeks to get chemotherapy for up to six months, and the catheter stays there. And then you come back so really, giving more of the same of the chemo into the liver. We think at UC Irvine, maybe complementing the systemic chemotherapy, the IV chemotherapy, with some radiation from inside, might be a better strategy to further shrink these tumors. Why is the liver important? Liver does a lot of things. It’s a storage for vitamins, as everybody knows, it’s an organ that does the drug metabolism, detoxification of all the things that go through our system. It helps with heme breakdown, all the red blood cells, billions and billions of red blood cells that we have, and only a few days in the system, it it makes sure that the thyroid hormone levels are regulated from from from T4 to what we call this, the active hormone level, T3, importantly, many, many important serum plasma levels like albumin, are made in the liver. And if your albumin levels dropped, and you’re more prone to get swelling and edema, right? And importantly, it makes bile, and the bile salt is then stored in the gallbladder. And every time you eat something fatty, some of that bile goes into your small bowel to help with digestion of the fat and the other so the liver is a more, if not the most important organ for your life, if you’re a patient with stage four colorectal metastases, so the name of the game is preserve as much liver function as possible and kill as much cancer in the liver as possible. The rationale, or the way why radio embolization, or Y-90 treatment to liver metastases works is based on anatomy. Turns out there are two separate parallel blood flows through the liver, the majority of the lower body, and all the draining blood from the bowel, where the food is absorbed, goes into the portal vein. So all the blood drain from the small bowel, from the colon, all the nutrients go through there. And this portal vein goes through the liver, and it’s full of nutrients and really supplies the majority of the normal liver. And then from there, it’s drained and goes through the inferior vena cava into the heart and goes through the lung to be reoxygenated. Whereas the tumors, they’re not part of that system, they’re part of the separate system where the aorta, which brings the oxygen-rich fresh blood into the organ, so they get oxygen through the hepatic artery supplies the tumors. So as you see here, these are a couple of the tumors in the liver. They’re almost exclusively fed by the hepatic artery, but the majority of the normal liver gets their blood supply from the portal vein. So now, when you go through the groin, through the artery, and go right up into the organ, and you start showering these tumors with with with these radioactive Y-90 SIR-Spheres. They preferentially go where the tumors are, but try to avoid the normal liver, because it’s a parallel highway system of drug delivery. And that’s really the basic principle why Y-90 works in patients with liver metastases, especially in patients with colon cancer, liver metastases. So what are Y-90 SIR-Spheres? These are resin spheres. Tiny, tiny, tiny. They have a half life of 64 hours. That means in about every 64 hours, the activity drops by 50%. The penetration is very small, 2.5 millimeters is a 100th of an inch. So that is part of the principle why you can treat the tumor. Because these tiny beads – you see here, these are tiny, tiny beads that you shower into the hepatic artery. They go and they distribute where the tumor vasculature is, and they kill the tumor from inside. But because they don’t have a huge range, shortly, a 100th of an inch later, you spare whatever normal tissue is outside of the tumor. And that’s the principle why you can, what we call internal radiation. You give it from inside. It goes through the bloodstream into the tumors and from inside, radiates them without trying to damage the normal liver outside. And that’s how it works. As you can see, you guys have heard of transarterial chemoembolization, embolizing with those – you take particles for embolization. Embolization works differently. You take big particles and you put them through the artery, but then they get stuck right before they actually reach the tumor. What they do is, embolization cuts off the blood supply to the tumor, so anything beyond that just gets hypoxic – the oxygen level and tries to kill it by suffocating it. It’s much more toxic. It causes much more inflammation, and maybe not the best treatment for colorectal whereas, if you give SIR-Spheres, Y-90 microspheres, these tiny things, they don’t embolize, they don’t cut off the blood supply. So the blood supply keeps going, meaning you can afterwards still deliver chemotherapy. Because here, once you cut off the blood supply, afterwards, you can’t give any more chemotherapy. It’s all done. But here you sent these small spheres. They go locate into the tumor, start radiating it from inside, and what we do at UC Irvine, two weeks after Y-90, the patient comes back and restarts the chemo, systemic treatment to further damage the tumor and try to avoid damaging the normal liver. So: what are the basic criteria to find the optimal patient for Y-90 treatment with SIR-Spheres? Well, there are some basic things that you have to think about. Obviously, if a patient is a surgical candidate, we send them to surgery. Importantly, at UC Irvine, we try to make them surgical candidates by giving them Y-90 first to get additional tumor shrinkage, and then we present them again to the surgeons. I’ll show you that in a second. They’re not qualified for ablative therapy, meaning it’s not a small tumor. Liver-dominant, meaning the majority of the disease has to be in the liver, so maybe one or two tiny lung nodules, maybe half an inch fine, or a couple of lymph nodes outside of the liver, fine. But if a patient comes and the lungs are full of tumor and the liver is full of tumor, those patients don’t benefit, but the majority of the patients will actually have liver-dominant. Radiation takes time to work. That’s something to realize. It’s like sunburn. You do it, but then the the the sunburn comes maybe hours later or the next day. Similar with radiation. You do the radiation, you don’t see the effects the next day, you see them over the next weeks. So you have to think about it, refer the patient. Consider Y-90 at a time where the patient actually has enough time to start seeing the benefit.
Dr. Dayyani 17:45
If your physician refers to, down the line after you went through 10 different chemo treatments and says, “Oh, I don’t have anything else, let’s try Y-90” a) your liver is way too predamaged, so you’re more likely to get toxicities, but you might not have enough time to actually see the benefit of the radiation. Good performance status, meaning the more active you are, the less damage from the prior treatment, the more benefit. This is an absolute for us, and your doctor will check the bilirubin level. A lot of patients when they have liver metastases, they present with jaundice, or they turn yellow, and then they have to have ERCP and stent placed. That’s because of the back of the bilirubin that then goes from the liver into the skin. So a bilirubin less than two is very, very important. Again, that happens earlier in the disease course, the longer you wait, the longer the damage, underlying damage deliver, the more likely that your bilirubin is going up. Lung shunt is something technical that you don’t need to be worried about in the preparation for your Y-90 treatment, the radiology intervention radiologist will determine that. That basically needs to make sure that when you shower through the artery, when you give these small beads, that not more than 20% of that goes through the bloodstream into the lungs, because then you get pneumonitis or inflammation of the lungs, but that’s all done as part of your workup. Right-sided primary tumor, I’ll talk to you about that. In the United States for two decades now, the SIR-Spheres, the SURTEX Y-90 beads, are indicated for the treatment of metastatic liver tumors from colon cancer. It used to be in adjuvant into intrahepatic artery, but we don’t do that anymore. We do it now at UC Irvine be embedded into the systemic treatment, meaning chemotherapy, biologic therapy, shrink the tumors, then go with Y-90, shrink them more, and then maintain with chemo to see whether the patient can go to hopefully curative, intense surgery. So what does the procedure look like? Patient is presented at the tumor board, as I showed you. Everybody comes together. Everybody. It determines if this patient is a good candidate for Y-90 treatment based on what I showed you, the evaluations are done – the tumor mapping. You do a vessel mapping, an angiogram to exactly determine which vessels or which arteries the interventional radiology radiology should be looking for, for injecting. Then the team looks at the imaging, does the dosimetry, how many beads do I have to deliver, based on number and size. Then you go for the treatment, and then right away, the radiologist can see if the treatment was delivered correctly. That’s shown here. So prior to the treatment, you do imaging to see if that’s where it should go. And then afterwards, you repeat the imaging to see if the beads went there. You can actually image those beads, the activity to make sure you got it to the rat. In terms of practical premedication, and analgesics. You know, Tylenol you don’t need. Most patients will not require narcotics. Proton pump inhibitors, antacids or H2 antagonist – so famotidine or omeprazole, or any of those is recommended to be started and maintained for a couple of months afterwards to minimize the risk of gastric ulcers, and I talked about that a little bit. Whether you give steroids or not, that’s based on your institution. We don’t routinely give antiemetics or antibiotics unless we think there is a risk for infection or there’s signs of infection, but really reducing the risk of gastritis and gastric ulcers with PPIs or H2 blockers, that’s, I think, good practice to do. Is it safe if a patient is treated with Y-90 for the people around them? Yeah, it is. You know, the further away you stand from the patient, the less radioactive they become. So if somebody is standing three feet away from a patient who just had Y-90 they get the same radiation they would get if they flew from, well, I guess from Orange County, where I am, to San Francisco. That’s an hour, right, which we do all the time, going back, back and forth. And the important thing is, the further you go away from a patient, the lower the exposure. But the exposure even within three feet is very slow. The half life is about 2.6 days. So by about 13, 14, days, all the activity is actually done. So that brings me to our tumor board, and how we sequence patients. Every single new patient with colon metastatic liver metastases is presented at tumor board. If they’re resectable, meaning a surgical candidate, no question. We give them a little chemo, send them to surgery, remove the liver, ablate the liver, remove the primary tumor, give them some — (inaudible) and then we watch them, as I told you, unfortunately, more than half of those will have recurrence. The disease will come back. But 80, 85%, 90% of the patients, depending on population, at the time of presentation, there’s just too much. The surgeon can’t remove all of it. So those patients, we start with the best systemic treatment we have: chemo plus biologic based on the sidedness and mutation status. We shrink those tumors for about three months. And if you know FOLFOX, FOLFOXIRI, these are two week regimens. Three months is six rounds of chemo, only six rounds of chemo. After that, we’ll take them back to tumor board. And if the tumors are small enough that they go to surgery, for sure, send them, because the goal is to remove all invisible disease that gives the patient the best chance for long term survival. So whenever surgery is possible, that we do. Again, that happens only maybe 10, 15% of the time, but when we get to that point by three, three and a half months, the best chemotherapy has not made it possible for the patient to go to surgery, more chemo is not going to shrink it, especially if you give your best treatment anyway. That’s where we think you go and give radiation, because radiation is not cross resistant, or resistance to chemo doesn’t mean resistant to radiation and vice versa. So after the initial three months of chemo, if the most of the tumor is in the liver, but still not surgically removable, that’s where we think you send the patient for radioembolization – Y-90 treatment. That extra kick from the radiation might actually further shrink the tumors, and two, three months later, we present them again. And if they’re surgical, we’ll send them, and I’ll show you cases of what we’ve done with our patients like that. We try to cure everybody, and for that, we need to remove all disease. We can’t cure if we don’t prolong survival. We can’t prolong survival if we don’t delay disease from growing, and a disease that doesn’t grow improves the quality of life of the patient, especially if your treatment is less toxic than the other available options. And I’ll show you cases for all of these, including a case of a very, very sweet Vietnamese lady who went through years of treatment and couldn’t take it anymore, but had this huge liver tumor that was causing a lot of pain. And for that patient, we used Y-90 for really palliative but based on what I showed you, this is usually where we try to bring in Y-90 before the liver is beat down, before the patient has seen three years of chemotherapy where everybody is ready to try to get them to surgery. Conceptually, TARE means transarterial radio embolization – is basically another term for Y-90 treatment. The more disease in the liver, the more likely we use Y-90. At the same time, the less chemosensitive, the more likely the radiation will work. And that’s why, in the beginning, when the tumor is more chemosensitive, meaning likely to respond to chemo, we start with chemo, shrink it, then as resistance to the chemo starts to come up, that’s where we go and do radioembolization. What this tells you is that colon cancer is not colon cancer, – it’s not colon cancer. It’s hundreds of different diseases based on which side of the colon we’re talking about. This is called the left side, towards the rectum. Where the colon starts, is called the right side, transverse, and different mutations. The issue is, even if you normalize for all these mutations, these tumors on the right side: cecum, right sided, ascending colon, appear to be less responsive to chemotherapy. You don’t need to understand these curves, but it just tells you the same patients on the same trial, if you separate them by whether they started on the left side or right side and whether they received anti-EGFR or anti-VEGF, had four very, very different outcomes in the same trial. So a right-sided tumor with anti-EGFR only 13.7 months, perhaps a left-sided tumor with anti-EGFR for 40 months and in between, but what you see is orange and yellow, the right-sided tumors have worse survival, even in the best case, worse survival than left-sided tumor. That tells you, in a trial that was testing chemo with biologics, that right-sided tumors appear to be less chemosensitive. So we need to, early on, think about, how can we control the disease? Because they’re not going to benefit for too long from the FOLFOX or FOLFIRI, or FOLFOXIRI that I’m giving them. Some of the data we have for that come from the so called FOXFIRE analysis. We don’t need to get into the weeds of that. But the bottom line is, patients with colon cancer and liver metastases were randomized to get FOLFOX bev or FOLFOX wet with Y-90 between cycles one and two. What I want to highlight here is if you look only at the patients within that trial who had right-sided tumors, you see early integration of radioembolization or Y-90 treatment with SIRT improve the survival by about five months from 17 months to 22 months hazard ratio .64. Is it perfect? No, but it’s certainly better than they did with chemo alone. Importantly, the increase in what we call objective response rate, or the tumor shrinkage rates, by about 10% tells you even if the tumor might be resistant to the chemo I’m getting, the radiation will still give us the extra kick of tumor shrinkage. That’s the message here. They actually did a secondary trial out of that FOXFIRE data. What you see is they basically took seven liver surgeons. They didn’t tell them which patient received Y-90, which patient didn’t receive Y-90, they just showed them the CT scans, and they told them which of these livers are surgically removable and which are not. At baseline, it was exactly the same, because the patients were randomized. But importantly, after treatment, at the time of best response, the surgeons did not know what treatment the patient had received. They just looked at the liver on the CT scan. 38% were potentially surgically removable with the addition of Y-90 versus only 28%. So, you do see some response to chemo, as I said, about 10, 15 but you get another 10% extra, which is a lot. If you have 70,000 patients, 10% is 7000 additional patients who might go to surgery and remember, removing all disease is the first step into long term survival. It’s not a guarantee, but it’s necessary. What are the side effects to look for?
Dr. Dayyani 29:35
It’s feared, radiation, radioembolization, induced liver disease, but it’s very rare. 99% of your patients will not see it, maybe less than that, seen within the first four months. Really try to avoid it by don’t refer patients who are too beat up. Livers that have seen too much chemo. There’s too much liver disease, right? The ulcers, that’s more common. Gastritis Patients will ??(inaudible) be aggressive with it. Give antacids, give PPIs, add a H2 blocker, if needed. Be very aggressive with the management of the gastritis. And there is some less common side effects, mainly if your intervention radiologist is not very experienced and there is leakage of the beads, for example, into the lung or to the other organs, then you might sometimes get pancreatitis, etc. It’s not very common. And the more you do and the more experienced you are, the less your team will see these guys here. So one way to do that is you start a patient with newly diagnosed disease and your best systemic treatment. And the reason I say systemic is because it’s chemo plus something else, right? Anti- EGFR, anti VEGF, biologic. Shrink it for about 2, 3, 4 months, not more than four months. At UC Irvine it is usually three months. And then, if they’re not surgically removable, and the majority of the disease is in the liver, that’s where we go and try to radioembolize with Y-90 and further shrink the tumors. So that was the introduction, and maybe for the next, last seven to 10 minutes, I’ll show you actual cases. And some of these patients are still around, like this gentleman, 44 year old gentleman, two daughters, comes with rectal cancer with unresectable liver metastases. Here are the MRIs. 2019 – So that’s five years ago, more than five years ago, five and a half years ago. It was diagnosed late 2018 but by the time he came to see me, — the important message is he only got six cycles of strong chemo, and then I stop. Six cycles of FOLFOXIRI panitumumab, shrink the tumors. Then after six cycles, remove the chemo so a) I don’t damage the liver more from oxali and irinotecan. The patient has less nausea, less fatigue, less anorexia, less neuropathy, numbness, tingling. Then I send him, because he’s not a surgical candidate, I SIRTex or Y-90 the right liver in between, we give him a little panitumumab – that’s not chemo, just a biologic to control the tumors. Then treat the left liver and look at that. A year after his diagnosis, we further shrunk the tumor so it could go to surgery, right liver resection, microwave ablation. Long-term survival means that we remove all tumors. So what we did two months after the liver resection, we removed his rectal cancer, because that’s where it all started. I gave him a little bit of chemo afterwards, mop-up chemo with capecitabine. A year and a half, there’s one site of recurrence where it came back on a PET scan, we removed that. He finished two years from his diagnosis. So, diagnosed March ’19, March 2021 – he finished all chemo. He went off all treatment. I checked, his circulating tumor DNA in the blood remained negative for three years off anything until last year. So for four years, this gentleman, who was diagnosed with stage four in 2019 had only six cycles of oxaliplatin irinotecan. Talk about quality of life. Unfortunately, he had recurrence, and he’s now in a clinical trial, but he’s still walking around, and he actually married during the time, and had a second kid. So a different case, 51 year old lady sigmoid, as you can see here, the spots in the liver presented the same. The remarkable thing about this lady is I met her within a few months of joining UC Irvine. Within six months. I gave her the same thing – she was young, 50. I gave her six cycles, only six cycles of oxali, irinotecan, I shrank the tumors. I maintained her with a little over 5FU maintenance until we set up for radioembolization, Y-90 in June and July, a month apart. So we only gave Y-90 to the liver. Never went to surgery. Two months later, I removed the colon tumor, because you have to remove everything. This lady has been in surveillance for the last five years. September, no, seven years now. CEA negative, liver function tests – great. Four years out. Without I actually discharged this lady from my clinic last year. I said, You’re five years out, you’re cured. Never had surgery. You cannot tell me that chemotherapy alone would have done that, because the disease didn’t disappear. With chemo alone, it shrank, but we had to bring in radiation early on before it got out of hand, because smaller is better for radiation. So you wait for tumors to grow more and they’re three dimensional, then you have a much harder time. Even if you shrink them, you have a much harder time to get them to go away. This is an engineer from Syria who came to me with a very high CEA, as you know, three and a half is normal. It was 3400 times higher, with lots of big tumors in the liver. I gave him the same. You see the CEA going down. Your biggest bang for buck from the chemo upfront is really the first three, three and a half months. Afterwards, you just maintain it. You just give toxicities. So the same here. He had some complications from the chemo that he didn’t like, so it took a bit longer, but we brought his CEA down. Tumors get smaller, but they were still not resectable. I presented a tumor board. Then we do Y-90, the CEA takes a second dip, as you see here, the CEA was going up, the tumor marker, and we radiate and boom, it goes down to normal. And a year out, we go and remove his colon with minimal, minimal exposure to things that give you neuropathy, numbness, tingling. Unfortunately, not all patients are diagnosed at UCI. This lady was diagnosed somewhere else with stage III, had surgery, chemotherapy, and unfortunately, the tumors came back with a vengeance, as you see here, multiple tumors in the liver. I gave her standard FOLFIRI, Bev for six cycles. That’s the theme. Three months, if it works, you’ll see it. And then after that, you have to find a different mechanism of action. We had a very young and talented Dr. Utrich surgeon with us. She came in and did a huge six, seven hour surgery, removed everything, but within two months, two small spots came up. I cleaned it up with some chemo, and right away sent her to radiation for that lady. Again, another case of this huge tumor. So remember, this is the liver, and virtually all of it is replaced by this big, huge tumor. But everything gray here is actually normal liver function. The same thing. Three months of chemo, bring the CEA down, maintain it. Now you see the tumor shrank, but there’s still a lot of tumor left, especially the whitish part is still live tumor. So that represents a) I can’t get any more mileage out of my chemo, but I have side effects. So we treated both sides of the liver a bit with radioembolization, Y-90. And now you see a lot of this is now calcification. You see calcium deposit. That means the tumor is dead and the CEA normalized, so quality of life and efficacy. And the last case I want to show you is the lady I told you, 72 year old. Lovely lady, her son was a pharmacist who’d come with her all the time. She had everything. She had brain metastases, brain surgery, radiation to the brain radiation to here. She was done. But this huge tumor in the liver was really causing her a lot of pain, pushing and all the pain meds didn’t work. We took her to radioembolization Y-90 to shrink it and remove the tumor from the capsule that causes the pain and that got a great palliation for the time she had left. So what’s the rationale? To summarize a benefit of giving Y-90 in colorectal liver metastases, it’s because it’s selective, meaning the majority of the blood supply to the tumor is from the artery, that’s where you go in and shower the tumors. But the normal liver gets their blood from the blue one, the portal vein. So you spare normal liver, but you attack tumor from inside with radiation, which is not the same as resistance to chemotherapy. Most patients go home the same day. You can treat many tumors or very large tumors, and still try to spare as much healthy tissue as you can, because remember, it’s only about the 100th of an inch the rate radius of the beads radiation, and it works synergistically with the chemotherapy drug. That means when I refer patients to Y-90, I already know they come two weeks later and get more chemo and they go back. So it’s really integrating it in your spectrum, rather than just to send them and say, “Okay, let the radiation work now”. No, we collaborate. We synergize as a team, but also as different treatment modalities. So colon cancer is heterogeneous. It’s hundreds of different diseases based on sidedness, molecular profile, patient profile. Systemic treatment is more than chemo. You have to do your molecular profiling and add an appropriate biologic to further shrink tumors. You really need a multidisciplinary team and multi modality: systemic treatment, chemotherapy, biologics, immunotherapy, radiation, radioembolization, surgery and Y-90 treatment in the majority of the patients. You can’t bring the Y-90 at any point, but sooner is better, because the patient is fitter. They have still have a chance to go to surgery, and their liver is not beat up, meaning they’re less likely to have the toxicities. Obviously, we’re all working on further clinical trials and research to to provide or define better when, and in whom to use and when to use Y-90. — So I’m going to stop here. Okay, this is my email, and happy to engage in any discussions. I think we wanted to talk 40 minutes, and that’s pretty much it.
Betsy Post 40:10
We definitely have some questions for you. I have some questions that were sort of pre-submitted, so a lot of those have to do with the HAI pump, which you sort of alluded to a little bit. But we have a large patient population of liver mets patients, and they’re a lot of times they’re really torn between HAI and Y-90. So if you could elaborate a little bit on the Y-90, HAI and specifically, one of the things we get asked a lot, can you do Y-90 after HAI? And can you do HAI after Y-90? Those are two big questions, but we’d love for you to elaborate on that HAI, Y-90 conversation.
Dr. Dayyani 40:54
So, hepatic artery chemo infusion, if the UR is a pro-drug of 5FU. In modern times, as you saw, my patients, the majority get FOLFOXIRI, if they’re fit or FOLFIRI or FOLFOX whatever, and we treat them to best response. So the idea is, if you give hepatic artery infusion, there’s there’s a quality of life, and there’s efficacy. The data are there, you know, there’s some efficacy in there. But what I teach my trainees, fellows, when they come and my pharmacist and other people, is start thinking conceptually. The premise of hepatic artery infusion is that you deliver very high dose of the prodrug, of the drug 5FU that you already gave the patient, that you can deliver higher doses than you would be able to deliver in an IV fashion, but it’s still the same drug. If a tumor cell becomes resistant to 5FU then it’s unclear if a higher dose will actually eradicate the disease. The analogy that I use is this, if somebody is hard of hearing, then you can speak louder and they will hear you. So if a tumor is sensitive, you can give a higher dose and it will shrink. But if somebody does not speak a word of English, you can scream as much as you want, they will not understand a single word. That’s resistance. Radiation, that’s what was my point, is not cross-resistant to chemotherapy. And in 2024 where we give everybody per NCC and guidelines the best IV chemo up front and the all IV chemo up front has either capecitabine or 5FU in it. By the time the tumor stops responding, they have seen a lot of 5FU. So conceptually, should we go and give them just a higher dose of 5FU? So what I’m saying is maybe the tumors are starting to speak a different language, or we start screaming at them in English. Or should we go and find the language they speak, meaning radiation, and further shrink it? That’s the efficacy part, the conceptual. Now, having said that, there is no head to head trial between HAI and Y-90, and because of that, there’s zero good, high level data in terms of sequencing. So anybody who tells you you should do HAI first, and then Y-90 or vice versa? Maybe they have a little bit of experience, but they don’t have a large experience. And there’s no published good level data how to sequence again, how safe it is. We are looking into that. But the second part is quality of life. So you have radiation that is not cross-resistant to chemo, and you shrink everybody with chemo upfront anyway. So if you need to treat the liver, would you like to go for an outpatient procedure? Boom, get the right liver treated with radiation, go home four weeks later, come back. Boom, get the left liver treated. And you’re done. Or would you want to come and get every two weeks, 48 hours being hooked up to a pump that will also, over time, damage the liver. That’s why they don’t give it indefinitely, right? Three to six months. Quality of life, all the patients after bad maintenance, tell me, can I go on a pill? Now you want to treat the liver with the same drug, just at a higher dose? So these are things you should discuss with your doctor and everybody, based on their experience is biased, obviously, but there’s not enough data for anybody to be confident. To tell you that’s how you sequence it, or you should sequence it like that. In my practice, I never use – maybe because I didn’t treat – we do have HAI. We do offer it. I think there are situations where HAI makes sense. For example, a patient with stage III who had surgery, all disease removed, but we know this patient is at risk of tumor coming back in the liver. We actually have data that if you go and do hepatic artery infusion in that patient, you might reduce the risk of recurrence. But there is no tumor that we can’t treat with Y-90. So it’s a completely different patient population where I think it makes sense. But what we’re talking about today is stage IV patients metastatic disease to the liver, who are all treated with 5FU or capecitabine, upfront combos and now become resistant or stop responding. Should we really give them just higher dose of 5FU, or should we give them something else? And I hope that answered the question.
Betsy Post 45:39
Thank you so much, I have some questions in the chat for you. So for those of us that are heavily pretreated, think 50 plus rounds of chemo in, is Y-90 dangerous for us if we are running out of options, is there a way to do it safely?
Dr. Dayyani 45:56
So that’s a very good question. Unfortunately, the reality in the US is exactly this case, cases like yours, and that’s why we have very, very strict criteria performance that is 01. Patient is minimally impaired, able to do almost all their daily activities. Maybe they don’t function at 100% but otherwise they’re able to live their daily lives. Their bilirubin is less than two, the albumin is greater than three. So there is criteria that minimizes the risk that the liver is predamaged enough that you might get toxicity. But the majority of the cases currently in the US referred, are patients after 50 cycles. Remember anything beyond three months of oxali and irinotecan starts to give you underlying liver damage, it microscopically, you don’t see it, but it sort of increases. Is it safe to do? for sure. That’s the majority of the patients, who get Y-90 in that setting, what we call salvage setting. But you have to be very careful to do it somewhere where there are experienced – have high volume, and are not too cavalier that they say, “Oh, okay. Bill is three, that’s fine”. We have certain hard stops to minimize the risk of toxicity.
Betsy Post 47:16
Thank you. It seems like the patient stories that you shared indicated that Y-90 decreases the risk of recurrence. So why not add that on for those who are already resectable, just with chemo? Is it weighing a risk and benefit of radiation?
Dr. Dayyani 47:35
Yeah. And so if a tumor is already resectable, you remove it. There is zero points to give more radiation, because, remember, the reason we give chemo before we send them to surgery, if they’re resectable, is not to treat the tumor that’s going to come out anyway, the surgeon is going to cut it out. We give chemo because the fact that there is some tumors visible, increases the risk that there’s other tumor cells we don’t see, so we want to kill them before the patient goes to surgery. So when the surgeon does their job, the risk of the cancer coming back is lower. That’s why you give chemo IV, if you remember what I showed you, Y-90, goes directly where the tumors are visible. It doesn’t go to places where there is no tumors, because it can direct them that way. So there is no benefit to shrink a tumor that’s going to come out anyway, but that’s only 10% of your patients. So to change the answer to your question in the majority of patients after the initial chemo, they’re still not candidates for surgery, maybe because there’s too many tumors, or they’re too big. There we go and Y-90 them and shrink them further, and remember, 38% response in the RESECT trial, and then we send them to surgery. That’s where the benefit is. If you have a small, two centimeter tumor, less is more. Take it out. Be done with it. But if your tumor is five, six centimeters and you need to get it to three, that’s where we do the radiation.
Betsy Post 49:14
Thank you. Is Y-90 safe for patients with innumerable liver tumors?
Dr. Dayyani 49:19
As a matter of fact, the prime treatment is patients with innumerable liver lesions as long as it’s done before it’s too late, meaning the liver is so damaged that the numbers are LFTs, liver function tests are up. But the prime patient is a patient who comes with innumerable liver metastases, never gone into surgery, had their three, four months of chemo. The CEA came down, but now it’s plateauing. How can I further reduce the disease burden? Y-90 radioembolization. Yeah.
Betsy Post 49:52
So for a patient that’s had 50 plus doses of chemo since 2021, colon liver resection. Her liver has a tumor that has not responded to microwave ablation or histotripsy. The last scan showed two small additional subcentimeter lesions, six lung nodules, which they call stable. Would this patient potentially be a candidate? The interventional radiologist at Sloan Kettering thinks so.
Dr. Dayyani 50:20
I would agree with that. The extrahepatic disease, meaning the tumors outside of the liver are stable. And lung nodules are not going to get you in trouble. A couple of half centimeter, one centimeter long, if they’re stable, then the action is in the liver. And based on the description, the treatment would not be actually huge. Maybe they can do radiation segmentectomy and remember, the liver had never seen radiation. These tumors had never seen radiation. So certainly, I think that would be our recommendation as well. I agree with the Sloan colleagues.
Betsy Post 50:55
What size of tumors are ideal for Y-90 are three centimeters and above, too big?
Dr. Dayyani 51:01
No, it’s the opposite. There’s tumors that are too big for surgery or TACE or ablation, anything bigger than the three centimeters too big for ablation, for example. We Y-90 those. But obviously, I’m a medical oncologist, so all of these decisions are done based on tumor port, looking at the actual pictures, location, etc. But there is technically no upper limit for Y-90, whereas there’s upper limit for the other ablative therapies.
Betsy Post 51:27
What is the follow up like to determine whether Y-90 has worked?
Dr. Dayyani 51:32
So that’s a great question. Because you cause inflammation and you kill tumor, your CEA will spike. So we don’t check CEA within the first four weeks, because it really gets freaked out. Radiation works over weeks and weeks. For example, people who have rectal cancer, when they get chemo radiation, we wait six weeks before we see what’s going on. So do not get the scan too soon. Don’t get too excited. There will be some inflammation, the tumor will grow or get a bit bigger from the inflammation before it gets smaller. And sometimes it might not get smaller, but it dies from within – the color changes. So we recommend not getting any scans until six to eight weeks after the Y-90. Sometimes, if the patient is doing well, and the CEA is coming down, and we do a liquid biopsy, it’s coming down where we know it’s responding. We sometimes image them by three months, but in reality, we do it by about eight weeks, six to eight weeks after the second Y-90, not the first. Remember, each lobe is treated separately if needed. We wait till we treat the second time, and then about six to eight weeks after that.
Betsy Post 52:41
How does HER2 positive status affect eligibility for Y-90?
Dr. Dayyani 52:46
Remember I said systemic treatment. You use your best systemic treatment. And in a HER2 overexpressed or mutated, you have an anti-HER2, you shrink the tumor. But even in those cases, at some point you will stop shrinking, and HER2 overexpression is not resistance to gradiation. So you use whatever your biomarker has, the best systemic or biologic treatment for that biomarker, and then when it stops shrinking, where you plateau, that’s where you’re going with radiation. That’s what we think.
Betsy Post 53:18
Great. This is a question we get a lot from our BRAF patients. So how does the BRAF mutation affect eligibility for Y-90 and outcomes?
Betsy Post 53:28
Same answer, same answer. A lot of the BRAFs are very aggressive, right-sided, as you know, very little response to chemo from FOLFOXIRI, Bev. We have encorafinib, cetuximab. But even there, the PFS is, what, four months, five months, right? And the majority of patients, those are the patients that are right-sided where you want to start thinking about radioembolizing in between, or earlier on. So none of these biomarkers is a contraindication or exclusion for Y-90. It’s all about the timing issue, and again, smaller response better. So if you have one of those biomarkers, for sure, I give my patients the targeted treatment first to shrink these and at the smallest size, that’s where I go and radiate to give the extra kick.
Betsy Post 54:17
How many times can Y-90 be performed on a liver if there are recurrences in the liver?
Dr. Dayyani 54:23
That’s a really good point. You can repeat it. The longer the interval, the better, the less the risk of toxicity. There’s, reports of patients who have had five times. In our hands, we usually try to wait 18 months, minimum 12 months or not. Because, we have trials and remember, these patients, my patients only get three months of oxali or irinitecan. So if a tumor is growing after the Y-90 3, 4, 5, 6, months later, I can still give them a little FOLFOX or a little bit of FOLFIRI. I buy them time to remove them. But you can certainly re-challenge patients, as long as the liver function is appropriate and all the criteria I told you, yeah, we certainly, we treat patients as well.
Betsy Post 55:11
I asked my husband’s oncologist, about Y-90, and he said it had a high risk of death, and totally dismissed me. Is there a reason he would be so hesitant?
Dr. Dayyani 55:20
Because they probably never trained with it and never used it. The problem is, medical oncologists are not exposed to Y-90 treatment. That’s something that the interventional radiologist does. So unless the attending you trained with was knowledgeable and using Y-90, you’re a medical oncologist, right? You’ll never heard of it, and you just go by hearsay. The fellows that come through my clinic, when they go into practice, they will think about it differently. I was at MD Anderson, the largest fellowship program in the country, in the world, and I was not exposed to Y-90 until I became junior faculty, started treating GI and worked very closely with our chief of intermission radiology. He said, “hey, we can Y-90” and, I was like, “What are you talking about?”. And then you start doing it, and doing it now, the last 10, 12, years. That’s where I’ve specialized. That’s why. I would definitely get an interventional radiology consult.
Betsy Post 56:15
I love that answer. At what point is Y-90 no longer a viable option?
Dr. Dayyani 56:24
If the patient does not fall within the criteria: performance status, underlying liver function, elevation, bilirubin is too high, or there’s so much disease. Sometimes you wait so long and four years, three, four years. There’s so much disease in the liver that you take a 10 inch tumor and you shrink it by one inch, it’s still a nine inch tumor. That’s too late. Take a one inch tumor and do it. Shrink it down to a quarter inch. Now you changed it significantly, or a patient where the life expectancy is, unfortunately, three months or less because of the disease volume, radiation doesn’t work tomorrow. It takes weeks and weeks to work. So these are the cases, and the problem is, it becomes a self-fulfilling prophecy. I’m sure the colleague that said that, if that colleague sends their patients two months before they’re expired for Y-90 because he wants to do something. But he or he or she went through everything already. That patient has so much disease that even a small shrinkage is not going to change anything, and the liver is so damaged that the patient is more likely to get toxicity. So it becomes a self-fulfilling prophecy. We’ve published our data. We’ve published our data in earlier line of treatment, 42 months median survival. So the problem is, that colleague has never referred a patient who is newly diagnosed after three months for Y-90. So that colleague has never seen the actual tolerability. Try to give it to this same patient who has had 52 rounds of chemotherapy. Now tell that patient, ‘okay, I’m going to give you FOLFIXIRI Bev’, see how that patient will tolerate FOLFOXIRI Bev. Not at all. And then say FOLFOXIRI is toxic. So it’s all about timing, right? That’s what it is. It becomes a self-fulfilling, because we do not train – as medical oncologists, we do not train with radioembolization. That’s a problem.
Betsy Post 58:27
And I have one last question for you. It’s seems that you follow CEA pretty closely for response to treatments. What do you do for individual patients where CEA is not a good marker?
Dr. Dayyani 58:42
20, 30% of patients don’t have a tumor, so don’t have a CEA elevation, or very minimal CEA elevation. So I use a holistic approach, all hands on deck. Every single decision point will help. All my patients get liquid biopsy, tumor-informed or nontumor-informed ctDNA. That’s, especially for those patients, it’s a must for me to to monitor ctDNA. Obviously, imaging, but if I use liquid biopsy and the tumor is responding and the patient looks good, then I don’t even have to do CT scans every six weeks. People just reflectively do scans every six weeks. If I’m knowing the tumor is responding and the patient is doing well, I wait till the ctDNA starts going back up, and then I do my scan, right? So in 2024 for stage four patients, especially if the CEA is not very high to start with, liquid biopsy, to me, is a must. The other thing is they can check CA 19-9. About 15% of the tumors will have CA 19-9 elevation and you can follow with all these old tumor markers, CEA, CA 19-9. The higher you start with, the more reliable as a marker. A patient with a lot of disease and a CEA of 10, that CEA is probably not a very good marker. It’s as bad as someone with 3, but the short answer is, we use circulating tumor DNA and other modalities to monitor response.
Betsy Post 59:28
Thank you. I did get one last question, if your cancer center is not experienced with Y-90, where would you recommend a patient go to look for a Y-90 consult?
Dr. Dayyani 1:00:18
Well, I can give you a list of places, or a first good step is to find an NCI disease cancer center, where you deal with people only CGI. I don’t treat breast cancer, no lymphoma, you know? I refer them, so that’s the first one. But I think asking for an intervention radiology consult, those people will refer you. If they don’t do it, they know who does it in their neighborhood, because they are the ones doing it, and they’re invested in it. Intervention radiology consult seeking that, and they can. I’m not sure who else is from maybe Sirtex is on the call and maybe there might be actually a list of centers that you can access. I know, I know my colleagues. When people come to me I know who were to send them; to Stanford, to UCSF or East coast, or MD Anderson. But not everybody has that. So if you ask for intervention radiologists, they will tell you.
Betsy Post 1:01:18
I do see one last question. This is the last one we’re going to take since we’re over time a little bit, and you’ve been so generous with us this evening. Thank you so much. Would you recommend someone newly diagnosed to seek this treatment out, essentially from the beginning?
Dr. Dayyani 1:01:37
Well, from the beginning to us, means by three months or so of best treatment. Too early does not make sense, because they might not benefit. You need – and part of the reason we give the first three months, the best chemo plus biologic is to kill everything else outside of the liver, but also to kill as much of the colon tumor. So when I’m doing my Y-90, the rest doesn’t go crazy and grow outside of the liver, right? So early to us is about three, three and a half months. Should they be thinking about it? Yeah, if you do your three, three and a half months of your best treatment, and the surgeon says, “I can’t take it out”, seek it out, see an interventional radiologist, ask them to think about radioembolization. The more chemo you get, the more underlying liver damage, the more likely you have toxicity. So early for us is about three, three to four months.
Betsy Post 1:02:32
Thank you. So I’ve learned so much tonight myself, and I’ve run the COLONTOWN groups for liver for years. There’s a lot of thank you’s in the chat for you. People are saying they’ve learned so much that you’ve given a lot of hope to them tonight. I just want to thank you on behalf of all of us here at COLONTOWN. And if there are additional questions, you guys can send those to me. So please just you can send them to me through private message, email me, chat me. Dr. Dayyani also did provide his email address, so we’re happy to take some follow up questions if needed. Thank you all so much for joining us tonight. We really appreciate it and Dr. Dayyani thank you once again. This was fabulous. We really appreciate it all. Thank you everyone. Thank you.
DocTalk
2024
Dr. Dayyani
Liver
Stage IV
Y90
In this DocTalk, Dr. Farshid Dayyani from UCI Chao Family Comprehensive Cancer Center discusses Y90 for liver mets. Recorded in August 2024.
