The Liver, Pancreas, and GI Oncology Update Conference at Wake Forest Baptist Health is designed for general surgeons, medical oncologists, gastroenterologists, radiation oncologists, nurse oncologists, physician assistants and nurse practitioners.
Objectives:
• Discuss regional therapy options for patients with primary and secondary hepatic malignancies (indications and outcomes).
DR. BRIAN KOURI: Many of you might have heard the term interventional oncology, and that's basically the subset of interventional radiology that focuses on these techniques. So when you're talking about liver directed therapies for primary and secondary liver malignancy that we can do in interventional radiology, there's quite an extensive list of different techniques that we can use. As you can see, they're boiled down to two main categories-- there's the ablative therapies and there are the transarterial therapies. I'm going to boil it down even further, because these are the five that you're basically going to see at almost every center in this country. And again, they're split it into two different categories. On the ablative side we have thermal ablation using heat, either with radiofrequency ablation or microwave ablation. Radiofrequency ablation is more common. It's been around longer. However, many centers-- including Wake Forest-- are going over to microwave ablation exclusively because there are many benefits to microwave ablation relative to radiofrequency ablation, which I'll talk about later. As far as transarterial therapies there's three main ones that you'll hear about. There's chemoembolization or conventional chemoembolization, which is referred to often as cTACE. There's drug eluting beads chemoembolization, which is a newer technique. And then there's selective internal radiation therapy, which is commonly referred to as radioembolization. Again, subgrouping these further, if you're looking at why we do these different techniques, ablative techniques are usually used for curative intent and transarterial techniques are usually used for palliative intent. So curative meaning that the type of patient is usually going to be considered for surgery, and palliative are nonsurgical patients. So we'll start with thermal ablation. This is going to be a whirlwind talk, so I'm going to have to go through this very briefly. But this is a pretty simple concept to understand. This, in this diagram, kind of lays it out. Basically, you have a liver here that has a tumor in it, and then using some sort of imaging guidance-- usually either ultrasound or CT or both-- you place your ablation probe into the tumor. When you have it where you want it you turn it on. It ablates the tumor, you take it out, then you have your ablation zone. And-- like surgery-- we're trying to get a margin around this tumor of about one centimeter. And so these patients will come in the morning of the procedure. We do it with general anesthesia at Wake Forest. Some places do it with moderate sedation but we use general. Patients go to day hospital for the day and almost all patients will go home that night. And this is how it works. Basically, all these different devices come with a cookbook where on the right here you can see that if you want a certain ablation zone you basically look at your diagram here and then decide at what wattage and how long you're going to turn your device on. So, for example, if you turn it on for four minutes at 100 watts you'll get 3.6 centimeters in the craniocaudad dimension, and about 4.1 centimeters along the shaft. These are approximate ablation zones but they tend to hold up, particularly with respect to microwave ablation. So, again, what this diagram shows down here is you put your probe in, and the longer that you leave your ablation probe on, the larger of an ablation zone that you're going to get. So the indications for ablation. Again, usually we're doing this with curative intent, meaning we're trying to eradicate all known disease that we can see by imaging. So these are patients that would have gone to surgery based on their disease burden, but for whatever reason are not good surgical candidates. So that's the first thing. Secondly, these are usually patients with small tumors and small tumor burden. And so, in general, regardless of whether you're using radiofrequency ablation or microwave ablation, both of them are going to work best with tumors that are three centimeters in diameter or less. Once you get above three centimeters the predictability of getting an adequate ablation zone starts to decline. So three to five centimeters is a gray zone where many people will still treat with ablation, but greater than five centimeters these patients really aren't good ablation candidates. And also the patient typically needs to have a limited disease burden. If the patient has eight different tumors it's unlikely you're going to be able to treat that successfully by sticking eight different ablation probes in. So most institutions use a rule where they'll do ablation on three tumors or less. So this is a typical case that we've done at Wake Forest. So this was a 72 year old female with metastatic colon cancer. She had a single met. She was a nonsurgical candidate. So she has this tumor back in the right lobe of the liver. It's a little bit larger than three centimeters but we decided to go ahead and try ablation on it first. And so here's what it looked like by CT before the procedure. This is what the ultrasound looked like. And so I typically do these procedures on a CT table with ultrasound so I can place my probe using real-time ultrasound guidance, as well as confirming it with a CT. And so this is what those images look like. We have the probe going into the tumor here. I confirm it with CT. Do the ablation. Do an immediate post-ablation scan. And this shows us that we've got a good margin. So this is the typical microwave ablation case. So when you look at outcomes for ablation it's generally compared to surgery, because surgery is the gold standard for this population. The results of the very many trials that have looked at this basically show an overall trend-- or overall acceptance-- that currently the thought is that surgery is going to lead to a better overall survival, as well as a lower risk of recurrence for this patient population, particularly patients that have tumors greater than three centimeters. At the same time, these studies also generally show that ablation has significantly less morbidity, shorter hospital stay, much quicker recovery, and less cost. And so where that leaves us is are these studies really showing us exactly a head to head comparison? And so many of the studies are significantly limited. Almost all of them that are out there are retrospective in their subject to selection bias. Usually the candidates getting ablation are nonsurgical candidates. So it's hard to really know if this is a true head to head comparison. Secondly, almost all of these studies are with radiofrequency ablation, not microwave ablation. Microwave ablation has been around commonly now for several years. It's got many advantages over radiofrequency ablation. It's hotter. It's more predictable what ablation zone you're going to get. And so it's likely that it may have better outcomes. In the future, as the focus goes more towards value-based healthcare, ablation may begin to play a bigger role. Predominately in patients with tumor size less than three centimeters. So we'll just have to see where that goes. At the very least, we may finally be able to get some good studies or head to head perspective. So moving on to transarterial therapies there's basically three main types of transarterial therapies that you'll see. There's chemoembolization, and that's subdivided into conventional chemoembolization and drug eluting beads chemoembolization. Conventional chemoembolization is often referred to as cTACE and drug eluting beads chemoembolization is often referred to as DEB-TACE. And then there's selective internal radiation therapy, which is referred to as radioembolization. So-- real briefly-- all of these to the external eye look like very similar therapies. In all of them you place a catheter usually in the right common femoral artery here, advance it under x-ray guidance up into the liver, and then once you have the catheter in the artery supplying the tumors that you want to treat-- depending on what therapy you're using-- you infuse something. And so with chemoembolization-- this has been around the longest-- you infuse a mixture of chemotherapy and something called lipiodol, which is basically a poppy seed oil which acts as your contrast agent to see where the chemotherapy is going. Once you've injected your chemotherapy mixture then you inject particles behind it to embolize or occlude the vessel. So you're treating that tumor with both cytotoxic chemotherapy as well as ischemic necrosis. Drug eluting beads chemoembolization is a new iteration of this that's been around now for about 10 years. And basically, instead of having a two-part injection you're taking your chemotherapy and you're impregnating that onto the beads and just doing one single injection where you're injecting beads with the chemotherapy impregnated on it. The thought behind drug eluting beads chemoembolization is that the chemotherapy then elutes off of those beads over the course of the next days to weeks. So you get a much higher and longer exposure to chemotherapy locally to the tumor, in a much lower serum plasma level. So the result being is that many patients will tolerate this procedure better than conventional chemoembolization. And, lastly, there's radioembolization, which is really a misnomer. Embolization means blocking off blood vessels. With the radioembolization you're injecting microscopic particles that emit beta radiation but your goal is not to embolize anything. These particles are a tenth of the size of the particles that you use with chemoembolization so they're really not embolic at all. Really what this is is transcatheter micro brachytherapy. That's how you're treating tumors with this. So the goals of care with transarterial therapies is typically a totally different population than with ablation. These patients typically have more extensive disease in the liver, they're nonsurgical, and that your goals are basically palliation. And so, in general, it's thought that with both primary and secondary liver malignancy the main determinant of overall survival in the majority of patients is going to be overall liver tumor burden. So our goal with these treatments is to try and prolong survival by controlling that tumor burden as long as possible. In some cases we also do this to maximize quality of life by treating symptoms. So with a patient that has symptomatic neuroendocrine cancer these types of treatments can help them with their symptoms and reduce the dose of sandostatin that they may need. In some situations we're able to actually downstage patients to a curative therapy-- either surgery or transplant-- and every now and then we'll actually get total eradication of the disease and actually get a cure, meaning that we've eradicated their disease that we see. OK. Indications for transarterial therapy. So right now it's for primary or secondary liver malignancy that's unable to be treated by surgery or ablation. The main tumor types that we use this with are hepatocellular carcinoma, metastatic colorectal, and metastatic neuroendocrine. We use it with other tumor types but these are the main three by far. Secondly, these patients need to have liver dominant diseases. So the way that that's typically defined is, first of all, there's liver-only disease, where these patients only have disease in the liver. And then there's this category of liver dominant, which is loosely defined and somewhat subjective. And what that basically means is that it's thought that the hepatic component of the overall liver tumor burden is the vast majority. So that's the most likely to contribute to the patient's morbidity and mortality. So if the patient has a bunch of liver tumors and a single lung nodule, or a couple retroperitoneal nodes, these are patients that we're still going to treat with these techniques. And then, lastly, we use these techniques when systemic therapy's either not an option or not a good option. So in hepatocellular carcinoma or neuroendocrine cancer there's not a lot of great systemic therapy options. So this is more of a first line treatment for those patients. Or we use this treatment when it will enhance systemic chemotherapy. And so either in the salvage setting or-- as I'm going to talk about in more detail later with the SIRFLOX trial-- it can enhance systemic therapy earlier in the therapy process. Now, I've talked about these three different techniques that we use, and the first question is which one do you use for which indication? And that's a very complex answer, which these are the factors that I look at when I see patients in my clinic and talk to them about all their various options. So clearly I can't get into why I would use one versus the other, but the main point being is that there's lots of different factors that go into it. So here. This is a typical case using conventional chemoembolization. So this is a patient had a 3.4 centimeter mass, imaging diagnostic of hepatocellular carcinoma, and was a non-surgical candidate. So 3 1/2 centimeters is a little bit bigger than what we typically like to try with ablation. This is in kind of a tough spot for ablation. So we decided to go ahead and treat it with chemoembolization first. And this is what a chemoembolization procedure looks like. We have our catheter here, the tips and the common hepatic artery. I do my first angiogram and it shows the hypervascular mass in the right lobe of the liver. I get my microcatheter all the way out to the main feeding vessel of this tumor. At this point I've already injected the mixture of doxorubicin with lipiodol and then I follow that with bland embolization. So this is actually a static image showing all of these vessels are now occluded, with the tumor taking up the majority of the lipiodol. When we're done with this procedure they go and have a non-contrast CT scan immediately afterwards to confirm the location of the deposition of our chemotherapy mix. And so this is what it looks like. Lipiodol is a very radio-opaque agent, so this shows that we've got it concentrated predominantly in the right lobe of the liver and the tumor has really taken up the majority of it. So this is what we want to see. And, sure enough, this patient has been followed now for two years with serial MRI, and at two years he still has no evidence of any residual viable tumor there. This is a radioembolization case. This is a patient that had metastatic colon cancer that had progressed through two lines of therapy. Was a K-ras mutant. So it was basically in a salvage setting. Had bilateral tumors. This is the left side that we treated. Had a very large left lobe tumor here. I injected the radioactive particles. After we're done with that procedure they go immediately down to nuclear medicine and we get a SPECT scan to confirm location of where the particles are. And this is her follow-up MRI three months later. So very nice response there. Sometimes we'll combine these techniques. And so in this situation we had a hepatocellular carcinoma. The tumor was about 4 1/2 centimeters, so definitely too large for ablation by itself. Again, that's in kind of a tough spot. So we did the chemoembolization first, and here's our angiogram showing the main feed vessel, this hypervascular tumor. Went down, got the CT afterwards. Had good uptake in this tumor, but as you'll see there's a chunk that's kind of missing right there. So we get the follow-up MRI about a month later and it shows there's still viable tumor right there. So this is a patient that we would then take and then we would do an ablation on to clean up any margins that we feel that we need. So this is one of the images from that case. And this is just getting this margin. I basically did the ablation where I put the probe here, a blade here, ablate the tumor, and reposition the probe and ablate this margin also just to make sure that we get everything. And this is the post-MRI ablation about a month later. And this was a separate tumor that we had treated in a different session. OK, so where do these treatments fit into various treatment algorithms? Most of you are probably familiar with the BCLC algorithm. And so as we see here on the left these are patients that are going to have low volume tumor burden and well-maintained liver function. And these are going to fall into the curative treatments-- usually either resection or transplant-- and if they don't qualify for those then ablation. In the middle here is where we typically use our transarterial therapy. So these are going to be the intermediate stage patients that have more tumor burden. And we'll treat them with either chemoembolization or radioembolization. And as they progress they may go on to sorafenib and then ultimately just best supportive care. When you talk about outcomes, there's a lot of different studies out there. I'll just summarizes them. Basically, if you look at all of them, there's a surprisingly consistent median overall survival. And basically the conclusion is that for all of these techniques with hepatocellular carcinoma the median overall survival is going to be about 20 to 24 months. This compares with about 11 to 12 months for sorafenib and about seven to eight months for best supportive care. And the interesting thing is that nobody has been able to show any significant survival advantage comparing radioembolization to chemoembolization. There's one trial that shows, potentially, drug eluting beads chemoembolization is slightly more effective than conventional chemoembolization in advanced disease, but in general nobody has really shown that one of these is better than the other as far as overall survival. What most people would agree, and what most studies show is that radioembolization and drug eluting beads chemoembolization is much better tolerated than conventional chemoembolization. With radioembolization and drug eluting beads chemoembolization the majority of these patients come in, have the procedure, stay in day hospital that day, and go home that night. They may have a little bit of nausea, a little bit of pain for the next couple days, may have some fatigue, and that's usually about it. With chemoembolization they'll typically have some more pain, a little bit more nausea. I typically keep all those patients overnight for one night just to manage their symptoms, but almost all of them go home the next day as well. This is the NCCN guidelines for unresectable metastatic colorectal cancer. This is obviously a very complex algorithm. I'll boil it down. I'm not an oncologist, so I understand there's a lot of nuance to it that I'm leaving out here. But, just to simplify it, most patients with unresectable metastatic colon cancer to the liver are going to be treated with something like this, where first line they're going to get a combination chemotherapy, plus or minus a biological agent-- typically avastin. Once they progress on that we typically switch to the other combination chemotherapy. May add avastin if they didn't get it before. May continue avastin. Once they progress on that, if they are-- depending on their RAS status, they may go on to have a biological agent like cetuximab. Once they progress on that then they're left with regorafenib or the new TAS-102. Where we are currently with transarterial therapies is usually radioembolization and drug eluting beads chemoembolization with Irinotecan-- and otherwise known as DEBIRI-- is usually saved for the salvage setting. And so this is a table showing all the various studies out there, showing radioembolization's effect on overall survival in the salvage setting. And this compares with best supportive care here, and it looks at regorafenib here, and some of the anti-EGFR agents here. And so what this shows is that there's many studies that have shown that radioembolization currently has a very significant and beneficial impact in the salvage setting, particularly compared with systemic chemotherapy. And what's interesting about where we're going now-- I'm going to finish by talking about the SIRFLOX trial. Many of you may have heard of this-- is this is the first really large prospective randomized control trial that we've conducted for radioembolization in the first line setting for metastatic colorectal cancer. It's not the only trial. There's three trials currently ongoing. They're all going to conclude in 2017. And when they're combined we're going to have a total number of patients of 1,100. The first results from SIRFLOX were reported to ASCO in June. What they did was they took over 500 patients and prospectively randomized them into two different arms. One was standard FOLFOX with avastin, depending on whether the oncologist wanted to use avastin or not. And the other was SIR-Spheres used in the first cycle-- three days after the first cycle-- with a modified regimen of FOLFOX, meaning they reduced the oxaliplatin dose somewhat for the first three cycles, then took it back to the full dose at the fourth cycle. And they held avastin until the fourth cycle. So essentially fairly similar regimens. Here's the randomization. Definitely very good randomization. What I do want to point out here is that 40% of both patient populations had extrahepatic mets. So this is a pretty aggressive tumor population that you're looking at. In addition, 90% of them had synchronous mets. So these were not the good biology type patients that we usually think about. They looked at toxicities of 40, 80, and 120 patients. All of them, they didn't find any significant toxicity difference. And when you look at the data they reported so far, really the only main difference is that there's a little bit more neutropenia in the radioembolization arm, but it wasn't that significant clinically. Some of the complication rates that they talk about here with the radioembolization arm are actually higher than what's usually reported. The thought behind that is this trial's been going on for about seven years and some of these complication rates were early on, before the technique has been modified and actually improved. The main results of this trial so far that we've seen are-- number one-- the objective response rate for the radioembolization arm is significantly higher. Not to mention the fact that the complete response rate is three times that of just FOLFOX alone. The most important result that we've seen so far, though, is that the medium progression-free survival in the liver is significantly greater in the radioembolization arm by about eight months. So the main points we take away from SIRFLOX is that when you add radioembolization to first line induction chemotherapy with FOLFOX it's safe, it's well-tolerated, it didn't reduce the ability of any of these patients to have the full duration of standard chemo. It significantly increased their response rate, tripled their complete response rate, and adds an additional eight months of progression-free survival in the liver. These are all significant results. And so the question I would have is, if a drug came out tomorrow that had the same profile-- it was safe and well-tolerated and gave you all these benefits-- that would be implemented pretty quickly to standard care, I would think. So where we're looking at placing radioembolization, potentially, as the data comes out. The top line here is currently where we're at. Usually, like I said, we have our first line chemotherapy. Once they've progressed we go to second line, eventually third line salvage. And somewhere around here is where I come in and do radioembolization, usually. What the data from this trial definitely supports-- if not definitively yet, but once we have overall survival data in 2017-- this is where we're kind of looking at going. And so, currently, this could either be used in a situation where, after induction, patient gets to a point where they can't tolerate oxaliplatin and now they're on maintenance until they progress. That's likely where radioembolization is going to see its biggest benefit right now-- by giving eight months of additional progression-free survival. Potentially in some patients that are too frail to have FOLFOX and may not be able to tolerate full combination chemotherapy this could be given first line with induction. And, again, this is a table kind of showing where we think this is going to go. And so these are all the various trials here. This is FOLFOX. This is FOLFOXiri, which currently seems like the best combination therapy as far as overall survival. And this is where we think combination chemo-radioembolization is going to go. So, lastly, the promise of all these techniques that we use is that they're very effective direct treatments of liver malignancy with low systemic toxicity. Ablation is a particularly good option for a very low volume hepatic disease in nonsurgical patients. It may become a more widespread option as value-based healthcare becomes more of a focus. Transarterial therapies add meaningful survival with low toxicity, and radioembolization, in particular, is where this field's going, particularly with respect to metastatic colon cancer. So thank you. [APPLAUSE]
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