The Role of Locoregional and Systemic Therapies in the Management of Colorectal Liver Metastases
Somewhere around 50 percent of patients with colon cancer spread to the liver cannot be treated surgically. The hepatic artery pump is a highly effective way to get them to a point where they can undergo surgery,” says
Jason Castellanos, MD, assistant professor, Fox Chase Department of Surgical Oncology.
In this video, Dr. Castellanos explains the role of surgical resection in the management of liver-confined metastatic colorectal cancer and using hepatic artery infusion pump (HAIP) chemotherapy for treating resectable and unresectable colorectal liver metastases.
Epidemiology of Colorectal Liver Metastases (CRLM)
Role of Liver Resection for CRLM
HAIP for Unresectable CRLM
HAIP for Adjuvant Therapy
All right, good morning. My name is Doctor Jason Castellanos. I'm an assistant professor of surgical oncology, specializing in Hepatobiliary surgical oncology at Fox Chase Cancer Center. Um It's my pleasure to talk to you about the role of local regional and systemic therapies in the management of colorectal liver metastases. And we'll kind of break down different paradigms as we go through the talk. Just so as we start, I want to let you know, I have no disclosures and there was no commercial support associated with this activity, our learning objectives uh at the conclusion of this activity, um hoping that you'll be able to understand the role of reception in the management of liver confined metastatic colorectal cancer, as well as the role of hepatic r infusion pump chemotherapy for the treatment of both resectable and unreceptable colorectal liver metastases. We'll talk about the epidemiology briefly of chore mets, the role of liver resection, hepatic art vision chemotherapy for unresectable and then also as an adjument therapy for colorectal uh liver Mets. So this is a very common problem in the US as well as worldwide with 100 and 50,000 estimated new cases and 53,000 deaths per year. Uh in the year 2020 about 50 to 60% of these patients develop liver metastases with 15 to 25% of them presenting at the time of initial presentation. And the rest developing metachronous uh metastases later on. Half of these patients with metastatic disease are isolated to the liver. But the majority of these about 78% are unresectable at the time of presentation. We know from prior studies and natural histories that the outcome of untreated colorectal liver metastases is dismal with the immediate overall survival benefit of assuming overall survival of 5 to 10 months. But you know, starting in the nineties and into the two thousands, we learned that resection of these patients was not only feasible but beneficial. Uh This survey is uh data from an international consortium uh of 25,000 patients across 71 countries and they compare patients who either had resection of liver metasis. Uh You'll see that in the red line or those who did not have resection and you'll see that at five years of survival is vastly different. 42% versus 9% and with 25% long term survivors at 10 years versus none in the non sect cohort. So, liver section is a very important part of a curative intent uh therapy for these patients. This has been driven by successive technical advances in the treatment of all liver malignancies, but in particular, colorectal liver metastases in the 19 eighties. The paradigm was that liver metastases from colorectal cancer, no matter how small or isolated were not operable. This was a mark of bad prognosis. Then they started to come out. There was some reports of long term survivors as the field of research advanced in the nineties and two thousands resection criteria were broadened as understanding of what was feasible, surge broadened as well. In the 2020 tens, uh advanced techniques became popular such as non an atomic or sections or we sections using portal embolization to accomplish two stage hypert ab and then there's been a resurgence of interest in hepatic art in and pump chemotherapy as well. Defining resectable chore liver metastases is AAA matter of both anatomy and oncology. Uh from an an atomic standpoint, the liver is eight separate segments. And so you've gotta be able to maintain an adequate amount of liver like 30 to 40% in a patient uh for them to have adequate liver function after a resection in any bill do that by preserving negative margins, drainage and vascular inflow and outflow. From an oncology perspective. There are some sites of extra pac disease that are not amenable to curative resection, such as retrain lymph nodes and things like that. But some sites like lungs and ovaries have prognoses that are better. And so liver rec section can be entertained and while not curative intent, uh can prolong life significantly some have suggested a biologic indication such as the number of tumors or the ce a level, uh which are both associated with worse overall survival. But again, it all really comes down to uh the anatomical and technical components. Uh when those patients who are liver confined, the risk of recurrence is high. However, after a liver recession, with 50 to 75% of patients recurring at a median time of uh a year and a half to two years. And so this is why chemotherapy is typically used in conjunction with this therapy. 43% of those patients will recur only in the liver and we can sometimes resect a blade or radiate these metastases. Uh and then 21% will have a combined intra and extra paic recurrence. We can stratify the risk of recurrence upfront using a number of different memo grams, but nothing really seems to do better than the score uh published in 1998 nine. This is a pretty simple heuristic that you can do with all the the modalities you've you've done to stage these patients. Is there no uh positive disease in their primary tumor? Have they had synchronous disease or a disease for, you know, at least one year or not. Is there more than one tumor? Uh is the largest tumor greater than five centimeters, is a ce a greater than 200. And based on the number of factors you said yes to you have either a low risk if this score is 0 to 2 or a higher risk, if it's 3 to 5. And we can see in the figure here, the blue line is the high risk score and the black line is the lowest score is a Kale Myer curve showing years from resection and the proportion surviving. And so we see a significantly better survival percentage in those patients with a low clinical risk score. Although there are still long term survivors and those with higher clinical risk score, you also will notice that there is a leveling off of the survival of 10 years. And so this is what we typically think of as our threshold for cure those patients who can make it to 10 years without recurrence disease. Uh We don't really see recurrence beyond that point. I'll move on to our next portion of our talk, which is about hepatic arty infusion pump chemotherapy for unresectable coral direct the liver metastases. Then we'll talk about adjuvant chemotherapy uh with a pump. This is Doctor Nancy Kenny, who's at Memorial Sloan Kettering and has been one of the pioneers in stalwarts in this field. Uh And here's a little visual depiction of uh what hepatic artery infusion pump chemotherapy entails. There's a pump that's implanted, subcutaneously and a catheter that's guided into the abdomen and implanted into the gastro artery to still chemotherapy directly into the liver salt. Explain why that makes sense as a strategy and what the data behind it is. We've got a number of different local regional therapies for unresectable colorectal liver metastases. And so it can be quite overwhelming. And I guess this is another slide is emphasizing the importance of having a liver surgeon or someone dedicated to battle be surgical oncology involved in the care of these patients because there are a lot of things we can do that other practitioners may not be aware of from a technical standpoint. There are two stage hypert toy or Permal preservation strategy of wedge resections. Increasingly there's been interest in liver transplant for select patients after selection. And then there's a blade of approaches, either with microwave ablation or with radiation, which is increasingly able to target small lesions in a very focal way from a vascular perspective. Uh Studies have looked at the use of trans Artal chemo and radio embolization. But I think a lot of the the data will go through. That's compelling comes from the data looking at hepatic arterial infusion pump chemotherapy. So colorectal liver metastases are interesting because they the liver is the main site of spread for colon cancer. And while the normal liver is perfused mainly by the portal vein, these metasis are mainly perfused by the artery. So you can take advantage of that fact because you have a direct conduit there. You have an uh an artery here, the gastro duodenal artery which can be used to place that catheter to go directly into the liver and then you have a drug, uh floxuridine, which is very effective against these tumors, but also almost completely metabolized liver that allows you to increase the dose almost 400 times while eliminating any systemic toxicity. There are side effects which we'll talk about. But in disease with liver may be the solitary side of disease uh beyond the primary, the ability to target the liver aggressively with an effective therapy makes a lot of sense. So this isn't a new thing. It's a little quote from Ecclesiastes, but you know, this has been defined and refined since the 19 fifties. That's when the ANTO basis came out of basic science studies and animal models. The actual pump was developed in the 19 seventies. The pharmacology defined in the 19 eighties and pump chemotherapy had been has been going since that point in the nineties, it was abandoned by many centers with the advent of Full Fox and Full Fury. But as we understand the limitations of those therapies and the curative intent treatment of these patients and also in the face of logistical challenges and pump uh program management, uh toxicity and morbidity of of pump placement and the FUDR. Uh there's been a renewed interest given the advances in management of these patients. And uh I think that's also born up by the data. So Floxuridine is a permit analog similar to five FU is to TAB 25 FU in the liver, but the liver metabolizes it about 94 to 99% of that during the first pass. And so you can see the ability to dose this with five fu if you give it directly to the liver, you could increase the dose 5 to 10 fold. But with FUDR, you can increase the dose 100 to 400 fold. And that's done very carefully with a medical oncologist. Um We look at the liver enzymes very carefully every two weeks. And if there's any elevations, there's an mammogram to reduce the dose or hold a dose. The main worry we have is inducing biliary sclerosis and that incidence was as high as 20% of the studies. We've learned a lot about how to limit that both with dose reduction or dose cessation and also giving dexamethasone concurrently with the pr in fusion pump chemotherapy. The current risk is about 2 to 5%. Now that dexamethasone is now routinely given and these patients cannot get bevacizumab because that also potentiates uh the biliary sclerosis risk from a technical complication standpoint during the operation. Uh There's a general operative morbidity in the literature, about 20% issues that may arise or extra hepatic perfusion. So we need to make sure that this thing is only infusing into the liver, it can perfuse the duodenum, the pancreas or the stomach or even the diaphragm on certain occasions if you're not careful about arterial dissection. And so if those issues aren't, are not an or they can present problems with dosing and require ir to help uh with embolization. Later on, you also worry about incomplete hepatic perfusion. So if there's accessory vessels, so those need to be ligated, so that the liver gets the chemotherapy on both sides, ulcers as part of the extra pedic perfusion. Long term, you worry about arterial catheter problems. And so early on, they can thrombose later on, they can also thrombose and they can erode into adjacent structures like the duodenum and with any uh vascular operation or any operation with a uh implantable device, you worry about infection and hemorrhage. Early complications are mostly sal salvageable such as bleeding or extract perfusion. But thrombosis tends to not be salvageable. Late complications are rarely salvageable with about only 30% able to save the pump. So the the pump is inserted into the gastro artery directly during an operation. This requires a dissection of the port of hepatis, making sure there are no accessory vessels and then the pump is in uh placed in the subcutaneous space during the operation. We instill methylene blue into the pump directly to see that it perfuse the liver on both sides and that it doesn't perfuse the stomach or the duodenum or the pancreas. If we see sites of extra paic perfusion, we'll continue dissection to eliminate those blood vessels. If there's perfusion from accessory vessels, we often ligate them and the liver is able to handle that through cross perfusion at the, the level of high. The pump is an interesting uh mechanism. It's, there's no mechanical parts. It uh is a basically a size of a hockey puck and it has a reservoir here with bellows. And so there's a central uh fill site just like a port where you insert a needle and it fills its bellows and it increases the volume and it expands and can hold 30 CCS. And the way it runs is that the chamber is uh surrounded by Freon. And so that Freon is compressed when it's uh under uh when the reservoirs full, and then the patient's body heat slowly uh gives energy to the Freon to squeeze the bellows at a predefined rate. Uh That's calibrated at the factory. It's usually 1.2 to 1.4 mils per day. And so dosing is determined by that. And so, while dosing is on a two week, on two week off basis, when uh patients are treated, the pumps gotta be filled with 30 mL of the uh the, the treatment or with the fill uh in between uh treatments, they're filled with Heer and Saline. Um, patients are bound to, you know, duty bound to come back to the clinic every two weeks while they're on active treatment. But when they're not on active treatment, they can come back every two months if we fill it with something called glycerin, which is a more viscous fluid that runs slower and is able to keep the catheter open. This is a very logistically involved and multidisciplinary treatment. It involves pretty much everybody involved with outpatient oncology. I'll just walk you through the flow of a patient to give you a sense that uh that, that burden uh in addition to a surgical consultation, these patients need a dedicated medical oncologist who is familiar with pump chemotherapy. We need special radiologic scans, thin cut CTAs. We need close collaboration with nuclear medicine as we need to do a flow study after pump implantation to verify lack of extra paic perfusion. There have been shortages of FUDR in the past although that's better now that supply has been integrated with the company that makes the pump when we get to surgery. After multidisciplinary consultation, agreement on the plan, patients are generally in the hospital for five days. Uh There are some centers who do uh robotic pumps routinely and those patients can leave earlier. Uh the or needs the equipment, the circulators and scrubs and need to be familiar with the pump uh placement in the pump device. We typically have a rep in house as well to help us with that. The or pharmacy needs to be involved as well as there are a lot of different pills and things like that to, to get in the time of or implantation and then the infusion needs to be involved because they'll have to empty and refill the pump before the patients go home. Interven interventional radiology has also got to be aware of these devices because if there are any complications such as extra paic perfusion or concerns about malperfusion, they need to be able to help us troubleshoot that. But once we get them through the inpatient hospitalization course, they get a pump study. So in nuclear medicine, the pump is accessed and filled. Uh excuse me, not filled. But um uh the an angiogram is performed through uh the pump using a special needle to insert ra labeled albu through the pump to make sure it doesn't perfuse the stomach through DM pancreas or any other structure. It only perfuse the liver and then it goes to both sides of the liver. After that, they're generally on treatment for about six months, sometimes indefinitely if they have active disease, uh that's not recyclable uh treatments on a two week, on two week off basis. So on day zero, they would get FUDR plus heparin saline index. After 14 days, they would come back, the pump would be emptied, it would be filled with heparin and saline dexamethasone. If the LFTs were elevated, this involves close coordination with the infusion Center oncology clinic and then pharmacy and triage as well just in case there are issues and this can happen indefinitely. And then, as I mentioned, glycerin can be used to fill pumps that are inactive and this lasts six weeks to eight weeks in general and gives them a little uh longer leash between um hospital visits. And especially if it's for advent therapy and then pumps are typically kept in, they can be removed after two years of uh survival, no progression or uh recurrence if patients desire. Uh but uh some patients are happy with being left in with little to no maintenance, contra indication, septic arty infusion pump chemotherapy. The main one is disease. Although that can be relative depending on the low burden of lung meds or if we talked about ovarian metastases, uh liver insufficiency and I are a big contra indication. We don't want to flip a patient into liver failure, don't want to put them through an operation. If they can't tolerate it, some patients will have too much tumor burden over 70% and then we worry about flipping them into liver failure as well. A po vain thrombosis is also a contradict. Primary sclerosing colonitis is a contradict because it's, it'll be hard to define if they have sclerosis from that preexisting condition or the pump chemotherapy and the pump chemotherapy may potentiate um Delio sclerosis. Prior radiation is a relative contradict, especially in the era of focused SP RT. Uh But that's a situation where we'll be very careful, especially in a patient who's gotten y 90 prior. And finally, the patients got have feasible arterial anatomy. So there are many arterial variants, but almost all are workable. Uh and some will require vascular uh standby for conduits and things like that. So how does this do? Uh I think the first interesting uh question is what proportion of unreceptable patients? Does this therapy with chemotherapy convert to reception? This is a trial done by Doctor Dalia. One of my mentors from Moral Slum Kettering. Uh historical conversion rates of chemotherapy alone have been 15%. But retrospective data from Memorial Slum Kettering where this uh treatment has been pioneered and uh implemented for many decades. So their rate of about 47%. So the doctor Dali and his team took patients with unresectable core, the liver metastases. After first line therapy, they uh took them to um operation for uh implantation of pa art in pump. Um with chemotherapy initially, they used bevacizumab. But after uh the 1st 24 patients noticed uh that there was tremendously abu toxicity. So that was removed and now its contra indicated the treatment of these patients. Uh And so the patients got hepatic Art infusion pump chemotherapy with FUDR and also Leuco plus systemic therapy. The primary outcome of this study was the conversion of resection. And what they found was uh about a 50% conversion to re respectability meshing with the uh retrospective data. And also in those patients who were able to get to reception within one year, their survival rate at five years was over 50%. And so very promising uh therapy for those patients. How about patients with receptible disease. I talked earlier about the resection rate. Uh excuse me, the recurrence rate being 50 to 75%. So obviously, we want to do things to minimize that recurrence rate. And so if recurrence rate is high and it's predominantly in liver, why not treat the liver uh aggressively? And so this is a trial done by Doctor Ky in 1999 looking at those patients who are status postle recession of all their liver metastases receiving pump chemotherapy with five FE, which was the standard at that time with five FU alone. And their primary outcome was to your overall survival. And what they found was that if we looked at hepatic progression free survival, so lack of recurrence in the liver plump plus chemotherapy patients did much better over the course of five years, almost to 10 years with a uh hepatic progression free survival rate over 70%. Whereas those with +55 FU alone were just a little less than 50%. But what you'd expect from based on historical rates, overall progression free survival, it was also improved, although not as dramatic. And so we see, you know, the pump is very effective in the liver. But other sites do uh present a challenge. But still the combination of pump chemotherapy and um uh systemic chemotherapy was better than systemic chemotherapy alone in terms of five FU. And finally, overall survival was improved at two years. Uh 86% versus 72%. So admin treatment with a combination of a tic arterial infusion flux and uh intravenous five if you improve survival of two years, uh statistically significantly, this is a treatment that's now being implemented across the nation and across the world. This slide is already outdated from when I put it together a few months ago and it'll probably be outdated by the time you see this slide. Um But there are centers across the US and uh with a high concentration in the northeast, but also in Canada, in Toronto and the Netherlands. Um And so we now have an international consortium to help guide this treatment. And that's led to a trial. Uh That's gonna be starting pretty soon with the Eco Akron in looking at those patients with unreceptable chore metastases and specifically comparing hepatic artery infusion with modern chemotherapy to modern chemotherapy alone. So, we're very excited about this trial. Uh One thing to note is that uh in this trial, we are gonna be able to consider those patients with five or fewer small pulmonary nodules. And so this often comes up as an issue. Um You know, the patient may be liver limited, but they may have some small pulmonary nodules concerning for metastases or not, concerning for metastases. Uh So those patients will also be able to be included. Uh So in summary, hepatic art infusion pump chemotherapy and systemic chemotherapy, improved conversion to respectability, adjument, hepatic a pump chemotherapy plus systemic therapy improves intra paic recurrence free survival and is associated with improved overall survival. And I think hopefully I've hammered home, the fact that multidisciplinary care is key to optimizing the outcomes and and management of color deliver METS. So while this therapy may not be implemented in every single center, we hope that you're nearest center that is able to offer this because I think it's a very important tool uh to help these patients live as long as they can hopefully beat their disease. Uh A lot of acknowledgements, we have a huge team here at uh both Temple and Fox Chase. And uh and the folks at Memorial and Duke have been tremendously helpful in getting our program start up as well. So all that uh I'll end my talk and thanks so much.