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HAI for metastatic CRC: Dr. Connell

Doc Talks

In DocTalk, Dr. Louise Connell from Memorial Sloan Kettering discusses HAI for metastatic CRC with Betsy Post. Recorded in January, 2024.

Betsy Post 00:01
Welcome, everyone. Thank you so much for joining us this evening for our latest DocTalk. I’m so pleased tonight to be with us here for our COLONTOWN DocTalk. Dr. Louise Connell from Memorial Sloan Kettering Cancer Center. Dr. Connell, I think is very well known in COLONTOWN. So if you’ve been around for a while, you definitely know her name. If you are familiar with liver Mets, and especially if you’re interested in the hepatic pump, I know that you definitely have seen her name. And our groups such as Liver Lovers Lane and HAI Pump People, I’m sure that we have some of her patients here tonight to support her as well. So we are so thankful for your time, Dr. Connell, especially for doing this after hours so that we could get maximum participation from our patients and our caregivers. So thank you, again, for agreeing to do this, we’re really excited to hear from you on how you treat patients specifically with the pump. I know that you have some things about the future about the pump, which is really exciting. I’m very excited to hear that. And then we did have patients and caregivers submit questions in advance. So we will get to those questions at the end of Dr. Connell’s presentation. So at the end of her talk, she will, we’re going to do some Q&A based on some questions that we received in advance. As she is presenting, we would ask that you please stay muted so that we can make sure we’re being respectful of her presentation her time, but do put your questions in the chat. So please do use the chat feature to submit your questions. And we will get to those live questions at the end of the presentation and the pre-submitted Q&A. So with that again, Dr. Connell, thank you so much for being here. The floor is yours.

Dr. Connell 01:55
Okay, thank you, Betsy. And first of all, I just want to say thank you very much for the invitation to speak here tonight to you all. COLONTOWN is is a resource that I hear so much about from my patients, and a platform that I think provides so many of you with information that you bring to the clinic, to advocate for yourselves and to, you know, advance your care. And I think, you know, it’s been such an important resource that, you know, if there’s any way that I can help provide additional information, particularly about the liver pump. This is an honor to be asked to do this. So tonight, my slides section is small on purpose, because I really wanted to give you all an opportunity to ask questions. And I would encourage you to submit any questions that you have for me. I did just want to provide some background on you know where we are today, today in terms of metastatic colorectal cancer treatments, and in particular, the role for HAI therapy. I think many of you already know much of this information. But in particular, for patients and caregivers who perhaps are new to this or maybe considering a pump, I did want to provide just some background slides on the pump treatment.

Dr. Connell 03:15
I’m going to just advance my slides here. So first of all, I just wanted to put up this disclaimer to acknowledge some of my consulting work. But truly the presentation today is purely for informational and educational purposes. And it’s really based on my clinical experience with patients and my knowledge in terms of pump management.

Dr. Connell 04:16
And at diagnosis, we see approximately 20% up to a third of patients will have liver Mets at diagnosis whereas the majority of patients will go on to develop liver metastatic disease during their follow-up. The question is what are our treatment options nowadays for metastatic colorectal cancer and, I’ll just briefly run through this on this slide on the next slide. But essentially we have or our cornerstone standard of care chemotherapy treatments, and we combine these drugs with biologics. I think increasingly we’re hearing about biomarker-driven approaches and I’ve highlighted here are the four key targets that we look for in patients who are newly diagnosed being microsatellite status. Their RAS status, BRAF status and HER2 status. 

Dr. Connell 05:00
And, of course, you know what I think I’ve always in patients because of the work that I do is the role for local regional approaches and particularly in patients who have liver only disease or liver dominant disease and looking to intermix this and combine it with my chemotherapy drugs and with biomarker-driven approaches to get the best outcomes for patients. So in terms of patients with liver dominant or liver only disease, you know, I consider resection, ablation, of course, hai therapy and also y 90 as well as I should mention radiation treatments to the liver. And also, I think local regional approaches have a role to play in patients who have lung metastases or illegal metastatic disease which is out where you may have an isolated tumor or a small tumor. And you know, maybe you can be more localized with your treatment approach and for the lung that would include ablation resection and also stereotactic radiation. D=So the progress that has been made in the last you know, 50 years is phenomenal. Unfortunately, a long time ago, when patients were diagnosed with metastatic colorectal cancer, and there were no drug options, the recommendation was for best supportive care and, then over time, really, it was single agent 5FU. And this slide shows where we are today in terms of drug treatments. On the left hand column, you really see our cornerstone drugs, which is the Fluorouracil, Capecetibine have been being the oral version Irinotecan and oxaliplatin, and this is what we all know, as, you know, fall Folfox, Folfirir, the combinations of these drugs, looking at VEGF inhibitors such as Bevacizumab, EGFR inhibitor, centuximab, or, or panitumumab in patients who are RAS Wildtype and then on the right column, we see the newer drugs that are out there, right. 

Dr. Connell 07:01
So with patients who have BRAF mutated colorectal cancer, the combination of NRAS and Centuximab, HER2 is now you know, very to the fore in terms of drug therapy, which a centuximab and trust panitunamab. And then there’s been a lot of focus recently in terms of MSI, high disease and Immunotherapy options. And what I always say to my patients in clinic is that this is very important to determine for patients, but it’s such a small group of patients that we see.

Dr. Connell 07:21
And then the third line drugs you know what I would say briefly about these drugs Regorafenib Taz 102, which I typically combined with Bevacizumab, or for Fruzaqla is that these are drugs that, you know, have limited clinical benefit, and they have a high side effect profile. And I’m very selective in terms of which patients I decide to use these drugs for. More commonly, I would personally use TAZ102 with Bevacizumab and but that differs from patient to patient. And what I’ve highlighted on the far right is what I consider the star of the show which is liver directed treatment. And I think it’s so important to think about it in our patients and the core drug that we have is fluoxetine, and then we use Mitomycin you know, further and, you know, down the line for patients or if they’ve, you know, beginning to develop progression on fluoxetine, and I can talk about that a little bit more in the question and answer section.

Dr. Connell 08:52
So what is a Hepatic artery infusion treatment so traditional chemotherapy is delivered through through a vein. You know, in colorectal cancer, we typically have a meta port in place because of the fight through fluorouracil being given in an infusional form. The drug travels through the body’s bloodstream to reach the liver, and only a small portion of the drug will ultimately reach tumors in the liver. And as many of us who are patients and on treatment know, and it comes with side effects and typically, you know, issues such as diarrhea, mouth sores, you know, low blood counts such as neutropenia has. The benefit of hepatic artery infusion therapy is that it’s delivered through a pump first of all, which is implanted just below the skin in the abdomen. The drug is administered through the hepatic artery, directly to tumors in the liver, and it delivers up to 400 times a higher drug concentration to tumors in the liver. So we’re really getting to directly to the problem. And this is just a graphic showing. You know how that works with the pump.

Dr. Connell 10:13
Basically that the liver is a unique organ in that it has a dual blood supply. And we manipulate this information through the use of hepatic artery and fusion treatment. So there’s essentially two vessels which supply the liver, the hepatic artery and the portal vein. And liver metastases are perfused by the Patek artery, whereas what we call normal parenchyma, or normal liver tissue is perfused, primarily by the portal vein. So with hai therapy, we’re delivering the fluorouracil, which is a prodrug of 5FU or so into the hepatic artery, and we get very high concentration of the drug to the liver. And as I mentioned in the previous slide, it’s almost 400 times higher than those achieved by intravenous administration. And, and the important thing here is that essentially, the drug is entirely soaked up by the liver around 97% of the drug, it has a very short half life. So there’s minimal systemic exposure for patients and toxicity from the drug.

Dr. Connell 11:42
So I have two very brief slides just looking at some of the clinical evidence. And on this slide, we see the clinical evidence for HAI therapy in patients who have unresectable colorectal liver metastases. So the first study highlighted here was published in 2017. And basically, this was a case control study, which looked at the use of HAI with modern systemic chemotherapy combinations compared to systemic chemotherapy alone. And you can see even from the bar charts, there’s a there’s a difference there that’s quite visible between the purple bar, which is essentially the combination treatment and the orange colored, which is systemic treatment alone. And what was seen in this case control study is that median overall survival was doubled in patients, when they received combination treatment at around 32.8 months compared to our modern systemic chemotherapy options, which was 15.3 months. And this was even when conversion to resection was not achieved in patients. And this was statistically significant.

Dr. Connell 12:43
On the on the right side, then we see another paper and this was published in 2018. And this looked at like long term results from a prospective trial, and which again, looked at the response to hai therapy, and with systemic treatment, and basically, the overall tumor response rate to the combination of HAI with systemic chemotherapy was 73%. And there was a very high response rates in patients who were chemo naive. So when it was given in the first line, it was 86%, whereas in patients who were previously treated, it’s still very high, it’s 67%. And what we saw here is that 52% of patients were converted to resection with the combination treatment, despite the fact that the majority of these patients had what we would consider a high disease burden within the liver, and many of them had had previous chemotherapy.

Dr. Connell 15:19
I just briefly put up here, and this is really to January questions, you know, what’s the future for HAI therapy? Or how can we further advance what we know? And I think there’s two very important points to bring up here. And I know, these are questions that come up for me in the clinic is, you know, can we combine hai therapy with other systemic treatment options? One that’s very topical, you know, is kind of get it with Immunotherapy. And another would be, you know, some of these other newer drugs that are out there, you know, in particular for a patient to perhaps is her2 positive, BRAF mutated patients. So, you know, can we give them and right now, the honest answer is we don’t have the safety data to combine these drugs together. But it’s something that we do need to consider going forward in terms of trials. And, and also, I would like to highlight the HAI Consortium, and I think that’s a very important group. And it’s essentially a group of centers within the United States and also outside the United States, where we’ve come together, and we’re trying to generate trials. And there is a trial, which has been activated, which I know has been previously discussed here. And I think this is going to be a group that’s going to help propel forward future trials on hai therapy and and help all of you as well as patients in the future going forward. And it’s a very important collaboration to be able to replicate. I think what we’ve seen achieved at Memorial Sloan Kettering in particular with HAI treatment, and can we, you know, replicate that throughout the United States and more globally for patients.

Dr. Connell 17:01
So, what does it mean for a patient then to live with the palms, so just to get to some practicalities, so it does require a surgery to place the pump. And that’s important to say to patients and the majority of patients it’s placed at the time of an open surgery. In some patients where, for example, the colon primary, or the rectal primary has already been removed, and there is going to be no liver resection. There are some newer techniques such as robotic, placement and minimally invasive which are done by some of our surgeons. In terms of recovery. The honest answer is you can you can travel. And you can also continue to do most of the activities that you’ve enjoyed doing before. And during active treatment, the pump has refills every two weeks, you do not get drug every time it alternates between fluoxetine with heparin saline. And it is important to be mindful of the travel schedule. And I do say that to my own patients, because there is a residual within the pump, but you do not want the pump to run dry. So it’s very important to you know, mention any travel to your your treating physician and to try to accommodate that for patients as well. And otherwise, what I also want to highlight, and I mentioned this a little bit with the consortium, but there’s been a huge increase in terms of the number of centers since 2019, that are able to put in a level upon number one, and also for local refill centers. And this is something that is continuing to gain momentum. I think this is something that I learned, I’ll be honest with you during the COVID pandemic was so important for patients because there was huge difficulty in in people being able to commit to coming here every two weeks to New York at for pump refills and, and there’s a lot more physicians out there, and who who can now help assist with local refills. And that can be huge for patients, even if they’re not able to get the flux your dean locally, for example. But coming to coming to New York once a month is much better than having to commit to traveling every two weeks for example. And, and you know, it is important to also to mention that and we are trying to help train local oncologists also who maybe don’t have experience with the pump, but to be able to help some of some of you and some new patients who really want to commit to this to have refills locally. And then just to briefly mention, you know, some of the safety elements with fluoxetine. So, the anterior pump is indicated for the use of fluoxetine and it is contraindicated to the use of this and patients who have extensive extrahepatic disease or if you have limited liver function. And then always important to mention, you know some of the adverse events that can occur with the pump which are rare but serious and we can discuss them a little bit further in the q&a section.

Dr. Connell 19:59
So with that, I’m going to hand it over to Betsy, and we’ll go through the questions. So I’ll stop sharing here.

Betsy Post 20:08
Great, thank you so much. And then please, as we go along, if you do have questions, actually, I have one, two for the end, please do put those in the chat and we will get to those shortly. So the first question we have Dr. Connell is Why is HAI therapy generally done at the same time as systemic chemotherapy?

Dr. Connell 20:31
Yeah, so, you know, this question comes up a lot. And I think the important thing here is the there is a synergy between fluoxetine through the pump and giving it with systemic treatment in particular arena Tekin, and our EGFR inhibitors, but also importantly, we have to protect against the risk of extra hepatic disease, right. So if I have a patient and they’re on track to try to get to a liver resection, what is absolutely devastating for a patient is to get to a surgery. And the procedure is aborted because extra hepatic diseases detected and or for something to develop on a scan prior to surgery. So it’s really to help protect outside the liver, to allow us to focus on the treatment of the liver metastases with the flexibility and treatment.

Betsy Post 21:23
Thank you. How do you determine which systemic regimen that you’re going to use with the metastatic colorectal cancer liver met patients? And how does having a pump alter that?

Dr. Connell 21:35
Yeah, and so the first thing to say is that, while we typically and in the majority of patients give systemic chemotherapy with the HAI therapy, the dosing is automatically lower than it would be if a patient was receiving systemic chemotherapy alone. Because we have to balance the toxicities from using the two in combination. And so there is a different standard dosing of this systemic FOLFOX, for example, as opposed to somebody who’s on FOLFOX own in terms of what to use for patients. So there’s a few things to look at. I think the first thing is, in a patient who is previously untreated, the standard would be to use Folfox.

Dr. Connell 22:19
With the liver pump, and in somebody who possibly comes and they’ve had both treatments, what I take into consideration is I look and see, you know, what response, did the patient get to each individual systemic treatments previously, right? Did their cancer previously progress on Folfox? Do they maybe have stable disease on full theory, but they didn’t get enough of a response, and also the side effects that patients have had from previous treatment. So if somebody comes into me in clinic, and they have very severe neuropathy from previous oxaliplatin, I’m not going to jump to using that drug. So I think what’s important to consider is how the patient’s cancer has responded to previous drugs before the time interval that they’ve had from a particular regimen to perhaps another recurrence or something else developing and also the side effects for the patients from previous treatment.

Betsy Post 23:13
Thank you. The next question is, are there any situations where the HAI therapy might be done without systemic chemotherapy at the same time,

Dr. Connell 23:27
Um, very, very rarely, I have one patient since I began practicing here that I’ve done it in so I very, very select patients. In general, the preference is to give with systemic chemotherapy. Again, you know, in, in the scenario where I decided not to do it, it was a very detailed discussion with the patient about why we were not doing it and the risks of of not doing it together. But in general, it’s given. It’s given with some form of systemic chemo. And, you know, what I prefer for my patients is at least we give a single agent even if a doublet such as you know, 5FU with oxaliplatin or 5FU with Ironotecan is too much. And but as I said, it’s very rare that I do it. I’ve only done it once since I’ve been practicing here and had very real reasons for not doing systemic side effects may be possible in the liver area during HAI therapy.

Dr. Connell 24:28
Yeah, so the side effect profile is very different to systemic chemo. The two main things that I say to patients is we learned early on and many of the studies that were done with the liver pump the the risk of ulceration in the gut in the GI tract, so all patients are put on a medication to help prevent reflux. So pantoprazole protonix, and in patients who say to me that they’re having increasing reflux symptoms, for example, or they’re having some pain or discomfort, you know, just under the chest, and I’d have a very low threat To get an endoscopy to look for an ulcer, so that’s the first thing. But it’s much less common nowadays because we’re routinely giving protonix with it. I think what the big thing is, you’ve got to watch the delivery of blood work very closely. And in the majority of patients, you don’t come to clinic with any symptoms, right? You feel fine, you feel well, in general, patients feel better than they felt on previous systemic chemotherapy because okay, I’m still giving it but I’m giving a little bit less than you would have had previously. And what I always say to people, actually, when they come to me is it can be a little bit frustrating, right? If you fly to me from San Francisco, or you come from Canada, and you feel great, and then I see the liver enzymes, and I say, sorry, I can’t give the drug today or you know, we’ve had to give a few weeks holding off on the drugs. So the honest answer is we’ve learned from experience that we do have to be very mindful of the liver bloodwork, and then the majority of patients picked up on the bloodwork and the patient doesn’t have any symptoms themselves. However, in some patients, if you begin to develop any symptoms, such as jaundice, you know, anything like that, then a very low threshold to get your liver enzymes checked. And even if you’re local, to check them to see because that’s the biggest thing that we have to watch for is liver toxicity.

Betsy Post 26:16
How long does active treatment last? And what is the average number of treatments? And does this change? Does this change if the HAI therapy is being done before or after liver resection?

Dr. Connell 26:30
Yeah, yes. So the answer to the final question is yes. So if somebody has had a liver resection, and we’re using this as an adjuvant treatment, it’s six months of treatment. And then we stop. And in the majority of patients, we’ll get four doses in of the fluoxetine of the liver drug in the six month period, when we look at, you know, liver enzyme alterations, but we stop automatically at six months, and however many doses the patient has managed to successfully get that’s it. And in a in a person who is not resected, or I’m trying to convert to resections, when unresectable disease or in the conversion setting, there really isn’t a limit in terms of the number of doses that a patient can get. And the it really depends on how their liver is tolerating the drug, you know, what kind of response that we’re getting, you will have to make a change to the to the drug dosing. And what I’ve seen in practice is that typically, that happens around two to three months into treatment. It’s not uncommon, that it could happen even after the first dose, but there will be some dose modification. And patients can still respond on low doses. And that’s also important to say, because again, I also acknowledge that, you know, really, you’re committing to come in here for these treatments or to hai center. And it’s very disappointing, if you hear you’re getting a quite a significant dose reduction. And but you still respond to this. And it’s different to what we know about the dose reductions that are done with systemic chemo.

Betsy Post 28:04
Thank you. Is it possible to do treatment again, with the pump later on, if needed? 

Dr. Connell 28:14
Yes, exactly. Yes, you can. And this is why, you know, our, our preference is for patients to keep the pump, right, because particularly, what I would say to patients is, if you are using it as adjuvant therapy after liver resection, or you’ve been converted to resection from the pump, at the time of surgery, the recommendation, so your NED at that point, right is at least two years. Ideally, we prefer patients to keep the pump in longer. But the highest risk period for recurrence is the first two years and the rationale behind that is because the pump is not something that can be put back in right a little bit like a metal porch, right? So we want to keep that option open. Particularly if, if it’s helped you get to your surgery, number one, and you know, so that we can use it again. So absolutely, yes, you can use the drug again.

Betsy Post 29:11
Thank you already answered the next one, which was does the pump stay in when active treatment is done? And for how long?

Dr. Connell 29:18
Yes. Yeah. Yeah. And so yeah, and this question comes up and the honest answer is as well what I would say is i i Never tell someone to take a pump out I wait for them to tell me that they’re ready for it to come out because I think it’s a very personal decision. I think it’s something that for many patients has been you know, revolutionary, I guess and and I think, you know, we can educate and guys and that but it has to feel right to you as a patient to know when is the right time to remove it. If somebody really wants it out within six months. I’m like, please keep it for two years but beyond that, I really leave it up to the patient’s decide

Betsy Post 29:59
Are there other drugs ever used in the pump like oxaliplatin?

Dr. Connell 30:05
Yeah, so, oxaliplatin has a very low extraction rate into the liver. It is used in Europe because they have a slightly different device there. We don’t routinely use it here. But we do use Mitomycin and that’s something I referred to briefly during my talk. And I have seen patients who perhaps are beginning to develop some resistance to Flox your deen or maybe are beginning to run into more issues with their liver enzymes. And I’ve used Mitomycin in those patients and seen you know, some very good responses with the middle myosin what I would just say about that is you can give it in combination with fluoxetine. So you can give both drugs at the same time if your liver enzymes are good. So if the liver bloodwork is good, if the liver enzymes are high, tickling the outsource or perhaps the bilirubin, and that it’s safer to give Mitomycin on its own, but that’s typically our second drug that we use. We don’t give oxaliplatin.

Betsy Post 31:09
What are the causes for the mitomycin following HAI therapy with the traditional treatment?

Dr. Connell 31:19
Why would we give it right?

Betsy Post 31:21
I think you already spoke to that. 

Dr. Connell 31:24
So yeah, yeah. So I think if you’re getting a slowing down in response, possibly to flux, your routine, maybe you are getting some response, but you’re beginning to run into some of these liver toxicity issues. And so they would really be the main reasons that we do it. And really, I would use it in a situation where it’s liver only progression, of course, like I wouldn’t use it if there was signs of anything happening

Betsy Post 31:47
Um, and then since I’m not an oncologist, I might mess up these names. But what are the views on the use of Bev, which I know is Avastin. So we’ll take that one first. The new third line or a drug that was just FDA approved for colorectal cancer, liver Mets, or the EGFR inhibitors. So what are the views on those three and maybe address them separately? Because I know it could be different after the HAI therapy when the pump is running glycerin.

Dr. Connell 32:18
Okay, so I’ll start with EGFR inhibitors first, because that’s probably the easiest ones you can give EGFR inhibitor is at the same time that you give fluorouracil safe to do works very well with the liver pump.

Dr. Connell 32:32
And you can also give it after liver treatments. So there’s no limitation at all with EGFR inhibitors and actually works very well with with FUDR, or Avastin is something that we’d urge early on, that should not be used the same time that we’re giving fluoxetine. So it’s it’s a combination, so it should not they should not be used together. And but a patient can have Avastin or Bevacizumab later on, if you’re simply just getting glycerol through your pump. And so, if for example, I have somebody who the liver is still no evidence of disease, there’s, you know, issues arising outside the liver in the lung, perhaps or lymphnodes. Have I given Avastin? Absolutely I have, I generally prefer to try to delay the use of Avastin further out from using the liver drug because I have seen in some patients some delayed issues with billary complications if I’ve tried to use the Bevacizumab a little bit too quickly after stopping the liver pump treatment. And but yes, you can use them separately but not together and then forget never the honest answer is we don’t know yet. Because it’s such a new drug definitely would not use them together. And I think you know, you would think along the same lines as you know, what we do with Stivarga, etc. You know, they can be given but not together. And the honest answer is and I kind of led to this during my sliders, I really reserved the use of any of these drugs too much, much later on for patients. I think if you can do something like long ablations or radiate, I think you’re helping the patient more than jumping to any of these newer, third fourth line drugs that are approved.

Betsy Post 34:17
Thank you. And these are questions that we see in Colin town all the time, and these were the most frequent questions that I received for you. So these have to do with Y90 So if a patient has had Y90 How does this affect their ability to receive HAI therapy after?

Dr. Connell 34:38
Yeah, okay. So this comes up quite a lot. The honest answer is if I see a patient before a Y90 Maybe they come with a second opinion we usually prefer to give the pump before Y90 that’s the honest answer. So usually what I say to patients is, you know, pump first and any of these proceed procedures like Y90 or radiation I would reserve for later on. And have I had patients who’ve had y90 And I’ve given pump treatment to absolutely, I think we have to look at those cases individually. And it’s something that we would show at our tumor board. And we would really look at the extent of the Y90, for example, how the blood vessels in the liver look after the Y90.

Dr. Connell 35:24
Often you need to dose reduce the flux your routine a little bit faster in those patients so I can get the drug in for the patient, but I can’t get as much drug in. And but I’ve had people respond after y 90 I think our preference is to do pump first.

Betsy Post 35:45
If a patient has HAI therapy, and then does Y90? Would the patient be able to use the HAI pump again, if it is still functional?

Dr. Connell 35:56
Yeah, and so this is an interesting one. I haven’t personally ever done that myself. I think from a technical point of view, it would come back to what I said previously, is that you’d have to really look structurally at the liver and see, you know, there’s there’s newer Y-90 techniques out there. And I know whether our interventional radiologists here they do more selective Y90 So if perhaps, you know, there was a regional Y90 And then you’re trying to treat the rest of the liver. Technically, you could. I think just with with my own practice, and the way that I view it, because I keep Y90 for Later on, it just hasn’t worked out that way with the patients that I’ve seen. But again, I think this is something that you would have to have the right imaging, it would have to be viewed as a multidisciplinary team, whether that’s the right thing for the patient, you know, including an interventional radiologist, including a radiation oncologist right, is radiation safer than Y90 A surgeon and a medical oncologist to decide what’s the right thing for that particular person.

Betsy Post 36:56
Some additional questions have to do with transplants. This is something that we’re hearing more and more about, especially for unresectable disease, obviously, and we have patients a lot of times that are making a decision, sometimes between the pump or transplant, but something that we’re hearing now is the question first, could the pump be used as a bridge to liver transplant?

Dr. Connell 37:18
Yeah, so this is very typical? I think without intentionally setting out that way. And I’ve had some patients who’ve done very well with transplantation after pump treatment, I think the tricky thing about the transplant process is that it’s a long process for patients. Right. So my own experience with my patients has been is that sometimes they’re waiting like 12 to 18 months. And I’m trying to control everything with the pump at the same time. So I have used it but not intentionally. I’m on discussions with transplant centers. And speaking with surgeons here, this is something that I think we’re going to need to study. And we’re going to need to collaborate on to see if we can help more patients by combining the two techniques.

Betsy Post 38:37
Another question, how do you consider the option for liver transplant as part of your overall treatment plan or approach for patients?

Dr. Connell 38:47
Yeah, so. So when I see patients, you know, this can often come up. And I think with transplant, what I say to people is we got a real sense of how the pump is helping a patient in unresectable disease, like, you know, about six months in, you know, look, and you’re talking back and forth with the surgeons, you know, do we think that we’re going to be able to convert to resection here? Do we have any of these options like why nine tear or radiation? And I think it’s always appropriate to get an opinion from a transplant center, and particularly if it’s something that the patient themselves is questioning, right, because you want to hear directly. And there’s a little bit of bias right between different different specialties and obviously I’m very Hai and but I’ve certainly collaborated with transplant centers, and then you know, when somebody is listed for transplant in practice, what I do is I follow what they want me to do, so I don’t change any treatment, you know, they tell me what they want to do. The important things about transplant is a few things. So you cannot have any extra hepatic disease obviously so there can be no evidence of extra hepatic disease. And the second thing is that the primary tumor has to be removed.

Dr. Connell 40:03
So, you know, they would be the two things. But if you have liver only disease and and resection is not feasible, and you’ve heard that from the liver surgeon and you’ve heard that from your medical oncologist then then I do think transplant is something that needs to be considered. And they removed the pump at the time of transplant as well. 

Betsy Post 40:26
So is there data available to show how successful ATI therapy is? And I know that we did talk? You talked about that earlier, but I didn’t know if you wanted to elaborate on that a little bit more.

Dr. Connell 40:39
Yeah, so we do have data. And I’ve shown some of the data here, I think what’s important is that we need more randomized to data. And I think, you know, that’s what the consortium is going to help with and why we’re trying to collaborate with other institutions. And I think trying to address this question of, is the pump so successful? Because it’s given here in New York or you know, Kansas, can I get the same level of care? Or in Chicago, or, you know, Atlanta? And I think the honest answer is there’s so much more knowledge out there about the pump. And we do need to do more trials. And also, I also mentioned this as well, there’s so many newer drugs out there, right. And patients want to know can kind of get them together, is it safe to get them together? And this has to be done in a trial setting.

Betsy Post 41:27
So another question we get quite a bit. So now that Dr. Kemeny has retired, how was care being distributed for patients that are being seen at Memorial Sloan Kettering?

Dr. Connell 41:39
Yeah. And so what I would say about that is, honestly, all of us can can can do pump treatment, I think a huge part of Dr. Kennedy’s legacy. What’s visible to patients and caregivers is is what she did for you, right? Understandably, a huge part of her legacy for us at Memorial is the teaching and training that she gave to us. And, you know, she was a phenomenal mentor to me. And to many of my colleagues.

Dr. Connell 42:10
All of our practices differ a little bit. So some of us do more pump than others. But honestly, all of us can do pump in terms of her practice. And it’s been divided between Athol I think for for active patients, understandably, because I was mentored under her I have many of her patients. I think, what’s also important to say, though, is that, for any of you who have, you know, some complex decision making, there’s something to be to be, you know, figured out, you know, is it now the right time to think about y 90, you know, have I achieved what I can with the pump, that’s never a decision that’s made in isolation by an individual, whether that’s a medical oncologist, it’s our tumor board is a huge resource for people and, and that’s often what I what I see myself as like, You’re not coming here to memorial for me, you’re coming for the expertise from the whole group. And never think that a decision a very important decision like that, look, will I say to this patient that you should go and get a transplant opinion, you’re not going to hear that just for me, I’m going to speak with my surgeons I’m going to speak with with them, and we’re going to show your case at the tumor board. And I think that’s very important to know, is that there’s huge collaboration amongst us as medical oncologists, and also multidisciplinary team involvement in any major decisions for patients.

Betsy Post 43:31
I know that you spoke about the Consortium, and that all the pomp programs, especially since my team that have opened up, but How can patients across the country get good access to HAI therapy?

Dr. Connell 43:44
Yeah, so I think there are more centers, who are implanting the pumps, number one, and also so many more centers where, you know, they’re able to assist with with local fields, I think the consortium is really helping with that. I would also say that there’s a huge collaboration between us, you know, I definitely speak with medical oncologists at other institutions. You know, I relied on mentoring, when I started off with this, and I try to share what I’ve learned in the nuances, you know, with oncologist with other centers, I think, when you start off, you know, what I always say to people is, you have to be comfortable with the person that’s treating you, right. And whether that’s having a pump or not having a pump, I think, number one, you have to be comfortable. So, you know, and you also have to think from a practical point of view, you know, look, if financially and with my family or my work commitments, is it feasible for me to fly up and down to New York every two weeks? And for many patients, it is for others. It’s not. Do I have a local doctor who can do this? Did I did We did our personality match? You know, and but I think there is so much more knowledge out there nowadays and there’s also huge camaraderie between us and sharing of knowledge. And, I think the consortium and the trials and everything that’s going to come out of that is going to further reinforce that for patients.

Betsy Post 45:11
One more question, and then we’re going to take the live questions, we have quite a few. How does the start of that new pump trial impact the ability of new patients to receive HAI therapy?

Dr. Connell 45:23
Yeah, so it’s a very relevant question. And you know, what I would say about the pump trial, it’s a very, very select group of patients, right? It’s a very important study, right to help answer this question, in a randomized setting of, you know, conversion to resection for patients with HAI versus modern systemic chemotherapy. So it’s for patients who’ve had more than three months, but less than six months of systemic chemotherapy in the first line. So it’s a very small group of patients. And the honest answer is the reason that we’re doing that is because we don’t know the question, right, we are the answer, we wouldn’t be doing it if we already knew that one was better than the other. And that’s important to say about any trial. If you’re a patient who is untreated, you had no chemotherapy, you can have a pump off trial, if you’ve had more chemotherapy, like you’ve had a year of chemotherapy, you don’t, you don’t qualify for the trial. So it’s a very, very select group of patients. And that will be explained to you as well, in the in the in the clinic setting.

Betsy Post 46:30
So moving on to some of our live questions, we have one, is there a certain temperature that you have to keep your body under while you have a pump?

Dr. Connell 46:42
Yeah, so this question comes up quite a bit, you know, I think you have to be sensible, right? So he will speed up the rate of infusion of the drug. Hot tubs are a no, no, you can get in a swimming pool. And so body temperature can affect us, I don’t give anyone like a specific number. But I just say like, you have to be mindful of it. And I have a patient who said they have a hot tub with that, put it on regular temperature. So you know, swimming, and all of that is fine. But sitting in heat, you don’t want to put heat pads directly on the pump. If you have pain in your back for another reason, you can put heat out there, but you just want to do want to put it directly over the pump.

Betsy Post 47:25
Is it true that you can’t lift more than 10 pounds when the pump isn’t?

Dr. Connell 47:31
Yeah, so again, this comes up quite a bit. So usually I say around 15 pounds to patients. In the beginning, I think you have to be very mindful of that similar with any surgery to be honest with you. Over time, honestly, what happens is you have a very good sense of your pomp and also scar tissue forms. And so I tell patients that, you know, using a binder, you know, be sensible. But a lot of people say, Well, you know, my toddler is 30 pounds, you know, and I’m never gonna say to somebody, you can’t lift your child up, you know. So I think within reason, and I think if you’re, you know, the further out, you get the sense you have your palm, the binder, scar tissue, and, and, you know, for lifting children in the beginning, I usually say to people, you know, sit down and lift them up onto your knee, you know, things like that. So I try to be creative with how you do things. But I do think we have to be practical in that regard. And the concern about the weight lifting is the connection between the catheter and the pump, and also the risk of, you know, the pump flipping, and the more secure it is over time that the lower the risk of that

Betsy Post 48:39
Um, there’s a question about the drug and mutations. And I know specifically, we do have some BRAF patients here. So question, there’s a question about, is the HAI therapy equally effective for all mutations?

Dr. Connell 48:56
Yeah, so it’s a very good question. I think what I would say to you is, is that we do use the pump and in all patients, I certainly have myself patients who have BRAF mutations, and I’ve used the pump, and I’ve seen some very good results with it. So I wouldn’t discriminate based on that. And but I think it’s something that we’re going to need to study a little bit further to see how we best serve people going forward. But I definitely have patients who’ve done well. And you know, maybe later on I’ve used the combination I mentioned earlier, such as graphics to toxic map, and but if they have liver only disease, we still put pumps and we still get flux your routine and I’ve definitely seen good responses. I have a patient who was probably an outlier but from from early 2019, and still NED

Dr. Connell 49:47
and had, you know, resection, had liver pump to get your resection and as BRAF mutated, you know,

Betsy Post 49:55
right. I think you answered this, but I’ll ask it for those pursuing liver resection, is there a recommended number of fudr treatments from the pump before considering surgery?

Dr. Connell 50:10
And so the honest answer is there isn’t a set number per se, if somebody has unresectable disease. So what we do is we scan every two months because we want to keep a close eye on the response that we’re getting and how the liver is tolerating it, right? So you’re scanned every

Dr. Connell 50:29
which is a little bit different to the adjuvant in the adjuvant setting, you’re scanned every three. But what I usually say to people is that honestly, at two months, it’s it’s not very common that patients are ready for surgery, it’s typically around the four to six month mark, but there isn’t a set number is really depends on the location of tumors, the technicality if somebody has liver, you know, bi lobe disease, so both the right and the left side involves the surgeon will say to me, Look, we need to do these portal vein embolization, you know, certain procedures to help get to a second stage liver surgery. So the some of those factors to come in. But there’s no hard and fast rule with the number of doses that a patient has to have

Betsy Post 51:13
HAI pump decisions require very close coordination between the medical oncologists and surgical oncologist Are there any best practices from that cross specialty communication that you would highlight is beneficial to apply? Even beyond the HEI application?

Dr. Connell 51:31
Yeah, so, you know, what we’ve learned to serve patients best is that multidisciplinary involvement is so so important. Right? And, and I kind of, you know, said that earlier on, like, any major decision point you need to think about, you know, how am I helping the patient right now? And also, how is this going to affect what I want to do in the future for the patient? Right. So in my own practice, here, I do my clinics alongside the surgeons at for that reason. And you know, when I asked some of these questions, we also have very heavy input from our interventional radiologists. And I think that’s very important is to try to get the different options there. And sometimes there is there’s two options, right maybe let’s say for the liver, it could be resection or it could be ablation, and then we can see both and help make the decisions by getting the input from from both specialties for example.

Betsy Post 52:32
Are there restrictions on jogging and working out?

Dr. Connell 52:37
Okay, so what I would say about that is if you put 20 of us in a room, a mix of surgeons and medical oncologists, everybody would say something different and it’s very controversial. And I allow my patients to light jog and the the concern again is really the connection of the catheter to the pump. And again, what I say to people is exactly what I said weightlifting you know, if someone comes in to me and you know jogging is your is your your cam time, you know, your therapy so to speak. You know, it’s very hard to say to somebody, you know, don’t jog and but I say you know, try to be sensible about it, have a binder on Wait a while and I do allow patients to do like jogging. The surgeons do lap people jog and there’s other medical oncologists who say no, and we love stationary bike. We love the peloton. That’s, that’s probably the safest thing that you can do and the best thing and a good form of workout. But yes, I do say to patients, they can jog.

Betsy Post 53:41
So if there is a patient that has, for example, ovarian or peritoneal disease, but the patient was potentially able to have all of that removed. Could they still get pumped?

Dr. Connell 53:56
Um, so for over a yes. So if you have liver and ovary because we know that colorectal metastases to the ovary, are quite resistant to chemotherapy, so in general, the bias is to lean towards surgery in that situation anyway. So you would often do if you can do a liver and you would also remove the ovaries at the same time. So yes, with peritoneal disease, there’s a little bit of pause. I’ll be honest with you. The tricky thing about peritoneal disease is that you often can’t fully appreciate peritoneal disease on scans. And and it’s only at the time of surgery that you really have an understanding. And I’ve had some patients where perhaps there’s been like limited peritoneal disease, you know, a year ago it was removed and maybe they come looking for a pump. And and usually if there’s, you know, a period of time, typically a year, year and a half, not thing happening in the parish name again, then, you know in select cases we’ve put pumps in. And but I wouldn’t say to you upfront that I’ve put a pump in for a patient when they have active peritoneal disease at the same time.

Betsy Post 55:14
For every two to three months scans, do you do CT MRI, and I’m gonna throw in there you PET scan stew? Might as well add it in.

Dr. Connell 55:24
Yeah, and, okay. Um, so in that regard, what I would say to you is I started off using CT and patients. So I do routinely, CT chest, abdomen and pelvis. Over time. From looking at the CT scan, you understand with the individual patient, whether you’re seeing things clearly in the liver or not, if not, particularly in patients who maybe have, you know, a lot of chemotherapy prior to the pump being placed, because the chemotherapy changes the texture of the liver, what we call like fatty liver change, or sclerosis. So in those patients in MRI may give additional information. So the honest answer is, my starting off rule is CT only, I’ll involve an M or liver if I feel like I’m not seeing things clearly with a CT. And I really don’t routinely use a PET scan, unless I get to a point in a patient where a specific question has come up on a on a CT, for example, I do a patch, and I see that the patch is giving more information than the CT has. Similarly, if I do a patch on a patient, and I see that I’m not getting anything different from it, then I don’t routinely follow with Pat. And I think that would be the standard approach. For most patients. The tricky thing with PET scans is there can often be you know, false positive things on a PET scans and something lights up. And it’s it’s not anything related to the cancer and then it causes, you know, a lot of concern, understandably. Yeah, so that’s how I would view it. But I do have some patients where I know that only MRI shows that are only pet shows that and then once I learned that with the patient, then I continue to use that imaging modality. But I still always do my CT as well.

Betsy Post 57:12
We have one more question about I think exercise I see here. What about horseback riding? I’m a serious equestrian.

Dr. Connell 57:21
Yeah, so this came up for me recently. The issue with with horse riding is the bouncing activity. Right and the concern for the catheter? Again, I don’t think it’s a complete contraindication I think, and I know I’m repeating myself a lot but wearing the binder, a similar lead to what I’m seeing with light jogging. I mean, you can I don’t even know the word for isn’t trotting. for horse riding, you know, you have to be mindful of that. And but I wouldn’t, you know, I wouldn’t say you can’t do it again, if that’s something that a patient is passionate about, and it’s their form of relief, or escape from what’s going on, then I think that’s important to consider. So have a binder be mindful. That’s what I would say.

Betsy Post 58:07
We just have two or three more. So how would you know if there’s a problem with the connection from the pump? Perhaps from over lifting, etc?

Dr. Connell 58:19
Yeah, the honest answer with that is that most patients don’t know. And it’s picked up on scans. That’s the most common scenario. And that’s really where we see it. If somebody has, you knows, for example, they’ve had a trauma, you know, so So I had a patient a few years ago, and they were in there on a regular bicycle, and they flipped over the handlebars, and they were like, This doesn’t feel right, you know, so I scanned and you know, there you knew there was some incident proceeding, and you would check for it or they had pain afterwards. But the honest answer is in the majority of patients picked up on scans and you don’t feel any difference.

Betsy Post 59:03
Let’s see, I know I’m gonna mess this this word up.

Dr. Connell 59:08
So what are the thoughts around using the capecitabine with the pump while receiving radiation to treat the primary replacing traditional systemic treatment? Okay, yeah, so this comes up quite a bit. So when patients have a rectal tumor and you know, you can treat them with chemo radiation. So we do, you know, and you know, that’s in terms of a rectal tumor, the surgery is much more life altering. So if you can effectively get a complete clinical response or fully treat the rectal tumor than chemo radiation is recommended. What do I do in my patients? So the issue with Capacetibine Xeloda is that it causes more increase in liver enzymes, and it can affect the dosing of the fudr. So what I do for patients is if

Dr. Connell 1:00:00

We have a rectal primary and we’re doing chemo radiation. And we’ve just put a pump in for liver disease, you can give the fudr you can give the liver treatment during the chemo radiation. But instead of using the Xeloda and or capecitabine of being I use fluorouracil which is sort of the old way that they that they used to do chemo radiation. And because again, I want to try to maintain the higher doses in the pump and keeps it being tends to interfere with that more. So.

Betsy Post 1:00:36
I think I got to almost every question, one of my questions that I have, if I can just sneak one in I know it’s 802. But with all the centers opening up, I feel like we’re seeing some oncologists are using the Urso dial and some are not. And I don’t know if you feel comfortable speaking to that, and how you use it in your practice and how the decisions made to use that or not?

Dr. Connell 1:00:59
Yeah, it’s a very good question. I mean, I think what I would say to you as well is there’s even differences in the practice here at Memorial as well. I, I use it quite early on in patients, because I think, you know, the two ways we manage the liver inflammation are the steroids through the pump at the time of the flush as well as versatile. And, and in the long term for patients being on steroids continuously. You know, there’s this kind of late side effects with that there’s the weight gain that comes from steroids, there’s a few patients where versatile can be a little bit tricky. So sometimes patients can notice the very loose stool. So if I have a patient who’s struggling with, you know, diarrhea issues or anything like that, from arena Tekin, or even five floor yourself, I kind of hold off on the earth a dial, but I tell them why I’m not doing it, you know, but I do tend to use it early on. And I also tend to keep it on board longer, even after I’ve weaned down the steroids in the pump, and I have someone off treatment, because I think it helps with the liver inflammation, I typically start off on twice a day in some patients, you may have to go up to three times a day. But again, if you even select 10 oncologists here at Memorial, everyone would do something a little bit different. But I give the options to patients. And I also explain, as I said, when I don’t use it and what my concerns are for that particular person.

Betsy Post 1:02:31
Well, it’s 8:04. And I think we have gotten to most of the questions. There is one here that I’m not sure we may have to get back to because it’s you know, the top centers for ATI. And with so many new centers that have opened up since 2019. I think by volume, we’d have to kind of look into that to see who they are. I know Duke is one of them. I know they’re very, they’re a high volume center now. But with the opening of the consortium, I know we have a lot more centers throughout the US. So I can take that offline. And definitely I can talk to the folks at inteiro on that as well. Just about the volume at the other centers. But yeah, so I just wanted to say again, thank you so much for your time, I learned a lot. And it was so good to hear just from a medical oncologist. So in addition to Dr. Kemeny and hear how you’re using it, your practice, and I learned a lot of just about the trial and other things. And your take on that. And I really appreciate it. I know you were so generous with your time and answering all of these questions for the patients. And we really all appreciate it. So thank you so much. And I know we’ll be in touch if we have additional questions. So thanks for everybody that attended tonight and thanks for all your participation. We really appreciate it. So have a great evening. Thanks again. And we’ll see you soon.

Dr. Connell 1:03:46
Thank you everybody. Bye