Patients with metastatic colorectal cancer can benefit from a variety of liver-directed treatment approaches, and some patients with stage IV disease can achieve durable remissions. This discussion-based CME moderated by Thomas Karasic, MD with short presentations and representation from a multidisciplinary team of specialists on liver-directed interventions from surgical oncology, radiation oncology, and interventional radiology to review the many options available for patients.
Panelists stress the importance that early and precise staging, together with a multidisciplinary discussion can make the greatest impact on treatment.
Dr. Karasic’s physician profile
Dr. Roses’ physician profile
Dr. DeMatteo’s physician profile
Dr. Soulen’s physician profile
Dr. Ben-Josef’s physician profile
Hepatic Artery Infusion (HAI) Pump at Penn Medicine
Gastrointestinal (GI) Cancer Program at Penn Medicine
Liver (Hepatic) Cancer at Penn Medicine
Welcoming New Physician Leadership in Cancer Care at Penn Medicine Alright I think we can probably get started. I'm sure we'll have more join us in the next few minutes but we can we can get started for those who are here. Um So this, thank you all for attending. This is our cmi session updates on colorectal liver metastases. A multidisciplinary approach. My name is tom Jurassic. I'm a gi medical oncologist, european. Um And I'm joined today by an outstanding panel with dr di matteo and dr Roses of surgical oncology. Dr Sue Ellen of interventional radiology and dr Ben joseph of radiation Oncology. Um Here are the objectives for tonight. Um So we're going to review evidence supporting liver directed interventions and colorectal cancer, explore current and novel treatment approaches for colorectal liver metastases and discuss patient selection criteria for each therapy. Here are the disclosure of streets of the panelists and please be sure to claim your cmd credits. You won't be able to do it tonight. Um But in a week you'll get an email with an evaluation and instructions on how to do how to claim your cmd credit. And this is just an overview of what we're going to discuss tonight. We're gonna have a series of 10 minute lectures to hear about the various treatments available for colorectal liver metastases. I'll start first by discussing systemic therapy. Um Dr Roses will discuss surgical resection dr di matteo, discuss the paddock, arterial infusion, chemotherapy. Dr Susan will discuss interventional radiology interventions and dr Ben joseph will discuss external beam radiation and then at the time at the end we'll have a case based discussion. Um Please submit your questions in the queue Q. A box and we will answer them between sessions as time allows. And then at the end. So first I'll start with a simple case just to kind of get everybody thinking about colorectal liver metastases. This is a somewhat frail 67 year old patient that I met a few years ago who presented with abdominal pain and vomiting, nausea, underwent a colonoscopy which showed an ascending colon adenocarcinoma. Uh and a CT showed no additional sites of disease. Ceo was normal, so underwent a laparoscopic right chemical ectomy which showed a T three N zero, moderately differentiated adenocarcinoma involving 0 to 21 lymph nodes with no limp of vascular or very neural invasion. Um And based on this being a low risk stage to do not receive adjuvant chemotherapy at that time. Um And then underwent surveillance imaging was getting MRI's because of some CKD and 18 months later showed up with a new 1.3 centimeter segment two liver lesions, no other sites of disease and the CIA was normal. So I think most of us, you know, have an idea of how we would approach a patient like this in our own practices. But I think you know what I'm hoping that you will gain from these lectures tonight. Is there actually are a variety of options available for patients like this. Um and you know that they're this patient has has many potential treatment options. Um and there are many patients like this. Um there really thousands of patients every year in the us with colorectal liver metastases. It is a huge issue. Um you know, it's estimated that about 15% of patients with colorectal cancer will present with synchronous liver metastases and an additional 15% will develop metaksa anus or recurrent tumors within the liver. Um and that does vary by stage about 4% of stage one patients, 13% of stage two and 30% of stage three patients will develop recurrence in the liver. Um and other research has really found that liver intestines is the main cause of colorectal cancer death attributed to half to two thirds of of colorectal cancer deaths are due to hepatic disease. And with five year survival rates really stuck around 15%. I think there's a tremendous need for more progress in this area. And tonight we're going to again look at some of the options available for these patients. So historically, uh surgical resection has been the gold standard. Um and this is one of the old old series that was published that really was in the era prior to chemotherapy that looked at surgery versus no surgery and those with respectable disease and showed an improvement in survival of 30 months and those who got surgery versus 14 months and those who didn't get surgery and note that those with under a sectoral disease had an immediate survival of about eight months and again, this is reflecting the natural history of untreated colon cancer. Most of these patients didn't get surgery, but this is sort of what established the basis of using surgery in this disease. More modern series um have had different rates of survival at five years, ranging anywhere from 20 to 50% but most of them seem to center around 20% 10 year survivors. And one of the series by Tomlinson in this chart that you see um sort of looked at that and saw that about a third of patients Who are alive at five years ultimately dying of their cancer between years five and 10, Whereas very few patients die after year 10 from cancer. And so 10 years really has been the benchmark um in terms of long-term survival after metastatic to me for this disease, there are a variety of risk factors that have been looked at and calculators out there. Um and this is just one of them. Again from the large series from Sloan Kettering, um you know, giving five points for a variety of things. But what I mostly put this graph in there for is is to draw your attention that even in those who have high risk disease who had, you know, all of the risk factors and most of the risk factors, there are people still who have long term survival and there are ultimately patients who if they undergo are zero liver resection, even with high risk to us can be rendered disease free and have for a long survival? We as medical oncologist. So I think are are often actually um uh huh or for for decision makers about who should undergo surgical evaluation. And and I don't think that will surprise any of the surgeons in the audience that really medical oncologists are not are not the proper people to evaluate patients for respectability. Um this is a study of uh 10 different CT case is given to a panel of a 190 medical oncologists and they were deemed to be respectable, convertible or un respectable by a panel of surgeons. And as you see, the first eight cases were felt to be respectable. The 9th case was convertible potentially with Chemo and only the last case was under a sectoral. But as you see from the graph, the blue line sort of shows the referral rate um or the, you know what, the potential referral rate of medical oncologist for a surgical evaluation and and even by the middle where the cases are getting a little more complex, only about 40% of patients would be referred to a surgical oncologist. So, you know, I think we as medical oncologists, um, you know, again, are are reluctant, I think sometimes with higher risk patients to refer them. But I think as you'll see tonight, it's really imperative for these patients to be reviewed. You know, both the diagnosis and during their treatment by a multidisciplinary panel always looking at potential liver directed options. What about patients who really do have unrestricted disease? What what can we do as a medical oncologist to help get them there? Um There's been you know, a variety of studies um and this is just a couple of studies that are out there. Kind of looking at conversion to reception. Um This graph on the right is a panel of reception rate in various clinical trials of systemic therapy correlated with response rate to the systemic therapy. And there is a correlation um As you see there is slightly higher rates of reception with uh chemotherapy backbones that have higher response rates. And then as you see on the graph on the left um This was a randomized phase two study of basically doublet chemotherapy for Fox versus full fury knocks. Um and it showed that again there were slightly higher rates of R0 or R1 resection rates in patients with colorectal liver metastases that needed chemotherapy for conversion. And so you know, again, while the data is still um relatively uh relatively modest in terms of the differences I think in patients who are candidates to get triplet therapy, I will typically use a triplet for convertible patients if they're able to tolerate it. And in those who can get E G. F. R inhibitors to further boost the response rate? I think that's an additional option we have available patients. So we typically try to choose the chemotherapy that the patient can tolerate that has the highest response rate. And those who are potentially respectable were convertible. Adjuvant therapy though is is a is an area that is actually a little bit less clear what the role of a german therapy in these patients after they undergo liver resection. It's been pretty clear from a variety of clinical trials that adjuvant therapy after a liver tumor resection does improve disease free survival. Um But studies have not consistently shown an overall survival benefit. And as you see in the graphs on the right, which are from this most recent study that J. C O G 0603 study out of japan. Um There's actually worse survival in that study with chemotherapy versus just surgery alone. But we'll go through quickly each of the trials just to discuss. I think what the evidence we have shows the first is the 900 to study, this is an older study out of europe with bolas, a german five F you for six months versus observation. And as you see, it did improve disease free survival at five years, it was statistically significant. 33.5 versus 26.7. And a trend towards improved overall survival. 51 versus 41% at five years. I'm not quite significant. Um but getting close. Um But that's sort of the follow up study to that was the intergroup uh 40983 study. And this actually looked at peri operative and with full fox now instead of just five f you alone. Um And again showed an improvement In PFS 37.9% vs 28.6%. But a very very modest change in overall survival. Only a 4% improvement at five years. And this again it was underpowered. This is a secondary analysis but only had the highest ratio of .88 and was not statistically significant. And then again the most recent study which was published last year in the Journal of Clinical Oncology. The J. C. O. G. Study um looked again at a judgment full fox after surgical resection. Um and saw that, you know, again disease free survival. The primary endpoint was significant, 49.8 versus 38.7% But the overall survival actually favored surgery alone. And again this was still an early analysis, there weren't that many events. Um and and so it was sort of preliminary but in the published study again, the hazard ratio actually favored surgery alone in these folks. And these actually were not patients who had been exposed mostly to chemo, only about 17% had gotten prior chemotherapy in this study. Um they were low risk, you know, generally 1-3 tumors as in all of these studies. Um And so we don't really know how this data applies to those with higher risk tumors. But certainly I think um raises you know raises questions about the utility of chemotherapy and these folks. Um And I think in those with low risk disease I think um it should at least be considered um those in high risk. We really don't know how to apply these. I will say in my own personal practice I will typically give a german therapy to those who have not gotten therapy before. Those who presents a with synchronous metastases or didn't get a judgment from attack Cronus diseases are the initial case was but I don't typically do it in patients who have already received prior chemotherapy. Um And hopefully we'll have better data in the next few years about how or who should get adjuvant chemotherapy as we learn more about how circulating tumor DNA can guide this. Um So circulating tumor DNA has really been proven and there are a couple of FDA approved now tests um that it really has a very high specificity for our current colorectal cancer and typically C. T. D. N. A. Positivity precedes radiographic recurrence by a few months. Um But essentially anybody who gets a positive C. T. D. N. A. Test will recur um And so it's specific that way. It is not as sensitive. Not you know not everybody will will have a positive result. Um But as you see from the largest study now out of japan. This was presented last month at Gi asco you know patients who are negative. Also for C. T. D. N. A. Have very very good outcomes and this is even at four weeks you can see that there are very few workers those who are negative at four weeks. Um As compared to those who are positive and if you look And had four weeks and 12 weeks those who are negative at both four and 12 weeks either because they were negative all along where they converted to negative during adequate chemotherapy have very very good outcomes. Whereas those who are positive or remain positive despite chemo do very poorly and riker fairly quickly. Um And they actually broke down in this study um You know looking at outcomes with adjuvant chemotherapy and they really seem to be no benefit and those who are negative at four weeks um and consistent benefit across all stages to two through four. Um With a german chemotherapy in those who are C. D. D. N. A. Positive at four weeks. And so again these are observational data. We can't yet apply them to clinical practice but there are a variety of ongoing clinical trials um using this to both intensify and de intensify chemotherapy and to help select patients. So hopefully we can use this in the future because in this study is interesting only 30.7% of patients with resected stage four disease were C. G. D. N. A. Positive. So if it it is validated um as as a way to select patients, we may be able to actually spare a large number of even stage four patients from a german chemotherapy. Um So that I will end my talk and turn it over to dr roses. But I can take questions if there are any before dr roses. I'm sorry I didn't. Let's see is there anything in the Q. A. We have no questions so far so I can let and like dr roses. Okay share his screen. No I'm sorry I'm still sharing. Alright. Thanks. Thanks very much tom. So I'll apologize that some of the content at least in their early slides um is um similar to times but I'll use it to a slightly different and then I'll move quickly or I'll try to move quickly through. Um So so Tom showed up a um an early series on reception colorectal liver metastases. This is another early series and here the patients were stratified by burden of disease and one thing to point out is the overall burden in this series like and many of the early series is low. I mean these are largely patients with single lesions or two or three lesions but the signal from this study and a lot of other studies like it is clear that in a subset of patients who receive surgery there's this long and elevated survival curve and another study similar to another, another slide similar to one of Tom's but an aggregate table looking at a lot of the series on reception, larger series over an earlier period and moving towards more contemporary series really focusing on studies that have Actuarial survival out five years and then 10 years. And you can see that that signal from the early studies holds up And that a subset of patients are doing well at 10 years, usually in the 20-30% range. And and that type of survival is really only achieved in the surgical series. Um and so that provides the clearest rationale really for surgical management of liver metastases diseases to benefit this. Um Not small but but large minority of patients who will live long term after surgical management or complete surgical management. So the early studies, as I said, um focused really on patients with a very small burden of disease. The paradigm has shifted over time and there are a lot of reasons for this. In general stage four patients are doing better and that reflects both better systemic therapy but also improve safety of liver surgery and broader application of liver surgery. Um There are also new adjunctive techniques and in some of the latter talks will will hear about those in all mentioned portal vein embolization. As an adjunct to surgery to really improve or extend the indications of the indications for surgical management. Um And this is a this is an iteration that kind of gets at the contemporary definition of respectability for colorectal liver metastases. There's a little wordy but um what it what it boils down to really is that um respectable means you can remove all of the liver metastases with negative margins and preserve a functional liver remnants. So I'm going to frame the talk or the brief talk around two cases. Two really distinct cases on opposite ends of the spectrum. So this is a 74 year old male who originally underwent reception of a node negative sequel cancer. And then about five years later presents with this isolated tumor in the right liver. Um It was biopsy confirmed his colon cancer because of the long disease free interval and in contradistinction, very different case A patient with a sigmoid cancer and synchronized by levar liver metastases. I can't show all of them in these cuts. But he had two lesions in the left liver and five in the right. He was minimally symptomatic from his primary tomo which could be traversed with the telescope. And so the question is where did the where did the different um treatment modalities? How do they how do they benefit these patients? And what should we prioritize? So so back to the determination of respectability. So here I've distilled down that word, Your definition respectable is the ability to achieve negative margin resection with sufficient reserve. So what sufficient reserves in a patient with a normal liver. It turns out, you can take out about 80% of the liver preserve a 20% remnant. And most of those patients will do well in a patient with intrinsic liver disease apps and portal hypertension. You need a much bigger liver remnant. And then the group of patients who have had extensive chemotherapy Which will define as six cycles or more 30% somewhere in the middle. And that's pertinent. When we talk about sequencing of of surgery rank chemotherapy I'll move through this quickly. But but I have this here only to say that in cases where the remnant is small we have somewhat objective ways of defining what is enough using three D. C. T. Volume a tree tom alluded to patients selections. So not all patients benefit equally. Um The same reference from tom's talk from Memorial. There are other risk stratification schemas but predictors of outcome things. You'd expect extra hepatic disease positive surgical margins. No tal um metastases for the primary tumor. A shorter disease free interval, bigger tumors, more tumors. Hi C. E. A. Um Not all of these have held up in all of the series but but there are some recurrent themes but other predictors response to systemic therapy which is the subject of controversy. Um And we'll talk a little bit more about that and then kind of the evolving science of biomarkers. Rast mutation status. Community co mutated rest. Tp 53 these are starting to enter into the into the calculus for um uh surgical management of colorectal liver metastases ease. So the E. RTC study which tom alluded to um is pertinent because this focuses on relatively low risk patients. They randomize patients with up to form a task disease either to surgery alone or peri operative chemotherapy. Um As tom said the study wasn't powered to detect an overall survival advantage and it didn't show one. This is actually the figure that looks at eligible patients. So this is a post talk figure. Um And it eliminates the patients who fell out before surgery because of progression. And it reaffirms the idea that chemotherapy at least preoperative chemotherapy can used can be used to guide candidacy for surgery but note that the amplitude of the benefit overall is small. What about the higher risk patients? The patients with more metastases outside of inclusion criteria. So um in those patients in general we tend to use chemotherapy. Peri operative chemotherapy sometimes preoperative sometimes just a juvenile. What are the advantages to each. So in the new agreement setting. Well if the patient's un respectable chemotherapy is obviously self recommending. But even in patients are respectable there are times when we can down stage disease fair parang come up. Um Is there a decreased recurrence for some of the studies have corroborated that idea. The more philosophical idea of gauging response and and as as a way of guiding postoperative or adjuvant therapy. Um But there are pitfalls to and and HIPPA toxicity from chemotherapy is not trivial and in patients who are going to have a marginal liver remnant. Um It can be very significant. And then also the pitfall associated with disappearing liver metastases which um um which can complicate surgical manager, another word on toxicity. So um different patterns of toxicity with different regimens. Yellow livers, ketosis, Seattle hepatitis associated with the reno thi can based regimens the so called blue liver associated with with absolutely flat and east regimens. And these haven't always translated to worse outcomes. But again, in the context of larger receptions, a smaller liver remnants, they can be relevant. The more complicated patients for us to manage are the ones with synchronous disease and particularly patients with synchronous disease in the context of erectile cancer. And there are a lot of moving parts. Um Is the primary symptomatic. Is the liver disease respectable or not initially. Um Where does neo adjuvant fit in the mix? Can you do the operation state combined or do you need to stage them? And if you're going to stage them, do you do the liver resection first or the primary first and then other factors as well. So the age and co morbidity of the patient. Um And then finally access to and availability of care. Um But but there's still down there are really three basic approaches. The so called classic approach resect the primary and then come back after. Usually systemic therapy for reception of the metastases the reversed approach. A reverse approach where you clear the liver first and then respect the primary at a later time. Um, and finally the combined approach, often starting with chemo therapy but not always and then respecting the primary and and my task disease at the same setting. So this is a this is a figure that I included only to say that all of these approaches have a role and the sequencing becomes personalized and depends on a lot of factors extent of disease in the liver, the symptomatic or asymptomatic nature of the primary etcetera. And this study demonstrates equivalent survival in all groups but really speaks to to rational judgment on the part of the care team selecting the best approach for a given patient with the given spectrum disease. The combined approach surgery on the liver and the primary at the same time has has gained momentum over years and is safe for the majority of patients. And and we to operate in a combined setting for a majority of patients within inter abdominal primary tumors. In other words, excluding rectal cancer. But there are pitfalls and they bear mentioned so complications from colon surgery are poorly tolerated if there's a marginal liver. And um and so there is there is reason to give pause I think to the idea of doing for example, a prostatectomy for locally advanced rectal cancer and an extended or a major HEPA tech. To me. Um Buy, low bar disease in the liver may not be respectable in a single stage alone. And so the notion of a combined operation isn't always feasible or practical. Um and finally, early morbidity from a big operation may limit subsequent treatment options in patients with unfavorable tumor biology or high risk disease. And and just to reaffirm that or to to emphasize that this is a study, a large study of HEPA techniques and non psoriatic patients and note that um combined or associated procedures were a dominant predictor of poor outcome of mortality. Um all cause or liver specific. Um So what about the staged approach? Well, there are obviously two staged approach is liver first and primary first. So why choose one or the other? Um uh it's a complex, a complex calculus. But um some of the circumstances where where it becomes more clear when there's a greater burden of tumor disease of tumor in the liver. Um Often liver first. Um, If there's a need for pelvic radiation or long course pelvic radiation, which often represents a long delay in treatment. And you've already had a response to chemotherapy for let's say, an outside spectrum of disease in the liver often will deliver first. Also to capitalize on a market response in the liver. Um, liver first. Um in contradistinction to patients who have a bulkier symptomatic primary tumor in the coal. And that really mandates local control of the primary tumor. Um um we mentioned or I mentioned the concept of portal vein embolization and two stage hepatitis B. So a little bit more about that. What is to stage hep attacked me? This is an approach for patients with buy low bar liver metastases usually involves partial left to protect me the clear left side of disease. And then portal vein embolization to hypertrophy, the liver remnant. Um And this is a cartoon of a Nipsey lateral approach. Their multiple approaches. I don't know if Michael will get into that at all but um it's a way of preconditioning the liver remnants and enhancing the safety of um an extended operation. Um And and just a word on the outcomes from the two stage approach to this picture from a study by broke, it highlights kind of the binary type of survival that you see in patients who are initiated on a two stage approach. And so you see the patients who complete the approach do exceedingly well. And these are largely patients with with a high volume disease or high risk disease. The patients who don't get through the sequence don't do so well. So it's a way of super selecting patients at high risk for failure. Um so coming back to our two cases, the 74 year old patient with attack Cronus disease underwent resection alone for an isolated tumor never occurred after that operation. And the second asian with more complex by Wilbur pattern of metastases in a sigma, primary underwent laparoscopic sigmoid collecting and laparoscopic partial left to protect me then portal vein embolization and then write. Help protect me. Ultimately rickard years later in the long actually, I mean so with that I'll end. Thanks very much. So it doesn't look like we have any any additional questions from the chat. So I think we can move on to dr di matteo. Okay. Can you see my slides? Okay. Yeah. Alright. So I'm going to talk a little bit about intra intra arterial hepatic pump chemotherapy. It it goes by a variety of names. Sometimes we call it H Ai hepatic arterial infusion. And this is for colorectal metastases. Uh We also occasionally do this for interpreted calandria carcinoma as well. So this is a sort of schematic of the approach that Dr. Kemeny at Memorial Sloan Kettering took in the 90s. She had been using the pump for quite some time prior to this sort of landmark trial. And this is in the adjuvant setting. We use the pump in the adjuvant setting and also in the unrestricted ble Colorectal liver metastasis setting. So she did the following trial. About 150 patients they underwent complete resection of all the liver metastases and they were randomized inter operatively to systemic Standard chemotherapy at the time was five if you look at Boran or systemic plus pump. And so I've kind of shown you this here this is sort of a rite HEPA tec to me. And that this is standard arterial anatomy where the gas redo Dino artery which you can sacrifice comes off of the paddock artery. And then a little tube gets put in that stump of an artery and eventually connects to a pump that looks like this. This pump is about the size of a hockey puck very different than a meta port. But it's also a pump. You don't need to be connected to an external pump to to use it. And so this pump gets filled every few weeks with either sailing or with chemotherapy. And the basis the whole rationale for doing this is number one. Colorectal liver metastases are preferentially supplied by the paddock artery as opposed to the portal vein. And then also there is a derivative of five F. U. Which is flocks Gordon or F. U. D. R. And it has a very high first past extraction in the liver. So the concentration of the drug is quite high. And here's just some other drugs that were tested in comparison. And if you look at the date on this, this was figured out many many years ago. So F. U. D. R. Is pretty much the main drug that's used through the pump. Uh Miss thomas. And see I've seen in some cases where F. U. D. E. R. Was no longer working. So uh I was at memorial for 20 years. And uh I'm going to show you really some of dr companies data, some of which I participated in. So the original new England Journal trial that I just showed you about, you know, 70 80 patients in each arm. H Ai pump meaning pump plus systemic versus systemic alone. These are the progression free survival. And I'm not showing you the actual original article, I'm showing you the extended follow up. The original article showed a difference in overall survival at two years and that was what got it into the new England Journal. The difference was 86% in the combined arm versus 72% in the systemic only arm. But this is here, I'm showing you a progression free survival and uh there's a bit of a curiosity here which nobody's really ever answered. I mean, the obvious question, the obvious answer is that, you know, well of course it works better within the liver because that's what you're targeting. But you know, in terms of total PFS essentially patients who are not getting the pump are are recurring elsewhere besides the liver. And so that difference is not as striking when you look at PFS anywhere in the body. So the pump is very good for what you set out to use it for, which is uh hepatic progression free survival in terms of overall survival. Well, it's a little stickier uh you know, sort of as you saw with the adjuvant uh european trial where there was a difference in progression, but not so much of a difference in overall survival with extended follow up, even though there was a difference at two years as I already told you, uh extended follow up, the difference was not quite as dramatic ah and was not actually statistically significant. So this led to a variety of Phase two trials done at memorial led by Dr. Kemeny and some of the surgeons as well. And this is sort of a compilation of multiple sort of Phase two trials that were done using newer agents at the time. And this is not a randomized trial. This is sort of accumulation of patients that were sort of coincidental in time. And this publication was in the annals of surgery some 10 years ago. And uh looking at recurrence free survival and overall survival here was even more dramatic with the more modern agents at the time. You can see combined therapy for recurrence free survival or progression free survival in the adjuvant setting had a much bigger difference than just systemic alone. And then overall survival, you know, five year overall survival in after resection is somewhere between 50 and 60%. But you can see it was closer to 75, in in combined use of adjuvant postoperative therapy. This was a different study because again, it was really just that one randomized study that was done uh And in fact, there's another more modern randomized study that's being done in europe right now in the Netherlands by one of our graduates from Memorial. So hopefully we'll get a more modern randomized trial set of data soon. But this was another sort of retrospective or prospective lee collected data analyzed retrospectively. and during this time frame, 1992-2012, there were, You know, 23:00 liver re sections done at Memorial. And this was just sort of all comers in a propensity matched way. Uh 759 were selected that just got surgery and got chemotherapy. But but no pump. And 785 got the pump. And again, not, you know, It's not a randomized trial, but there clearly was a difference in overall survival between the two groups. Now, 1992-2012 covers a variety of systemic chemotherapies that were available. Of course. You know, uh Dr Rose has mentioned uh KRS status briefly and there's been a number of papers looking at outcome dependent on care? S status even, you know, in the primary setting, but also in the metastatic setting. And um you know, this paper was done by another one of our trainees. And she basically found that it doesn't really matter whether you have a career as a mutation or not. In either case you're doing better if you get a pump in the adjuvant setting. So this is a wild type plus wild type, meaning no mutation in keras plus pump chemotherapy in red and down here, you can see in black is the comparison group. And then uh mutant care as with the pump is blue versus black if you didn't get a pump and you have a presentation. So uh sort of just the general theme that the patients do better. And this again is overall survival. This is the last slide I'm going to show you. But again, I'm happy to answer any questions. This is in the other settings. So everything I showed you there was in the adjuvant postoperative setting. This is really in the unrestricted ble disease setting. And this was a paper written by one of the medical oncologists Who works at memorial and she basically took 110 patients who had already failed three lines of chemotherapy. And you know, the results are kind of interesting. This is response and the green is basically patients who by resist had a 30% reduction. But you know, there's a there's a large group in here that didn't meet the 30% but you know, at least had stable disease are not quite a full response. And then you can see the patients who had immediate progression of disease is a minority of patients. And so, you know, even if you failed one or two lines of chemotherapy and in this case three lines of chemotherapy, there's still some benefit to using the pump as far as we can tell, at least in a single armed fashion. Like like I'm showing you here and then in terms of overall survival in patients with only a paddock disease that had failed three lines of chemotherapy, you know, you can still keep them going for a while. So the pump, you know, it takes a village to have a pump program. Uh And and and you really need all the people on the call that you see tonight. You need uh you need surgeons to be able to insert the pump safely. There's there's variability in a paddock arterial anatomy. Not every patient is eligible for a pump just based on how their arteries branch, but the most are. And uh you know, you need medical oncologists who are committed two sort of fine tuning the dose ng of F. U. D. R. Because there's problems, you know, everything comes at a cost. And and one of the most common costs of pump chemotherapy is is uh Damage to the bile ducts. And about 5-7% of patients will need a stent in their bio duct because of damage most, most of the time that's happening in the adjuvant setting, not the unsuspecting ble setting. You also need interventional radiologists because things go wrong with the pump or occasionally there's a dislodge mint of the pump and you need to either put a stent or MBA lease the paddock artery. Uh So it takes a lot of people and uh you know, there's not that many centers across the country now, I do have to say that a lot of the surgeons that have trained at Memorial have gone out in the world across the country and there's and trained at other places too. But there's a lot of there's a lot of centers now using the pump and you know, hopefully we'll get some more modern data to prove its use. I'd just like to say one other thing about adjuvant therapy um and dr roses didn't didn't go into it in too much depth. But you know, when we're looking at a german therapy were were we're talking about clearing the liver of disease and you know, clearing can be done in a variety of ways. The two most common are to remove a tumor. But you know, sometimes when they're small tumors that are deep, we can oblate them using microwave ablation. Our radio frequency ablation was a little bit older technology but in livers that are generally normal where we can see deep inside them with ultrasound. We can often do ablation and resection to clear, you know, a variety of hummus and we, you know, we would still count that as then giving them adjuvant therapy. So that's going to be it for my presentation. I will stop sharing. And I have a question for you from the chat. This is from doctor Sami minority. Is there any sub analysis liver PFS data for patients with replaced right hepatic arteries, there isn't. But you know, we can often when someone has a replaced right of paddock artery usually the gastro duodenal artery which is our artery of choice to put in the catheter is uh It is still used because it's coming off the main a paddock. And so we would in the case of a replace right. Which happens in 25% of the population. So we see it all the time. We usually just tie off the vessel and and you get pretty quick cross profusion of the liver. The only time that it's really a problem is when you have a very large tumor in the center of the liver and then you somehow those little arterials can't communicate like they normally can. But it's fascinating in the O. R. You can tie off the right of paddock And 10 minutes later inject the pump which is coming through the GTA. And you'll see plenty of profusion into the right liver. So occasionally we have to sacrifice a major vessel which can have implications down the road depending on what surgery we're doing. So that that was the only question we have for now but certainly feel free to continue to send questions through Q. And A. And now we can turn it over to dr stolen. All right. So you're saying my sides. Here we go. So I'm going to talk about other forms of liver directed therapy. Um So when I see a patient, you know I might immediately look at them and try to put them in three buckets are the respectable, they should go to dr Rosen's dr di matteo. Maybe they need a little help from us with the normalization. Maybe not. Maybe they need to be downstage. But you know that's one group then in the patients who have liver disease but they aren't respectable but their liver still works in which case we think about ablation trans material therapies or some combination thereof. Also a systemic therapy. And then of course there are the patients who aren't appropriate for the security at all and reinforce what Tom said. You know most of these patients with metastatic colon cancer die from the liver mets and in fact 38% died with liver mets only without disease elsewhere. So this is a big group of patients who need our help. Um So obviously I'm focusing on this middle group of patients, the ones that aren't going to go to surgery but potentially could get some form of image guided therapy. Now unfortunately happens in the real world is tom alluded to at the beginning is they all get seen by medical oncology and they all get systemic therapy and then they get more systemic therapy and then they get more systemic therapy. And then when you're done we get the tire of the poor and the weak that are still standing at the end of all that time. And what I'm hoping to encourage you to do is this is at least get you know, just like you should think about surgical consultation, you should think about by our consultation earlier in the course of disease. You're still going to give her systemic therapy. But don't we want to see these patients for the very act. You already heard very nicely presented by dr roses. How even patients with very big disease can still potentially cured. So I always look at the scans, they are the receptive or can we make it respectable? So here's this patient with this giant dumba taking most of the right lobe, in fact that they should have two of these, one above the other. Um But you know, with a little portal vein embolization, right lobe shrinks, the left lobe grows and the patient gets curative surgery. Um And as dr rosa showed you, you know, with or without portal vein embolization. If you get respected, their survival is way better than if you don't. But I usually deal with the other end of the spectrum of patients with smaller lesions. Uh and there's nothing more frustrating than referred a patient for trans arterial therapy. And I looked at their scans and I realized that like six or nine or 12 months ago the disease is actually applicable. So maybe they couldn't have, maybe they didn't have anatomically respectable disease. But if the lesions were less than three cm potentially patient that had curative ablation instead of waiting six months for them to progress. And then saying that when they no longer are eligible for any curative therapy and ablation actually works quite well among the patients that can be a bladed. So this is data from Alex villains in London. Ah And it's 10 years old but she is one of the world's experts in this area. This was using our F. A. And what you can see is that even with you know up to three centimeters tumors and up to three tumors or even up to 55 centimeter tumors. You know at five years. The survival rate is very similar to what you see among patients who get surgical resection. So ablation is clearly in the N. C. C. N. Guidelines either alone or in conjunction with surgery as long as you can oblate all disease. Um So but we need to get these patients at an earlier stage. The other nice thing about ablation is that it's repeatable. So you ablaze someone you know if they don't recur great but if they do recur in the liver often you can inflate them again. Some patients maybe a medal of this therapy more than once and get them to restore a disease free state. So you know if you played someone and they have no liver tumor progression there meaning survivals five years if they recur but you can rehabilitate them. You still got the median survival of four years versus if you can it drops down to about 2.5 years. So another nice thing about ablation is you can do it more than once in the same patient over time as meeting. And there is a randomized trial looking at chemotherapy alone versus chemotherapy plus a blade of therapy. This is the clock trial was done in europe. Now, when I say a blade of therapy, it could have been just R. F. A. Or it could be a combination of RFK in surgery. But regardless, the patient had to have all the disease extirpated. And you can see that overall survival was markedly improved in the patients. Were you extricated all the liver disease versus just giving systemic therapy. So just think about those early patients and and give us a call. Now, you remember that all that data is really from the RFK era and as dr David alluded to now, we pretty much use the microwave. So, you know, ablation is actually technologically improved tremendously in the last few years. So microwave has essentially replaced R. F. A, which gives things much hotter, much faster. We've also learned our limitations. So now most people realize that we're gonna do a presentation. This ablation. You really want to send a precise limit in the 2 to 3 centimeter range. Many people use 2.5 now. So we're not trying to do lesions bigger than that because the failure rate is pretty high. You need to think about other modalities for that. We've also got more sophisticated about locations. So we know near the highland is not safe because the bile duct injury. But we used to think that your big blood vessels was a problem. But now microwave, you know, it's so much more powerful than our F. A. That we can overcome the heat sink. So now we can treat cardiovascular lesions and then the sub capsule location. There's still conflicting data. That's that sorted it out yet the other thing that we've learned is that margins are extremely important. So the graph at the bottom shows you uh local tumor progression free survival rates. If you have no margin a margin less than five cents five millimeters. A margin of less than 10 millimeters or a large in bigger than 10 millimeters. And basically, you know, as your margin gets bigger and bigger, your occurrence rates goes down. So you actually do quite well above five millimeter margins. And in fact, if you have a 10 millimeter margin, there's no local recurrence. So we've learned that we actually have to monitor these margins in real time and achieve them. So it used to be, we just to break the patient and get a scan a month later and our local failure rate was almost half the patients. Now we do intra procedural cone beam ct. So we actually ct the patient at the time while we're still on the table with a dual phase contrast injection. Looking at the material and venus phases and if just doing that and realizing when you may have been a little short on a margin. You can cut that recurrence rate in half down about 25%. And now we have three D. Ablation confirmation software. We actually segment your ablation zone. You register it in three D. With the original tumor and it will automatically calculate in three D. Your margin for you and show you much better than your eye can perceive if you kind of shave one edge too close and you can go back and touch it up and if you do ablation confirmation software and get a circumferential 3 60 10 millimeter margin. The local recurrence rate is zero. So with this improvement in technology the uh the benefit of ablation by carefully selecting the right lesions in the right location and then doing a better job technically is really going to improve outcomes. And we're actually just launching something called the acclaimed trial which will be a multi center international trial where we're doing ablation of colorectal maths under 2.5 centimeters with ablation confirmation software with the goal of demonstrating that the efficacy is equivalent to a reception. Let's move on to trans arterial therapies. I'm gonna start with trans arterial radio globalization or tear. Sometimes that's called cert or um selective and generation therapy or sometimes people just abbreviate Y 90 because that's the isotope that's used. This originally was used primarily in the salvage setting after the failure of 1st and 2nd line chemotherapy. So there's data on thousands and thousands of patients where this was used later in the course of disease. For patients who still had liver only liver dominant disease, we know it's safe and tolerated these patients consistently. The median overall survival is 8 to 12 months in the salvage setting, which is way better than any third line systemic therapy or best supportive care. The question is, can you move this up and do it with standard 1st and 2nd line chemotherapy? So, fortunately all the combinations with drugs have been studied. So we know you can give five or fewer keep sight of being with no dose reduction with y 90. You can give a realty can or in a full fury regimen with no dose reduction. Excellent plant needs dose reduction because you get unacceptable toxicities. So while you're doing your realizations, you need to drop your salad platter dose from 85 to 60 mg should be your square for about three cycles while until the patients recovered from their Y- 90 therapies. A vast and athleticism and we like to hold it for four weeks before and after. And that has to do with the complications. We see in surgical procedures and patients on athleticism. Abso it's best to find for surgeons that we know there's problems with wound healing and the Hisense and bleeding. And so for example, we have a two week hold on this if we're just putting a chessboard in the data for catheter based therapies is a little less queer. But the general thumb is you need to be off at four weeks before and after and then for the e g F R inhibitors, we don't really have any data on safety issues combining with White Knight positive or negative. So what happens if you try to move this up and combine it with systemic chemotherapy? So first that was tried in first line, so this was the Foxfire Sir, flocks and Foxfire Global studies. They had 1100 patients randomized to full Fox with or without. Uh Why 90 realization of the first line as you can see from the left hand curve. The realization did what it was supposed to do in the liver, it cut liver progression in half. However, that does not translate into overall PFS benefit or overall survival benefits. Similar to some of the data you saw with some of the surgically directed chemotherapy. So this was obviously disappointing to us but it does show that while you can treat liver mets in the early stages, if you do it. First line, basically that benefit is lost in the soup. Uh and the outcomes globally do not improve. What about second line. So this study just came out in general local oncology at the end of last year. This was the epoch trial where which was essentially the same design patients who have progressed on first line chemotherapy can go on the second line team chemotherapy regardless of which, you know they could be there for fox or foal theory but when they went on the second line they were then also randomized to realization or not. Now this was not an OS powered study. So this was the primary endpoint was actually co primary endpoints of PFS and hepatic BFFs and they hit both. So both a pack of progression free survival and overall progression free survival statistics. Scientifically improved when you gave realization with second line chemotherapy versus chemotherapy alone In terms of some of the secondary endpoints, the objective response rate was also significantly improved with Y 90 overall survival. Not significantly improved slightly but really pretty close. But again the study wasn't powered for Os nor was it designed to measure OS because they allowed crossover. So patients who got chemotherapy only if they progressed, once they progressed went off study they could and many of them did get liver directed therapy at that point in time. Um So based on all this we have new N CCM guidelines saying that are truly directed Catherine therapy in particular. Real globalization is an option for selected patients who are chemo resistant refractory is that failed at least. First line chemotherapy who have liver dominant disease. I'm gonna just finish up mentioning chemo embolization. So criminalization of course there's a historical therapy has been around for 40 or 50 years, conventional chemo embolization although it was widely used in colorectal mets never got a lot of traction. But again with advances in technology we now have drug eluding a bollocks where we can load chemotherapeutic drugs that are more specifically designed to treat colon cancer. So DeBary, which is a drug eluting B with a rito T can can be used to deliver a high concentration bot can directly into the liver metastases. Um And there's some sort of encouraging looking phase two data, some of it randomized some of its single arm mostly out of europe where they have looked at patients again in the second line setting. So they failed first line chemotherapy and then they were randomized to fulfill real full fury plus delivery administration to deliver mats and and then they continued on chemotherapy after that. And what you can see is in both PFS and Os. And this study actually significantly improved in the patients of dr berry. So Again encouraging looking but not you know, very small study, only 38 patients per arm. Um and but there are now about half a dozen perspective singular for for two armed studies in this space. And we're actually starting a debris trial at Penn for metastatic colorectal cancer where we're combining it with um hydroxychloroquine and exited to try to potentially the anabolic effect. So uh this is encouraging but much more work needs to get done in the demobilization space. So that's it for my presentation and we'll see if any more questions does not look like we have any more questions in the chat. I'll stop sharing. So we'll move on now to our last lecture from Dr Ben joseph of radiation oncology, you're still muted. Okay. How about now? Can you hear me? Yes. Um Well, okay. So I said I don't have much time, so I try and be brief um and for some reason this is not advancing the way over there. Okay. Um you know, radiotherapy has not been used in a in many years. Um Because there was this report of radiation toxicity back in the 1940s from Stanford University. So they call it radiation hepatitis. And I'll show a slide on this in a second. But Because of that for about 60 years, we have not been using greater therapy in for liver cancer, any sort of metastatic or primary. And um but today we do and we have a lot of catching up to do. So we don't have a lot of clinical trials. I don't have a lot of clinical rights to show you. Just a few. And I'll try and convince you that red therapy is effective, probably similar to the different methods that you've seen by international radiology, fairly similar. Uh and maybe with high those proton therapy or high dose radiation um even similar to to the gold standard, which is surgical resection. So the approach is really based on size and size relative to the volume of living. Because just like uh in the sort of surgical approach, you have to spare a certain amount of non involved liver in order for this not to be toxic. And so for larger tumors, usually more than six centimeters, we use fraction it with therapy sometimes with or without really uh chemotherapy agent, radio sensitize owners. And for the smaller one there was less than five or six centimeters still to everybody. Ready step is a very good treatment. So we talked about this toxicity that was reported before his radiation hepatitis. That was a big problem. And it was it had to do with really rudimentary planning and with truly not understanding the tolerance already of delivered to radiation therapy and consequently you can get what we call radiation induced liver disease. Nothing to do with hepatitis. It's a misnomer. It's actually a xeno inclusive disease and it manifested society. It's a powerful medellin jaundice um usually obstructive pattern, No treatment for that. And rarely but not rarely, it could be fatal. Uh the big change occurred in the 1990s. My previous chair, TED Lawrence um at the University of Michigan had started a series of study to understand liver tolerance to radiation therapy and consequently they were able on to develop this model for normal tissue complication, probability essentially tells you. It plots what you see here is the risk of radiation use liver disease by the main liver dose. And once you understand that and you understand how much radiation you can actually give. You can actually bring down the risk of a complication fairly dramatically. And based on that at the time we conducted a one of the first trials of radiotherapy was a phase two trial of liberated therapy in patients with Uh metastatic disease, psychological cinema or HCC in three different cohorts. A total of 128 patients. I'm not gonna dwell on the details. But each patient received the highest radiation does that they could receive based on uh them uh on an estimated normal tissue complication probability not greater than 10 or 15%. And this was done with a paddock, artery infusion as a radio sensitize. Er And I reported this back in 2005 in J. c. o. And some of the things that we have learned from that trial, one that we too had actually Long term survivors in this trial. And you can see there are about 20% of patients that received hydrotherapy. We are long term survivors. And the most important factor was the radiation does so at the highest radiation dose patients did reach that plateau at five years and later. Ah And on a Multivariate analysis that you see here the radiation does was the most important factor for overall survival in these patients. This was in an era where really there were almost no systemic therapies except for five of you. So the question was then, how do you increase the radiation dose to make this more effective today? We have a variety of different methods that we could use. Um So intensity modulated radiotherapy, volumetric modulated therapy, protons, all of these things allow us to um increased the radiation does and do this safely with reduction of the risk of a complication. What you see here is, for instance, one method. This is the problem facility um down at at P. CaM at our main facility in downtown philadelphia. Um And with protons as you may know, you could target the tumor in there that you see with actually giving very little radiation does at the entrance those on the way to the tumor or past the tumor. That's part of the character of physical characteristics of protons where they have what we call a Bragg peak, where they posit the radiation dose. So you could give much much higher radiation doses with a far lower risk of a complication. And just to illustrate this thing you can see on the left side, a typical radiation dose distribution from something like the MAC. That's a photon based method. And you can see how much low to intermediate those radiation you spread all around the lesion and on the on the right hand side you can see the pradhan those distribution. This is a fairly rudimentary form of problems. We have much more conform along methods today with protons. So you can spare a lot, a lot more liver. This is what I'm trying to say here. Uh Now there are no large series of colorectal cancer is treated with high dose therapy. Um but there are eight CC uh series and the japanese have been using problems therapy for hepatitis carcinoma for more than 30 years. And this is one of the good series from University of Tsukuba Nakayama for instance, published a overall survival in more than 300 patients of 45% in five years for anyone familiar with the HTC literature, this rivals results of surgery in this disease. Just to show you that control can be accomplished. I am not going to talk much about survival because survival heavily depends on how you select your patients for therapy and all the speakers before, before we had discuss this selection and how it influences survival. It's a high, it's a high bar to meet. But control rates could be extremely high in the leather. Okay, now onto the simplest stuff things that we could do for smaller humans less than 600 m in size. And here we used the third And this is a very good method for these smaller tumors. We can give very high radiation in 3-5 fractions. Uh This is a seminal trial. Published in J. C. Oh maybe about 10 years ago, maybe more, maybe 15 years ago now. Uh And uh up there in 2000 and nine. It was a phase two trial from the University of colorado. But it was a multi institutional trial Uh and essentially enrolled a variety of different types of metastases. Um and treated them all in three fractions 20 gray each. Um and the constraints were that you had to spare more than 700 disease. So more than 700 disease had to receive less than 15 grade. I'm not going to show survival again because that is heavily dependent on selection. But look at the actuality local control and deliver. So it's over 90% at four years. Um So how does this compare to radio frequency ablation? I'm not going to show you all the different trials but this is a good paper from the University of Michigan where they have compared S. B. L. T. Two to RFK. Um And you can see uh sort of it's a retrospective analysis but a good number in each in each arm. And you can see that the things where the arm deferred were mostly in in peacock performance status was actually better in the R. F. A. Group and a diameter which was smaller in the group and it was statistically significantly smaller. Ah Yes. The results show that the sort of local control, I was slightly better numerically and this almost reached statistical significance with therapy and on the right hand panel what you see is plotting the hazard ratios for failure for local failure in the liver in the lesion that were treated versus the size, the diameter of the geometry in And what you see there. Those um that's the best estimation with the 95 confidence in Terrebonne and where it crosses one Is at around two cm, essentially. What this means is that still a tactic by the way, therapy was better in control in tumors that were sort of bigger than two cm. Uh And on a Multivariate analysis in that same trial, the hazard ratios of R. F. A. This is therapy was 4.75 highly significant. So uh in this particular series, therapy was superior to RFK Um and particularly for lesions greater than two Sunday you know, it's a small series retrospective. I don't think that one should put too much emphasis on this, but I hope that this convinces you that the attack anybody way therapy for Lesions less than 5-6 cm is fairly equivalent to an ablation. Uh these are the conclusions from that trial and just to finish up with a Phase two trial. Specifically dedicated an Italian trial To um colorectal metastasis in three fractions 75 grade and again ignore the survival on the right. I think that has to do with selection. Just look at the local control on the left And at four years it's 80 85%. I have most lines but I we are short on time. So I think I can stop here and see if there's any questions so we don't have any questions in the chat and we only have we have five minutes remaining so please if you have questions um you know enter them now and certainly you know feel free to I think email the various presenters a few questions afterwards as well. Um You know it I will quickly show a case just in the last five minutes uh for discussion um and then but certainly feel free if you've gotten your fill to drop off if you were done with lectures now. Um But it looks like the question just came into the chat but I've had trouble pointed out just ask if there's a link for the reporting. Sorry what was it you were asking about? A link to the recording? He's got it, got it. Um Alright so I'll start with you know the second case that I was going to present just to give you know again one of these complicated ones with a rectal primary um and synchronous liver metastases. This is a patient who presented with rectal bleeding and fevers and showed again the pet scan for liver lesions actually had two primaries of sigmoid and erectile which were biopsy proven us uh was well differentiated adenocarcinoma um And some peri rectal impact in apathy on that pet scan. Um So I just wanted to ask you know again the panelists, you know, what would your be, what would your approach be in a case like this, you can ask rob and and Edgar and and what would your preference be about how to order these various therapies here? You want me to start? Sure. Yeah. So it's a little bit hard to gauge what the extent of the liver operation would be with selected imaging. Um But what's clear is the the operation for the primary is going to be complex. It's a very low lease and there's there's synchronous lesions in the rectum and sigmoid that's a relatively high risk patient with with synchronous disease. So my usual instinct would be to start with some induction chemotherapy. And then in the context of a response, try to build the liver resection in early before there's too much toxicity. Um If you can clear the liver, then that may be an appropriate context to to think about chemo, radiotherapy. If it's still pertinent and then protect me at the end of the at the end of the sequence. Um And Edgar, what do you what do you feel is the role of you know, of radiotherapy to the rectum and in cases like this? And and what are the different options, I think for for radiation and these folks, um you know, um I'll start with saying that we don't know anything in a definitive way in in in this setting. Um But I think that the the metastatic risk and the risk in general is very, very high. So I think whatever we do I would probably recommend it to start with chemotherapy and uh then I would just like robert said leave the management of the rectal and sigma at the very end because it may or may not cause a clinical problem as you manage the metastatic disease. And if you actually are able to clear the entirety of the liver metastases with one method or another or combinations of methods then you can get to treating the the pelvic tuners. And I think a lot depends at the end if we are treating these patients for cure or not and if you are able to clear the metastatic burden uh and you are then starting to talk about a potential curative treatment. Then I would recommend radiotherapy to the palace as well to um to enhance the local control in the pelvis and to ensure that there's no recurrence in the in the pelvis. But others have done it in in different sequences as you know. Um But that that would be my inclination to start with chemo, see what happens with those metastases. Try and clear the metastases and then deal with the local disease. Yeah, tom can I comment just to say um that we have selectively omitted radiotherapy in the context of metastatic disease after a really robust response to systemic therapy. And usually that um Breakpoint is managed at the discretion of the colorectal surgeon and repeat pro project task api and a careful exam. And so I think that the added benefit of radiotherapy in the pelvis and the context of a really um outsized response to systemic therapy is largely untested and I think there is a role for for really personalizing that decision making. I would not disagree well but I I think you're right. I uh and we have a trial that we are waiting in different settings to see if created 30 makes a difference um in patients who have robust response. So I certainly do not disagree. I mean I guess maybe one other thing Edgar you could comment on. Maybe not in this case but but um maybe as a forerunner to a combined operation short course radiotherapy. Where do you think that fits into the mix? It's a very good treatment option. Not practiced a lot in the United States. We're talking about five treatments to the pelvis followed a week or two later by surgery. Um and for patients where you just want to get where you clearly have a sort of a humor that would require in the context of a curative approach. Radiotherapy to the pelvis, you can just do the radiotherapy, get it out of the way and um and then concentrate on the other modalities, chemo and surgery. And there's many trials that have that have shown that it's equivalent to anything as that we would accomplish with longer courses of radiotherapy. We do have some sort of a bias in the United States against this short course. But it's catching up. I'll just show actually what happened with this patient just because I think it brings us to some of our other modalities. So actually, this patient was treated elsewhere and started with long course chemo radiation, which I don't think any of the panelists um, you know, suggested was was probably the right first step for this patient. But, you know, and unfortunately in that time had additional liver metastases. By the time I I I saw him back. Um, and at this point had about seven total liver metastases. And this is just, you know, again, his M. R. I. Including a lesion in the left now. Um and then actually proceeded at that point to the O. R. Um but was found to have even more disease at the time of the operation. Um, and reception at that point was aborted and ended up getting an H. A. I pump placed and started full fury uh, NH AI F. U. D. R. Um and then this, you know, this ultimately is the response again after about six months of full fury. H. A. I. F. U. D. R. Um, you know, they had a good response, no new lesions and shrinkage or disappearance of some of the tumors and was able to undergo ultimately a curative intent surgery with this is dr di matteo is patient um, and underwent ablation Zor receptions of the various 10 tumors that were found in the liver Eventually regarding the loans and then later in the liver, but but did quite well with disease free interval of about 18 months after this. Um I think we probably are having dropped off of our panel at this point, so I will end but but if there is any any additional questions, please send them in now. But I think that will probably end the session. I want to make one more comment actually on this case, yep, you I mean you alluded to the fact that we might have done something different or most of the panelists would have done something different, but I think it's a good example actually this case of of how the kind of opening flourish of care really does set the stage for for the follow through and and and I think it's important to to to reaffirm or to to to emphasize that really careful initial staging and a good multidisciplinary discussion at the outset can make a bigger impact. I mean, this patient progressed through the kind of opening stages of, of treatment which we wouldn't have selected and then had a follow up operation that was sort of disappointing, um probably in the absence of really meticulous staging. So I think maybe it's a good way to say um one of the things that we we really should spend our time doing in the early stages staging really carefully and having a good multidisciplinary discussion and figuring out what initial therapy is going to make the biggest impact. Yes. No, absolutely. I think there's often a rush to get started with therapy and these folks. Um but but I think it is really imperative to make sure all parties who are gonna be treating them have been involved and and make a consensus decision. All right, thank you everybody, thank you for those who stayed on to the to the end here and we'll end the session now. Thanks very much Tom and Amy and Sarah. Thanks for all your help getting this together. Thank you.