Peritoneal metastases: Drs. Klempner, Sgarbura, Gongura, & Hübner (2023)

This is an automatically generated transcript.

Manju George 00:00
Hello everyone. Welcome to Doc talks. I’m Dr Manju George, the scientific director at pal town Development Foundation, the nonprofit that supports golden tone. Thanks to Laurie for organizing this and to Dr. Sgarbura. So what we will do is that we will first go around and introduce the panel, and then, as Dr Scarborough has, you know the agenda we will go according to that. So let’s start then.

Dr. Sgarbura 00:24
Good evening, everybody. It’s very it’s an honor to be here and to meet you all and to organize this webinar, especially with this with this panel. So my name is Olivia Sgarbura. I’m a surgical oncologist at the Institute of Cancer in Montpellier.

Manju George 00:40
Okay, then Doctor Huber, do you want to introduce yourself?

Dr. Huber 00:46
Sure. So it’s also a privilege for me to to be invited here, and I’m very curious. I’m, I’m a colorectal and oncological surgeon at Lausanne University Hospital.

Manju George 01:02
Okay, thank you. Dr Klempner do you want to go next?

Dr. Klempner 01:05
Yes, also happy to be here and making a slight deviation into the lower part of the GI tract from the stomach. I’m a GI medical oncologist at Mass General in Boston.

Manju George 01:18
Okay, thank you. Dr Gongura, do you want to go next?

Dr. Gongura 01:20
So I’m saying it’s really a pleasure for me to be here. And I’m a researcher. I’m working in Montpellier, France and so, so I will, I will, I will give you some some new, some new, some new events and some some new models on that, on the research for COVID cancer.

Manju George 01:47
Okay, thank you very much. As Dr Klempner is sharing his screen when you when you hear the talk and you have questions, please type them in chat, and then we will go over the questions after each section,

Dr. Klempner 01:59
Alright, so I think I probably have the least exciting part of this. I know everybody’s always very interested in the newer surgical techniques and the new translational models, but I’m going to sort of walk through the standards, because I think it’s always important to have a sense of starting from the same place and understanding what sort of the standard management is so these are my disclosures, some stuff I get paid for, some stuff I don’t this is a reminder of what we’re talking about. I know that this audience is probably particularly advanced among patients and caregivers, but sometimes explaining the peritoneum is not so straightforward, so I’m still working on the best analogy. But if you think about it as a wall, the front of the wall, like what you see the drywall is the front of the abdomen, and then there’s this space, and then there’s the backing. And this is sort of an easy way to think about it. Another way I’ve thought helpful is thinking about meat at the grocery store, where there’s this very shiny layer of saran wrap over the meat. And that’s, that’s kind of like, like the layer that all of the guts are wrapped in, in the abdomen, the peritoneum. And it’s, it’s a coding thin layer over the most of the organs. So this is obviously a person cut in side view, and you can see, sort of what this looks like. You have this layer of saran wrap that’s really wrapping all of the organs in the peritoneum in a very tight layer. And that’s where we’re when we’re talking about disease in the peritoneum. We’re talking about things on top of the saran wrap that aren’t really supposed to be there. There’s a lot of really interesting biology that we’re still learning. And others here know more than me about this, but if you think about tumor cells trying to live in this environment, it’s quite different than some of the other environments, like the lymph node or the lung or the liver, where there is more of an established sort of soil for these tumor cells to live in, with blood supplies and other organ function in the peritoneum, tumor cells have to adapt and make some changes in order To survive, and some of these are the ability to basically initially circulate around in the peritoneum and then stick on to the surface of that saran wrap and then hide from the immune cells. That job is to sort of monitor for abnormal cells and then grow. And so these are some several steps that are required for these tumor cells, and we’ll probably hear a little bit more about this in the talk later on, so I don’t want to tell spend too much time about it, but it’s really important property, and it’s probably one of the reasons why peritoneal disease behaves somewhat differently than disease in other locations when we. Someone with new involvement of the peritoneum, whether this is recurrence from a stage two or three cancer that has come back, or whether, like some percent of patients, they presented and the first time they found out about their cancer, they had peritoneal involvement right from the get go. So in general, I think it’s important to have some of these important shared decision making, and this is just a framework for thinking through all patients. This could be for any cancer. So we have to all be on the same page about our goals. We all want to prolong survival and palliate symptoms and make quality of life good. We do want to follow evidence, because just because we can do something doesn’t mean we should. We have to be really transparent about what are the expected outcomes if someone’s going to go through a big operation, say a cytoreductive surgery, you know, we have to be all on the same page about what are the expectations realistically and then we have to continuously reevaluate this for all of our therapies. This is probably an oversimplified slide for this audience, but I think we use a lot of jargon and talk about first line and second line and third line all the time. But when you’re diagnosed with advanced colorectal cancers, first line is generally the first chemotherapy you get, and then at some point, if that starts losing its efficacy and it needs to be changed. You go on to second line therapy and so forth, and so. These are the most common combinations used in the front line, FOLFOX, FOLFIRI, and then increasingly FOLFOXIRI. And the choice among these depends a little bit on the goal some drugs. When you combine more drugs, you get a higher response rate, but you also get additional side effects. And then all of these can have biologic agents, so non chemo drugs, such as Bevacizumab, cetuximab or panitumumab added based on the tumor biomarkers. And we’ll come back to that in a minute. So why? Why do why are we even having this talk? Why do we talk about peritoneal approaches? So when we give chemotherapy in the veins, it is generally less effective in the peritoneal metastasis than in other metastatic sites, such as the liver, lymph nodes and lungs. And this is something that we’ve learned over the years with the help of our surgeons and everybody else. And there’s probably several factors that explain this. Simple ones may just be drug access and penetration into tumor cells from the vein when the cancer cells are sitting on top of that thin peritoneal layer. Obviously, that led to the obvious idea of, what about putting it right where the money is, as in into the abdomen. And this is sort of one of the underlying principles and hypotheses of all peritoneal directed strategies, that we could improve exposure of drug to the tumor cells, and therefore improve the chance that we can kill the tumor cells in the peritoneum and similarly in the same vein. If our therapies in the vein are less effective in the peritoneum, maybe we should try to debulk the tumor out of the abdomen, so that if our therapies are less effective there, we can continue our good systemic therapies, but have other tools to manage the cells in the abdomen which are less responsive. So these are sort of the over altering principles. I want to dive a little bit deeper into some of the updates we’ve had. So this is from 10 days ago at ASCO Gi, and this is a series from MD Anderson in the US. And essentially, they looked at all colorectal cancer patients. So these are all patients who have peritoneal metastases. And then they were looking back to try to understand, if we know something about the tumor, can we understand the biology a little bit better? So for example, if you have a BRAF mutation, you are less likely to do well with your peritoneal disease than someone who has peritoneal disease and no BRAF mutation. The reason I’m highlighting this is that the more we understand about each patient’s individual tumor, we really want to start to use more and more of this information into thinking about our decisions about who’s the right person for peritoneal directed strategies, if someone has a really aggressive biology, just that’s the way the tumor is built. It may be a more difficult situation, or potentially a higher risk situation, to undertake a very large and potentially high risk procedure. So we want to really understand as much as we can about the tumors. This is a similar effort, largely from a Dutch group, looking at colorectal, peritoneal metastases, again, trying to understand the biology. So what you’re looking. Here in the top left is primary tumor, so the colon tumor versus peritoneal metastases, and immediately you can see that the green bar is much bigger in the people with peritoneal metastases, and the green bar represents a subtype of colorectal cancer called CMS four. And you don’t have to remember that, but CMS four is associated with some more aggressive biology, less sensitivity to immune therapies, high levels of TGF beta, which is an immune suppressive factor. And so we’re learning a little bit more about what are the types of cells that are living in the peritoneum, and what adaptations have they made? And then we look at mutations over here in the bottom left, and you see that there’s an enrichment for KRAS alterations in peritoneal metastases, and these are also features that are associated with a little bit more aggressive biology. All of this is just to say that we’re learning and now we’re really studying this in a better way to understand more about the biology of peritoneal disease, and how is it different than the primary tumor or a liver metastasis? This really highlights maybe one of the key points of this whole sort of intro like talk, is that peritoneal disease, just like the rest of colorectal cancer is becoming a disease of subgroups. Over here is the standard tools, chemo, standard biologics, other chemo drugs. But now it’s really over all about the right side of this story. Now, for example, we don’t really know if someone who has a her two amplification in colorectal cancer, our newer drugs are quite good at targeting HER2 and there was just an approval for a new combination 10 days ago. So if someone has a really actionable or a tumor type that’s very likely to respond to our good therapies is that someone that we should think about maximizing the systemic therapy before we think about peritoneal directed strategies. So again, the point is really that we need to understand our tumors as well as possible and start to factor that in into thinking about peritoneal disease. Again, a lot of people ask about what is the standard? Well, well, the standard of care for managing colon cancer with peritoneal metastasis is systemic therapy. That that has been the standard therapy for a while, whether this is or FOLFIRI, or FOLFOXIRI or whatever. The surgeons have done some beautiful work, and I think we’re getting closer to understanding about who are the people that may benefit. But to date, in our medical oncology perspective, we have yet to see a very large phase three trial that has reliably shown survival in colorectal cancer with peritoneal disease there. There are some very nice trials that suggest groups of patients, but as we get better at modern chemotherapies and combinations, we are actually doing a little bit better overall. There is a future here for sure, which involves novel therapies into the peritoneum, so you can give Oncolytic viruses. And here is an example from a clinical trial that’s published a couple years ago, and this author continues to build on and then there’s a lot of other immune therapies, including drugs like immune checkpoint inhibitors, consideration for right into the abdomen. There’s a trial in Singapore looking at nivolumab, OPDIVO given into the peritoneum with intraperitoneal chemo for gastric cancer, and I think we’ll start to see some and more of these strategies coming to colorectal cancer. So again, I think it’s about patient selection that’s one of the key themes. And this is from the prodigious seven trial, which we may hear about from the surgeons, but it was looking at essentially the amount of cancer in the abdomen, among other features here as identifying groups who might do the best. So here’s everybody got surgery. Some group gets Hipec, other group didn’t get hipec. And then you say if you had a lot of cancer in the abdomen, so a PCI score that was over 15, your average degree of benefit from hipec was minimal, whereas if you had on the lower end, and some of these numbers here are relatively small, you may be more likely to benefit so again, it’s just pointing us towards the idea of patient selection. And I come back to this theme of just because we can doesn’t mean we should. So I think that’s the end of my talk. It’s really a high level summary of improved biologic understanding. We know peritoneal disease is a big problem. We need to do better. There’s no doubt about that. We need help from our scientific colleagues. Make better models to understand the biology and test whether someone with her two positive disease really is getting the same amount of benefit as someone with her two negative disease. We need better drugs and better delivery. So thinking about other tools into the abdomen, and then really patient selection in clinical trials, really picking the right people to give these therapies the best chance of working? Think that’s been one of the criticisms is that the populations of patients in the trial are very mixed, and so there’s clearly some people that benefit in but maybe on average. We haven’t been able to prove it, so I will stop there. And very interested to oh, this is where I like to spend the rest of my time on the farm I grew up on. Happy to take questions at the end, and I will turn it back to Dr Sgarbura,

Manju George 14:16
Thank you. Thank you, Dr Klempner, for that great presentation. I was wondering, since you have to leave, can we take some of the chemo related questions right now? Is that okay?

Dr. Klempner 15:57
Yeah, I can stay for another half hour or so. So whatever you prefer.

Manju George 16:01
Yeah, like, let’s just quickly go through this, and then we can do the other sections. Dr Sgarbura, is that okay with you? And the rest of the panel? Okay? I think we can start from the top, like the surgery questions we will leave for later. One of the question is, like, is a combination of kRas, G12C inhibitors with Cetux recommended for appendiceal adenocarcinoma. I mean, this is a little bit, you know, away from what we are discussing, but if you can provide an answer, that’d be great, yes.

Dr. Klempner 16:30
I think it’s all coming back to the same theme. So KRAS G12C is a very hot target in all GI cancers that have that mutation, but G12C is a mutation for which we have drugs that can target directly, and a lot of this is published, but in patients and in tumor types where there aren’t clear standards, like appendiceal cancer, for example, from a chemotherapy standpoint, I would very quickly try to reach for and offer a G 12 C combination to a patient with appendix, ideally on trial. You know, these drugs are not yet approved, broadly approved for long, but not yet colorectal and appendiceal. All of us at academic centers are lucky enough to have these trials. And so I know actually one of my, a patient on this call currently, has benefited from the strategy. So I can tell you that, yes, 100% I would be looking to try to get G 12 C for someone in that scenario. And I do think combination is the way to go, like with Cetuximab or other combos.

Manju George 17:41
Okay, the other related question is Keras G 12 C inhibitor with Avastin. Do you think that adding Avastin is a good idea for Peri mets?

Dr. Klempner 17:51
Yeah, I do. I think we don’t have much data there, but I think that the G 12 C agents broadly work better in combination than alone. We don’t know exactly what’s the right combination. You can make a case for Avastin, you can make a case for Cetuximab, you can make a case for immunotherapy. But I think in in peritoneal disease, we have seen some benefit for Avastin, at least in patients with particularly fluid accumulations, like like ascites. So I do think it’s a very reasonable combination.

Manju George 18:22
Okay. Thank you very much. The next question is, do we know why TGF beta inhibitors do not work in CMS for

Dr. Klempner 18:30
that’s that is a great question. I think it remains a very attractive target based on the biology, some of it is maybe our failures as drugs, including the optimal way to target and also, more deeply the understanding of the biology. You know, just removing TGF beta may not be enough to sort of reorient the tumor towards response. You probably need to do more than just that. So I think that a lot more to come. The best strategy to target TGF beta, whether it’s soaking up the circulating factor, inhibiting the receptor using a small molecule inhibitor, is is not known. There are several trials still doing this. Novartis is actually doing a very big, I think, phase two or phase three trial and in colorectal cancer with their TGF beta drug. So I think we’ll we’re going to learn a lot more, but it’s clearly not a one size fits all.

Manju George 19:31
Okay Thank you very much. And then the next question is, when it comes to looking for new mutations to guide treatment in Peri mets, should be used tissue biopsy versus liquid biopsy? Is there, you know, is there a preference and why?

Dr. Klempner 19:45
Yeah, interesting question. So people with peritoneal disease, for whatever reason, don’t tend to shed a lot of circulating tumor DNA, and so a lot of times the drawing a blood test will not have added. A quick amount of circulating tumor DNA to either perform the test or have high confidence that you’re seeing all the alterations in the tumor. So when possible, we do prefer to try to get a tissue sample from the peritoneum and do the sequencing from that. It’s not always possible, so sometimes we wind up doing both. But if I had to pick I would choose tissue. If tissue wasn’t possible, then I would try the blood, understanding that it may not be as complete a picture.

Manju George 20:31
Okay, I’ll ask one broad question, and then maybe we can go to the next section. So with peritoneal disease, if you look at very broadly when you’re counseling a patient, what would be the broad goals of care? Is it just removing that? I mean, what would it be with respect to, you know, quality of life, or delaying the inevitable, like, how would you think about the whole process? Yeah,

Dr. Klempner 20:55
I think this is really a question probably for the whole panel. Maybe, maybe a good one for the end of the of the of the talk, when we’ve heard from everybody else. But I think the there’s a lot of things you can do, and the goal of the patient and the physician are very important. Sometimes it’s palliating a symptom, sometimes it’s reducing accumulation of fluid. You know you can do laparoscopic, high pec and things like that. Sometimes it’s going for one of those long term, durable remissions or even cures, which, which we know can happen. It’s really just about finding the right patients and matching it to the right strategy. But I’ll, I’ll, I’ll maybe save the rest for the end, for that’s a great question for the end.

Manju George 21:39
okay, okay. Then there is another related question. So you talked about the oncolytic virus trial and similar trials, right? So again, from the patient point of view, who would be an ideal patient for such trials, like, what should they think about when they’re, you know, looking at these trials?

Dr. Klempner 21:55
So I think that basically, anytime we’re doing something that’s not proven, the best way to do it is on a trial. And so I think you’ll hear from all the surgeons and everybody else that you know, most of their work is done in the context of a trial, and where people think that the trial evidence is good, we start to do that outside of a clinical trial. And certainly that’s generally how we do the same thing in medical oncology patient selection. I mean, if you have a biomarker for the virus, like it targets a certain expression protein on the surface of the tumor cell, like car T cells do, then, then obviously patients who have that target are going to be a better group of patients. If the virus seems to work best when there’s a lower burden of disease, then you probably want to think about people who have not an abdomen that’s totally full of cancer, because that may not be the right choice. And then, of course, we need to do the trials to understand like, who are the best populations, because sometimes we go in thinking and then we’re proven wrong. It’s actually someone who has peritoneal disease and no liver metastases and box, check, check, check. So I think I don’t know that I know the answer to that question, but broadly It depends on if they have the target of the strategy, and I think disease burden is important.

Manju George 23:16
Okay, thank you very much. So maybe then we can move to the next speaker. Dr Sgarbura.

Dr. Sgarbura 23:22
thank you very much. Thank you. Dr Klempner, I’m really sorry about my voice, so it’s not really in its perfect fit, but I will try to do my best and present properly. Let me share the screen with you. Okay, so we’ll try to talk a little bit about surgical treatment. Now, I have nothing to disclose, and you’ve already had a very, very good description of the peritoneum. How it how do we get, how do does a patient get peritoneal meds? Well, the tumor is very bulky. It’s very voluminous. Some of the cells are detaching. Some of them might go into the blood circulation, and they might eventually lead to lung mats or liver mats or lymph node mats, and sometimes they are detaching outside towards the peritoneal cavity, and in that case, they will follow the flow into the abdominal cavity, which means that they will start fixing themselves either on the omentum or on the on the peritoneum from the diaphragm, which are the sites probably most frequently involved in this situation, what makes them hard to treat? So you’ve already heard quite interesting information from Dr Klempner. There is, there are several things that make them hard to treat, but biological characteristics are something to look into. There is a description that was done in the late 80s, and that probably needs to be re challenged now with the with professional and modern technologies. But. This description shows that there would be a plasma peritoneal barrier that prevents the trans passage of intravenous drugs into the peritoneal nodules. And this explains, on one hand, why, when we are treating the patients with systemic chemotherapy, it might not necessarily lead to the diminishment of peritoneal nodules, and the other way around, why it might be interesting to perform intraperitoneal chemotherapy, and because it might not be accompanied by system high systemic effects, as it will not go back into the blood in high quantity, as you’ve seen, they’re quite frequent. So this is so this is a problem, quite an important problem, for patients with colorectal meds, and sometimes when they when they appear this metachronously, that means for uncertain distance, more than six months from the primitive primary tumor. Sometimes they are difficult to detect because peritoneum nodes are usually very, very small tumors um they are often less than one centimeter or more, even more, often less than five millimeters. And we know that 50, more than 50% of the lesions less than five millimeter are invisible at CT scan. So I chose this imaging from a recent review in a journal from the nature group. So it illustrates quite well that we see some of the things when the nodules are big, we see them with different imaging techniques. So number one is a CT scan. So this is a longitudinal vision of the human body with a liver. Here, there was spleen. Over here, you can see the major blood vessels and so on. And where you see the arrows, it’s there is evidence of some nodules, either in the omentum or in the in the pericopic gutter, you can see the same, but maybe smaller in size. At the PET scan positive emission tomograph, you can see the same in the MRI, but actually you’ve seen no evidence of disease on the small bowel. But when, sometimes, when we open the patients, or when we prefer surgery, we do see this on the spa on the bowel. That means that imaging techniques used to underestimate the importance of the disease, and that always, we can have some surprises. We are estimating the extension of the peritoneal mets, using a peritoneal cancer index, the maximum score is 39 so this is some in colorectal and the specific setting of colorectal cancer. This is a rejectability criteria. We have a definition for a threshold of 17. This is quite our relative value. It was shown on a monocentric series, and I think it can be challenged by some other factors that are important for rejectability. You’ve heard some of them. In Dr Klempner’s presentation, we are taking a look at that as a histological subtype, whether this is a liberal union subtype or mucinous adenocarcinoma. Mucinous adenocarcinoma have have usually, usually has larger peritoneal nodes with a lot of mucin inside, and we might extend our surgical medication to higher PCIs, because usually the lesions are easy to detach and we can spare a lot more organs. Other factors that might be important are the presence of simetring (signet ring?) cells. We probably have lower respectability threshold for simetring (signet ring?) cells. Mutations are also important in some of the cases, and molecular subtypes are not really part of the clinical decision now, but probably will become, in a way, in the future, also from the same from the same nature review I presented earlier, you can see that many, many factors are related to the respectability of the disease. Some of them are, of course, related to the peritoneal disease, per se, as I told you earlier, to the tumor factors, but some of them are simply related of the patient, to the patient’s condition, and, of course, to the experience of the surge and of the entire team in the center treating The patient. So probably this will be an oversimplified representation or summarization of how we might treat a patient with peritoneal meds, depending on the extension of the peritoneal disease, we might perform an induction treatment, so usually a first line of metastatic chemotherapy. As you’ve seen also in the presentation before, after that, we might want to perform the Cytoreductive surgeries if the patient is eligible ed or not, at hipec. And we’ll talk about that. And probably there would be a treatment after that. So our part is really in the middle, I would say, most of the time, it comes after systemic chemotherapy, rare archeologists and some country specific situations where cytoreductive surgery might come first. But as the middle is our role, I will focus on that. And I would just start by saying that cytoreductive surgery needs to be complete in order to be beneficial, because otherwise, if you leave too much tumor behind, if, if we leave any tumor behind, it might get into into all the places where we where we try to dissect. So that’s bad. Therefore it should be performing next person. So the learning curve, it’s important the threshold. So that would be the number of cases performed per year. It’s important also because the team needs to stay trained to this specific procedure, and when I say the team, I mean the surgeon and their team, but also say anesthesiologists, medical oncologists and so on. So of course, it should be discussed in the tumor board in order to find out the optimal way to articulate that with systemic chemotherapy. And we sometimes choose to provide HIPEC. And of course, it will welcome back to that. And the idea of HIPEC is to destroy the remaining unfeasible disease, because when we take out the tumor burden from the peritoneum, we try to be complete as far as our eyes can see. But as you’ve seen, sometimes cells can be detached, and they might go through the abdominal cavity. And HIPEC was born from the idea of killing those cells before they get back into circulation or they fixed again. So one of the randomized control trials that tested this hypothesis was was born also in Montpellier. It’s my mentor that you see in the photo from soKine was the principal investigator of the produce seven trial once the complete surgical resection was achieved at the operating room. He randomized the patients to with HIPEC versus without HIPEC. But the HIPEC he chose at the time was the one that was proved interesting in France. It’s oxaliplatin based high dose short durations, or 460 milligram per square meter during 30 minutes. And this, there was no stratification of PCI. This was not known as a prognostic factor by that time, but there was stratification on other factors, and these are survival lines. So the two lines, the four with high pec and without hipac are perfectly going together throughout the time, so which means that there is no difference in survival between the patients that received high pec and those that did not receive high PEC, based on oxaliplatin within that study. But as you have seen already in Dr Klempner’s, there is this subgroup of patients with intermediary PCI, so an extension of of the disease that is not very small, but not very important either, sorry. And in this group, there would be a signal that might favor HIPEC so the idea of the entire community of hiPEC surgeons was that, if we did not get a huge benefit in this trial with oxaliplatin based HiPEC, maybe based on retrospective studies, other types of HIPEC might work. So we might, of course, perform a good cytoreductive complete surgery with that and propose it without HIPEC to our patients. But there might be situations in which HIPEC could be interesting, and therefore international access for the use of HIPEC in peritoneal surface malignancies was took place in the last through the last couple two years. You see here the core committee, than there were disease specific committees. It involved 145 experts throughout the world, and their opinion concerning hipec In today’s practice is that it could be interesting after primary cytoreductive surgery, and it would be also interesting late recurrence after cytoreductive surgery, and their regimen of choice was Mitomycin based. So that means that the dose of Mitomycin C we propose is 35 milligrams per square meter, but it should be administered during 90 minutes and three fractions, half of it first and then the. A card of a quarter of it every 30 minutes, for patients that are not eligible for for surgery for different reasons. So mostly of them is high PCI, or even if the PCI is not that high, but disease diffuse diseases can be found on the on the serosal surface of the small bowel, a second line of chemo is of course of use, and a new drug delivery technique in the peritoneum called pipac, intraperitoneal aerosol chemotherapy was proposed as something that could be administered alone or in association with systemic chemotherapy be usually beyond the colorectal second line, sorry, in colorectal cancer, because, as you’ve seen earlier on, we’ve got a lot of lines that can prove themselves useful for these patients. And we did a consensus on what type of pipac, what type of molecule should use with pipac in colorectal cancer? So oxaliplatin was find is as a good pipe drug. And then my colleague, Dr Huber, gathered the cohort, the International cohort, for the use of pipac in colorectal patients. And we’ve seen that there is quite an interesting response in terms of diminishment the radiological imaging histological response, and even sometimes in terms of symptom control, and there is some sort of survival benefit as well. But of course, the cohort was a bit large bitter journals to finally conclude on that similarly, there is response on this on the basis of the same criteria in appendices cancer, and also a survival that can be considered interesting, given that it’s beyond the second line, and for a pathology where we don’t know So much about what we should use in systemic chemotherapy. Also, Dr Hubner draw that in in another nature, primers review we did so this is a way of to articulating different treatments, systemic and intraperitoneal. Different types of intraperitoneal can be HIPEC, pipac and catheter based chemotherapy, IP chemotherapy in the setting of different peritoneum mets, including colorectal, colorectal peritoneum mets. So the take home messages I would retain from isspp When we discussed all that, so is that all patients with peritoneum mets should be discussed for surgery, depending on the disease extension. But HIPEC per se should be discussed case per case. If we we decide to go for HIPEC, probably it would be a great idea to follow the consensus of the experts, so to use Mitomycin C as the first choice. We now know, as Dr klempner showed as well. Landscape of colorectal cancer gets richer by the day. We know more and more, and we should finally, slowly find out how to integrate that into practice. And although the therapeutic options are growing, the peritoneum remains a particular model, and I will end it by thanking you for attention with a few photos from the isspp,

Manju George 38:23
okay, thank you very much. Dr Sgarbura, it was excellent. So maybe we’ll look at a couple of questions. So I think one of them was like, if someone had CRS hipec With Mitomycin C and they have a recurrence, would you recommend doing it again with Mitomycin C in the second surgery?

Dr. Sgarbura 38:40
There is very so there is some some evidence based on that, but really the level of the evidence is not that high. In order to provide with a definitive answer, what I would say is that maybe we should follow the expert consensus, even if that’s not based on a very, very high level of evidence. What they propose is that if the surgeon in the tumor board decides to go for a high pick for the recurrence a second, a potential second line could be an association of cisplatin and Mitomycin. C

Manju George 39:12
Okay. Thank you. And then the next question is, for patients who were who were ned for a while, and then ? and have low burden peritoneal disease, is it better to go straight to surgery, HIPEC or to do systemic chemo? What do you suggest?

Dr. Sgarbura 39:29
So very good question. This was for a while a reason of debate, usually between Netherlands and France. In France, we tend to do in the adjuvant chemotherapy for patients that are metastatic, even when the PCI was low, Netherlands has a different attitude, suggesting the peritoneal mets are a local extension of the disease and not a systemic extension. So I would say that except for. Very, very low PCI, which means, like, two or three nodules near the tumor, the evidence would still suggest we should probably go for chemo in the first place, and under, under Dr Klempner’s control, because he still here, there is a new Foxtrot trial coming from from the UK who showed that maybe, maybe, I would say it’s a signal even in locally advanced colorectal cancer, sometimes it could be of interest. So not, not on metastatic, but locally advanced. Sometimes it could be of interest to use FOLFOX preparatively.

Manju George 40:36
Okay, I think there’s another question this person is really asking about one troublesome, you know, 2.3 centimeter times 2.3 centimeter met in the peritoneum, whether that could be surgically removed. And I was kind of wondering, like, what you said, you know, what is seen on scans and imaging might be very different when you actually look inside, right? Do you want to comment on that?

Dr. Sgarbura 40:58
I agree. So if we only have some some radiological report. It’s hard to decide. So we need to explore further, maybe do a laparoscopy to find out about the situation after that, 2.2 on 2.2 of course, theoretically, that’s resectable. Now we have to see the location and the report with different vessels, etc. So it’s a bit more complicated than that into practice, but, but it’s up to —

Manju George 41:26
thank you for putting all the questions in chat. Keep them coming from the Prodigy seven trial. Do you think that then the more importance is for the Cyto reductive surgery, or is it more of a an effect of the oxaliplatin in the chemo that was used,

Dr. Sgarbura 41:43
So the question was whether the results in the produce seven are related to surgery? Well, I would say the results are related to surgery, because these are the best results we’ve had with Cytoreductive surgery since the beginning of the procedure, and this under randomized control trial. So the survival we obtained through this trial are really, really good. So I would say definitely the quality of surgery is a must. In this sense, the trial was a success because it eventually put surgery as a very interesting part of obtaining a good prognostic for these patients.

Manju George 42:22
Okay, thank you. Okay. Dr Huber, you can go ahead.

Dr. Huber 42:25
So that’s very good, and you can hear me. So I also have some problems with with my voice. I apologize, so I will do my my best. So I have a topic. It’s the first time I’m talking about this. How can we involve patients with peritoneal metastasis of colorectal cancer and clinical research. But I think the question should be broader. How can we involve patients in many things of patient care, not only research? This is very important question, because the perspectives can be really different. It’s very easy for me to share the doctor’s view with you, we define successful surgery as a combination of correct indication, high quality surgery, of course, but also embedded in optimized perioperative care. And high quality surgery is typically warranted by long training, high volume and lots of dedication, we had tremendous improvements of of clinical outcomes through an enhanced recovery pathways to optimize power up care, but somehow we still struggle sometimes to Put the correct indication. So I think this is closely related to the topic of the talk, what do we consider as good outcomes in oncological surgery? So we want to have low complications, short hospital stay, good overall, and disease free survival. So these are typically our metrics, but indeed, and especially for patients with advanced disease, we can argue if shorter survival with good quality of life is not better than endless suffering. So here we, we, we truly have to to, to have a a discussion between doctors and and patients. And look, this is quite normal in business. If you, if you want to design a new website, first thing you should do is to ask your client, same thing. If you, if you want to construct a new hotel. Of course, you should, should know what your your clients want, because otherwise you will probably not have success. So should we really, really inquire what what our patients need? Should we? Should we take a broader look beyond clinical and oncological outcomes and take into consideration a Social. Professional, economic factors, and also the psychological and emotional side. I’m convinced that we should, because patients need and treatment goals are largely unknown by clinicians. Patients. Evaluation is frequently incomplete. It’s a shame, but it’s a truth, and the communication between patients and doctors is sub optimal. Just take a look at this shocking study published in the New England Journal of Medicine, 69% of lung cancer patients and 81% of colorectal cancer patients with metastatic disease under palliative treatment. We are not aware that the chemotherapy is not likely to cure the disease, unbelievable. So and this being said, if, if the communication is incomplete, how can we make sure that the standard treatment, what we consider as a standard treatment, does really fit to the needs of the individual patient, and we can avoid, and we should avoid, the mistakes. So this is a study which Olivia shared with me. Very interesting. The authors of this study dissected four breast cancer and nephrology trials, 44 studies. They sorted out 46 primary outcomes, and then they did an interesting thing. They asked 30 patients and 12 healthcare professionals involved in care of those patients, inquiring what they think of the primary outcome measures chosen by the investigators. 13 out of 46 were judged to be optimal. Meaning, in other words, the investigators got it wrong in 72% of of cases of studies Look at this. So we’ll stop here, because I saved my voice for a couple of minutes. So Mick Marshall was really very happy to to hear what women want. So I would like this as well, but I’m as much interested in learn what our patients want, and so this is the rationale behind our prospective observational cohort study, to to assess patients perception and preferences. So we brought together an international collaborative with the three aims to evaluate the patient in a more global way, to define a preference and set realistic expectations and to evaluate perceptions and satisfaction of care and results, we have foreseen four different cohorts, and three are touching patients with peritoneal metastases, which is the topic of the webinar today. The fourth cohort, which is a kind of control group, concerns non metastatic colorectal cancer, the quite ambitious project where we want to evaluate the patient in very different dimensions. You see the dimensions and the test service estimated time on the left side. And we will then evaluate those things at different time points, outpatient setting, at discharge and 30 and 90 days after surgery, we will ask our patients a lot, namely, to invest at least two and a half 10 hours of of their time. So here, patient involvement is very important. The study has been approved. The consortium is established, the online application is developed, and the pilot phase has started, and I hope to to give more results in a couple of years. One of the problems for this kind of project is lack of funding. We tried it in Switzerland, rich country, but we didn’t get it so far. We tried it also in France, with our French partners and maybe some patient groups have ideas how to get alternative funding for those really patient centered projects, the patients view much more difficult for me, of course, without those results to to find out, and we are All in the same, same same situation, but we are convinced that we have to go into direction, especially for patients advanced disease of patient reported outcomes, not only pain function, quality of life, but many other dimensions. And here I give lots of credits to my dear colleague, Abdel Taibbi, who is a surgeon in limosh who is reaching for the stars with his with his “comade” study. So he put together a study to define a specific patient, reported outcome and experience measures for patients with peritoneum metastases, and when he started to. To to do this work here, he realized that we needed a different group of investigators for this study, and namely patients, which appears quite obvious, but which is really the case. So here he had first to train a group of patient experts, which is quite a challenge in the field of peritoneal surface malignancies, because unfortunately, prognosis is bad. So first part of the study, nice name pillops, where we formed 35 patient experts who helped us in the second part to define a set of nine specific peritoneal specific outcome and eight peritoneal specific experience measures. And, of course, for new scores, they need to prospectively validate it. And here, this is the second phase, which is launched by a comade two study.

Dr. Huber 51:03
Third project, just want to, want to share this beautiful picture. It’s a consensus process on optimal endpoints in peritoneal disease, which is shared by Olivia Sgarbura. She’s working very hard on it and pushing us to deliver and she will make sure that we will get some results within this year. Challenges are multifold. Sometimes it’s very hard for for busy clinicians to find the time, to find motivation, and especially for those kind of projects, also to find money. So patient and public involvement PPI is, of course, urgently needed, and I just summarized a couple of points. It’s kind of it’s kind of a brainstorming. We need you for better communication between doctors and patients, for optimal studies and for dissemination of knowledge. We need you to choose the relevant trial end points, to set priorities in reachers for funding, potentially to help this patient accrual, tailored treatments, maybe even for to help for physician well being. Could also think of this. So we clearly need you to define together with us what really matters and many more things. So PPI is a no brainer. Definition of a no brainer is an obvious choice or decision where you do not even need a brain to make this decision. Because what we want, in the end, is to bring the two perspectives together. We want to offer to you, to our patients, what fits best to your individual needs. So I would really want to reach out to you, to ask you to give us a hand to do it better. And if you, if you want to get in contact, please send me an email or get in touch with me by any other means. Thank you very much for your kind attention.

Manju George 53:02
Doctor, you know, thank you very much for that. And it’s, it’s really important for us to know that these initiatives are going on and, you know, related to that, like I would have one question is, you know, when you look at peritoneal mets, one of the problems that we see is like the detection of them, right? Like, if you’re lucky enough to have surgery and they find peritoneal mets, then you know you have peritnoeal disease. But for many patients, unless there is, until it becomes really widespread, you don’t come to know of it, right? So I was kind of wondering, you know, what kind of things are being done to improve the detection rate. That’s the first question. The second thing is, from the patient perspective, you know, if you’re an early or metastatic colorectal cancer patient, and right now you don’t know that you have peritoneal mets, what are some of the things to keep in mind so that you can check back, you know, I mean, like, for example, mucinous tumor or signal disease, or, you know, some particular mutations, like, what are those factors that would make you go back to your care team and say, I want to check, or I want to make sure that I don’t have new penitential disease? I mean, this would be a question for the entire panel.

Dr. Huber 54:18
I will, I will try my best to give you a brief, brief answer to this very complicated and complex question. So we have considerable improvements in the imaging techniques over the last year, so a test become much better and an expert radiological hands in expert centers, that imaging is is has become quite good. So we cannot state anymore that that imaging is useless for for detection of Peltier meds, but it’s really specific for expert Center. Is the big then question still is, do we need in high risk populations? Second look laparoscopy, we don’t know. We don’t know. It makes perfectly sense with the two rationales. Frequently, early disease is not detectable by modern even modern than imaging, and we can treat this disease, then only with decent chances, if you detect it earlier. So clearly, there is a rational for second nuclear proscopies. Trials which investigated the study strategy failed, failed to to show improvements in survival. So we have to acknowledge, acknowledge this, and we do not even know when the good moment is to do a second look laparoscopy. So is it directly after an adjuvant chemotherapy in high risk patients? Is three months later? Is it six months later? We do not know. We do not know we have a study performed. The results are not not published yet, with very then elaborated kind of score to define the optimal moment for second look laparoscopy, but we do not know so in concrete terms, in patients with high risk and constellations t4, perforated tumors, synchronous resected meds and ovarian metastases, at least in young patients, I would suggest to do second look laparoscopy within three months after the end of adjuvant chemotherapy.

Manju George 56:37
Okay, thank you very much. The other members of the panel. Do you want to add something to it.

Dr. Sgarbura 56:44
In terms of radiological imaging, many of the radiologists are also working on radiomics as hoping to be a little bit more exact on the detection of the peritoneum at so that’s a sort of molecular testing, but in in radiology. So hopefully this will help us even more in the future.

Manju George 57:05
Okay, Dr, Klempner,

Dr. Klemper 57:09
yeah. I mean, I think I share the opinion of everybody else I’ve over the years in gastric cancer, come to appreciate the information that comes from laparoscopies a lot, and I think it’s, compared to many other procedures, relatively less invasive. So we think about repeating diagnostic laparoscopies when it might change, how we think about the next steps, but I think it’s a, definitely a tool that we use when we have limitations of the imaging. I know that our group here is looking at MRI pet as another tool and doing instead of a pet, CT doing an MRI. Pet, some of the radiologists have told me they think that it allows them to detect peritoneal things a little bit better, but it’s still a big unmet need,

Manju George 58:02
okay. And then this is like a low level question, like, what about ca 19-9 Do you guys like to use that? How does that reflect peritoneal disease better than CEA? Do you have any comments?

Dr. Klempner 58:17
I’m not aware of anything that says it’s better at peritoneal disease then then CEA. I think some tumors make ca 19 nine. Some make more CEA. And so whichever one is is elevated or both, we will just follow routinely during any form of therapy, whether it would be hiPEC or systemic chemo.

Manju George 58:36
okay, so we can go to the next speaker then and then look at all the questions together. Thank you, Dr Klempner, for answering the questions in chat. Yeah, do you have to leave now?

Dr. Klempner 58:50
Yes, I have a one o’clock patient, so unfortunately I do need to leave.

Manju George 58:54
Okay, thank you very much. Thanks for joining and for the talk and answering all the questions.

Dr. Klempner 58:59
Yeah, this was great. I look forward to seeing you guys at the next one, and hopefully in person for some of you.

Manju George 59:05
I’ll have the video up on CTU and I can send you a link. Okay, thank you.

Manju George 59:12
Okay, we can go to the next Dr Gongura.

Dr. Gongura 59:16
Oh, yes, hello. So Hello again, everyone. It’s a again, the pleasure for me to present the new research model for advancing treatment. So So Before describing the new models that have been developed, I wanted to share with you the condition on how to develop such a model. So it is important to know that the predicting the efficacy of anti cancer therapy. He is actually the holy grail of drug development, and to achieve this goal, researcher require pro clinical models that can screen anti cancer agent with robust clinical correlation, of course. So the research community tried to develop more. That can accurately capture the diversity of a tumor ecosystem and to predict how tumor will respond or resist to a treatment. And the most important to take into consideration is that the tumor are made up of heterogeneous landscape comprising malignant cells, obviously, a normal and abnormal stroma, immune cells and genomic microenvironment containing chemokines, cytokines and neural growth factor. So just for for cancer research today, we must develop patient derived models. So this patient models will introduce inherent, inherent, sorry, biological complexity will preserve the interesting dynamism of cellular heterogeneity and maintain the three dimensional architecture of a native tumor. So such a model will lead to improved strategy cultural development. So the patient derived model consists in using a patient biopsy to perform different experimental approaches, including DNA re extraction for wall exam sequencing and arenasec, the patient derived xenograft, patient derived organoids, organotypic tumor spirit and organ on G(?). So what I wanted to do is to give you some example of these experimental approaches focusing on very recent model and results. So I will start with sequencing of clinical samples. So the HANA sequencing maybe, as you all know, consists in extraction of RNA from the tumor samples and to sequence it in order to obtain the relative expression of genes of this particular samples. And I wanted to share with you publication that already presented in the previous presentation. And so the team of (?)) and the Dutch team has performed this experiment, this experiment, this are in a second tumor from 52 patients in order to obtain molecular characteristic of colorectal cancer, peritoneal metastasis. So before showing the result of this publication, it is important to know that colorectal cancer has been classified in 2015 in a four different consensus molecular subtypes depending on the transcriptome analysis. So CMS one is MSI immune subtype, CMS two is canonical subtype, CMS three is metabolic subtype, and CMS four is mesenchymal subtype. So this molecular classification is the basis for clinical certification, as you can see here. So depending on the classification of the of the tumor, the survival probability would be different. So this molecular classification is also the basis for subtypes, sorry, based targeted intervention. So Vermillon team did the exact same classification and reveals that colloidal cancers are mostly CMS for as you can see here, they represent 85% of this septal in the pool, and moreover, they were able to divide it in three separate categories, the CMS for subtype, and they called it PM, A, B and C. And these categories are again the basis for patient stratification and to define patient at high risk. And indeed, this group shows that the CMS 4, PM A and C, sorry, I don’t see it very well. A and C, have a better prognosis as a CMS 4 subtype, PM, B. So to continue on, the models that can be set up with clinical samples, there is also the graft of this clinical sample into mice, and this is called PDX, for patient derived xenograft. The main advantage of this model is to properly represent the tumor heterogeneity, but to have several flows like there is, there is no, no immunotherapy can be tested because we, we have immuno deficient mice. And this is not possible to perform high focus screening. So other model, in vitro model, so PDO or tears are organ tips. So PDO are patient derived organoids, and the tumor is dissociated and future in a semi solid matrix, and generally is mature gel increase in presence of high concentration of growth factor and treating culture the best. The important thing of this video is that is is keep the endogenous architecture of the of the tumor, the cancer heterogeneity, and it displays the exact same driver mutation, but it does not retain the stoma cell, which is a problem. So concerning the OTS organotype tumor spray, it is the same thing as organoids or PDO, but this time with the addition of Somal cells. And I will give you some example. One example in, in the next slide. And finally, what we can do also with special model, is organ on chip. And it consists in, in in in recovering tumor slice, and we sorry, and we loaded the this tumor side on a chip, and this chip can monitor some biological parameters, and this model is only one that preserves the free environment of the nature chief tumor. But the problem is doesn’t last long, so we cannot keep it more than more than one week. So as I just told you, I wanted to to show you some new results concerning the OTS organotypic MOSFET, and by showing the recent work of the team of Constantinos votanopolis. So this team has has created a procedure to to to produce some patient derived organoid with immune cells. So what they have done is that they sorry again. They have, they have taken the tumor cells and they perform tumor cell isolation, and they culture them in in organoid in Matrigel, and this these tumor cells, and mix it with the immune cells, either from the blood of the same patient or with a lymph node of the patient. And they cocured them at least, at least sorry for seven days. And then they treat this, this PD 2 with different drugs, and especially with immunotherapy. And then the to look at the drug effect they can live with, they can see with immunofluorescence or cell variability. So in this, in this work, botano pulas compares the efficacy of three different immunotherapy here. I don’t know if you see pembrolizumab or nivolumab, which had to be on to be one or one or four on the six different patients. And for instance, we would see here, sorry again in in a patient four, that when we mix the tumor as a tumor sample with with immune cells, either from a lymph node or from blood and treated with here is, is pembrolizumab has a high efficacy on this tumor compared to new volume up that has no efficacy at all. So this, this dissipative and this, this work of what an opulous team shows that this, this model allow pre clinical testing of immunotherapy on patient samples, and this, this model is a real asset for our personalized research. So to finish, I wanted to share with you a model that we have developed in a team with the help of Dr Sgarbura and this is a syngeneic auto topic, tumor graphed into immunocompetent mice. So syngeneic graph means that we graft urine cells into a mouse of the exact same genetic background. So this means that the mice will be fully immunocompetent. And this make this model really relevant for studies of immunotherapy. Orthotopic means that that the growth of tumor cells is into the corresponding tissue here, for the here’s a peritoneum, and this will make the tumor cells growing in a relevant tissue micron biome, and the monitoring of the tumor progression will be done by two ways, first with bioluminescent and also by assessing the PCI score on the mice exactly the same as it is done significant. So in the lab, what we have identify a new protein, your kinase, which is called ATR and which is responsible for oxaliplatin resistance. And we have shown that if we combine an inhibitor of this ATR kinase that we called ATR inhibitor, with oxaliplatin, the combination is highly synergistic, as you can see here. And we demonstrated that the combination of oxaliplatin ATR inhibitor is is able to kill the tumor cells, but also is able to induce anti tumor immunity. So with this result, we raised the hypothesis that we may improve treatment by a new therapeutic combination, including oxaliplatin power, standard chromotherapy, ATR inhibitor to limit oxaliplatin resistance, and immunotherapy, immune checkpoint inhibitor on TPV, one that will fortify the immune system To eradicate tumor. So we injected the immune tumor cells into the peritoneum of the mice, and we treated the mice with a combination of oxalic cutting HR inhibitor and anti PD one. And here is a result. So it is a non treated mice group, and here is the mice treated with the combination. And as you can see here, we cannot detect any more tumor growth in in this group. So we continue. So now what we are doing is we trying to understand the role of the immune system on the efficacy of this treatment. And with the doctors, we are creating ipto to test this treatment, on on on the on the clinical samples, on patient samples. So with this result, I will end the the my my presentation, and I will be happy to take questions. And thank you very much for for your for your attention. Thank you. Goodbye,

Manju George 1:12:23
Doctor Gongora. Thank you very much. So I think the next question that we would ask is, like, from your disease, from your you know, pre clinical models, is there a pipeline so that you can move it towards a clinical trial in patients?

Dr. Gongura 1:12:38
Not yet, I have to say. So it’s still —

Manju George 1:12:42
— In your consortium, it would be great to have, like, the next step of whatever is, you know, promising in mice, in mice that you can move it forward to clinical trials, right, like with the oxalyplatin and ATR inhibitors and anti PDL one, that’d be like a great model to test in a small phase one trial or something.

Dr. Gongura 1:13:01
I totally agree. I totally agree with you

Manju George 1:13:06
And then, yeah, I was really interested in Dr Huber, you know, comments about the repeat laparoscopic, you know, look to see if, say, Early Stage patients after adjuvant therapy, you know, whether they’re likely to develop peritoneal mets. I was kind of wondering, you know what, what would be needed to have a trial like that, like for early stage patients, with the main idea, you know, where you pre select a high risk population and then have trials where you’re doing laparoscopy look and then doing peritoneal washes and CtDNA or something like that. I mean, what can we do to, you know, facilitate a trial like that, like, as, from the patient, you know, from our side, because that would be very useful, right? Like detecting these disease, peritoneal mets early, when people can do hipec and, you know, change the, you know, the course of the disease, right?

Dr. Huber 1:14:01
Yeah. So, so what we know is the most important risk factors for development of of peritoneal metastases. So this we know, but we don’t know what to do with these patients. And two, two large scale randomized trials failed to prove benefits of of a prophylactic or an adjuvant strategy, you know? So we have the Dutch the Dutch colopick study, which which applied the prophylactic, IP, chemo, siPEC in high risk patients before start of adjuvant chemotherapy, and the profilo chip study of the French consortium did it, did it after adjuvant chemotherapy, and both studies were negative, meaning that the treatment arm, which had both the second look. Are, at least in the profilo chip It was after adjuvant chemotherapy and profilo chip treatment failed to translate into into survival benefits. So we clearly don’t know. I think we should. We have to continue to investigate this also to correlate circulating tumor DNA, with results of staging microscopy, with tumor markers, we have to take everything. We have probably also use artificial intelligence to capture those factors which are not, not currently taken into consideration. But, but as of now, I don’t think we can give, we can give an answer. What are your thoughts? Olivia, so do you have more insights? Second Look, liproscopi?

Dr. Sgarbura 1:15:53
no, I completely agreed with the clinical setting in which you proposed earlier on, I agree with your interpretation on on the trials, there is another proposal of trial in France. We’re trying to do it with a different with a slightly different scenario. We’ll see if it gets funded next year. So we need to find out more about that before proceeding.

Manju George 1:16:17
Okay, okay, we are getting close to the end of the talk, let me see if there are any other questions. So I think there was a recent paper where they were comparing like, say, for example, the BRAF subgroup and then hipec and the results from that, right? So I was kind of wondering, even in the in the subgroup, where, you know, based on older studies, you would say that you’d probably not recommend hipec. Are there other factors to sub stratify patients? You know, even if you have, like, say, for example, a BRAF mutation, but you have continued stability on a certain treatment, or, you know, what other factors could patients know about that would help them say, okay, it at this time in my treatment, maybe now is when I should, you know, pursue Hipec and see what my chances are. I mean, what comments do you have

Dr. Sgarbura 1:17:10
So basically, we would not exclude a patient for Cytoreductive surgery and hipec merely on the criteria of BRAF mutation. But as as you mentioned in your question already, so we will probably take extra care when selecting these patients for operation. Will probably some of these braf mutated patients are patients with mucinous adenocarcinoma, so probably will tend to take on Cytoreductive surgery for BRAF mutated mucinous adenocarcinoma, but we’ll be very careful with the selection, with the PCI and other conditions, with the response to chemotherapy. And probably Dr Hubner would say more also about a score they developed in in Switzerland based on that.

Dr. Huber 1:17:58
So basically, BRAF mutated patients, most of them do not benefit of CRS and hipec. So, so just to make it clear, the main treatment is cytoreductive surgery, and hipec is just an adjunct treatment. So we shouldn’t talk about hipec but, but really, CRS plus minus hipec. This being said, I would not exclude categorically braf mutated patients, because if, if for than any reason, they have favorable than evolution, and if they fit, fit resection criteria, and if they, if they agree to to take The risk of the procedure, they might still be candidates, but, but overall, BRAF mutated patients, no good candidates for this, for this morbid procedure.

Manju George 1:18:50
Okay, thank you. My other question was about, you know, I think the PCI score, how, how it is looked at in Europe versus US is slightly different, right? I’ve heard that, you know, the surgeons in Europe are a little bit more lenient. Is that true? Or is that we should have probably asked when Sam was here?

Dr. Sgarbura 1:19:12
No, I would not say that. Well, we have clear criteria for calculating a PCI score. Now there are always question about how we can do it better. And several years ago, there was a tentative for a consensus on on how to quote situations that were a little problematic. Unfortunately, I did not see the result of that consensus published to say that now we’re everybody around the world is quoting the same thing. I would say those who quote a little bit different are usually Asian surgeons, because they don’t usually use the PCI score, but a rather p1 p2 p3 classification, and that’s mostly for gastric cancer. I don’t know. Dr Huber, if you’ve got any other opinion on that, yeah.

Dr. Huber 1:20:00
Well, PCI is, is quite complicated and it’s highly subjective, but it works incredibly well. It’s, it’s a very useful tool for decision making and also for for for prognosis. So, so despite all limitations, I don’t think that there are two important variations around the globe, and it it works really well in clinical routine.

Manju George 1:20:27
Okay, the other question is, like, a second HiPEC or second Cytoreductive surgery, you know, like, what are the indications where you would think that that is something that is realistic to do? Like, you know, for a patient, what advice would you give them? When can they think of a second CRS, kind of surgery

Dr. Huber 1:20:50
Well I should probably take this, I’m chairing the subgroup committee of the sogi(?) consensus on those questions for colorectal what there was weak consensus that redo CIS Hipec could be considered for early recurrence, defined as occurring so within the first year after after index surgery. But a very strong consensus to offer redo CIS HIPEC, for patients, is late recurrence occurring later than one year these, this is an expert consensus, and unfortunately, we have very weak than evidence to support than either decision.

Manju George 1:21:38
okay, so this is, this is a tricky way of me asking this, in your personal practice, what are the things that you would do? Like, I mean, apart from what is in the consensus, like, what, when you have a patient in front of you, what are some of the things that make you decide that, okay, I’m going to do a CRS on this patient? What would those be?

Dr. Huber 1:21:58
So I’m a, I’m a strong believer, to to walk the talk, and so if, if I am implicated, or even sharing a subgroup for consensus, we should stick to the final result, because otherwise it really doesn’t make sense. So so until we have better evidence. So so I would, I would explain them, limitations, hopes and and risks of the different treatment options, we have to do it always. So what are the possible treatments with risks and benefits and and then let the patient decide, and some patients so this is also an open issue. Some patients want to be guided, and some patients rather want to guide the clinician into the direction they want to have them. So here, it clearly depends also on communication, but it’s my duty to explain in a in a neutral way, the available than alternatives and and then if the patient fits so within our agreed standards. And I would, I would, I would offer this treatment option.

Manju George 1:23:12
Okay, thank you, Dr Sgarbura, do you have anything to add?

Dr. Sgarbura 1:23:16
Yes, I would say I agree with working through a talk on most of it, I would be a little bit more reluctant to say yes. I would do cytoreductive surgery in hipec for early reference, because early reference sometimes it’s a sign of high activity of of the disease. So we would normally not want to operate when the disease is very active, in order to not see it recur again very quickly. So probably for these patients, I would take extra, extra care to see that I don’t know systemic chemo worked. Maybe have a longer systemic chemotherapy, not not a short not after a short interval, rather after a long interval. Discuss also the decision with the patient.

Manju George 1:24:03
Okay, so the last question would be, in a palliative setting, what are the things that you would think about doing Sierra(?) surgery? Would you consider it at all?

Dr. Sgarbura 1:24:15
I would say, in the palliative setting, I would say the more important is to provide a very good quality of life to our patients, maybe with, let’s say, at least equal survival results. So probably it’s important to discuss the decision with them, but but also to to really take into account all the options that could provide with better quality of life than the one of palliative surgery that’s that can evolve a lot of morbidity and a lot of risk for for the following month. So I would say that probably it’s the setting where, for instance, pipac, or an association of pipac and systemic chemotherapy might work, might probably work better than palliative surgery.

Dr. Huber 1:25:08
So what is palliative surgery? And I’m not convinced that we we can take it as binary variable, yes-no. And most of so called curative surgery, like curative pancreatic resections for pancreatic cancer. We know that that nearly, nearly all patients recur, so despite complete resection, so we could also label this as palliative surgery. So, so I think this is very difficult to to say. CS hip is not more morbid than other major than oncological procedures, and despite the fact that it’s for metastatic disease, the outcomes are better than, for instance, for curative resection of pancreatic than cancer. So so it it has to be to be put into perspective, and those terms have to be to be to be carefully discussed with the patients. Because if you, if you mentioned palliative, many patients will will be shocked. If you say curative, you give false, false expectations and false hope. So it’s, it’s, it’s not so easy. And I would really, really be careful with those terms.

Dr. Sgarbura 1:26:19
I agree that actually, probably we add such to two different, or, I don’t know, clinical situations. So for me, palliative, when that setting would be like a partial surgery, like a debulking, like something aiming to reduce the tumor load. But I do agree that that’s a case by case scenario.

Dr. Huber 1:26:40
So debulking surgery can make sense in symptomatic patients, especially, but certainly no IP chemotherapy, no hipec.

Manju George 1:26:49
Okay. Thank you very much. I think we are at time, and this was wonderful. Thank you Laurie for organizing it, and thank you doctor Sgarbura for assembling a great team. And thank you very much. Thank you very much. Thanks to everyone for attending and for all the great questions.