PIPAC, ePIPAC, and other clinical trials for unresectable mCRC: Dr. Raoof (2024)

Betsy Post 0:00
Welcome to this evening’s DocTalk. We are extremely excited to have Dr. Raoof from City of Hope to talk to us this evening on colorectal cancer peritoneal mets. Specifically, he will be talking to us about PIPAC and other clinical trials for unresectable peri-mets. We are honored and very excited to have you this evening, thank you so much for your time. If you do have questions for him, please remember you’re going to be muted for the duration of his presentation, and please put the questions in the chat. So in the chat is where you’ll put questions, and then at the end, we will do a live Q and A, otherwise you will be muted, like I said, we’ll do the presentation, put the questions in the chat feature, and with that, I’m going to turn it over to Dr. Raoof. Thank you so much for being here with us. We’re so excited to learn from you.

Dr. Mustafa Raoof 0:56
Thank you so much for the invitation and having me. I just wanted to give my background a little bit so everybody knows. I work at City of Hope as a surgical oncologist, and I’ve been there for the last nine years now. My practice predominantly involves colorectal cancer, also appendiceal cancer. I deal with metastatic colorectal cancer. So basically peritoneal metastases and liver metastases and so, I’ve had a lot of patients who have been benefiting from all the activities that are led by COLONTOWN so it’s really an honor to come to this forum and talk to you all about what we’ve been doing for peritoneal metastases. Today our focus is regional therapy for peritoneal metastases. And what I will do is give you — so I do have a couple of disclosures. I have funding from Exact biosciences to study circulating tumor DNA and metastatic colorectal cancer, both liver and peritoneal metastases and some of the data I’ll discuss. The devices for the trials were given by Capnomend and Reger, which are European companies, but I won’t be discussing any or recommending any off label use for these devices. But just to give you today’s learning objectives, they are threefold. So we want to give you an overview and rationale for why we do regional therapies for colorectal cancer. I’ll discuss what the current evidence is for the use of PIPAC and ePIPAC and then I’ll discuss our efforts as part of the US PIPAC collaborative that we started in the year 2020, and so I want to give an update on the on the results from those trials, and what is next in terms of management, so just to kind of explain what peritoneum is. Peritoneum is an inner lining that covers, you can think of it, if you’re sitting in a room, the paint on the wall or the inner lining of the abdomen is the peritoneum. But if you can imagine that paint extends all the way onto the furniture, which are your organs, that would be the peritoneum. So any organ that gives rise to cancer in the abdominal cavity can then spread on the surface, on the inner lining, and it can create a lot of problems. And I think folks who have dealt with this know that it can cause bowel obstruction and can cause ascites or build up of fluid in the abdomen. It can cause abdominal pain. Many times it will make patients ineligible for clinical trials. So it is really a life limiting problem. And so we have lagged behind in developing therapies for the peritoneum. We think about regional therapies, which are therapies that are given directly to the anatomical area as a potential avenue, which can be different from IV therapies, which are given in the venous system, and they go all throughout the body. And the idea of doing regional therapies actually to spare toxicity while enhancing the efficacy. And so there’s two kinds of regional therapies. One of them is called cavitary therapy, and the other is vascular, and basically it is the avenue or the route we’re using to deliver the therapy. So for cavitary therapies, basically, you guys have heard of HIPEC, or heated intraperitoneal chemotherapy, basically directly giving the chemotherapy inside the abdomen. Infusion means you inject the therapy, you leave it, then in perfusion, means you circulate it, and then take it out. And so the same way vascular regional therapy involves infusion or perfusion, so examples are, for example, hepatic artery infusion pump is an infusion therapy that gives treatment regionally directed at the liver. And so there’s examples of that in surgical oncology, and there’s data to support their use. We talked about HIPEC, PIPAC is one such therapy where we infuse chemotherapy in the abdomen in the form of an aerosol, and I’ll talk a little bit more about that later. And then, so vascular, we talked about the hepatic artery infusion pump, where you put a catheter and give the therapy directly to the liver. For melanomas and outer tumors on the sarcomas on the leg, this is a type of therapy we give to treat it in the vascular system of the leg. The leg being an end organ, you can occlude return of the blood to the rest of the body, and so isolate the limb and then give therapy. So it’s called isolated limb infusion, or isolated limb perfusion. Regional therapy concept is advancing. So while we have thought about treating tumors in a certain anatomic location, certain organ, the more refined concept of regional therapy is that we have realized that colorectal cancer in particular, is not the same when it’s in the lung, in the liver or the peritoneum in the same patient. If they have metastases, and in these three common areas, when you look at it under the microscope, it’s a microenvironment is completely different. So the need, or the aspiration is that we will have therapies that target each and every individual site of tumor. So these would be considered regionally directed therapies. Because we’re directing, we’re still giving them IV, but because they’re regionally directed, they will have less toxicity, and they will act on that area. So this is just conceptually, this is how I look at it. You know, what is the goal post for success of any therapy we look at? There’s only two things: It’s quality of life and quantity of life. So there’s often trade offs when we’re talking about therapies, whether it’s chemotherapy or surgery. We always talk about these trade offs, and this is the bulk of my conversation in the clinic with patients is, yes, we can do that, but we are uncertain of the longevity, and we are sure that a particular operation, a particular chemotherapy, may reduce your quality of life by this much, so this is what we’re trying to balance. And so ideally, most people, if you ask them what kind of a quantity and quality of life they’d like to have, they will say that we probably want to be this person in light blue over here, where you have a great life. And then, at the end, you want to pass quickly. You don’t want to linger on in a pretty bad state. Unfortunately, for a lot of cancers, this is what happens here. You’re at the prime of your life, and you get, a diagnosis of cancer. And then all the therapies and treatments we give, sometimes they work and you’re on the blue path, but sometimes they’re not as effective, and then the quality of life declines, and you end up in a situation where the quantity may not be as important because the quality is so bad that it’s not a life worth living. And that’s very individual to each patient. So we’re going to assess regional therapy or even PIPAC in this context. And so this theme will re-emerge, and it’s really important to have sight on what we are actually trying to achieve when we’re talking about a therapy being successful. Why do we think giving therapy directly in the cavity is going to make a difference? There are three traditional rationales of doing regional therapy, and one of them is a newly recognized rationale for doing regional therapy, and I’ll discuss all of them. So first one is that modern systemic therapy, even older traditional therapy, is less effective in the peritoneum, and I’ll get to the data behind that. The other one is that peritoneal disease limits quality of life, so addressing this disease, even in the setting of vitally metastatic disease, becomes a priority. And so we want to make sure that the peritoneal disease is somehow addressed, and then when we give therapy regionally into the peritoneum, we anticipate there’s better efficacy and less toxicity, kind of like the hepatic artery infusion pump, also is that you get therapy directly in that area, and less of it is absorbed to the rest of the body and it doesn’t cause as much toxicity. And then the final rationale, the newer rationale, is that the peritoneal metastases are distinct from other sites. In the same way, liver metastases are distinct from other sites, and giving therapy that is ideally suited for that particular site of metastases may actually be beneficial. And so the evidence behind peritoneal metastases being worse than other sites of metastases comes from this key study. Everybody in the peritoneal oncology community has seen this study, and these data were eye opening when they were first presented in 2016. There were other similar studies that have talked about this, but this is patients. These are all the patients that are enrolled in clinical trials of first or second line chemotherapy regimen. So these are not people who have had surgery, necessarily, but their cancers were not considered resectable, but they were enrolled onto the trials. So when you segregate them by who had isolated peritoneal metastases, and who had peritoneal metastases plus metastases in other organ/s what we learn is that the survival is the worst for the patients who have non-isolated peritoneal metastases, meaning other organs are also involved. But even when you compare isolated peritoneal metastases, they fared much worse than patients who, for example, had non-peritoneal metastases in one organ. So these majority of these patients, are patients with isolated liver metastases, and you can see there’s that difference. So, why is it that the patients with peritoneal metastases do worse? There’s two possibilities. One is that the peritoneal metastases are just resistant to the current treatment, this is modern systemic therapy. Or the other is that perhaps patients, because they become symptomatic, they’re not getting the proper dose of chemotherapy, because they get obstruction, they are so symptomatic they can’t tolerate chemotherapy. So to answer that question, folks have looked at data from these clinical trials to see: patients who have peritoneal metastases versus not, do they actually have a similar number of chemotherapy cycles that they get? And the answer is, yes, they do. There’s no difference. For example, no peritoneal carcinomatosis. There’s different arms of the trial. There’s combination chemotherapy and sequential arm. But nonetheless, no matter how you look at it, patients who do not have peritoneal metastases versus those who do, they get a similar number of chemotherapy cycles. And this is another trial of systemic therapy, CAIRO 2 Trial, name’s not important, but the idea is that more or less people get a similar number of chemotherapy cycles. So it can’t be the dose density, as we call it, can’t be the amount of chemotherapy patients are getting. What is it then? So some data, and we haven’t seen this kind of data appear as much for the modern chemotherapy regimens, but folks have tried to look at what is the response rate of systemic therapy to – when you look at CT scans, does the tumor shrink or not? So, this is 5-FU based systemic therapy, this is older generation chemotherapy. When you when you give that, complete responses where chemo completely kills the cancer is very uncommon, even for liver metastases. Peritoneal metastasis, not documented by my experience, is about 1% to 2% with modern therapy, with partial risk for partial response, meaning some shrinkage. With modern chemotherapy, the liver shrinkage can be up to 60 – 80% if biologics are added, if you’re using three drugs, etc. But for the 5-FU, we were getting 36% partial responses. And in this particular study, you can see the peritoneum had the lowest response rate at 10.4% suggesting that perhaps the chemotherapy is not really that active in peritoneal metastases. I think the modern data that is around now is with modern chemotherapy, there’s a trial called CAIRO6, where patients get chemotherapy, with patients with periometasis, they get chemotherapy, then they get surgery, and then they get chemotherapy afterwards. So by giving them chemotherapy up front, they can evaluate histologically. After the specimen is removed, they can see if the patients have response or no response. And on that study, what they find is that there is 28% objective response rate with chemotherapy. Whereas, when you look at the one of the studies from for liver metastases, same similar design, where they get chemo, surgery and then chemo, it’s called the EORTC study, on that study was 43% response rate for chemotherapy. So, suggesting, even though it’s cross-trial comparison, this does suggest that perhaps there is less response to chemotherapy when it’s given IV. So then the question is, is the drug not getting in the tumor, or is the cancer cell really resistant, inherently, to therapy, whether it’s from being in that environment at the peritoneum? What is it? And so I think that question is not completely settled, but I think that’s something that that needs further investigation, but I think it’s probably a bit of both, and we’re starting to learn about that. So this is a failure of the oncology community. I think we haven’t done service to our peritoneal metastases patients, because patients with perit metastases have been underrepresented in clinical trials. And you can see, this is from Dr. Turaga, who I know has spoken on this forum before, and many of you are familiar with him. He’s a good friend and colleague, and he published his seminal paper in Lancet Oncology with Dr. Tseng. And what they talked about was they looked at all of the clinical trials, – a whole bunch of them. And here are 72 clinical trials with 45,000 patients. And in these clinical trials, the proportion of patients with peritoneal metastases that were included were between 10 to 20% so it’s very low, whereas we know that in autopsy studies, 20 to 51% of patients will have peritoneal metastases. So why aren’t patients being included in the clinical trials? It’s not an intentional exclusion, but it is a systematic exclusion. And so why? Why does that happen? Because when we are talking about clinical trials, one of the criteria to track the effect of a therapy is that you measure it on a CT scan and you see if the tumor gets smaller or not. And that’s called the RECIST criteria. It’s a radiographic response criteria. And for that to happen, you need to start with a measurable disease. The problem with peritoneal disease is it starts as a flat disease or amorphous disease that’s really hard to measure on imaging. And so when you have that, a lot of patients will not be eligible because they have RECIST non measurable disease. The other strike against peritoneal metastases patients is that usually they will not have the greatest performance status. Some of the patients will have obstruction or GI symptoms, and for that reason, they also get excluded from clinical trials, and this has really hampered our ability to make progress, for peritoneal metastases. And you know, the same study that Dr. Franko published, you can see that for performance status, this is ECOG performance status, so two is worse. Zero is is good. And so when you compare it for peritoneal metastases, patients with non-isolated peritoneal metastases or isolate peritoneal metastases, there’s more of the patients who have worse performance status on these trials. Even though they may cut off for eligibility and compared to non peritoneal metastases, you can see their performance is actually better. So, I think that’s why patients are getting excluded. And we looked at data from California Cancer Registry, and we compared colorectal liver metastases and peritoneal metastases on a number of performance measures. In terms of hospital, what is the lived in experience with this site of metastases? And what we notice is that no matter what parameter we look at, hospitalization per year of life, number of hospitalized days, need for supplemental nutrition, need for gastrostomy tube, it was higher for patients with peritoneal metastases. So it really brings home the point that patients are more symptomatic. So there are unique clinical trial considerations to to provide regional therapy for patients with with peritoneal metastases.

Speaker 1 19:21
There’s a pharmacokinetic advantage of giving therapy in the peritoneum. We know it from peritoneal dialysis. When you can dialyze patients, a lot of what is known about giving a drug in the peritoneum, and it stays there, has come from studies of peritoneal dialysis, and this has been extrapolated even back in the ’70s, where people realize that you can give a certain drug in the peritoneal cavity, and it stays in the peritoneal cavity and that does its effect, and there’s little absorption into the systemic circulation. But it highly depends on what the drug is. For example, hydrophilic drugs that have a high molecular weight and are ionized have a favorable pharmacokinetic profile, and you can really give that therapy more effectively without causing much more toxicity. That is the principle we use in preparing your therapy. So a number of agents have been tried in the peritoneal cavity. That includes Carboplatin, cisplatin, mitomycin C, oxaliplatin, paclitaxel, flouroracil, and you can see that some of them have synergy with heat in terms of their mechanism of action. You can combine it with either hot liquid, like HIPEC or people are doing hypothermic aerosol chemotherapy as well. And we don’t want the agents necessarily to be cell cycle specific, because only 30% of cells may be going through the phase where the chemo is most effective so we want the therapy to work in all phases of the cell cycle. And what we notice is that this is the pharmacokinetic advantage. So basically, the higher the number, meaning higher concentration in the peritoneal cavity versus the venous system. And so for some agents, for example, paclitaxel, happens to be a very good drug. If it has any effect, it doesn’t have a great effect in colorectal cancer, so we don’t really use it. But some of the other drugs, for example, mitomycin C and oxaliplatin, I’ll talk about, they have good pharmacokinetic advantage, and we use them. Cisplatin and carboplatin, are used in ovarian cancer, they don’t have great activity in colorectal cancer. One thing I will point out is that, penetration depth of these agents, with intraperitoneal administration is very, very low. It’s between point five to two millimeters or three millimeters. You can imagine that a peritoneal tumor can be viewed as, usually when you feel it, it feels like a rock. It’s very hard. It’s a pebble. So if you put water over it not much is going to go into it. Both cover the surface and so something like this happened. So PIPAC has been one of the benefits that has been reported, and I think it remains equivocal, I’m ambivalent about that, is that it penetrates deeper into the tissues because you’re delivering therapy at a higher pressure. But I think that remains to be contested. I’m not too confident that that is a true assertion, because some of the interstitial pressure of these tumors is really high. You know it’s like a rock. So even if you spray it with a high pressure, it’s still a rock, you know. So I think, the penetration assertion needs to be further tested, but it makes it really important to understand that just putting in a therapy in the abdomen is not going to cause it to work. People say, “Okay, well, I’m not a candidate for cytoreductive surgery. Why can’t they just put chemo in my abdomen?”. And this is why, because it will touch the top layer, it will cause all sorts of toxicity, but not really achieve much. So what can be put in the abdominal cavity? I think there’s a lot more that can be done. There’s a rationale to deliver therapy reasonably. We talk about surgery, we talk about cytotoxic therapy. We talk about hypothermia. These are somewhat established standards now but the newer therapies include biologics, antibody drug conjugates, nanotherapeutics, oncolitic viral therapies and cellular therapies. For example, CAR T-cell therapy. So there’s a lot of work that is ongoing, which I think will come to fruition in the near future, and will be realistic therapies in the near term future. So the delivery question, when you give a drug in the peritoneum versus when you give it IV, what does it look like? Is it really better when you give it regionally, does it get into the tissue? This is data from a paper by by Dr. Winner et al in cancer research in 2016. What they did was, – this is data from ovarian cancer. We don’t have this kind of data for colorectal but I think this could be very useful. They used cisplatin, which is the drug that is used for intraperitoneal therapy, and they delivered that in a mouse model of ovarian cancer. And then what they do is they do drug measurements, and then they do modeling to see how the drug penetrated, by measuring the concentration. So, it’s a really neat study where they show that, IP delivery of the drug eventually, when you give it…(changes train of thought) — These are small tumors. You can see that the drug goes into the tumor and you can change the number of vessels in a tumor. The drug gets taken away from the blood vessels so depending on the nature of the molecule, etc, there is drug, but then if there’s more vasculature, there’s clearance also. It gets absorbed into the into the bloodstream. But when you give it IV, you can see that the drug, the same dose, very, very little of it is delivered regardless of the vasculature. And this is true also for antibodies. So what about like anti-EGFR antibody, like panitumumab or cetuximab? When it’s given to IV, does it actually get into the tumor? And you see that when you give it IV, you can see some of it gets in there. It’s all blue. Regardless of how avascular the tumor is, you can get some of it in the periphery. But when you give it IP, and in this model, they’re using the drug Pertuzumab which is similar to anti-EGFR antibody, you can see that there’s more of it. So, I think there’s rationale to deliver these therapies in the peritoneum, regionally. And then this is the final point about the rationale is that peritoneal metastases from colon cancer is distinct. It’s a completely different type of cancer, if you will. You know when they go to the to the peritoneum, the environment actually may dictate how these tumors – what their gene expression programs are. How they’re wired inside, that depends on what environment they’re in. So, for example, this is a paper that was recently published by a group in Netherlands, where they they assessed peritoneal metastases and not only did they show that majority of them are what is called CMS4 subtype based on what genes they are expressing. These tumors within that, there’s three different types of peritoneal metastases. There’s the RAS mutation phenotype, and there’s a mucinous phenotype, and there’s the inflamed phenotype, and that has bearing on survival. This is a newer understanding of peritoneal metastases. What they did was really interesting. They looked at the primary tumor, and they looked at the metastases that have gone into the peritoneum. And what they’re trying to do is understand, are these cancer cells programmed the same way from the beginning, or do they switch their programming? It turns out, for peritoneal metastases, which is up here, this is their programming. You can see CMS3, CMS4. And this programming stays the same in the mass peritoneal metastases sample. So they don’t really switch their programming. These tumors were destined to have peritoneal metastases. It is very revealing about the biology of peritoneal metastases, which is not altogether surprising. We know the right sided tumors tend to be more likely to metastasize to the peritoneum. There’s some genomic markers also that tell us that they’re more likely to go to to the peritoneum. So, that program is embedded in the primary tumor, whereas for liver metastases, there’s a lot of switching. They start off as CMS1, and then when they get to the liver, they switch their phenotype, they change their program. So the liver has a really strong effect on changing the cancer program with the cancer cells. I think these considerations, we don’t know yet how this will impact therapy, but this is really important to understand about the biology. Nonetheless, because it’s a distinct biology, it requires unique consideration for therapy.

Dr. Mustafa Raoof 28:36
I think the summary for this rationale part of the talk is that regional drug delivery, the message is that it may overcome barriers to some of the systemic drug delivery. We know that regional drug delivery will treat tumors that are most likely to impact quality of life – I showed some quality of life data earlier – and then regional therapies are designed to minimize systemic toxicity that will happen with IV therapy, and I think future regional therapy should cater to the distinct biology of peritoneal metastases. So with that, this is the goal or the benchmark we’re going for. So now taking a back seat and kind of looking at the whole field of peritoneal oncology to see, how have we achieved this dream of regional therapy? Have you made any advances over the last several decades? The peritoneal oncology community and colorectal oncology community is very integrated. There’s a lot of cross-collaboration. There’s a lot of interest in trying to solve this problem, because everybody understands this is not a problem that one person can solve. This requires huge collaborative efforts, and there’s a lot of examples of good folks doing really amazing work. And what we have learned is that even though colorectal peritoneal metastases have a poor prognosis, we’ve made a lot of strides in terms of optimizing the tools we already have. So cytoreductive surgery, we know is standard of care. The PRODIGE-7 trial, which some of you may know, is a trial that showed that you can achieve really long term survival, median survival, 41 months, compared to what Franko had shown in the in the systemic therapy only trials. It was a huge improvement, even though it’s not a randomized comparison. But, it’s understood that you can’t achieve that kind of survival without doing surgery, in many instances, with just chemotherapy alone. So that is a huge win for the oncology community to be able to achieve that kind of outcome, cytoreductive surgery when Dr. Sugarbaker championed it at that time, it was a big operation. There’s a lot of learning that happened. The mortality was high at that point, and we had reduced the mortality nationally to single digits: 1 to 2% in most expert centers or even less than 1% if it’s being done in a very careful setting, even though it’s a big operation. We’ve improved how we sequence and deliver our systemic therapy. We’ve minimized the toxicity from that. We can have patients on systemic therapy and they can go to work and do their normal activities in many instances. We’ve also understood that there are unique quality of life considerations for patients with peritoneal metastases. We’re good good about recognizing obstructions or preventing problems before they happen. So all of that has led to improved outcomes over the years for patients with with peritoneal metastases. That is not to say that we’ve achieved success, because we’ve achieved some success, but we haven’t reached our goal. We haven’t cured patients with peritoneal metastases in a way we would like to. We would like to say a lot of patients will go into remission after we give them the therapies, and their quality of life is not as affected. But these are the challenges. The majority of patients I see in clinic will not be candidates for cytoreductive surgery because their disease is too extensive. It has not responded to therapy, or it’s involving some critical organs without which you cannot survive. We’ve shown that, so far, in our individual centers, that hypothermic intraperitoneal chemotherapy has some advantage but we have not shown it in a randomized trial. That is not for the lack of trying, it’s just a hard trial to accrue at this point. People don’t want to forgo that heated intraperitoneal chemotherapy, but the trial that we have is a negative trial so it has left us wondering if we are really helping patients by doing HIPEC treatment. We also know that patients will recur, whether it’s said or not said. But the reality is that the data says that 80% of patients will relapse after curative, intense surgery. And so that means we need to do something beyond surgery that is more effective. We know that systemic therapies, I’ve shared some data about the drug delivery and the survival curves from the Franko study that showed that systemic therapies have limited efficacy, and we have that kind of data for immune therapies also. There’s some promise there, but so far, we haven’t seen that they’re having a tremendous response, especially for microsatellite stable colorectal cancer, we’ve seen some good activity in microsatellite unstable colorectal cancer with peritoneal metastases. We think that the regional therapies have tremendous potential, but we need to generate that evidence. It’s very important that we generate that evidence so we can tell you with certainty whether a therapy works, or if it’s just a thought that it works, but really we don’t know. So, we have to overcome the aspect of conducting clinical trials, which has been challenging for patients with peritoneal metastases. So in a nutshell, this is what I’m talking about. Patients with colorectal peritoneal metastases, when it’s isolated peritoneal metastases, 30% will be candidates for cytoreduction. 70% will not be candidates for cytoreduction. And it is those 70% who we want to really move the needle forward for because I think that those patients have been neglected in our studies in the past. This is how I see the future of peritoneal metastases, peritoneal oncology and colorectal cancer. We need better personalization. We need better therapies, and we need better ways to deliver therapy. And so in terms of personalization, it could be based on your genomic profile, whatev our tumors collected, you look at the transcriptome and the genomic mutations, and you base therapy off of that. There’s some work that is being done in that space, and so far, nothing has panned out where, if you come to my clinic, I’ll do a test and tell you from a transcriptomic profile that this is the therapy that works for you. However, from a genomic standpoint, many of you may be aware that if you have a KRAS mutant tumor, it’s a right-sided tumor or KRAS mutant. You know that anti-EGFR therapy is not as helpful, so it’s already starting to affect how we prescribe therapies. Patients with BRAF mutations are candidates for BRAF targeted therapies, but for the most part, the genomic information is tricky. We haven’t completely realized that full potential. So that’s going to be an ongoing team – and this is something our community is working on. Avatar Platforms (Organoids and PDX), these are models. We take your tumor, we can grow it in the lab the aspiration is that we can test a whole bunch of different drugs and tell you which therapy is the most effective for your tumor type. There’s a lot of challenges with that. Trying to grow a tumor is not as successful, and to grow it in a way where you can do high throughput testing, that is a big challenge that needs to be overcome. There’s a number of examples of biologics and nanotherapeutics and viruses and cell based therapies that are in phase I trials, of different solid tumors, and eventually they will make their way into colorectal cancer as well. I think that’s where the future will be. And I will talk about the PIPAC and e-PIPAC as an optimized way to deliver therapy in the peritoneum. So with that, what is PIPAC? PIPAC, as I said, is an optimized way to deliver therapy in the abdominal cavity, and it is done laparoscopically. We put in cameras, we insufflate the abdomen with carbon dioxide, and that creates space in the abdomen. This is very standard for laparoscopic surgeries. People who’ve had robotic surgeries, this is how we create space. So that part is pretty standard. Once we’re in the abdomen, we take biopsies, assess the disease, and then after that, we place a cannula, a nebulizer, into the one of the ports, and on the back end, there’s tubing that connects it to this high pressure injector. Some of you may be familiar with this if you’ve seen this. This is the injector we use to inject contrast, when patients get CT scans, this is what we use. And so basically, you can air slice chemotherapy with the help of a nebulizer in the abdomen. Once it’s air sliced, it can go into the entire abdominal cavity in different places and the aerosol uniformly distributes the chemotherapy. It can sediment then on all surfaces. It’s a very good way to deliver small amount of chemotherapy or agent, it could be other things too, not just chemotherapy, throughout the abdomen. The procedure was invented in Germany, University of Tubingen, and then from there, after initial studies it has been adopted in Europe, even though high level clinical evidence is still lacking, but it is being done. So what have you learned from those experiences? This is a study in Lancet Oncology by Dr. Alyami who reported that in this collection of data from different centers is, the procedure is repeatable. It could be done multiple times and 64% of the time high dose therapy was delivered directly to the most threatening tumors. What they demonstrated was that patients have preserved or improved quality of life, and there’s some encouraging clinical responses. Now the definition of response is a little bit, not standardized for these studies. What they’ve reported is that there’s some response, as defined by the investigators, in a lot of patients, and the significant adverse events rates were 12 to 15% which is actually much lower than what you might get with full dose chemotherapy. So this made it a very promising approach. Sorry to put this picture out there. This is not human. This is a big model. In this model HIPEC was given over here, and PIPAC was given over here. This is an earlier study, and what you can see is HIPEC you you can get a uniform distribution of chemotherapy, but at the end of it, after laval, you have to take the chemotherapy out. So here, blue dye is used to indicate where the chemo would be. And so you can see there’s more blue deposited. This is one of the first generation devices. So you can see the distribution is more but it covers all of the surfaces, but in some areas, it’s more compared to others. The newer generation device has four nozzles and all sorts of fancy things that allow for even more homogeneous distribution. So when we do the PIPAC, we do this laparoscopically. We put a camera, which is mounted on a retractor, and the pen goes in one of the trocars. We use these things called balloon trocars, so the aerosol doesn’t leak out into the room. And we make sure we follow occupational standards, and it’s done with the utmost safety. When we are in there, we take biopsies of these peritoneal metastases, we score on what the PCI is or what areas are involved and we can do that sequentially. Every six weeks, when we do this, we can track if the patients are responding to therapy or not. So this is how it’s done. So everybody leaves the operating room after we set everything up. And you can see injectors over here. The pen is placed in the in the trocar, in the abdomen, and the screen is turned around so we can watch from this window. And this is our anesthesiologist who has a protective bound to come in if needed, but everybody is remote. The IV is hanging over here, and it goes out the door. The drugs and anesthesia can be administered remotely. And then the spray essentially aerosolizes the drug. After 30 minutes, the drug sediments, we come back in, we do some post PIPAC biopsies, and then we close. The initial studies have focused on figuring out what chemotherapy and what date dose should be used. They’ve not been really focused on determining if it works or not. But the first step is to say, “Okay, what is the dose?”. And historically for chemotherapy, we base it off of toxicity and the idea is that the higher dose is better as long as it’s tolerable. That may not be the criteria we use for more targeted therapies in the future, but at least for now, that seems to make the most sense. Folks have tried different regimens. For example, this is an ovarian cancer study. They’ve focused on Doxorubicin, cisplatin. This is a study from France where they had gastric cancer, colorectal cancer, small bowel cancer, and they used oxaliplatin. This study just said 90 milligram per meter square is the optimal dose. A study from Singapore here that included a whole different kind of cancers, demonstrated that 120 may be the optimal dose for oxaliplatin. And then this Italian group study and the Belgian group study, they have different regimens they’ve tested. But in colorectal, they think 135 may be optimal. And so these are the initial studies that have been done, and now phase II studies are ongoing. You can see there’s a whole bunch of clinical trials, but you will see that none of them are actually in the US. So, we’ve lagged behind in terms of adapting or evaluating this technology, and I think we’re catching up now. I think one aspect of the trials is that we want to make sure that the trials are including a well defined patient population. For example, trials that include a whole bunch of different pathologies, it’s really hard to make sense of whether or not there’s benefit in survival. What we should be doing actually, is focusing, for example, on colorectal cancer and looking at one type of therapy and ideally doing a randomized study so that we really know if it’s better than not doing the therapy. I think those kinds of trials are lacking so far. This is the largest study to date from European centers, specifically from Denmark. Essentially, this is a prospective study of PIPAC with oxaliplatin as the drug that they’ve used. Essentially, what this study is, is they had 110 patients who got 336 PIPACs. Median of three and 100 patients had prior chemotherapy. Some of them were chemotherapy naive, and half of them almost had bi- directional treatment. The chemos that they used were cisplatin, doxorubicin they did include different types of cancers, so gastrointestinal, gynecologic, including unknown primary PCI score was 11.4 so this is low. For an unresectable majority of these patients we will consider for resection, and histologic responses, which is graded based on a scheme that is shown here. I’ll explain that scheme were about 61% in those who completed all three PIPACs. So you have to look into that a little bit, because patients who are completing three PIPACs it’s excluding patients from the denominator who progress, so it over inflates the efficacy of PIPAC, so we have to be very objective about the data we’re looking at. But this is how we measure histologic response. There it goes from PRGS (4) to PRGS (1). PRGS means peritoneal regression grading scores. It’s a system that was described by pathologists. Essentially black is the tumor cells. We have more tumor, obviously, of less response. PRGS (1) is a complete response. You may have some mucin, you may have some necrosis, which is this great thing. You may have fibrosis, a lot of it, but you don’t really have any plaque. PRGS (2) is when you have some cancer cells. PRGS (3) is still a lot of cancer cells, but some response. It’s a pretty neat system to classify response on biopsies. Just to remind everybody, our success is not histology. We use histologic response because we think it might mean something for survival. We don’t really know that yet, and so when we see response, we do get excited that the therapy is doing something, but we don’t really know if it will eventually impact survival. And the reason why we don’t know that is because sometimes response is transient, it will respond, and the tumor may grow back. It may grow back right the next day after PIPAC, probably not. But the point is that we really don’t know how that impacts survival. In order to analyze that, what these others did was they showed that patients who had a lower PRGS had a better survival than patients who had a higher PRGS, and this is at PIPAC (1) and at PIPAC (3). Same thing. Patients who had lower PRGS had a better survival.

Dr. Mustafa Raoof 46:59
If you look at it critically, it still does not answer the question, if a patient had a high PRGS, meaning high tumor in the biopsy, and after PIPAC, it went down, did that correlate with survival? When we asked them to do that analysis, this is what happened. So if the PRGS increases or decreases, it had no bearing on survival so we really have to be careful about what the end point needs to be for these trials. PRGS overall tells us, if you have more tumor in the biopsy specimen, it’s not good, but so far it has not been proven as a good marker of response, or a good marker of overall survival in the long run. So I think that needs to be further defined, and it may be different for different therapies, too. One of the things I was asked to mention or discuss is ePIPAC. What is it? It’s a variation on the PIPAC technique, and essentially what folks have done is, during laparoscopic surgery, we will use smoke evacuators, because the surgical smoke obscures the vision, so everything is foggy, then you can’t really see and do the surgery. So this is repurposed. One technology to evacuate smoke is because smoke has charged aerosol particles. If you put an electrostatic electrode through the abdomen and you activate the charge, and you have a grounding pad on the bottom, the aerosol particles impact all of a sudden to the periphery. And in Europe, they said, “Okay, why not use it to sediment all of the aerosol?” and that’s what they did. Essentially, the biggest advantage of this is, once you give aerosol, you have to wait 30 minutes for it to sediment. But then when you activate the electrode the aerosol, it’s quite cool, the aerosol just impacts and sediments on the surfaces. Now, there are groups that have said that perhaps it may actually increase the depth of penetration into the tumor. I think that that claim remains to be tested in a more rigorous manner. I’m not sure, I’m not convinced that that is true. People have nonetheless done studies with ePIPAC to see what it looks like and you can get responses – complete or major responses – and histologic tissues in a high proportion of patients, and significant or worse transfer were comparable to PIPAC. So essentially, it seems very similar to PIPAC and there’s a suggestion maybe ePIPAC have a better histologic response. But as I said, measuring histologic response depends on the pathologist. It depends on the surgeon, where the biopsy… and we don’t know if that actually will correlate to survival or quality of life, so we have to take it with a little grain of salt, and these are not head to head comparisons with regular PIPAC, so that that study needs to be evaluated also. Now I want to talk about the US clinical trials. What we have over here, is we started this trial in 2020. It had two arms. It had the ovarian, uterine, gastric arm, and then it had a colorectal appendiceal arm. We enrolled patients who were refractory to the first two lines of chemotherapy. These would be patients who would go on to LONSURF or STIVARGO or fruquintinib. At that time, it wasn’t approved, but nonetheless, the third-line therapies. We said, “Okay, well, we’ll try this”. And so patients got the oxaliplatin PIPAC at week zero, and in between, they got no therapy. At week six, they got a small sensitizing dose of 5-FU, but not the full dose of IV chemotherapy. and then subsequently, they got oxaliplatin. And same thing at week 12. Then we measured the toxicity in the first six weeks and monitored them for side effects for 18 weeks. And so arm two was a complete accrual. We reported the results of it, but I’ll summarize them here. We had enrolled 12 patients. It’s refractory, colorectal, appendiceal. 67%, or 2/3 were colorectal and 1/3 were appendiceal – only adenocarcinomas. Feasibility was good. We had all patients complete one cycle of PIPAC. 58% completed two cycles of PIPAC, and half of them completed three cycles. The ones who didn’t complete their cycles was because their cancer had progressed, and so we did not have any surgical complications or those limiting toxicity. Those are the toxicities which says, you know, this dose is not safe to use. So, in this case, it was a well tolerated drug and a lot of grade 1 toxicities, which are minor deviations here and there. And, grade two, which are usually managed symptomatically, and very few grade three toxicities. Did it work? So we had two patients that underwent cytoreductive surgery after PIPAC. So that’s 17%.

Speaker 1 52:34
We had half the patients that had stable disease on imaging and half the patients that progressed. As I mentioned before, it’s really hard to tell responses on imaging, on a CT scan, because the disease is usually flat, so it’s really hard to tell that. Laparoscopically, when you look at it, we calculated the burden of disease. Half of the patients had decline in their scores, and the other half had progression of disease, or only had one PIPAC. And histologically, this is the PRGS: 42% of the patients had some decrease, 70% percent had stable disease, and 42% had progressive disease. And the plot here shows you the lived experience of these patients. Yellow means stable disease, red means progressive disease. Some of the patients had quite long-term stable disease, but many patients had stable disease while they were on therapy, but after that, their disease progressed, as you can see, and some patients did not benefit at all. I will skip this. This is trying to show that the response criteria need to be evaluated further because laparoscopic responses correlate with imaging stable disease, but histologic responses don’t necessarily correlate, so that needs to be further evaluated. What we notice is that the thing that tells us if the therapy is working the most is if their disease is stable on imaging or not. If their disease is stable on imaging, people have longer survival. If their disease is not stable on imaging, then it’s worse. Biomarker, histology response or laparoscopic response did not mean much in this cohort, and this is how the success had been measured in European studies. So we are looking at the data more closely to say, “Okay, what is really helping patients?”. So here we’re looking at good days, days out of the hospital and a life. It’s a low bar for a good day, but nonetheless, that’s a metric that is objectively measurable. If you’re hospitalized, you’re hospitalized. If you’re not, you’re not, and so we look at it, and then we compare it to our historical cohort of patients that were treated at City of Hope on third line therapy or clinical trials. And essentially, we compare the lifespan as well as hospitalization experience and we see that the number of good days are less for the systemic therapy cohort versus the PIPAC cohort. It really stands out at about one year. And you can see over here, these are systemic therapy folks. The blue bars indicate their hospitalized days. We really are reducing hospitalizations and improving longevity. Now, mind you, this is not a head to head comparison. There are other factors that could explain these results, other than PIPAC, but I think it’s hypothesis-generating that we need to validate in a randomized trial. When we compare survival, we see that PIPAC patients did live. Receiving PIPAC was associated with better survival, not so much on the progression free survival. And there’s an explanation for that, in that the PIPAC trial patients get very regimen-driven CT scans at certain intervals whereas patients on third line therapy, it’s more on the discretion of the clinician. So it depends when you measure, when you do the CT scans, because that dictates when you’ve assessed progression. So if you do it at three months instead of sooner at two months you may falsely conclude that the progression free survival is better, so when we saw that we had some success, but we really thought that this therapy could be improved, and we felt the need that for colorectal cancer patients. The biggest need is that when they undergo that laparoscopy and a surgeon comes out and says, “I’m sorry, you’re not a candidate for surgery, and you’re not alone. You’re part of 70% of people who will not be candidates for surgery”. At that point, it does not sit well to just say that you have no other option but to just go on systemic therapy. So we needed to provide an option for patients in that setting. And so we said, “Okay, patients who’ve had four months of chemotherapy and they’re not candidates for cytoreductive surgery, can we combine IV treatment and PIPAC together?”. Frequently, patients in that setting would be undergoing FOLFIRI chemotherapy, and we said, “Okay, we’ll use FOLFIRI chemotherapy as the backbone, because that’s standard of care. We’re going to add, we’re going to take one week out of that therapy, and we’re going to add PIPAC with mitomycin C.” The problem is we don’t really know what the dose of mitomycin C is that’s safe in the setting, because we’re combining it with the FOLFIRI. Even though mitomycin is expected to stay in the abdominal cavity, some of it will get absorbed and may cause hematologic toxicity, where your blood counts may drop to dangerously low levels. So we wanted to study that. And this trial was launched maybe a year and a half ago, and we’re on dose level three right now. It has been completed. We’re doing our assessments on that. Essentially the goal is to figure out which dose is the is the ideal dose. So far, those level one and two have been safe, and those level three is, we’re in the process of determining if it’s safe or not. Obviously our hidden objective, or the second objective, is to see if it works. We have all sorts of measures to describe what would be a success in this trial. So just to give you an update, so far, we’ve enrolled more than this, but this is, analysis is termed at those level two. And so we’ve enrolled 13 patients. Median age is a little younger than the average age of colorectal cancer patients. It’s equal proportion male, female, mostly non-Hispanic, Caucasians that are enrolled in the study. And in those level one, we had two patients who completed all three PIPACs, and one patient completed two PIPACs. And then we had this problem where we had a supply chain issue with the pens. The pens we had to return to the company. As a result, we had to take some patients off the trial because we didn’t have the device available. But nonetheless, this patient could have completed the third PIPAC, but we said, based on the information we had, dose level one was safe. So we moved down to dose level two. And here one completed two PIPACs. Two completed one PIPAC and then they were interrupted by a pen shortage. We didn’t have enough information, so we said, “Okay, we’re gonna repeat the dose level”. And so we did that. All three patients completed the three PIPACs. Then we moved on to dose level three. So this is a typo. This should be here. On dose level three, at the time of analysis two, two patients have completed one PIPAC, but now we’ve accrued the entire dose level three. So what have you learned so far? So up to dose level two, there’s no dose limiting toxicity. There’s no surgical complication. One patient did develop grade three ileus, which is severe ileus. They required TPM, and they were out for three weeks. But for this resolved eventually, after three weeks, and then after that, because of the supply chain shortage, we weren’t able to get them back on PIPAC, but they had a really good outcome in terms of efficacy, I’ll discuss that. As I said, dose level three is ongoing. These are some of the toxicities that are listed here. And you can see abdominal pain, ileus, nausea, are kind of the common toxicities, which are grade one and grade two. These are mild. Most patients are able to manage them, but grade three toxicities, like abdominal pain, ileus, happened in one patient, and it was quite severe.

Speaker 1 1:00:46
So in terms of, did it work? So we look at several measures. Laparoscopic, burden of cancer, histologic burden of cancer, and I’ve discussed this before, how we measure it when we look at it from PIPAC one, two and three. For the first two dose levels, you can see there’s a decline, and same with histologic response. These are all assessed. This is assessed by the surgeon, this is assessed by the pathologist so there could be room for error in this. But we look at the CEA level. What was interesting to us was that even if your CEA was somewhat normal, there was a decline in CEA uniformly across the cohort from from PIPAC one to two, and it stabilized on PIPAC three, with a couple of patients, slightly got higher, but still lower than their starting CEA level. And when you look at it from a radiology standpoint, as I mentioned, it’s really hard to measure this disease, so the majority of patients had non-measurable disease or stable disease. One patient had a partial response and one patient had a complete response to this combination therapy. So this is quite encouraging. We rarely see complete responses, as I said, only a chemotherapy you would see it maybe 1% of the time. Overall, what this is suggesting is that this is an effective combination. And so this is our plan for expanding this technology further, because we really can’t conclude that this is actually making a difference in terms of patients living longer with a good quality of life. Yes, we see some annotations of response, but we don’t really know what it means. And so to really answer that question, we have to do a clinical trial where we randomize patients to getting the PIPAC therapy with FOLFIRI or getting standard of care FOLFIRI. Now why should patients participate if they’re not getting the PIPAC 33% of the time? To my mind, that design is incorrect if you cannot have patients get PIPAC, even in the control arm. So what we do is we allow for crossover, meaning that, let’s say we do standard of care therapy for them, but if the disease is progressing, they’re offered PIPAC at that point. And so that way you’re with this study, you will be guaranteed to get a PIPAC. That question really is, should we do it first, or should we do it later? What we’re essentially measuring is, is progression-free survival. Meaning, how long does the treatment control the cancer before it starts progressing? And the reason we want we chose this endpoint is because it has correlated well with overall survival in the past in other studies and it will be important because we’re allowing crossover, we can’t really use overall survival. Let’s say the PIPAC works just as well if it’s used first or later, we will possibly conclude that there’s no difference in overall survival, because everybody did end up getting PIPAC. So those are some of the nuances of the clinical trial, but I think it’s important for folks to understand why a randomized study is necessary, so that we can then say to the insurers and to the guidelines, that we have the evidence that this therapy works, which has still not been generated for HIPEC. And so it’s really important that we do this study. So essentially, we will include patients who have gone through eight cycles of FOLFOX with or without progression. It does not matter. But they should not have received irinotecan, because that’s the backbone therapy, and they should not be candidates for cytoreductive surgery. We don’t think this is going to be superior to cytoreductive surgery, at least not at this time. And so you want to get a standard of care therapy first. And if you’re not a candidate for that, then we enroll you. And if you have extra peritoneal metastases, lung may be included if they’re smaller than one and less than five lesions, because those are usually ambiguous. But if you have more disease then you’re probably not a great candidate because what we’re doing is we’re diluting, we’re taking one FOLFIRI out. So when you have a systemic problem, you want to be emphasizing systemic therapy and not regional therapy as much, and so that that’s the way this trial has been designed. We’re actively figuring out how to fund this trial. There’s a lot of interest in the oncology community. My colleagues want to do this trial, and we’re confident that we will get this trial started, because that is what is necessary to move the needle in this field. So in conclusion, PIPAC is feasible. It’s repeatable. I think severe toxicity is uncommon. The patient that had the severe toxicity and came off of study, had a really good response to PIPAC, and that patient has been off treatment, last time we checked, for 16 months without evidence of disease. One of the things we don’t know yet is, you get scarring after PIPAC, and we’ve recognized that as we’ve done more of this, and perhaps a little more with mitomycin C than what we were seeing with oxaliplatin. So far, we haven’t seen consequences of quality of life, but we anticipate that if you get too much scarring in the abdomen, you can get bowel obstruction, and your quality of life can deteriorate. So it’s really important for us to assess that. We don’t have a standardized way to assess that yet, but we’re working on developing that and then, and as I mentioned, we’ve seen early signs of efficacy that is really encouraging for us. I just want to give a shout out. I don’t do this alone. Actually. I do very little of it. I have a phenomenal group of folks that are at City of Hope and other institutions that support me to be able to do this work, and really it takes a village to put something like this together. So with that, thank you so much for inviting me, and I’m open to questions.

Betsy Post 1:06:54
Thank you so much. I learned a lot. I’m sure that everyone did. This was phenomenal. We do have some questions for you in the chat, so just remember that I’m not a medical professional, so if I mispronounce something, you can just laugh at me. So since there are a lot of peritoneal mets in ovarian cancer, are there any drugs they’re using that should be tested in colorectal cancer?

Speaker 1 1:07:21
I think ovarian cancer tends to be – even though it is metastasized to the peritoneum, just like colorectal cancer tends to be – a very different disease. Sometimes I’m called to help on surgeries involving ovarian cancer, and I’m almost jealous, because platinum drugs work so well for ovarian cancer, and you see such good responses that it’s remarkable. And so we haven’t had that kind of success in colorectal cancer, to be honest with you. For example, the drugs that are used, cisplatin, carboplatin, have been used in colorectal cancer. They don’t work very well. Avastin is used in colorectal cancer. It’s used in ovarian cancer just as well. And then some of the newer generation drugs, like PARP inhibitors, have not been shown to work in colorectal cancers, because colorectal cancer does not have the same vulnerability of homologous recombination repair deficiency that you see with ovarian cancer. Then there are newer drugs that target alpha folate receptor in ovarian cancer that could have a role in GI cancers. I think that remains to be tested. And then, some of the fewer therapies, like CAR T therapies, are being tested. Dr. Rodriguez is pictured here. She’s running a clinical trial of CAR T therapy and ovarian cancer. It’s a CAR T that’s targeted to a molecule called TAG-72 which is on ovarian cancer, but also it is on colorectal cancer. I think next, if we see some success in ovarian cancer, and it’s thought to be safe, we’ve talked about expanding those studies into colorectal cancer, so I think your point is well taken. Therapies that already exist, maybe the lowest hanging fruit to repurpose them and but, I think people are looking into it so far. There’s nothing that off the bat, but there are some potential leads that need more data.

Betsy Post 1:09:34
Okay, another question is, “Does getting a surgical consult right at the start a good strategy if shrinkage is limited on first line chemo?”.

Speaker 1 1:09:45
I think the best strategy for peritoneal metastases is a multidisciplinary plan. So when at our institution, for example, if somebody comes in with peritoneal metastases, almost immediately, you know they will be connected to a surgical oncologist, a medical oncologist. The new cases do get presented at the tumor board. And so sometimes it does not make sense if, especially if somebody’s traveling from far away, or has a travel burden, to set them up with more appointments. We try to expedite it, where you can see everybody on one day, but it does pass the eyes of a surgical oncologist, or medical oncologists, either ways, very early on. I think that’s the best strategy, is you want to get all of the team members involved early on, so they are looking at long term outcome from different perspectives.

Betsy Post 1:10:47
Great. This is a question that came up when you were starting to talk about quality and quantity of life. We have a patient that asked, “What’s your view on the role of the BRAF mutation with CRS, HIPEC and/or PIPAC and the quality versus quantity of life”?

Speaker 1 1:11:06
Yeah, I think so. BRAF, for folks that are not aware of BRAF mutation, BRAF mutations tend to be more aggressive. The cancers tend to be more resistant to therapy. There are targeted therapies available, like encorafinib and cetuximab combination that have efficacy in BRAF tumors, but the efficacy is short lived. So we know that patients with BRAF mutations do have a tougher time because their outlook is not as good and so in that context, when we are thinking about surgery, I think of surgery and peritoneal metastases as a way to reset the clock. I don’t tell patients that the surgery will cure you once it has gotten to the peritoneum. For some patients, they will be in remission for a long time. With BRAF patients, it becomes harder to make that argument, because I know for certain that with near certainty. I will say there are exceptions. I’ve had patients who have not had a recurrence with a BRAF mutation, but most patients will have a relapse with BRAF mutation and the relapse maybe sooner, not 14 to 16 months on average, but, but maybe six to seven months down the road. So with that in mind, what we’re doing is resetting the clock, but maybe not by as much. So then it really matters what surgery we are proposing? So if the surgery involves doing extensive bowel resections and ostomy and essentially altering the quality of life for the rest of the life, then it may not be worth it to trade that. And I think, to be honest, it becomes an individual decision. How much are you willing to trade. It’s an unfortunate situation that we’re asking patients to do that, but that’s the reality of the way things are. And so ultimately, we individualize. I will frequently do a laparoscopy to assess the situation and understand the magnitude of the surgery we’re proposing before we actually just get into the surgery itself. I would highly recommend that that we take a full assessment of where the disease is and then decide, I think with BRAF mutated cancers, with PIPAC, I think that it’s very new, to be honest. I don’t think we have enough data to make any definitive conclusions, but same considerations will apply. The advantage here is that PIPAC tends to be less invasive. Patients go home the same day or the next day, and so it is overall, a less concern about quality of life, but more so, can we actually get an effect with BRAF therapy?

Betsy Post 1:14:05
Great. Thank you. Would you recommend CRS in the setting of numerous lung mets that can’t be treated with local therapy but are controlled well with systemic? Could CRS prolong life in the setting of those concurrent peritoneal and lung mats?

Speaker 1 1:14:25
Yeah, I think it’s a challenging question. So far, CRS is considered standard when you have peritoneum limited disease. I think when you have extra peritoneal disease, meaning metastases to the liver as well, and metastases to the lung as well, or metastases to the retroperitoneum, it becomes tricky, as far as whether we are getting advantage, the same kind of advantage. So coming back to resetting the clock analogy, we feel that when you have distant metastases you reset the clock less. You know, it is true that lung metastases are not frequently life limiting. If you have the entire lung full of lung metastases, perhaps then that could be a life limiting problem. Usually, peritoneal disease is the life limiting problem. So one would say, “Okay, let’s go ahead and address the peritoneal disease”. The problem is it’s the biology of the cancer. When you have disease in the liver as well, or lung as well, it is also telling us about the biology of the peritoneal disease, telling us that if you go and attack it with surgery or regional therapy, it’s going to come back quicker than what we anticipate. So having said that, I think there are instances where we would make an exception or challenge the rule of not operating on patients with extra peritoneal metastases. I think it really boils down to a multidisciplinary discussion. I think each individual case is very unique. We have to look at the whole history to say, “Okay, how many lung metastases? Where was the response? What is the rate of progression? What are the therapies beyond the current therapy?”. And that allows us to come to a consensus about whether we should or should not do cytoreductive surgery. I will say that generally, if there are a dozen lung metastases, it’s probably not a good strategy to just focus on the peritoneum and take you off of systemic therapy. But I think it’s a very qualified answer. I won’t be able to give a black and white answer to this, because really we have to look at all of the pieces of information and really come to a consensus amongst the treating physicians.

Betsy Post 1:16:48
Thank you. What can we do as patients to help bring about clinical trials that address peritoneal meds? How can we best find and participate in trials for peritoneal mets?

Speaker 1 1:17:00
Yeah, that’s a great question. I think you know, so I think the challenge is that one, you know, greater advocacy. I think Colin tan does a great job with that. I think you know, having patient advocates, you know, like manjus on this panel too, and and having, having patient advocates in not only where funding is being decided, but also as part of you know when the clinical trials are being designed, you know, in cooperative groups and such, it’s super important to make sure that that voice is heard. This is at the level of the trial design. You know, going to your representatives to increase funding for peritoneal metastases is a big, you know, important task that we all have to do it together, you know, I think there’s a lack of understanding of what this disease is, and that needs to be highlighted. And then the third thing is, you know, and this is really important, and it’s a hard one to do, is when we open a clinical trial that is a randomized trial, that’s going to answer a question definitively so that patients can stand to benefit, insurances will pay for therapies that we’re doing in the better, yeah, is to support the randomized trial. What ends up happening, and has happened with hi back in the past is, you know, when a trial is open and you go to a surgeon who says, you know, we really need to answer this question. Here’s a trial. We’re going to randomize patients to trial. And granted, the trial design has not allowed patients to get, you know, high back at a later time, etc. You know, patients will find somebody else you know at a hospital next door to get that therapy. And essentially, you know it, it prevents accrual into the trial. Nobody would want to sign up for the trial, and as because of that, we haven’t had the evidence to do that, I think the the trial design has to be fair to the patients you know, which is why patient advocates are very important when we’re designing the trial. But I think from from the oncology community as well as from patients, the plea is that, you know, please support the randomized trial as long as it is fair. If it’s not fair, obviously you want to get the therapy wherever you can get it, but as much as possible, if a therapy is not proven, get it in the context of clinical trial, because it’s safer for the patients to do that. There’s an IRB, there’s a data safety monitoring board that looks at the data and says, this is, this can this is this can be problematic for the patient, that protects the patients, and so it’s really important to do or participate in clinical trials.

Betsy Post 1:19:40
Thank you. When you were discussing the pipe pack and the delivery and those types of things, that’s when this question came up, what happens if you have a lot of scar tissue?

Speaker 1 1:19:53
Yeah, great question. One thing, it was on the slide I didn’t talk about as much, is, think of PIPAC as fumigating the abdomen with chemotherapy so you have to have space to fumigate. So if,there is scar tissue where everything is stuck to each other, and there’s really no space to aerosolize, then, PIPAC is not the best strategy in that setting. So I get a lot of patients who reach out to me have had their surgeries already. They’ve had extensive site reduction, and now their cancer has relapsed. And while I don’t say “no” without looking, I think the chances that we’re able to put in a camera and find that their space is low in that setting, unless the site reduction was very focused on one area of the abdomen. And so I think scar tissue is a challenge because it it prevents patients from getting, you know, pipe back.

Betsy Post 1:20:54
Thank you.

Betsy Post 1:20:56
When you were talking about the hospitalizations with regard to the trial, they said, “Does hospitalized also include infusion days or only inpatient days?”

Dr. Mustafa Raoof 1:21:09
Only inpatient days, yeah.

Betsy Post 1:21:14
What is the best scan to see exactly where the cancer is, the peritoneal mets? It seems like CT scans just don’t seem to pick it up.

Speaker 1 1:21:25
Yeah, great question. I see a lot of patients getting PET scans, I see a lot of patients getting CT scans, and some institutions are doing MRI. So all of the modalities fall short in assessing peritoneal disease. And I wish I had an imaging technology that I’d say is really great. We’re not there yet but I will tell you that at my institution, we’ve agreed on contrast enhanced CT scan with the peritoneal protocol. So, Dr. Jung is shown on the picture on the bottom left. He’s a radiologist who focuses on peritoneal metastases, and he developed this protocol. Essentially, it’s a thin slice CT scan that has a little bit higher dose of radiation, but it it allows us to see the peritoneum in more detail, and a lot of the scans are actually read by Dr. Jung, or one of his colleagues, who focuses on peritoneum, and so you really need a trained eye to be able to pick up better than the old disease. I think that’s part of that. I think we can improve maybe a little bit, maybe like 10% on the scan, but really if the data is not there, it doesn’t matter how good your radiologist is, they’re not going to be able to assess the disease. I will say that PET scans are disappointing. I understand that a lot of patients have had disease picked up on PET scans. I think it’s useful in some instances, but the data would say that for disease that is less than a centimeter or even flat disease, the chances that the PET scan picks up sensitivity is only 30%. So if it’s smaller than a centimeter, or if it’s flat, the chances are very low that the PET scan will pick it up. The PET scan, the CT that’s done with the PET CT, has very poor resolution, so it’s not a great test to follow patients. It’s also very expensive. A contrast enhanced CT can be very helpful. MRI is very institutional-specific, so you know, if it’s a designated peritoneal protocol MRI, that some institutions have, they have expertise with that. I think that’s a good strategy. It’s probably comparable to a really great CT scan. The problem with MRI is that it’s a longer sequence. So you’re asked to hold the breath. So when you’re asked to hold the breath, you really hold the breath, because there’s motion artifact. And if the diaphragm moves, that’s where a lot of peritoneal diseases, and you get a lot of haziness. So you can’t really tell, even if the it’s a three Tesla magnet, it’s a really good quality magnet, it will be a blurry picture. Same with the bowel. The bowel undergoes peristalsis. It’s a longer sequence, unlike CT scan, which is like two seconds. The bowel, if it’s undergoing peristalsis, it’s gonna be a motion artifact, and you’re gonna miss disease on the small bowel. So I think, you know, some institutions have optimized MRI, it works really great in their hands, or radiologists are very good at it, but it’s really hard to generalize it to all the institutions.

Betsy Post 1:24:27
That’s very helpful. Thank you.

Betsy Post 1:24:31
Do perineural invasion and lymphovascular invasion still make you high risk of perimeters? What scan regimen or schedule would you recommend for a high risk perimeter patient?

Dr. Mustafa Raoof 1:24:44
I think, yes, LVI, as well as perineural invasion, have been linked to a higher chance of peritoneal relapse, same with nodal metastases, patients who have obstructed cancer in the past or perforated cancer. Those are high risk for peritoneal metastases. It’s not a given that if you have that, you’re going to have periton metastases. The surveillance recommendations are based on stage of the cancer and those are in the NCCN guidelines. They’re very standardized. Having said that, the peritoneal metastases, we understand that the way the current surveillance works, we don’t have the right tools to be able to catch everybody early on with their peritoneal metastases so a lot of patients will get missed until their disease is more advanced, and so that is an area where we need to make progress. There’s some hope with the circulating tumor DNA assays. Unfortunately, for peritoneal metastases, the current generation of assays is not good at all. For example, the studies have shown that for patients who have radiographically detectable peritoneal metastases, or you can see peritoneal metastases in other ways when you look at the circulating tumor DNA with existing technology, only 30% of them will have it detected in the circulating tumor DNA. So whereas for liver and lung, it’s high 70s and such. I think there’s opportunity to improve on the circulating tumor DNA assay which is in the works, and some of my work is in that space also. I think that could be a blood-based biomarker to survey patients, where we will perhaps, if your marker’s positive and imaging is negative, we may advocate for laparoscopy sooner, which is an invasive test. Certainly I don’t recommend doing laparoscopy right now, because the risk of doing a laparoscopy and injuring an organ is just too high to be able to do it repeatedly, to surveil somebody. But I think more is needed in that space.

Betsy Post 1:27:02
Thank you and thank you so much for being very generous with your time. We just have a couple questions left. Can you talk a little bit more about why immunotherapy does not work as well in peri-mets and what can be done to overcome that resistance?

Speaker 1 1:27:18
Yeah, great question. So immunotherapy does work in MSI high peritoneal metastases. We know that it works in certain contexts. Why does it not work in peritoneal metastases? It’s a big question we’re trying to address. And so there’s two components that are immediately recognizable to us when we study colon cancer, peritoneal metastases in my lab, what we’ve learned is that the cancer associated fibroblasts in the micro environment are very different than let’s say, liver metastases or other sites of metastases, and then the myeloid compartment, which is predominantly your macrophages that are abundant in the CMS4 subtype of cancers, you know, also have a crosstalk with a fibroblast. What crosstalk it is, what is the signaling mechanism that is then creating an immune suppressive environment so the T cells that actually kill the cancer cells are not being permitted to get in, or work as efficiently, those circuits need to be deciphered better so that we can block the circuits and allow the immune therapy to work. So that’s where the field is at. And we’re hoping that breakthroughs will happen once we understand that crosstalk. It’s complicated, it’s not straightforward. There’s work that’s ongoing in my lab, and I know other folks are probably working on that as well.

Betsy Post 1:28:57
Thank you. Are there any studies involving intraperitoneal cellular therapies like TIL or CAR T infused into the peritoneum?

Dr. Mustafa Raoof 1:29:06
Yes. So there’s been some work where Dr. Katz, who used to be at Roger Williams, where they did first generation CEA directed CAR T-cell. So this is a T cell. T cell is the killing immune cell, basically. And it’s a smart immune cell, because it recognizes the cancer cells specifically and kills it. And o what they did was they they put recognition molecules for CEA. And as you know, a colon cancer, produces, CEA, a vast majority of colon cancer does. And so that way you could target the CAR T-cell directly to the tumor. The summary from their study, the long and short of it, is that, they found that it was safe to do, however, it was not very effective in the first generation. It’s not very effective and there’s many reasons why CAR T-cells cannot be effective in certain situations, for colon cancer. Beyond that effort, I’m not aware of any further efforts that have given regional cellular therapy in the abdomen, but I think it’s still a viable part. The reason that T-cell didn’t work is probably because of the immune suppressive microenvironment. It could also be because, I think this is a less likely possibility, but in other instances where CAR T-cells have been given. The reason they haven’t worked is because the target that they were targeting, once they killed all the cells with that target, the cells that did not have that target, they grew. It’s called antigen escape, and that’s what happened but I think all colorectal cancers, it’s mainly because the microenvironment says that any sort of T-cell, energized T-cell, whatever, when you put in the environment, it just does not work as efficiently. However, another problem is the drug delivery challenge, because when you have disease that’s all over the abdomen, as opposed to injecting the therapy directly into one tumor, it’s really hard to put the cells in all of the tumors and so the work that’s going on with the tag 72 CAR T-cell ovarian cancer at our institution is hopefully going to open the doors. We will learn a lot about how cellular therapies are behaving, and it’s a target that could be repurposed for colorectal cancer very quickly. So we’re optimistic that once that CAR T is refined, we should be able to move it to colorectal cancer.