A multidisciplinary team from Mayo Clinic Comprehensive Cancer Center discuss the best options to optimize outcomes for patients with nonmetastatic pancreatic cancer. Experts include Mark J. Truty, M.D., M.S. , surgical oncologist, Christopher L. Hallemeier, M.D. , radiation oncologist, and Ajit H. Goenka, M.D. , radiologist. The conversation was moderated by Tanios S. Bekaii-Saab, M.D. , medical oncologist.
These pancreatic cancer experts discussed disease staging, measuring for optimal treatment response and the novel curative intent surgical options available for patients today.
Well. Hello and uh welcome to today's session. My name is Dr Tanya. I'm a medical uh G. I. Oncologist with the Mayo clinic comprehensive Cancer center in phoenix and Scottsdale in Arizona. Uh Today we're getting a glimpse into the future of medicine uh and uh specifically in pancreas cancer, one of the most difficult uh if not the most difficult cancer to treat and achieve optimized the outcomes. We have some fantastic uh colleagues and experts in the area that will speak on optimizing outcomes for patients with non metastatic pancreatic cancer. So we're gonna focus on those patients with uh non metastatic disease from our Rochester Minnesota campus we have with us today our surgical oncologist who is internationally known for his work in pancreas cancer. Dr Mark Trudy also uh one of our international experts in radiation oncology focused on gastrointestinal and hepatic pediatric cancers and pancreas cancers. Dr Christopher, Palin Meyer and then again a radiologist who specifically focuses on G. I. Cancers and more specifically HP hip ato pancreatic biliary cancers. Dr going to so a fantastic panel that will guide us through uh you know how to optimize care for our patients with non metastatic pancreatic cancer. We'll have three topics each one about 30 minutes. So we'd love to hear from you. Once we open the discussion to questions following each topic. So we'll have the opportunity to actually discuss some of your questions. So we're gonna start with the first topic and that's um essentially focused on on on staging and understanding some of the intricacies of uh you know how we we we uh stage our patients with pancreas cancer going through a multitude of modalities from the an atomic to the biochemical to procedural. Uh so pancreatic cancer staging does affect the work of each of our panelists here today and and and and likely all of you listening as well. And of course, our patients at large from each of your practice and research backgrounds and I will go certainly through a number of these to understand the standard of care, pancreatic cancer staging and what we may be doing differently in our practice at Mayo Clinic, that ultimately, you know, will translate to changing the way we uh we should be staging our patients across. So I'm gonna start with you, Mark and I I know you wanna perhaps share a slide and they're just at a high level. How do we think about an atomic versus metastatic staging of our patients with pancreas cancer? Thank you Tony for the introduction. Uh and for this webinar. So, you know, as as anyone who treats these types of cancers and the patients and their families, they're well aware that pancreas cancer is the least survivable of all malignancies. Now. I mean, if you say that out loud, I mean, it's it's it's pretty dramatic statement, but it's true and the reason for that is because of its predilection for metastatic disease, whether that's obvious or whether that's a cult. And I'm gonna share a kind of a simple slide here that kinda exemplifies the point. So although it is a highly lethal cancer, fortunately it's not terribly common. About 62,000 patients in the United States were diagnosed last year, half of whom have already obvious radiographic metastases. Those are the patients were not necessarily discussing today. Uh the other half of patients have no obvious metastases And they've been traditionally uh classified as either respectable, meaning that tumors are localized to the pancreas itself or uh classically unrestricted. We now know these as borderline or locally advanced, meaning the tumor has grown outside the pancreas to involve critical blood vessels. Now, although these 50% of patients, we don't see obvious metastases If we follow these patients over time, the vast majority, 80-90% do develop metastases, either hematology anus in nature or through peritoneal dissemination or through some combination thereof. Hence it's critical that we stage these patients appropriately. Otherwise we're gonna have a poor outcome. Thanks, Mark. Yeah, absolutely. I mean, I think adequate staging makes the world of difference for our patients and understanding where they at, you know, with one guide them through the right path to the type of therapy they are most eligible for, but also refined further, you know, who may be eligible for potential curative resection. So doctor going to, you know, thinking about, you know, the changes that we've seen over the last few years about increasing and enhancing the sensitivity and and the accuracy of radiologic staging can you, you know, go over what what is considered standard. What kind of things we're doing a little bit differently at mayo? Specifically with the pet m ri pros and cons. What's on the horizon, please? Yeah, absolutely. And thanks again. 20 for the introduction and for the invitation. So I think when we talk about what this candidate of care, I think there is a clear consensus in the community that the standard of care is a multi faced pancreatic protocol city for those patients who don't have obvious metastases at the time when the pancreas cancer is diagnosed. Now, what has happened over the years is that of course we have now the ability to do much higher resolution imaging compared to what we were able to do a few years back and as a result of which we have become much better at local regional evaluation of the pancreas cancer. So what that specifically means is that whether or not that humor is encasing any of the major blood vessels like celiac access. There's a may or any of its branches, we can go down to their 2nd and 3rd order branches and give accurate information to our colleagues like marks so that they can plan those complex surgeries. Unfortunately, when it comes to metastasizes, I think an atomic imaging has kind of reached its plateau. So despite the fact that we have this increasing higher resolution. The challenges that on something like city we probably don't have the level of soft tissue resolution that we need to be able to pick. Those subtle metastases in the liver or in the peritoneum. And I think that kind of alludes to what Mark had mentioned earlier is that many of these patients eventually develop metastases and it's not that they didn't know what probably development actresses. It's just that we are not able to detect them at a stage where we should be doing that. So, you know, a few years back when the Mayo Clinic decided to invest into new technologies to improve the care of our patients, One of the things in which we invested heavily was in Ap Tamar and Mayo Clinic in Rochester was the first century in North America that installed what we call as a fully integrated pet um are. And what we mean by fully integrated is that it is something which has the state of the art solid state detectors which is something called as a photo multiplier tubes. And these tubes allow us to have simultaneous acquisition of the M. R. Data along with high signal to noise ratio pet data. And because of the fact that we are able to acquire them simultaneously, what it allows us to have accurate co registration of the an atomic data as well as uh molecular imaging data from the GPS component. And as some of the data that I will demonstrate to you in some of the slides that I will share. We have found that this pet M. R. Is much superior compared to cT scan for detection of those subtle peritoneal and hepatic metastases. In addition to that, what it also allows us to do is that it allows us to accurately capture the molecular profile of pancreas cancer. Because the challenges said traditionally, if you speak to people they'll tell you that well pancreas cancer is not really an fdd avid cancer so you should not be really doing pet in them. But I think one of the reasons why we are being able to utilize by technology to the best advantage of our patients is because with the increasing detector technology we are able to capture the ability of the tumor much better than what we were able to capture with the first generation pet ct scanners and as a result of which we are able to follow up these patients for things like response assessment. So in short, what I would say is that high resolution city of the pancreas protocol is certainly the standard of care for the local regional evaluation. It's also very good for looking at metastases in the liver but still not cutting the mustard when it comes to detection of those subtle and early metastases. And for that we have now been able to use F. D. G. P and M. Are here at Mayo Clinic in Rochester. We've published our data on that. In addition to that, we also have the privilege of having to NIH R one studies. Now one of them is prospectively validating what we have been doing in our practice combining that with other biomarkers. Such as that from liquid biopsy and the second arrow one is that on a new radio tracer called fibroblast activation protein, innovative pet. Which is also something that we will discover as we move along in the discussion. So I mean what are the goals ultimately that you would like to see being achieved with those new modalities that you're looking at the future? Yeah. Absolutely. So I think the main goals that we have is that for colleagues like dr Trudy we should be able to tell them as to which of the patients actually fulfills the criteria that they want them to fulfill before they decide to take them onto this extremely highly morbid surgery such as whipple's procedure. And for that what they want to know from us is that they don't want a patient where we miss out some metastases in the liver or in the peritoneum and the patient goes through the whole drill of new adjuvant therapy and only goes to the O. R. To be able to find metastases or they don't find metastases let's say at the time of surgery. But shortly after two months later the patient presents with hepatic metastases. So that's not the goal that any of our colleagues want to give to the patient and that is reasonable. The main goals. In addition to of course characterizing whether or not the tumorous involving any of those smaller branches of the arteries is also to be able to pick up those subtle and tiny metastases. The third goal, which is more of a semi futuristic, is to be able to predict the aggressiveness and the biology of the tuba. And again, you know, when we discuss about response assessment, I'll show some of the biomarkers that we have identified that can help us make those decisions. That will help us to risk ratify this patient and prognosticate them in a much better way. This is great. Well, this this certainly, you know, sounds very promising and certainly we look forward for more results, Mark, I want to get back to you. And so we have, you know, our traditional radiologic uh staging. How about biochemical molecular staging, What are we doing here? That's a little different. But also thinking about our colleagues in the community who may not have the same access, which we hope ultimately everyone will follow parts what kind of things are we doing and what kind of things you think should be done to adequately stage patients. In addition, you know, to the standard radiologic staging, yep. So there's something that can be done everywhere and we're doing some things on top of that. You know. The the key thing is we want to risk stratify these patients and a patient who otherwise has adequate imaging without any evidence of metastases. We still need a little bit more information. And so we use biochemical staging specifically using tumor markers such as C. A. 99 which everyone is familiar with. Now. See a 99 is not just a passive molecule, it actually has a mechanism, it is the ligand for endothelial cells. Selected. Those patients with an elevated c. A. 99 have a higher predominance of hematology nous metastases. Now we've known uh it's not a very good screening tool because there are false negatives and false positives. 10% of the population lacked the few castle transfer is necessary for expression. So if you check it, it reports as less than one. Those are non sequiturs. Uh One third of patients have normal levels and then some patients they're seeing 99 can be elevated for a variety of other benign reasons such as biliary obstruction etcetera. Uh And everyone, every single major institution has published their cut off, you know through an R. O. C. Curve but no one seems to follow it. Uh And then I'm gonna share a slide here which is a very important a paper that came out. This was out of Germany and in Germany they this is all data of every patient with pancreas cancer who is seemingly uh respectable. They take them directly to the operating room with an upfront operation and they stratified their survival, strictly by their baseline C. A 99 now look how beautifully this stratified it almost looks like fake data, you know because it's it's so amazing. But as you can see the higher the C. A. 99 the worst the subsequent survival. And those patients with the c. n. 99 above 1000 at diagnosis, those patients had a median survival of less than one year after seemingly curative intent reception. Now most places consider, you know, over 1000 as consensus criteria for very high risk. They should get neo edge of it. But the question arises, what do you do on someone who's less than 1000 but higher than normal sort of that middle ground? What do you do with the patient with the big bulky tumor? You know, does that explain the tumor marker elevation? And what about those patients who are jaundice which a large proportion of patients are? How do we interpret their C. 99 the setting of biliary obstruction? You know? So we specifically looked at that this is a paper published by some of our colleagues in radiation oncology and Dr Hell Meyer. And what we found and these are all patients onto an upfront resection with a tumor marker uh measured and we found that that C. N. 99 actually didn't correlate with billy Rubin. Okay. Nor did it correlate with tumor size. The only thing that C. N. 99 correlated with was their survival. And we found that those that were normal or non sequiturs had similar survival. But those patients that had any elevation of above normal regardless of extent, did significantly worse in both for recurrence free and overall, we then took a look at a larger dataset. We looked at the N. C. D. B. Over 100,000 patients of all stages. And we confirmed these results. Non sequiturs have a identical survival to those that have a normal C. A. 99. But any CA 99 above normal lends itself to a worse survival stage for stage. And the largest detriment was actually in those patients with localized tumors undergoing resection. What was that detriment about a 50% reduction in their survival. That's the same reduction we see with a positive margin operation. So that's why we use a 99 specifically in these patients. Uh and anyone with an elevated level, we consider them high risk and indication for neo adjuvant uh Tony, you ask, are we doing anything you know, on top of this? You know, we are, you know, we're in the era of you know, genetic testing and and technology where all these uh deep sequencing is available at relatively low cost. And a couple of years ago I was in an elevator and one of the laboratory uh scientists that was commenting on cell free DNA. They had developed a cell free DNA essay in blood for mutant care as they were initially developed for colon cancer. And I said we really we have this like it's clinically approved. And so I started using it. And so we we used a prospective trial and all patients with seemingly non metastatic cancer. It's a blood test that measures a variety of mutant Kras mutations. And we found that one in five patients had an elephant had a detectable mutant care as in their blood. Now, you know logically you shouldn't have mutant cancer, D. N. A. And your systemic vasculature. You know that would suggest your metastatic And here are the results of that initial nearly 800 patient trial. Those patients that had detectable mutant care as in their blood had a significantly worse overall survival than those patients who was not detectable. And so this is now standard of care at Mayo Clinic and Rochester. And it's a simple, relatively inexpensive test using it on all patients that we're hoping to get this now pushed nationwide. So Mark, this is very interesting data. Do we know what the sensitivity level of this plasma keras testing and early stage pancreas cancer. You know? So and about 800 patients. About 20% of those patients were positive at diagnosis when we tested patients who have already received some chemotherapy, that number drops significantly. So that does lower the sensitivity, any type of treatment. But that makes sense. You're getting chemo you're hopefully treating it obviously as the technology improves. We may find every patient has detectable you know mutant cancer. D. N. A. You know based on obviously they're known history of having a cult mets but this is something that's readily available and it's very useful for prognosticating patients. Uh whether we do up front surgery or consider neo adjuvant. So for those patients who may actually have that keras avail you know available then then it is part of your overall algorithm about how you decide on on moving forward. And we'll talk a little bit more about you know how do you think about your treatment strategy and how you integrate those tests chris I want to just touch upon with you very briefly smacked for you know there's been in the past a lot of you know talk about smart for and how it relates to local more local regional disease versus with aesthetic disease. And it came from some of the data came from one of the R. T. O. G. Study that included samples that measured that for any any follow follow up on this. Is that an important you know a biomarker uh that has a clinical utility at this point of time. Do you do you even care about it in your clinical algorithm? Yeah that's a great question Tony most of the data looking at small bad for was from patients who had upfront surgery and then predicting the risk of distant metastatic disease afterwards or from autopsy studies. You know patients who died from pancreatic cancer and whether uh mad for and the tumors uh you know was associated with more locally predominant versus a metastatic phenotype. And and it is associated with um you know locally predominant versus metastatic. I think it's of limited utility uh in clinical practice it requires a fair amount of tissue in order to be able to do the test which if we're doing a diagnosis based on an US just to confirm that the patient has pancreas cancer with an intent to do initial upfront chemotherapy. I think it's a less relevant in the neo era. And certainly there are much more exciting biomarkers. Blood based biomarkers as Mark Trudy is discussed in addition to um you know better radiologic tests which I think are gonna be more clinically useful currently. And moving forward thank you know that that that's quite helpful Mark. You know in addition to radiologic staging, you know biochemical molecular staging. Do we do you do you do peritoneal uh laparoscopy. So laparoscopy ease. Do you integrate those? What's the role of undisc opic ultrasounds? How much do rely do you rely on it versus you know a good city angiogram and a pet M. R. I. These complementary how how do you think about you know these procedures as they relate to the other forms of staging and pancreas cancer. So I'll start with your last question first you know us versus C. T. Uh if you have a good you know triple phase uh cT scan pancreas protocol that gives me everything I need to know uh basically about the tumor and vascular relationships. Now occasionally we may find an E. U. S. Report that differs you know suggesting more vascular involvement than the C. T. Would suggest. Uh And I would I would defer to the U. S. Over the C. T. If it's worse because again a C. T. Scan if it has vascular involvement it almost certainly does. But it's not a microscope. Okay that's what differs between the C. T. Scan and and the U. S. It's a little bit more higher resolution regarding do we do any other staging procedures? In addition to good imaging? You know blood work we do. That's where we also differ from the rest of the country and that we do staging laparoscopy on every single patient who has no obvious metastatic disease prior to determining what we're gonna do. Uh interestingly Historically about 30% of those staging laparoscopy is decades ago were positive. They have found uh hepatic or peritoneal metastases. But the performance of staging laparoscopy has really plummeted in the neo edge of an era presumably because we think we have better imaging the issue is the biology hasn't changed. You know people still have peritoneal dissemination that hasn't at all dropped. And so we've recently looked at our experience in the modern imaging era of over 1000 patients and I'll share a slide here just to kinda show you that. And so we looked at our last five years of our staging laparoscopy experience. Uh and we found that one in five patients had a positive laparoscopy uh positive laparoscopy is either we see gross disease, liver or peritoneal or those who don't have gross disease. But we do washings and they have a positive psychology. Uh That's a significant number. And this is in the modern era and this is in patients who've had triple face pancreas protocol, peta mars et cetera. When we look to see who are the patients at highest risk of having a laparoscopy, we did find several risk factors on multi varied analysis younger patients, less than 60 years of age. Those patients with a larger tumor greater than two centimeters tumors in the body or tail. And then any patient with an elevated C. A 99. And you can see how our patient, you know, the 1000 patients uh distributed here. Uh If you had no risk factors, you know, your risk of a laparoscopy being positive extremely low. But that was a small fraction of patients. Uh 23 quarters of our patients had two or more risk factors. And those patients had at least 20% and, you know, some in some cases over a 30 to 50% risk of having a positive laparoscopy. And that's something that would have otherwise been missed if we hadn't done that and it helps to restage them better and then alters their treatment. And so this is something that we consider and I think every institution should consider the laparoscopy. We also do it before any neo adjuvant therapy. The other thing that I didn't show here uh is that those patients that had a laparoscopy after neo adjuvant, there was a lower yield. Why is that? Probably because we're masking some of those metastases with the neo adjuvant and those are the patients that are more likely to subsequent get peritoneal recurrence. Thus we want to do this early on as possible to stage our patients better. Thanks Mark. Uh So uh we'll have a couple of minutes for questions. If you have any questions, you know, for the audience, please uh make sure you include them in the Q. And A. And we'll try to answer them, but I want to jump just quickly too. I mean when when we think about peritoneal disease, which is essentially, you know, the hidden disease in many ways. So laparoscopy, um and uh you know, and and and and potentially, you know, measuring care as uh and peritoneal fluid, but radiological e what what are some of the more sensitive methods that can guide us into understanding whether the patient is at risk versus not. Yeah, so I think peritoneal disease is a tough cookie to crack on any kind of an imaging modality. But I think we're imaging really shines is in its positive predictive value. So when you see enhancing the clarity in the peritoneum or when you see located a scientist in the pelvis or you see enhancing not using the pelvis in the dependent areas which you can especially see on the city component of what we do. Then I think the positive value is quite high uh in terms of the new image modalities that we have the pet em are where we are not only combining an atomic resolution but also the molecular component that is also improving us sensitively to be able to pick up those disease. And then finally because of the emerging properties of the new radio services fatty which is still under investigation and we do have another one for that. That is where I think we are most optimistic about where hopefully it would decrease the number of laparoscopy or diagnostic laparoscopy is that somebody like Mark has to do because there's certainly a cost, there is involvement of the surgeons, time or time, so on and so forth. So improving the outcomes. We also want to make it more cost effective. And our hope is that once we finish those studies, once we have the the approval hopefully will reach a stage where imaging would be as good for detection of peritoneal disease that it is for liver disease right now. Thank you jean marc quick question. You know, this is mostly pertaining to adenocarcinoma. There's a question you know from the audience is you know, do do we think about pancreatic neuroendocrine humor's a little bit different. They understand that there are certainly a lot of nuances across across the board from the rest stories in 99 but at least from the high level staging. And and how we think about neuroendocrine, is your thinking different in in those patients? I think it is primarily just because, you know, one is it's less certainly less common, but it's also a much better prognosis prognosis to have a neuroendocrine tumor. Now, like any type of cancer is you can have a spectrum of behavior. There are some neuroendocrine carcinomas that are terrible. They're worse than adenocarcinoma. So, those patients with higher grade neuroendocrine tumors, I would typically kind of approach them like I would a pancreatic adenocarcinoma just because of their their risk of, of metastatic dissemination and poor outcomes with upfront surgery. But for the garden variety neuroendocrine tumor we definitely manage and address very differently from the radiological standpoint. Um, can you tell the difference most of the time? So I think we can tell the difference most of the times and the reason is because as you know, the majority of the neuroendocrine tumors, they tend to be hyper enhancing on the arterial phase, which is something that we don't see with the pancreas cancer, which tends to be hyper dense in the early arterial phase as well as in the pancreas phase in addition to that, the nature of the vascular relationships with pancreas cancer, which is more of an infiltrated uh no plasm tends to be way different than neuroendocrine tumors, which typically tend to be large but usually more circumscribed. And likewise, the imaging appearance of the labor metastases is also very different because again in pancreas cancer they tend to be more hyper tense, whereas the neuroendocrine tumors, they tend to be hyper enhancing. So I think there is a world of difference and you know, speaking of neuroendocrine tumors, I don't want to take much time there, but you do know that we also have gallium Dota Tate now, which has completely revolutionized the way that we image and treat the patients with neuroendocrine tumors. So that is another big difference where the emerging tends to pivot off kind of tumors. It's great, thank you. I mean this, this was a great session. I think we we come to the end of this first topic but it's clear that, you know, we're getting much better with the way we're staging patients integrating radiologic, bio biochemical molecular staging, procedural staging. You know, that this is not just 11 scan do it all, but it's it's a puzzle and we're including a lot of these pieces together to actually have a clearer picture about, you know, how to best optimize the care for our patients with non metastatic disease. So this is this is fantastic. So moving on now to the second topic and and primarily this, this this topic is focused on, you know, now, now that we we had our patients staged uh and and we certainly confirmed that they have a very low likelihood of micro metastatic disease or metastatic disease. And uh and then uh we want to consider uh their surgical options. Um One of the important elements that we have seen emerging over the last uh the last few years and certainly has become our standard for the overwhelming majority of these patients with with non metastatic disease is the value of actually neo adjuvant therapy for patients with respectable disease. And we'll go through some of the nitty gritty of what makes the most sense for these patients. But as we started moving more and more to the new agreement setting based on data that at least new achievement therapy would certainly help us select better patients who biologically would benefit the most from surgery. The other token would be, you know, who are those patients, even though they may have localized disease, that biology dictates otherwise. Uh And so that becomes an important one aspect of neo adjuvant therapy. We know that this disease is Dr Trudy mentioned initially, you know, it's it's primarily systemic disease. You know, out of all the cancers, we treat this probably is one where even when when all these elements we talked about point out to a local, local regional disease, there's a good chance this is already metastasized, a really good chance that this already metastasized. And and and we just are unable to detect that metastatic disease. And neo gene therapy will give us that time to test the biology and Tony, you know, the, you know, the, you know, the data, the most data that we have, as you're aware is in the edge of in setting, you know, adjuvant chemotherapy, you know, we've had for a couple of decades now, data for that that shows that improves survival. The fact that adjuvant chemotherapy improves survival after resection proves your point. These patients are metastatic at the time of reception. You know, so it's kind of silly when people say, oh, you know, they're not metastatic, well they are. Otherwise, those studies would have been uh not at all effective. Absolutely. And and, you know, to your point, we know that about a quarter of the patients after surgery, if we haven't given them that piece before surgery are unable to get a job in therapy post operatively. And we know that that's, you know, adds to their survival. And so I think, I think, you know, as we move it more to up front, not only that we're testing the biology and we're certainly, you know, picking the right patient for surgery, but we're also making sure that more patients are exposed to that other modality that enhances your the likelihood of patients surviving their cancer, you know, theoretically. And and and and mark, you you can talk a little bit more about this. you know, it does improve, also surgical outcome in some ways. You're improving the r zero resection rate, lymph node, uh negativity, local recurrence with downstage patients, but whether that, you know, ultimately affect survival or not is unknown, you know? And and to your point as well, you know, some some some concerns always arise. And we know that, you know, patients come with these questions or even, you know, uh physicians referring physicians is what what if we miss that window of opportunity for surgical resection and we know that if a patient never makes it to surgery because of all the elements we're gonna be discussing. Uh They actually are the patients who should never get surgery anyways, those are the patients who would not benefit. And arguably those are the patients that may actually experience more detriment than than the benefits. So, there's quite a bit of good reasoning to move to the Neo Adjuvant and total Neo adjuvant therapy. Uh And I think as you know, as we were getting more and more along the lines of of uh genotyping uh checking for inherited germline alterations, but also genotyping humors whether through liquid biopsies or tissue biopsies. We also have a good glimpse about what maybe some of the drivers. And now chemotherapy remains. The mainstay will get to, you know, which patients may be eligible for radiation. Chemotherapy remains the mainstay for patients uh with non metastatic pancreas cancer that would proceed to surgery. We have two options, two major options that are available to patients, they seem to win. That put head to head, they seem to actually be relatively uh equivalent. But then when we start understanding a little bit the intricacies of where safe versus paclitaxel performs better, we understand that let's say in the presence of a Bracha one to or paul B two alteration or hrd in general, that perhaps full in CISplatin. Uh and arguably and until we see more data, paclitaxel and CISplatin could be favored versus those that are not or these mutations are absent or jim said to be nah paclitaxel may as actually end up being a little preferred. There are other uh there are other elements as well that are being looked at uh within the histology of the tumor that may help decide of one versus the other. So more is coming to help us decide on what patients may be optimized for one versus the other. I would say that, you know, as we move more and more to the new agreement world, we're actually overall are improving the outcomes of our patients and that's what we're going to continue seeing. There are studies that are looking at pre versus post although at mayo our standard is neo adjuvant for most patients next generation sequencing testing uh you know is almost a must now since it helps us not only with the pick of chemotherapy but also may add biologic options including on triumph for our patients, but also inherited uh panel uh testing that can help both of course with risk stratification for other family members, but also important for picking the treatment. But you know, most mostly what what we have integrated into our neo adjuvant approaches is this whole concept of chemotherapy switch strategy and Mark you being one of the pioneers of this strategy and it certainly yield significant benefits. So I think this has actually revolutionized how we care for our patients and has, you know, led patients to improve the outcomes. So I'm gonna give this to you. So you can go through what that means to to our patients and how how, you know, not just at mayo, but how do you think this well, essentially translate to patients who may be cared for outside Mayo. So uh that's a critical point Tony. We are, I think, you know, across the country there is a movement towards Neo achieve it. Okay. And we're not really arguing that much about neo adjuvant upfront surgery as much anymore. Uh So that's not the question to answer the question. The answer is if we're giving neo adjuvant, is it doing what we hope it's doing okay because we're giving that preoperative chemotherapy in the hopes that it would change an outcome uh compared to doing an upfront operation. Therefore in order to get that outcome, we have to prove that it's actually effective. So I often pose a question to my trainees. I said if you had pancreas cancer, you know what? Neo adjuvant treatment would you want? Would you want six months of chemotherapy or would you want six months of chicken nuggets daily? And they look at me and think I'm joking. I said I'm dead serious and they all invariably say oh I'll take the chemo. I go well actually depends because if you get six months of ineffective chemo you might as well have six months of chicken McNuggets and have the same outcome. And so the question is how can we know that the chemotherapy we're giving is effective. Now, any other tumor type we'd ask dr Goenka, you know, is the tumor shrinking isn't responding? Uh And then hopefully I can comment as well. But unfortunately for pancreas cancer, radiologic response is a very poor surrogate of response. It has no correlation to pathologic response or survival tumors that involve vascular structures. Uh never pull away. They're always there. And that data is so strong that neither the N. C. I. Nor the N. C. C. N. Considers radiologic response a clinically relevant endpoint. And so therefore although we keep repeating these ct scans, we're really not expecting much to change. And so if it's not changing is it working Our second way of assessing response is looking at those tumor markers. We mentioned that see a 99 and if it's elevated and it comes down that is a good surrogate. However, as we mentioned, 10% are non sequiturs. 30% of patients have a normalcy in 99. So right from the start, 40% of your patient population you can't use it. Also once it goes to normal, it can't get any more normal than normal. So once you normalize that if you normalize it early, you can't use it any longer. And so thus we're stuck. Okay, we can't use CTS very well. See a 99 helpful in some but not in all. And so thus we've had to come up with alternative ways. And that's where our institution has used metabolic imaging. Specifically pet, Either pet ct or Pet M. R. And hopefully I can kind of comment. But we routinely use pet at the time of diagnosis. And then we follow with pet after therapy. And we found that pet scan highly predicts response to chemotherapy. Uh and that also has been shown to be path shown the correlate with pathologic response object. Maybe you could comment because obviously you've looked at more pet scans than anyone for pancreas cancer. Yeah, absolutely. And uh uh images. So let me start here. Yeah. So I think mark has already alluded to the fact that we have seen 99. That has very limited clinical utility for all the reasons that he has very eloquently described. Now, what we traditionally used on any other solid tumors or Syria or M. R. is what we call the resist criteria which basically measure the two dimensional uh size of the tumor. And then we make sure that after treatment and as Mark has mentioned, unfortunately in the case of pancreas cancer, the tumor just gets replaced with fibrosis and as a result of which oftentimes there may not be a down staging. And even if there is down staging, as he has mentioned, that may not necessarily predict good outcomes, which is exactly why we want these patients to undergo new and gene therapy. So we clearly need reliable biomarkers, not just to guide therapy but also to reduce toxicities and costs from an ineffective chemo. And that's the reason Marcus history needs to rather have chicken McNuggets instead of getting chemo. In addition to that, we also need to think about the next generation of the chemotherapy and immunotherapy that is on the horizon. And for that we need to be able to design clinical trials that have got optimal outcome points. And finally, you know, we also one of the reasons that Tony you mentioned, we are giving new achievement is to select the right biology of a tumor that really needs to undergo surgery. And that's the reason we need to be able to have markers that not only predict response but also give us some information about the biology of the tumor. So right now what happens is that typically they get the beauty of chemotherapy at most of the places uh and those centers that don't have access to anything beyond C-99 or city patients will inevitably go to surgery if they don't have any progression of the local disease or if they don't develop any metastases. And then it's only after the surgery that we come to know if all of this chemotherapy has actually worked or not. And that in the era of precision medicine is not really the ideal way to do things. So what is it that we have done here at Mayo? So, you know, just like MArc mentioned about liquid biopsy with care A. C. T. DNA. Where he had this elevated conversation with another basic scientist and they decided to that similarly, we had an elevated conversation centered around to Tamar and you know, when we installed tomorrow here at Mayo Rochester in 2016. 1 of the indications that we started doing is pancreas cancer. And it's not just something that is based upon anecdotal evidence, it is something that we have systematically evaluated. We published our is this a couple of years earlier and that paper got selected for the most impactful paper of the category in the journal Mark. And I were also invited to present that as a webinar and it also got selected as editors choice award. So what exactly did we find in this particular category. And what is it that we're doing right now as part of our standard of care for response assessment in these patients. So what we're doing is that is what we found in this study which is that the biomarkers that we were able to quantify frumpy tamar for these patients. They first and foremost we found that those patients who eventually had major pathologic response which is basically where either they have no cells left on the specimen or they have got very limited ourselves. They had significantly longer overall survival compared to those who did not have complete or major pathologic response. Which is something that we already now know very well. And the biomarkers that we specifically looked at was something called as a CMR or complete metabolic response. We looked at the relative change in the S. U. V. Max which is a very commonly used metric. And then we also used what we call as a delta Suv globe which is basically an suv max that is normalized to the blood glucose of these patients. Now one of the things that we also know which we often don't talk about is that majority of the patients with pancreas cancer. They tend to have either hyperglycemia or they tend to have diabetes and as you know that for doing F. D. Pad we need them to have global glucose control. Otherwise the bread doesn't really work very well and that's the reason we normalize the V. Max to the glucose of this patient so that we would get an optimal idea of how their humor is behaving. And then what we found is that these biomarkers, they have an extremely high negative predictive value for major pathologic response. So what that effectively means is that if you have a patient who does not achieve complete metabolic response or who does not have a threshold decline in a C. V. Max or suv groups in response to your gene therapy is unlikely to have major pathologic response even though everything else may look okay. The other important point for these kind of biomarkers is that they need to have excellent inter rater agreement. So that let's say one of my colleagues read the scam, they should not have a completely different results compared to let's say I reading the scam and we found that these biomarkers had excellent inter rater agreement which is what makes it which adds to our ability to consistently deliver the excellent results that we want. And finally in this study we found that C- 99 was neither associated with response not overall survival. And one of the reasons could be the different things that mark mentioned that compromises our ability to use the 99 in this particular context. Now some of you may wonder why pay tomorrow and why not pet ct. So one of the reasons that I earlier mentioned is that when you look at the silicon multi multiply detectors that are part of this P tamar as well as the scanner geometry. So what we mean by scanner geometry is that if you look at the axle field of view of this P. Tamar it's about 25 centimeters compared to much smaller axle field of your pet ct. So when you combine those technical advantages it gives you a much higher ability to pick up these photons from the tumor which makes it possible for us to interrogate pancreas cancer. Which yes we know it's not as bad as other soft tissue new blossoms but we now realize that about 90 to 95% of these tend to be a D. G. Avid which is how we define them as S. U. V. Max more than four. In addition to that because of the fact that we're requiring the M. R. And the pet data simultaneously. We have excellent co localization and we are also able to use the full spectrum of them are soft tissue resolution. To be able to pick up those subtle hepatic and peritoneal metastases. So one of the unique parts of our freedom our practice which is what we use for pancreas cancer. Is this imaging protocol that we have designed essentially what we do is that we first do a whole body interrogation for metabolic imaging with metastases and then we do what is called as a focused to more of the abdomen where we acquire a long 15 minute pet of the upper abdomen. In addition to that we do diffusion weighted images. We do EU West enhanced M. R. And therefore we get the habitability 20 minute sequence which as you know, is considered to be the reference standard for looking at liver metastases. And it's because of these that are paid. Um Our practice has been steadily going in the context of Tamar and you see that majority of these patients that we have are due to the pancreas cancer which is quite unheard of in other institutions that may have paid. Um are so how are we using that in practice? And this is very important is because so you have a patient over here with the baseline P. Tomorrow. You can see that the lesion is intensely of D. G avid. There is how it looked on the M. R. Component and all of these patients as we discussed earlier also undergo Triple face City. So on the Triple Face City this is how the tumor looked like. And post a few cycles of chemo radio chemotherapy. There was some shrinkage of the tumor but this may or may not be enough because we still see some soft tissue. They're both on the C. T. S. L. S. M. R. Component. But look at what has happened on the pet component. This is what we call the comm complete metabolic response. But there has been complete resolution of their DJ uptake that we saw. And this is one of those patients that Mark would like to take up for surgery because this is the kind of patients who will achieve complete pathologic response which as you know is not the most robust prognostic factors in these patients. We also discussed as to you know, the incremental utility of pay tomorrow over city. So for instance here is a patient who underwent a triple face cT scan. There was a non specific hyper density along the vessels which was considered to be a vascular etiology. But when this patient underwent peta mar two weeks later we found that that area was actually intensity of DJ. David. In addition to that we found a couple of other areas that were also intensity of DG avid and all of these were proven to be metastases. And again these are not the patients that we want to go to the O. R. And we also discussed about the second part of our um our protocol which is where we do that focused one. So here we had a lesion on the M. R. Component that was vocally enhancing. When we did the first part of the day tomorrow we could not see any focal lesion there. But when we did the second component of our pet um are we found this focal FDJ uptake over there which confirmed the suspicion that this was actually metastases. So this is the beauty of Tamar is that it helps us to pick up those subtle metastases in the liver which as you know is the most common side of these patients. So, you know, we have compared our ability to stage these patients with Tamara Sora City. These were the results that were presented by one of our fellows at a recent meeting that got him a young investigator award. And I know what goes to the busy slide. But essentially what we found is that Tamar was far superior to a multi face city for the detection of hepatic metastases. And we also found that pet um are correctly classified. Majority of the patients where there was discordance between the findings of city and to Tamar and City was able to do that only in two of the 22 patients where there was some discordance. Here are a couple of examples as to how again P Tamar does better than City. So here you had a very tiny lesion in the dome of the liver on the city. There is no way we can pick that up. It looks absolutely normal. But look at the EU West enhanced component where we can clearly see this region and with the presence of the uptake, this definitely tells us that this is metastases another patient here. Same thing. We see focal finding here on them as well as a pet. Nothing is seen in the city. This is again, something that was proven to be metastases but you know, Mark mentioned that some of the patients, we do have to do Pet ct And the reason for that is because not all the patients can undergo pet um are you know because of the fact that the pet detectors are inside their margon tree. You know it only has about 60 centimeter board which is smaller than the 70 centimeter board that we have in the typical M. R. And you know some of the patients may be claustrophobic because of the coins that we have to place and therefore you know many of them uh They get motivated because dr mentioned to them the advantages of Tamar but still it cannot be done in every patient. And that's the reason some patients have to do per city. And Mark mentioned about how we also need to be able to predict the outcomes in this patient. And this is a study that he and we published recently where we found that had highly predicts the pathologic response as well as outcomes in these patients. So maybe I'll stop there and resolve this for the next part of our culture. That's excellent. Thank you. Thank you for sharing this. So you know I wanna spend the last few minutes actually moving on to you know thinking about you know when do we introduce the concept of new management radiation into the next pre operatively? So chris uh pre operative chemo radiation. What type and when we have time Tony to go into the you know we have as much time as he needs. Yeah so you know we spent a lot of time talking about the metastatic potential of pancreas cancer. Which which certainly is um not to be understated, but I think it's also important that we don't understate the local regional infiltrated nature pancreas cancer which is also a hallmark. We know from surgery first series which historically was the treatment approach that the majority of these patients have a cold invasion of adjacent organs, invasion of major blood vessels. This type of cancer likes to hop on the nerves that go to the pancreas and grow towards the aorta through the celiac and S. M. A. Plexus. And the majority of patients, even if they do not have an apathy on scans when they go to surgery will have evidence of nodal disease. And again the surgery first series demonstrate this very nicely. And really it's no surprise that with the surgery for strategy a majority of the patients or significant percentage of the patients have positive margins which we know leads to inferior outcomes. And the historical approach was to try to do postoperative radiation to clean up for uh inadequate surgery or perhaps poorly timed surgery, meaning doing it as the first step in treatment. Um As we moved towards a neo adjuvant treatment paradigm, I think the role of of radiotherapy and the management of this disease becomes more important. We know from other gi malignancies that doing radiotherapy and a preoperative setting is far more important, more efficacious, like less toxic than doing it in the postoperative setting and data that had been published in the past couple of years have really shown that notably pria plank trial. This is a randomized study done in the Netherlands that took patients with respectable pancreas cancer. They randomized either surgery first or pre operative chemo radiotherapy using gem side being in in a three week course of radiation. And what we see is that the patients who got pre operative chemo radiotherapy at higher r zero resection rates. They had uh um lower lymph node involvement and with longer term follow up had a significantly lower risk of local regional recurrence and actually with long term follow up had better survival. Um So I think in the in the preoperative setting there's elevated interest and importance in utilizing chemo radiotherapy in select patients. And notably those are patients who have localized disease after we've done the extensive initial work up as well outlined by dr Trudy and dr guanica. They get optimal chemotherapy and are demonstrating a response to that chemotherapy um A local response or a biomarker responses indicative of response not only of the local disease but also potential micro metastatic disease. Um So picking the patients that are having a response and are potentially candidates for ready for a surgery and then utilizing preoperative radiotherapy to help optimize local regional control. Um At mayo clinic in 2022 we've moved towards using a three week radiotherapy regimen. Similar to the previous bank study, We use um fairly sophisticated planning and delivery that allows us to optimize delivery of the radiation to the pancreas tumor and the at risk tissues notably the pathways of spread that we know pancreas cancer likes to follow. Um In the preoperative setting. Our goal again is to sterilize the field to help optimize local regional control to have the best chance for an R. Zero resection and prevent local regional recurrence. And so we've generally treated um the op operative field or the at risk area which is more than just the pancreas itself which we know that dr Trudy is is highly capable of removing. We want to we want to treat the edges of what he's not removing because we know that that's where the cancer comes back. And so um there are different modalities that are that are used are different techniques. One extreme example would be something called S. P. R. T. Which is tolerant which is targeting a very very focused um area which is where we think the cancer itself is and and that's it. Um But I think some of the data that's come out in the past few years have shown that that's probably not the optimal strategy when used as an adjunct to surgery. Um So we're using preoperative radiotherapy again in in appropriately selected patients and particularly those that have borderline features we talked about. You know predominantly this is an atomic features of patients with vascular involvement that are at a higher risk for positive margin, we also use it in some patients that have other borderline characteristics like borderline biology. Um you know maybe they haven't had an adequate response to chemo and we've tried everything and Um a little bit hesitant to go straight to surgery due to um you know concerned about occult disease. Um shifting gears and using local regional therapy also can be beneficial because it gives some time off of systemic therapy where we're only targeting the local disease and then restaging 4-6 weeks later and seeing if there's any evidence of occult disease that's manifest itself. Yeah, chris you know, there's not gonna be much controversy and you know, doing good staging or given chemotherapy. Radiation seems for whatever reason to be still a little controversial in the preoperative setting. As you know, I'm in favor of preoperative radiation for pancreas cancer and as you mentioned, uh you know, everyone focuses on data. Now there may be some mixed data in terms of level one for direct survival benefit. But there is level one data on the effect of radiation on margins and lymph nodes, both of which have a direct influence on survival and thus, you know, probably at minimum preoperative radiation has an indirect on effect on survival because of the benefit of those two aspects. And like you mentioned, we also time is a component of this. Uh there's no window of opportunity, there's no rush to go to the operating room, you know, the actually the longer we wait before an operation and if the patient is still localized, the more likely that that operation will be of subsequent benefit. And so to have that period of time, you know, with the brakes off, so to speak off of full, you know, systemic chemotherapy and as long as things are stable uh then we could move ahead. We've had multiple examples of patients who we seem to have a good response. They go on to get radiation and then all of a sudden we see the marker rise and we see some some indeterminate lesions that actor, you know, ajit uh sees on scan. And we've basically been able to prevent a completely futile and in some cases a pretty morbid operation because of that delay. Yeah, that's that's a great point, Mark. And certainly we've seen patients where, you know, we do chemotherapy, there's a response. Then we do radiation treatment which we think is going to be pre operative. We do the restaging before the planned surgery and the tumor gets a little bit smaller. But the CIA 99 goes up and that is a big time. Put the brakes on this patient needs further evaluation. Uh And you know, Mark. I feel like that's that's oftentimes a you know, again a big stop sign uh we need to do further evaluation and and Mark, what specifically would you do in that setting in terms of re assessing this patient? Uh you know, so again, if there's nothing radiographic lee obvious on a good ct or pet um are uh then we would basically just watch I'd bring him back and you know, in a short interval period. Watch the tumor markers, repeat the scans. If I'm really concerned we put them back on chemotherapy or called considered, you know, different second line therapy if necessary. But that is a big flashing red stoplight. And if you don't heed that unfortunately, you know, our experience that those patients don't do well if you don't listen to those warning signs. Alright, well thank you. Thank you both. And uh I think, you know, this establishes the importance of, you know, the correct assessment of of response, judiciously integrating all the biomarkers on hand to decide one on the type chemotherapy at the time of switch for chemotherapy and then at the time to decide on radiation, the type of radiation. So this is a very complex care around the patient and certainly requires, you know, all elements of our melted multidisciplinary group working together through the whole continuum to optimize the care of patients. Now, you know, want to move on to the to the next topic which really follows through on a lot of what was discussed is, you know, with this accurate response assessment with integrating all these pieces together and and able to consider, you know, the type of of therapy that leads essentially to the patient who would go to surgery. So Mark, can you speak to the surgical options available? And and also, you know, how do you decide on respectability criteria? You know, when do we take a risk on expanding these strict criteria? To a little bit too loser criteria? Uh and and you know, it's more from the surgical technique. Uh and and the limitations of what what you're able to do you bet Tony. So the term respectability is actually my least favorite word. Uh because people, you know, they want me to look at the scan and what they're they're not really asking me is it respectable? They're asking me is it removable? You know, can I separate the patient from the tumor. Now for any type of cancer surgery, the goal is not to just separate the patient from the tumor. Uh it's to prolong survival. Okay. And so I'm gonna share some slides because again, pictures tell 1000 words here. Now the problem with the term respectability and that enhances the problem with surgeons in general. What one surgeon feels is respectable. Another surgeon feels it's not and this has a direct impact on the patient because they may either be pushed into the operating room with a bad outcome or they can be potentially denied a curative intent operation. Now, when we operate the biggest thing from a surgical perspective uh that I have control over is my margins. And we know that with level one data, the importance of achieving a negative margin. This is based on not just single institutional retrospective studies but Level one studies particularly in the edge of a setting. Now in order to combat margins. Uh With modern imaging, we've created these respectability classification systems and they're based on modern cross sectional imaging and any degree of vascular involvement of the veins and arteries. Uh Fascinatingly this is very unique to pancreas cancer only. There is no other cancer that has specific an atomic criteria. And when you have something that's specific to one cancer, it kind of raises, you know the dubious origins of these classifications. But nonetheless we have them and we have respectable, we have borderline and locally advanced. Now these are based on two critical assumptions that need to be remembered. These systems were developed only to predict a margin risk in patients undergoing upfront surgery, meaning no neo adjuvant chemotherapy or chemo radiation. And they were based on patients undergoing a standard anatomical plane based operation meaning no vascular resection in the absence of one. The other. Or both. These categories are completely meaningless in my opinion. Okay, because now we're giving new edge event and we can now consider more advanced re sections. So, you know, what are these vessels that we're talking about? Well, we'll start with the venus anatomy. Uh This is the uh the veins that we have to worry about. We have to worry about the portal vein. We need to worry about the confluence. We need to worry about the S. M. V. We also need to worry about all the various branches and the goal is to resect with a negative margin. And in some cases we have to resect the segment of vein and rebuild it. Uh That raises the complexity and raises the risks. Uh And therefore if we're gonna be doing a major vascular section we have to have some upfront treatment with response. Now veins have become relative vein resection is relatively common at a major pancreas cancer center. Uh but the other area of controversy has to do with tumors that involve arterial structures. Now historically these have been taboo. We attempted this in the 70s and patients had terrible outcomes, both short term and long term. However we're now starting to reassess the benefit of an arterial resection in this modern neo edge of an era. And here in Rochester we actually have the largest us or probably western hemispheric experience with unblock arterial resection. And as you can see in the modern era we've had a dramatic rise in these more complex cases, tumors can involve the hepatic artery or arteries replace vessels. They can involve the S. M. A. They can involve the celiac or any combination thereof. And thus now we're able to offer operations to patients and we're literally creating new custom procedures that are strictly limited by what we can technically resect and reconstruct now these operations as they get larger in complexity. Okay. Uh they have a increased risks of the operation to justify those increased risks. We have to balance them against the ankle logic benefit. Okay. To make it worth it and thus what we look at here in Rochester are three things that we call the modern parlay. We need all three together. The first is responsive. Itty as we alluded to early. Uh we need to prove that what we've given the patient in the preoperative setting is actually demonstrably effective. We use C. T. We use biomarkers and then in our practice we use a lot of pet, either pet ct or pet amar. And if we could demonstrate a response to therapy, those are the patients that we will now consider for a possible operation. The second component is we we call reconstruct ability. This is determined at the time of diagnosis. I can either patient is either reconstruct herbal or they are not. Do they have adequate distal vascular targets that I can rebuild uh in order to provide blood flow to and from any critical organ. It's a very simple concept. But if we can those are patients that are potentially reconstruct herbal and then finally just as importantly is recoverable Itty, what are the risks of that operation on this specific patient? What is this patient's expectation of their quality of life afterwards because obviously the larger the operation, the bigger consequence and thus we measure all three of these things if a patient is responsive there, reconstruct herbal and we anticipate a reasonable recovery. Those are the patients that we would consider for some of these more more advanced receptions, and that's how we approach these patients uh Currently here in Rochester Tony, thanks, Mark. This is great, you know, good, good summary of this and, you know, assuming that we have this patient who does great on neo management therapy and then ultimately gets gets to surgery. There's always this question of successful surgery. R zero resection, arguably some, you know, are one, although, you know, in your hands, that's unlikely. The question is of course, you know, when when do you when do we consider further treatment if any? Adjuvant therapy? I mean, as we move more and more into this total Neo adjuvant therapy setting, uh you know, I I certainly think that uh you know, we we have to move away from this whole concept of more is better. In fact more can be less uh for a lot of these patients that have been already gone through a lot of of of treatment and I think there's very low likelihood that further treatment will actually enhance uh you know, enhance their uh their survival. Uh there's an interesting parallel to that and that then again, often comes as, you know, and those patients who haven't had the best response to neo adjuvant therapy, you know, ultimately following surgery, uh the those patients actually are the ones that are least likely to benefit from chemotherapy because you've already done the chemo test. Um Same goes for those species had a fantastic response. Do they really benefit from any further treatment? Uh So more more to come, you know, there are some studies assessing the further need. But I'd say, you know, from the Chronicle standpoint, those patients who have had their fair share of treatment prior to surgery probably wouldn't benefit from further therapy after adequate uh treatment. Now, there is a particular the particular case of those patients who actually do go through Neo Adjuvant therapy and we try our best and ultimately, you know, through our discussion here with a multidisciplinary team, you know, marquis decide well, you know what, this patient is not going to do well on surgery. Uh they remain non metastatic. And then the question is, you know, how long would I want to continue treating them with chemotherapy or the likes? And this is where I actually would go to dr to chris and say, you know, do you think this is time for us to consider uh you know, other forms of treatment, radiation for those patients? So, chris who are those patients where we think, okay, we can transition now from chemo to radiation, perhaps eventually go back to chemo at some point, but those are the local patients, local, local regional that are not unfortunately deemed respectable at this point or operable. Yeah, it's a great, great question. And um you know, in this situation we we want to make sure we're getting as much benefit from the chemotherapy as we possibly can and for as long as possible. So typically we want to see, you know, at least three months of systemic therapy, ideally, you know, six months or so. And then, you know, eventually we get to the point where the patient is just getting too worn down from chemotherapy. You know, they're experiencing neuropathy and the chemotherapy is needing to be uh dose reduced or delayed due to to the side effects. And we still have local disease as best. Uh you know, we can assess based on all of the multitude of excellent tests that we have now. And they visit with Dr Trudy and Dr Trudy says, you know, I can't take this out that this is too high risk. And you know, if Dr Trudy says that then you're not going to find another surgeon in the country that would offer the patient resection or should offer a patient resection for that matter. Um And so that's generally when we would think about doing local regional therapy as a means to provide local control and give them a chance to um to stop the systemic therapy for some period of time. And so again, that's typically at least three months. Oftentimes more like six months of systemic therapy. And uh, you know, we do have modern radiotherapy techniques that allow us to give the treatment over a shorter, shorter period of time than was done historically. If you think back 30 or 40 years ago when we had fairly rudimentary radiation techniques, we were treating a huge volume in the abdomen. We just treat a big box and made sure we didn't miss the tumor. But we treated a lot of normal organs and we didn't have anti medics and patients tolerated treatment relatively poorly. And the only way to get around that was to do small daily doses over six weeks, which really is not too uh too good of a pill to swallow if we're talking about an aggressive palliative treatment. Oftentimes. And so fortunately there's been significant advances in our ability to safely give radiotherapy regimens over a shorter period of time. More targeted, better tolerated. And we can do courses of treatment in three weeks as a common regimen that's used or even one week in in situations like this. And um really, that's become the standard in terms of radiotherapy for for unrestricted ble disease. Um Oftentimes again, we will stop systemic therapy after administering local therapy and say, all right, we're gonna we're gonna watch things will hold further systemic therapy for uh if or when there were to be disease progression or recurrence. And oftentimes patients can can have an interval of time, Sometimes quite a long time off of systemic therapy with good preservation of quality of life. And, you know, there's newer series coming out, including some work for memorial Sloan Kettering. Looking at, you know, modern cohorts of patients, multi agent chemotherapy, good response still have localized disease doing focal radiotherapy and showing that median survivals and that select cohort can actually be um pretty promising on the order of a couple of years and sometimes even longer. Um So, you know, it's interesting things kinda go in favor and out of favor then back in favor and radiotherapy kind of falls falls into that uh that category. I think as we're getting better with staging and systemic therapy and patient selection, I think we're doing a better job of identifying cohorts of patients who do benefit from more aggressive local therapy if they're not candidates for surgery. Oftentimes, you know, there's this this question that comes about from referring your oncologist or or patients themselves about well, how about proton therapy versus other forms of therapy? Does it make more sense? Why? Why and why not? Yeah, proton therapy is just a different way of giving external beam radiotherapy. Um It's a less common type of radiation treatment just because there are fewer facilities in the United States in the world that have it for some types of cancer. Um there can be benefits to it for other types of cancer. There may not be any tangible benefits for patients uh for pancreas cancer. It's a type of cancer. Unfortunately, there really isn't a big benefit with using proton beam radiotherapy. There are some circumstances where there could be some advantages. For example, the patients had previous radiation to the advent. For another reason, you know, decades ago, uh if the patient has sort of strange anatomy or altered anatomy, things like a single kidney or has had bowel resection for Crohn's disease, and we really want to make the radiation as focused as possible. There are some niche roles where it has some advantages, but um for many patients, um it's it's probably not going to change the overall tolerable. Itty and long term outcomes. So it's um it's not a mandatory treatment technique for this type of cancer. So selectively there may be patients who may benefit Mark. How about I. R. E. You know? So I was just thinking of that. Uh so remember our first duty is do no harm. Okay. And so the standard of care for a patient who has locally unrestricted ble or unreconstructed pancreas cancer. You know, the here and elsewhere. It's gonna be chemotherapy plus or minus local regional and I don't call it palliative radiation, I call it definitive. Okay, palliative is a negative connotation. You know, you're doing it for, you know, as if there's no other option. Uh There are lots of new devices that are being propagated now for local control. One of these is this reversible electro operation. Uh we have it here, We've tried it uh and it promises, you know, minimal risk and and great benefit. Our experience however, has not shown it to be of any significant benefit. However, it has led to some significant complications, some of which have been very life threatening and thus we do not consider it. And uh there's actually a moratorium here specifically for that. Only very few indications would we consider that, But you may go to another center and they may really be pushing something like that. But again, it is a non curative modality. Okay, It's not purely a native. Uh It's probably at best equivalent to an R. Two resection. Uh And we know what the benefit of an R. Two resection is that there is no benefit Tony. I wanna come back to the topic. You have talked about adjuvant after? Neo adjuvant. Okay. We can predict which patients are gonna do poorly. Uh The biggest predictor is their path response. So let's say a patient gets full for Knox, they undergo resection and the pathologist says there's no treatment response whatsoever. Uh predictably those people are going to recur quite rapidly. Would you ever consider giving them edgy event? And second line chemo that they weren't exposed to number one. And what is the role for, you know, the minimal residual disease testing. You know, some of these uh platforms where they send the tumor a blood test and they develop biomarker to see if anything is detectable in the blood. Would that be a patient that you would offer edge of in therapy too because there's another marker. I think these are fantastic questions. Mark, let me start with the first and then I'll get to the M. R. D. So when thinking about uh you know, they're all a further adjuvant therapy again, you know, we go to the principle that you elicited is do no harm. Are we going to help the patient any further? Unfortunately, you know, these patients tend not to be cured or add to their potential for a cure with with chemotherapy adamantly if they actually have failed to have maximum response to neo adjuvant therapy. Now of course, you know, if if we decide that it makes sense and I would say if because I I would believe that you know, the most likely the most likely benefit if we decide on this would be a disease free survival but not necessarily an overall survival benefit which has methods to it. You delay, you know, the real currency delay symptoms, you perhaps improve quality of life in the meanwhile then to your point, you don't want to go back to the same exact regimen. It failed. You've already shown it failed. It didn't do at least the job then it makes more sense to switch. And now we have at least, you know, one or two options that we can switch to. So I think, you know, it's important to have patient by patient case by case discussion for that thankfully. Again, you know, to go back to our overall discussion thankfully. You know, with with the new agreement approach. You know, we've we've developed through Mayo clinic that you've pioneered and others on on this, on this webinar. Um you know, we are able to predict pretty nicely who are those patients who actually will do really well and ultimately benefit from surgery. But those are the patients also are most likely to benefit from the regimen of neo adjuvant chemotherapy and perhaps radiation prior. So we the window of losing opportunity continues to shrink with appropriately selecting those patients out regarding M. R. D. You know, it's it certainly is has its challenges but has its potential benefits as we move more and more into understanding its predictive role in colon cancer. We understand we're starting to understand a little bit more work to place it. Although we're not there yet uh impact Prius cancer not there yet. The good news is that we have a number of clinical trials that are assessing actually the role of M. R. D. Specifically M. R. D. Positive disease. And what that means essentially, you know, minimal residual disease positivity you take the tissue which is the best way the higher the more sensitive way to do it. You take the tissue you match the blood to the tissue. This is called, you know, tissue informed there's also the tissue uninformed, which I don't think has enough sensitivity in pancreas to rely on. So the tissue informed, minimal residual disease assessment can tell you whether there is a positive disease. The only caveat is as you you had your prior discussion with care as uh in in blood. Is that the sensitivity can suffer because of the low shedding rate of this disease. But certainly you know, we'll have a role and I foresee that in the future it may actually be a very important role as long as we're able to identify you know better targets than just the non specific chemotherapy. Uh That is a question uh in the in from from the audience and that relates to adjuvant therapy. This is you know a patient Who had negative c. n. 99 assuming lesion in the body, no vascular involvement. Postoperative it was two centimeter lesion. Stage one B. Uh Do we give adjuvant therapy? So this is the patient that did not go through the protocol so Tony. What is the standard of care for a Stage one be resected two centimeter pancreatic body lesion 99 assuming healthy and fit uh or nothing. What would you say? I'll give that and then I'll throw it back to you to see if this is a patient you will take directly to surgery. You would send back to us for. So the answer is this is a patient with negative margins, lymph node negative. So stage one B. two centimeters. The risk of recurrence remains pretty high. And those patients actually were included in the uh adjuvant trials, 70 year old is relatively young in today's world. And this patient would if again, if no other significant home or visit recovered nicely from surgery. Uh that's a patient. I would rather go with full fare knocks rather than with have been given the significant survival benefit that we've seen between the two. You know, this patient would be would be eligible for full fare knocks. The question, of course, is is that the patient, you know, if you you've seen this patient mark, is that the patient saying, you know, this patient is someone I may consider surgery first. Or this patient would go into the new achievement strategy, yep. So, you know, the question is is there any patient who you wouldn't use, in my opinion? I have? I do have my own personal criteria. It has to be a young. You know, healthy fit patient can tolerate an operation. Uh They have to be have a small tumor less than two centimeters. They have to have a normal or non secrete Earthsea in 99. They'd have to have a negative peripheral blood keras. Uh They would have to have a negative laparoscopy. Uh They would also need to have a body tail lesion that's a minimal to a laparoscopic or minimally invasive resection. And it should be a non avid uh tumor on pet because if it's not avid, they don't ever see a 99 giving Neil a given in this particular subset circumstances. There's no way to tell if what you're giving is effective. So those would be my criteria for an upfront resection. Uh the likelihood of a patient like that, and I can count on my fingers how many I've seen, but on occasion there are or some patients who just prefer to have it taken out uh if it's in the head of the pancreas, a whipple is a whole different story. Uh in terms of, you know, recovery and complication rates than a distal. Yeah. So so so, you know, for for practical purposes, almost every patient that we're gonna see is going to go on on the Neo adjuvant protocol except the incredibly few. And again, it's important to have everyone involved in the discussion and most importantly, the patient. So, want to jump to you just, you know, uh talk a little bit about what's what's coming next, What other modalities can we consider uh you know that that would continue to move our field forward? Sure. Before that, can you give me an idea of how much time do we have left uh for a few minutes? Yeah. Alright, so let me share my screen again, because So what's coming next is this thing called as fibroblast activation protein inhibitor. So we do know that there is something that goes into the new plastic cells of the pancreas cancer. But we do know that about 70-80% of the pancreas cancer is actually this trauma and the cancer associated fibroblast is the main constituent which actually drives the aggressive biology of humor. So F. A. P. Is something that is hyper expressed on the CFS and this flappy is an inhibitor and here is an immuno history chemistry. All this dark brown that you see is the F. A. P. And this is the control slide that shows that how intense it is expressed. So we now have a radio tracer for this fab which is called gallium 68 happy some of you who know gallium 68 to date. So essentially what we do is that we remove the floppy, we remove the date component and attach the fatty. We have compelling data from europe and Asia that have used this bed that showed that even in some of those tumors where there may not be as prominent in the tumor for whatever reason, the gallium 68 fab, it tends to be present because you know every tumor of that size would need a Strama. And in addition to that it can pick up those metastases which may not be seen on either CT scan or on the D pad. You know, these are some of the other images from the literature you can see that it also has multiple other advantages for peritoneal disease which may not be amenable or seen on the D. Pad. So there are some workflow benefits because we have to think about the patients as well with patients have to fast for about six hours with fatty. They don't have to. Blood sugar is not 11 for happy, which is a big advantage especially for patients with pancreas cancer. We saw that there are a few patients who may not have a habit humor, but all of them have happy positive because all of them needs trauma. And the most important is that allows us to have P. R. R. T. For patients with adenocarcinoma. Somebody asked about neuroendocrine tumors. We do in neuroendocrine tumors that PRT has provided to us a revolutionary treatment option. So why not for pancreas cancer. And the reason why flappy can fulfill that need is because unlike F. D. G. We can replace the gallium 68 component of the root of happy with the loutish in 1 77 which is a parameter or the cranium to 25 which is an alpha emitter. And this is something that we can give to those patients who have expression of happy on their tumor. So this is like a precision medicine paradigm where you see if the patient would respond based upon hyper expression and only then you give the treatment, you know a couple of months ago we got the second arrow one that I mentioned to you for looking at flappy pet in patients with pancreas cancer. And here we are doing the same thing. We are using that happy pet in the head to head comparison with F. D. G. As well as combining that with the rest of the biomarkers and the interest of time. Let me show you what's the study scheme that we are doing? We are taking those patients with new adjuvant therapy. They'll undergo the standard of care that we discuss which is multi city labs, C 99 keira ct DNA which is a liquid biopsy, Mdg pet. And then they will undergo the flappy pet and the pet will be repeated every time there is a restaging and it will be compared on the immune history chemistry with that of the surgical specimen. These flabby patty measures will be blinded to referring providers like chris and mark. And ultimately we will compare to see if they pick up more processes if they predict the response better, if they predict the outcomes better. And ultimately we have a few trials here right now in Rochester where we are taking those patients with metastatic disease that have failed the first line chemotherapy and in them we are giving them loutish um tag happy as a treatment option that is being investigated as part of the lumia study. So I think this is an exciting part of the practice that I'm looking forward to personally. I know this is exciting, certainly, you know, I mean it's exciting to see all of your work just in how, you know, you and and and and and mayo clinic on moving the field forward. And one of the toughest, you know, cancers and in the world, you know, and and as we think about about pancreas cancer, you know, one cannot but think about, can we identify, you know, risk factors? Can we screen for pancreas cancer? Are there patients who may be at higher risk? One of one of the common uh common root, let's say, routine findings is this pancreas cyst or pancreas and normality, uh what is maybe a jit and then and then Mark, you know, what is, what is the, what is how do we how do we identify and stratify the risk and follow up on patients say with an incidental cyst. Uh and what what what are potential science that the patient may be at risk for future malignancy? Yeah, so I think that's quite a big problem because as you know that more than 5 to 10% of the patients over the age of 50 who will undergo a cT scan or an M. R. I will have a pancreatic cyst. Now the majority of these cysts will communicate with their main pancreatic duct and so they will be I. P. M. S. But I. P. M. S. Are the only known precursor lesions of pancreas cancer that we can right now modify in some way, shape or form the challenges that majority of them will not turn into pancreas cancer. But the problem is again is that the patient anxiety and the impact on healthcare resources. The short answer is that right now, the only thing we have is a periodic follow up with M. R. And M. R. C. P. In these patients. If there is increasing the size of the cyst more than five within a period of two years, if they have enhancing modularity on the city or the M. R. or if they have other features such as, you know, if they unfortunately going in case another vessels and we know that they have turned into malignancy. But just I mentioned about fatty, you know, the cancer associated fibroblasts are the critical component. That is one of the earliest events that happens in carcinogen icis. So what we're doing now is that we are doing some immune history, chemistry studies on those patients who had reception for the cystic lesions. And if we see positive signal there, we can launch an imaging trial where we could do a limited single bad abdominal fat people on those patients to risk stratify them better. And again, you know, even with this right area that I mentioned to you on imaging all the patients who undergo surgery based upon those criteria, even in those patients, only 30% of them will actually have pancreas cancer. So which means there is a big need for us to be able to make a difference there. They have some of the blood based and the pancreas juice based biomarkers that are in various stages of investigation. And finally then we also have hope with ai which is something which may be outside the scope of our seminar, but you know that there's a lot of work that is ongoing in that domain. So Mark, I mean when when when do you even think about? So the key thing is figuring out, you know, your differential diagnosis, You know, is this a congenital cyst? Is this an acquired cyst? And more importantly, is it a neo plastic cyst? You know that that's the big question. Even for neo plastic cyst there's there's different risks of potential malignancy. Uh We're talking about I. P. M. N. That's what were you know, mainly concerned about. Uh as dr mentioned, we're looking for high risk stigmata and imaging either M. R. M. R. M. R. C. P. As well as us findings. You know, solid nodules from a historical perspective for the patient we want to know is this symptomatic or not? How is this identified as an incidental? Also an I. P. M. N. By definition communicates with the pancreas duct, we do know that branch duct or those more peripheral ducts have a much lower risk of malignancy than uh an I. P. M. N. That involves the main duct and then you have what we call a mixed mixed type component. Somewhere in between. Uh the question from the one of the audience members looks like a five millimeter cyst within the body. Uh no incidental, no symptoms uh and the absence of any other risk factors. This would have a very low likelihood of either harboring or developing a malignancy. We would also recommend follow up in one year with an M. R. Unless there's any other high risk features like a family history of pancreas cancer, elevated C. N. 99 the blood, things like that. So the one that the audience member referred to very very minimal risk and negligible risk of cancer. But again, there's a spectrum of the of these, of these cysts that we consider for resection. All right, Well this was a wonderful discussion. I think we've got a little bit over time. But you know, I mean, how couldn't you with this group that's moving the field forward and, you know, a complete understanding of, you know, where we're going next uh you know, through this discussion, you know, we understood how, you know, we think about best selection of patients to ultimately good surgery, how to optimize essentially uh staging, whether radiographic, including biochemical genetic markers, procedural staging, also understanding the role of preoperative treatments are moving most 99 plus percent of our patients to the new admin setting. Talked about, you know, some of the chemotherapy options for our patients. How do you think about one versus the other, of course. The the one key element in our new address strategies that the chemotherapy switch for many patients who may not have an optimal response. And how to define that optimal response. Again, including all the the markings of radiologic, metabolic, biochemical and meta and molecular. Then of course, you know, more and more understand who are those patients who maybe most eligible for radiation prior to surgery? Uh And then and then talk we talked quite a bit about, you know, how how do we uh you know, how do we establish criteria for respectability, expand this? Uh You know, dr Trudy Mark talked about responses, response, reconstruct ability and recovery ability and how it's important that the three hours essentially as part of uh you know, of the equation for decision making processes for for for surgery. A little bit about the role of agile in therapy, about minimal residual disease assessment. Do we decide on giving further treatment? Who is that patient? Do we have enough data, the answers, you know, at this point of time? Not much. Although, you know, these studies are actually evolving. We have some of these studies running here um then then talked about definitive chemotherapy and radiation. Uh The devolving role of I. R. A. Uh some of the palliative procedures and and and uh you know talked quite a bit about some of the advancements and imaging modalities and and to top all this also your understanding not only how we want to treat patients uh in the early stages, but how can we essentially screen even sooner those patients at risk and intervene? And hopefully at some point even prevent some of these patients from developing cancer. So hopefully into our audience, you know, this gave you a really good view uh everything that's uh that's happening in the world of non metastatic pancreas cancer, specifically the mayo clinic view about how to optimize care of our patients from the pre cancerous all the way to the cancerous uh and non metastatic lesion. So I want to thank our illustrious pan, thank you all of you are doing some fantastic work to move the needle forward. It's obvious through your scholarly activities, your clinical excellence uh and uh and and everything else, and how well we're doing and moving forward with pancreas cancer. Thank you. And I think we'll close it here.
