Chapters Transcript Video Updates in the Multidisciplinary Management of Localized Pancreatic Cancer Hello everybody. Thanks for coming to our webinar. I have no disclosures. Them. The topic is multidisciplinary management and updates in the treatment of pancreatic cancer and mainly the message would like to um uh through is the regarding the new are given the role of neo adjuvant therapy in the treatment of uh pancreatic cancer. The objectives of this talk will be talking about some pancreatic cancer facts, uh definition of respectability, some updates from clinical trials and new advances in technology and their conclusions. Uh The pancreatic cancer is not the most common cancer actually, Actually the lifetime risk of development councils approximately 1.6% for men and women in the us. Um The prevalence of pancreatic cancer in 2015 is about 68 mm hmm 1000 people who have pancreatic cancer. However, Uh an estimate of 44,000 will actually die from the disease. So you can see the rate of diagnosis versus mortality is approximately 1-1. And that's the impressive finding of pancreatic cancer. Now The place is surviving approximately for five years. The five year survivals when all cameras approximately 8.5%. It's quite quite low. The majority of patients are diagnosed with better study disease uh and more than half of patients. Um And you can see here in this light that uh there again, it's not it's not the most prevalent cancer, however, has a very high rate of mortality. For instance, For patients that have lung cancer, 254,000 diagnosis, 1 84 deaths for pancreatic cancer, 55,000 diagnosis, 45,000 deaths. So the mortality despite this, only 3.2% of all cancers is quite high. The pancreas is a retro peritoneal organ. The head of the pancreas is attached to the duodenum and uh then we have the neck of the partners would see it. Mhm. And both the S. M. A. And S. And D. The body of the pancreas as well as the tail. It's called this plane. No um one definition that would like to go through and we live we'll give very very broad and uh you know we're not going to a lot of detail unless there is a question is definition of respectability and we have to use that are now clearly acceptable to us that are locally advanced and borderland receptor. Boy. So why is this the stability important? It is important because patients that have and marks and positive reception either in a macroscopic level which is our tourist section or in the microscopic level which are one section they have a very poor survival. And in some series the survival is as low as the places that didn't have to go operation. So we see here in this line that paces will have posed the margins after a section. The median survival is Half spaces that have uh zero reception. And that's why defining their suitability pre operatively is very important. So how do we classify the very common classification is respectable, locally advanced or acceptable in metastatic? This is um now yeah, a more uh correct definition will be respectable locally advanced and or unacceptable patients. And uh in the middle of the border, a group of places are called borderline receptacles and there are multiple criteria from uh cancer centers from that and sincere and guidelines from H E. B. A. S. S. A. T. S. S. O. And the alliance definition for clinical trials. And these definitions are quite detailed. And again, we're not gonna go over these few details I want to mention is that the acceptability or the definition of border except aboard is associated with the contingency to the veins and the arteries around the pancreas. And again the definitions are very they're not you know, they are very similar but they have significant differences. The most recent definition is the alliance trial definition which is most was widely accepted nowadays. Um uh an idea, the idea that goes through all these definitions is modern unacceptable is that are those patients that we think probably we have a high probability not to achieve a microscopic negative margin. In other words, bodily respectable are those places that we think that we might not receive negative margins or have a complete resection. And that's just a way of putting this. Now we'll see here at cat scan the um the white dot around the pancreas is this is a patriotic timor. The white dot with the second arrow is the S. And D. Right next week, the S. M. A. And you can see that you're about both the smb and this may. But however the S. M. A. Is less than 1 80 degrees. So this is this us a clear definition of ordinary acceptable to more. And this is clearly that you know that's clearly acceptable. You can see there is a fat plane around the artery and the vein. And another picture like that. You see a body humans abandoned the spleen of portal junction. This is the two more and this is that you know that is not about the spirit portal actually this examples from our series and this picture is not very clear. This much clear. You can see during the dissection. You can see the main, the portal vein that's Branson and behind the S. M. A. Which involved by the U. S. So we have to reserve a portion of the men and reconstructed this place had terrible by the way. So what is the point of neurological therapy? How defined the original therapy chemotherapy. We talk about patients that have chemotherapy and radiation before reception. And the point of neurological therapy are either too give us an idea of the biology um of the cancer preventing the interval time while giving treatment. Give us an idea how aggressive this cancer is and how if the basic has already made a start disease. Because many basic scientists that uh you know, they're doing basically sets of pancreatic cancer. They have shown have multiple models and they have shown at least individual and in vivo in small animals that pancreatic cancer is actually metastatic at the time of diagnosis even in early states. Uh Therefore patients that are stable during the national therapy are better selected for those ghost surgery. Also, since we if we accept the possibility of having early microscopic disease outside the pancreas neurological therapy might provide treatment for those questions Furthermore, to downstairs the maximum and maximize the potential the possibility of R0 section. And I think this is one of the major uh uh factors that I personally think that radiation therapy is very important, both for providing negative margin, as we call it, sterilized the margins, but also in the peri pancreatic leave notes. And certainly a very important fact is that almost all patients can tolerate chemotherapy, especially aggressive chemotherapy pretty operatively than patients that uh that those places that can tolerate based chemotherapy post operatively um pancreatic to me is a major procedure. It takes a lot out of patients, even if a patient goes through without major complications, uh needs some time for recovery. And only Um 60% of patients able to tolerate chemotherapy after. While, more than 80 to 100% of patients tolerate the chemotherapy before surgery. That's one of the big benefit for neurological therapy. And you can see the slides from my paper from 2014 days from the other show that in the first graph above, you can see the blue line, so the dark line the survival of places that had surgery and chemotherapy either before or after british pieces that have only surgery now. In the below, you can see the survival is significant. Either you have the chemotherapy before or after, and you can see a better graph below the differences places between Newark driven driven and north therapy. You can see again that the survival benefit of those who have chemotherapy new are driven or argument is significant. Uh So if we accept that uh more patients to lead the chemotherapy in at the new words was setting than the agenda setting? Well, it makes sense to give the therapy no one's going to give the patient the benefit of survival. So uh we discussed about the watchman therapy for acceptable or unacceptable disease. Uh The classic approach, the therapy results on to 23 months of media survival. After optimal treatment. There is uh trials nowadays that uh especially the produced trial that's sort of uh survival of 60 months after asthma therapy. However, in this trial, uh the patients were selective and randomized to have treatment after a section. So many places that have surgery that either didn't do well after surgery had multiple publications who did not undergo. So, so this person in this trial of very well selected. This is an average number I give you from um from previous trials. So in terms of clinker trash from the chemotherapy for um uh it's a very busy slide. But the only thing a region I want to show you is that uh most trials had various definitions and ah thank you. And they have included patients that either have locally advanced of border acceptable to us. So it's very difficult to draw clear conclusions. Uh This is probably the most important slide uh that I would like to discuss. Uh This is an up to date slide regarding patient that have either upfront surgery followed by adjuvant therapy and travels that have places with neurological therapy. The first one is the just the trial that was done in Japan that so that faces that have surgery and have vaginal therapy. Either each one of them set up in and this trial was randomized And so that person will have S1 chemotherapy had a significant uh benefit. However, one thing I want to mention this trial is that the local recurrence, it was between 19 and 26%. This trial did not include radiation therapy. Another important finding this study is, As I said, this is an average of one certain study and 28-42% of basis discontinued the therapy before completion. So you can see even in very up to date trials, the number of places that this continued trip in the regional center is unacceptably high. The second trial is an expect for trials that again uh patients had adjuvant therapy at the age when setting setting any wash a comparison between a job and jim set up in virtues algebra James hadn't been or keep shopping. Uh The group, the different, there was no different survivals starting significantly. However, again In the group specifically, they had the James had been captured treatment about 45%,, 45%. Almost half of the patients did not complete the treatment. Again, this child did not add, Had a local recurrence rate about 40-53%. And again, because of the treatment regimen is becoming more and more important. We'll see much more local recurrences as patients survive more. The last trial is the trial are briefly missile before the project trial that had the argument for Philly knocks modified for funerals virtual uh, engine set up in therapy. This a loudmouth trial that changed the therapy in the original setting because so that the three year disease free survival was uh, much more superior as well as the overall survival for the full spirit. Next group them again, the in this trial, uh, this pine been well selected because these places were randomized after the surgery About 33.6 In the fulfillment group and 21% in the same group aboard. Did or did not complete adjuvant therapy. Now let's go to the Neo adjuvant setting. Uh One trial that was completely recently published was the period punk trial that it was a chemo radiation trial. Uh This virtues upfront surgery. This trial did not improve overall survival. However, there are zero sexual rate was 71 uh And one significant findings. This again a trial that saw that had uh chemo radiation only in the neurological setting had significantly better decrease disease free survival and much better local regional control. Now the Another study the pre op so to this up of five trial again approach surgery with adjuvant chemotherapy versus neurological therapies. Again, the trial in Japan that you should have been or H1 the overall survivor was improved with the use of neo adjuvant chemotherapy. last trial I want to mention is the expert five trial which is has not been published yet. Is only we have the reports from a conference and abstract and it was forum study that uh compared surgery up front virtues keep set up in and capture them as an original setting fulfilling Knox has an original setting or chemo radiation and their very survival was improved with the original therapy which was a secondary. At the points. At one point I want I won't go over the study very much because we don't have the published paper but these are the data so far. Uh These are the other from that from a previous institution that we um so our outcomes for places that have upfront surgery, very shoes accumulation virtues that nobody was setting virtues, total knowledge of therapy um And totally natural therapy. We define a chemotherapy followed by chemo radiation followed by surgery. Which is the way we we would although this was studied over little space study over almost uh it's more than a decade. The total natural therapy was either jim based or for for for the last few years. Uh And what we did we did um chemotherapy yeah fulfilling oxidants. Three states in um with uh cat scans then followed by radiation, chemo radiation that followed by surgery. Now this there were difference in that for instance I like to perform a diagnosis laparoscopy before the Chemo radiation. That's a personal preference and also painting that didn't respond well either by saying 99 or other findings uh with change therapy without uh but we can talk about the details later. Uh and this is the survival issue. The green line is spaces that have totally arjun therapy and the survival and local regional control was much better. And this is another up slider saw the same thing this of course retrospective study how about mesotherapy receptacle patients again? What the first thing I want to mention is that the completion of therapy Is which is 100% in a study from the other son from our Foxes was for 83%. My previous solution. uh and you can see this between 80 and 100 And the curative resection uh progression during the nutritional therapy was uh between eight and 13% and 20%. However uh huh. Local progression was only 2%. Dropout 6% in total, only 8% of cases did not receive etc for reasons other than metastases. In other words, the majority of places that did not go to schedule it was because they have progression of disease. The number of places did not go schedule because the original therapy had significant toxicity is something that we have to consider very, very carefully in a natural setting. No. How about no original therapy for local advanced cancers and local advanced cancer. Usually we talk about places that either involved the silly taxes or the S. M. A. And this is a patient of mine uh that you can see an extensive large cancer involvement. Their origin of the party party as well as the cilia taxes a young woman uh that this original has come. Yeah, the patient Received shaddup in uh the C- 99 did not. A significant decline will change to fulfill knocks. Then she had of course you had chemo radiation. Also receptions he had category section which was subtitled protecting you would see like Alex resection And then they they say 99 dropped after the surgery. Uh this was 2014. Uh there was negative emergency 031 notes. This is the slide of the pathology. Can see significant fibrosis up to 90%. Uh and you can see here again the significant fibrosis that you are now. We had a previous study that showed that the patient has significant benefit. On the other hand, therapy and even higher cure rates. One of the fibrosis rates above 95%. This was 90% the patient. This post op cuts. Can you see the absolute number and select access? However, this patient had the council disease approximately three years after and see which we give. She was under the clinical trial and see survived five years after the original surgery. Uh So we studied there are places that have uh locally advanced us and after the chemotherapy resulted after the chemotherapy versus paces that have borderline respectable to us. This was very and very well matched patients. Um and try to see uh the survival. Um the survivability of places with local advanced cancers. And you can see all the spaces had celiac artery disease. And most of the patients had also seen like artery as well as total various sections these 13 patients that over uh several years, most of the spaces by my meadow Dr. Three of these places reminds us to be uh Exactly. And you can see that actually the time to recurrence. I was not different from places that have bottle acceptable. And again this survival plot for places the silica paces with the blue line and the control or places that have marginally acceptable was or in slides. So, you know, this person with local advanced disease can be treated for with neurological therapy and should not be discarded from surgery. Also, if you think about surgical techniques, the Oculus hell of uh surgeries, pancreatic click and various methods have been uh huh Used. This is a picture after will be procedure before the construction. And this is with recently uh submit for publication a new technique for decreasing the possibility of pancreatic league that it was partially imagination. Hopefully there uh the patriots. And if you can see a video can show the video that we have this. And but this modified the vegetation technique for the patient that had a robotic prostatectomy. With a similar technique. Obviously this video is uh uh I think it's uh huh three times the speed. And you can see this is the neck of the partners that were transacted with scissors just above the S. And D. You see here the bank account that that's it. There's a completion of the transaction, the pancreatic make. And this is a reconstruction with the partial imagination addressed. Issue some stitches in the pancreatic duct to help keep the door open. And a similar technique that we can do open. We can do with the help of the robot. You can see the fabulous imagination. Yeah. Okay we're gonna stop the video now. Thank you. Now I have uh more things to discuss However uh over my time if there are questions about other things that uh other techniques like a civil seat. So in conclusions um conclusions them patients. The new ones from therapist should be a first transit at least. Um In our view although standard of care is a driven treatment after a section. I have to stress that at the level one died about uh treatment Now, probably studying this should be um a standard of care. However, there are more and more more more data about new vaginal therapy. Mm hmm. And multi drug chemotherapy. Red smells like 4ft Knox. And more advanced reds. Most certainly will improve the outcomes. Uh There are many studies that it's difficult to drive. Draw conclusions from all the literature. However, the point is that um new actual therapy especially totally logical therapy including chemotherapy, radiation therapy and that surgery there will be I think more and more used in the future. Thank you for the attention of this is my product formation, my cell phone and we have a couple of questions. Dr carrie christos. The first is who is a candidate for new adjuvant therapy. But that's a good question. Um Now I would say all all persons uh that's I'm not I'm not saying that lightly, especially places that they have T. One disease. And no, they have not only found nobody. There is not much data to show that they will improve in even without adjuvant chemotherapy. So why these patients should be uh exposed to the complication of nutritional therapy? And that's that's a valid argument because as I said, the audio therapy has complications. And uh about 8% of cases will not undergo curate the century because of complications of chemotherapy. However, uh cat scans and mris and even in the scope of culture, some tends to understand the disease and uh certainly places that have been uh stay just till one. Um You can have a more advanced uh states. So therefore, I would say almost everyone excluding places that have once the limited human that's extremely rare. Excellent. Thank you. And now we can turn it over to dr tully. All right. Good afternoon. Sorry. Good evening, everybody. Uh Thank you for joining us tonight and taking time out of your evening to hear about pancreatic cancer from Doctor Care christos tonight. So, I will approach many of the similar topics that you just heard from. Dr Carey christos, but perhaps more so from a radiation oncologists perspective. Yeah. So, with pancreatic cancer, like all cancers, we attempt to sub select based on prognostic and predictive biomarkers and associated therapies. Unfortunately, we have not had too many successes to date, although I will highlight a few prominent ones. And as you've heard, uh these clinical criteria are what typically what are typically used to help us sub select our patients. So not biologic criteria, but radiographic criteria. Ah And I'll try to highlight some of the deficiencies associated with these criteria and how we might think about improving on them. Dr care christos has also shown you this slide um and suffice to reiterate that patients who have margin positive receptions. I guess my cursor is not working. But the fourth column there uh have outcomes that are as poor as if they did not have uh receptions from the get go. So certainly begging the question as to how we are selecting these patients for for upfront surgery. And this is a good contemporary example. It's a 700 plus patients study that was run out of Europe, the CS Pack for study and this study investigated the benefit of two different chemotherapy regimens. Um and some points to highlight relevant to our discussion are that 60 of all patients in this study underwent at least are one receptions. And keeping in mind here that are one in pancreatic cancer is defined as as tumor at inc As a result, local regional recurrence rates were around 50% and both arms and the Uh not not unsurprisingly positive margins predicted for worse overall survival with a hazard ratio of 1.27. So really begging the question, are we appropriately selecting our patients for surgery? This is uh a similar randomized study. This was I called it an oldie, but a goodie. It was done probably 15 15 years ago. It came out of the R. T. O. G. Uh And this was conducted in the US with all patients receiving radiotherapy in conjunction with either jim side of being or five F you after reception. And although a large proportion of patients within this study also underwent positive margin receptions, uh positive margin status was not an independent predictor of survival. Nor was it a predictor of local regional recurrence. And so this really leads us to question uh the value of adjuvant radiotherapy with or without the presence of microscopic residual disease. These are data from the johns Hopkins University investigating the role of chemotherapy and radiation versus observation and patients who have undergone the whipple surgery. And in this study, chemo radiotherapy improved survival independent of margin status yet was more beneficial in patients who had microscopic residual disease. As you can see in the right panel panel. Be relative to panel. A Of note. Even in this study, 45% of patients underwent margin positive receptions. And so for us, this really begged the question as to how we are defining margin positivity in pancreatic cancer. Unlike breast cancer, we really have very limited data indicating the benefit of clearing margin beyond ink. Again, the U. I. C. C. Definition as well as the definition put forth by the Royal College of Pathologists uh indicate margin positivity as tumor at inc. These are two large retrospective studies. One came out of europe. One is our one represents our experience that was published a few years ago and the data is rather the the the outcomes are are similar in both studies indicating that clearing the margin beyond 1.5 to 2 millimeters uh has a direct impact on on survival. And this was uh an independent predictor based on multi variance analysis. And so margin clearance at ink in fact may not be, may not be adequate to serve as a as a negative margin. And so based on all available data. The national radiation oncology society released guidelines of which I was a cost or a couple of years ago. This was from 2019 uh indicating that agile and fractionated radiotherapy with chemotherapy in select high risk patients was only conditionally recommended. And so it has been our practice. And I think the practice of other higher volume centers to typically recommend radiation in patients who have multiple lymph nodes and or residual disease present after reception. And so I would like to highlight uh the ongoing Phase three randomized study which is the R T. O G 0848 study which is randomizing patients with respected pancreas cancer uh to either chemotherapy alone versus chemotherapy followed by chemo radiotherapy. And the study has gone through several different iterations of uh what the adjuvant chemotherapy regimen should be. Uh fortunately keeping up with the standards including the use of of agile and full fare knocks based on the prestige uh produce study. And so this study closed a few years ago and data are maturing. So it is certainly anticipated To help us decide uh in whom we might use radiotherapy. And I would also add that with better systemic therapies and better systemic control. As noted in the produce 24 study. Will the impact of local control become more important to overall survival? And I'll share some of these data are with you in just a moment. So locally advanced in borderline, respectable pancreas cancer is dR K has indicated represent about 40 to 45% of all diagnoses. We see. We can make the argument that that number is probably a little bit higher, maybe 5 to 10% higher. Based on the data that I've shown you today, in which a large portion of patients undergo surgery who probably should be receiving definitive and or neo adjuvant chemotherapy and radiation. The current standard of care for locally advantage and borderline, respectable pancreas cancer include multi agent chemotherapy and depending upon who you ask. Chemo radiation, uh Either standard fractionated radiation or stereotype. Actiq body radiotherapy. Also known necessary a tactic, a bladed body radiotherapy. And the difference there is really just the duration of therapy, typically 5-6 weeks with the former and 1-2, weeks with the latter. And again, we're utilizing clinical selection here, you might argue. It's certainly biologic selection uh with absence of progressive disease after chemotherapy perhaps indicating utility of radiation. However, if you look at contemporary clinical outcomes, they are poor with both chemotherapy and chemo radiation. In the um uh Hamill study that was published in the new England Journal median overall survival of 13 months. You can see the patients passed very shortly after progressing. And all of the studies that have presented their indicating the lack of benefit from effective salvage therapies. Well, what about down staging in these patients? It's certainly rare, but it's important uh in these studies and others in particular, the median overall survival of patients who are down staged, initially diagnosed with locally advanced disease were downstage and respected survival triples. Um and again, median overall survival if these patients remain unrestricted on the order of approximately one year and importantly, about a third of these patients die from progression of local disease. There's been excellent data that's come out of chris Sacca buzios lab when she was at Hopkins, uh and more recently out of Memorial Sloan Kettering uh indicating based on rapid autopsy studies, that uh that these data certainly hold true. In spite of this, down staging rates are quite poor. Again, the Hammel app oh seven study in which patients receive chemotherapy and randomized to plus or minus chemo radiotherapy As part of a two x two design, the resection rate was only 4% of which 63% were margin negative. And the single arm uh phase this was a single arm phase. To the lapack study of jim started being on abraxane. Are resection rates were only 15% of which only 40% 44% were marching negative. So this you know, I think leaves us with the open question of post neo adjuvant therapy. I've brought up how important it is. And dr care christos has emphasised how we initially stage these patients who are treatment naive. But what about after chemotherapy and radiation? How should uh these images be be interpreted and how should they help us uh dictate next steps for for our patients? So what about specific to uh to radiotherapy? What can we do? Uh We're certainly working on improving techniques of dose delivery to increase efficacy and reduce toxicity. Certainly not mutually exclusive. And we are doing this through uh through a few different ways, including escalating the dose using techniques such as simultaneous integrated boosts which I'll touch upon uh adding in sensitize ear's and modifiers were appropriate. And certainly trying to identify appropriate uh predictive markers of response to these particular therapies and at the same time trying to protect the normal tissues using advanced imaging, respirator, respiratory motion management and a better understanding of the gi tolerance of the normal tissues. This is an example of a study that we published a few years ago here, looking at four dimensional magnetic resonance imaging using a technique without contrast, that allows us to uh that allows the vessels to enhance. So this can be used on a daily basis. Free treatment and during treatment with the appropriate capability to be certain that we're directing our treatments where they are supposed to go. And one might argue that probably the, the uh, the most relevant location to be receiving high dose should be the tumor vessel in her face. There's another study where we looked at the relationship of the tumor to the surrounding organs. You can see that you are outlined in red on the CT scan and the surrounding normal tissues, which we try to avoid. That. You can see the duodenum, the stomach and bowel, which on certain respiratory phases can be a budding and on other respiratory phases. We can certainly get some some day for mobile shifts between the tumor and, we've noted, is patient specific. What also provides us an opportunity to give higher doses while protecting the normal tissues. And this is an example of what an integrated boost for pancreatic tumor would look like Here we're giving as you can see outlined in the pink, a lower dose, lower but still high dose to the entirety of the tumor plus a margin and any involved nodes. And giving a significantly higher dose at the same time during the same treatment to the tumor and the vessel interface, hoping that this will uh improve, not only not only control but also um uh respectability. And so how do these uh technologies translate out clinically? Well, we have a few studies now that have been published looking at higher dose radiation and patients with inoperable pancreatic cancer. This is a multi institutional study that came out of washoe and MD Anderson and other studies. Uh And you can see here, we're looking at higher dose radiation compared to standard dose radiation. In patients who have completed chemotherapy and have not experienced progression. And you can see local control Uh noted on the right panel on the order of about 80% at about two years and certainly significantly improved survival compared to standard fractionated radiation. Similarly, this is the M. D. Anderson experience. This was published about five years ago and you can see uh B. E. D. Is biologically by the biological equivalent dose essentially. Again we're looking at standard fractionated radiation which is highlighted by the blue curve and higher dose radiation by the red curve. And you can see that not only are we getting improved survival but we're getting an increased frequent uh proportion of patients who are surviving longer and hopefully for all intents and purposes cured. Uh This is data from my previous institution which we published just this year and this probably represents the largest study and also the most aggressive radiation dose regimen that has been used in patients with locally advanced disease. And this is a treatment that we're now offering here at T. G. H. Where you can see patients getting the a blade of dose radiation which we're giving uh fraction ation schedules ranging from three weeks to five weeks. Uh And the decision is made based upon the proximity of the tumor to those normal tissues and how we might best spare them. But the dose doses are essentially equivalent between both regimens. And you can see that there's a relatively significant improvement and overall survival. Uh With the higher doses compared to lower doses, what I've not touched upon are the associated toxicities. And you can see specific to this study. The likelihood of both short and long term G. I. toxicities are quite low. You can see one of one of the biggest concerns with higher dose of radiation is longer term damage to the bowel, including bleeding. And grade three toxicities were less than were less than 10%. What about biologic selection? I won't delve too deeply into this except to say that uh we in spite of excellent uh research and and insights we really have not come very far. This was a study that was published in cancer cell a few years ago and it was a comprehensive integrated genomic characterization of patients who had uh low and pancreatic cancer adenocarcinoma with a low uh tumor mutation all burden. And you can see um hard to see what the left panel, the most frequent mutations of KRS C. D. K and to a uh mad for N P 53 are present in the vast majority of patients with a myriad of assorted mutations and the remainder of patients, the vast majority of which in fact not all are not target herbal. This is the practical application of these data. These were published by Eileen O. Reilly's group a couple of years ago looking at the action ability of next gen sequencing in these patients level one representing targets that have uh FDA approved therapies ranging to level four in which there is no FDA approved or N. C. C. And compendium biomarker target. And you can see that the vast majority of patients who undergo NGS uh do not have um uh target herbal mutations. And so what we're really left with are these sort of one off cases. This is a patient Who presented to us 35 year old orthopedic surgeons. So not in the usual presentation. He had just started practicing, collapsed in the operating room and was diagnosed with this large, very large, locally advanced non metastatic adenocarcinoma of the pancreas. It was encasing all vessels he received full for an ox. And you can see, based on the bar graph going from A. To B. To C. 99 increased his tumor size increase. As you can see in panel B. Um We thought hard about how to treat this patient, phoned a few friends and ultimately decided to proceed with elected nib. I'm sorry. This patient on NGS sequencing uh was uh which was conducted after full fare knocks, Had a care as wild type p 53 intact tumor with an al Khoury arrangement. And so based on this information, we elected to treat him with electronic radiation. Uh and capeside of being very delicately watched him under a microscope. And so I have seen 99 normalize his tumor shrink. Uh and uh he was able to be respected uh to margin negative reception. And he is back in the operating room um functioning well uh with regard to um uh biologic selection within pancreas cancer. We're hearing more and more about DNA damage repair deficiencies and being able to capitalize on Bracco 1 to 80 m 80 are mutations. This is a study that was also published at Memorial Sloan Kettering a couple of years ago. This was in patients with advanced pancreas cancer stages three and four. I was a Phase one B study looking at Jim City beans. His platinum the Park inhibitor of deliberate patients were not stratified upfront. And you can see that patients who have a germline B. R. C. A mutation had a more than doubling of overall survival with the regimen. Um probably benefiting from the park inhibitor compared to those who didn't. This is our experience combining the same drug genocide of Bean and radiotherapy in patients with Stage three disease. Uh This was a study that we've also published a couple of years ago and you can see here based on transcriptome analysis, looking at RNA transcripts when we stratify based on the proficiency or deficiency of the ability of tumor cells to repair their DNA. You can see that patients who are deficient have a significantly higher uh survival compared to those who do not. As an example, patients who are deficient and nucleotide excision repair had a 10 month improvement in overall survival and those with mismatch repair deficiencies uh Similarly benefited from part inhibition. These data culminated in this seminal paper which was published in the new England Journal just a couple of years ago where patients received maintenance Orla prib after standard of care chemotherapy in the absence of progression. Um and this study was limited to patients who had B. R. C. A. One and two mutations. And what they found was that there was a statistically significant improvement in progression free survival. This was the outcome almost a doubling that led to the approval of Allah prib as as maintenance strategy For patients with BRCA 12 mutations and pancreas cancer. Of note. Uh Only about 5-7% of all patients we see present with Barack 012 mutations uh and pancreatic cancer. So a small wind but a wind nevertheless uh I will not touch too much upon immunotherapy. We have not seen too many successes um in patients with metastatic disease. There have been a few publications looking at C. T. L. A. Foreign inhibition and combination with PD L. One and P ONE inhibitors which have really shown a minimal signal. We conducted a are actually conducting a Phase one expansion study looking at the PD L. One inhibitor, their value mob in combination with high dose radiation in patients with locally advanced pancreas cancer. Uh These are the 1st 18 patients who have been treated. Uh The study is ongoing at Sloan Kettering swindle open here at at T. G. H. But you can see that uh yeah, patients who are receiving the value map and the the high dose radiation are experiencing a dramatically improved survival compared to those who aren't. Uh and I think importantly the vast majority of patients in the study are locally advanced. We're seeing 50% uh down staging and um uh all of these patients have had margin negative reception. So it'll be interesting to see whether this these data pan out in a larger subset. So I will just wrap up here um and give us a few minutes for questions if there are any. Thank you. Yes. Great. Thank you doctor too early. We've got a couple uh going back to radiation therapy. And what scenario would you recommend this? Um Yeah so I think you know there there's probably some nuances to to answering that question. I think with regard to patients who have undergone whipple and have received the appropriate uh event, multi agent chemotherapy, whether it's full fare knocks or otherwise. Uh I think radiation therapy should be considered in patients who at a minimum have microscopic residual disease. Uh And also you might give consideration to patients who have no positivity. I did not present some of that data but there is some robust albeit retrospective data indicating benefit of radiation. So you know, I think probably the least relevant of the three therapies but certainly has a role in respected pancreas cancer and with regard to patients who have locally advanced and borderline respectable um disease. Uh you know, I think you can make the argument that it can be given and probably should be given to all patients again who have received chemotherapy have at a minimum stable disease uh and they should be treated aggressively. I think that's the point that I'm trying to make here is that the failures that we've seen with radiation and this setting have been with low dose and we're starting to see a much better signal with our with the capacity to give higher doses. Excellent. Thank you so much. We have one more question in the queue. So I want to let the audience know if you have any other comments or questions, please use this time to type them in the chat box. This one is for dr cara christos. Uh what can you talk about patient a patient progress during the neo adjuvant therapy? Right? Uh I guess it's the uh patient progression of disease, assume. Uh And yeah, this is this is uh something that we uh considered very very carefully. Um Two things very carefully in places with uh individual therapy. One is progression during the vaginal therapy uh which says about 12% average. And I think this place is that patients that starting chemotherapy and the cancer progress during the individual therapy and the pace is not eligible anymore for reception. And that's that's that could be considered treatment failure. But I don't think it is. I think those patients are exactly the patients that will be found with metastatic disease three months after surgery that, you know the spencer should never have surgery. And this is the place is actually that dropped out um at you because of progression during the chemotherapy. So actually the way we see that is that individual therapy help us select the places that maximally benefit from reception. Uh instead of having a resection, they have an early recurrence, which is hopefully, you know, that this basis should never have surgery. So if I might just add my two cents on top of that, I think, you know, the take home, which I I probably didn't go well enough, which uh you know, Andrea's highlighted is that and you're not going to hear this from a surgeon too often? Is that all patients, whether respectable or not, would likely benefit from the attachment therapy? I think you can make the argument that you're doing your patient of this service. Otherwise I would agree. Hey, that's all we have. So I just wanted to say thank you everyone for joining us and thanks to dr carrot christos and dr too early for your time this evening, Just a reminder. I'll email everyone with directions on how to clean your credits within the next couple of days. So one final thank you from everyone at T. G. H and have a good rest of your night. Published June 21, 2021 Created by