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RIPAL GANDHI: Good evening. My name is Ripal Gandhi. I am one of the interventional cardiologist and interventional oncologists here at the Miami Cancer Institute, a part of Baptist Health. And I want to welcome you to this evening's program. I'm one of the course directors in combination with Dr. Horacio Asbun, who is the chief of hepatobiliary surgery here.

Tonight's session is going to be on new advances in the management of pancreatic cancer. And I think this really serves as well as this month is really Pancreatic Cancer Awareness month. And there's really been a lot of advances that have been made with pancreatic cancer. I'm going to be going through some of these during this next hour and a half.

We're going to start with three of our hepatobiliary surgeons at the Miami Cancer Institute, including Dr. Horacio Asbun, who's the chief of hepatobiliary surgery. We have Dr. Ramon Jimenez, who's the chief of sarcoma surgery, and Dr. Domenech Asbun. And they're going to start with the overview of the different surgical treatment options for pancreatic cancer. And also, that's going to be followed by a discussion. I'm going to go ahead and hand it off to you.

DOMENECH ASBUN: Thank you very much, Dr. Gandhi, for the introduction. I'm Domenech Asbun. I am a hepatobiliary and pancreas surgeon, one of the three partners in this group. And I'm joined, as you can see, by Dr. Ramon Jimenez and Dr. Horacio Asbun. So we want to discuss new advances in pancreatic cancer surgery and where we see them moving forward. We have no disclosures, no relevant disclosures to this presentation.

So three areas which have seen significant developments that have helped us provide better care over the past few decades are listed here. One of them involves some of the topics that Dr. [INAUDIBLE] so nicely explained to us-- neoadjuvant therapy in the treatment of pancreatic cancer, particularly in borderline resectable cancer-- we'll get into that in a second. The idea of centers of excellence that treat pancreatic cancer and the benefits associated with going to one of those centers has also been a major development. And there are a handful of other surgical advances that are also improving patient care.

So borderline resectable, this table that you see here is from the National Comprehensive Cancer Network Guidelines and Recommendations, the NCCN Guidelines. There are a lot of details and nuances to it. But essentially, it has to do with the tumor relationship to very important blood vessels in the area.

Now, as we look at this drawing, it's a little more clear. But essentially, this, as you are all aware, being the pancreas here in the middle. Some of the important blood vessels that are in proximity to where pancreatic cancers grow are circled. And when these are compromised by the tumor, we have to ask ourselves if resection is worthwhile for the patient.

In a surgical resection of pancreatic cancer, the goal is an R0 resection, meaning that no microscopic tumor is left behind. And when the tumor invades these structures, as we can see, sometimes we ask ourselves whether or not offering a surgical resection would benefit the patient. Dr. Ramon Jimenez, would you care to just mention specifically some of these arteries and how we evaluate them on a CAT scan or an MRI?

RAMON JIMENEZ: Yes, thank you, Domenech. So all these vessels, this is a medical illustration here, but when we get our imaging these days, whether it be a CAT scan with IV contrast, or better yet, an MRI, you can see all this anatomy as beautiful as we can see it on this medical illustration. So advances in imaging technology here has really revolutionized the way we evaluate these patients pre-operatively.

In our tumor boards, we spend, I would say, the great majority of the time looking at imaging studies showing this exact anatomy here. And that helps us determine which patients are good surgical candidates and which are not. The vessels of interest here, of course, are-- I don't know if you can see my cursor. I don't think you can-- but obviously, the celiac axis up on top here artery in red. There is a hepatic artery that comes out of there. There is a gastroduodenal artery that you see going south from that area. Those are relevant for patients who are undergoing, say, a Whipple procedure.

The superior mesenteric artery that you see below at maybe 6:00 also very important as tumors can get really close to that vessel. And then in blue is the superior mesenteric vein, and up north at 12:00, the portal vein, which are vessels also that need to be evaluated pre-operatively to determine whether surgery is a good option or not.

But what Domenech mentioned before, it is very important in that many patients who in the past would have never been surgical candidates, today, we can downstage with chemo as we'll talk about in a little bit and then bring them to have a surgical option.

DOMENECH ASBUN: Exactly. And Dr. Asbun, would you mind discussing some of the advantages that we've seen with giving chemotherapy first, neoadjuvant chemotherapy?

HORACIO ASBUN: Thank you. Good evening, everyone. Well, it has been fantastic to see the changes that Dr. [INAUDIBLE] has already explained. And when I say fantastic, it's because if, as Dr. Jimenez, we have been doing this for a while, we for the first time are seeing that pancreatic cancer is no longer a death sentence and that the response to neoadjuvant therapy on some patients is amazing. Like the one that we had recently last week, we had only a six-millimeter residual tumor after neoadjuvant therapy.

Number one, the first direct immediate benefit is that we can give more hope to the patients and that we see people that before would not have been resectable as you mentioned, Domenech, and that now are approachable because of the reduction of the tumor, no question about that.

And the amount of, as you said, increases in terms of chemo completion are significant because we're giving the chemotherapy ahead of the surgery. We have several publications that chemotherapy that is completed before the surgery, it is more advantageous because many of the patients do not follow a full chemotherapy treatment after surgery.

DOMENECH ASBUN: And one of the other important things that we discuss often at tumor boards is, how can we assess the response to neoadjuvant therapy? As we mentioned, different tumors depending on their molecular biology will respond differently to the chemotherapeutic agents we give.

And so some of the things we look at is a biochemical response by measuring the tumor marker CA 19-9. There is a correlation between higher CA 19-9 and a higher likelihood of there being metastatic disease even if it's occult. And we also evaluate the radiographic response. Now, this is something that can be a little difficult to definitively say is useful when we're trying to decide if the cancer has progressed, especially because some of the neoadjuvant therapy that we use, particularly radiotherapy, can sometimes induce a desmoplasia, a fibrotic reaction around the treated area, which can sometimes look like a progression.

But that being said, what we are seeing more and more is that after a surgical resection, what appeared to be a desmoplastic reaction to radiotherapy is actually just a-- I'm sorry-- what seemed to be a progression of the tumor on pre-operative imaging was just a desmoplastic reaction.

And so this gives us hope because whereas before, a certain MRI finding may have been a bad sign for the patient and for the surgeon, now we are realizing that there still may be hope when we take that piece of information in combination with everything else that we're evaluating.

Now, one question that we are still looking to answer more clearly is, what are the effects of neoadjuvant therapy on the surgery itself? And in particular, does that make the surgery more difficult? So would you two care to elaborate on these? I guess I'll ask you first, Dr. Jimenez.

RAMON JIMENEZ: Yes. Horacio, Let me do chemo, and then you do radiation because radiation these days-- [LAUGHS] we'll see. Well, chemo, usually chemo is going to make the surgery easier, in my opinion. So I see smaller tumors, less positive lymph nodes, some patients with complete responses. And many times, when you operate a patient who hasn't had chemo, if there is a proximity to the portal vein, it's hard to separate the tumor from the portal vein and leave a positive margin. And once you have chemo, you improve all these different areas.

For me, chemo can make the surgery more "difficult" in quotation marks in that the patient is coming to surgery with a little bit of a systemic injury. They've been receiving poison, therefore, for a while, and so they are not coming with a totally full tank. So these patients in terms of intraoperative and post-operative management, you need to be really attentive because missing a little detail, a small wound infection or something like that, can be overwhelming for a patient who's coming in already somewhat injured. So the chemo does make the surgery easier, but maybe taking care of the patient will be a little bit more difficult. Now, radiation is a different story, Horacio.

HORACIO ASBUN: Thank you, Ramon. I love you, too. You want me to be the one talking bad about our radiation colleagues, huh. No jokes apart, radiation is more difficult. There is no question. And it is what Domenech was saying. The tissues are fibrous. They are stuck. And it's difficult to know sometimes what's tumor or not.

And I do have to say, Ramon, that even though I agree with you that chemotherapy makes in general the operation easier, sometimes when there has been an extensive reduction of the size of the tumor, there's this fibrosis that you don't see the vessels and where the tumor was. You don't see where the pancreas starts and where the vessel ends.

Radiation replicates that almost in every single case, especially the type of radiation that we're doing today. The audience is going to hear from Dr. Michael Chuong, and the results and the potential are amazing. But that makes an operation more difficult. I was talking to Adeel, one of our other radiation oncologists today on the phone. And I was telling him that they should not be close to the OR when we're doing surgery because we keep cussing at them.

Having said that, we do it with pleasure because we know that the therapies that they are doing are helping the patients as we have seen sometimes complete responses, or as I mentioned, the case of last week where there was only a six-millimeter residual tumor. Everything else had been melt away.

Then having said that, I think it's a matter of us learning. And when I say that is we need to learn what's the best timing to go to surgery after radiation. We have all inherited the "you need to do it between six to eight weeks," but what is the evidence of that? And I think surgeons are so pragmatic, and we inherited some statements.

And we follow it for years until something like this happens and you start asking yourself, why six to eight weeks? Where is the evidence for that? And you go back, and you see that the evidence is not solid, that it was maybe somebody that mentioned it or some old publication like in this case. Then, as you know, Ramon and Domenech, we're trying to learn what is going to be the best timing. And I'm very optimistic based on what we have already seen that we will be able to get to do the surgery at a stage that it is not the one that we're seeing today.

DOMENECH ASBUN: Thank you. Now, on the topic of pancreatic centers of excellence, there are multiple landmark papers that have shown that as a hospital increases its volume in terms of pancreatic resections, the outcomes improve as this table down here at the bottom reviewed a lot of previously published papers. And you can see comparing high-volume centers to low-volume centers, the mortality was significantly different. In the first paper out of New York in the mid-'90s, there was a 2.2% mortality compared to 19% mortality. And this repeats itself.

What, however, we sometimes fail to realize is how much actually goes into creating these pancreatic centers of excellence. Here, Dr. Asbun, I'd like for you to evaluate on that a little bit. What is it that really qualifies a center not only as being high volume but actually a center for excellent care?

HORACIO ASBUN: Yes, and that is a very important point, I think. It's very interesting how across the country everybody says, oh, well, we're a multi-specialty group. Oh, yes, we're a cancer center. But the reality is to create a true pancreatic center of excellence, you do have to have a dedicated team.

As we have done here at the MCI and Baptist, you have to have an anesthesia group that's only the anesthesiologist that you're going to use for HPV. You have to have a group of pathologists that have particular interest. You have to have what I think is extremely important and I will recommend no pancreatic surgeon goes to practice without a rescue team because we all know that despite that we may be extremely good, we will have pancreatic leaks. These are very high complexity procedures.

Then it's no longer that the surgeon is the only one that has to be good. You have to have great interventional radiologists. You have to have a team like hopefully, you all, the audience, are going to be able to have a feeling today of oncologists, radiation oncologists, interventional oncologists, and radiologists that we all interact together and gastroenterologists, of course, and we all discuss the cases together as we do on our board.

And we develop some pathways of care as it is clearly stated on the slide. The communication has to be clear. You cannot just try to think, OK, just write a note on the chart or leave things unturned. And many of these things are not remunerated. Then traditionally, unless you have a group of people that are very committed to create a pancreatic center of excellence, you won't be able to be successful.

And the amazing thing, though, is if there is people that are interested, it becomes almost like a brotherhood or sisterhood that we all are working together and are able to have a feeling that we get our backs. And it becomes, oh, you know what? I have this problem. I'm going to talk with the people on the board. And that is extremely important to have a true multidisciplinary approach, not just one that you write in the paper for advertising.

DOMENECH ASBUN: Couldn't agree more. And within this idea of creating centers of excellence, we have seen marked improvements in perioperative morbidity and mortality. I mentioned just in the comparison of a high-volume versus low-volume center. But overall, for the Whipple procedure, for example, historically, the mortality was as high as over 20%. And now, we expect to have a less than 5% mortality for arguably one of the most complex procedures that anyone can undergo, at least in the abdomen. What are some of the changes that you've seen, Dr. Jimenez, that have contributed to this improvement in morbidity and mortality?

RAMON JIMENEZ: I think there's a manifold, Domenech. I think it begins from choosing the patients right at the tumor board, as we have all mentioned, discussion with all of our colleagues. But picking the right patients for surgery, I think that's super important. Every time you see a surgical series, the first thing that is mentioned is that there's surgical bias here. Of course, I'm not going to operate on poor quality patients. You choose the best patients to have the best results. That's one thing.

But you can't forget about our colleagues in anesthesia. Some of these cases require high attention as they're high maintenance cases. Sometimes the anesthesiologist has to be present for most of the case, not just the CRNA. We have to have support in the ICU when it's necessary for some patients whose surgery was more difficult or they had complications or longer surgeries.

I will tell you that one of the things that Baptist offers to us is we don't really have any budget on this surgery. So any equipment that we need that is going to make the patients do better, Baptist is there for us. And as we know now with the minimally invasive procedures, there's always a new toy out there, and they're not cheap. And we need them.

And that's never been a holdup for us in terms of having all the laparoscopy tools that we need, robotic surgery tools that we need, and when we do an open case also, whatever tools we need. So I always appreciate our working environment here and the type of resources that we have that I know are not available everywhere.

DOMENECH ASBUN: And that's a good segue into the next point. All three of us are minimally invasive surgeons, and as long as it's safe and feasible, we like to use minimally invasive approaches for pancreatic resections. Dr. Jimenez, it's clear that some of these benefits include shorter length of stay, quicker return to work.

There are multiple studies that show that patients that get minimally invasive approaches may have a shorter time to return to their chemotherapeutic regimens. If patients have not had neoadjuvant therapy or not a complete course of neoadjuvant therapy, then it's important for them to start therapy after surgery as soon as possible. And there are other important factors, such as less post-operative pain. From the surgeon's standpoint, Dr. Jimenez, what are some of the advantages, for example, of robotic approach to these procedures?

RAMON JIMENEZ: I think I will tell you one thing that I know Horacio shares with me is that the visualization, the imaging that you get from a 3D laparoscopic camera or a robotic-- the standard robotic camera is also 3D. But the type of closeup and the detail that you see with the camera is unmatched.

I mean, you can have surgical magnifying glasses that we call loops. With the highest magnification, you're not going to have that type of detail that you get with the laparoscopic and the robotic cameras. I think that for me is one of the biggest advantages of the minimally invasive procedures. We end up seeing better than you will see in the open case. That's super important.

But I'll tell you that a lot of the tools that we use today even for the open cases were actually developed for the minimally invasive cases. So with the open cases, we benefit from-- it went backwards in a way. But I think this stuff is, patients request it. It's important. And as long as we do as good of a job as we do in the standard case, it's outstanding, superb.

DOMENECH ASBUN: And as a good example of that, of how we can in a way almost work backwards, doing a minimally invasive surgery lets us see things and see areas that are much harder to see in an open procedure. Now, this here is a diagram of the pancreas and its relation to the colon and the spleen. It's just tucked up, as we all know, under the left side of your ribs. And it can be a difficult area to access surgically.

Dr. Asbun, I'd like for you to elaborate on the clockwise technique. It's a procedure that you developed. It's a specific technique for accessing the distal pancreas, this left side of the pancreas near where the number two is essentially. And how has the development of this technique and its implementation contributed to the idea that a minimally invasive approach can lead to a better surgery?

HORACIO ASBUN: I'm going to thank you, Domenech, for putting this up. This actually illustrates very nicely what Ramon has said because the minimally invasive approach allows you for the magnification but also allows you for having better access to areas where open surgery, yeah, you can do it, but it is much more difficult access. And you just mentioned it very nicely.

This is all under the ribs. Then normally, we need to put retractors. And it's not just a matter of the size of the incision, particularly when you're doing a big and complex case, right? I mean, in gallbladders, adrenals, then the size of the incision, it's very important. But if you're going to do a really complex case, we're not doing it just to be cute and have a small incision.

We're doing it because we truly believe that the minimally invasive approach is going to give us advantage over the open approach. And that's the case on this distal and subtotal pancreatectomies. And this is not just an appreciation. Now it's pretty clear with a variety of prospective randomized studies and retrospective studies.

Then if you go back a little bit to the prior view, if you can see the spleen, then what we do is we use the advantages also of gravity. When you're doing open surgery, you can use gravity but in a very limited fashion. When you're doing laparoscopic surgery, you insufflate the belly, and you have a closed box. Then you can really rotate the patient and use gravity as your assistant.

On this case, we put the patient on his right side in a lateral position. And then when you start mobilizing the colon, the colon drops to the right. And it carries along, especially in obese people, all the adipose tissue, all the fat. We do the same thing with the stomach. And then you have a very nice access to the area of the tail of the pancreas and the spleen just because we have used gravity to this. And that allows you to do a much better surgery.

DOMENECH ASBUN: And this just highlights that. This is a review of more than 360 patients that had a distal pancreatectomy using that technique. And just to emphasize, one of the important things we look at during these procedures is the rate of a pancreatic fistula, which is where you get a continuous leakage of pancreatic enzymes from the cut end of the duct.

And in this series, again, many patients across more than 10 years, the leak rate was only 7%. And that's markedly lower than the majority of other published series. And so again, it just goes to show that these advances in surgery and pancreatic surgery are really helping us provide better care to patients.

Some other things that are still being developed, that are still up and coming and some of which have been around and some of which are still newer are listed here. One of these, for example, is fluorescent imaging. Dr. Asbun, do you want to elaborate that a little bit?

HORACIO ASBUN: Yeah, this is basically on the developmental stages. As you showed on the prior case, when we were starting doing the clockwise technique, we never thought that one day we were going to be publishing 365 patients with such great results. Then, we don't know if we're going to be able to do the same thing with these new things we're doing, but so far, very encouraging.

We're using fluorescence imaging to try to be able to delineate the tissues better and to assess the flow to those tissues. In some cases, this has been remarkable and have allowed us to very clearly differentiate the areas of the pancreas that we want to expose. And at the same time, we are separating what we call the uncinate process for those that remember that it's attached to those vessels that Domenech showed in the very beginning.

We are able to depending on the timing be able to very clearly delineate the vessels. And as you know, the surgeons know, the separation of that part of the pancreas from the vessels, it's probably one of the parts of the procedure that's the most complex. Therefore, having something that allows you to visualize and identify better what's vessel and what's not has been very useful.

Having said that, we're still in the process of learning what the utility is because we have seen that in some cases, it doesn't help us a lot at all. And that is usually in cases that there has been chronic pancreatitis or sometimes too much fibrosis because of the chemotherapy.

But again, this is on the developmental stage. And the beauty of this is this does not affect the patient negatively in any way. As far as we know, there's nothing that we have seen as a side effect. This is a very clear technique that has been used in a variety of other procedures like on common bile duct stones or biliary identification. And we're just extending it to this.

I think, again, as we learn more about the timing and the dosage, we will be able to assess better how far this approach is going to go. I don't know if we should ask Dr. Jimenez to talk about intraoperative ultrasound. And Domenech, I would encourage you to talk about enhanced recovery.

RAMON JIMENEZ: I'll be quick, Domenech. The ultrasound is an old tool, but it's super useful when it comes to all of hepatobiliary surgery. And a lot of us in surgery obviously are not radiologists so we learn how to use these tools literally by doing the cases. But you become facile with ultrasound intraoperatively, and it definitely helps you to plan for the surgery, improve your margins, even determine the order in which you get things done during the operation. And so the ultrasound, even though it's older definitely than, say, the fluorescent imaging, it still has a big role, I think, for a lot of our cases.

DOMENECH ASBUN: Definitely. Enhanced recovery after surgery, it's sort of a general term for many advances that are bundled together. There is data from the early 1990s that showed that a lot of the things that we used to do as surgeons were not based on hard evidence but just on tradition in a way, our surgical dictum, as Dr. Asbun mentioned earlier.

And so there were a lot of changes, for example, to when you start feeding someone after surgery that were attempted and found to be beneficial to the patient, especially when used in conjunction with other similar changes-- limiting how much narcotics a patient might get after surgery, early ambulation after surgery, et cetera. And so they seem like simple things, but it's remarkable how many different aspects of a patient's post-operative recovery are improved when these things are all used in conjunction.

Now again, this highlights the importance of being at a center of excellence for cancer care because we have available to us the resources, the protocols that we need to make sure that all our patients are getting this type of recovery. And these enhanced recovery protocols actually begin even before the surgery with certain amounts of patient education. It has to do with how things are given during the surgery as well. And so all in all, this has been a huge change in all fields of surgery. But especially in pancreatic cancer care, we really have seen the benefit. So that ends our discussion. Thank you all very much for being present.

RIPAL GANDHI: Thank you very much, a really, really nice overview on all the advancements in pancreatic cancer surgery. I have to tell you. The first time I saw a patient after a minimally invasive pancreatic Whipple surgery, I was impressed. The patient had just a few little incisions, and I honestly didn't even know that that could be done in today, in the modern day. So it's really, I think, a tribute to some of these techniques and to our surgeons here.

It's my pleasure to move on to the next speaker, Dr. Michael Chuong. He's the medical director of radiation oncology here at the Miami Cancer Institute. And he has a lot of expertise and experience in treating gastrointestinal malignancies, including pancreatic cancer. So I will go ahead and hand it off to him.

MICHAEL CHUONG: Hello, everyone. It's really a pleasure to be here with you today. I'm Michael Chuong. I'm a radiation oncologist with a focus on treatment of gastrointestinal cancers here at Miami Cancer Institute. And really, the goal over the next 10 or 15 minutes or so will be to share with you some of the exciting data that has come out of several institutions, including ours, around ablative radiation therapy using an MRI-guided radiation therapy delivery technology and technique that is really revolutionizing how radiation therapy is delivered fundamentally, especially for very challenging tumors like pancreas cancers.

Here are my disclosures. Really, the only relevant one is my relationship with ViewRay around research and as well as my participation on their advisory board. So to give an example of really the application of MRI-guided radiotherapy and dose escalation using that platform, let's go through a typical case that we might see in our clinic.

So this is an 80-year-old gentleman who was referred to the radiation oncology department here with an unresectable locally advanced tumor in the pancreas. And you can see quite extensive vascular involvement here of the SMA and celiac axis. So this patient initially received FOLFIRINOX, had local progression only, and then was referred for radiation therapy.

And as is typical in really any modern radiation therapy center, a simulation CT scan is performed, which gives us the anatomy to develop a treatment plan. And you can see here that there's normal organs that are defined as well as the target, which is the gross disease. And then there was a treatment plan that was generated, a very highly conformal, highly-targeted treatment just to the areas at risk.

And when the patient comes for treatment, there are ways to generate CT scans on the treatment machine, something called the Cone Beam CT. And you can see here that there is soft tissue definition here, but the image quality really is not the same as a diagnostic scan and certainly not as good as the stimulation CT scan used for planning. And this is really the state of the art at most centers and really is a standard of care for image guidance.

Now, we've imaged the patient beforehand. We've made positioning changes in how they were set up on the machine. And now we go to image during treatment to ensure that has been maintained. But that, in fact, does not exist with current Linacs or current radiation delivery machines.

In fact, this is actually sort of what we see in a way in that this is the treatment platform, or the treatment console, rather, and we can see the patient lying on the machine and the machine moving around the patient. But actually, the internal anatomy is not visualized with standard CT-guided radiation therapy. And when the patient comes for, again, the first day of treatment, that original treatment plan is delivered. And when the second day of treatment is delivered, the same thing is delivered and so on and so forth every single day.

But we, of course, know that the anatomy each day will not remain the same. And there will be some small but potentially large variations in the anatomy. And this is really not able to be accounted for in a short period of time on a day-to-day basis. And therefore, it's really, the same treatment is delivered each day regardless.

Now of course, not being able to visualize inside the body during treatment is certainly not ideal. And this is obviously a bit tongue in cheek, but effectively, the limitations and what I described to you in terms of imaging or not being able to image during treatment and some limitations with the quality of soft tissue imaging with Cone Beam CT has led to non-ablative radiation dose being a standard of care for a long period of time. And again, even today, non-ablative radiation therapy is a standard of care at nearly all centers.

To give it a sense of the outcomes from this approach, after chemotherapy with non-ablative radiation, whether it's with standard fractionation treatment from the LAP07 randomized trial or with lower dose SBRT-- so somewhere in the 33 or 30 gray range in five fractions-- we can see that two-year survival really is quite poor, around 20% or so.

Now, there has been emerging data, and for example, this one study from M.D. Anderson published in 2016, that suggests that perhaps in highly selected patients where a higher dose could be safely delivered because, again, the anatomy here is very important to consider given that the stomach and the intestine sit if not abut the tumor, and these organs at risk really are not very tolerant of high doses of radiation.

But nonetheless, higher doses of radiation for some patients seems to potentially improve not just control, but also, excitingly overall, survival. And in this study, a biologically effective dose of over 70 Gray was associated with an approximate doubling in two-year survival. So of course, very exciting, but clearly, more data needs to be generated to support this as a relevant strategy for a broad population of patients.

Now, obstacles to delivering ablative radiation dose are those you can see listed here. Soft tissue resolution, of course, as I mentioned before is limited with CT. There is respiratory motion of these tumors that need to be accounted for. Imaging during treatment, again, is not possible.

There are some uncertainty margins that are inherently used, and this can overlap the bowel and the stomach. And that can limit how much radiation dose we can give. And there's also, again, an inability to account for changes in the stomach and bowel position prior to each treatment.

Now, MRI-guided radiation therapy really overcomes all of these obstacles and directly addresses all of these challenges. And we are proud to feature the MRIdian Linac, which is the second clinically operational MRI Linac in the United States beginning in 2018. And this is one of many state-of-the-art radiation therapy platforms that we offer patients here.

And really, this is very unique. And we are not aware of another center actually in the world that offers the complement of state-of-the-art radiation therapy machines that we do here. And this really allows us the opportunity to personalize the radiation therapy options for each particular patient, whether it's a pancreas cancer patient or a breast cancer patient or a brain cancer patient. And for pancreas cancer patients, the MRIdian Linac has become clearly our treatment of choice, and I will show you why.

So inherently, MRI scans provide superior soft tissue resolution compared to CT. And these are images from patients treated here at our center. And you can clearly see that scans obtained with CT scans, really, you cannot nearly as well define the internal anatomy as MRI.

And I will play this video here. You'll see another really important capability of an MRI Linac is that there is continuous imaging with an MRI scan throughout the treatment. So remember, with standard radiation machines using CT scans, this is not possible even just to get one static image.

So this is, with MRI, a real-time what's called a cine MRI that's obtained throughout treatment. And what you see here is an example of how when-- this is a sagittal view here, tracking the pancreas. So you can see that this is actually a capability in which soft tissue can be automatically tracked by the system.

And what you're seeing here is that there is a boundary or a margin around where that tumor sits in one position. And so when that tumor moves because of respiration and it moves out of that boundary, the machine recognizes this as having moved, and the machine automatically will turn off as a safety feature. And also, we don't want to obviously treat the intestines when the tumor has moved.

And this is something that is automatically, again, recognized by the treatment machine. And when the tumor comes back into the right position, the treatment will automatically turn back on. So this is an automated process, which is very unique. This also allows us to treat a much smaller volume of tissue because we can now have the certainty that we know where the tumor is at any given time.

So again, with the typical paradigm of treatment delivery, remember, we typically will give the same treatment each day regardless of the changes in the internal anatomy. With an MRI Linac, we're able to now repeat that whole process each day. So there is a simulation each day. Essentially, there's new images. The organs at risk and the tumor is redefined each day on an MRI Linac.

There is a new plan that can be generated. There's the independent QA process and then delivery of a brand new treatment plan each single day that can account for these changes in a short period of time and on a daily basis. And this really allows for a personalized radiation therapy treatment and really the most accurate treatment.

And you can see here, across five days of treatment, for example, there can be significant changes, and we can address that prior to each treatment within a few minutes. And this is really unique and a significant tool to allowing us to achieve significant dose escalation to patients with these types of challenging tumors.

Also, very beneficial for the patient is that this is done as an outpatient. Really, in total each day, accounting for all of the assessment and replanning of treatment and delivery, it takes about 45 to 60 minutes per day. Most treatments are delivered in five days but can be done in less than that. This is entirely noninvasive. There is no anesthesia or even an IV for IV contrast.

And there is really no patient downtime. So patients typically will be able to work or carry out their normal activities. And this is really ideal for patients traveling from a great distance for treatment. And we do have a significant population of patients who will travel across the country or even internationally for this type of high-dose, unique, short course radiation therapy.

Now, this is all great that we can do these things, but does it actually matter? And so the data that are emerging suggest that, in fact, this matters quite a bit. This is a retrospective study from several institutions using the technique I just described to you, something called adaptive MRI-guided radiation therapy for inoperable pancreas cancer.

And long story short is they also looked at outcomes based on the dose delivered with a higher dose being achieved using these very sophisticated MRI adaptive type of techniques where the treatment is modified each day and the monitoring is done during treatment. And similar to the M.D. Anderson study that I showed you before, there was a statistically significant improvement for the higher dose patients with two-year survival being about 50% versus 30% in a standard dose group.

Also exciting was that despite the higher doses that were delivered, there, in fact, were no grade 3 toxicities are higher in the higher dose arm. And in fact, in the lower dose cohort, there was some toxicity, and that perhaps is because those patients were not offered or not delivered treatment with the adaptive component, the replanning each day component because it was at that time felt not to be needed because it was a lower dose of radiation. So perhaps, the adaptive component matters.

Now, we were really the first institution to publish outcomes of inoperable pancreas cancer patients treated with a dose-escalated ablative regimen in five days on an MRI Linac. And this was published in 2020 in a fairly small number of patients, 35. But the early outcomes here showed that there was really no significant toxicity associated with this, and the early outcomes were very encouraging.

And I know the text is small, but really, the exciting longer term follow-up results of that I want to focus on here-- and these were data presented at ESTRO earlier this year in Madrid-- and this was a 50 consecutive patient series treated at our institution. I won't read through the demographics here, but you'll see that the majority of patients had locally advanced disease, had good performance status, had a very high prescribed dose-- so this is 50 Gray in 5 fractions for a biologically effective dose of 100 Gray. And for those of you who are not radiation oncologists, this is upwards of twice the prescribed dose that is typically given with various fractionation schedules on a standard Linac.

The median follow-up was 18 months from diagnosis, and we were very excited to see the outcomes. So local regional control was a median of 32 months and at two years was almost 75%. Overall survival was a median of 21 months, which of course, we were thrilled to see with the historical outcomes being somewhere in the 12 to maybe 14-month range with standard radiation doses.

But also exciting was that we were seeing a hint that, in fact, the two-year survival mark, in fact, was significantly better at least than compared to historical control of 20%. And we saw in our series an estimated two-year survival of 50%. And also, very exciting to us was that the grade 3 toxicity rate was very low, so acute 2% and late 10%. And there was no grade 4 or 5 toxicity. So very well-tolerated and the efficacy outcomes with longer follow-up seem to be very good.

Now, why does this matter? And why might we be seeing these outcomes? And in fact, it turns out that patients with pancreas cancer die of metastatic disease, of course. But even those who have distant metastases can have significant morbidity and also mortality from local progression.

And this is a really pretty well-known study from the Johns Hopkins group of a rapid autopsy analysis of 76 patients documenting that about one-third of patients will die of local progression or consequences of local progression despite the presence of metastases. So perhaps if we're able to achieve better long-term local control, this may meaningfully impact long-term survival.

So this was actually an email from a patient's daughter of mine who received this ablative MRI-guided radiation therapy. And it really is rewarding to see that this type of novel treatment directly impacts patients. And she wrote to me and said that mom has been doing better than ever. Her pain is greatly improved. She's eating better and feeling well.

They just went to Hawaii where they hiked Diamond Head Crater and did all these other fun things. Six months ago, we didn't believe that these things would be possible. And now we believe that anything is possible. And it's just incredible how much better she's been doing after the radiation therapy.

So she really had a tremendous response to treatment and had a meaningful, I think, long-term tumor control outcome. And she had really a great outcome. And this is not representative of just a small percent of patients but really very common to see in patients in follow-up who've received this treatment.

There are prospective trials ongoing looking at this very exciting and novel type of treatment. There's something called the SMART trial, which is an international trial looking at this five-treatment regimen using an ablative dose. And I was fortunate enough to be invited to be a part of the national PI group for that. So this trial will be closing to accrual hopefully by the end of the year, and we should have results of that early next year.

So in conclusion, MRI guidance represents a paradigm shift in radiation therapy. Ablative dose can be delivered for pancreas cancers as well as others in challenging anatomic locations. And there really are very unique applications of this for other cancers that I don't have the time to go over today but really exciting that we can benefit a broad group of patients, including pancreas and other cancer patients.

There is increasing evidence that this is critical for inoperable patients, can potentially prolong survival. And again, the SMART trial is the first prospective evaluation of this approach for inoperable patients. And we'll, again, complete accrual likely later this year. With that, I want to thank you for your attention.