Experts in surgery, medical oncology, and radiation oncology describe the benefits of a multimodal approach and identify novel treatment paradigms for colorectal cancer. Watch lectures, a case-based study, and Q&A with Simmons Cancer Center physicians.
my screen. Alrighty let me start beating. Um So thank you everyone for joining us. Um This evening for our one our women are titled updates and multidisciplinary treatment of colorectal cancer. My name is Nina Sanford. Um I will be first going through the agenda briefly and then introducing our fantastic panel of speakers before handing it over to our first speaker. Um wanted to let everyone know that if you have questions please put them in the chat box. We will be checking them periodically and either addressing them during the talk or at the end depending on what makes the most sense. So let me all right so we have a gym packed one our agenda as I said, I'll first go over um who the speakers are. Um then we will have three short lectures followed by a case based discussion of two different patients in A. Q. And A. Um So we'll start with our surgery talk and then our medical oncology talk talk by me, radiation oncology and then uh discussion Q. And A. We have a awesome of five speakers going first will be Dr Javier Salgado pogatchnik. He is an assistant professor and section chief of co inter actual surgery. As also program director of the Colorectal Surgery fellowship. Um Next we will have dr Syed ali cause me he is an insistent professor of medical oncology um and also co lead of the gastrointestinal disease oriented team. Um Then we have case based discussion by dr georgios Karagounis and Dr Fadwa lee both assistant professors in the department of surgery. Um And sorry before that I'm going to be talking about radiation therapy and clinical trials. So without further ado um I will let dr Salgado go ahead and share his screen to get started with our first talk. And again, please please please put question in the chat. We want this to be as interactive as possible, even though it's it's a virtual meeting. Okay, thank you stanford. Um let me show you my screen if I find it just worked now, it's not working one second, apologize. We just tested and I was working. So okay, do you want me to maybe keep trying otherwise I can share. Go back to sharing. Okay, here we go. Okay. I applied I do apologize about that. Thanks everyone for joining and everyone's busy. So we'll try to be extremely pragmatic and and delivery very precise message in terms of how we approach and treat rectal cancer um in uh in this new era of power medicine. So, uh the objectives of my short talk is to talk about a bit of the evolution of the concepts where we are compared to where we were years ago and the best way to approach this type of disease, which is without any doubts. A more disciplined approach. I did avoid using surgical expertise in my objectives because I do believe it's expertise of all the team members, not only the surgeons, which is important in the treatment of rectal cancer. So obviously we do know that rectal cancer is it's a big problem in our society. Um, the incidence is, is well established. We're seeing a bit of a change in the incidents uh age of presentation of these cancers unfortunately with a bit more new early onset presentations. But the truth of the matter is that um, it is a important problem that requires a an important solution or strong solution to approach this in a multiple discipline fashion. So the it's not only the the incidents and the prevalence of of colorectal cancer in our society has continue to grow, but it creates a huge economic burden into our society. For approximately cost is 4.1 million. That's that's the medical cost of course the concept care we know from extrapolating data from, from other programs that patients with no pleasure in this, in this, in this, in this opportunity, colorectal cancer. Probably a second group of patients that utilize more the health care only after IBD patients. So it's important not only that we know how to treat it, but it's also important that we become efficient between character cancer I did to the uh significant um medical costs that implies. And and for that reason that this has been evolution of this concept and it's important that we see what we were, you know, many, many years ago where surgery was the The only approach for rectal cancer and slowly over the years incorporating other specialties such as real therapy in the mid 90s, uh chemotherapy and and slowly shifting from experience based treatment to an evidence based medicine. Uh And that is, it's truly the message that we want to deliver during this presentation. Um talking about Circle X experts, I have to talk a bit about the history of um you know, the people who had truly impact impacted the circle care of these patients. And starting with Paul Krajewski were in the 1930s, he made very um popular the reception of the sacrament Kocsis and actually gave is sacred colostomy um followed by Sir Ernest Miles. We all know Miles procedure Um in the 1970s with huge mortality, 50 very significant local recurrence. Talking about surgeons who were elite in what they did at that point. And and and in the 19 fifties, approximately, uh Clinic Dr Jackson described the low interest section and I haven't seen anastomosis with improved survivals five years. So we're talking about um experts in their fields um with not too great outcomes. And that's why it's important to understand what the more disciplined approach and that includes people who impacted on how we treat this disease. And this is dr Phil quirk pathologist from ST Mark's Hospital in London, uh he um identified there was a huge variability between surgeons Um outcomes between surgeons correct for the 40% in in terms of mortality and local recurrence and this had to be due to inadequate circle receptions and someone who worked with him as was dr bill healed the surgeon also from Marx who worked very closely with dr Phil quirk and described what we all know now as as the abc of fertile cancer, which is the total mystery relaxation And published in the 1990s. That with what we called the TME accession um local recurrence rates did decrease to below 5%. And and and this is what we now know as the concept of the T. V. Surgeon. So the skills are based not only of the surgeon but also upon knowledge of anatomy and biological behavior of of the so again, it's it's I don't think there's circle expertise. It's it's the most important thing on how we treat rectal cancer patients. I do believe it's a multidisciplinary fashion working with um all colleagues from other subspecialties what we were and where we are right now, we can see that, you know, overall we're we have improved, we have a lot of work yet, but we have improved and we know that the survival has has increased overall survival. We also know that the local recurrence rate has decreased. And we also know that the percentage of permanent colostomy has diminished. So we we are becoming better between rectal cancer doesn't doesn't mean that we are perfect yet. We we have a long road ahead of us uh and work to do and and truly that's how we approach the patients. It has to be, there's no other way but doing it a multi disciplined approach. This concept is extrapolated from their informative bowel disease patients. And it's what it was. What they find in that sub specialty as a as a medical home is where the patient truly is the center of the universe and everything is around the patient. And it showed a couple of things. Number one the expense in health care decrease. Number two The outcomes improved uh and number three the satisfaction of the patients also improved. And this has to do and it's actually difficult to achieve but it's absolutely doable where we coordinate all the care of the patients um and allowing the patient to focus on what they should, you know, very difficult times of their lives. When we approach this, it does not mean that all the cancer patient has to be done at a single institution. A lot of our cancer patients are from different um geographic locations far away. So it means that you can coordinate all this curve with local colleagues but also with colleagues from other places. It's a lot of communication, a lot of work but it is in its best interest of the patient care um and to follow that american culture of surgeons developed what is defined as a national accreditation program for cancer. This is the N. A. P. R. C. And we were extremely happy to announce that you test of Western has become um has has become activated as of two days ago. And dr medical director for the medical Director of that. So we're very happy uh and it's truly the summary of how we want to do this is basically approaching these type of cancers from all different perspectives, working with all the different teams communicating well and allowing the patient to have overall better outcomes. So we're extremely happy to to be part of this journey with the patients. And we're always very happy to work with colleagues from other institutions in a in the same approach. And with that I think that um it's important for us and appropriate to a process. As as I mentioned, it's important to understand how we work at these patients, the patient selection for each different treatment better and knowledge obviously of this physio pathogenesis of disease and the medical surgical treatment options that we have in our armamentarium. So I would like to truly thank everyone for their attention and I'm happy to discuss any questions. Great, I don't see any questions in the chat again. I'm going to encourage folks to type in anything that comes up as the talks go on. Um otherwise we will turn it over to dr cause me if you want to stop sharing your screen dr salgado and then we can switch to dr cause me sharing his screen. You should have the screen dr it still says you cannot hear while somebody, yep, thank you. Can you guys see the presentation, yep. Make it a slide show. Okay so the basic, thank you very much. You know dr for doctor Sanford for kind introduction. The topic that I'm going to discuss today is the role of chemotherapy and localized rectal cancer. Whenever I approach a patient in regards to chemotherapy for rectal cancer, I sort of in my mind create three buckets. So what is is this an early stage cancer meaning cancer localized within the confines of the rectum not spread to lymph nodes, no high risk features and in that situation there is no role for chemotherapy. I think that's also important for us to know when not to use chemotherapy patients. Um The second you know, basket will be locally advanced disease where the cancer is still within the confines of a pelvis. Maybe it has spread to the lymph nodes or to the surrounding organs. And then in that situation, you know, as dr mentioned we work together as a multidisciplinary approach to give a person the maximum chance of achieving a cure from this disease. And that approach may incorporate um upfront use of chemotherapy and radiation treatment upfront. Use of chemotherapy alone after that and followed by surgery and in patients who do not receive up front chemo part they can get chemotherapy after surgery or we use the word um for metastatic disease patients also, especially patients who may have respectable metastases there is you know we start off with chemotherapy and then work as a multidisciplinary team to optimists when to give radiation when to do reception. So that's also a significant multidisciplinary approach that we take for these patients. The main purpose of this talk will be focused towards locally advanced disease. This is historically what we have been doing in us for the last several decades. So we whenever a person diagnosed with locally advanced rectal cancer historically in us we have been giving them a combination of chemotherapy and radiation treatment here. I say radiation plus minus chemo because there are two types of radiation that dr Sanford is going to talk about short course and long course with the long course radiation is where the benefit of adding floor of limiting based chemotherapy has been proven based on german study this in community. Usually the chemo radiation therapy after six weeks to eight weeks followed by surgery where total misery relaxation is performed. And then in patients um technically all patients who received chemo radiation should also follow with adjuvant chemotherapy for four months. The main issue that people recognize with this approach is that after surgery sometimes the recovery can take long or if suppose there's a you know complication potentially that can occur after surgery, then delays in starting agent chemotherapy and some patients did not even begin chemotherapy. So for that reason a concept of total new regiment therapy has been um slowly and gradually taking root and not just an academic center but now also in community practice as well. But his total new regiment chemotherapy so totally new, totally urgent chemotherapy may consist of two forms. 1 is radiation but you know chemotherapy it could be a short course radiation, it could be a long course chemo radiation followed by up front 3-4 months of new urgent chemotherapy and surgery as a last step. And in some patients who are really lucky they may undergo active surveillance and select patients and Dr Fahd wali and she's going to talk about that. Another form of that will be starting with an upfront New regiment chemotherapy for 3-4 months followed by radiation pressure. It could be a short course radiation. It could be a long course chemo radiation followed by surgery or active surveillance. I will focus the next few slides on total new regimen treatment and share with you some of the recent data and see and try to help you a certain which approach may be preferred in different situations. So this was recently presented in um s scope. So I presenting that slide here. So the first study that I'm talking about is called a rapido trial. This is basically comparing short course radiation treatment followed by chemotherapy before surgery versus a long course chemo radiation therapy followed by surgery followed by optional urgently And they included patients with high risk features more than one high risk features such as T4 disease and to disease vascular invasion, lymph node positive disease. And they found that the short course radiation followed by chemotherapy as a TNT approach followed by surgery as a last step had higher local disease control with 28 pathological complete remission. And also showed lower disease related treatment failure in the intervention arm. The next study, which is a german study and they recently presented their long term outcomes. And basically in this study they were looking at chemo radiation therapy plus induction or consolidation chemotherapy as a total new regiment approach. In locally advanced cancer and surgery as a last step Again, patient had to have advanced disease 2, 3, 4 and plus. And they also showed that in the intervention of which was chemo radiation first followed by chemo and followed by surgery. There was more there was better, Significcle better disease control, 25% pathological cr and you know, without compromising any disease free survival, overall survival. And a very interesting trial that has come along recently is the Opera study. It's unique because it is looking at watch and wait and organ preservation. It basically compares, you know, rectal adenocarcinoma patients with the TNT approach. You get chemotherapy first followed by long course chemo radiation and in responders or near complete remission or a complete clinical response watch and wait versus surgery. You know, versus start with keyboard radiation followed by chemotherapy. And then the same watch and wait in here complete responders versus team. And they found that organ preservation was as I was statistically significantly higher and people who started with the chemo radiation first followed by chemotherapy without compromising the long term survival outcomes. Prude. Each study also is a very interesting study study study looked at more intensified chemotherapy. So fall Philly knocks as in the first three months of treatment followed by chemo radiation followed by surgery Followed by 6 3 more months of Fall Fox. And they found that pathological cr it was 28%, so better disease control in the intervention arm. And again even disease free survival Was significantly better, 76% vs 70%. And then the stellar study looked at short course radiation followed by chemotherapy followed by T. M. And then some more chemo versus a more standard approach that you currently is in us. And again showed that early radiation led to better pathological complete remission, meaning better local control without compromising disease free survivals. Um everybody has heard about this recent study that was published and any GM. And also presented in esco we're pd one blockade in mismatch repair deficient, locally advanced rectal cancer. But right now we know that we know that mismatch repair deficient cancers are highly responsive To immune checkpoint innovator. Now we have the data from stage four disease. Um There is also some new energy and data that has been presented in conferences from MD Anderson as well. This study was unique because it was looking at trying to see if he can um you know, follow these patients and especially with the complete clinical responders without surgery and without radiation treatment and without chemotherapy. So it was unique in that sense. And early results have been very encouraging, you know, focus on early results because and this study had To enroll 30 patients total right now. They're presenting patients only with the 1st 14 And in the 1st 14 patients, you know, mindful that some of only a few patients had long term follow ups. Most patients had less than six month follow up. almost 100% of patients had complete clinical response defined by endoscopic best response and the rectal MRI scan best response. So these results are highly encouraging and maybe in the future going to be practicing and some people might even argue that they are now practicing even right now. But I think we have to wait for more data. Long term follow up and then also enrolled patients on other newer immunotherapy based trials to get better sense whether you know, practice should change now versus you know, you have later. So in conclusion TNT approach can improve early provision of chemotherapy and be laying distant metastases hence overall improving survival outcomes. TNT approach can also allow for watch and wait approach in complete clinical responders and then in MSC high rectal cancer anti PD one based upfront approach has potential to eliminate the need for chemo radiation and surgery. Um So I'll be happy to answer any questions at the end of the meeting, but let me stop sharing my slides. Thank you. Great. Um I don't see any question in the chat, but I wanted to ask you a couple of questions about um the PD one inhibitors for M. S. I. High rectal cancer because I feel like that is definitely received a lot of news coverage and is what everyone is talking about. So I guess um you know, we talked a little bit about this offline, but how would you recommend treating a patient who comes into your clinic tomorrow um with a locally advanced M. S. I. High rectal cancer. Um And then the second part is, what do you think should be the next step in in studying that patient population? Um In addition to completing enrollment on that trial, other studies could be ongoing or other study designs. Would you recommend for those patients? Sure. I think that's a very good question. So, the patient who may come tomorrow in my clinic, I think it will have need to have a serious conversation, you know, for it's a small group of patients. We have to be mindful. It's only in my opinion, 3-5% of patients with rectal cancer that may have M. S. I. High disease. So we have to be mindful that a small group of patients that may benefit from it. Um I think it will have to have a conversation because the data is very early, it's not long term follow up. So whether the complete clinical responses are going to be sustained long term that's unknown. Um and whether we can avoid completely radiation treatment. Um So I think it has to be a conversation with a patient before making that conclusion secondly. Um the you know, currently there are two main types of immunotherapy available in EMC two. So one is anti Pd one agent alone and the second one is diabetes, one agent combined with um anti CTL F four treatment. So and you know if you go by uh and the volume of combination and there are clinical trials being done in new regiment setting with that. But you know with that sort of a combination, especially in M. S. I. High metastatic disease. The combination immune checkpoint may have better outcomes. So maybe they might have even better outcomes long term sustained outcomes in that population. So, participation in clinical trials with dual agent checkpoint Is you know, one logical next step that I envisioned for this disease. Great. Uh Thank you very much. So I will go ahead and start showing my screen. Okay so I uh here we go. So I will be talking about radiation therapy in rectal cancer and also discussing a couple of the clinical trials that we have ongoing southwestern. So I like to start kind of explaining how high expectations how colon and rectal cancer are different. So we we often refer to one entity of colorectal cancer um Since they are similar biologically, although there actually are some differences but overall similar biologically and and um come from sort of the same m biologic origin um but different anatomically in that the colon is more in the belly. Um That's easier to access from a surgical perspective, whereas a rectum sits in the very narrow pelvis which especially in male patients, can be quite narrow. Um And that leads to a higher rate of local occurrence with surgery alone, although as dr salgado mentioned, the surgical techniques have improved um dramatically over the past several decades. Um But still there is a greater need for radiation therapy in rectal cancer for which it's standard versus colon cancer. That's why I'll mostly be talking about rectal cancer. Um However, not all parts of the rectum are equal. So we divide the rectum into upper middle and lower. Um And we know that as we go deeper into the pelvis or more distantly, um the risk of local recurrence increases. Um Surgery may entail a permanent colostomy if it's involving the anal canal, their anal sphincters. Um And based on those two points radiotherapy, maybe more needed. So doctor cause me touched upon this study but I just wanted to bring it up again. Um it's now almost 20 years old. Um but this is a German rectal study. Um it's important because prior to this which was done into that which was reported in 2004. Um Upfront surgery. So surgery first um was the standard of care in locally advanced rectal cancer. So this was a trial of 421 patients who were randomized to pre operative chemo radiation followed by surgery as the experimental arm versus upfront surgery and then post operative chemo radiation. What the study found is that pre operative chemo radiation resulted in lower rates of local failure. Almost half the rate of local failure increased sphincter sparing. So of patients whom the surgeon felt we needed. A pr Um 19% vs 39% ended up getting a pr when they got pre op radiation chemo radiation. Um Less toxicity. However, no difference in overall survival or disease free survival. Um After this trial, pre operative chemo radiation became standard care for locally advanced rectal cancer Um has shown here. So really the standard for the next 10, 15 years in the US after the study was long course chemo radiation surgery. Um and then a giant chemotherapy. Um and also as Dr. Cosby pointed out, there are really two main flavors that radiation comes in. One is long course chemo radiation um that's about 25-20 treatments. Lower dose per fraction that's given with a radio sensitizing chemotherapy agent. Um which is either five a few or the oral form of that which is capeside a bean. They're also short course radiation which is five treatments given consecutively for a total of 25 gray and that's given without chemotherapy. Um And below I just have a an example of a radiation plan. Um So on the picture to the left, the red circle is a tumor, whereas a purple outline is a radiation treatment field. So I explain to patients that if we just treat the tumor with radiation, you know, that doesn't really help because that comes out with surgery. We really need to be treating around the tumor that there can be my topic disease. So we treat the tumor in the miso rectum and also in the lymph node areas where there could be a disease spread even if it's a cult on imaging studies. So um From our standard for the last 15 years more recently, things have become quite a bit more complicated. And Doctor cause me talked touched on a lot of these studies already. Um but I'll briefly mention some of them. So um starting with the top sort of at 10 o'clock one standard which I'll mention first because we actually do a lot at our institution is starting with short course radiation chemotherapy and then that followed by surgery at the end. And as dr Cosby mentioned one of the recent studies showing the efficacy of that, that that regimen is a rapido trial. Um There's also been a lot of interest in preserving the react um for patients of a complete response. Um There is there are ongoing trials of short course radiation chemotherapy followed by non operative management, including a trial that I'll touch upon here. Um And now just kind of going clockwise. There's also long course chemo radiation, chemotherapy and surgery. That's probably the most commonly used sort of total new argument therapy regimen. Um And there have been several studies demonstrating that that is efficacious and locally advanced rectal cancer. Um Going below that. There's also a potential for omission of radiation um particularly for as I mentioned, upper rectal tumors for which radiation is probably less helpful because of the risk of local recurrence is lower. Um So there's a trial assessing that called the prospect study that has finished a cruel and should be reported next year. Um Looking at that sequence. Um And then two studies on the bottom two sequences on the bottom come from the Oprah study which is a study run out of Memorial Sloan Kettering which also Doctor Cause me talked about looking at pre operative chemo radiation versus chemotherapy first. Um And then for patients who achieve a complete clinical response going on to non operative management. Um And then below. Um There is an energy study. Nrg 002 looking at chemotherapy. First followed by chemo radiation and then surgery and then finally um immunotherapy alone in M. S. I. High rectal cancer. Um which was recently reported at asco and published in the journal of Medicine. So obviously there there are a lot more options now. Um And not even included in this diagram is recent studies looking at the role of radiation dose escalation um looking at instead of non operative management or TME something in between which is a less invasive surgery for residual tumor. And also many advances in systemic therapy. Um So there have been definitely a lot more advances in the treatment of locally advanced rectal cancer. The way that we show that these work that they improve outcomes and or reduce toxicity is through through trials. Um And we have two ongoing studies in rectal cancer at UT Southwestern that I wanted to highlight. So the first study is called the innate study uh stands for immunotherapy during the different therapy for rectal cancer. It is a phase two randomized trial of new advent short course radiation within without a cd 40 agonist for locally advanced rectal cancer. Um And the P. I. Is one of our radiation oncology colleagues, dr Todd Aguilera. So sort of the background we already talked about a little bit um but but highlighting the increase in rectal cancer is specifically in young patients um and they need to improve outcomes for all patients but especially for young patients who may present with more aggressive disease. We know that immuno therapies have been effective and in fact very effective in patients with tumors with mmR deficiency. Um However thus far they have really been not very much effective in patients with stable micro satellite um uh genes. So the premise of the study is whether or not adding immunotherapy during radiation and chemotherapy can can improve outcomes. So the immunotherapy agent used in the study is a CD 40 agonist which um is intended to increase macrophage and dendritic cell activity against tumor cells importantly potentially synergize with radiation as well. Um And this is work from Dr Aguilera's lab looking at radiation and cD 40 agonist together. So on the figure on the left, um I'll just briefly go over these um on the Y axis is a tumor volume and on the X axis is time. So you can see in the line and red here which is the combination of radiation and a cd 40 agonist it love. And the most depression On figure on the figure um are different immune effect ourselves when given a combination of radiation in a CD 40 agonist. So there is certainly pre clinical um suggestion of efficacy of the drug and with a synergistic effect with radiation. Um so what happens on this study? So this is again a study in locally advanced rectal cancer. Either stage three or high risk stage two Um patients are randomized in a 3-2 fashion to are one of the standards that I talked about which is short course radiation chemotherapy and surgery. Um whereas those on the experimental arm also received the CD 40 agonist infusion that is done on day three of radiation and then five more times during chemotherapy. Um thus far so the study was opened in June of 2020. So a little over two years ago. Obviously enrollment was a little bit slow during during Covid. Um But now we are open at four centers. So our center as well as O. H. S. You Wake Forest. And recently Arizona and we have 27 patients enrolled. As of that should be 2022. So as of Yesterday we have 27 patients enrolled and are actually pending open in seven additional sites. Um so with a 3-2 random Ization 17 have gotten the study drug and 10 have have not. Um And an example on the right is just an M. R. Of a patient who did receive the study drug. Um And and had a really nice response after radiation study drug and chemotherapy. Um Of course we need to wait to continue enrolling um all patients to to really see if this drug is efficacious. Um So I wanted to quickly touch upon another trial ongoing um in locally advanced rectal cancer of of non operative management. So um this uh this uh this trial is called personalized ultra fractionated steri attacked IQ adaptive radiation in locally advanced rectal cancer. The abbreviation for that is pulsar. Um So just a little bit of background, we know that traditionally radiation is given daily um with the same dose given every day. The radiation plan is sort of made at the beginning. Um It doesn't change to account for any tumor growth or tumor response or growth. Um Or really any changes in patient anatomy. Um Weight loss, any other internal orient changes. Um There is a push just like in chemotherapy to personalize chemotherapy. Well why can't we also personalize radiation? So that leads to the idea of adaptive radiation which adapt means to change to respond to new information. Most often change relates to a shrinking um Such as shown below the initial tumor is outlined in red and over time it shrinks. Um So you can adapt to change in the tumor but also can adapt to changes in organ that risk or normal organs. So the idea of pulsar is you know, can we give really large fraction sizes based out um to adapt each dose to tumor response. Thinking that if we wait enough time between treatments will have more opportunity to see change. Um But also delivering a large enough fraction so that the tumor doesn't grow between the treatments. Um So again pulsar um is really adaptive pulses of radiation. Each pulse sort of stands as its own treatment. Each is individually planned which we think may adjust treatment to account for tumor growth or shrinkage. Um And also this is more hypothesis generating is that, you know by spacing the radiation treatments out. Um Is that potentially more less immuno suppressive. Um. Go ahead and step outside. So on the study um I'll just go with the schema is intended to represent. So patients enroll they have locally advanced rectal cancer. Um They receive chemotherapy ongoing for six months. So standard of care chemotherapy full Fox or Fox for six months. And then during that chemotherapy every four weeks, they actually get a pulse of radiation. Um The thought is again, by spacing the treatments out. We can actually re plan to account for what the tumor looks like after shrinking with the chemotherapy. And that also by spacing the treatments out. We can safely deliver a higher dose of radiation. So at the end of the six months we do a scope and then of the patients who have a complete response um that they go onto surveillance without surgery. Um And then if they don't have a complete response that they go that they undergo surgery. Um there are three dose levels on this study um where the first dose level um Give sixth grade to the tumor. So a little bit higher than the standard five grade. Um and goes up to 8th grade. So we have now completed enrollment on the first level On our on this on to the 2nd dose level and the primary endpoint is organ preservation. So really excited to continue on the study on both this study and the innate study. We are collecting a lot of correlative data um on tumor tissue samples, blood stool. Um We really hoped to use that data to really understand, you know, which tumors respond to chemotherapy and radiation immunotherapy and really hopefully tailor the treatment to the individual tumor. So with that I will stop sharing uh and turn it over to our discussions um with our our surgery are Dr Fatwa Ali and Dr georgios Karagounis. Okay, well thank you Dr Sanford and thank you everyone for joining this afternoon. It's wonderful to have the chance to discuss some interesting developments in rectal cancer and also um get to uh hopefully answer some questions at the end of the talk, which I think would be fantastic. Now the wonderful talks by Dr Salgado Dr Kaz me. Dr Sandford gave you an outline of where that recent developments in the management of rectal cancer are. But it is sometimes interesting to see this from the other perspective of specific cases and how it all applies to the daily clinical practice and the case that I selected that I will be talking about. I think highlights two very important concepts. One which has been mentioned several times already, is the need for a multidisciplinary team approach and having members with different expertise and different toolsets that can contribute to the care of these patients. But the second thing that I also wanted to point out is sometimes how you start with the planning of the management of a specific patient may not be the way that you complete that management because unfortunately patients and their tumors do not read and follow the N. C. C. N. Guidelines and sometimes they skip pages in the management of the course of their disease. So the patient that I will talk to you today uh initially presented as a 42 year old man at the end of 2020 otherwise healthy. Again. Unfortunately highlighting this really alarming rise in young patients with rectal cancer. He did have a colonoscopy for bright red blood per rectum and this indeed showed the presence of a low rectal mass which was adenocarcinoma and pathology with intact mmR proteins. These are some endoscopic pictures to orient yourself again on the top two pictures you can see that this is a load fairly close to the anal canal and it looks ulcerated and say mr confidential. So starting from there we proceeded with the staging and the first part of that was the M. R. I. Against some pictures below. For um reference where you can see that this was a. T. Three tumor. Again involving the peri rectal fat with several suspiciously enlarged lymph nodes was staged as A. M. R. T. Three and and two by our radiologist and confirmed that the multidisciplinary conference with the threatened are involved circumferential resection margin interior early so with that in mind we recommended the total new adjuvant therapy approach which dr Kazmi explained a few minutes ago. And in specific and relevant to Dr Sandford's mentioned of the in a trial the patient enrolled to the in a trial and ended up randomized to the standard arm which was short forced radiation followed by chemotherapy following the completion of that treatment. And as we were as planning for the next step which would be a repeat assessment with either organ preservation, watching weight or proceeding to surgery. We got a new M. R. I. Which did show that at that point the tumor had responded marginally. But unfortunately that at the time this lymph nodes remained suspicious and um the circumstantial protection margin was again involved. But what was more important is that the M. R. I. At the time also highlighted the presence of suspicious liberal lesion that was concerning for metastatic disease and deliver. And that forced us to now switch our paradigm around come out of this pathway of total new adjuvant therapy, focusing on the primary locally advanced rectal cancer and rather further investigate and manage the liver lesion. And this is exactly the picture that shows the tumor which again is very saddle. It was a small lesion in the Type of Segment six. So for that we decided to proceed with the liver first approach and uh took the patient to the O. R. for a robotic resection of the leader in segment six. Now at the time in the operating room the um ultrasound showed that two additional allegiance in uh in segment three and segment five. All three tumors were reflected in the O. R. And were all consistent with metastatic adenocarcinoma. And considering the a partial response of the primary humor and be now the presence of metastatic disease that presented despite the treatment with fall Fox. The patient was transition to a second line therapy with full theory and this is a mob. With the plan to Offer this and restage after three more months. Surely enough. At the end of august, the patient had a new M. R. I. Which this time showed further improvement in the primary tumor who stages A. T. Three B. And zero. But as you can see here and also commented at the conference, there was almost complete resolution of the issue at that point again, highlighting both the importance of further time, from the timing of radiation to the time of restaging, as well as reflecting the differences in treatment. So with that in mind and with the treatment complete and no other evidence of disease. The patient eventually was taken to the operating room in november uh and given the very low location of the tumor that I showed you the approach that was taken was a robotic trans abdominal transactional approach to perform a low anterior resection. That was all the way down to the end of the rectal mucosa and was accompanied by a hand sewn collar, anal anastomosis and under the protection of diverting colostomy. Now the other thing that was would be surprising perhaps to see is that the final pathology for this tumor remained a Y. P. T. Three and to a which again is a very critical point to bring back to the idea of how clinical staging and pathologic staging can very significantly and how one must pursue this watch and wait approach with caution as it takes um significant team expertise to recognize for the patients who have a true, complete response and who are the patients who may have an impressive response on imaging but may actually not have a complete response and maybe at higher risk for proceeding with an organ preservation approach. Now, unfortunately, and again, discussing how we we don't always know exactly what direction the patient's disease is going to take after all this treatment, The subsequent restaging scan in March, which was three months after the low interior section showed. Now a new suspicious lung nodule in the left lung. But there again different events bring necessitate different approaches to to manage them. So again, we had to re um structure our approach and figure out what the next or the best approach for this. Now, new finding would be. And here the tool that we used was short, sorry, the attack being radiation therapy to that nodule to definitively treated and hope and expect that in the future there will not be additional nodules as this was an isolated single presentation after extensive treatment by that point. So the latest update for the patient is that now last month he had easily be reversed and thankfully he remains without evidence of disease at this point. Although of course with high high degree of alertness from our perspective considering several um curveballs that his disease has thrown at us so far. Okay this concludes my case and I'll pass on. Oh screen to dr ali thank you mm. Don't. All right thank you doctor carry guns and thanks to everyone for joining us. Um I wanted to use this opportunity or to present this case to actually highlight or watching weight program and I think like everyone in today's panel discussed um The exciting part of taking care of regular cancer patients is that we have a lot of options. And not only do we have a lot of options but it's also important that we can now involve we can tailor the treatment to the patients individual and we can involve the patients in the decision making. Um so this is a patient who's relatively young. She was 49 years old at the time of her diagnosis. Um she's relatively healthy. With the exception of hypertension and diabetes. She presented with bleeding correct um and had a colonoscopy Which showed a digital rectal cancer. Um about five cm from the anal virgin the biopsy confirmed the diagnosis and of carcinoma. And the tumor was microsatellites stable. She then underwent the staging work up including um erectile protocol um M. R. I. And her clinical stage was T. Three. Um And one so we can see here on the image on the left that the tumor was extending into the rectal fascist. It's a T. Three tumor and they're some of the lymph nodes were enlarged and on the image on the right side we can see that um the circumferential resection margin is free. However there is one left note that's really close to the circumferential resection margin on the right side. So the margin is threatened. So um the patient presented 2018 she was discussed at tumour Board. Um And again this is the M. R. I. Showing the five centimeters from the universal it's a thoroughly distal tumor. Um And an oncological perception will most likely require either and a pr with a permanent colostomy or performing a very extremely local adrenaline esteem assis. So the care of the patient was discussed at our multidisciplinary tumor board. Um And uh the way this was approached was using total new adjuvant treatment. Um At the time we were participating in the N. R. G. G. I 002 trial which dr Sanford had mentioned earlier in her talk. So the patient received induction chemotherapy with eight cycles of full Fox. That was followed by a long course chemo radiation. And part of the trial patients were randomized to either receive or not. So she was in the intervention arm she received um primarily in addition um to key Mariah duration and induction chemotherapy. Um After completion of the totally a german approach, we have reassessed the patient's response. Endoscopic lee and the M. R. I. And both both actually showed evidence of complete clinical response. Um And it's very important that we achieve concordance between the M. R. I. And in the endoscopy. Um And you can see here this is the image on the right. This is the typical endoscopic appearance of a tumor with complete clinical response where there is resolution of any mucosal abnormalities and there is just sort of a still its car in the background. Um So options were discussed with the patient and the patient has agreed to proceed with the botching weight program as selecting the patient is very important within a watching a program because it requires very strict surveillance particularly in the first two years when patients are at most risk for recurrence, particularly in the Luminal recurrence within the wall of the rectum. Um So within our watching weight program we perform surveillance including a digital rectal exam prep to SKA P. And M. R. I. Every four months for two years. Then every six months for three years. Um In addition to doing cereal, see a levels as well as actual imaging to rule out distant disease. So now has been four years since the patient's initial diagnosis with cancer. She has sustained complete clinical response and remains with no evidence of disease. And I just actually the image I should was from the patient's colonoscopy from last week when I performed her surveillance Prock Tosca P and she's extremely um happy and satisfied with the outcome and essentially avoided a major operation and the possibility of a permanent costume. Great! Thank you. Um So I don't see any questions in the chat. So I will actually ask a question myself since we have a few minutes left um for um the surgeons on the call um on the webinar. So there, you know, historically the treatment has been total music rectal excision. Now there is a lot of interest in watching wait. Um can you comment on uh transitional excisions or like less invasive surgery for residual tumor? I feel like that has not been discussed as much. There are some emerging studies like what what do you think about doing that? Um if there's a residual disease versus going to TME wrote whether the downsides the upsides. Um but I think we got a lot less and there's a lot less research on that. I think I will I will volunteer to answer that question. So, so I think that this is a very interesting and intriguing question in and of itself and it is one that I think we have to almost constantly reassess which Way we answer. I think that the question to that would be the answer to that would be different 10 years ago. It is different today and it may be different in the future and that reflects not only our revolution in understanding rectal cancer, but also the differences in the way that we deliver our our new adjuvant therapy and the way that our paradigm has transitioned. And what I mean by that is in historically, a lot of thought was put in the idea of doing a local excision with chemo radiation for example, for for earlier stage rectal cancers. And that was an approach that even though it didn't achieve the same success as the traditional TME, it had very robust results near those of the traditional approach and could be used in select populations. Now as we move into the watch and wait approach and we have these patients that achieve a complete clinical response and going to non operative management. What that does is also select away the patients with the most favorable biology. So if you were to say take the the results of the opera trial where about 50% of the patients ended up with organ preservation. Those were by definition the 50% of patients who had the most responsive biology. So the candidates, the theoretical candidates for a transitional excision would be would come from the other half of that patient pool and therefore there overall prognosis and outcome would be expected to be worse because again, we would have filtered out the ones with the best prognosis. So it is it is an approach to be taken to be considered depending on the patient's comorbidities, depending on the response to therapy, depending on what we're trying to to achieve overall. Um I mean as a matter of fact, just earlier today we we performed a transitional excision on a patient who had new adjuvant therapy for for a variety of reasons. But what I think is the other side of this that I perhaps feel fairly strongly about is if the transitional excision is performed in the setting of a patient who had an early good response to total new adjuvant therapy, then many times the the better solution is to wait a little bit longer. So when patients have this near complete response that we see sometimes after 68, 10 weeks after the completion of totally a gene therapy, there is no harm in waiting or we don't think there is a harm in waiting another six or eight weeks and reassessing because sometimes that near complete response will turn into a complete response and no transitional intervention will be needed. I'm happy to see if anybody, any of my colleagues will have anything else to add. I um I echo what you said, Jarvis. I think that patient selection is extremely important in these cases. I also think there has to be a consensus on how we treat these patients, you need to make the different providers, right? And instead of the realistic expectations to the patients. So um all the only about very important it's another option that we have in our environment terry um It's it's good to have different options. Ah I just saw that there is actually a question. The chat. I'm sorry I was looking in the wrong window. It's in the Q. And A. Um So I'll answer it quickly because we're at 6 30. So which patient would you recommend? Short versus long course radiation for TNT. Um So we talk about this a lot in our tumor board. Um I think in the preoperative setting um if the patient is going for surgery um then there's equipoise between the two um And our preference in terms of cancer outcomes um based on randomized studies. Our preference for logistical reasons for convenience and to get chemotherapy in earlier would be to do short course radiation. And now you might ask, well you know what if they have a complete response um You don't know that from the outset. Um Is there you know which which one would you do if you know they don't know if they would do surgery um If they were to have a complete response or they don't know you know whether or not they would go for watch and wait or whatnot. Um I think in that setting there's more data for the long course chemo radiation. Um Yes. Um Just because the doses higher. Um So I think that is what we would tend to recommend. Our study of the patient really was interested in watching wait. Um That being said there is emerging data in the world of short course radiation for that, including one of the trials at our center that we talked about. So we would also encourage enrolling onto a clinical trial if the patient was interested. So we are at 6:32. Um so I just wanted to thank everyone for joining us and of course also to our discussion this evening. Um And I hope you enjoyed the webinar um and please reach out to us um If if we can be of any help. Um And and that's it. Thank you everybody. Thank you. Thank you.