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Oh, everyone. So uh welcome everyone. Thank you for joining us for the 20th, the research uh collaborative Journal Club. Um We're really pleased today to welcome Mr Bhaskar Kumar. Uh who I'm sure you all know is an esophagogastric consultant in Norfolk and Norwich um who is also um the author of a book. I think that's got either a lot of you through the exams or will get a lot of us through the exams. Um So we're thrilled to have you. Thank you very much. Um And Alex Low, uh who's an S ta trainee in Luton in upper Gi uh who's going to very kindly take us through um a very interesting uh paper and talk a bit about that. Uh And, and together you're both gonna give us all some advice and tips and tricks for the academic station uh in Frcs. So, thank you very much. Indeed. Thank you for a very kind introduction. Um Thank you for this opportunity to present to you all and to all of you for making the effort to attend this. Um Before we go on to the paper, I thought it would be useful to present a few facts about OG cancer because not all of you would have had an opportunity to do an OG cancer job in your rotation. Um So it would make sense to give you some background info leading up to the paper. Uh at which point I'll hand over to Alex. Um Alex has taken the exam recently successfully. Um He's already done one or two postings within an OG cancer job as well as benign upper gi surgeon and having taken the exam recently, he's in a very good position to bring you up to date. Um, and I'll chip in from my experience over the years as well. Um, having coach candidates for the exam. So I've just got a few slides of background information on the OG cancer, which I'll try to now share a screen. That's perfect. Has that come up? Yeah. Yep. Fine. Has that come up in full size? You, you can see it? Ok. Um You could, you could make it presented to you if you wanted it to, but we can see it. Is that better? Ok. II think that's probably as far as I'm going to go, so I'll, I'll start with that. So we don't lose time just to check. Um, has, uh, if you scroll, are we seeing your, your screen live? Did just you know that uh, no, it doesn't seem to want to roll on. Did, um, is it, is it possible? Uh, how about now? Yeah, that's perfect. Is that ok? Perfect. So, um facts about OG cancer. Um Here we go. Not good news, I'm afraid to begin with. Um, stomach cancer is the second or the third most common cause of cancer related death worldwide. Um And it is not a cancer that we see a huge amount of in western practice. Obviously in the far east, there's lots of it. Um, but this just gives you a little bit of background um feel as to how lethal this disease is. Uh And I've put stomach cancer in particular here. I if if you look down it does feature esophageal cancer and it's very easy to look at the two together. But in fact, they're quite different diseases which share have very similar staging and treatment. But biologically stomach cancer overall is an awful disease to have. Uh And the reason I've mentioned stomach here is to give you an idea of the biology of the disease, which is very aggressive. And unfortunately, this is what we see all too often. Um Obviously, there are multiple liver mets in the right lobe. Um And it, it's, it's very interesting to see how the entity has evolved over the course of time. Uh And there's no doubt nowadays, we're seeing more metastatic disease, we we're encountering more frail elderly patients. So there's been a definite paradigm shift, I would say since uh the pandemic days for whatever reason that is. Um And, and we honestly can't cover ourselves in glory with this cancer side. Um A lot of patients are unfortunately doing very badly. Um Our percentage of patients who do very well has dramatically improved over the last decade or two, but we still have a long way to go. And I thought this slide which is some data from one of our um MD students illustrates how bad this cancer site can be. If you develop peritoneal mets, we actually have a chap on the ward downstairs who had uh a total gastrectomy less than a year ago. And he now has ascites from peritoneal Mets as well as liver mets. Uh And he's looking at an overall survival now, according to this data, 3 to 6 months, it is abysmal when that were to happen. So how do we cure these patients? Well, we can and we increasingly are and we would like to see this improve. But following staging, once we've deemed a patient to be operable, the ideal pathway is here on the right where the patient has perioperative chemotherapy followed by radical surgery, followed by adjuvant chemotherapy. So, neoadjuvant surgery and adjuvant this flow diagram on the left straight to surgery is not a healthy one. And the more of this that I do, the more I see recurrence in people who have haven't had systemic treatment. And uh as much as we think surgery is the main uh curing modality for these patients, systemic treatment is really important. And I think leading up to Alex's presentation, we do need to understand the importance of chemotherapy in all of its forms along with various adjuncts that are now available. Um Some years ago, the standard chemotherapy was ec ec F as per the magic trial which Alex will mention to you. But we've now moved on to FLT chemotherapy. Um Flot is less toxic, it's more effective and a very good trial has shown that the survival benefit is significant and we continue to see better results with that. Um As a result, flot has become the standard of care for OG cancer at the junction and the stomach, the flot trial did not include esophageal cancer. That's a separate discussion. But increasingly we've recognized the systemic value of this treatment. So that's pretty much the gold standard where this all gets confusing is where chemoradiotherapy comes in. But that's a separate discussion itself. Staging the disease can be difficult. Um The staging pathway for OG cancer is very complicated. Um It can involve up to 10 to 15 separate investigations. But generally speaking for a gastric cancer, any of these cancers which involve the junction and abdominal component, you must perform a staging laparoscopy. And the reason for that is peritoneal disease can be very subtle. Um Often CT scan will not pick it up and you have to pop a camera in to have a look around the peritoneum. And it can be surprising how often you do see peritoneal nodules, which if present, unfortunately, to, to some extent deem the patient inoperable. So as an example of a staging lap, um if this were to play uh 61 year old man who's never been in hospital, he, he uses a ppi for reflux uh presents with early satiety weight loss. Um This is a staging lab that I did for him. And uh you, you can see the cirrhosal positive, very bulky gastric cancer. You can see how it puckers, lesser omentum, it looks quite fixed, but in fact, it does lift off the head of the pancreas and the tail of the pancreas. There's a lot of adhesions nearby. This is a dreadful cancer and this patient had cytology positive disease and actually went on to have a biopsy taken of the peritoneum. Here's one nodule of a few which has proven cancer. So it's really important with these patients that you stage them adequately so that you can decide whether they're operable or not. Um There are some other oddities with gastric cancer in particular, one of which is the fact that gastric cancer in particular can present as an emergency more than esophageal cancer. Uh And that's important because once they come in as an emergency, often, more often than not, you can't give them neoadjuvant systemic treatment, not always. Um But in the majority, if they come in with Melena hematemesis, um gastro outlet obstruction perforation particularly, then you can't give them systemic treatment. So they go straight to surgery and the tendency to develop recurrence is really quite high. So here's an example of a patient, um a, a young Portuguese patient actually who developed um a prepyloric cancer. You can see the cation here, the thickening of the pylori from the, from the tumor, um significant air fluid level in keeping with gastro obstruction. So if, if, if we were to see this patient through the MD tube, we would generally get the patient across, admit them, uh decompress them with an NG tube and optimize them as quickly as we can because it's not, not a surprise that they'll be quite deconditioned. And, and this particular lady if you managed to get her neoadjuvant chemotherapy as a result. So if you come across as presentation, it is in many ways a emergency or at least an urgent case. Uh And I would urge you to refer the patient quickly. Um with the idea being to resuscitate them, get them to neoadjuvant treatment if at all possible. And the same patient, um this is the POSTOP specimen um distal gastrectomy where you can appreciate how distended that stomach is and that wouldn't have happened overnight. You can see that the cirrhosis involve T four A disease. Um All of us um in fact, involving the omentum. So this patient's at really high risk of free intraperitoneal recurrence ascites. And it's really important to have good systemic treatment. How else can we improve? Um Well, if if we can establish early diagnosis that would really help. And there's a lot of work going on nationally now about uh quality control with upper gi endoscopy. Those of you familiar with colonoscopy will know that colonoscopy is way ahead in terms of um performance indicators uh particularly with the bowel cancer screening program. But there's quite a bit of national work going on of which we're one of the contributing centers uh to look at cases where cancers can be picked up quite early. And this being one example, um this is a real patient, 72 years old had a history of Gord um found to have a few fundic gland polyps which they all get with PPI S down there. Uh But also found to have esophagitis grade B treated discharged back to the GP 2.5 years later, bulk conjunctional tumor, widespread infiltration and liver mets. Um And there is quite a significant number of OG cancers who've had an endoscopy within the previous three years. Um So quite a bit of work going on with quality control with upper gi scope, which as you all know, is quite easy to perform, but also easy to mis lesions here. Um So I think this is the timeline for these cases you see here in 2019. Uh The area of interest is quite nodular, there's some Barts along there. Um So, so really that should have been biopsied a lot more extensively and followed up. And then later on hr two or three years later, you find there's a, a cancer there. Um look out for this for all of you guys training in endoscopy. There are gonna be key performance indicators coming out. I think this is really important. Um Our O GD lists everywhere are overbooked in Japan. They would spend 45 to 50 minutes per scope, They would take about 50 pictures. I'm not suggesting we do that, but the um move towards quality control endoscopy is really important. Um And this would all come out within the next few years allied with national training programs in pathology detection. Gastric cancer is also a little bit of a funny one in the, in its tendency to, to be associated with other inherited cancer syndromes. Um hereditary diffuse gastric carcinoma CDH, one gene mutation, uh being one of them association with F AP. And I'm sure you're familiar with all these names. We've actually in the last couple of years had a lady with menetus Disease, which is extremely rare where the patient develops. Rugal hypertrophy, very high risk of um gastric cancer. Probably never see one again. II saw one as a trainee years ago up in Newcastle. Uh but this lady was only 49 her mother had gastric cancer, um had an operation, mother's doing well and this lady went on to have a prophylactic laparoscopic total gastrectomy. Luckily, with no cancer within the specimen, which looks like that you can see the hypertrophied and the patient actually lose a lot of albumin and was um hyper proteinic. Well, what do we do? Well, um, radical surgery is really important and I'll show you a slide which shows better outcomes with um good radical operations. It's really important to not only do a good oncological wide margin but also to take out the relevant lymph node stations which are grouped according to the Japanese Society classification, which I'm not gonna go on about. But essentially there's two groups, those down the lesser curve, the greater curve, uh those are the perigastric nodes and then the visceral nodes are marked as you can see over there. Um surgical approach um varies from center to center. He's looking very happy with himself there. Um Radicality of surgery is important. So here we've done a gastrectomy of some sort, probably a total here and we've completely skilled and nice the celiac trunk um take off of the left gastric there, splenic artery coming across there. The lymph all to be playing is between the head of the pancreas here, common hepatic artery, which gives the gastroduodenal there and the hepatic artery proper. So your ideal lymphadenectomy, it should be like that and it could be that with technology like robotics, it would help um those to achieve this type of result which can be achieved with open as well as laparoscopic surgery we take out quite a bit. If you're doing a total gastrectomy, it's really important to take those lymph and have quite a wide margin above and below, take the whole omentum, which shares the same blood supply as the stomach. Um We, we'd see a lot of these cirrhosal positive aggressive cancers and there could be argument to give these patients additional treatments such as hype C. Um So hyper, as you all know, um heated intraperitoneal chemotherapy um not established at all for gastric cancer. But um it, it certainly has a role as per nice guidelines, approval for um Onco gyne and colorectal malignancies. It is actually approved for gastric, but the evidence base for it is still being formed. Um We've performed two cases now. Um Well, I should say one with a year ago and the other one's only still on the ward. So I dare say that we've done two. We've, we've done our second case on Monday. Um And it's very radical. This, it's the gastrectomy plus the high peg plus um cyto reductive surgery whereby we have to take out quite a bit of the peritoneum appendix, mobilize the colon to get to the retroperitoneum. It's a big, big job and this particular case took about 12 hours. So not harping on about how good our surgery is, but this is more a demonstration of how desperate we are for these patients because um they're, they're fighting for their lives aren't they and we have to do all that we can to help them within reason. So hopefully, that gives you a feel of how systemic og cancer is, how difficult it is to treat. Um which, whichever surgical tools that we have, whichever treatments we, we must try and get an earlier diagnosis. I think it's really good that endoscopy is now a part of the IC um curriculum. Um There's a great shortage of endoscopies and we need to improve our endoscopy standards driving towards earlier diagnosis, but ultimately, without better systemic treatment, uh we're not gonna see an improvement flot has made a big difference. We have a lot more in the way of um complete pathological response as a result. So we're hoping that our long term data will improve. Um This is our own data with minimally invasive esophagectomies. And we find that um on the Kaplan Meyer two age groups, but essentially we're achieving about somewhere in the region of um 50% 5 year survival. And this would never have been the case say 1020 years ago. Uh II, I'd love to say that we would take the credit that the MO approach is the main reason for this. But far from it, I think it's the improvement in systemic treatment per operative career, better surgery, many factors that go into that. Um So thank you for your time. Hopefully, you've heard me or I've been talking to myself for 19 minutes. Um we'll now lead on to Alex's presentation. Great. I can't hear anyone. So Mr Kumar, if you're able to just, I think uh reli on the present now that should uns share your screen. Uh Yeah, and then Alex, you should be able to uh share your screen. Now, let me just a moment. What am I clicking present now? So, so that the the the in the middle of your next to the video microphone video, there's a the middle buttons are square with the arrow pointing up and if you click that it will uns your screen. Oh yeah, perfect. Done. There you go. Thank you. Thank you. Hopefully you heard me or I was talking to you. No, fine. You often worry about these things. I would have warn you before. I'm sure. Hm The share button is uh it's blanked out for me for some reason. Oh, no, I got it now. I got it. I got it. I got it. OK. Perfect. I can see myself infinitely. Yeah, this is perfect. Yeah. Go for it. Thank you. OK. Right. Uh So the topic of today's uh journal club is the paper keynote 585, which is the usage of perioperative pembrolizumab in locally advanced gastric or G OJ adenocarcinoma. Yeah. Um Mr Mr Kumar has given us a very nice comprehensive overview. I'll just dial down into the details that you do have to know for the FRC S and this is a must for anyone with an upper GI themed FRCS, whether it's benign or cancer, you do have to know cancers, cancer in and out. These, these questions will come up and even in colorectal themed FRCS examinations, they do come up as well in the emergency side. Um So these are just a, a brief run through of the facts uh to know of uh esophageal cancer. It's mostly lower in the UK. It's mostly adenocarcinoma and SEC is only 20% here. But uh you should be aware that worldwide it's the complete opposite. That SEC is the overwhelming majority. Yeah, I, I've written here, local versus systemic that will come into the treatments. Um In general, the, the thought behind the treatment is that uh adenocarcinoma carries a more systemic burden than sec, which factors into the treatments. You should know about the risk factor profile that adenocarcinoma essentially. Um although there are different cancers, they are treated the same for gastric and esophageal for the purposes of the exam and the risk factors for proximal gastric cancer and distal esophageal cancer in terms of adenocarcinoma are the same. And for sec, it's a different profile. We're talking about deprivation, smoking, alcohol, uh hot tea, if that's your thing. So you should know about barrett esophagus in, in fine detail, the treatment of low grade dysplasia, high grade dysplasia, early cancers and of course sid calcification, uh which ties into all the treatment on the gastric side of things uh it's overwhelmingly adenocarcinoma. You don't really need to know about S CCS. I've written that submucosal tumors, of course, we all know gist are the ones that will be tested. So you do have to know it in inside and outside as well. Proximal versus distal cancers. Uh D one versus D2 gastrectomy. Again, risk factor profile, H pylori and coreus cascade that, that will come up um in the, in the sort of basic science station. And of course, again, early cancers and the treatment, current guidance, I highly recommend looking up these uh these two guidelines and just to briefly run through uh just expanding upon what Mr Kumar said, early cancers can be treated via, can be treated endo endoscopically, uh sec and adenocarcinoma on the sec side, chemo ra is what you should know about a driven nivolumab. This will be the bonus marks that you get at the end of the station. This will what get you, this will what this is what will get you to an eight. Um And of course, for adenocarcinoma flot E CF, we'll talk a bit about the landmark trials. Uh After the discussion of the paper also worth knowing about is uh advanced esophageal adenocarcinoma. Her two and nivolumab comes up again and second line pembrolizumab in higher microsatellite instability. Uh Cancers don't really have to know about the other three. Ramucirumab is not in, is not licensed in the UK. Um uh This is just asthma guidelines, right? Fundamentals of immune immune checkpoint inhibitors. Um It's a very basic but very nice image from Wikipedia that essentially summarizes what immune checkpoint inhibitors are. So PD one programmed death one, that's the receptor PD L1 program programmed death ligand one. So you can see PD one is expressed on T cells. Um essentially activation of PD one causes the T cell to uh stop it, stop its function of apoptosis, uh slightly convoluted but do remember that. So, Pembrolizumab nivolumab, these are PD one receptor antagonists and the rationale behind this is that cancers produce PD L1, the ligand, which interacts with the receptor on T cells to stop its ability to induce apoptosis in the cancer cells. It's, it's written here, non small cell lung cancer. But conveniently, you can actually just say it's a gastric or esophageal adenocarcinoma because these exact drugs are all trialed in uh og cancers as well. Bevacizumab. You can forget about that. It doesn't work for og cancers and increases the leak rate. Um CT la four ipilimumab that's worth knowing. Uh That's part of the um SCC pathway which you may see in the guidance, diving into a little bit deeper CPS, TPS. These are uh abbreviations that you will see in trials. CPS is the combined positive score which measures PD L1 expression on both tumor and immune cells and TPS is a tumor proportion score. It measures only on the tumor cells and the reason for this is that adenocarcinomas, the tumor does not express PDR one. Hence CP S can only be used uh in the, in the, in the setting of adenocarcinomas, you can only use CPS. But for S ECs, both TPS and CPS apply right. Moving right along to the study essentially. And all of that, that's essentially perioperative fibrosum added to perioperative chemotherapy. Uh That's the long and short of it. This is the lead author. Um He's a Japanese uh oncologist. That's his uh ivory Tower in the bottom right hand corner, but you can see the of the authors nationalities. Um There are several, it's essentially a multicenter it 100 and 30 100 and 43 medical centers, um very uh global study. I would say methods as you'd expect locally advanced cancers patients who are fairly fit. Um and look at the exclusion. If you have a look down at the second last line, it excludes autoimmune disease within two years. Uh active treatment within two years, patients with immunodeficiency and active infection. And this is very specific to immune checkpoint inhibitors which have a unique uh side effect profile and the enrollment you can see of 2017 to 2021 which leads into our next point. The majority of the study was done with a, with a main cohort of chemotherapy with CISplatin and five fluorouracil or CISplatin and Kitine. And there was a safety cohort added in with the flot cohort with the flat cohort is only about 200 patients versus a main cohort of 800 patients. And of course, as, as we may know, flot was only introduced in sort of 2018, 2019. And although flot has become the standard of care, unfortunately, this study is a little bit behind the time. Um And essentially pembrolizumab is given in the three weekly uh cycles, uh mimicking the schedule of, of CF. They've measured the CPS, they've measured MSI adverse events, recorded outcomes. They had a very wordy paragraph on the outcomes, but essentially, they're measuring the same things as every other trial, pathological complete response, disease free survival, which they have termed event free survival here. And overall survival statistical analysis is as you'd expect um fairly rigid protocol with three interim analyses of which this study reports, the first three ana uh interim analyses and the final analysis is awaited. Uh They've done power calculations leading to their specific P values which are quite tight as well. And of course, some of the statistics which uh which are lost on me. They are very clearly written that the funding sources from the company and they had a very heavy hand uh in the design and report and writing of the report um which makes the results all the more interesting, right, main cohort uh very wordy image, but it's worth having a little look um as you can see median age. So of 64 versus 63 male. As you'd expect the majority of patients are male, about half are Asian, half are white uh geographical region. Uh you know, about half of it was from Asia and half of it from the rest of the world performance status as you'd expect zero and one majority are gastric cancers with 20% G OJ and the tumor stages, as they said, uh locally advanced, meaning um node, node positivity or T three and above histological subtype doesn't make much of a difference in this context. But it is worth noting the PDL one status CPS more than 10, it's about 25 to 30%. Um So you would expect people uh patients with a higher CPS score to respond more positively to pembrolizumab MSI high about 10%. And the rest of it is uh chemotherapy uh study profile. Again, another wordy image. It is worth noting the flow, the patient's flow within um the uh sort of a treatment regimen. What's important to know is that about half of the patients managed to survive the entire regimen of perioperative chemotherapy with pembrolizumab, 20% discontinued, of which you can see the adverse drug reactions. It's 9% in the pembrolizumab group versus 3% in the chemotherapy group. And this is on the regimen of CISplatin and five fluorouracil, which many would argue that it is a kind of regimen than flat. Uh So it would be something to think about uh in a more modern setting, 80 versus 75% are not resections and 5 to 65 versus 6% of unresectable cancers. Um overall, right, the first, the first major uh outcome, they're looking at pathological complete response. About 11% difference between both groups. Pembrolizumab achieved 12.9%. PCR and, and the chemotherapy group 2% they've done a combined cohort here which is fairly similar. Yeah, these results were from the first interim analysis and uh that's, that's the result that we have event free survival. Not significant. You can see the, the charts look a little bit promising, but it is not significant according to their own calculations. But you can see there is a fairly uh large difference in event free survival, 44.4 months versus 20.6 months. Um So there may be something here, but unfortunately, this did not lead to an improvement in overall survival. You can see 60 months versus 58 months and hardly any difference at all adverse events. Uh This is just to highlight uh the unique uh sort of toxicity site profile as we all know, chemotherapy is not nice for anyone. And these are patients who are in good shape. You can see grade three events, 78% versus 74%. We've talked about treatment related adverse events, isolating it from surgery. We've talked about discontinuation rates 26% versus 20%. And in grade 3 26% versus 24%. So, on the main cohort side, you could argue that the addition of pembrolizumab has not really made a difference uh to the rate of adverse effects. But in their safety cohort in the flat cohort, they've noted 44% versus 20% and discontinuation 32 versus 17% which is quite significantly uh different. Another quick look at the chart, they have listed all sorts of side effects, but they have written specifically adverse events of interest and infusion reactions. Uh This is actually referring to the unique uh toxicity of immune checkpoint inhibitors. And you can see these are not mild complications ranging from anything from uh adrenal suppression, pituitary suppression, uh renal dysfunction. It's even type one diabetes, um guillain-barre syndrome and a little refresher in terms of what the what the grades mean for adverse events. One is very mild, two limiting age appropriate ADL S3 limiting self care of which hospitalization or prolongation of hospitalization is recommended for life threating five death. Overall, the interpretation of this in interpreting the results as an increased pathological complete response. It's possible that it increases the event free survival, although this was not significant, but it does not seem to uh change the overall median survival. And the side effect profile is significant and it is something that needs to be uh considered uh for the patient strengths and weaknesses, strength. It's high quality RCT. It's robust methodology it's a novel highly relevant topic. Um As Mr Kumar said in the field of OG cancers, we are desperate for better drugs and better treatments to uh avoid dis the dismal outcomes. But um on the weakness side, there was no mention of operative strategy, there's no mention about the, you know what kind of operative approach is adopted, the influence of industry cannot be discounted uh even though the results of the study are, are negative. And of course, cost effectiveness is not necessarily a knock against the study, but it is something to consider. And I suppose nice will have something to say about it. Um Before I dive into the UK context, it is also worth knowing that there are two other studies um similar in the newer in the perioperative setting. One is Matterhorn which tests uh diab which um if anyone's interested in Cholangiocarcinoma, you should, you may know that diab is indicated in Cholangiocarcinoma. Interestingly, the results were quite similar. It's not, again, it's not uh the full results are not out yet. Uh It's resulted in better pathological complete response. Uh but overall survival does not seem to have any benefit. There is another study uh measuring um a uh a a at, at a ZZZ, something like that. Um You may have seen it in the Wikipedia picture. Again, the results were somewhat similar, we can compare the trial to the UK context. Uh These statistics are a little bit different from what Mr Kumar has presented. But these have been lifted directly off the cancer research UK site. And you can see specifically stage 35 years survival for esophageal cancer is 20% and for gastric cancer is 24%. Of course. Keeping in mind, these statistics include um patients of all presentations and all uh sort of, um and all sort of uh all sorts of comorbidities and fitness and um not directly comparable, but it's something to think about uh in terms of the positive outlook of the study versus uh the reality of the cancer. These are further questions which may or may not be addressed in the final analysis, the impact of the combined positive score, whether a higher score translates to a better outcome, the impact of flo I don't think it can be addressed with this study, but I suspect future studies may be looking into this question and the impact of surgical technique. OK. Uh That concludes the paper side of the presentation, maybe um analys to do the candidates. Um The trainees want to ask any questions about the paper before Alex goes onto the FRC specific area. Anything they want to go over again. Yeah. So it would be really great to have some audience participation on this because it's nice to get some sort of a chat going. So, um I'm just starting to look. Um So, so Brett's uh Packham has put up a question, I'll just read out and he says he's not sure if we know enough about why there's a geographical difference in esophageal cancer. And is it so is grouping um Western and Asian together? Is that ok? And um it says maybe the mix of both arms compensated for this. That's a good point. Um Brett Alex. Do you want me to take this one? Yes, please. Yeah, we, we, we never discussed who's gonna answer the questions or maybe take it in turns et cetera. Um Thank you, Brett. Um You're quite right. It, it, it's an interesting approach, isn't it to group um Western plus eastern patients together. Whereas in fact, um in the Far East through screening, they get a lot of early cancer presentation and biologically for whatever reason that would be, their cancers are nowhere as aggressive as what we see in Western practice. And it was very interesting talking to um a surgeon from Hong Kong, er Simon Law, who is a very established um surgeon within OG cancer surgery. And just talking to Simon, I asked him about his experience of dealing with adenocarcinoma of the esophagus. And for someone who's got a huge dataset on es esophagectomies, he's barely done an adenocarcinoma. They're all squamous cell carcinomas. And it's obvious talking to colleagues from the far East that the biology of this disease is very different. They have a lot of patients with prolific supraclavicular and neck node involvement. So I II think for this paper, it may be, I don't know what the, the percentage spread from one side of the world to the other is, but mixing it together probably wasn't. Um, the, the, the best thing to do that balanced against the fact that you've got an author, leading author from the far East who has to increase his numbers through worldwide collaborations. It's slightly a tricky one, but it's, it's a good point. I hope I've answered your question by the way. And, and so, and um just something that I was wondering so the, the way that they include, included this sort of latest subanalysis with uh using flot as the comparison like Alex, when you, when you were looking through it, do you think that this is, this is the right move for them to have done this or like or do they should have stuck to their guns and stuck with the initial analysis? Like, and how much can we really take from the subanalysis using flot? Um So for them, they said that they include, they include a flat for a, they, they termed it a safety cohort. So they, what is that? Because II didn't quite get what they meant by their terminology. Yeah. Um What I got was that they were not intending to get any real results from the cohort, but it was more of an experimental cohort to see how the drug is tolerated alongside the chemotherapy regimen, I suppose. Uh It's uh the company planning for future trials uh when they're seen um with the introduction of flo now cos uh CF is not really relevant for young patients anymore. I think that's a really important point that um industry involvement can really contaminate the trial and, and this is really an example of that, isn't it? Was it MST that was the company that was involved in this? Yeah. Yeah. Has anyone got any more questions? Um There's nothing else on the chat at the moment. I mean, if while the questions come through, I'll, I'll bring up a few points of discussion. Um Alex, can you go to a slide about PCR? So pathological, complete response as you know, is complete obliteration of the tumor found on POSTOP histology. And PCR is a concept which varies from cancer site to cancer site. And those of you who are colorectal driven will know that a high PCR rate unequivocally translates into better survival for colorectal cancer. It's very different with OG um unfortunately, so I II remember a 51 year old I operated on it was about, I don't know, five years ago, um who had a complete pathological response from a squamous cell carcinoma, who died of brain mets about 6 to 8 months POSTOP. And I remember getting his PCR histology with great elation and telling the patient of how good this result is. So though they look at PCR here and that was significant wasn't it Alex 12% versus quite a good result. Yeah. Yeah. So, um that as a numerical value is encouraging, but it doesn't necessarily translate into end benefit. Sadly, and that's II II don't know how hepatobiliary cancers compare with this, but certainly with an OG, we don't get necessarily that excited about a PCR anymore. It's better than uh other grades. So the, the way you grade PCR is through something called a Mandard regression grade, which is a tumor regression measurement. Um That is a little bit variable from one histopathologist to another. Um A Mandard one is a PCR. It's a complete response through to Mandard five in which there's hardly been any response. Most would be Mandard 3 to 4. It's, it's also worth noting that I did get a question in the exam about scores and they did ask about histological features of each category just very briefly. Yeah. And that's quite a tough question to be asked about the histopathology. You, you must have been doing well. Um Alex, what are your thoughts about the um event free survival between the two groups? Have you got your slide on that? Cos that's a really important one, isn't it? Because overall survival can be affected by so many other things? But um the P value for this one I seem to remember came close nt point 192. What, what, what are, what are your thoughts about these codes? Cos I think this is important. I thought, I thought, I thought it's quite promising. Actually. I thought that it means that there may be more to these drugs that, that, that these drugs can offer. Um, personally it would be, it would be quite nice for a patient to have, you know, a, a pro, a longer event free survival. It's just that, you know, the fact that it didn't translate to a, an improved overall survival. Yeah. Yeah. There's a big question about why that is, I'm not sure there's any good explanation at the moment. Yeah. So let me tell you guys about Mr W who was um 8 79 80 year old granddad who's very fit and very able came in on the emergency take to our eegs team with a perfect gastric ulcer um had an patch repair. They biopsied it quite rightly and the biopsy came back as gastric adenocarcinoma. Um No criticism but the sur at the time did not look for peritoneal meds because you don't. And unless it's an over cancer, you don't go looking for it. And this chap was then deemed to have a perforated gastric cancer. I think this is a really important point because again, this is where this cancer is a bit odd. Um You would think a perforated gastric cancer should be metastatic. This chap did very well with palliative chemotherapy and one year later, everyone's wondering what's going on here. He's doing very well and his primary has actually shrunk and almost disappeared. So I've done a gastrectomy on him about um six months ago and it's come back as a complete response and he was on pembrolizumab and I don't think palliative chemotherapy alone would have achieved that. So you had palliative chemo plus pembrolizumab. So, from my own personal experience, whenever, whenever I've seen Pemra being used, they've actually done quite well from it. So I think this trend probably is consistent with that and it reaches near significance, doesn't it? Um And these are very potent drugs. I remember when, when I was a trainee that did the Bevacizumab trial and that was a disaster because all these thoracotomy wounds de hest and leaks and so on. Uh And, and that was, as Alex said, um, put down to Bevacizumab. So you're dealing with really potent agents which have made a huge difference for other cancer sites. So probably these two grafts are fairly exciting for us and that it does show a trend. And I think if you were to retrial this with flot alone, we'll actually see quite a big difference. I hope. No, definitely hope so. Um But there was an analogy that I could, I could think of in terms of cardiology where, you know, everyone celebrates the introduction of stents and PC and stuff. But what they found was it actually, it, it, it lengthened their sort of, uh, you know, symptom free survival. But they seem to, to still die. It didn't seem to lengthen the overall survival. They just had another massive heart attack at some point. So I wonder if there was some kind of analogy that can be drawn in in this situation, Alex, you mentioned about operative approach and um our recent critique about neo ages, which is a different trend about chemoradiotherapy. Um Again, some of these big trials because they're clumping together uh different surgical units. And OG is one where um of course, the robotic operation is so much better than the open operation. My open operation that I've done for 30 years is so much better than robot. There's a lot of difference in approach. There are those surgeons who do a very radical operation which I'm a um enthusiast of that proponent of that I should say uh whereas others would just take the primary out and leave a lot of lymph nodes behind. Uh And there's good evidence. Um I had a slide I could have shown about that actually, which shows a good lymphadenectomy radical surgery with high quality control make really does reduce your local regional recurrence rate. I guess the equivalent within colorectal would be the TME how well you achieve that. There's a measurement isn't there for how good your TM E is. Um Whereas for OG cancer, we should work towards um having that, maybe you can develop that Alex quality control for lymphadenectomy. But II think that's an important point because um we have no idea in this trial, what surgical technique was used by the different surgeons. There, there's absolutely no mention of that at all. And that could make quite a big difference here. We, we ii don't think we even know about resection margins, do we? Uh the only mention that are not uh rate again is that, so there's two resection margins within og work the longitudinal margin and the circumferential margin. So they are not that they mention again, we don't know whether it's R one circumferentially or longitudinal. No, there's no mention of the number of lymph nodes, no mention of lymph nodes. No, I suppose they might have put some of that in the additional maybe in the supplementary data, but they should have really made it into the full study. And so, so Alex, um thank you very much if you were to sort of summarize. Um You know, uh do, do you think this was a deserving paper of, of being in the lancet? It sounds to me like it's got a lot of promise, but it's not really the full picture yet and that there's quite a lot of more work to do on it really. I mean, it's a, I mean, it's a major, it's a major trial and a novel topic. So it was always about to, to land in some uh high, high impact journal. Um I think the more important takeaway is that um I think immune immunotherapy you know, it's, it's being heavily trialed in OG Cancers, OG, you know, immunotherapy and OG Cancers is lagging behind other solid other cancers such as uh as we all know, colorectal cancers. Um And I think the algorithm that I showed earlier from ESMO is bound to change radically with each revision um as more and more drugs and more therapies are trialed. So uh certainly uh a fast developing space I would have to say. Uh but at, at the moment, not the standard of care, there's a lot of um debate within the OG oncology community about um other treatments. Herceptin is now standard for metastatic gastric cancer. And you probably will mention that in a minute, Alex um uh micro satellite instability mentioned in the paper. So we now tend to test for that. Um Those are all adjuncts which didn't exist 10 years ago. Um Hopefully now with nivolumab also, um um having arrived will make a difference. But do you want to go on to your F RC trials bit because we can expand a bit more on that? Yeah. Right. Landmark trials for Fr CSI think, I think everyone gets bogged down on these things. Uh But I think it's important to know that this is this, this is not the, this is not what gets you the basic marks in in the station. Uh This is sort of the higher marks. Um So you don't have to know every single trial about these basics. You, you do have to know about these few trials on the screen here. So, uh Magic, that was the O EO two was the original, uh which talked about two cycles of new Adjuvant CISplatin and five fluoruracil with uh with a benefit 23 versus 17%. Um You don't really have to know the numbers either, but you should know the name of the trial. Uh You should know the year that it was published. Um, and you should have a rough idea of what it was, uh, uh, uh what, what the trial was looking at. So, O eo two you can see is, uh, adenocarcinoma and squamous cell carcinoma magic. It's a UK trial, uh, looked at epiRUBicin CISplatin five fluorouracil of which is three cycles of three weeks, uh, and is perioperative. So, before and after surgery, um, and it resulted in a better five year survival. Um, you should know that E CF is probably an outdated regimen and that people would choose oxaliplatin or CISplatin. Um, in present practice cross, this is the important trial that you probably should, uh, commit to heart cross is a Dutch trial. 2012, looked at Adeno and squames. It looked at chemoradiotherapy of which the regimen is carboplatin and Paclitaxel, uh given, uh, with, uh, what 40 grays of radiotherapy and 1.8 fractions over five weeks. Um, you can see it's, it's resulted in both an improvement in adenodes and squames but the benefit in squame is much higher. And this is the basis behind the difference in treatment behind uh adenos and squames as per the guidance. And for S ECs chemoradiotherapy is the standard of treatment. Um You should also know that the Dutch and in the USI suppose that they are very heavily pro chemo ra for uh adenocarcinomas as well. But the general thought um in the local context is that uh perioperative chemotherapy provides better systemic control as opposed to uh chemoradiotherapy. And flot flot is the must know perioperative flot, fluorouracil, leucovorin, oxaliplatin and DOCEtaxel four cycles times two weeks. And flot is a German trial 2019. Uh compared the flot regimen to the magic regimen, median survival, 50 months versus 35 months. Uh And the study claims equivalent toxicity. But I suppose in practice, you should be aware that flo is more toxic than it is more poorly tolerated than the magic regimen. Alex. Can I just weigh in a bit on that one? Um If you don't mind. So, um they're not going to expect you to know um the exact paper um when it was published, et cetera, but it, it's the broad principles of these trials that you will be expected to know. So there's not many cancer sites where perioperative chemotherapy makes a big difference and it doesn't og so perioperative chemotherapy means neoadjuvant followed by surgery, followed by adjuvant and it's really important to try and get the patient through 12 and three. Um, if neoadjuvant fails, the patient comes straight to surgery with compromised systemic treatment and therefore poor outcomes. If your patient has surgery has a big leak or a big septic episode, they may not be fit to have adjuvant chemotherapy. They may decide I don't want adjuvant chemotherapy because it's all a bit too much. It's a huge burden on these patients over a year to go through all of this. So, um what magic showed it was the first trial to demonstrate that perioperative treatment can lead to a 13% improved survival. So that's Cunningham, I think from Marsden, forget about two really cross is really important as Alex said. Um So internationally practice varies. Um generally within the UK, they're very chemotherapy driven. Um some parts of the world, particularly in Holland chemo Radiotherapy and the idea of chemo radiotherapy is to nuke the tumor to bring it down and you increase your arnaud resection rate. But there's one big problem with cross and that is the chemotherapy. The systemic component is only enough to sensitize the primary to radiotherapy. So your systemic treatment with cross is very limited and that's all you need to know. Uh Most of the patients were Squam in that trial. Uh and S ECs have a very good uh chemo radiotherapy response rate. SCC you have a bit more in the way of options because squamous cell cancers, you know, are radiosensitive. Um and then in comes flood, which is Al Batra German trial, as Alex said, uh so subsequent to magic, this is the next substantive perioperative chemotherapy trial. Four cycles of um flot. Now flot requires for the fluorouracil a PICC line to be put in. Whereas the ECF of magic, you can pretty much have a lot of it at home. Um because they, they, they're tablet based, whereas flot you need to have a Picc line. So often these patients have a Picc line through uh neoadjuvant surgery and adjuvant as well. Um Our data shows that and this is local data only that flot is actually less toxic than F and II would agree with that. We're definitely seeing better PCR rates. Um And actually, and very importantly for our Norfolk folk, elderly patients tolerate it much better than ECF. So that's pretty much the flow of all of that. And if, and if you can regurgitate some of that, that will be plenty. You don't need to know very specific trial details. You need to know what's what, what, what's the main take home message from the trial? Is that fair to say Alex? Yes. I mean, there will be some who will try to be funny with you, but that's probably because you were doing very well. They pushed you um and something a little bit more recent uh neo ages and that was mentioned earlier, which is cross versus perioperative chemotherapy. Um Well, they studied underpowered and incomplete. So kind of pointless. But you go, it showed it showed equivalent outcomes uh that one was not inferior to the other. And of course, it just fed into uh the biases. So the Dutch will say, why put the patient through perioperative chemotherapy if you get an equivalent outcome with better local control. And of course, it doesn't sway the minds of those who believe in perioperative chemotherapy. And of course, we also have to acknowledge the limited flat group uh in the trial. So when, when cross came along, they coined the term the Dutch mafia that were running cross. Um So Neos was to compare the cross mafia work with ECF because CF was at the time the only really effective magic chemotherapy. So whoever was running this trial, Reynolds, they, they, they must have felt terrible when flot came along because it completely was the trial because you suddenly had a very effective chemotherapy. So your ideal trial is now Abec which is flood versus cross. But I suspect that that will be superseded when the next immunological comes along as flood came along with neo ages. But again, with neo ages. Uh I mean, we, we, we, we wrote a letter about this. Um they had no standardization of surgery. There was some thoraco thoracoabdominal mcewen, every um approach to OG cancer appeared in that trial. Um Brett is just asking uh on the, on the messages. So if you need to have a pick for the fluorouracil um uh would using capsine uh be an alternative. And is that ever done in, is that done much in? Yeah. So I ask you a lot of questions, Brett. Um You, you're quite right. That's a good point. Um Capsine can be given orally. The problems are two fold. Um One is a lot of these patients are obstructing, um obstructing esophageal cancers. So, um they would have variable intake of capsine. Um We also know that the thrombogenic rate of Capecitabine was higher than fluorouracil. So the point Brett's making is that uh now let me get this, the right way around capsine is the pro drug to fluorouracil. So if you can give it as a tablet, it's converted to five, a few anyway. And that's better than giving infusional. But the infusional one, Brett um is more reliable. So we've stopped having to put feeding tubes for these patients since flot to come along. We, we, we do a lot less in the way of feeding geos is because otherwise you had to put a feeding tube in for them to get their capsid to in. No need to apologize, just pulling your leg. All right. Brilliant. Thanks, Alex. Um Is that the end of, do you have any more slides on that? Um This, I would say this is all we need to know with regards to trials. If you look, I'm sure there's other trials out there. Um in revision materials that I've read about comparing D one versus D2. But no, no, no, I think that's a great summary. I think that's just exactly what we all need to have in our mind. Um Brilliant. So, uh we'd like to move on just for the last sort of 1015 minutes just to um any sort of broad strokes to the exam. Alex, you mentioned quite a few things already. Um But we'd love to just, yeah, if you want to take us through the academic station, your experience and any other um advice from Mr Kumar, that would be great, right, Alex. So with regards to the academic station, I think you need to know that the examiners, they are not, you know, they are not, they're not all professors, the vast majority of them do not care about any kind of uh medical literature and they are bored, extremely bored listening to the same thing over and over again. So you should expect a paper um that's fatty shoddy in its uh in its nature. So there will be plenty to criticize some uh in my, in, in my, in my sitting. Uh half of them got a paper that had no stats at all and it was something like a like some kind of letter to the editor. So they had no clue how to really approach it. Uh and they all scored very well. So I think the academic station is a little bit of uh as long as you can, you know, talk about the paper, um you, you will score well, and I think the main thing is systematically breaking it down, like, you know, you would do for any journal club. And the they want to hear what is your opinion on the paper and what is your practice? Uh So you should, you should know that the, the exam is always about what you want to do and what you would like to do. Um So the paper should always be evaluated in that context. Um Or your experience. Uh For example, my paper was something about um um non colorectal surgeons having a worse outcome in emergency colorectal resections. Um And it was like some kind of swiss paper or something. Uh You know, I was halfway through it, slamming it and the, the examiner, he had zero interest and he, in the end we came to the agreement that it was a rubbish paper and we sat there for three minutes in silence waiting for the next uh sort of question to begin. So there was a really sort of awkward moment, aren't they that every candidates taking the exam will come across some odd body language from an examiner. Um in my critical care station, I remember it was so late in the evening, the poor chap was in agony. I was fine but he was suffering and he actually turned his back to me and put his hand on his head. He, he just could not take it anymore. So you must never think that that body language equates to you doing badly. It's just sometimes the examiners have had a long day and they're looking to get out and you've passed, you've done, done very well. I would say one really important thing which I witness this is if you start arguing with the examiners don't, ok. You, you've, you've got to back off from, you've got to resist. Even if you have an authority within that particular paper or the, the topic in to hand, just keep it simple. You're just trying to get through, don't engage in a, um, your right over them type of approach because that, that's gone horribly wrong for a number of a number of candidates. And I think it's just the stress of the occasion, which can, which can do that. Um So keep it really simple. We, we've had one, um, colleague of ours here who, when he took his exam, the academic exam, the statistics, the examiner asked him. So what do you think of the stats here? And the candidate said, II, don't know if it's too complicated. I don't understand it. And the examiner said, well, I don't understand it either. So let's just move on. So the stats bit is not going to be in a huge amount of detail. And as Alex said, sometimes it doesn't even feature, does it, what what I think does matter for the um academic station is Alex. Can you go back to your lancet slide? So when you, when you get the paper don't panic, if it's something which you don't know too much about the theory, but you need to demonstrate the principles and I would present this along the lines of, um, I don't know. Thank you very much for an opportunity to discuss this paper with you, which is published in Lancet Oncology very recently. And it raises a very important topic within OG um cancer surgery. That is systemic treatment for blah, blah, blah. It's a sizable study which is Multicenter International um and was published in wherever in whichever journal you can mention the impact factor. So you, you talk about it in a way that you convey, examine that you've read a paper before that you have a bit of a system to analyze it. Um And they're not looking for um real fine detail. I mean, looking at that, I can see that Al Batran who described the flot trial, who ran the flot trial is on there. So if you know that by all means, mention it, you can critique where the authors are from if the authors have a particular um notoriety within um what whatever the field is mentioned that you can say, um Shata has run a number of OG CANCER trials before. So whatever you know, to set the scene, well, could make a big difference and a lot of the exam and I welcome Alex's view on this. A lot of it is first impression. How do you begin? You do not want to begin any station particularly badly cos if you begin, well, generally they'll, they'll go along with it. Um, and then have a system for how you present the paper. And if you can demonstrate the system, it shows that you've got the ability to pick out the key points, put it forward and you can tell them, I enjoyed reading this paper. This um has given me some new insights into OG cancer management. I wasn't aware of um immunologics before. I'm aware of that immunological um agents have revolutionized cancer care within Melanoma and lung cancer and so on and keep on talking. They're bored, they're looking, they're looking to pass you. Yeah. No, always, always put a personal spin, always try and make it, you know, unique to, to your, your approach. Um They don't want to hear cookie cutter answers, they're bored of that. Um Try and entertain them if you can. And um you know, it is a very personal exam. So uh you know, use it to your advantage. Um Don't, don't think along rigid lines. Yeah, that's a really good point. Talk from your experience. You're all by that stage going to be very experienced as trainees. You would have seen a lot of thanks to the UK training. A lot of breadth, maybe not so much the depth in training, but you would have seen a lot. So you're well placed to be able to comment on um, some of these papers quite well from, from some angles. So if it's a hepatobiliary cancer, talk about it from your expertise within breast cancer or um og or whichever other cancer site because the oncological principles apply. So don't panic if the subject is not something that you know, a huge amount about because it's, it's an exam where you demonstrate principles as a, what is it? Day one DGH consultant. That bar is not that high any more slides. Alex. Have you got a bit more at the end? And I think that's it. I think you're nearly there, aren't you? Ok. Oh, there you go. Last slide. So it's interesting that they have such a range of papers in the exam and that you can get something without statistics. But I think it's that you said it's just about having a structure, whatever it is. And the idea of trying to, um, make their day slightly better by saying something different or interesting is, uh it's quite a good point because I'm sure it's very easy just to get caught up in the um exam and personal experience. I'm someone who reads a lot into body language and what looks somebody has and so on. And I can tell you having organized the exam being at the other end, I'm sure, in many ways, there's more nerve wracking than taking the exam itself because you're so worried as the examiner, particularly for a new examiner about getting this wrong. So if your examiner looks very serious and tense, they may be more nervous than you are. Don't forget that. And there's quite a few junior examiners now, particularly who are not particularly well prepared with the process. So don't read too much into it into the body language. That is well, thank you very much. Um I uh really delighted that you were getting this um advice on how to do it all and Alex thank you very much for going through that paper in depth uh and, and presenting it so nicely so that we could all follow the important parts and there's lots of thanks coming through on the chat right now. Um And I'm sure that's a very good place to, to call this to a close. So thank you everyone who's been listening, Mr Kumar. Thank you very much for your No, thank you for the invite and thank you all for making an effort to attend so late. Uh and I, and we'll call it, call it an evening. So, Alexa, thank you very much. Cheers. Thank you. Good night. Good night. Thanks Alex. Good.