So, so I was going to, I know, so I know it's come up a few times and so this is going to be a very quick run through the studies in adjuvant radiotherapy for endometrial cancer, why we currently recommend what we do. So I'm apologising, that'll be quite quick. But when we're going through, just quickly, the background, obviously, as soon as radiotherapy was sort of isolated in terms of radium, initially pre-operative radiotherapy with brachytherapy was standard of care, really up until the 1970s, when the move was much more to post-operative radiotherapy based on pathology, because it was noted that actually the outcomes for stage one endometrial cancer was so good that really there were concerns about over-treatment. And I would say over the last 50 years, a lot of the studies have been looked at de-escalating treatment and very much focusing on trying to identify those patients that are particularly at risk of recurrence. And those are the patients we should think about adjuvant treatment. So in terms of the sort of studies that have happened that have compared pelvic radiotherapy to no radiotherapy, or to vaginal brachytherapy, we had a sort of a group of studies and I've just put all the numbers and you can see it's over 2,000 patients in these studies. And just when I go through the studies, it was to say that the staging has changed. So when I talk about the studies that were there, the key trials I think that I was going to start with are the CORTEC trial. And you'll see this is the oldest staging. So stage 1C is now stage 1B. These were patients that did not have lymphadenectomy, but were randomized between pelvic radiotherapy and no further treatment. And within this group, there was no difference in overscore survival, but there was a reduction in local recurrence, 40% to 4%, but much greater toxicity. And we had similar results in the GOG99 studies, same randomization, but these patients did have lymph node dissection. Again, no difference in overall survival, but reduction in local recurrence and significant increase in toxicity. But I think from these, both of these studies, it was really quite key to look at, can we identify those high risk features? So GOG99 identified the risk factors of high grade, age, LVSI and deep myometrial invasion. And in the high intermediate risk group, the risk of recurrent local recurrence was 26% without radiotherapy down to 6% with radiotherapy. And very similarly, independently, the CORTEC trial had similar conclusions. Again, local regional recurrence, if they had two risk factors of over 60 years old, grade 3 or deep myometrial invasion, risk of recurrence came down from 23% to 5%. And CORTEC group also applied the GOG criteria and got very similar results. So it shows that radiotherapy can reduce recurrence, but at the risk of toxicity. So we look at the sites of relapse within those trials, and whether or not patients had lymphadenectomy, there was great similarity in terms of patterns of recurrence in that the majority of the pelvic recurrence, over two thirds of them in both studies, occurred in the vaginal vault. So it led to the CORTEC-2 trial, which then compared external beam radiotherapy to vaginal vault brachytherapy for that cohort of patients with the original study. So two risk factors, intermediate risk, we would call patients with that. And again, within that, there was absolutely no difference in overall survival or disease specific survival using brachytherapy versus external beam radiotherapy. And that really led to our standard of care for this group of patients that we would offer brachytherapy rather than external beam. And in this data, it's whether or not they had had lymphadenectomy. So the conclusions were that the benefit of external beam was limited, there's no impact on overall survival. And actually, some of that is because you can salvage local recurrence, but that radiotherapy with external beam has significant toxicity. But I always add in that we have to say these conclusions are only valid for this group of patients, and with those treatment techniques that we used at the time. And the reason I say that is when we're thinking about adjuvant treatments, it's always balancing what's the additional benefit for survival versus the toxicities. And I mean, I'm talking because I'm conscious that when we're thinking about adjuvant therapies, it may be very different, depending on which techniques you have available to whether or not you consider that increased toxicity a sufficient balance. So in terms of vaginal vort brachytherapy, your target volume is just the vaginal vort. So we're aiming to treat the lymphatics around the scar. So it's only a depth of three to five millimetres that we're actually aiming to treat. And we treat the top three to four centimetres of the vagina. So it's a very small target volume. The treatment is given with three or four insertions into the vagina or after external beam a little bit twice. And in terms of toxicity, really, there's no significant late toxicity reported with this, even in large cohorts. The impact on bowel and bladder is exceptionally low. What we do have from the CORTEC-2 trial and the quality of life is it can impact on sexual function. So younger women who actually lower risk of recurrence may consider not giving any adjuvant treatment. What about external beam radiotherapy? Well, again, this is conventional radiotherapy. And this is where we have to think about the techniques we're using, because the target volume here are the pelvic nodes, the parametrium and the upper vagina. So much more higher when we're looking for higher risk patients, those that are node positive, we want to include the nodal region. But if we look at the CORTEC trial, actually, there was very significant toxicity. And in the CORTEC trial, the techniques used was either two field, so coming through and through the whole pelvis, or a four field brick. And there's significant toxicities there are up to 20% of the four field brick. So that probably doesn't justify, you'd have to have a high survival advantage to be considering some of these treatments. Of course, where we are moving to, and if it's available, is now would be the standard of care is intensity modulated radiotherapy, where you can fit the dose more conformally to your target volume. So to treat the pelvic nodes, you can shape it around a lot more of the bowel and the bladder. And there's very significant reduction of toxicities in this technique. And if we look at the RTG study, NRG, which is really our first study, looking at comparing conventional to IMRT, the primary endpoint here was patient reported outcomes. And we see both with acute toxicity and late toxicity, but with IMRT, there's very significantly reduced toxicities. And that leads into the studies that I'm going to just talk about in the last few minutes of the more recent trials, where we're starting to see IMRT being used, and we can see that then the toxicity becomes dominated not by radiotherapy, but by chemotherapy. And the other reminder really is why I talked about you've talked about the cohort of patients is in the randomized trials, all of these up to now looked at really what we'd call intermediate risk. So low to intermediate stage one disease, not a high risk patients. We look at the incidence of endometrial cancer, the majority of patients have grade one, grade two disease. But if we look at the depth, that's actually not the patients that die from endometrial cancer. It's our grade three, it's particularly patients with serous, this didn't include but also carcinosarcoma, those are not patients that have been included in the trials. The PORTEC trial did recruit patients with grade three, old one stage C disease. And again, when we look at the bottom here, looking at the local regional recurrence, and all of these patients got radiotherapy, but you can see the distant metastases compared to the PORTEC trial arm to the high risk patients significantly increases to over 30% and overall survival drops. So we're looking at a different group of patients here. And I think it has to be remembered when we talk about using adjuvant treatments, that you can't apply those early studies in patients. Other histologies, just a reminder, these are the survival curves, even stage one disease with serous carcinoma do badly and carcinosarcoma even worse. Only the final factor that was identified, again, PORTEC has been really seminal to a lot of our work that we that we use to define our groups, was looking at the impact of lymphovascular space invasion. And whereas before we may talk about just if it's present or absent, actually now we recognize that if there's substantial LVSI, and again, Gustavo may be able to tell us that there's variation in how that's defined. So whether that's three or five foci, but substantial LVSI in much higher risk of developing. So that leads to the sort of three trials that we had over the past three years that have all reported that I think have really clarified now where we're going with our treatments. PORTEC 3 looked at high risk patients, so they all got adjuvant radiotherapy, but it's whether or not you include chemotherapy in that cohort. And overall survival for the whole cohort was a small survival benefit with chemotherapy. But particularly, there was a significant progression free survival benefit in patients with stage three disease. So if they have lymph node involvement, the addition of chemotherapy to radiotherapy is now the standard of care. What we also have, and that's just shown here, what we also have is GOG 249. Now, part of the argument for that was if radiotherapy has such high toxicity, is it preferable to give vaginal brachytherapy and chemotherapy? And so patients were randomized between the two. And I think there was some surprise with this in terms of the results, but we can see the two arms absolutely overlap, so no difference between the two approaches. But in this trial, the majority of the patients had IMRT. And what we start seeing is actually there was more toxicity, certainly more acute toxicity with chemotherapy rather than radiotherapy. There was more local regional relapse, obviously, in the cohort with chemotherapy. And actually, the conclusion from this is external beam remains the standard of care as it was prior, although there can be discussion about serious carcinoma, which would be out with this. The final study, just very quickly, when we're looking at adjuvant radiotherapies, GOG 258, which was looking at advanced disease, so stage four, stage three with residual disease. And so much, much higher risk patients. And this compared chemotherapy to chemoradiation and chemotherapy. And again, overlapping arms. The big difference, there was this patient, all of these patients, we have to bear in mind, almost all had lymphadenectomy with a lot of lymph nodes removed, which is now not the standard of care if we've moved to central lymph node. But the difference in terms of site of relapse was there in terms of local regional relapse, much higher in the cohort with radiotherapy, more distant, potentially, to those that had less chemotherapy. So lots of discussion, but I think it's started to show us how we should be managing these patients. So that leads into our sort of guidance on risk groups, and that's how we consider our treatments. And these are the 2014 ECHO ESMO consensus guidelines that you may all be now familiar with in terms of the categories. And that was really based on these trials and identifying the risk groups. Following this, we sort of, with the risk groups, then break that down into who gets vaginal brachytherapy or external beam. The most recent update following from these guidelines is the addition of molecular classification. And I'm not talking about this, we could fill a whole hour, but just to sort of remind you that we now identify different risk groups based on molecular classification, individual cancer. And again, here we see the PORTEC, this is pulled data from the PORTEC 1 and 2 trials. So you see how beautifully the PORTEC trials have given us information on these risk groups. And the bottom line is those are people with serious carcinomas, but how we could be basing it on classification. So really, my final point when we look at this is these are now the latest guidelines that we have from the ECHO ESMO. Whether or not you know the molecular classification, but the difference based on the other studies is that what was previously called high intermediate risk has moved to just intermediate risk, other than those that have extensive LBSI. High intermediate risk group now relates to high risk stage one disease, where external beam radiotherapy would be the standard of care, and high risk are those patients where chemotherapy comes in. And I've just summarized this on my final slide in terms of the risk groups, so low risk patients with no further treatment. Intermediate risk, so those that either have low grade tumors of grade 1-2 with deep myometrial invasion, or stage one disease with high risk histology, and that also includes 1A non-myoinvasive serious or carcinoma, so another change in the classification. High intermediate risk, we'd give external beam radiotherapy, but could give Volk-Brachytherapy if they've had no staging, and then high risk get external beam and chemotherapy. Thank you. That's my oversight.

adjuvant radiotherapy

endometrial cancer

toxicity

chemotherapy

current guidelines