And can you also see my cursor? Yes. Okay. Excellent. So now this presentation actually, even though it is given as a didactic, but actually it is not actually a presentation. I'm just trying to introduce certain concepts and, uh, uh, I don't mind people asking me questions right in the middle of my presentation. If there are concepts which are difficult or not very clear or I'm not able to express well, please interrupt and ask questions in between. It's it's fine. Now this is a very interesting, uh, review paper which people may want to read. Uh, and it actually gives the pathological prognostic factors and historically one of the first, uh, a paper that came out, which, which classified endometrial cancer into type one and type two was by Bookman in 1983 and we know now good prognosis and bad prognosis or the endometrioid and the hormone dependent versus the other. And about soon afterwards, uh, Creaseman with GOG study showed the importance of histological grade and myometrial invasion. And that came around, uh, 1987 and then it took quite a few years before Odichino, uh, described the importance of lymph nodes and it was only around about that time, about a year or two later that the staging of endometrial cancer from clinical actually became surgical because of the prognostic significance of nodes became quite apparent. And relatively recently, many, many people have described the importance of lymphoblastic space invasion. Now this is a publication of FIGO report 26, a 2006 report, uh, it is based on the contribution from all around the world as patients as they came to the clinic and were managed with the curate, with the, with the curative intent, if they were curable and there were 8,807 patients. And if you see that patient as they present in the clinic, as they walk into the clinic, most of the patients are actually stage one, all 71%, then a stage two and three are 12% and 14%. And there are very few, which are actually stage four. Now if you look at the distribution, according to the grading stage, again, uh, the bulk of the patient as they walk into the clinic actually belong to a stage one and two and grade one and two. There are relatively fewer patients who are grade three endometrial, uh, or, uh, and when I say grade three, they include serious and clear cell. And in stage three and four, again, there are quite a low number of cases. So the bulk of the patient as they present, they are actually stage one and two and they are grade one and two. Now if you look at the grade and myometrial invasion and the node positivity, again, you will find that the bulk of the patient who actually are stage one and two, they sort of tend to be a inner half of myometrial invasion and node positivity is only 2% or 4%. But when the grade three, uh, disease is seen, even in the inner myometrial invasion, you have 8% node positivity and the outer half of myometrial invasion in grade one, two, and three is given here. So now most people actually do not do lymphadenectomy in all cases. Now of course, because they can do sentinel node biopsy, they've started doing lymph nodes in all the patient, but normally they will open the uterus intraoperatively and see grossly whether myometrial invasion is seen or not seen. And whether it is grade one and two, then they may decide not to do lymphadenectomy. But in case your impression is that outer half myometrial invasion is involved or it is grade three, then I think these patients would benefit from lymphadenectomy. Now you can see that the study such as Aztec study have shown that there is no benefit in therapeutic benefit in doing lymphadenectomy, but you can imagine if the vast majority of patients are presenting, which are like this, how on earth are you going to show the difference in the lymphadenectomy or not lymphadenectomy? It will require thousands and thousands of patients. Now of course, it would help if you are able to assess the myometrial invasion even before you operate. And that is where, for example, you have also done MRI scan to at least have some idea. So if you can see the myometrial invasion through imaging, then you may decide even before you are operating and if it is grade one and two, whether you should go ahead and do a staging or not. We wrote a review about the role of imaging in the endometrial cancer. I think it's a reasonable review. Ming-Yin is my colleague, Andrew is a radiologist, Orla is a gynecologist, and you probably are familiar with Nadeem Rustam who is Central and North Biopsy and a lot of work on endometrial cancer. Now based on the historical knowledge and so far, we have come to this matrix and this is what is actually used more or less around the world when you have clinical stage one and two disease and the lymphadenectomy is not done. So if you have stage one and two disease, there were no suspicious node, but you did not do a lymphadenectomy, then this matrix is what is used. So here you have grade one, grade two, grade three, and on this side is no myometrial invasion inner half and outer half. So if you have patient in these category here and there, then they don't need any adjuvant treatment. But if they are grade three, there's sometimes, even if there's no myometrial invasion, occasionally we still give water break therapy. Otherwise, if lymphadenectomy is not done, then in inner half myometrial invasion, whether it is grade two, it is questionable whether you should do or you shouldn't do it. But certainly if it is grade three, you will do the lymph node dissection or rather give external beam radiotherapy if you have not done the lymph node dissection. If there are outer half myometrial invasion, then obviously you will give pelvic radiotherapy if you have not done the lymph node dissection. Now we looked at the histology lymphovascular space invasion and nodes in 2012. Our conclusion based on near about 325 patients at that time was that for overall survival, it was only the lymphovascular space invasion which was significant. In particular, in present of LVSI and nodes, histological type, grade, and myometrial invasion actually were not significant either for relapsed free survival or overall survival. So that is interesting. And the reason it is interesting is that how does the tumor volume, myometrial invasion, and the type of histology then interferes. Now here is a concept that you need to grasp and then you'll be able to follow the rest of the presentation a little bit better. Now when you have an advancing front of tumor and once it penetrates the basement membrane, the tumor cells have access to the terminal lymphatics which are found everywhere in the tissues. If it is well differentiated, then even the infiltrating tumor actually still makes gland and is somewhat bulky and is not very easy for such a infiltrating edge to be sucked into the terminal lymphatics. But if it is poorly differentiated, then there are single cells floating around and it is quite easy for those cells to get diffused or passively sucked into the terminal lymphatics. Now from terminal lymphatics, it goes to the lymphatics and from lymphatics, obviously it will go to the lymph node. But throughout the body, there are lymphatic venous anastomosis happening everywhere. So what can also happen is that cells which are in the lymphatic space, they of course they do go to the lymph node, but at the same time, if there is a back pressure or something like that, then the cells from the lymphatics, even before going to the lymph node, can go into the systemic circulation. So if the more stations of node are involved, then this surface area of the lymphatic venous anastomosis also increases. So you will notice that if many nodes are involved, then possibility of systemic metastasis is also higher proportionately. Now we studied over a thousand patients between 1996 and 2014. And although there were few postoperative cervix involved in this, they ignored those patients. But here, all I'm trying to show is that all comers, as they came, they have been included in the study. So there has not been any patient selection, as you can see. And our referral pattern has stayed the same. So now I am showing you the survival and the outcome in endometrial cancer patients who are treated by surgery and adjuvant postoperative radiotherapy. And these are 1,187. And FIGO stage 1 to 3, because FIGO stage 4 is difficult to treat curatively, so I have only included stage 1 to 3 that are all treated with curative intent between 1996 and 2014. And the adjuvant pelvic radiotherapy consisted of either pelvic radiotherapy, adjuvant treatment was considered either pelvic radiotherapy or adjuvant ball brachytherapy. And few patients would have also received systemic chemotherapy, but this is a minority of patients. Histology included the endometrioid and mucinus, or clear cell and cirrus. And survival and patterns of failure were studied in relation to the histology grade tumor volume, myometrial invasion, and LVSI status and the nodal status. So the step one was to find out the significance of the tumor volume, histology grade, and myometrial invasion in absence of LVSI and node. Now that is important. So we should only include patient if we are trying to find out the significance of the tumor volume, histology grade, and myometrial invasion, that we remove this factor, which is quite prognostically significant, and let us see how these things interact. So in order to do that, it was necessary to only take patients who were in FIGO stage 1 and 2. Why? Because most of the time, of course, the myometrial invasion is seen in the uterus, and LVSI is usually also scored in the uterus. But suppose if you were to take stage 3, then there may be no LVSI, for example, in the uterus, but there may be LVSI, the disease which is outside, and you haven't scored it. So in order to find out this relationship, I chose only stage 1 and 2 patients. So there were 483 patients. Grade 1 and 2, I had combined together because they behave similarly. So there were 314, grade 3 were 90, clear cell 34, and CS were 45. Myometrial invasion, 291 had inner half and 192 had outer half. If you look at the tumor volume, it varied from 0.2 centimeter to 15 centimeter, and the median was 3.5 centimeter. Now you will see that if the tumor is directly going, the tumor cells are directly going from the tumor into the circulation, then larger tumor with larger volume will have more chance of going into the systemic circulation than this small tumor, because of the blood volume and the capillary volume is obviously much more in the larger tumor than the small tumor. So let's see what we find. Now here is the freedom from the distant metastases. Now I particularly taken distant metastases because the general belief is that the distant metastases occurs because tumor cells from the tumor go into the defective blood capillaries and are disseminated. Now if you look at first on this, I have dichotomized the volume because the median value was 3.6 centimeter. So less than 3.6 centimeter volume, there were only 23 relapses, so 8.5% relapse. When the volume was higher than 3.5 centimeter, the relapse rate is still the same. So in other words, if patient does not have lymphovascular space invasion, then a large tumor doesn't necessarily is worse compared to the small tumor. Now if you look at the myometrial invasion, you will notice that inner half and outer half, 291 inner half, outer half 192. And again, the rate of metastases is 8% and just 10%. Now if you look at the histology, these are adenocarcinoma grade one and two, adenocarcinoma grade three, then clear cell and serous. And again, you see that there is actually no difference in the metastatic rate. Now there are large numbers. These are all intermediate and high risk patients. So I haven't got any low risk patient. So out of such intermediate and high risk patient, you've got such a large number of patient where actually they are not showing any difference. That means histology, if it is showing the effect, it is actually not showing effect because it is biochemically different. It is showing effect through lymphovascular space invasion. Is that so far any questions on this at all? Now the other interesting thing was all patients who did not have LVSI and who did not have lymph node, if they were poor grade or what we perceive was high risk because these patients have been treated since 1996 and the knowledge accumulated slowly. So we did not know whether we should give valve brachytherapy, we should give pelvic radiotherapy. So sometimes we gave valve, sometimes we gave pelvic radiotherapy. But the interesting thing is this. So if we look at the valve brachytherapy, these are broken lines. And if you look at pelvic radiotherapy, they are solid lines. And these are the relapses. So what is the relapses? Here is the vagina vault relapse. Now there's hardly any difference and these are the percentage that has relapsed. So first of all, in absence of LVSI, very few are relapsing. No difference in the vault relapse, no difference in the pelvic relapse, and no difference beyond the pelvic relapse in the green line. So whether you give vault brachytherapy or you give external beam radiotherapy, it makes no difference. And the histology doesn't make any difference if LVSI and nodes are negative. Now, the second step was to actually now having eliminated the tumor volume and the myometrial invasion. And so we then wanted to see how does the histology grade in presence of LVSI and lymph node get affected. So that was the step two. And we again, in this case, the entire cohort was taken. So it is 1,187, stage one, two, and three. And these are the numbers of different patients. Now, overall, LVSI positivity was 53%. Now, this is a very high percentage. And the reason it is very high percentage because they are intermediate and high risk patients. So we do not have any low risk patient. And the overall node positivity was about 18%. Now, if you want to see this in perspective of what happens in the general population of endometrial cancer, well, these are the ASTEC figure here, where it was published in Lancet. And you can see that 80% were endometrioid carcinoma. And our case is also 80% are endometrioid. But of course, others are clear cell and serious. And in this case, there were many other types. But you can see that the LVSI rate is about 20%. So having LVSI rate here is that they are high risk patient. Now, the other thing is that the node positivity in that study was about 9%. And of course, we have got 80% nodes. Now, in LVSI positive patients, the node positivity was 28%. But in LVSI negative percent, node positivity was only 6%. Now, it is not possible that there was no LVSI and you have got lymph node metastasis. The thing is, when you see the LVSI, you only see it as an embolus, which is sitting in the lymphatic space. Now, it may not be there because it has all been washed away. So not necessarily that you will pick up every LVSI. And here is the result. Now, this is a little bit complex table and big table. So I'll be a little bit slow. And this is the main thrust of the presentation. If you look at, so what are these? These are the columns. First column is showing different categories of prognostic group using just plain histology. Here is the column of lymphovascular space invasion, whether it's present or not present. And there's the nodal column, whether the node was positive or negative. And these are the relapses. So if you look at the grade 1 and 2, LVSI negative, the relapse rate is about only 9%. And there are quite a lot of patients here. If you look at grade 3, LVSI negative, no negative, relapse rate is only 9%. Clear cell relapse rate is 11%. Serous relapse rate is 18%. Now, one of the reasons it is slightly higher here is because I believe, as you know, the origin of serious cancer is supposed to be from a particular kind of epithelium that is also seen, for example, in the fallopian tube. And many of these patients who are LVSI negative, node negative, they still relapse. They actually relapse not in the pelvis. They can relapse even in the abdomen. So there can be two things. Firstly, that it is probably spreading through the coelomic axis into the fallopian tube and going this way. Or it is actually a new primary because it is not uncommon to have a multiple focus of the serious cancer. So that may explain why it is slightly higher. But otherwise, through lymphatic dissemination and relapse rate, there is actually no difference between the histology and the relapse rate. Now, if you look at the LVSI positive, but node negative, so you can see that the tumors start to disseminate here. And now we can see that the relapse rate actually start to increase 21%, 26%, 32% and 22%. But most of the relapse, which is actually happening is in endometrioid grade three, clear cell and serious. Here, if the nodes are positive, interestingly, relapse rate hovers between 51% and 64% and they're almost identical. And the reason for this is that the dissemination of disease is happening when the grade is poor because there are many more fragmented cells and they can get into the lymphatic space and they can metastasize. Now, if you are going to do clinical study and if you keep recruiting patient who are clear cell, but they fall in this category, if you recruit also clear cell, which are falling in this category, now there are 40% patient who were included in the PORTEC3 study, which according to them were high risk, but actually they were LVSI negative and not negative. And therefore the relapse rate was so. So the first time when the result came out, it was actually not significant. So if you really want to select high risk patient where you want to see whether the systemic chemotherapy is effective or not effective, there's no point in taking low risk patients like this, but rather that you should take this group in which if it is effective, then it will be effective. Now, the other interesting thing is that whatever treatment we have given, whether it is WALT brachytherapy or the pelvic radiotherapy, the pelvic relapse alone has been very, very few and not only very few, but a whole lot of people have been able to salvage if there was isolated pelvic relapse. So whatever we are doing, as far as the pelvic control is concerned, from the present criteria and the present management, we have got excellent pelvic control. The problem actually arises outside pelvis. And as you can see, these are the relapse rate. So in other words, if 9% patient have relapsed here, then 72% of the 9% that have failed, they actually failed outside pelvis. And again, it is quite remarkable that when patient fail, the percentage who failed outside pelvis is almost similar except for in the first two categories. You see, it is almost always same. So when you look at the patterns of failure, those who fail, the pattern of failure always shows multi-site failure. So again, this shows to me that the tumor is disseminating using the same pathways and it actually doesn't matter whether it is endometrioid or it is clear cell or it is serious. If it is failing, then the pattern of failure is similar. Now, this is actually, if you look at these columns, this is the vaginal vault relapse. Here is the pelvic relapse. This is the pariotic relapse. And this is the distant relapse. Sorry. So each row is one relapsed patient. So as you can see that most of the patient have failed in multiple sites. If you want to see only the distant, then only these patients have failed in the distant metastasis, like lung and so on. These patients have failed in pariotic area and distant. These have failed in the pelvis, pariotic and distant. And these have failed in all sites. If I shuffle in another way, then this is the only patient who are here on the left hand side corner who have failed at the vaginal vault and all of them have been salvaged. And few of them have been salvaged here who have failed only in the pelvis and everything else has failed at the multiple site. And we also looked at the time to failure. Now this, of course, this slide doesn't belong only to the endometrial cancer. There are also about couple of hundreds postoperative cervix is involved, but here I'm simply trying to explain a concept. And the concept is that if you look at the LVSI negative, node negative, LVSI positive, node negative, pelvic node positive, pariotic node positive, and these are the failure rate. So the freedom from the local regional failure and the freedom from the distant failure, there is actually timeline, there is no difference. So what it means to me is that the failure that happens distantly are not the distant metastases which remain undiagnosed at the time of treatment, but rather that after we have surgically staged them, and then we are treating it. So either they are disseminating during surgery or they are disseminating during radiotherapy afterwards. And that's why the time to relapse in different site is still the same. And we submitted this hypothesis in a nature review in 2017. Does the mobilization of circulating tumor cells during cancer therapy cause metastasis? So having explained how the pathological factor alone can significantly stratify patient in different prognostic group, here is our recommendation as to how adjuvant treatment using radiotherapy we can use. So the criteria for vajanavar brachytherapy are for stage one, that is node negative. Grade one and two, inner myometrial invasion, LVSI negative, or even if LVSI is positive, we will not give any radiotherapy. In grade one and two, after myometrial invasion, if LVSI is negative, then no radiotherapy. Grade one and two, after myometrial invasion, if LVSI is positive, then we might give wall brachytherapy. I must say, I still do not know whether LVSI can be effectively treated with wall brachytherapy. But for want of anything else, for want of any other evidence, we still give wall brachytherapy. Grade three, no myometrial invasion, no small primary, we won't give anything. But if it is grade three, large primary, then we might give wall brachytherapy. In all other grade three, with any myometrial invasion or any LVSI status, if the nodes are done and they are negative, we will only give wall brachytherapy. In selected grade three, with heavy LVSI or deep myometrial invasion, nodes are done and they're negative, we may give central pelvic radiotherapy. And I'll explain what is central pelvic radiotherapy. Now, I'm skeptical about the Vajanan vault brachytherapy, and the reason is this. Here are a collage of the different Vajanan vaults that we put KY jelly with barium in order to see how the vaults, Vajanan vault look like. And you can see the Vajanan vault can vary from something like three centimeter to almost nine centimeter. And these are the Vajanan vault applicator that we use. Now, it is almost impossible to put Vajanan vault applicator and try and see that the dose is uniformly distributed in Vajanan vault. It is just not possible. And if you see things like this, the vault will, applicator will come here, but this area will not be treated with the vault brachytherapy. So, I'm pretty sure that we are giving vault brachytherapy to a whole lot of patients and we think that it is effective. In fact, they may not even need vault brachytherapy because vault brachytherapy is very imprecise. And you can see why it is imprecise. Now, criteria for the adjuvant radiotherapy in a surgically staged patient are that if for stage two, if there are no negative, a non-invasive mucosal deposit in endocervix should be treated just as a stage one and we don't give any brachytherapy. In invasive deposit in endocervix, we will give Vajanan vault brachytherapy. Heavy LV side, deep cervical invasion, we may give central pelvic radiotherapy. And I've looked at the results of central pelvic radiotherapy and Vajanan vault brachytherapy. I actually can't see much difference, but then there are not enough patients for me to comment on that. For stage three, if there are no negative, like the patient that we have discussed just then, if the nodes are already done, then I think we will give pelvic radiotherapy, but we will not actually give higher dose to cover the nodes and things, but we will give rather peritoneal coverage in order to see. And then of course, systemic chemotherapy would be given. Now, concurrent chemotherapy is not indicated. Now, all node positive patient may be treated according to PORTEC3 protocol, that is concurrent chemo radiotherapy and systemic chemotherapy. Now, this is what I want to show you. If you want to cover the Vajanan vault and the surrounding area and barometria only, then forget about this blob because this is actually positive node, so I boosted there, but actually it is this part that you can treat with external beam radiotherapy more effectively. And that is what the central pelvic field is like. Because if the nodes are already done and the nodes are around here and they are negative, then what is the point in treating this area? Because the nodes have already been done, they've been removed. And if you want to treat nodes, then of course you need to treat patients like this. So when you are giving a radiotherapy where you want to treat Vajanan vault as well as the nodes, then you combine these two kinds of fields and then the radiotherapy field becomes like this. Now, just look at this, the white area, hatched area, these are the small intestine. So it is better that if the nodes have been done and they are negative that you don't treat whole pelvis because you are treating a whole lot of intestine and causing mobility. So it is better to treat central pelvic like this. So summarizing at the end, if you have the histology and if you are able to see whether you need to do the lymph nodes or not through the imaging, then nearly LVSI and the lymph node is going to tell you much more about who is going to do better, who is not going to do better than all the molecular staining in the world. Thank you very much.

endometrial cancer

prognostic factors

histology

LVSI

lymph node status

adjuvant treatment

radiotherapy