very briefly because I have only 20 minutes. So I just want to talk about the adjuvant treatment for endometrial cancer. I would go over the current guidelines and the current practice, and I will briefly talk about the new molecular classification. So as everybody knows, we all know the majority of the women with the new diagnosis of endometrial cancer are diagnosed at an early stage and have a febrile prognosis. The primary treatment for endometrial cancer is surgery with a lymphadenectomy is controversial, and now more and more centers are doing a sentinel lymph node dissection of biopsy as an alternative to a fully lymphadenectomy. Historically, and we still do it, the indication for the adjuvant treatment have been primarily based on the clinical and pathological factor, such an age, grade, histological type, depth of myometrial invasion, presence or absence of a lymphovascular space invasion, and sometimes a lower uterine segment involvement. As I said, I want to go very briefly to review some of the guidelines for each stage of the endometrial cancer, and I will start with the endometrial histology. And in this group, I will start with the low-risk patient. When I say low-risk, it depends how we define, how you define the low-risk, but now I want to talk only about the endometrial cancer with endometrial only or a superficial myometrial invasion, grade 1A2, with no LVSI, and I think the consensus in this stage would be observation only in most of the guidelines. There is no need for adjuvant treatment. The second group in the endometrial histology would be the high-intermediate-risk patient, and here again, it depends how you define an intermediate and high-intermediate-risk group. There is the GOG definition and the PORTEC definition and the ESTO definition, but basically, mostly those are the patient with either a superficial or less than a 50% myometrial invasion with high grade or the deep myometrial invasion with a grade 1, 2. And for this patient, we know from at least three studies, from the GOG in 99, from the first PORTEC, the PORTEC-1, and from the ASTEC, we know that when you give external beam radiation therapy, you reduce the chance for local recurrence by around two-third, but you would not affect the chance for survival. You wouldn't affect the overall survival. And since a study published a decade ago, the PORTEC-2, the standard of care has been to give those patients vaginal back therapy with the reason of most of the local recurrences would be limited to vaginal valve. And when they compared adjuvant external radiation with vaginal back therapy in this study, they showed equally vaginal recurrence and no difference in survival rate. And hence it is now the standard of care. Again, it's a bit of a consensus with most of the guidelines published for endometrial cancer. Now we go to the high-risk group. The high-risk group is very heterogeneous group. It contains a few histologies and different stages. And the consensus here for the adjuvant treatment is much low. The level of consensus is much lower than the previous two groups that I mentioned before. First of all, I wanna talk about the stage one, grade three, deep myometrial invasion, where they have up to a 40% chance for recurrence. And here the recommendation would be either to give them pelvic radiation plus minus brachytherapy boost or to give them chemotherapy and a vaginal brachytherapy. And this is according to a study published a year ago, the GOG 249, which compared, it was a study for early stage with a stage one or two, but it contains also clear cell and a serocystologist. And it compared three cycles of a carbotax and vaginal brachytherapy to a pelvic radiation therapy. And as you see, it showed equivalent result, exactly the same risk for a recurrence at three years with more pelvic and parotic recurrences in the arm that got the chemotherapy that didn't receive the pelvic radiation. And hence, we usually say that for the grade, the one big grade three patient, you can do either pelvic radiation or to give them a chemotherapy and vaginal brachytherapy. Now, I wanna talk about the stage three patients where the overall survivor rate is much lower than the early stage, where here most guidance would recommend a combination of chemotherapy and radiation therapy, but the preferred sequence is yet to be defined. So why do we give chemotherapy? First of all, there was a meta-analysis published six years ago, which took only a stage three patient with endometrial cancer and compared adjuvant chemotherapy with adjuvant radiation. And it showed statistically significant improvement with the administration of the adjuvant chemotherapy. The second reason is this study. It was published, the long follow-up of five years published last year at the Lancet. And it took only the high-risk endometrial cancer patient and compared pelvic radiation with or without the addition of chemotherapy. After the long-term follow-up, we saw that the overall survival and the failure-free survival was better for the patient received the combination therapy, the chemotherapy and the radiation therapy. But when you look at all the stages, you can see that the most beneficial group was the stage three patient and the CR, so clear cell histology, where they benefited more than 10% in the absolute risk for a recurrent. Of course, there was more toxicity in the group that received the combination group with more acute hematological toxicity and more long-term neuropathy. Here you can say that the stage three tumors and the cirrhosis tumors benefited more in respect to the overall and failure-free survival. So now we understand why we give the chemotherapy. And now we ask the question, why do we add the chemotherapy for those patients? And it's a bit, and again, it is less, it is more controversial because we have this study published at the New England in 2019. They took only the very advanced stages, stage three and four endometrial cancer and compared the same protocol of combination of chemotherapy and radiation therapy, but compared it to only chemotherapy. The doses of the chemotherapy was a bit different. Here they gave six cycles and here they gave only four cycles with a bit of reduced dose with the AUC5 instead of six. And they of course gave the chemotherapy just after they finished the pelvic radiation with the concurrent cisplatinum. In this study, they've shown no difference in respect to the recurrence-free survival and the overall survival. And when you look at the patterns of recurrence, you can see that there were more vaginal and pelvic pyelotic recurrence in the group that didn't get the radiation therapy. And you see more distant recurrences in the group that didn't receive or in the group that received the combination therapy. And then you ask yourself, why if both groups get chemotherapy, why were they more, why there were more recurrences, distant recurrences in the group that got radiation? And there are a few explanation for this. First of all, they reduced dose of the chemotherapy. Second of all, the delay of the chemotherapy, they started it just only after they finished the radiation therapy, which was two, three months after the delay of two, three months. And if you want to treat the micro-metastatic disease, you probably do it less effectively if you delay the treatment. And the third reason might be that, I think 25% of the patient couldn't get the full dose of the chemotherapy because they had toxicity from the radiation therapy. And those reasons are the criticism about this study. And even though it didn't show any benefit with the addition of radiation therapy, people still recommend giving radiation therapy for the stage three patient, for those reasons that maybe if we would have given the chemotherapy at a different schedule, the result would be different. As I said, the sequence of the chemotherapy and the radiation therapy is yet to be defined, is a subject of controversy. Many center prefer the sequential treatment, giving the chemotherapy first, like we do in the other malignancies when you want to treat the occult metastasis or to treat what is called micro-metastasis. And you first give chemotherapy and some centers prefer the sandwich therapy. And this is due to a retrospective analysis that showed improved spheres outcome. And recently more and more centers prefer the combined chemotherapy and radiation therapy schedule based on an odd RTOG study showing excellent result for stage three and four. When they give radiation therapy with cisplatinum at the beginning and the end of the radiation, and then it is followed by four cycles of a chemotherapy of carbotaxel. And if you ask my opinion, I think you should individualize the treatment, the scheduling of the treatment based on the assessment of the risk related to local versus distant metastasis. For example, if a patient has predominantly risk factor for local recurrence, parametrial involvement, cervical involvement, LVSI, lower grade and negative node, you might better get the radiation earlier and not do the sequential treatment when you wait just after six cycles of chemotherapy to administer the radiation therapy. Now, I just want to talk very briefly about the non-endometrial histology, the serous, the clear cell, the carcinosarcoma. And here we usually adopt the ESMO, ESCO, ESTRO recommendation when they give or they recommend a brachytherapy. I'm sorry, they recommend chemotherapy for most of the patient with those high-risk histologies. The only stage, the only case they consider omit the chemotherapy is for the patient with stage 1A lymphovascular invasion negative. They suggest to omit the chemotherapy and given only a vaginal brachytherapy. For all the other cases, they recommend chemotherapy. Sorry. And with regard to the external beam radiation, they suggest to consider adding external beam radiation therapy to all the stages above 1B. Ofer, do I have more time? I think we should stop. I mean, you have probably about 10 more minutes or so, or how much time do you have? Five more minutes. I mean, you're going into a different subject, and I think we'll add it for the next meeting if you're willing to do so, okay? No problem. Yeah. Okay. So. Is there any questions? No. Thank you for the thorough review and the update. And we'll adjourn at this point, and we'll see you next month, everybody. Thank you, everybody. Bye. Bye-bye. Bye, everyone.

adjuvant treatment

endometrial cancer

lymphadenectomy

chemotherapy

radiation therapy