A lot of these slides came out of a lecture that was given two months ago, so I stole some slides from the fellow in UNC-Chapel Hill that gave the lecture. Next. So some of the background. Endometrial cancer certainly is increasing in incidence in developing countries. It's the most common gynecological cancer in the developed world. Believe it or not, in the United States, 3.1% of American women will have the diagnosis of endometrial cancer sometime in their lifetime. Approximately 8% to 10% of all patients with postmenopausal bleeding will be diagnosed with a cancer. Approximately 75% will present with early stage uterine-confined disease, which makes the outcome good, but certainly poses a lot of questions in regards to how to treat adjuvantly. So the endometrial cancer staging 2009, this we've seen in many lectures. I just wanted to point this out because there were some areas where the staging of 2009 by Figo did not address, and that's around stage three and stage four. And Dr. Quinn had a question about what stage would a patient who has a nodule in the pelvis, which stage is that? Would that be, that really wouldn't be stage 3A because 3A is tumor invades the uterine sclerosa or involves the fallopian tube or the ovary, or would that be stage 3B? Because stage 3B would be vaginal involvement, either by direct extension or very rarely do we see an isolated metastasis, or is it parametria, just growing just like cervical cancer? In stage four, you have 4A, which is bladder or bowel, but you have 4B, which is distant metastasis, including upper abdomen or inguinal. So next slide. So the next slide, you can see there, and I wrote the answer there, but if I was better, I would ask Dr. Quinn, where is, you see the patient with the picture of the pelvis, you see the uterus, you see the colon, and the arrow there pointing to a, maybe a mass in the cul-de-sac. So that is not anywhere defined in the Figo staging. I call that, at least places that I've worked, Joyce and Dr. Lin and Anuja, if you want to weigh in, we would call that stage 3B because it fits the best out of all of it because it's still in the true pelvis. And I think that's the question that you have for me, Dr. Quinn, if a nodule in the pelvic sidewalk, it's in the pelvis, it's 3B. The other picture where the smiley face with the arrow, that is a metastasis, let's say in the upper abdomen in the, near the splenic flexure or the hepatic flexure in the peritoneum. That would be outside of the pelvis in the upper abdomen. So similarly, an omental met is stage 4B, a nodule out there would be stage 4B as well. Next slide. So when we talk about adjuvant therapy, we all know about primary treatment, which is surgery, but then we have to talk about what to do after surgery. And so one of the ways that I think about is, and we all think about, is trying to divide patients into groups. And one of the groups that we all hear about is this high intermediate risk group. And I'll show you low risk group and high risk group later, but this high intermediate risk group, and we defined it as patients who have roughly a 25% chance of recurrent cancer at five years. And that came out of a GOG study that was one of the first GOG studies, I think. And this was published in 2004, and it found some factors. If you are getting older, increasing age, you have higher risk. If you have grade two or three, you have higher risk, and age is greater than 70. If you have lymphovascular invasion, again, increases your risk of recurrence. Or if you have outer third myometrial invasion. Now remember that before 2009, the staging for grade one is divided A, B, and C, A being endometrium, B is less than, I'm trying, now I'm forgetting here, is less than one half, and C is, sorry, stage, you know, I better stop there because I totally forgot the staging prior to 2009, so I won't go back there. But outer third myometrial invasion, what we call stage 1C prior to 2009. Next slide. So next slide. I did, I changed it. Okay. So go on to the next slide, I think we, all right. So when we talk about risk stratification, there are some patients that we think are relatively low risk. It's grade one or two, and it's confined to the endometrium only. And there's no myometrial invasion whatsoever. Those patients don't need further treatment. Low intermediate risk, then we think of those as roughly stage 1A, grade one or two, and again, those patients don't need any treatment. Then the high intermediate risk, which we just went over, and that came out of a study by Dr. Settlers in New York, GOG99, and what he defined as high intermediate risk for that study is grade two or three, the presence of lymphovascular invasion and outer one half myometrial invasion. And you add age to that, if you're earlier, if you're younger than age 50 with all three risk factors, age 50 to 69 with two risk factors, or age 70 or above with one risk factor, then you're in this high intermediate risk and you would do better with adjuvant therapy. Next slide. So putting it all together by Dr. Paragamian, who gave this lecture or a similar lecture about two months ago, the low risk patient, we're pretty comfortable with observation. The low intermediate risk, we would think about observation as well. The high intermediate risk, at least at UNC Chapel Hill, they would do vaginal brachytherapy or occasionally external beam radiation therapy. Now today, I like to focus on this high risk group because that potentially is the patient that you may be dealing with for your first patient today. High risk, and you can look at two groups. High risk, whether it's stage one, B grade three, or stage two, or high risk because you have high risk histology, you have serous carcinoma or clear cell carcinoma. Next slide. So high risk endometrial cancer can define similarly like this. You have a stage two endometrioid. You have any stage, clear cell or serous carcinoma. You have stage 1A grade three with lymphovascular invasion. Stage 1B grade three, any stage three endometrial cancer. So usually that would involve lymph nodes or, and also all of those things, these patients would have a five year overall survival with treatment of around 65%. So these truly are high risk, poor prognostic women. Next slide. So some more definition or statistics associated with this high risk disease. So stage 1B grade three without a third involvement, the distant metastasis rate for these things is around 31%. That's quite high. The overall five year survival is 58%. What if you have lymphovascular invasion? That is an independent risk for relapse, especially distant metastatic disease. And the five year instance that you may have a recurrence is about 39%. And of course, unfavorable histology, serous or clear cell carcinoma. There's about a 40, nearly 50% chance that when you first find the cancer, it is already advanced disease. Sometimes a lot, many people think that at least serious, it's very similar in behavior to a grade three type cancer. Next slide. So what do we believe in the treatment of high risk endometrial cancer as far as after surgery? The standard treatment is radiation. And for radiation, we believe that it reduces the risk of pelvic relapse, but overall it doesn't have any impact on survival. And the reason is that survival is influenced by distant metastatic disease. So when you talk about distant metastases, you really want to treat that systemically. So is chemotherapy the thing that you want to do? Next slide. So talking about chemotherapy for endometrial cancer, there's many studies that suggest different types of chemotherapy regimen have some activity, even more than 20% or so. And so for many years, the standard therapy is adriamycin and cisplatin. So AP for short. Well, in a study in America, we have this thing, if two things are good, three things must be better. So more is better. So by the time the 90s came out, Paxil, Paxil was the exciting new drug. So in GOG 177, they treated patients, randomized controlled trial using Paxil, adriamycin, and platinum versus adriamycin and platinum alone. And as you expect, three is better than two. You have improved response rate, overall survival, regression-free survival. And that sounded great. And you're wondering why we don't use that, because it was a very toxic regimen. 39% had severe neuropathy, 14% could not finish therapy in that trial because of toxicity. So 45% of patients asked to stop treatment. So you have one out of five patients who could not finish. Either they asked you, please, don't treat me anymore, I'd rather die, or they have so many toxicities that they are unable to continue. So how did Taxol and Carbo become the standard treatment? When we were talking this weekend, you mentioned Taxol and Carbo, and that is correct. And the reason is there is a trial published in 2012, GOG 209, that looked at Taxol and Carbo versus TAP. I think a little bit different TAP with GCSF support, so with bone marrow support, to make it better tolerated, and it showed equivalent response, and equivalent progression-free survival, but Taxol and Carbo was significantly less toxic. That's why now we use Taxol and Carbo for endometrial cancer, next. So it's hard to talk about chemotherapy for endometrial cancer without talking about some trials, and for the sake of time, we'll just go through this slide, and we'll skip the next couple of slides. And the key, at least for chemotherapy, historically, is GOG 122. Prior to that, we were all using radiation therapy. And this trial looked at patients with stage three or four disease, and treated with what we call WAR, whole abdominal radiation, versus chemotherapy, seven cycles of adriamycin, platinum. And I thought, what a wonderful treatment, you know, WAR, it's a great name for treatment. And guess what? Chemotherapy won. Chemotherapy was better, overall survival and progression-free survival, 55% versus 42%, and the whole abdominal group had significant complications with bowel obstruction and fistulas. But this was one of the first trials that showed there is an improvement with radiation therapy. Now, remember that WAR, there was also this pelvic boost. So it's not the same as how we would do pelvic radiation, but it's thought to be not exactly similar, but that's how they did it back in the 1990s and early 2000. The other trial was published also in 2006 out of Italy, I believe. And it looked at patients with stage 1C grade 3, or stage 2 grade 3, but with greater than 50% myometrial invasion, or stage 3 patients. And they compared pelvic radiation therapy versus chemotherapy. And they showed no differences in progression-free survival or overall survival. So again, if the thought is that one or the other is the same, what about if we added both together, combining chemotherapy and radiation therapy, would that be better than each one alone? And that led to some of the other trials, which later led to CORTEC-3. Next slide. So the current trial here that we want to talk about is CORTEC-3. It's a randomized trial comparing chemo radiation therapy and chemotherapy adjuvantly with pelvic radiation therapy for high-risk group patients. Next slide. And this is the randomization here. Patients are at stage 1 grade 3 with deep myometrial invasion or lymphovascular invasion, stage 2 or 3 endometrioid, or any stage, stage 1 or 3, high-risk systology, serous or clear cell, randomized to pelvic radiation alone or radiation alone, or radiation with chemotherapy followed by four cycles of chemotherapy. Next slide. And this slide, you can see that what it showed is that for certain groups, chemotherapy plus radiation is better than radiation alone in terms of progression-free survival, but not overall survival. So for example, if you look at everything that I highlight there, it looks like anything that is bad, you can probably do better if you do chemotherapy. If you have serous or clear cell histology, if you have lymphovascular invasion, if you did not do lymph node dissection, so potentially in that group, there are some patients with lymph nodes that you did not know about, you would probably do better if you over-treat. If you have stage 3 disease, you would do better if you do combination. In general, you do better with progression-free survival, but you do not influence overall survival, which is obviously the key result that we're looking for. Next slide. So if you look at the overall survival, as I mentioned, there's no difference, 82% versus 77%. However, if you look at some subset, particularly with serous carcinoma, there is a potential improvement. So five-year overall survival and the graph C on top, you can see that for chemoradiation therapy, there's a 71% five-year survival versus 53% if you did radiation therapy alone. Also, if you have stage 3 disease, you will do better if you do chemotherapy plus radiation therapy. So next slide. So that's where we are. So you will decide after on that first patient, after you operate on her, whatever you decide do with her ovaries, then you will decide if that lymph node is positive, that you only saw by MRI, if she truly has stage 3C1, then she would fit potentially in this study. You will not influence her overall survival, but you may improve her progression-free survival. So some questions is that, is combined modality, is that the right thing to do? How many cycles? Because in PORTEC3, they only receive three cycles of truly true chemotherapy with taxon carbo. And what is the right treatment for clear cell and serous? I don't think we have a clear answer yet. Many of us now, at least in Mayo Clinic, we will give them chemotherapy six cycles and then potentially radiation depending on factors such as lymph node involvement, whether or not they have cervical involvement with their disease. And I think that's it. I think the next slide is a final slide. That's all I have. I apologize.

endometrial cancer

incidence

treatment

staging

adjuvant therapy

chemotherapy