today about adjuvant therapy and endometrial cancer. I have nothing to disclose. I do have a disclaimer which is that management of early endometrial cancer is very controversial even here in the U.S. There's a significant disagreement about a lot of the decisions about how to manage these patients. So I'll try to be very clear about what the data shows and then how we extrapolate from that data. So I want to start by reviewing that our goal in managing early endometrial cancer is to decrease recurrence and improve survival while minimizing the toxicity of treatment. And minimizing toxicity is really important with early endometrial cancer given that so many of our patients would be cured by surgery alone. So given this desire to minimize toxicity, there's general agreement that women at very low risk of recurrence have little to benefit from adjuvant treatment. Patients with stage 1 grade 1 cancers without myometrial invasion or LVSI are at extremely low risk of recurrence and observation is safe for those patients. On the opposite end of the spectrum, there's general agreement that women with stage 2 or greater cancers and those with serous or clear cell histology are at high risk of recurrence and need treatment. But what about the remainder of patients who fall into the category of intermediate risk? So PORTEC-1 and GOG-99 were large randomized controlled studies that asked whether intermediate risk women benefit from radiation therapy. PORTEC-1 enrolled women with stage 1 endometrial cancer of any histology and grade depending on myometrial invasion. Patients in the trial did not undergo routine lymphadenectomy. Following surgery, they were randomized to external beam radiation or observation. PORTEC-1 found that adjuvant radiation decreased recurrence measured at five years from 14% in the observation group to 4% in the radiation group. However, there was no difference in overall survival. And even though these curves are different, the lower curve is the patients who received radiotherapy. GOG-99 had a similar design to PORTEC-1 but slightly different enrollment criteria. They enrolled women with stage 1 to 2 endometrioid histology of any grade with myometrial invasion. In contrast to PORTEC-1, patients were required to undergo staging with pelvic and periordic lymphadenectomy. And following surgery, they were randomized to external beam radiation or observation. So GOG-99 showed a decrease in recurrence measured at two years from 12% in the observation group to 3% in the radiation group. Like in PORTEC-1, there was no difference in overall survival. So we have two randomized prospective trials showing a decrease in recurrence but not an overall survival with radiation in intermediate risk patients. So the authors of GOG-99 performed a post hoc analysis to determine whether there was a subset of women who benefited more from radiation therapy. They identified uterine risk factors and varied the number required to fit into that high risk higher risk category based on patient age. They found that this high intermediate risk group accounted for one-third of the patients in the study but two-thirds of recurrences. So for the higher immediate risk group, radiation decreased the risk of recurrence from 27 to 13% at four years. The risk reduction in the lower immediate risk group was comparable in magnitude but less clinically significant reduction from 6 to 2%. So in a long-term follow-up, the authors of PORTEC-1 also identified criteria for a high intermediate risk group that benefit from adjuvant therapy. These are the GOG-99 high intermediate risk criteria from the previous slide just so we can see how they compare. And note that LVSI is included in the GOG-99 criteria but not in the PORTEC criteria. So back to just a review, GOG-99 and PORTEC-1 evaluated the benefit of radiation in intermediate risk patients and found a decreased rate of recurrence but no survival benefit. Based on the subset analysis of these studies, we can use the presence of certain risk factors to refine this group into a low intermediate group that has minimal benefit from adjuvant radiation and a high intermediate risk group in whom radiation is justified. In both PORTEC-1 and GOG-99, the majority of recurrences were vaginal. So PORTEC-2 asked whether brachytherapy was sufficient treatment for this high intermediate risk group. PORTEC-2 enrolled patients with endometriate histology who met the high intermediate risk criteria or who were stage 2a. PORTEC-2 was a non-inferiority study powered to detect a difference in the rate of vaginal recurrence. PORTEC-2 found no difference in the rate of vaginal recurrence. Those lines are pretty much the same. The five-year local regional recurrence rate was 5% in the vaginal brachytherapy group versus 2 in the external beam radiation group, but this difference was not statistically significant. And there was no difference in overall survival. So based on this trial, for many GYN oncologists, vaginal brachytherapy became the preferred modality for treatment of this high intermediate risk group. However, there may be some patients at higher risk of pelvic sidewall recurrence in whom the benefit of external beam radiation outweighs the increased risk. Remember that the PORTEC studies did not require a pelvic lymph node dissection and LVSI was not included as a high intermediate risk factor. So Bossy and colleagues in 2018 performed a retrospective multivariate survival analysis using pooled data from PORTEC-1 and 2. On central pathology review, they found that just under 14% of patients had any LVSI and about 5% of patients had substantial, which they defined as multifocal LVSI. Patients with substantial LVSI were at significantly increased risk of pelvic recurrence, distant metastatic disease, and death. And EBRT reduced this risk of pelvic recurrence in patients with LVSI. So based on this study, many of the providers at my institution favored treating unstaged patients with substantial LVSI with external beam over vaginal brachytherapy and often will consider using external beam radiation in patients with substantial LVSI even with negative sentinel nodes. So while vaginal recurrences were common in GOG-99 and in PORTEC-1, distant recurrences occurred in 20 to 30% of patients and are very lethal. So GOG-249 looked at combining vaginal brachytherapy with three cycles of chemotherapy as adjuvant treatment of high intermediate risk and high risk early stage disease. Women were randomized to pelvic radiation with optional vaginal cuff brachytherapy or to vaginal cuff brachytherapy with three cycles of carboplatin and paclitaxel. The five-year recurrence-free survival was 76% for both groups and overall survival was also the same for both groups. So GOG-249 showed that three cycles of chemo with vaginal cuff brachytherapy is not superior to external beam radiation and is associated with more frequent and severe toxicity. However, there's some major criticisms of GOG-249. First, the study included very heterogeneous groups. The high intermediate stage 1 patients, stage 2 patients, as well as patients with both stage 1 and 2 disease with the high-risk histologies, where many people in practice even prior to this study would have treated these patients differently, recommended different therapy for these patients. Additionally, many people who believe that serous and clear cell histology should be treated with chemotherapy think that three cycles is inadequate. And so this trial ultimately showed us that the regimen they used didn't work, but it left many questions unanswered. So finally, I want to mention PORTEC-3 briefly. PORTEC-3 enrolled high-risk early stage patients as well as stage 3 endometrial cancer patients, but approximately 55% of the patients were stage 1 and 2, so it's worth mentioning when we have this discussion of early stage patients. They were randomized to pelvic radiation plus chemotherapy versus pelvic radiation alone. And the updated survival analysis of PORTEC-3 that was published in 2019 showed that the combination chemo with radiation improved both progression-free survival and overall survival compared with chemotherapy alone. However, the benefit was primarily seen among women with serous histology or stage 3 disease or both. And in the subset analysis, if you look at patients who had stage 1 to 2 disease, there was really very, there was real, there was no difference, no statistical difference in those two groups, while there was a very notable difference for patients with serous histology. And unfortunately, there were too few patients to break down that serous category into the stage 1 to 2 versus stage 3. So, and here is just the survival curves for the overall survival and recurrence-free survival for serous cancers in that study. So, putting it all together, the risk of recurrence in the low-risk and low-intermediate risk groups is so low that the toxicity of treatment outweighs any benefit, and we recommend observation for those patients. For the high-intermediate risk patients, the risk of recurrence is approximately 20%, which is substantially reduced by radiation. And for most of these patients, vaginal cuff brachytherapy adequately reduces that risk of recurrence, while for some patients with LVSI, we may still consider external beam. This high-risk group is a little bit more controversial still. It should probably be broken down into the stage 1b grade 3 patients and stage 2 patients with endometrioid histology versus those patients who have serous or clear cell histology. And at my institution, we're treating patients with who are in this first category with a combination of external beam and vaginal cuff brachytherapy, and then for the high-risk cancers with the combination of chemo and radiation. And that is all I have. So, I'll open it up for questions and comments.

endometrial cancer

adjuvant therapy

recurrence

survival

treatment toxicity