Okay, now I think we can start. You think I can start Mila? Yes. Thank you. So thanks so much for inviting me to talk about the CONSERVE study. Many of the people on the call have lived through this with me, Georgia, and Andre, and Marcelo, and Mila, and Ellen. So we're really excited to finally be done with this study and be able to present the results. I have no disclosures, and we were super excited to publish this last month in the IGCS journal and the International Journal of Gynecological Cancer. And I think this study is very important for Mozambique because as we've started screening more and more women, I think we'll have patients who qualify for conservative surgery. And the reason we did this study is that, as you all know, the standard of care for early-stage cervical cancer is radical hysterectomy, or if a woman wants fertility, radical tricholectomy. Both these procedures require removal of the parametrium, which has the nerve fibers that are associated with bladder, bowel, and sexual function. And so as a result, these surgeries can have many surgical complications, as we're all aware of, such as hemorrhage, bladder and ureteral injury, and fistula formation. I think also we need a provider with specialized training in gynecologic oncology, and now we are very fortunate to have the three of you. But in many parts of the world, and even the rest of Mozambique, there isn't a specialized gynecologic oncologist to do these surgeries. At the time when we started this study, more than 10 years ago, less than 1% of patients that met this criteria, and I'll talk about the favorable pathologic characteristics, have parametrial involvement on radical hysterectomy specimens. So when they did studies, they looked back at cases of radical hysterectomy and looked at the pathologic specimens and saw that very, very few had any involvement of the parametrium. And so our hypothesis was that maybe we didn't need to do such radical surgery in women who had very low risk early stage cervical cancer. So we did a study to evaluate the safety and feasibility of conservative surgery in this group of women. It was a prospective single arm study, so not a randomized study, involved many centers that I'll go over. We had a sample size of 100 patients, but 100 valuable patients. All the pathology was reviewed at MD Anderson. So the slides and the blocks came from all over the world to MD Anderson to be reviewed. Because this was a big change from standard of care, we had the study monitored by the MD Anderson Data and Safety Monitoring Board. So this is an independent group of people at MD Anderson, not associated with the study, who would look at our results every three or six months and decide whether it was safe to continue the study. So these are the inclusion criteria, and this is really important because when we talked about low risk patients, we need to make sure that they truly are low risk. So it was anyone with stage 1A2 or 1B1 cervical cancer, and that's using the FIGO 2009 staging, because that's when we started the study. The tumor has to be less than or equal to two centimeters, and that's by exam and imaging. No lymphovascular space invasion, squamous cell histology, we included any grade, and adenocarcinoma grade one or two only. So we excluded grade three adenocarcinoma, because at the time we were really concerned that they were higher risk. Patients have to have a cone, all patients got a cone, either a leap or a cold knife cone. And the cone margins, as well as that ECC or endocervical curatage above the cone bed had to be negative for malignancy. And through the study, you were allowed to do a second cone. So if the first cone had positive margins, you could do a second cone to get negative margins. Everyone had to have a negative imaging test for metastatic disease, and that could be a CT scan, MRI, or PET scan, whatever was available at the institution. And then as the study went on, we added some more inclusion criteria. And one was that the cone margins and ECC were negative also for high-grade dysplasia for CIN2-3 and adenocarcinoma in situ, and that the patients had to have less than 10 millimeters, less than or equal to 10 millimeters of stromal invasion. And I'll explain when we added those in a minute. So there was no randomization. So the patients got to choose their surgical option based on whether or not they wanted fertility. So again, normally these patients would get a radical hysterectomy or maybe a radical trichlectomy if they wanted fertility. So with this study, if they met the criteria, those who wanted fertility got a cone and ECC. And then if they were eligible, again, they could have one repeat cone. They underwent a subsequent surgery with pelvic lymph node assessment only. So no hysterectomy, no radical trichlectomy, just a cone and lymph nodes. And the lymph nodes could be a full pelvic lymph node dissection, sentinel lymph nodes or sentinel plus full dissection. And again, that changed based on where the site, what their standard of care was, and then also what training and et cetera, the surgeon had. The second group, so group two was patients who didn't want fertility. So normally they would get a radical hysterectomy and instead they got a cone and ECC. If the margins were negative, they met the criteria. They then underwent a second surgery with a simple hysterectomy and pelvic lymph nodes. And then we also included this third group. And these are patients who had undergone what we call an inadvertent simple hysterectomy or a cut through simple hysterectomy. And so these were patients who, they didn't know they had cancer. They had a simple hysterectomy. And then on the pathology, they found that there was cancer, but if the cancer was small, less than two centimeters, the margins were negative. They met all the criteria, then they could be in the study. So they had their hysterectomy, usually at an outside institution, they came, we saw they were eligible. So we enrolled them and conserved, they signed a consent. And then they went for a second surgery where we removed their lymph nodes. So these were the three groups. We followed patients every three months for two years, and we did quality of life questionnaires. And those were not reported in this publication, they'll be reported later. All the data was collected in REDCap. This was actually the first study we did where we used REDCap. We had some stopping rules just in case too many people recurred so that we didn't keep the study going for 100 patients. And so you can see here, we enrolled 100 patients between April 2010 and January 2019. So more than eight years, Andre put the last patient on in 2019. And we had 14 institutions in nine countries. So you can see here, they were really from all over the world, but mostly from Latin America. We didn't have any sites in Africa, but now for the next study, now that we have all of you collaborating with us, we can include Mozambique. But most of the patients came from MD Anderson, 36 of the 100. And then Rene Pareja was one of my co-PIs along with Pedro Ramirez, and in Colombia, they put 14 patients on. And then you can see Peru, Barretos, Brazil at that time, both Marcela and Georgia were at Barretos, Argentina, Andre's institution in Sao Paulo, Cochiba, Brazil, Mexico, Bangkok, Australia, Italy. So really we had sites from everywhere in the world. We had to enroll 140 patients to get to 100 valuable patients. Because remember, every time when the patient had a cone, the pathology sites had to come to MD Anderson for review. And after review, we had 31 patients who were ineligible. And most of the discrepancies were due to the presence of LVSI. And I'm glad Gustavo was on. But what we found is that it would be read as LVSI negative at the primary site, but then when reviewed at MD Anderson, they would find LVSI. And I asked one of the pathologists and I said, oh, if you look hard enough and carefully enough, many times you can find LVSI. We also had a few patients where the stage changed or it was pre-invasive disease. So a discrepancy between the pathologists of how much invasion there was, or also in the histology. So again, even though we only needed 100 patients, we had to enroll 140 to get to the 100. You can see here our results, and this is just a table from the paper, but the mean age was 39. Interestingly, more patients had stage 1B1 disease, 67%, than 1A2. 48% had squamous cell carcinoma and 52% had adenocarcinoma. One thing about the study is that the LAC trial results were not available. The LAC study looked at minimally invasive surgery, which we no longer do for radical hysterectomy, but at the time we were, and actually 96% of our patients had a minimally invasive approach. 83% had laparoscopic and 13% had robotic. And that was just whatever the standard was at the institution. And then most of our patients had a full lymph node dissection. This is again, the table from the paper, and this shows our results. So in the first column, it's the patients who had the cone and then just lymph nodes. And we had 44 in that group. In the second one, it was those who had a simple hysterectomy and we had 40. And then the inadvertent or cut through hysterectomy was 16. Five patients across the groups had positive lymph nodes. So five of a hundred or 5%, which was higher than we thought. And so I think this really led us to say, even with these very early stage cancers, you can have positive lymph nodes, so we have to continue to do lymphadenectomies. Those five patients, when they had positive lymph nodes, they were taken out of further analysis and they all underwent chemo radiation because of the positive lymph nodes. And then you can see here, we had three patients that had recurrent disease, one in the cone group, zero in the hysterectomy group, and two in the inadvertent hysterectomy group. And again, those patients were taken out of the analysis, and I'll talk about each of those cases. These are the five patients who had positive lymph nodes. There was nothing higher risk about them. So just a reminder that even with very early cervical cancer, you can have positive nodes. There was one patient of the patients who had a hysterectomy that had residual disease in hysterectomy specimen. This we were also surprised by, but the patient was probably not the best patient to go on the study. So she had a long history of adenocarcinoma in situ, and as you know, you can have skipped lesions with the AIS. So she had a conization that showed a grade two adenocarcinoma with three millimeters of invasion and a positive margin. So she was able to undergo repeat cone for the study, and that was completely negative, and an ECC. So then she had a simple hysterectomy and public lymph nodes on the conserved study, and she had a two millimeter focus of carcinoma still in the uterus, so a skipped lesion above. Her margins were negative, her lymph nodes were negative. So she was taken off the study because of this residual disease, and she underwent surveillance and is without cancer at five years. But again, this scared us because if this patient had been someone who wanted fertility and we did just a cone and lymph nodes, we would have left cancer behind, but it only happened in one patient. Our follow-up is 36 months, 33 months. We have three patients who had recurrent disease, one patient in the cone group, zero in the hysterectomy group, and then two of 16 in the inadvertent simple hysterectomy group. This is just the details, and I can send you all the slides of the patient who, first patient who had a recurrence. It was one of our first patients at MD Anderson, and she actually had positive margins for CYM3, and she had more than 10 millimeters of invasion. And so we decided after this, it was very, very early in the study to change our criteria to make it more strict with depth invasion and negative cone margins. And then our other two patients are patients who recurred after a cut through hysterectomy or inadvertent hysterectomy. And so again, these patients didn't have a cone done first. They just went right to hysterectomy and then were enrolled and could serve after. But in these two cases, they both had, it was two of 16, so 12.5% recurrence rate. So we had to stop the study, and we then excluded this group of patients from conservative surgery. We only had two patients who had significant adverse events. We had one patient who died 26 days after surgery, after a laparoscopic lymph node dissection of a presumed pulmonary embolus. So again, a known complication before any surgery. And then one of my patients actually had significant bleeding 12 days after a CKC, and she was home outside of Houston, and she went to an outside hospital and had a reoperation where they put some sutures in the cervix to stop the bleeding and gave her a transfusion. We have 14 pregnancies reported among 11 of 40 women in the group that had the cone and lymph node assessment. One or two of these are André's patients. And of the 14 pregnancies, 13 delivered at term. One had a fetal demise at 22 weeks. We didn't follow all the women to see who was trying to get pregnant. We just know of the ones who did get pregnant. So we're super excited about the study. The strengths are that it's the first prospective study of conservative surgery and low-risk early-stage cervix cancer. We reviewed all the specimens at MD Anderson, so it was very, very carefully done. We also had very good quality and safety of the study procedures monitored at MD Anderson, and a lot of that was with Mark Munsell's help with REDCap and then having the DSMB. And we're super excited that this trial had multiple sites from countries all over the world, high-resource and low-resource, which I think is important to show that this surgery is safe and feasible in all settings. Our limitations is how long the study took, almost nine years, and part of that was it's hard to find these patients because of the strict criteria, but also it was really hard to open the study and keep the study running with all the requirements from all the IRBs, all the translations, all the different bureaucratic issues also of carrying out the study, but so that it's done safely around the world. The other downside of this is that the study requires two or more separate surgeries with a cone, maybe a second cone, and then definitive therapy. And so that's a lot for the patients and the surgeons, but it's really important so that if we do conservative surgery, we make sure it's done really safely. A lot of controversy, as you know, over the minimally invasive approach with the LAC trial published by Dr. Ramirez, but the LAC trial didn't really impact us because it was published during our last year of accrual. We finished accrual in 2019 and then had to wait two years until 2021 to see the follow-up of the patients before publishing it. But the LAC trial didn't change our approach, and 96% of our patients had undergone an MIS approach. When we look at the group of people that had a cone with complete removal of the tumor because they had negative margins before simple hysterectomy, even though it was done MIS, none recurred. But when we look at the 16 patients who had a hysterectomy that was inadvertent and still had the tumor present, 2 or 12.5% recurred. Both of them had undergone MIS surgery, but we really had to take those patients, stop that arm of the study because of the high recurrence rate. And so our study wasn't designed at all to address the question of MIS in conservative surgery, but in this group, it does appear to be safe. And again, if we look at our two-year recurrence rate, it's low overall, 3.5% overall. But when we look at the different groups, the group that conservative surgery really seems safe in is when we do a cone first and then do the simple hysterectomy lymph node assessment. So in conclusion, you know, we think conservative surgery is safe and feasible for early stage breast cancer, as long as they meet all those criteria. So it's really important to have good pathologists like Cecil Tina and others looking at the specimens very carefully to make sure they truly meet the criteria. Conservative surgery is not recommended for women who have this inadvertent simple hysterectomy. I mean, they've already had conservative surgery, but the cone wasn't done first and we see higher recurrence rates in those patients. We're still not quite sure what the right treatment for them is. There are two other ongoing studies that will help us answer this question as well. SHAPE is a study that Marie Plant is leading. That's a randomized study comparing simple hysterectomy to radical hysterectomy. They've finished accrual and now they're just waiting for the follow-up. And GOG 278 is another study that's almost identical to ours, and they're also almost finished. So we'll have those results probably in 2023 for both of them. So we have many, many unanswered questions. So there's still lots of research to be done. And then just some final thoughts. We're really hopeful that the results and findings from our study will spare women the early and late morbidity associated with radical hysterectomy. Again, a very small group of narrow group of patients, but in these patients, we think it's safe to do conservative surgery. And this is especially important in Africa and Latin America and other areas. And even in the U.S. in the more rural areas where there aren't a lot of specialists, yet a high rate of cervical cancer. And then we're really excited to, you know, this is how I got to know many of our collaborators, but we've built a great network around the world to facilitate a pathway for future treatment. And then I'll show you this. This is a picture of my two co-PIs in 2010. And again, our group in 2019, actually at the ITCS meeting in Rio when we finally had enrolled, Andre had enrolled the last patient and we were just waiting for the follow-up. And then here's, again, a picture from the ITCS of many of us, including Andre, and all the collaborating sites that we were super excited to work with.

CONSERVE study

conservative surgery

early-stage cervical cancer

low-risk patients

radical hysterectomy

radical trichlectomy