so much Alexei and thanks everybody for for joining. I just also wanted to say I wanted to thank everyone for your amazing enthusiasm and participation in all of the Echoes from Russia that have taken place in this year 2021. This has been a great collaboration and we truly obviously want to also appreciate the the contribution of IGCS and the team from IGCS in making this possible. So really I personally I want to thank everyone for for being part of this as well and and of course also for the the co-speakers as well. Anna thank you for always joining and giving your input from Pathology. Anuja said she couldn't join today as well but really has been a really great 2021 and I hope that we continue this tradition in 2022 as well so thank you for that. As Alexei was mentioning the CONSERVE trial this is a study that when we initially discussed initiating this study there was a lot of controversy particularly also obviously in our institution where we felt that proposing something other than radical surgery for patients with cervical cancer was really deviating from the standard of care and there was a concern that at that point that we would be potentially harming patients by trying to do something less than a radical hysterectomy for cervical cancer. So this was a study that when we put it together myself, Dr. Kathleen Schmaler, it was not received very warmly by you know by our colleagues, definitely by the radiation oncologist and everyone felt that this was not a good idea and that this wasn't the way to proceed but obviously we felt that there was enough evidence in the literature to suggest that potentially patients particularly also younger patients who had early very early very low risk cervical cancer didn't really need a radical hysterectomy and in fact didn't even need a radical trachelectomy. So the question was can we do something less than a radical hysterectomy or radical trachelectomy so that we can potentially do something for these patients that is less morbid, something that would allow them to maintain their pregnancies or keep the hope of fertility. So then the idea began with you know developing a lot more support and therefore we put together this CONSERVE trial. The CONSERVE trial is one of three studies that have looked and explored the same question. Can we do something less than a radical hysterectomy in patients with early cervical cancer? So it was finally published in our journal recently and I think that we shared a copy of the article with all of you and the idea for this presentation is to go through some of the details of the study and then hopefully have a discussion as to what your thoughts are with regards to the data, what we should do moving forward, should we potentially offer patients this option and as Alexei was mentioning this is something that likely in Russia is not something that would routinely be offered to a patient, that being just doing a simple cone or a simple hysterectomy for a patient with early cervical cancer. So the initial publication that we when we looked at a review of the literature was actually back in 2014, so about almost eight years ago where we said what is the data to potentially support just using conization or simple trachelectomy or even simple hysterectomy as part of the management of these patients and the idea for that review was that we were seeing more and more studies being reported where you know individual institutions were sharing their results with regards to just doing a simple cone or a simple trachelectomy or even a simple hysterectomy in patients with stage 1a1 with lymphovascular invasion, 1a2 and some of them actually even doing it in patients with a 1b1, so tumors less than two centimeters and at that time we gathered all of the data that was there and certainly you know at least there was a suggestion that perhaps by doing something less that it was safe to perform these procedures but again this was from retrospective data, none of this was prospective but we saw obviously that were there were a number of institutions particularly in Europe and in Canada that were actually already offering this as an option to patients and of course obviously notifying and consenting patients that this was not a standard of care and that therefore that the patients would be potentially taking a risk in having this this procedure. There was also a publication by Jason Wright of a national database evaluation and they wanted to identify the use and the outcomes of simple hysterectomy compared to radical hysterectomy for women with early stage cervical cancer. This was back in 2019, this is a large series of patients and what they noticed from that study was that there were in fact there was an increasing trend in offering just a simple hysterectomy for patients with stage 1a2 and 1b1 in the United States, so certainly this again supported the fact that even though there was no prospective data that individual surgeons were already offering either just a cone or a simple hysterectomy for early cervical cancer what they found was that in this database analysis was that for tumors with 1a2, so obviously microscopic tumors, it didn't really make a difference whether you did a radical hysterectomy or a simple hysterectomy that the outcomes were the same and what they did found that was that for tumors that were larger 1b1, so you know certainly gross tumors, that there was a 55% increase in mortality for women who underwent simple compared to radical hysterectomy, but again this was not a prospective study, this was a retrospective evaluation of a national cancer database, and why is that important? Because in those national cancer databases you don't know what were the criteria for selecting patients to do a simple hysterectomy versus a radical hysterectomy, many of these were patients that had a simple where the surgeon didn't even know that the patient had cancer, so it was sort of like one of these incidental findings, but nevertheless again another paper suggesting that at least for very small tumors perhaps a simple hysterectomy would be okay. So the three prospective trials that I mentioned are the CONSERVE, that one is published, the SHAPE, that one has completed accrual, in other words it's not accruing patients anymore, but it has not been published because they're following patients for further oncologic outcomes, in other words they're looking at disease-free survival and overall survival, so that's not published yet, and then the third is GOG-278, and that one is still open and is still accruing patients. So the primary objective of the CONSERVE trial was to look at safety and feasibility of conservative surgery in early cervical cancer, so again this was not a study looking at disease-free survival or overall survival as part of the primary objective, it was just what was the safety and feasibility, in other words we wanted to find out what were the outcomes of patients undergoing either a CONE or a simple hysterectomy. As secondary objective of course we were going to look at recurrence rates at two years, evaluate the rate of pelvic lymph node involvement to assess the morbidity associated with these procedures, and to also do a quality of life sexual function and healthcare decision analysis on these patients. As I mentioned the background was because when we looked at the literature we saw that less than one percent of patients with favorable pathologic characteristics had parametrial involvement, in other words patients with tumors less than two centimeters, tumors that were 1A2 or 1B1 less than two centimeters, the likelihood of parametrial involvement is less than one percent, so therefore the question is why perform a radical hysterectomy when the only difference between the radical and the simple is the parametria, and if the parametria is involved in less than one percent of the patients, why are we removing the parametrium? So that was one of the principles, and then the other was that in 60 to 65 percent of patients a radical trachelectomy specimen has no residual disease, so in other words suggesting that why are we doing a radical trachelectomy, why are we doing a radical hysterectomy when most of these patients don't even have disease in the surgical specimen after you remove it. So certainly the hypothesis was that radical surgery was not required for patients undergoing a diagnosis of early cervical cancer, so this was the study design in the options for the protocol, and it's important this was not a prospective randomized trial, this was a prospective trial but not randomized, so the patients received a cone biopsy and or lymphatic mapping with or without sentinel lymph node biopsy if they desire fertility. So if we had a patient who was 28 and she met the criteria, then we would say well you're interested in fertility, yes I am, then the patient will get cone and then the lymph node assessment. If a patient said I do not want any more children, then the patient would undergo a simple hysterectomy with lymph node evaluation either by lymphadenectomy or with lymphatic mapping. It was prospective, it was single arm, it was many centers, the sample size evaluation was 100 patients for looking at safety and feasibility, all the pathology was centrally reviewed, so this is important and again you know later perhaps Ana can comment on this as well, but this was actually very important in that these patients were undergoing treatment that was not considered standard, so we wanted to absolutely assure that the patients that were being entered in the study were truly low-risk patients. So from every center before the patient underwent surgery they would have to send the pathology to MD Anderson from the cone biopsy and then determine whether the patient was a candidate or not and then there was obviously a data safety monitoring board at MD Anderson. What were the inclusion criteria? So patients had to have a 1A2 or a 1B1, so less than two centimeters either by exam or by imaging, no lymphovascular invasion and we can talk a little bit about that in the discussion because some might say well so what if they have lymphovascular invasion that's still a candidate. At that time when we were trying to propose the study the institutional review board really wanted to make sure that we were just doing patients that had very low risk of disease that patients were being accrued with very low risk of disease recurrence, so that's why when they say well histologic type squamous cell any grade but adenocarcinoma they said only grade one or grade two not grade three. The cone margins and an endocervical curettage had to be negative for malignancy, negative CT, MRI and or PET scan for metastatic disease. The cone margins also had to be negative for cervical intraepithelial neoplasia or adenocarcinoma in situ and the stromal invasion had to be less than 10 millimeters, so as you can see very low risk patients. So this is again a study that enrolled 100 patients in eight years, so obviously this is a very selective criteria, 14 institutions in nine countries, so you can see there was a there was involvement of countries all around the world, United States, South America, Asia, some countries in Europe, so this is obviously an international collaboration. The total patients enrolled were 140 patients. And you might say, well, if you needed 100 patients, why did you have to enroll 140 patients? Here's the reason. 31 patients had to be excluded because when the local pathologist said, this pathology meets all of the criteria. In other words, this is the histology, this is the grade. When that pathology came to MD Anderson, our pathologist disagreed with the outside pathologist. So it tells you that in about 22% of patients, the pathology on reevaluation by expert pathologists changed. So when they said there was no lymphovascular space invasion, then the MD Anderson pathologist said there is a lymphovascular space invasion. When an adenocarcinoma was a grade one, then the MD Anderson pathologist might've said, well, this is a grade three. So that's really important, again, for the quality of the pathology evaluation. Seven patients withdrew from the study and two patients have positive pregnancy tests at the time of surgery. So here's the reasons for the pathology discrepancies. The presence of lymphovascular invasion was the most common reason of a difference in opinions between the pathologists. Patients that were thought to have 1A2 had 1A1 or actually have pre-invasive disease rather than actual cancer. And then there was a difference in opinions about the pathology in about 9% of the cases. So with regards to the findings in the patients themselves, obviously the majority of patients were young patients. The majority of patients had gross tumors, so 1B1, equal distribution of histology. Because these patients were operated on before the results of the LAC trial, the majority of patients had the procedure done by laparoscopy. In other words, either the simple hysterectomy or the lymph node evaluation was done by laparoscopy or robotics. So 96% were done minimally invasive, again, because this was before the LAC trial. And as you can see here, lymph node involvement, assessment, lymph node dissection, full lymphadenectomy in 58 patients, sentinel lymph nodes plus full lymphadenectomy, 38%, and 4% only had sentinel lymph nodes alone. And I think also, again, that reflects the change in practice over time, over those nine years, where before we used to do full lymphadenectomies, and then we changed gradually over to sentinel lymph node mapping alone. So this is the distribution of the patients. 100 patients, 44 patients had a conization followed by lymph node assessment. 40 patients had a conization followed by simple hysterectomy, so only a cone in 44, simple hysterectomy in 40 patients. And 16 patients had what is called an inadvertent simple hysterectomy. That means that the patients on the outside, in an outside institution, had a simple hysterectomy, and then the specimen met the criteria of low risk for cervical cancer in the conserved trial. So that was a small number of patients. Let's look at recurrence. So of the patients who just had a cone and then had lymphadenectomy or lymph node assessment, 2.4% of recurrence. In the patients that had a simple hysterectomy, so cone followed by simple hysterectomy, recurrence rate was zero. And then in the patients where there was what is called an inadvertent simple hysterectomy, the recurrence rate was high. And we'll talk a little bit about that because we don't think that those patients are candidates for conservative management. These are the results in terms of the patients that have positive lymph nodes. Because one of the questions that comes up is, in these low risk patients, what's the likelihood of positive lymph nodes? If you said these are patients that are so low risk, what is the likelihood that we're going to find those positive lymph nodes? And it was 5%. So 5% of those low risk patients still had lymph node involvement, which tells us that even though you're doing conservative management, most likely you should not abandon the lymph node assessment. So because some have questioned, well, can we just do a cone and that's it? No lymph node evaluation. Or can we just do a simple hysterectomy and that's it? 5% will have positive lymph nodes. And those positive lymph nodes, as you can see, sometimes in patients with very microscopic tumors, 1A2. So obviously the lymph node evaluation should still be performed. So what were the results? The median follow-up, 36 months or about three years. Three patients developed recurrences at two years. That's overall. So what you said of the 100 patients that qualified, then how many patients developed a recurrence? So there were three patients. So the reason you might say, well, why is it not 3% rather than 3.5% if it's out of 100? The thing is that there were four patients that went on to have immediate surgery or hysterectomies or didn't qualify and then went on to having a radiation therapy. So then those, it was basically three out of like 96 rather than three out of a hundred. And that's why you see the 3.5. As I mentioned before, cone with lymph node assessment, 2.4% recurrence. Simple hysterectomy with lymph node assessment, 0% recurrence. And then the inadvertent at 12.5% recurrence. What were the complications? There were two complications in these patients. One patient died after surgery, 26 days after surgery. The patient had been discharged and she had a pulmonary embolism at home and she passed away. And one patient had significant bleeding 12 days after the cone and she required transfusion and a reoperation with sutures of the cervix. So what is the complication rate in conservative management? 2%. This is also obviously of interest, particularly for patients who did not have a hysterectomy. So there were 14 pregnancies among 11 of 40 women. So the pregnancy rate of 27.5%. Of these 14 pregnancies, 93% delivered at term. So again, these are patients who just had a simple cone and this is very consistent with patients in the general population. So certainly that was favorable. And one patient had a fetal demise at 22 weeks. However, it is unknown how many additional women have attempted to become pregnant. The other obviously is the strength of the study. It's a prospective evaluation of conservative surgery in low risk early stage cancer. There was central pathology review. And as you saw the importance of having that, there was quality assessment of the study that were closely monitored by the data safety monitoring committee at MD Anderson. The trial also included multiple sites around the world showing that conservative surgery is safe and feasible, both in high and low resource settings. Obviously, what are some of the limitations? This was a long time. This is nine years to collect a hundred patients. Sentinel lymph node biopsy was implemented at some centers, but not all the sites. One could also argue the surgical approach. We don't know obviously the impact of laparoscopic robotic surgery in the majority of those patients, but obviously the recurrence rates were exceedingly low. So obviously in those patients, it didn't have an impact. And our study protocol required at least two separate surgeries. So in other words, a patient had to have a conization first, then in a separate surgery, then the patient had to have either just a lymph node evaluation or a simple hysterectomy with a lymph node evaluation. So again, this is not the type of surgery that you just do the cone and assume that all the margins are negative and proceed with a lymphadenectomy. And then that's it. There were two procedures that were included as well. And then there was an amendment during the course of the study where we said patients who had an inadvertent hysterectomy will not be candidates because of this high rate of recurrence. Now, what about the impact of minimally invasive surgery? Obviously the LAC trial, as I mentioned, was published during the final year of accrual of the CONSERVE trial. 96% of patients on the CONSERVE underwent minimally invasive surgery. Of the 56 patients who underwent a simple hysterectomy, zero recurred. Obviously of the ones that had the inadvertent simple hysterectomy, 12.5% recurred. So this leaves the question, can we consider minimally invasive surgery when doing conservative surgery for cervical cancer? And obviously we don't have a study that answers that. But at least in this setting, when the patients had a simple hysterectomy by laparoscopy, the majority of them did not recur. So that also gives you a perspective on how to potentially counsel patients with regards to this question. So in summary, the rate of positive lymph nodes in this very low risk population, 5%. The rate of residual disease in the hysterectomy specimen following colonization was 2.5%. So many times some will say, well, what's the likelihood that if I take a cone that there will be disease in the remaining uterus? 2.5% in this low risk population. And again, I should stress in this low risk population. So it should not be said that if you have a patient with a three centimeter tumor, if you say, well, let me just do a cone first. And then let's see what's the residual in the cervix. We don't know what that is. This was in this low risk population, 2.5%. And the two year overall recurrence rate was 3.5%. Conservative surgery is safe and feasible for early stage cervical cancer. And we consider that it should be offered to women who meet the low risk criteria. And again, very, very important. You have to assure that they meet the low risk criteria. Conservative surgery is not recommended for women having an inadvertent simple hysterectomy. And of course, obviously we consider then we have to wait for the results of the SHAPE and GOG 278. If those studies show similar results, in other words, if those studies show that you can do a simple hysterectomy or just a cone, most likely there will be a change in the standard of care moving towards just cone or simple hysterectomy in this very low risk population. So what are some of the unanswered questions? We don't know the long-term outcomes of conservative surgery, the role of minimally invasive approach for conservative surgery. Again, we don't have studies to support safety of minimally invasive surgery in that setting, although it seems safe from this study. The impact of conservative surgery on quality of life, we're going to publish that in a different manuscript and that's being evaluated now. The other element is what's the definition of low risk criteria? Because some might say, well, you were too strict. We think that grade three, even when it's a grade three in a small tumor, that that's still okay. Some might say lymphovascular space invasion, that's still okay to do conservative. So we don't know exactly, obviously, what is the true definition of low risk criteria. We think that we have the overwhelming majority of data to support how to define this patient population. But again, I think it's still work being done. And then, of course, then the question is, we have talked about patients who are less than two centimeters. What about that patient that is two to four centimeters? Obviously, for those patients, we do not recommend conservative management, but there is a study called the Contessa trial where neoadjuvant chemotherapy is being given to those patients and then seeing whether those patients could undergo conservative surgery. Just as I mentioned in summarizing, the SHAPE trial is one of the ones that we are awaiting the results of that trial. That trial is complete. There's no more patients going on that trial. That trial is a randomized trial. Of the three studies, this is the only one that is randomized. So the randomized patients, two, the control, which is radical hysterectomy versus the experimental arm, which is simple hysterectomy. As you will note in the SHAPE trial, they take all histologies of squamous, adenocarcinoma, adenosquamous carcinoma, grade one, grade two, grade three, and those patients can have lymphovascular invasion. So this is a little bit higher risk population than the population in the CONSERVE trial. And then this is GOG278 that, again, has the same distribution, conization plus pelvic assessment versus simple hysterectomy with pelvic lymph node assessment. So with that, I want to thank you all so much for your attention, for the opportunity to share these results, and then I'm happy to answer any questions. Thank you.

CONSERVE trial

less invasive surgery

early cervical cancer

low-risk patients

safety

feasibility