Options for Female Fertility Preservation: Pediatric Oncofertility 2017

So as we move along we'll get set for our next presenter as we're polling and getting that information and the next presenter that we will have is our. Options I think we're gonna move ahead to the female and male options and then the final part of this session will be the ethical concerns hoping that everyone had an idea of what the options are prior to talking about the ethics of those so I think we'll get started then um with Doctor Hefkin. Doctor Hefkin is gonna talk about the female options and then we'll kind of comment and try to include all those age groups in that discussion. OK, did you wanna put it off till later, maybe in the ethics question or I, I think it's more of about from Jody Skiles about reintroduction of cancer. Great. Point Todd, I hadn't mentioned that, uh, yeah, that's something we'll include. I think you'll hear a little bit of that in the female option session. Jody might be able to share a little bit with us as we converse during the session, but definitely there has been some questions regarding getting these programs in place, particularly the investigational nature of the ovarian tissue cryopreservation, and sometimes the review committee asks a lot about how will you be checking if there's any malignancy within the tissue. And I think that there are some opportunities for that even later at the time of then thawing and then thinking about transplant. So there are some steps at the time of removing the tissue, right, and looking for that. And then there are perhaps some opportunities before deciding about transplanting. And so I think if I were to say today, and Doctor Hefkin would comment as well is that. The opportunities may be different in the future for us to do that testing and so we have said that probably that's not a reason to not cryopreserve now because the development of the technology to test in the future as elucidated today by Doctor Woodruff, that there are some new mechanisms that we could deliver those safe follicles in an artificial ovary without bringing. Back those contaminated cells. So again, sometimes it's hard for the questions to see what's really the heart of what they're trying to get at, but it sounded like this was maybe a review committee question about approving an ovarian tissue cryopreservation protocol, and it seems that the response could be that that could be assessed prior to transplant and not necessarily the time of acquiring the ovary, which is a great lead in to the female options. All right, do you have my slides? Just so you know, the way, I'm 80%, 78.6% are pediatric and adolescents. 21% is just peds. OK, OK. Awesome. All right perfect so I'm gonna talk to you first about the uh female uh fertility preservation options in our pediatric and adolescent patients um so I've broken these down into um those that are standard of care options and those options that are still experimental and I'm gonna start with those options that are standard of care. Um, so embryo cryopreservation has been standard of care for some time, uh, but oocyte cryopreservation, um, was more recently, um, taken out of experimental realm and made standard of care by, um, the Society for Reproductive Medicine in 2012. Um, and this really has taken, uh, a lot of barriers away from our adolescent, um, and young adult population, um, because now it does not require, um, a long term partner or sperm donation for them to be able to utilize more standard of care fertility preservation, um, so the use of oocyte and or embryo cryopreservation both basically begin the same with medical controlled ovarian stimulation. Um, and then monitoring of that stimulation, um, by ultrasound, usually in a trans or vaginal approach, um, to get multiple mature oocytes which then are retrieved again tech standardly in a transvaginal approach, um, the good part being that this is a minimally invasive approach, but we usually require some type of sedation for patients. Um, for the most part, um, success rates, uh, can vary based on patient factors, so the age of the patient, their previous fertility status, Obviously in patients who have had some previous, um, uh, oncology, uh, treatments that are gonadotoxic, their success rate may be lower than those patients who have not. Um, and it can vary based on the clinic that the patients are getting their treatments at. So because of this, the Society for Assisted Reproductive Technologies does list success rates by clinic, um, and that, uh, is available on their website. They also have a very nice, um, app on their website where the patients can put in their, um, personal, uh, health information and get, um. Success rates that are um specific to them, but on average it's around 33 to 5233 to 52% um live birth rates for embryos and oocytes are um you know with increasing technology and freezing and thawing techniques becoming um closer and closer to being equal to embryos. Um, you know, there is limited data in adolescent and oncology patients specifically, um, but the, so that this is areas that we can continue to advance, um, but we do do these, um, in these patients, um, quite often now there's obvious barriers to our patients being able to utilize these, um, the number one thing that we think of automatically is this time delay, right, um, because we wanna get our patients to treatment and we wanna get them to treatment quickly. Um, historically these treatments have required between 4 to 6 weeks for patients to be able to stimulate ovaries, uh, the ovary, and be able to, um, to harvest the oocytes. Um, however, more recent protocols now can be stimulated in the luteal phase, and some of the papers now are stating that they can go from consultation. Um, to, uh, cryopreservation of oocytes in less than 2 weeks. So this takes, you know, some of that burden away. Uh, a lot of the other barriers that we see have to do with cost and insurance coverage. Now we can talk to our patients a lot about how to diminish those costs or decrease those costs for them. Uh, we always want to talk to them about many of the philanthropic funds that are available specifically to oncology patients to decrease their medication costs, and we can decrease their costs of storage and shipping, uh, for their tissue or for their oocytes and their embryos, but that still does leave a large cost burden on on. These procedures, as many of them are not covered by insurance, um, and even the patients that are lucky enough to have infertility coverage, they don't fall into that definition of fertility as it is, you know, stated because they're not technically infertile yet and they're not falling into a category of having ovarian insufficiency at the moment. Um, but it seems like our advocacy must be working a little bit because I'm, I'm not sure how many of you are part of, uh, ASRM or are getting, uh, emails, but any of you who may be on the email blast that was kind of sent out recently, um, can see that Connecticut is now the first state who, um, does have, uh, mandated fertility preservation coverage for, uh, fertil for patients. The way that they did this was they changed the definition of fertility, so instead of previously where the definition of fertility and I wanna get this right was um to look at otherwise healthy females, right? And so you looked at healthy females who had tried to um try for fertility for 6 months to 12. Months and were unable to get pregnant, they took that language out and they changed it to medical necessity. So now patients can, you can talk with your doctor you can figure out is there a medical necessity of why you would need to be trying for fertility treatments and now our patients can fall into that category. Now it's not perfect because patients would otherwise need to have fertility coverage, but it's a first step in in looking towards that. Um, patients also have concerns for procedural technique and side effects. Some of these side effect concerns may be warranted concerns. Some of them may be myths. So we wanna make sure that patients are getting, um, patients and providers are getting evidence-based, um, information and education. So that is always gonna be important. But other things are considerations that we want to make for a more adolescent friendly protocols. Some things that clinics have tried to help this population is thinking of, you know, smaller transvaginal probes that that may be more useful for this population or even trying to limit the amount of vaginal procedures by doing abdominal ultrasounds for monitoring and then limiting that vaginal procedure to just the sedated uh retrieval at the end. Another procedure to consider in patients that are undergoing pelvic radiation, um, because this can lead to significant amenorrhea and then subsequently infertility, especially in patients receiving higher dosages, is to consider surgically moving the ovaries or transpositioning them out of the radiation field. Um, you know, this can be done most of the time laparoscopically, which can decrease the rates of complication, and you can do it unilaterally or bilaterally depending on where the radiation field is. Um, the complication rates are gonna be similar to other. Laparoscopic techniques, but something the things that to consider specifically for this is that you can have an increased risk of torsions, um, or, um, bowel obstructions that may be a little higher than other laparoscopic surgeries, but all in all this is a safe procedure. Um, the success rates are pretty good with 50 to 90% reductions in radiation to the ovary and a 30 to 50% maintenance of ovarian function, but how that plays out clinically for fertility preservation is, is still really unknown, and it's not well studied in our pediatric population. So again, further study is needed to see how this actually, um, manifests for fertility preservation, uh, in pediatrics. So then looking towards the experimental uh options I did put GNRH analogs into this as you know many of you who may um work in uh in gynecology may know this kind of falls in and out of favor back and forth. The idea is a good one, right? If we can mimic a prepubertal ovary, we have seen that prepubertal patients seem to be able to handle chemotherapy better, um, so if we can mimic that, can we, you know, be able to, um, to give the patient. Patients a better chance at decreasing uh the uh um the gonadotoxicity to the ovary. Also, these are simple procedures. You're just giving the patients injections. You don't need a lot of time. It would be something that um that we would really want to be able to utilize if it would, if it would work. The problem is, is there with the early design studies, you know, the, the efficacy was difficult. There were small numbers. They were retrospective. Their definitions of, of what constituted, um. Uh, uh, lack of, um, you know, what they use for POI definitions, what they use for infertility was, was just not very good, so it was hard to tell what, what the, what were good studies. Now the more recent studies have been better. They're doing prospective studies that are more randomized. Um, they're using, uh, better definitions and so these more recent studies, there have been 3 studies in patients with breast cancer that are showing a decrease in amenorrhea. Um, and then 3 studies that are showing, um, but then after that 3 studies in patients with, um. Leukemia that we're showing, I'm sorry, with lymphoma that were showing no protection in ovarian reserve, and two of those studies even had to be stopped early because there was just no good results coming from the studies. So because of that in 2013, um, ASCO did put out guidelines recommending that patients did need to be informed that there's just insufficient evidence to recommend GNRH analogs as a form of fertility protection. Um, so at this point that is where we stand with the GNRH analogs. Um, it is important to notice the POLM study though, uh, which is the prevention of early menopause study, and this specifically looked at patients with breast cancer and the use of Gosarellin. So the patients were, um, randomized to two, groups, one with Gosarellin alone, um, and goscerelin chemotherapy versus chemotherapy alone, and in those patients, the patients in the gossarellin arm did have. Have a reduction in uh ovarian failure that was statistically significant and they also had a decrease in their odds ratio for their pregnancies and this was the first study that actually used pregnancy as one of its um factors for which it looked at so it is important in that realm now what that will mean for um guidelines as far as the use of GNRH analogs we don't know um but possibly it could be useful in certain populations. Um, so the last thing that we will talk about, oh sorry, I made the wrong one, Wrong way. The last thing that we all talk about is ovarian tissue cryopreservation if I can get there, um, so ovarian tissue cryopreservation is important because this is the only method of fertility preservation that is available for our prepubertal patients. Um, it is also available for post pubertal patients who may not have time to fulfill, um, those standard of care procedures that we discussed earlier, um, or who opt against those procedures for one reason or another. Um, it is completed by the removal of a hole or a portion of one ovary. Uh, the ovary is then separated, uh, the cortex from the medulla, and then. Um, is cut into small strips of about 1 millimeter thickness. Um, those strips are then cryopreserved. Currently cryopreservation, um, standard is with a slow freeze technique. Um, there have been multiple studies looking at slow freeze technique versus doing a vitrification. Majority of, um, labs would like to do vitrification, right, because that is what we're utilizing for oocytes and embryos. And actually the studies are showing that the vitrification is likely a better technique. Um, however, until we, um, have some outcome data from the vitrification, it's, it's not currently considered to be standard and shouldn't be considered standard until there is some outcome data on that. However, it's very promising that that that could be the case. Um, the tissue is then sent for long term storage, um, until the patient is ready to utilize that for future fertility. Um, the, the, the reason, the, the ways for using previously cryopreserved ovarian tissue have been discussed a bit by Doctor, um, Woodruff in her talk, um, but the, the main source of utilization thus far has been through retransplantation, um, into the patient, um, mostly through orthotopic transplantation. Or putting the back into the patient um into the pelvis, um, so, uh, placing that either into the ovarian fossa or where the ovary was previously removed or into to the contralateral ovary, all of the live births um in the literature thus far have been through orthotopic transplantation. Um, there are also studies, um, showing, uh, heterotopic transplantation or placing the ovary outside of the pelvis, usually in the forearm or in the abdominal wall. There are no live births from this, and then, as Doctor, uh, Woodruff so wonderfully gave us the update on the. Literature for the use of things such as in vitro maturation, um, which is kind of the future of what we're looking towards, um, to be able to kind of, um, move towards not having to put ovaries back into the patient and being able to get away from those risks as, as we've already talked about a bit here. Um, so, uh, there have been 86 live births, um, in the literature thus far from orthotopic transplantation. We are gonna have a separate discussion about that, so I'm not gonna go into that quite a bit right here, um, but of those 86, 2 of those have, uh, been from patients who were in the pediatric population, so two of those in patients who were not yet monarchical, um, only one of those. Been reported in the literature thus far, um, so both the removal and the reimplantation of ovaries at this point are still considered experimental and must be done under IRB protocol. What I do wanna talk about a little bit is, uh, some of the safety data and some of the considerations for actually removing ovaries. Um, so from the Judul study that is up here where they reviewed, um. Some of the larger numbers of uh tissue cryopreservation procedures or removal of ovaries that have been completed, the things that I thought were interesting to talk about today is that they really did show a very good safety measure for proceed for this procedure. So out of the cases that they have completed, they had only 5 minor complications, um, and 1. Major complication for which they did have to go back um and do a repeat surgery for bleeding after an ovarian tissue cryopreservation and they did an extensive review of all OTCs that have been completed and noted in the literature and there has been only one death um which was noted from a procedure for uh removal of an ovary for the purpose of ovarian tissue cryopreservation in all reported literature. Um, they also have done a number of, uh, pediatric patients in their literature. So of all of the patients that they completed, so of the 545 that you see here, 30% of their patients were under the age of 18, and, uh, 15% of those patients were pre-pubertal. So there are a number of patients even, you know, outside of what we're doing in strictly pediatric, um, centers here in the United States that, that, that do show uh a number of, of this is, you know, safe in pediatric populations. Um, a number of the other things that we like to kind of discuss is some people have brought up the idea of, you know, let's make sure that we are doing these experimental, um, protocols on patients that are going to be able to utilize them or on patients who, who, who we know are are gonna be wanting these. So some things that are always brought up are the survival rates of patients that we are performing these on. Um, they noted a, uh, deceased rate in their, um, overall patients of about 10%. It was slightly higher in their less than 18 year old patients of about 13.5%. Um, they did only a 4% utilization of the tissue rate thus far, um, but they compared that to patients, um, oncology patients who come back and use their semen. Um, and that is less than 10%, so I think overall that's kind of a trend, right? You want to save your tissue because you don't know what's gonna happen in the future, but you may not end up needing it, and that's kind of what we tell the patients in the beginning you're, you're saving this just so that you, you have that, um, in case you need it. But I think what was very interesting about this study, um, was that they said 96% of the patients who they surveyed said they were satisfied with the fact that they had this procedure. And that included the patients who did not end up utilizing their tissue, so even the patients who gave their tissue back to research or discarded their tissues still had an overall satisfaction with having the procedure done, um, basically showing that it's the idea of having the choice, um, more than whether or not they ended up needing to utilize their tissue. Um, so I wanted to go over because you know a lot of people have questions about um what the protocols are and and what we are doing here at Cincinnati Children's. So our protocol um allows uh ovarian tissue cryopreservation for females ages 1 to 1 month to 41 years of age, um, basically any patient undergoing, um, surgery, chemotherapy, drug, or radiation that's going to put them at risk for, um, loss of ovarian function. Um, patients who are either not a candidate or choose not to undergo the standard of care treatments and with FSH is less than 20, you'll notice that our protocol is left very broad and we do not have restrictions based on risk assessment. This is going to vary from center to center every. is going to be a little bit different. There are many centers whose IRBs do place restrictions on them based on risk assessments, and that will just be, um, different depending on on how that's allowed at your institution. But the good thing about having a broad protocol is that it does allow for case by case, uh, evaluations. Um, so we did, uh, do an evaluation of the, um, protocol or the patients that we saw. Basically this, uh, was when we had done 52 patients, so about a year and a half ago we've done over 70 ovarian tissue cryopreservations at this point today. Um, our patients at that point ranged from 0.6 to 33 years old with an average of about 10 to 11 years of age. Um, of those patients, about half were malignancies or half being hematologic disorders with a small amount of immune and metabolic disorders. Um, 31 of the 52 were bone marrow transplant patients, with the remainder being chemotherapy plus or minus radiation. And interestingly, even though I kind of just told you that we leave our protocol really broad, the vast majority of patients who are still electing to have ovarian tissue cryopreserved are those really high risk patients, um, with a small amount of those intermediate risk. And when you look at the patients who are opting for it, as you would most likely suspect, the vast majority are pre-monarchical or those post-monarchical patients that fall into a time frame where they do not have time to be able to do um oocyte cryopreservation. Um, the other, uh, things to notice in our, um, in our study was that in the time frame, um, that we, uh, looked at our data, we also noted, uh, safety of our procedures. Uh, we had, um, 4, complications, uh, 3 of which were very minor complications, and 1 patient who had a small bowel obstruction 1 year after her procedure. However, this patient also had a very. Um, complicated course with, uh, bowel graft versus host disease, so we do not believe that that was a complication of her current course, um, and we are, um, uh, numbers for patients who were deceased after their procedure was very similar. We had 5 patients deceased, none of which. Which were related to their ovarian tissue cryopreservation, all related to their primary disease, um, coming up to a percentage of about 9.6%, um, and, uh, so that is similar to the previous data that was stated before we have had no complications since this data was reviewed. Um, and so I would be happy to answer questions there if there's some pending or we can move on to Andrew to look at the mail. So, um, interesting as always. I, I thought Todd, we wanna keep our participants interactive in the session, right? So I was thinking there's some questions as Doctor Hefkin was presenting. Um, I, I guess I will ask you a bit on the spot because you said that there is Doctor Ponsky, that there are some surgeons who are participating. Is this something that surgeons know much about when they're involved in asking, let's say, to place a line in a patient prior to their chemotherapy starting? And so that probably factors in, and I wondered again in your institution, your experience with that. No, and, and, and I think it's institution dependent here they probably. Would ask more because it's, it's something that's more, uh, talked about and, and they're educated. I, we've discussed it so many times at our meetings, but I've never once felt that it was my place to make that suggestion to the patient. I see. And so, uh, I'm curious. I mean, when should I, we always are in an odd place to for us to be able to assert something like that if we're off. So, uh, but that's probably the time to do it and so that should be a discussion between. The consult the oncologists and the surgeons about who's going to talk to them and then how we do it, right? I think those are probably some questions that's probably some of the participants have as well, meaning that not many institutions have a formalized program that's really running, I would say smoothly. At this point, and I think probably learning from all of our experiences about how that unfolds, many of those patients could benefit from that discussion, although who in a pediatric facility, not all have pediatric gynecologists or easily accessible pediatric urologists right on the spot to provide that counseling and information. So I was kind of encouraging it because maybe some of the pediatric surgeons who are participating might be able to also provide us some comments or really their exposure interaction. I think I recently received a survey in our institution. From a pediatric surgery trainee, really getting some idea about how much exposure pediatric surgeons have to the idea of fertility preservation. The only, this is interesting, our national meeting, there were two presentations about it, and before that, probably none. And so this is something that it's good that, by the way, we've got totally squashed. The pediatric surgeons are now only 11% of the people. Uh, mostly oncologists, um, but it's something that there are, but in the last two minutes there's been about 6 questions put up on the thing here, but, uh, once the program has started, this is a multidisciplinary thing that we need to figure out who's tall and who what, and, um, we've been very eager to get involved with this, um. Do you want to start? Do you want me to start going through some of these, or do you want? Yeah, I was gonna say we could, uh, maybe perhaps, um, some of them may relate also. I just wasn't sure if we should progress to the male section or we should hit a couple. I think one of the questions was about the actual ovarian tissue removal, and that might relate at this point and then we could maybe transition on. I think the question here, um, for you, Doctor Hefkin, is there a preference for a surgeon versus a pediatric gynecologist to do the actual ovarian tissue removal? And with that, how do you determine how much tissue you take? Do you take cortical strips? Do you take a biopsy? Do you take the whole ovary? And that may be an important question even for the pediatric surgeons who are listening as well. So let me ask you a question before we answer that. In your survey of the country, how many centers. Have pediatric gynecologists in a free standing children's hospital. Yes, the survey came to us from another investigator. Um, we can say that we have a national meeting and there are the minority of free standing pediatric centers. That have a fully functional pediatric gynecology service that would provide that say more on a timely basis. Oftentimes they're gynecologists coming from the adult world we can come in a few days we have clinic once a week, so that may not fit for this particular indication. The great thing is there are pediatric endocrinologists that are based mostly at the children's hospital and could get an idea of sort of the risk for the patient and then to collaborate with a gynecologist or urologist. So there are different ways I think that you could set up the program in different institutions depending on your resources. We're quite lucky to have gynecology and urology here 24/7. So we can turn things on pretty quickly, but as Doctor Hefkin said, we collaborate also with the adult world, right, for U sites. We also collaborate for sperm cryopreservation, you know, there are all kinds of collaborations, and I think communication and relationships get you going on that. So we can give some advice. I think that after the break today we're gonna talk about building a team and how can you build those collaborations. So maybe, um, we can give your comment about who gets the ovary, how do you do it, and then move on to Doctor Shrine after that. Uh, yeah, I think you already said that, um, yeah, I mean, so I think it's just, you know, like Doctor Bree said it's just dependent on the availability and of what you have at your hospital, right? So there's, uh, multiple different team models depending on who has an interest and, and who you have available to work to be part of your team. So, um, you know, many different teams you you utilize, uh, pediatric surgeon to do both, you know, maybe one person. is doing the males and the females to do their TTCs and their OTCs. Other people have a model kind of like ours where you're using a gynecologist and a urologist on both ends. So I think, um, neither of those models tends to be a right or wrong answer. It's more about the resources that you have available, um, at your centers because, you know, like we're saying, there's, there's only a limited number of, of pediatric gynecologists and then a lot of places may also. Um, be using adult gynecologists for those adolescent young adult patients and then, you know, pediatric surgeons for the younger patients in coordination with a, with a gynecologist. So Doctor, Doctor Hopkin, I was wondering also like cortical strips versus whole whole ovaries. I think that was also one of the questions. So I don't know if you had some thoughts on that because I know you have much. More experience than I do in that right and that seems to be institution based as well. I mean, I think here we do a whole ovary, um, and I think part of the reason for that is that in the, in the very younger patients it it's very technically difficult to remove cortical strips on an ovary that's already very small. Um, a lot of the adult centers do do cortical strips because you're working on a larger, a larger portion, right, so then you can remove those cortical strips, um, so I think many of those, many of those are just institution based and maybe surgeon preference based, uh, on, on. What is, what is, uh, more, um, more important in those instances, um, there's limited literature on whether or not removal of one ovary decreases your, you know, your future potential as far as, um, fertility or hormone function uh, we're looking at that now at this institution to see if there's a difference in our patients between, you know, those patients who had an OTC versus those patients who did not so we're using. Um, you know, our BMT patients as a, as a model to see, you know, if there's a difference in, in their future, um, you know, fertility function or or hormone function with, with one ovary versus two to kind of help increase the knowledge in that base, um, the thought is that. Might not that there should not be but um there is you know uh a paper or two that may suggest that there could be so and those those are the important things that you would want to look at in the future to kind of help make a more definitive suggestion on that right but right now it's, it's more, um, provider dependent.