Fertility Preservation Program for Female Cancer Patients

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to be joined by Dr. Laura Detti, chair of Subspecialty Care for Women's Health at Cleveland Clinic. Dr. Detti is here today to talk to us about fertility preservation for female cancer patients. Welcome.

Laura Detti, MD: Thank you. Thank you for having me.

Dale Shepard, MD, PhD: Maybe to start, just give us a little background on what you do here at Cleveland Clinic.

Laura Detti, MD: I am a reproductive endocrinologist and infertility specialist, and besides working on the administration at the Cleveland Clinic, I also work in the fertility clinic. So I take care of patients with infertility issues, but as the definition says, I'm also a reproductive endocrinologist. So I also take care of all patients with any endocrinologic problem. I am also the primary responsible for the fertility preservation program here at the clinic, and that has been in since 2020.

Dale Shepard, MD, PhD: So I think it's probably safe to say that we don't think about fertility as often as we should as oncologists. So maybe you could just start by letting us know what are some of the fertility sparing techniques that are used for women with cancers?

Laura Detti, MD: That, of course, depends on the patient's age and the time that we have before they initiate chemo or radiation therapy, but there are mainly three techniques that we can use. The medical approach is the oldest and it entails using GnRH agonist throughout the administration of the chemotherapy. The other two techniques are purely surgical. One is the oocyte cryopreservation technique, and the other one is the ovarian tissue cryopreservation technique. If you want, I can go into a little more detail in each one of them.

Dale Shepard, MD, PhD: Sure, that'd be great.

Laura Detti, MD: So the medical approach is the oldest, as I said before, and it is based on a physiologic development on the follicles in the ovary. All females are born with a set number of oocytes in their ovaries and the oocytes are organized in follicles. Now there's two primary groups of follicles, so within the ovary. One is the primordial follicles, so which constitutes the majority of the follicles and they're also the ones that maintain the ovarian reservoir. The second group of follicles is the developing follicles. So there is a very important step the primordial follicles need to go through to become developing follicles and once they start development, they cannot go back to become primordial.

So if we have too many primordial follicles that enter development, we will have depletion of the ovarian reserve. I'm saying that because the generator agonist, which is the medical approach to fertility preservation, basically targets only the developing follicles but not the primordial follicles. However, by doing that, GnRH preserves the concentration of AMH, which is the anti-Mullerian hormone produced by the secondary and very early tertiary follicles, which maintains the primordial follicles in their dormant state. So if we destroy, for instance, with chemotherapy, the secondary and early tertiary follicles, we will decrease the concentration of the AMH hormone and as a consequence, we will have more of these primordial follicles that enter development, and then eventually we'll deplete the ovarian reserve.

So GnRH basically has only a transient effect on fertility preservation, and that has been proven in many studies before. So it's not the ideal method to preserve the fertility in cancer patients. Nonetheless, it's very useful to use it during chemotherapy treatment. Now, the other two approaches, which are the oocyte cryopreservation and the ovarian tissue cryopreservation are much younger as approaches, but they're the most effective that we have. Basically by preserving oocytes and taking them out of the ovary before starting chemotherapy will prevent those from going into destruction and apoptosis, and it will preserve these eggs on the side and they will be ready for fertility afterwards.

Now, the ovarian tissue cryopreservation entails taking and explanting part of the ovary or whole ovary, and then preserving only the cortex part of the ovary, discarding the medullary part. This technique has been proven very efficient and efficacious in preserving the fertility in these young cancer patients. Now, these two techniques that have indications that are different depending on the age of the patient, her pubertal status, and so it is important to always refer to a reproductive endocrinologist to make a decision on which one to use.

Dale Shepard, MD, PhD: Then from a safety standpoint, cryopreservation, you're actually removing tissue. Is it safer because you're not exposing the oocytes to cytotoxic chemotherapies that can alter DNA?

Laura Detti, MD: That's exactly the point, yes. So you will preserve that ovarian tissue in time before it's exposed to any chemotherapy so there is no way for the chemotherapy to destroy that ovarian reservoir.

Dale Shepard, MD, PhD: Now, you mentioned at the beginning about time and the time it takes for these. So one thing that we're very, very interested here is time to treat. So someone gets a diagnosis, how quickly can we get them treatment for their cancer? How did these techniques vary from when someone may be diagnosed? And we say, "Hey, we have to start chemotherapy to the cryopreservation or the medical fertility sparing." How do they vary?

Laura Detti, MD: So the medical approach, the ideal time of starting it would be two weeks before chemotherapy starts. But basically it can be started at any time during the process, as long as we remember. So there's no real downtime for that. The oocyte cryopreservation requires a stimulation of the ovaries for about two weeks, and then it entails also a minor surgical procedure to retrieve the oocytes from the inside of the ovary. So it requires at least two to three weeks before chemotherapy can be initiated. So it's not the ideal approach if a patient has to start the chemotherapy next week, for instance. The ovarian tissue cryopreservation entails a surgical procedure to explant the ovarian tissue, and so that could be done at any point, again, before the chemotherapy start. So theoretically it could be done just two or three days before chemotherapy starts. So that's very easy to perform because it doesn't require any preparation with hormones or other medications.

Dale Shepard, MD, PhD: When you see a patient, what sort of factors play into which of the options you pursue? What are the patient factors? Are there cancer related factors? How do you think through that?

Laura Detti, MD: We always do it in a team approach with the oncologist, the surgeons, psychologists, and of course the reproductive endocrinologist. It depends mostly again from the pubertal state of the patient and also when the chemotherapy needs to be started. So if a patient is pre-pubertal, we cannot induce ovulation. So we cannot basically have these secondary follicles develop into tertiary and then harvest the DX, because we need a mature ovary of a post pubertal woman in order to do that. So in a pre-pubertal patient, the best approach would be performing ovarian tissue cryopreservation. If the woman is post pubertal, but there is a very short time before starting chemotherapy, again, ovarian tissue cryopreservation would be the best technique. Otherwise, if we have at least a couple of weeks, like for instance in breast cancer patients, in whom, most of the time at last, we can gain those two, three weeks before starting chemotherapy, in those instances, we can perform ovarian egg cryopreservation. Of course, adding the GnRH agonist is something that is feasible for all these categories, including the pre-pubertal patients, even though normally we do not use a GnRH agonist in these patients.

Dale Shepard, MD, PhD: There are certainly lots of decisions that are somewhat complex to be made here. How often does this happen in the community? Is this something where people need to come and get the specialty sort of recommendations from an academic center, or is this happening in community settings?

Laura Detti, MD: So it is happening every time there is a young woman of reproductive age that presents to an oncologist in the community. It would be useful to think and counsel the patient about the option of fertility preservation, because that is something that unfortunately will never grow back. It will never grow back after chemotherapy.

Dale Shepard, MD, PhD: I'm going to guess that it doesn't happen as often as it should. Is that safe to say, that there are missed opportunities here?

Laura Detti, MD: Yes, especially in the past that there have been many missed opportunities. I have to say that here at the Cleveland Clinic, with this program that has now become much more structured, we miss very few of these patients. We have at least one patient every week that is referred to our center. In addition, we have about 20 to 30 pediatric female cancer patients that are referred to us every year.

Dale Shepard, MD, PhD: Tell me a little bit about the program. You said you have a program coming in place to work patients through the system. What does that look like?

Laura Detti, MD: Well, this is very exciting because up until now, fertility preservation was performed on a sporadic approach, I would say. Now instead, we have a fertility preservation coordinator. We have a nurse, her name is Shoshana, who basically coordinates all the patients as long as the primary oncologist or physician in general places an order, then we will be notified and reproductive endocrinologists will perform an initial consultation. Then we'll make a determination on whether this patient is basically a good candidate for fertility preservation and also what would be the best technique to use. Then they always confer back to the primary and the referring physician so that everybody is aligned and we can start a fertility preservation approach as soon as the following week.

Dale Shepard, MD, PhD: How do we raise awareness? How are you going about making sure people know what you're doing and getting people in to see you?

Laura Detti, MD: We're lucky here at the clinic because we have an excellent marketing team who has been putting out QD consult and also other approaches to spread the word about this program that is available to all Cleveland Clinic patients.

Dale Shepard, MD, PhD: So coverage issues, is this typically covered by insurance? How does insurance play into what is available in terms of options?

Laura Detti, MD: So typically it is not covered by insurance. However, we do have a compassionate care program for these kinds of patients with cancer, and we also provide the patients with a grant funding from our department and also from their own department. Many times they have some grant of funds for fertility preservation. So the bottom line is that the patients very seldom have to pay for these fertility preservation techniques.

Dale Shepard, MD, PhD: That's excellent. Research studies, is there anything going on here at the clinic in terms of new techniques or what's kind of on the horizon in this area in terms of other ways that we can do fertility preservation?

Laura Detti, MD: I personally am very interested in fertility preservation and I have done research on it. One very exciting result of all this research is that these AMH hormones can preserve fertility just by keeping the primordial follicles from entering that first developmental step. So we are doing as a group more research on medications that can mimic the AMH effect on the primordial follicles and then administer it to preserve fertility. But this research is in very early stages and of course this medication is not yet approved for any human use. However, it is very promising and exciting.

Dale Shepard, MD, PhD: Is there anything that is being done either from a medical or surgical perspective that is a little bit closer to fruition?

Laura Detti, MD: Surgical fertility preservation is a relatively young field and all the published studies are all of relevance, but what it is more exciting is that the amount of research has led to lift the experimental label from the two described oocyte and tissue cryopreservation. So the oocyte cryopreservation became of clinical use in 2012 and the cortex tissue cryopreservation in 2019. So physicians are treating cancer and using potentially gonadotoxic therapies are now compelled to address the options for fertility preservation to their patients, and that's the most exciting results of all the research that has been done.

Dale Shepard, MD, PhD: That is exciting. I guess, as they move away from that experimental consideration, is it likely that insurance might start covering this?

Laura Detti, MD: I believe so. There are a few studies where fertility preservation is mandated by the government, but not all the 50 states have been aligned yet. So that is still up to the single payers, basically.

Dale Shepard, MD, PhD: Where do you see the gaps, either from a technique standpoint, clinically, how we engage patients? What do you think are the biggest gaps? What do we need to fix?

Laura Detti, MD: I think the biggest gap is the financial burden for these patients. We have the technique down now, which is very solid and reproducible, and we have excellent of physicians that can perform these techniques, both of them. So the financial step is the limiting factor and hopefully with the grant funding and also with other venues, we try to overcome this major gap.

Dale Shepard, MD, PhD: Is it possible that we don't have some patients that could benefit even come see you because they're afraid of the cost and they may not know there's funding available?

Laura Detti, MD: If they present to us, we will make it very clear to them that whether they can afford it or not, we will be able to perform the technique for them.

Dale Shepard, MD, PhD: Just really quickly, double back a bit, success rates. When we're trying to look at each of those three techniques, how often can patients that go through these programs actually preserve their fertility and have successful pregnancies afterward.

Laura Detti, MD: Yes, and you said the word. The ultimate way for us to judge success is the achievement of pregnancy. So the oocyte cryopreservation technique, as I said before, is very solid and we can assure 95% chance of having a pregnancy or two, harvesting approximately 20 mature oocytes. So that's incredibly good. With the ovarian tissue cryopreservation, this technique is relatively younger than the oocyte cryopreservation, and there's only a few studies showing fertility and the achievement of pregnancies. But in the world, noticing that again, we don't know how many ovarian tissue cryopreservation patients actually had the tissue transplanted back inside their pelvis. We know that there is at least 150 live births. So it is very promising as a technique and as a pregnancy rate, it's being calculated in approximately 30% of these patients. So again, very effective and efficient.

Dale Shepard, MD, PhD: Well, you're doing outstanding work that's a really important part of what we're doing to take care of patients with cancer. So I appreciate all the efforts. Any additional comments?

Laura Detti, MD: The only thing I would possibly say is just to try to refer any patient that is at risk for undergoing a gonadotoxic therapy in advance of her therapy to us, so that we can assure efficient fertility preservation.

Dale Shepard, MD, PhD: Well, thank you very much for being with us today.

Laura Detti, MD: Thank you.

Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts, and don't forget you can access real-time updates from Cleveland Clinic's cancer center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.