The Oncology Podcast

Unveiling Ovarian Toxicity: Beyond Fertility in Cancer Care

• Professor Bogda Koczwara AM • Season 1 • Episode 10

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Welcome to the latest episode of Supportive Care Matters. Join Medical Oncologist Professor Bogda Koczwara AM and Dr. Wanda Cui as they dive deep into the often overlooked complexities of ovarian toxicity in cancer care.

In this engaging conversation, Bogda and Wanda go beyond the surface discussions of fertility to explore the vital importance of a woman's overall ovarian health after cancer treatment. They discuss the far-reaching effects of early menopause triggered by cancer therapies on cardiovascular and bone health, shedding light on the significance of safeguarding reproductive potential through fertility preservation methods.

Together, they tackle the challenges of measuring ovarian function in clinical practice, highlighting the disparities in menstrual recovery among different age groups post-treatment. By exploring predictive values and the effectiveness of indicators like menstruation, pregnancy rates, and hormonal levels, they provide insights into personalised clinical practices essential for addressing individual patient needs.

The discussion also emphasises the urgent need for improved research in ovarian toxicity, particularly within breast cancer trials where data is lacking. Supportive Care Matters isn't just a podcast; it's a call to action for greater patient involvement and policy change in cancer care.

Join us as we navigate the complexities of ovarian toxicity and strive for better support and care for cancer patients everywhere. Visit www.oncologynews.com.au for show notes and more information about Supportive Care Matters!

This conversation is proudly produced by The Oncology Network.

TO VIEW SHOW NOTES AND MORE INFORMATION ABOUT SUPPORTIVE CARE MATTERS, HEAD TO WWW.ONCOLOGYNEWS.COM.AU

Boga Koczwara AM:

Cancer diagnosis and treatment pose a threat to many aspects of patients' life. For young patients, one of the most distressing is the threat of their reproductive potential in future parenthood. To address this, researchers and clinicians need to understand the risk and measure the impact of cancer treatment on fertility and ovarian toxicity. How can that be done better? I'm Bogda Koczwara, and this is Supportive Care Matters. My guest today is Dr Wanda Cui. Wanda is a consultant medical oncologist at Peter MacCallum Cancer Centre in Melbourne, Australia, and a PhD candidate at the University of Melbourne. Her research focuses on oncofertility and cancer prevention. She is the first author of the American Society of Clinical Oncology research statement regarding assessing ovarian toxicity in cancer clinical trials. You can find the link to the paper in the show notes. Wanda, welcome to the podcast.

Wanda Cui:

Thanks for having me, Bogda. How are you?

Boga Koczwara AM:

Well, thank you. So let's talk oncofertility, and perhaps let's start with the definition what is oncofertility and why is it important?

Wanda Cui:

Yeah. So oncofertility, or really actually ovarian toxicity, is really important because we want to understand what a lot of our cancer treatments might do to the ovaries in particular, whether or not they might damage the ovaries and can result in early menopause. I guess, speaking more scientifically and from a bit of a background, we know that we're all born with a finite number of follicles, ovarian follicles. Throughout our life, these follicles get used up as we go through each menstrual cycle and eventually, once all the follicles are used up, a woman will go into menopause, and we know that certain treatments, such as chemotherapies, can accelerate that depletion of follicles and can result in early menopause, and that can then result in not only infertility so that's the oncofertility part that we worry about in our cancer patients but also can have quite profound negative impacts on general health, such as cardiovascular health, bone health, sexual health, and these are really important issues for young women as well as women who are transitioning from premenopausal to postmenopausal, when they're trying to make decisions about their cancer treatments.

Boga Koczwara AM:

So I think that's actually a really important point, because I sometimes find that a patient will be seen in clinic and somebody may say well, we really don't need to worry about the sort of risk of ovarian toxicity because they're not planning to have children. But it's not just the desire to have children that plays a role with regards to ovarian toxicity, it's also preventing premature menopause that might have adverse consequences. Does that sound about right?

Wanda Cui:

Absolutely, because we know that going into menopause at 35 versus going into menopause at 55 is very different in terms of the long-term consequences and also the general well-being of a woman. And even going into menopause at 45 versus 55 is very different as well. So I think we need to change the way that we think about oncofertility, and maybe oncofertility is part of the issue the term because we think about childbearing but we don't necessarily think about the other consequences of damage to the ovaries.

Boga Koczwara AM:

So ovarian toxicity might be important for anybody who happens to have ovaries, versus they may not necessarily wish to aim for fertility as a goal, exactly.

Wanda Cui:

And it's important because we have fertility preservation measures for people who do wish to try and preserve their fertility and prevent infertility in the future after their treatments. We also have medications to try and prevent or reduce the risk of early menopause as well, and so we should be thinking about both of those in a premenopausal person or a premenopausal woman, regardless of their childbearing wishes.

Boga Koczwara AM:

So how common is ovarian toxicity with cancer treatment?

Wanda Cui:

This is the big question mark. So we have really good data about how common it is with chemotherapies so about a quarter of women who are treated with alkylating chemotherapy. So these are chemotherapies that we use very commonly for curative treatments in breast cancer, hematological malignancies and sarcomas. We know that a quarter of women treated with this chemotherapy can go into complete ovarian failure after their chemotherapy has been completed. And in the studies the way that they define complete ovarian failure is complete sensation of periods but also using some blood markers as well. But what we don't know is how many women have incomplete ovarian failure. So the treatment has affected or damaged their ovaries. They're still having periods, but they might go into menopause at an earlier age than what they would have if they hadn't had that treatment. And we also don't know what a lot of our newer treatments, which are not chemotherapy, what they do to ovarian function and ovarian outcomes, because we haven't been collecting these data so there is a bit of unknown about how prevalent this issue is at the moment.

Boga Koczwara AM:

And, of course, that would depend also on what is the starting age when the person is receiving treatment, because of course, your fertility potential or your time of menopause, or time to menopause, will depend on whether you are 20 or 30 or 40.

Wanda Cui:

Exactly. So. We know that women who are younger at the time of having their treatment so generally under the age of 30, are more likely to recover their periods after chemo, whereas women who are older so you tend to be in their 40s when they're having their chemotherapy, are less likely to recover ovarian function after chemotherapy, but also the dose of the treatment as well. So we know the cumulative dose of chemotherapy also impacts on that.

Boga Koczwara AM:

So this is pretty complicated because there's a lot of moving targets in it in terms of where you're starting from, how much treatment you have, how old is the patient, at what point you do measure ovarian function, etc. So what are the measurements? What can you measure?

Wanda Cui:

Yeah, so there's a few things we can measure and all of them have some pros as well as some cons. So I guess the easiest thing to measure and the thing that we've been measuring most is whether or not a woman is menstruating or whether or not she's having regular periods, and that's easy to measure. But the downside of that is it's imperfect, because we know that a lot of women will stop having periods during chemotherapy but will recover their periods generally in the year after chemotherapy, and so by your period, stopping doesn't necessarily mean you've got irreversible damage to the ovaries. The other thing is we know that a lot of women who have periods can still have reduced fertility, and having periods doesn't mean that there hasn't been some damage to your ovaries as well. So it's an imperfect marker.

Wanda Cui:

We know pregnancy is the only direct way that we can measure fertility. However, often we collect how many pregnancies occur, but we often don't collect attempts at pregnancy. So if you think about if you had five women who got pregnant, but five of those were trying to get pregnant, then actually the fertility, the impact on fertility, is probably going to be very low. But if you had a thousand women trying to get pregnant and only five of them got pregnant then actually that success rate is very low and I think the way that we present our data at the moment is very difficult to be able to interpret that. So that's the clinical stuff.

Wanda Cui:

And then we've got some blood markers that we can look at. So traditionally we look at FSH and estradiol and this tells us if a woman's premenopausal or postmenopausal, but it doesn't really tell us about the in-between. So she might've had some ovarian damage from her treatment, but we won't be able to really tell that with those two markers alone her treatment. But we won't be able to really tell that with those two markers alone. And increasingly we're using AMH as a marker to try and potentially quantify how much ovarian toxicity or how much damage to the ovaries has occurred.

Wanda Cui:

Unfortunately, amh it's more sensitive than MSH for looking at ovarian toxicity, but it's not very sensitive or specific for fertility. So a woman who has a normal AMH might still be subfertile and vice versa. So it's an indirect marker and it's not perfect. And lastly, you can also count how many growing follicles you have with an ultrasound and that's called an antral follicle count and it measures something very similar to what AMH measures, but it can be difficult to access, especially in cancer hospitals, because we need specialist gynecological ultrasonographers. There can be variation in the counts between different operators and also it requires a transvaginal ultrasound as well, which can be invasive for many women.

Boga Koczwara AM:

So just to recap, in terms of the hormones, the estradiol is what ovaries produce. So if ovaries work then the estradiol will be elevated. Fsh and LH hormones produced by the pituitary that drive sort of ovarian function and they cyclical. So you could predict what the ovarian function is. And AMH is antivullerian hormone. Did I get it right?

Wanda Cui:

Yes, you did so. Antivullerian hormone which is produced or released by the growing follicles in the ovaries and, unlike FSH, lh and estradiol, which vary through your period, through your cycle, amh does not vary, so you can collect it at any time during your cycle and it should be relatively consistent.

Boga Koczwara AM:

So, as I think about it, there are two potential ways of using measures of anything. One is to tell you what happens after you've given cancer treatment, but the other one is to anticipate what could happen with the cancer treatment. So do some measurements before cancer treatment is started, to kind of say how close is the person to menopause and therefore how much of the cancer treatment would have impact. And I would imagine that if you'd measured both, you would also learn something useful.

Wanda Cui:

So how does?

Boga Koczwara AM:

it work in clinical practice at the moment, and how good are those measurements?

Wanda Cui:

Yeah. So I mean there had been some data to show that. It's mostly retrospective data though, that look at AMH in women who've been treated with chemotherapy in terms of predicting the likelihood of ovarian failure, and certainly women who start with a very low AMH at much higher risk of having complete ovarian failure after chemotherapy, which makes sense. But I think in clinical practice I don't think that these markers are being used routinely to predict for ovarian failure, because I don't think that we're super familiar with them as oncologists, first of all, and also they can be imperfect. So a low AMH does not necessarily mean that a woman's going to necessarily going to ovarian failure, and a high AMH does not necessarily mean that a woman's going to necessarily going to ovarian failure and a high AMH does not mean that she's definitely not. So I guess it's tricky to interpret that on an individual basis.

Boga Koczwara AM:

Yes, it's not the absolute contraindication to sort of to having treatment or not, an absolute discounting of the possibility of being fertile or avoiding menopause hard to provide advice.

Wanda Cui:

Yes, and also if a woman had a high AMH and you know it wouldn't necessarily change our recommendations in terms of seeking fertility preservation consultation or thinking about medications like gazerolin to try and protect the ovaries during treatment. So it's tricky in that way because it doesn't necessarily change treatment.

Boga Koczwara AM:

So it's a difficult area because the data is not necessarily perfect, there are limitations to the evidence and there are limitations to methodology, but you and your colleagues have done something amazing by actually pulling together recommendations, as they are today, based on best available evidence, into a paper published by the Key Journal of American Society of Clinical Oncology, and you were the first author on the paper. So tell us about the paper. How is it contributing to practice and research today?

Wanda Cui:

Yeah, so I guess this paper really came about as part of some of the work that I did for my PhD. So in clinical practice, one of the hardest things is you see a lot of young women. I treat breast cancer. I see a lot of young women in practice and we're using a lot of newer cancer agents now, and I don't really know how to address the question or the uncertainty about what do these treatments do to ovarian toxicity.

Wanda Cui:

So, as part of my PhD, I wanted to understand why we had such little information about these new agents, and I performed a systematic review of breast cancer phase three curative intent trials conducted between 2008 and 2019. And I found that only 9% of these trials assessed ovarian toxicity, so very few did so. Then I wanted to understand why that was the case, and so I interviewed a number of key stakeholders involved in clinical trial research, including clinicians, but also consumers, pharmaceutical company representatives, as well as regulatory agency representatives, and found that the main reason was that this issue was being overlooked and when it was being considered, people didn't really know how to measure these data and which data to collect, and so that was what formed the rationale for this paper, which is the ASCO or the American Society of Clinical Oncology research statement really calling to arms or kind of encouraging us to be routinely assessing ovarian toxicity in curative intent cancer clinical trials and enroll young women or premenopausal women, and so that was kind of the process of how this all came about.

Boga Koczwara AM:

So really, the paper focuses on what should be done in research, but it's got some important implications not just on research but also clinical practice and, potentially, policy that relates to clinical practice or research, because what you're really identifying is that there are certain aspects of health outcomes that are important to patients that we currently consider in an ad hoc way, in a way, rather than in a systematic way.

Wanda Cui:

Yes, because you think about clinical trials and we collect such detailed data about toxicity. We collect minute details about liver toxicity. We're now currently collecting cardiac toxicity data for many years after treatment's complete. But ovarian toxicity hasn't really been at the forefront of many people's minds and we know how important it is to a lot of people regarding their long-term survivorship and their long-term well-being, and similarly to kind of what happened with quality of life endpoints many decades ago. I think that time has come in terms of looking at some of those longer term side effects that we might have overlooked for the last few decades in clinical trials.

Boga Koczwara AM:

I think it's a wonderful justification for using expertise from patients to inform what would be meaningful for them to know about, and I think that, for example, in breast cancer trials, there's certainly quite an involvement of consumers in the design of clinical trials and in planning of which outcomes should be collected. And I think this is part of it, and perhaps also it seems to me that this is also a way of where, as a clinician, you identify a clinical gap and then you go and you try to address it, which is really what you've just described in how you came about into arriving at this paper.

Wanda Cui:

And we have had a number of consumers both involved in the actual paper as authors on this paper, but also as part of my PhD work for the qualitative work I did. Actually, the breast cancer trials consumer group actually really helped me with development of that project and that protocol as well, so there's been consumer input along the way and also through my qualitative interviews we found that one of the big findings, I guess, was that a lot of the especially pharma-sponsored clinical trials, the main decision makers in terms of what clinical endpoints just end up being collected are often the pharmaceutical companies, and what I found in my interviews was that one of their big considerations is whether or not the clinical endpoint will help meet regulatory agency approval, and so it was really important that for this paper we also included regulatory agency representatives, so there are authors from the FDA on this paper. You know that certainly they have a lot of pull and a lot of influence on the way that we design trials and the way that we conduct trials currently. Okay.

Boga Koczwara AM:

Because of course you are arguing that those endpoints need to be built into the clinical trials that look at the efficacy of drug treatment. But of course post-regulatory data collection on drug use could also allow for collection of that sort of information. But that can only be achieved if there is some way of collecting data in the original trials.

Wanda Cui:

Absolutely, and I guess one of the tricky things is that, yes, that's where some of my work is going now looking at collecting some of these data in real-world settings, and both prospectively as well as looking at retrospectively collected serum where we can now test for some of these ovarian markers. However, it would be ideal if these markers were collected, or these data points were collected during the trial, because then, when the drug hits the shelf, we know what the toxicities are at the time when they're first used in clinical practice, whereas one of the tricky things about the post-regulatory data collection is that then we're kind of going back and saying actually, we now know that these drugs may or may not affect ovarian function, but a number of women would have been treated with this medication by that stage.

Boga Koczwara AM:

Exactly, and of course, the population of people who might be using the drugs in real life might be a little bit different to the population of people that were recruited to a clinical trial, and if you have data on both, you could make that comparison. Otherwise it's impossible, absolutely, yeah, so tell us more about your PhD, because you just finished. But what else was involved in your PhD and where is the plan from the PhD to the rest of your research career over the next few years?

Wanda Cui:

So there was a few questions for my PhD.

Wanda Cui:

The first is why there was such little data about ovarian toxicity, and so the work with the systematic review, as well as some surveys as well as interviews, and this research statement forms part of that question, to try and work out why there was such little data about ovarian toxicity but also how to improve the current situation.

Wanda Cui:

But also the other part of my PhD is trying to look at what some of these newer treatments do to ovarian toxicity. At the moment, our collaborators, the Heart Lab at Monash, have some data from mice that show that mice treated with immune therapies immune checkpoint inhibitors as well as PARP inhibitors have a reduction of about a third to a half in their resting follicles, which is pretty alarming. But these are in mice and not in women, and there's no human data at the moment. So part of my PhD is to try and get some data by both retrospectively assessing stored serum from people who have had some of these newer treatments, but also prospectively assessing whether or not some of these newer treatments cause ovarian toxicity. Unfortunately, the prospective assessment is going to take many years, I think, to get results, but hopefully we'll have some data from the retrospective assessment in the meantime.

Boga Koczwara AM:

It's a real challenge because you've stated at the beginning that the gold standard, at least when it comes to fertility, is pregnancy. But of course the denominator is important and you would have to study a lot of women because only some of them would wish to pursue fertility and only some of them would be successful in being pregnant and actually get pregnancy to delivery time. So it seems to me that you need to study a lot of people to really get a full picture. Do we have the research infrastructure and the collaborative sort of network of researchers and patients to undertake that sort of research successfully?

Wanda Cui:

I think so. I mean, I think certainly we look at some big international and national registries and cohort studies which have many hundreds and thousands of people enrolled. And you know, we even look at some of the clinical trials that we're performing at the moment with some of these interventional drugs, where there's over 1,000 women recruited across the study. So I think that we do certainly. If we collaborate, I think we can certainly answer this question, but it takes collaboration to do that.

Boga Koczwara AM:

Indeed. So you have an opportunity to really lead a collaboration that has got very significant sort of global importance in a very high profile journal. What's it like to be a PhD candidate and a leader of this work, and also a cancer specialist at the same time? You're one of the very rare breed of oncologists who undertake a PhD. How does that feel like?

Wanda Cui:

I have been very fortunate in that my PhD supervisors, kelly Phillips and Louise Keogh, have been incredibly supportive and have been incredibly involved in driving a lot of the work. I mean, kelly is the senior author on the Lancet publication for the ASCO statement, so I think that that has been incredibly helpful, having very engaged and supportive supervisors who are also very well connected as well and can also help me with those collaborations, because as a PhD student or an early career researcher, you often don't have those connections or those networks to be able to tap into. And I think the other thing, it's incredibly rewarding because I think as doing this PhD being able to really deep dive into a topic that I find really interesting and to then also potentially make an impact with my research I find has been incredibly rewarding. And I think it's added to my clinical care as a clinician as well, because these are conversations I'm having in clinical practice with my patients now as well.

Boga Koczwara AM:

Well, because these are conversations I'm having in clinical practice with my patients now as well.

Wanda Cui:

Absolutely so any tips for an aspiring oncology registrar who would wish to dive into the field of PhD studies. So I think for a PhD because it's a long road it needs to be a topic that you feel passionate about or have a lot of interest in, because to be able to stay engaged for the three years or, in my case, because I did it part-time for the five years now it needs to be a topic that really grips you. I think having supportive colleagues or supervisors has been really important, but also, I think, finding time and trying to juggle clinical work, home life and also, you know, for me, I had a baby during my PhD and all of those things as well. Trying to juggle all of that. Some days you're not just not going to be able to write four pages of your thesis today, you're just going to have to accept that it's a paragraph, and I think that that's been a bit of a steep learning curve for me during my PhDs that you try and do it all but some days you just can't.

Boga Koczwara AM:

But I think it's an amazing example of how you could take an area of work that you could consider a little bit niche, a little bit specialized, a little bit small, and here you are and you've taken it and you've identified so many different aspects of it that are worthy of further exploration, that can inform how we do research, how we do drug approvals, how we deliver clinical care, how we drive health policy. So I think this is an example of how PhDs really change the field. So, from your perspective, what's the future for the field of ovarian toxicity research and practice?

Wanda Cui:

So I think the first step is to try and identify which medications or drugs cause ovarian toxicity. So that's a lot of the work that we've talked about already. But I think, once you've identified which medications can cause ovarian toxicity, the next step is trying to work out how, what's the mechanism and can we turn that mechanism off? How do we prevent ovarian toxicity? And I think that's where the future is. So I think there's a lot of work that there is to be done.

Boga Koczwara AM:

And I think this is again as a clinician, you always want to solve clinical problems. So all this research, however hypothetical it might be, at the end of the day it leads to the patient and addressing their needs Absolutely. So you are very close to submitting your thesis. We'll keep our fingers crossed for you. So what's the future after you submit, apart from your celebration and all the things that you truly deserve, like getting extra sleep and time with your family? What are the priorities for research for you after the PhD?

Wanda Cui:

At the moment I've got a couple of projects that I'm cooking up in terms of prospectively assessing ovarian toxicity for women treated with a number of different novel agents. So I think that's the first step to really identify which agents are causing ovarian toxicity. And certainly I've been working with some of our collaborators, such as Carla Hart and Amy Winship, with their mouse models as well, to try and help with that process too, and they've been helping with some of the human work, I guess, looking at serum from some of the retrospectively collected samples. And then, I guess, once we've identified which agents, I think the next step, concurrently with all of that, is trying to work out the mechanism. So that's one thing that the prospective data will hopefully be able to give us some light on and then, based on that mechanism, trying to find ways to prevent ovarian toxicity. I haven't quite cooked up the ideas yet, but hopefully that will come.

Boga Koczwara AM:

I have no doubt that there is going to be a long line of productive work and great ideas coming up and some amazing publications yet to come. So, before we close off, my final question on this topic of supportive care and ovarian toxicity. From your perspective, why does supportive care matter?

Wanda Cui:

I think it really matters because we want our patients to live, but we want them to live well, and I think that supportive care is so crucial to optimizing outcomes and quality of life, not just during treatment, but also after treatment's complete, and I think that it is incredibly important and should be part of when we think of the checklist of all the things that we need to think about when we're thinking about a treatment for a patient newly diagnosed. I think that supportive care is one of the top things we need to think about.

Boga Koczwara AM:

Fantastic. What a way to end the podcast. Thank you so much for joining me today, Wanda. Really appreciate it. Thanks for having me. That is all for Supportive Care Matters, a podcast created by me, Bogda Koczwara, for researchers, clinicians, policymakers and patients passionate about improving the lives of people affected by cancer. Thanks to Mark Tai, who composed the original music, and the Oncology Network, our producers, who composed the original music and the Oncology Network, our producers. For show notes, go to www. oncologynews. com. au. Subscribe to this podcast at your favourite podcast provider and rate us.