Mar 27, 2023
In this JCO Article Insights episode, Davide Soldato interviews Dr Frederic Amant from UZ Gasthuisberg - Katholieke University Leuven. Dr. Amant discusses his clinical trial update published in the March 10, 2023 JCO issue, "Cognitive and Behavioral Development of 9-Year-Old Children After Maternal Cancer During Pregnancy: A Prospective Multicenter Cohort Study", by Van Assche, et al. From the International Network on Cancer, Infertility and Pregnancy, the article reports the cognitive development of 9-year-old children after maternal cancer during pregnancy.
TRANSCRIPT
The disclosures for the guest on this podcast can be found in the show notes.
Davide Soldato: Welcome to this JCO Article Insights episode for the March issue of JCO. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Frédéric Amant, corresponding author of the manuscript titled ‘Cognitive and Behavioral Development of 9-Year-Old Children After Maternal Cancer During Pregnancy: A Prospective Multicenter Cohort Study’ (10.1200/JCO.22.02005). Dr. Amant is a professor at the Ku Leuven in Belgium and at the University of Amsterdam, and he is the head of the Department of Gynecological Oncology of the Netherlands Cancer Institute and the Amsterdam University Medical Centers.
Welcome, Dr. Amant.
Dr. Frédéric Amant: Hello, good evening. Thank you for the introduction.
Davide Soldato: So, Dr. Amant, you published this manuscript that reports the updated results of an ongoing prospective multicenter study. And this study is actually investigating cognitive and health outcomes in nine-year-old children that were born from women who were diagnosed and treated for cancer during pregnancy. So I wanted to ask if you could give us just a quick overview of the study design. What are the main outcomes that are investigated in the study, and also if you could give us some information about the results that you recently published in the JCO?
Dr. Frédéric Amant: Well, the study is a follow-up study of children that are now nine-year-olds. A large part of these children, we have been following up since birth. So the first paper on this cohort basically was in 2015. And at that stage, children were 18 to 30 months old. Well, what we have to say is that all these children, or the majority of these children, in fact, the mothers, were exposed to chemotherapy during pregnancy. So the results actually in children at 18 or 30 months were, in fact, reassuring. And at that time, that was actually a big novelty because it was the first study where children were prospectively followed up and when they were compared to a control group. This study was actually changed a bit; the idea that chemotherapy during pregnancy was not possible. From there, we started to further follow up to some extent the children, but also it increased the awareness that we can treat cancer during pregnancy, including chemotherapy during pregnancy.
This was followed up by a study two years ago in six-year-old children that was, in fact, also reassuring. Today, we discuss then the cognitive and the behavioral development of nine-year-old children when the mother was exposed to chemotherapy but also, in fact, cancer; all the diagnostic investigations, many women also received surgery, and actually, the children were controlled by researchers, by psychologists, by medical doctors to look into their general health. There were questionnaires to the parents, and then we assessed the IQ, we assessed memory tasks, and attention tasks.
Overall, the results are, in fact, reassuring for the several subtypes of treatments, including several subtypes of cytotoxic drugs, and there were no differences when we looked into the intelligence quotient, so the IQ between exposed and non-exposed children. We did see some interesting analysis, however. To some extent, we did see that, for example, the IQ score increased by 1.6 points for each week’s increase in gestational age. There was no difference in the full-scale IQ between the treatment types.
Actually, in children prenatally exposed to chemotherapy, there was no association between full-scale IQ and the chemotherapy drugs, exposure levels, or the timing of the chemotherapy during pregnancy. So overall, the results are reassuring and indicate that during a critical maturation period of the child, when complex functions start to develop already and rely on the integrity of early brain development, this is actually reassuring. Especially, this critical maturation period means that when children are nine-years-old, we can test or do more complex tests when compared to children that are 18 months or 30 months, or even six years. So that is all reassuring news.
Another finding, however, was if you look at the IQ, there are several components of the IQ, and there we see that the verbal IQ was, in fact, lower, and that was especially in children who lost their mother or for whom the mother was in a critical period. So the mother's health was not so good. So this could be correlated to the fact that the mother and the environment of a child at that stage actually had less attention to the child, resulting in effect that the verbal development of the child was suboptimal. That is one possibility. We need to say, however, that these children overall were also more preterm born. So that is also a confounding factor. So the lower verbal IQ is in children that were more likely to have a mother in a bad condition, but they were also more likely to be born preterm. So we don't exactly know if it's the preterm birth or the poor condition of the mother that actually contributes to this. Anyway, I think what it is in effect is a message that we need to or that we bring to the family that we need to pay attention to this verbal development of the child.
So if we look into the overall data, I think there are some subtle differences. But overall, these children do, in fact, very well. They, apart from that, have normal behavior, they grow up very fine, there are no other problems. So this is important for physicians, for parents to be, where a decision nine years before needs to be taken, whether or not to treat cancer during pregnancy. I think that these data are then very reassuring that mothers can be treated and can receive chemotherapy during pregnancy since, also, after nine years, the children do, in fact, very well.
And one can say children nine-years-old, but what about when they become older? So we don't have that answer yet, we hope to have that in the future. But what we can say is that if a child has a normal IQ and actually a normal development, that this is a very strong predictive factor that later on this will be normal as well. Of course, we don't know yet about fertility; we have no data on secondary cancers. Therefore, we need to follow up these children much longer, of course. But I think with this data, we can really reassure clinicians and parents to be that we don't have to interrupt the pregnancy or that we have to delay the maternal treatment, or that we have to deliver the baby very preterm, allowing doctors to treat after delivery. So it shows that we can treat the mother without delay and that the baby best stays with the mother as long as possible, and that maybe we can use these treatments to keep the baby as long as possible with the mother.
So I think these are the main results and the main message that we actually bring to our patients.
Davide Soldato: Yeah, exactly. I wanted to ask exactly that because from what you just told, so just to summarize for our listeners, we just heard that actually, exposure to cancer and treatment related to cancer during pregnancy actually is not associated with worse cognitive outcomes. And, probably, reading the paper, the strongest predictor of having a reduced IQ for these babies is more the fact of being born preterm compared to the fact that they are exposed either to cancer or to the treatments that are related. So I wanted to ask you exactly that if you feel that the main message that we can deliver to the oncologist community in general, but also to the parents and to the families that they are making a decision regarding the possibility of treatment, is that we can treat, we should treat. And probably the main objective, if you agree with me, is that we try to postpone the moment of the birth as long as possible, to allow for the development of these children.
Dr. Frédéric Amant: That is completely correct. I think when we started with this research, the general idea, the general practice was actually, well, we cannot treat. So we deliver the baby preterm, and typically, that was around 32 weeks because 32 weeks of pregnancy, that means that the baby is viable but still very preterm. But the baby is viable, but it's two months early. But that was generally accepted in the absence of any data on the safety for children. With the knowledge we have now that we built up and for which the paper we discuss now is like the last update of this follow-up, it shows, indeed, that we should not fear too much, and that indeed of cancer treatment during pregnancy, including chemotherapy, and that this is to be preferred rather than interrupting the pregnancy or having a preterm baby. Or what was done also is that the mother was not treated, and then the pregnancy was continued, for example, until 32 weeks of gestational age, and then the mother was treated. But all these alternatives are either suboptimal for the mother or suboptimal for the baby, especially if there is a termination of pregnancy. But even when there is no termination and preterm delivery, that is also not particularly good for a baby. So the best solution for all parties there is to treat during pregnancy, including chemotherapy.
And that is indeed the message that we need to bring, especially since the results confirm previous results and actually validate the previous results so, well, it adds to the solid results, actually, and that is really reassuring. And what we also need to say here, and although this is not really part of this paper, is that there are also not more congenital malformations because that is also a concern of many doctors, that actually these drugs are designed to kill rapidly dividing cells. We know they pass the placenta, they will go to the fetus, although in a bit lower dosages. But many people were scared about the increased chance for congenital malformations, and we know that this is not the case on condition that we give the chemotherapy after the first trimester. If you give chemotherapy during the first trimester, you will have an increased risk of congenital malformation. So that is a caveat that we need to take into consideration that it is possible, but mainly during the second and the third trimester. But of course, surgery, oncological surgery and even radiotherapy during the first trimester is possible. So it is only the chemotherapy, which is not possible during the first trimester. This is what doctors and patients need, that there is scientific data saying that this is possible, and that's why we are very happy that we could report on that and that the data validate the previous findings on this topic.
Davide Soldato: And I think that one of the concerns that were also associated with the administration of chemotherapy, particularly with anthracyclines, was kind of the concern that there will be some effect on the cardiac function of the children born from these mothers. Well, it's not actually the object of this specific paper, but you previously also published data that were reassuring also regarding cardiac function. But one other thing that I wanted to ask you, you said before that there were lower verbal intelligence scores from babies that were born from mothers who then died, especially in the first part of the life of the baby. And also, there were some signals that some of these babies, especially those who were born preterm or that lost their mother very soon, were in need of remedial care.
Although you say that once we arrive at the nine-year development, probably the development is going to be normal, but do you think that this kind of environment and social factors and difficulties in general in the family once we arrive to that stage of development could also lead to some differences for these babies? So more related to the social situation and loss of the mother than from the treatment that they received or that they were exposed to. And do you think it's important in general that we continue to follow up these now children also to kind of give an indication or somehow to raise attention on the fact that despite the cognitive outcomes, they are good, we still need to give social support or this type of help to these families?
Dr. Frédéric Amant: Yeah, I think that's an excellent remark, excellent question because it's true. I wanted to say at the first session, the first part, but when I was talking about the predictive value of our results, they are very strong, and we can actually already now exclude that also, in the long term, chemotherapy on these cognitive factors will not have an effect. And that in the meantime, when the children grow up, the new external factors, in fact, become more important than the antenatal exposure. It is the social environment. Children will smoke, will use drugs, will drink alcohol, psychological traumas, and so on. So these are more likely to influence the further development of the children. And that's why I think, and the older the children are, of course, the more likely that it is that these external factors will play a role, so that will be more and more difficult to really disentangle all these external factors related to antenatal development.
On the other hand, we also control for this, and we control for the maternal and the paternal education. We look at the education level of the parents. So this is all included when we analyze this, and it is actually interesting because now you refer to it. In fact, children do, well, or the intelligence outcome correlates to the maternal education. The paternal education is, in fact, less important in this. So just to underscore the fact that we look into this, so that will be maybe a bit more difficult to really explore in the future. But the future examinations, on the other hand, will give us more insight into, for example, fertility, the adolescence of the children, and their sexual secondary characteristics as maybe as a biomarker of fertility, which is not always the case. But at least it would be reassuring if we see that these sexual secondary characteristics develop normally and also, maybe later on, the increase on cancer development.
Until now, these are theoretical concerns, but today we have no indication that this is actually true. So we think we definitely need to further explore that. But again, this is theoretical because some children now are 12, 15, 18 years old. They are not part of the analyses. But we have seen the children already. The results are in the data set, and we have no indication of more cancers. And we have no indication or the patterns at least, do not report to us that these biomarkers for fertility, let's say, the secondary sexual characteristics, are actually delayed or absent from the information we have from the children, older children. So the adolescents and their parents, we have no indication that there is a problem. So we have no mention that they are worried on these topics. So from that point of view, this is also reassuring. But of course, this is not hard science, but this will be part of the future analyses. The reason why we don't have these analyses now is that the children, of course, need the time, and they need to grow. So we have to follow them up. But what we tell in our clinic is exactly what I say now is that from the non-scientific data, but from information from our patients, that we have no indication that there is a problem.
Davide Soldato: And of course, in the context of the study, you mentioned before that one of the previous reports was actually kind of a confrontation between these children that were exposed and normal controls. Do you plan also to continue the follow-up for the controls to have sort of normality to confront these children too?
Dr. Frédéric Amant: Actually, now you refer to a sensitive point, to be honest. In the ideal world, we would do that to check the controls. But we see that it becomes a logistic problem to follow all these children and that we, to be honest, lack the resources to have such a large group of psychologists, not only to follow up all the children that were exposed to cancer treatment during pregnancy, but at the same time a control group. It's not only the existing cohort that we follow up. The cohort is fueled by new cases, and all our cases that are born in Leuven or in the Netherlands, in Prague, and in Milan, all the new cases are added to this cohort so that multiplied with a control becomes a really large group of children. So in the future, it will become impossible. Well, we will not have the resources to have to follow up this large group. And we will more focus on certain populations of drugs where we don't have so much information, cytotoxic drugs where the numbers today are too small. And we will compare the results with standard results that we would expose in that population, in those children from that country. And well, that is also a very reasonable approach and this is the approach we will need to apply in the future. Maybe in a subset of children, we will use controls but that will really depend on the scientific question.
Davide Soldato: Yeah, probably for some data where we have less information gathered in the general population, maybe that would be a subset that we could explore a little bit further. In your opinion, do you also think that this prospective study will give us in the future also information that goes a little beyond the cytotoxic type of treatment? Also, referring to new kinds of treatments that could potentially enter in the clinic, I know there is also the problem of exposing these women to drugs that we don't know actually what they give in terms of safety for the children. But do you think this could be something that could also be explored in this type of study?
Dr. Frédéric Amant: I think what this study shows overall, is there is insufficient research in pregnant women. And it is always like ‘drugs - cannot give them to pregnant women because it's potentially toxic.’ Of course, I can understand the worry, but on the other hand, what we have shown actually is that we have investigated one of the most toxic drugs. When there is uncertainty, I mean, we took really the drug where we would expect huge problems with children and there it not to be so bad as we thought. Really. I've seen letters, I've seen doctors that told me babies will be born like monsters if you give chemotherapy. That was the idea at least of some people, of specialists, I mean, well-educated people. And then we can basically reverse that idea for that particular class of drugs.
50% of pregnant women take some kind of medication, and for most of these medications, it has not been investigated what is, in fact, the effect on the children. So I think that our research opens the door that we can also look in another way to other terminal conditions that need treatment and that we can really add to more data, and that it underscores the potential, not only the importance, but also the potential to investigate on this. So this is on a general idea, it shows that it is possible. Of course, when we then again focus on cancer treatment, there's a whole tsunami of new drugs, targeted drugs, the immunotherapy drugs. So we have to be also very clear, transparent that our research here mainly focused on chemotherapy. The number of mothers that took any other of these novel treatments is actually very low and they are not part of this cohort because that was nine years ago. Nine years ago, actually, there was no immunotherapy yet. There were some targeted treatments, but very limited. So that is definitely, let's call it a weakness of this study that we cannot report on that. Nevertheless, we have some data from other studies with a shorter follow-up, but very limited. So that becomes really a challenge, actually, the whole new drug class of drugs because they are small molecules, they're more likely to cross. And it will then really depend on what is the target of that drug. And if that target is also available in the fetus while it is likely that the fetus will also suffer from that. But if there is no target at the fetal site or if the molecule is too big, then there will not be a problem. So, the individualization will be much more important in the future.
Also because many of these drugs are actually more and more used in the adjuvant setting. When we started this study, these drugs were used only in the metastatic setting, recurrent disease. That is the clinical situation where women do not become pregnant. But now they're moving more forward into the oncological treatment and also the adjuvant setting, so children that are more likely to be exposed to these drugs. So that is an avenue for future research that we also want to further investigate.
Davide Soldato: Yeah, of course. And just on a personal type of question, was there something specifically that led you to this type of research in general, in cancer in pregnant women? Because as you said, there is not so much research in it. It's difficult to do because– Well, it's not something that is so uncommon. But of course, it's more uncommon than several other topics in cancer research. So I was just wondering if you could tell us a little bit if there was something specifically that led you to this type of research.
Dr. Frédéric Amant: Yes, indeed, there is such a thing. I did not have such an idea, just out of my mind. And actually, now we go back nearly 20 years ago, 2004. At that time, we were actually scared to give chemotherapy. We really hoped we would not see these patients because we did not exactly know what to do. And then, I was confronted with a patient with cervical cancer. She lost her first pregnancy when she was 20 weeks far in her pregnancy. And now she was diagnosed, second pregnancy, with cervical cancer. And actually, she was referred to do a radical hysterectomy to remove the cancer, the uterus, and the baby. And actually, she approached me and she said, “Listen, I was diagnosed.” She was asymptomatic. So she was diagnosed thanks to the pregnancy. So she said to me, literally, “I had an earlier diagnosis thanks to my baby, so I have more life chances thanks to my baby. So I want to do everything to save this pregnancy because it is my only option, my last option to become pregnant. And I'm happy to take any risks.” Because, of course, we discussed that we are unsure that there was little evidence on this. So we had a really open, transparent discussion on that. But we said there are options. But if you say unsure, that means that she may take a risk, then she said, “Well, I'm happy to take that risk because I want to give my child also a chance because it's thanks to my child that I also have an extra chance.” So that's actually where it started.
So that's 2004, we started to look into the literature, two big things actually. To some extent, chemotherapy had been given, but really the number of cases was very small. But importantly, the children were born normally. So there was also some evidence that it was possible, but there was no really no long-term data. So we said to her, listen, the data we have is when they're born, they do well, but we cannot say anything more than that. So that was particularly to that patient.
And secondly, it really showed us the complete absence of knowledge on that, on all the aspects. There were no prospective studies. We did not know how many chemotherapy crossed to the child. We did not know the long-term follow-up of the children. We did not know, for example, the dilution of chemotherapy because mothers get chemotherapy, the chemotherapy is diluted. What are the effects on the maternal outcome? Because that is also important. So many unresolved questions that, at that time, I decided to put a lot of energy into this project.
But to answer your question, it started with listening actually, that is also an important message, listening to a patient and trying to help the patient and to be open for her question. And to elaborate on that, I was very happy to work in a group that was also that was actually a young group of young students and young registrars that were also passionate about the topic and helped me to investigate this topic. And together, actually we treated the mother successfully and well. The rest is history.
Davide Soldato: I think that from where it started, you really actually helped us, a whole community of oncologists and of patients, to really receive the best treatment, the best option for the mother, for the baby. And now, with this manuscript that you published also gives us reassuring data that in terms of cognitive development, of general health, outcomes, of cardiac toxicity, there is all the possibility to give these treatments and to do well for the mother and at the same time for the baby. So thank you for your efforts in this really underserved research topic.
Is there anything else you would like to add?
Dr. Frédéric Amant: Well, maybe one general comment is that the diagnosis of cancer during pregnancy is not an emergency. It is always very confronting, and well, many physicians do not have a large expertise on that. And my advice would be that it's not an emergency. There is time to ask for an opinion, to ask for advice for your colleagues, and even to refer the patient. It's what we see. There is a diagnosis of cancer during pregnancy, and it's urgent. Everything needs to go quickly. And I understand this, and this is psychologically explainable. But it is better to take time, go for advice, allowing you, together with the patient, to make the right decision.
Davide Soldato: Thank you very much for this final remark. I think it's really important to deliver this kind of message that if we are unsure, especially in this type of situation, it's okay to refer, it's okay to ask for a second opinion. And thank you again for agreeing to be with us.
Dr. Frédéric Amant: Thank you, Davide.
Davide Soldato: So this is Davide Soldato in this episode of JCO Article Insights. We discussed with Dr. Frédéric Amant the results of the manuscript titled ‘Cognitive and Behavioral Development of 9-Year-Old Children After Maternal Cancer During Pregnancy: A Prospective Multicenter Cohort Study’. Thank you for your attention, and stay tuned for the next episode.
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