Episode Transcript
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SA: Hello and welcome to Practicing Paediatrics. In this series, we'll be showcasing the specialist work of the clinical staff here at Great Ormond Street Hospital. There are over 60 different clinical specialties at GOSH, providing tertiary and quaternary level care for many rare conditions. So if you are hoping to learn a little bit more about a unique condition or intervention, or just find out more about the advances at GOSH, this may be the series for you.
I'm Dr. Sarah Ahmed, a paediatric registrar and the current Digital Learning Education Fellow here at Great Ormond Street.
In today's episode, we'll be speaking with Dr. Hoong-Wei Gan, consultant endocrinologist here at GOSH, on the topic of brain tumour late effects. Along with a group of colleagues from across centres in the UK, Dr. Gan recently published the national UK guidelines for the management of paediatric craniopharyngiomas. What his work highlights and feeds nicely into is the importance of recognizing and treating the long term effects caused by brain tumours
Hoong-Wei, thank you for coming on the show today.
HWG: Hi.
SA: So before we delve into more detail, I wanted to start by asking – what would you like people to get out of this podcast?
HWG: I think mainly a greater awareness about uh, the kind of long term effects that brain tumours can have on children and young people's quality of survival, because quite often people think, “Oh, this child's survived a brain tumour”, but actually they've got long term effects that actually, do affect them for the rest of their life. And it's just being aware of those things and how we look out for them and what kind of surveillance they need.
SA: Yeah. And I think that's really important. We have this assumption that they've gotten through their cancer or whatever their cancer is. And it's all kind of hunky dory after that, but it isn't always.
HWG: Yeah, absolutely.
SA: So we're going to talk about brain tumour late effects, but I think in order to talk about that, we need to start by just talking a little bit about brain tumours.
Can you tell us a little bit about kind of the aetiology or the epidemiology of brain tumours in kids?
HWG: Yeah, sure. So, brain tumours are actually the second commonest childhood cancer. Obviously for most of us in paediatrics, the commonest childhood cancer that we deal with is leukaemias particularly acute lymphoblastic leukaemia. But actually brain tumours as a, as a cohort, they account for 25 percent of cancers in children. So even though they're rare in the paediatric population, at some point during your training or career, you will encounter children with brain tumours. And the kind of, there are various brain tumours which on an individual basis, they are rare, but we, as a whole cohort they're actually not as uncommon as one might think.
In terms of aetiology, for most cases, like all cancers, we don't really know why they happen. But they are, of course, obviously cancer predisposition syndromes that can result in brain tumours. So what some of the ones that we see fairly often are neurofibromatosis. They can cause low grade gliomas amongst other things. Multiple endocrine neoplasia can cause pituitary adenomas. And there's lots of other more tumour predisposing syndromes, such as Lynch syndrome or Lee Fraumeni syndrome, and those tend to cause much more malignant tumours. But overall, if you see a child with a brain tumour, most of the time, uh, you know, it's sporadic. We don't really know the cause.
SA: I didn't realize they were quite as common as they were. Are there specific types of brain tumour that cause worse long term effects, or do they all lead to kind of significant long term effect?
HWG: Well, they, they can all cause long term effects. And actually I don't really like the term long term effects because in truth, a lot of the impact of brain tumours can start from diagnosis. And the kind of impact of brain tumours, uh, really depends on the location of the tumour. So, from an endocrine perspective, the tumours that I deal with the most are the tumours that affect the pituitary gland and the hypothalamic area, so the sellar and suprasellar compartments, because those directly affect your pituitary function, and they also affect your hypothalamic function and therefore they have a lot of endocrine deficits.
The tumours in other bits of the brain can cause other the effects. So if you've got a tumour in the cerebral cortex, you can get cognitive issues. You can get things like hemiparesis. Certain tumours cause seizures, so epilepsy. So it really depends on the tumour location. And then obviously a lot of tumours compress the optic pathways. So, you can have visual impairment with that as well. And along with that, really, depending on the tumour type and the tumour location, they are then treated with different protocols. And those protocols in themselves can cause different long term and actually short term effects on the child.
So it is A, dependent on location and B, dependent on the histology of the tumour.
SA: Yeah, so like you said, it's that combination, isn't it? Of where the tumour is, and the very intensive treatment that we put these kids through.
HWG: Yep.
SA: Are there some types of treatment that cause more complications than other types? Like, does surgery lead to more complications than say radiotherapy?
HWG: Again, it depends on where the location of the tumour is. So, I'm primarily an endocrinologist. And in our kind of clinics, I would say that something like 80, 90 percent of brain tumour patients will have some sort of endocrinopathy. The kind of. side effects that you get, again, like I say, depend on the treatment type and depends on the tumour histology or the tumour location. And they are all different, really. I don't think we can say that one is more severe than the other because they all cause different effects. And obviously from an endocrine perspective, the tumours that are in that sellar, supersellar compartment cause the most severe side effects. The tumours that are away from that area, so for example, medulloblastomas in the posterior fossa, they get primarily side effects from, uh, radiotherapy, so a lot of them get craniospinal irradiation. The radiotherapy itself, when you irradiate the pituitary gland, you can get pituitary hormone deficits, although the commonest one that you see from radiotherapies is growth hormone deficiency, really. And, and, you know, that's not exactly a life critical hormone deficit, but obviously affects the quality of life of the child, because if they land up really short, then it affects their psychological well being, and they compare themselves to their friends.
The other thing you can get, uh, from radiotherapy is if you, you irradiate the spine, for example, so a lot of myeloblast tumour patients will get cranial spinal radiotherapy, and there are two side effects from that. One is your thyroid gland is in the path of spinal irradiation. So you can get an hypothyroidism. And the other thing is when you irradiate the spine, the vertebral growth plates actually start fusing more quickly. So even though they might develop growth hormone deficiency and you treat them with growth hormone, that effect is still attenuated by the fact that their spinal growth no matter how much growth hormone you give them, can be affected already by the radiotherapy. So you might predict that they land up a certain height, but actually in reality they might land up shorter than that because of the spinal effects. So it's not really that one is more toxic than the other. I mean, certain chemotherapy regimes can cause gonadotoxicity and infertility, and in girls that often causes pubertal delay as well and irregular periods.
And then there's other non endocrine side effects, so certain chemotherapy drugs cause cardiovascular problems, some of them cause kidney disease, some of them cause hearing loss, so it really, it's a variety of different side effects that you just, you know, as, as an endocrinologist that works in that area, you also need to almost have an understanding of, of what the oncological treatments involve. The oncologists are generally pretty good at looking out for these things. And certainly as the biggest brain tumour centre in the UK, the oncologists are pretty much on the ball here, with alerting me if they're concerned about anything and also screening for all these other non endocrine side effects. Most of the time there's some sort of protocol around it as well.
SA: Yeah. Should we talk a little bit more about some of the late effects in more detail? Do you have a way of classifying them or is it more just approaching things as they come up?
HWG: I mean, like I say, I, I'm an endocrinologist, so the way I think about things would be whether those effects are central. So whether they are involving the pituitary gland or hypothalamus, or whether they are affecting the peripheral glands. So for example, gonadotoxicity affecting the testicles and the ovaries, or like I've said before, spinal irradiation affecting your growth and your thyroid gland.
So that's how I classify it. But you can get a combination of things. So, for example, if you do craniospinal irradiation, you can actually get central hypothyroidism, but you can also get primary hypothyroidism. That can both happen at the same time. So when you look at the thyroid function test results, sometimes they're not that straightforward to interpret because it can be a combination.
And the same with gonadotoxicity, , you know, you can have, central hypopituitarism, so the gonadotrophins can actually be low, but at the same time with that, if they've had gonadotoxic chemotherapy, you can get testicular failure or ovarian failure. Again, you can get a combination of both. And it's, you know, it's not straightforward because it depends on what combination of treatments they've had really.
SA: Yeah, of course. So a lot of what you deal with as an endocrinologist, you were talking about like the hypothalamic area and the pituitary area. Can you tell us a little bit more about hypothalamic dysfunction?
HWG: Yeah, I mean, they're, they're both quite intimately connected aren’t they? So with hypopituitarism, you're talking about the deficits of the various hormones produced by the pituitary glands. So growth hormone, the gonadotrophins so LH and FSH, the central cortisolism, so that's ACTH deficiency. And you can get, central hypothyroidism as well, so that's TSH deficiency. And then the last thing is central diabetes insipidus. So that's where the posterior pituitary’s affected. And the most severe versions of this are usually the tumours that affect that compartment because most of the time with those tumours, for example with craniopharyngiomas, which are the commonest tumour in that compartment, most of the time the tumours have already caused damage at diagnosis. So before you've even started doing surgery or radiotherapy or anything like that, if you actually look back, even though we might not diagnose it necessarily till later quite often there's evidence that actually those tumours have already caused deficits in the various hormones. And no matter what treatment you give them, the damage has already been done.
But despite that, I always tell parents that even if we don't do any more treatment, if the tumour’s already caused that damage, then sometimes over time, the cells in the pituitary gland die off. So it might be that actually there's certain hormone deficits don't exist early on, but even if you don't do surgery, you don't give radiotherapy, you don't do anything to the tumour, you can still get new endocrine deficits over time. And that's why they need constant surveillance with the endocrine team.
In terms of hypopituitarism that the hormones that are really quite critical to diagnose are the ACTH cortisol axis and also central diabetes insipidus because those hormones are life critical and therefore missing those diagnoses can effectively make the child really unwell. And therefore, even at diagnosis, we ask for a full set of pituitary function bloods just to check those things and make sure that we're not missing it because, if you miss those things and you don't treat them and they go into surgery without correction of those endocrine deficiencies, then they could actually get really unwell quite quickly. Most of the time we cover them. We usually give them hydrocortisone, uh, stress doses at induction of anaesthesia, cause even if we don't know at the beginning, whether they've got this, at least covered during the surgery. And also if during the surgery, they damage ACTH producing cells and they actually become essentially adrenal insufficient during the operation itself, we've covered them.
We've got quite a set pathway at Great Ormond Street to look and monitor for these endocrine effects after surgery. So we've got a very clear perioperative guideline. They get all their pituitary function tests repeated about 48 hours after surgery, and then we've got a very clearly outlined protocol to look for particularly posterior pituitary dysfunction because that can be quite severely affected after an operation and you really need to look out for things like central diabetes insipidus, or sometimes they get SIADH after the surgery and they can actually flip between the two quite quickly so you need really quite careful fluid balance and sodium monitoring and that sort of thing.
SA: You're, you're checking for the hormones before they go into surgery and covering them and then you're checking really closely when they come out as well.
HWG: That's right. And quite often, you know, they need to stay in for a few days, sometimes even one or two weeks after the operation for us to be able to correct those things you know, diagnose whether they've got new hormone deficiencies and start hormone replacement. And then usually I aim to see them in my clinic fairly soon after they come out of hospital, just to make sure we've got their hormone deficits corrected appropriately. And making sure they're safe essentially, because for example, if you start something like hydrocortisone, because they've got adrenal insufficiency, then the parents also will need training about what to do when the child's unwell. They need to be given emergency hydrocortisone injection packs and know what to do with them. So there's a lot of education involved. So, you know, it might be that we say as doctors, “Oh, this child's got central adrenal insufficiency, they need to start hydrocortisone”, but actually our clinical nurse specialist team need to get involved with a really quite important ports of call for the, for the families and essentially the kind of the patient's key workers coordinating a lot of these things inside and outside hospital as well.
SA: So we've spoken a little bit about those central effects. Are there peripheral effects as well?
HWG: Yeah. So we've talked about the thyroid glands. If you irradiate the spine, the thyroid gland is, you know, inevitably in the field of irradiation, so they can get primary hypothyroidism. And again, that's treated with levothyroxine replacement.
And also if you give toxic chemotherapy that affect the gonads, so things like cyclophosphamide or I phosphamide or actually in boys, cisplatin, so the platinum drugs, those can affect your fertility. In boys, it's very different to girls because the fertility and puberty are quite separate in boys. So in boys, in the testicles, your leydig cells make testosterone and your sertoli cells make sperm, and they are quite separate compartments, so you can have boys who go through puberty, you know, entirely as expected, but if you look at their testicles, it's discordant because their testicular volume's small, so their fertility's been affected, but their puberty has not, and that's something you might need to counsel boys about because they might not be aware of that.
SA: Yeah.
HWG: And, you know, when they're older, you can talk to them about getting their semen analysed in the fertility unit, if they really want to know exactly what's going on. Nowadays with better blood tests, we can look at blood markers of fertility. So in boys, you can look at inhibit B, which is a marker of sperm production. And in girls, you can look at, uh, anti malarian hormone or AMH. And again, that's a marker of ovarian function. So those are proxies, but in boys the gold standard is to look at a sample of semen under microscope.
In girls it's slightly different because the puberty and fertility are quite tightly linked through your menstrual cycle. And you need both of the theca cells, which make uh, androgen. So they actually make testosterone in the ovaries and then the follicular cells convert that to oestrogen and also make eggs. So you need both cells to actually, have puberty, but also be fertile and have periods, so they're much more tightly linked. And because all oncology treatments affect the rapidly dividing cells, so in girls that would be the follicular cells, the egg producing cells, because they're also involved in producing oestrogen, you then get this very close correlation between puberty and fertility in girls. And like I've said, in boys it's different because those two compartments are very separate. So the sertoli cells, the rapidly dividing sperm producing cells are affected by most oncological treatments.
SA: It's, it's really an MDT approach, isn't it? It's not just the doctors and even within the doctors, it's you guys, but it's also the neurosurgeons and then the nursing team after that as well.
HWG: Absolutely. Yeah. And, and you're, you're quite right. You know we work as a team. I attend the neuro-oncology MDTs here at GOSH. And that, uh, has lots of people in it. It's, it's quite a big meeting, but essentially there are also neurosurgeons in there, the neuro oncologists, the radiation oncologists who are based at U C L H. And then the neuro radiologists, obviously they're interpreting scans for us. And then there's clinical nurse specialists, other allied health professionals and the physiotherapists, occupational therapists who all come together at that meeting and we all input into patient care via that meeting. So there's a lot of cross talk, and I think that's really important. Especially with, for me, with the neuro oncologist and the neurosurgeons, because when we come to make decisions about a child's, uh, neuro oncology treatment, all those specialties really need to be involved to kind of weigh up, the pros and cons of the different management strategies that we're thinking of.
SA: Do you have psychological support as well? Do you have psychologists on the team?
HWG: Yeah, absolutely. So we've got both psychologists and neuropsychologists on the team. So the difference between those two, which people don't always realize is that the neuropsychologists look at a child's cognitive functions. So they do a quite extensive cognitive assessments on children. So particularly in children, for example, who've had brain irradiation. So we know that when you irradiate the brain, no matter how you do it, healthy brain tissues is usually in the fields of irradiation, and that can cause cognitive side effects. But also children with sellar, suprasellar tumours, because those tumours are in the midline and they somehow affect the connections between the two halves of the brain they can get things like autistic behaviours, social communication difficulties, sometimes quite severe behavioural difficulties that are really quite difficult to manage. So those things all need the psychologists and the neuropsychologists involved. The psychologists are obviously primarily involved in supporting the families in terms of how they're coping with the diagnosis and the treatments and also supporting the child and sometimes their siblings in terms of what they understand about the treatments and how they are coping with that as well.
SA: And then once the child has been discharged, how long do you follow them up for and how often are you following them up?
HWG: So if, if they're at risk of endocrine deficits, they need to be seen by an endocrinologist for life. really. And that basically means any child who's had brain irradiation, or any child who's got a tumour in the hypothalamus pituitary region. So all those children will need lifelong follow up with an endocrinologist. Because like I said at beginning, even though you might have normal endocrine function, uh, at the beginning, you still can have new hormone deficits that evolve over time. And that's why I always tell parents, I tell them to look out for signs and symptoms of things like failure of growth or concerns about puberty which can sometimes be early in some children rather than just late, or tiredness, you know, falling asleep in class all the time, uh, if they have an infection and they've got cortisol deficiency, they might have difficulties coping with that infection, so they might have a prolonged recovery or they might have recurrent infections. And then things like polyurea and polydipsia, which would be suggestive of diabetes insipidus. So I do educate the parents around what to look out for which might be suggestive of certain symptoms and might require earlier blood testing.
SA: And so like could a child develop say diabetes insipidus a few years after being treated for their brain tumour?
HWG: Yeah, absolutely. So we looked at our optic pathway glioma cohort. So these are low grade tumours that affect the midline, can affect the hypothalamus pituitary gland, because they're quite large sometimes. And we looked at them over 30 years, and actually we had some patients developing diabetes insipidus 15 years from diagnosis. So it can be really late and therefore this constant surveillance is really needed and they can evolve over time. Definitely.
SA: And are there any new advances or research on the horizon?
HWG: Yeah, so for, for me, we don't understand very much about the hypothalamus. So even though, you know, the hypothalamus does control the pituitary gland in producing hormones, but the hypothalamus is also an important centre for lots of other things. So it regulates things like your weight and your appetite, uh, your temperature, your sleep wake cycles. It's also involved in other autonomic functions, so things like your cardiovascular functions, your heart rate, your blood pressure, they're all controlled by the hypothalamus in one way or another. The thing that really affects most of my patients is actually obesity. So some of my patients who have hypothalamic tumours, they get very, very heavy. Some of them have abnormal appetites. We call that hyperphagia. They, they want to eat all the time. They eat through the day and through the night. And that can be sometimes very difficult because if you remember, I talked about how hypothalamic damage can also cause autistic behaviour. And if you have that combination of increased appetite and autism, that's a really difficult situation for the parents to be in, because it's really difficult to control what the child eats.
And because we don't understand the hypothalamus, we don't have medications to help with those things. So we sometimes give melatonin for sleep wake cycle issues, but actually because the receptors in the hypothalamus, and sometimes the pineal gland have been damaged by the tumour, that's, you know, melatonin sometimes not very effective. There's research on the horizon for various drugs to treat hypothalamic obesity. And at the moment there aren't really any good drugs out there, but there are several research trials that are in progress and we're starting one at Great Ormond Street fairly soon um, to look at, you know, all these drugs to see whether they're effective. So far we don't have a magic pill that that works and that would be really nice. But I suspect actually these patients are quite a heterogeneous cohort in the way their hypothalamus is damaged. It's a bit of a spectrum because it affects whether it's where the tumour is, it's what surgery has been done. And I think ultimately we're going to need to figure out some sort of way of defining what damage has been done and what treatments we can offer them.
The second bit of research is really tied into the oncological treatments we give. So on the horizon and actually in use now, uh, what we call molecular drugs. So these are drugs that target specific receptors in tumour cells. And the idea behind that is it's more specific and therefore it doesn't cause a lot of the side effects that you see with traditional chemotherapy or radiotherapy. But actually as these drugs come out, you know, the molecular pathways they're targeting aren't just present in tumours. They affect other pathways in other bits of the body as well. And we, we're starting to see off target effects that are not expected for these molecular treatments. So for example with Trometinib, which is a MEK inhibitor that the oncologists use to target certain tumours such as tick pathway gliomas or Langerhans Cell Histocytosis we've noted that actually it can cause hyponatraemia.
SA: Oh!
HWG: So we've got patients who land up having low sodiums, and if you imagine in a patient who is on treatment for diabetes insipidus, sometimes that can cause a problem because then their desmopressin doses need to be decreased because of the hyponatremia. So, you know, what I'm trying to say is that essentially we, we need to be careful in saying that these drugs are more specific and you don't have side effects from them. The oncologist know how to monitor certain side effects for certain drugs, but actually we’re realising that there are endocrine side effects as we become aware of those things, we need to uh, raise awareness, I guess, to look out for the, those side effects as well. Again, I think that's an area that needs research. It needs documenting. And we don't have an idea in terms of how often these things are happening. Because no one's looking out for them, essentially.
SA: So a lot of really exciting kind of developments and also issues, I suppose, that come along with that in the future. It'll be really interesting to see how things pan out.
HWG: Yeah, definitely.
SA: Let's end with some quick fire questions. So what would you like the general paediatrician to know about brain tumour late effects?
HWG: So as I said at the beginning, it's being aware first of all, that late effects are a bit of a misnomer. They can happen at any time during a child's diagnosis. Second of all it's to realize that both the tumour location and the type of tumour, because that affects what treatments you get, can cause different effects. And the way to look at these effects is to look at those two factors to determine what you need to look out for and, uh, what the child is at risk of.
SA: Fantastic. And are there any useful resources that you would recommend?
HWG: Uh, absolutely. So the CCLG website, so the Childhood Cancer Leukaemia Group website, is publishing guidelines that we are developing. So, about 10 years ago now we had an overarching umbrella group of guidelines to talk about rare childhood cancers and in terms of how we diagnose, treat them and how we look up for effects in the long term. And there's an umbrella group out of which there were three brain tumour focused groups. So one of them was a craniopharyngioma group that I was involved with and we've recently published some guidelines in the Lancet. Another group was looking at what we call thickened pituitary stalks, which can be an indicator of germinomas or Langerhans cell histiocytosis. So again, they've published a guideline around that. So the CCLG website is actually quite a good resource for that.
The other that there is also a very old now actually CCLG produced guideline looking at late effects of all childhood cancers, which is on their website. So that's a very generic document.
That as part of a more international group, there's something called the International Guideline Harmonization Group, so it's called the IGHG for short. And they are an international consortium of multidisciplinary professionals developing guidelines to look again at these effects and how we monitor for those things in the long term. It's all childhood cancers, it's a broad spectrum of different effects, and those guidelines are also gradually coming up. So I think those are all good resources. If you Google guidelines, there's a whole multitude of them, but those are conglomerations of different guidelines as it were. And I think that's quite useful.
SA: Fantastic. And I'll make sure all the links are in the description. And we've touched on this briefly, but finally, what would be your three takeaway learning points?
HWG: So the first thing is, the endocrine effects of childhood tumours, brain tumours are really dependent on tumour location and tumour histology. That all children and young people who have tumours in the sellar/suprasellar compartment or who have had radiation of the brain or of the spine, need lifelong follow up with an endocrinologist and proper transfer to an adult endocrine team. And the last thing would be to be aware that children who are going to have surgery of tumours in the sellar/suprasellar compartment really need quite careful monitoring and they need to be in a centre with good endocrine support, that needs to be on site because they can have significant fluid balance issues after the surgery.
SA: Hoong Wei thank you so, so much for talking to us today.
HWG: That's alright. My pleasure.
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