Functional and Nonfunctional NETs, Aman Chauhan, MD, University of Kentucky

Functional and Nonfunctional NETs, Aman Chauhan, MD, University of Kentucky

November 2, 2019 0 By Jose Scott


Thank you for the lovely introduction.
Good morning everybody. Thank you so much. Elyse Gellerman and the wonderful team of
NET Research Foundation. This is my first opportunity to be able to talk at NETRF
event. I will be talking about how to treat functional and non functional
neuroendocrine tumors and I’m glad that you know I’m following Dr Chan’s
beautiful presentation. She kind of like really set the stage up and gave us
a beautiful primer about neuroendocrine tumors. These are some of my disclosures
as Dr. Chan mentioned there are various ways to classify neuroendocrine tumors based on the site of origin based on the grade and aggressiveness of the tumor but I
would be focusing on based on the the capacity of neuroendocrine tumor to secrete certain vasoactive means or otherwise known as hormones so broadly the neuroendocrine tumor can be classified into functional and non-functional
neuroendocrine tumors if they are secreting these hormones they’re called
functional neuroendocrine tumors and this is a minority subset based on what study we
cite up to 20 to 40 percent of all neuroendocrine endocrine tumors could be classified as functional and the remaining majority are usually non-functional neuroendocrine
tumors Regardless, both these categories of
tumors can cause symptoms . functional neuroendocrine tumors produce symptoms
based on the specific hormone they are secreting and the common hormone is
serotonin. We all heard about carcinoid syndrome. So serotonin overproduction can lead to flushing, wheezing, diarrhea. We will be talking in little bit more
detail about those, but there are other rare hormones sometimes produced by
neuroendocrine tumors like gastrin. An excess of gastrin can cause ulcers gastritis. VIP gets you terrible terrible diarrhea It’s usually produced by pancreatic
neuroendocrine tumor ACTH adrenocorticotropic hormone, this gives
you Cushing’s syndrome. The patient can have you know subcutaneous deposition of
fat and high blood pressure pigmentation of skin etc and very rarely these tumors
can also secrete insulin. Now our bodies naturally secrete insulin — when we eat
food but if it creates too much of it you can imagine that our sugars can dip
down critically low however the non-functional neuroendocrine
tumors, which are the bulk of our majority of our patients, do not produce
these hormones. However, they still suffer from symptoms and these symptoms happens to be because of the tumor bulk or the mass effect. So based on where the tumor
is, these symptoms can range from abdominal pain from these tumor being in
liver to bowel obstruction. If these tumors are in small bowel cancer in
general is a catabolic state so our patients can present with weight loss
loss of muscle mass fatigue so these are some of the symptoms which we can see in non functional neuroendocrine tumors. Most of my talk would be focusing on
functional neuroendocrine tumors especially the serotonin because this forms the
majority or the bulk of the disease burden from hormone secreting tumor.
Let’s dive into some history of serotonin. Dr. Ersperma discovered this
compound in 1935 so we’ve known about serotonin for quite some time he didn’t
name it serotonin he called it entramine later Dr. Rappaport and colleagues
discovered another compound with similar properties and named it
serotonin but was until ten years later than people figured one in one and this
was the same one in same compound since then we have known learned quite a bit
about search on it serotonin is manufactured from amino acid tryptophan
which we get it from our diets it is converted this amino acid tryptophan is
converted into serotonin in two steps by various hormones in our body
most of the serotonin normally is sick it’s produced in our GI tract but it can
also be manufactured in blood cells platelets and central nervous system,
brain. Serotonin is very important in our body we’ve heard about medication SSRIs,
which boosts up our serotonin because certain is needed for a normal healthy
mood. Serotonin is a compound which helps our body communicate the two neurons
communicate through serotonin. It’s a neurotransmitter in the brain. In the gut
it helps communication between the nerves and the gut and regulates the gut
movement so it’s a very important hormone if producing the right amount at
the right place and normal serotonin is it’s it’s stored in the cells and
is released when it’s needed and as mentioned before some of the serotonin
is also made in brain and helps in mood regulation and this serotonin is
completely isolated from the serotonin which is producing the rest of the body
because of the covering of the brain called blood-brain barrier majority of serotonin normal serotonin
it’s produced in gut about 90% normal and what’s the role of serotonin in gut
in a normal state gut moves continues to move every few minutes 10 15 20 30
minutes and these movements are called peristalsis basically that’s how we eat
and the food moves forward and we are able to excrete it eventually
and serotonin plays a role in that movement in the communication when the
gut should contract and move and the nerves communicate to the muscles of the
gut through serotonin but let’s focus on the pathology when things go bad so
neuroendocrine tumors can also produce this hormone and in very excessive
quantities the tryptophan which we eat in our diet can get converted into
certain and as I mentioned before in two steps and eventually turns into
serotonin which is also called 5-hydroxytryptamine 5HD it gets stored
in our neuron looking tumour cells in these vesicles called granules and then
something triggers it and it releases these granules in the blood and patient
have the the syndromic symptoms could be diarrhea flushing etc eventually in the
in blood it breaks down into 5HIAA which we measure not click in the
urine and that corresponds to how much serotonin our tumors are making make
sense from beginning to the end product neuroendocrine tumors not only make the
serotonin but the serotonin acts as an autocrine loop which means it stimulates
neuroendocrine tumors to make more of serotonin so it is a vicious cycle and
it encourages neuroendocrine tumors to grow more and more and secrete more and
more of this hormone and we also know from preclinical data and studies when
we add serotonin into neuroendocrine tumor cells in our culture in
labs it increases the growth of cells so we know that it also promotes neuroendocrine tumor growth so what are the effects of this
increased serotonin the body? Primarily it causes two important things. One it
gives you these functional syndrome symptoms. Secondly, it causes tumor growth. So we will tackle one by one. Let’s talk about carcinoid syndrome what
constitutes carcinoid syndrome it’s a conglomerate of various symptoms but
most commonly it’s flushing diarrhea carcinoid heart disease, wheezing, but as
you can see there are all sort of: fatigue, pellagra. Pellagra is a condition
of vitamin niacin deficiency, where you can have some dermatitis and and changes
in your tongue and skin cyanosis a bluish discoloration of skin especially
lips, edema , swelling of the legs, Telangiectasiasdictation, this is dilation of small blood vessels in the skin. Cramps. Some of you might be familiar with some of these symptoms. So carcinoid syndrome is not just diarrhea and flushing. it’s
actually quite broad one of the most bothersome symptom of
carcinoid syndrome is diarrhea and these diarrhea could be so bad that can prompt
the patient to leave their job and be completely homebound. I’ve seen patients
with twenty or more than twenty stools per day. I’ve seen patients who needed to
be admitted for diarrhea and been on IV fluids. So diarrhea could be a significant
quality of life-impacting symptom and carcinoid syndrome patients. Besides
diarrhea, excessive serotonin as I said can also result in fatigue –marked fatigue.
and you know it impacts their capability to do day-to-day activities. elevated
production of serotonin by metastatic neuroendocrine tumor is the driver of
symptoms of carcinoid syndrome most often elevated levels serotonin happens
when the tumor all is metastasized especially to deliver because when it
goes to deliver and this tumors are making all this hormone it it doesn’t
get metabolized because the liver loses some of its capacity to metabolize it
and it’s exposing the systemic circulation and then our patient usually
experiences some of these systemic symptoms. what’s the role of serotonin
and diarrhea? why do we get diarrhea? so as I mentioned earlier serotonin helps
in gut movement but excess of serotonin you’ll have a lot more of this paralysis
so patients very commonly experience bloating, cramping, not only that it
causes what’s called secretory diarrhea so our gut membrane is lined by all
these pores these different receptors which produces and secretes various
intestinal juices which are actually needed to digest our food a certain
enzyme stimulates it and causes excessive secretion some of
those juices and this is not dependent on whether you eat food or not so
patient can have diarrhea despite not eating and drinking and as a significant
risk of having dehydration from carcinoid syndrome as I mentioned before
has significant impact on quality of life so it is really critical to lower
serotonin and the way we do it I’ll be touching up on it briefly but it’s
broadly little bit of help off somatostatin analogs and we have a newer
drug called tell it reset and of course to treat the underlying issue which is
the tumor these tumors are making these hormones so we have various techniques
now including surgery embolization systemic treatments targeted therapy
PRRT to take care of the underlying issue besides diarrhea there is there are a
couple of other important things that I would like to highlight which could be
quite significant and really important to diagnose early manage early and
ideally prevent from happening one of those is called carcinoid heart disease.
what is carcinoid heart disease? excessive serotonin can actually impact
heart in various ways most commonly it damages the heart valve basically causes
it to get fibrotic which is kind of like a scar tissue becomes very thick and
non-functional and once become non-functional starts leaking it really
affects the capability of heart to pump and then eventually fails this is a
quite significant complication and needs to be actually ideally prevented but at
the very least detected early because once the cardiac failure sets in it is
irreversible there are some other minor mechanism of action for serotonin affects
heart and that it could – rhythm issues of palpitations and arrhythmias can also cause pulmonary artery hypertension where the the blood vessels
towards long gets taken and and pulls some resistance and then it can also
damage the heart heart muscle and affect its ability to pump this is important
data I would like your attention on the right side of the slide and what we are
seeing there is as the blood v urine v HIA which is a marker surrogate marker
of serotonin in the blood right as the level of v HR increases the 5-year
survival of our neuroendocrine cancer patient declines from 83 percent to 50
percent this is a significant drop that increase in serotonin one of the reasons
why that happens is developing a carcinoid heart disease there at a significant
risk of developing carcinoid heart disease. So on the right-hand side you
can see as the 5HIAA increases the incidence rate of carcinoid heart
disease increases and this increase is statistically significant so this is
really important one to monitor 5HIAA and to isolate
the patients who are at a higher risk and try to watch them very closely for
the development of coronary heart disease the way we monitor these
patients by doing echocardiograms some blood tests relevant to cardiac function
and also making sure that the team the multidisciplinary neuroendocrine tumor
has an a cardiologist which is in tune to to the needs of neuronal consumer
patients and is aware about this dreaded complication how do we treat carcinoid
heart disease if for some reason the carcinoid heart
disease or the hots already impacted and the valve has shown damage and changes
that needs to be repaired but at the same time we need to add on strategies
to lower the serotonin so medical oncologist and the cardiologists work
hand-in-hand to co-manage his patients very closely I would be touching on the
medical management aspect of it how to lower serotonin in a second
another dreaded complication fortunately rare but does happen with
elevated serotonin is called mesenteric fibrosis. Mesentery is a soft tissue
which kind of holds our gut together excessive serotonin production
especially in the midgut neuroendocrine tumor can cause scarring or fibrous
transformation of this mesentery and you can imagine if there’s a lot of scarring
in the belly area it can lead to obstructions and these are not trivial
obstructions I’ve seen patients with multiple obstructions needed to go to
ers had numerous surgeries and and unfortunately when this happens there’s
not a whole lot can be done except for surgical procedures help relieve this so
the key is to prevent this complication from happening by making sure the
surgeons under control or you know employ all our techniques to to manage
that beforehand so we talked about the role of serotonin in producing these
hormones carcinoid diarrhea heart disease mesenteric fibrosis but I also
touched on earlier it affects the tumor growth and that is also very relevant we
know from our studies patients who have elevated serotonin unfortunately also
have more aggressive disease this graph here shows the high urinary
HIAAA he patient with high urinary 5-5 HIA a median survival is about 33
months as compared to the ones which was relatively low this is a significant
difference so what can we do to lower serotonin well going back to this
original graph we eat amino acid tryptophan our body especially in
neuroendocrine tumor converse this tryptophan amino acid into serotonin in a two-step
process and then stores the serotonin granules and tumor occasionally
intermittently releases in the blood and caused these symptoms and complications
one way to tackle is to block the release of the serotonin to blood the
wavy doulas is with help of somatostatin analogues these are old drugs one of the
best drugs I would say they form the backbone of our treatment for new or new
consumer so so matter set an analogue work on serotonin receptors and
prevent the release of these stored serotonin one of the first studies which
looked into somatostatin analogs and and helping with these syndromes was back in
1986 I think I was one year old but but based on this really important
New England Journal paper is this this class of drug was approved to treat
carcionoid syndrome diarrhea the diarrhea show that with VIPoma’s etc and I
think it was a very revolutionary because prior to that we had no real way
to treat neuroendocrine tumor patients patients were treating being treated
with chemotherapy which don’t really work that well so this was quite
transformational later on we also found out that these agents this class a drug
not only helps with functional syndrome symptom but it’s also cytostatic it
prevents tumor growth and there were two pivotal trials done one called Proma
trial which evaluated sandostatin and looked into its role as it’s an anti
tumour agent and the more recent trial clarinet trial looked into lanreotide
as anti-tumor agent for neuroendocrine tumor progression feasible. I was the
bigger study of the to a randomized patient into lanreotide arm versus
the placebo arm and what they found was the lanreotide arm, the patient has a
significant improvement in their progression free survival we now have a
long-term follow-up data and the lanreotide arm the PFS is about thirty-eight
months as compared to 18 months in placebo arm that’s quite significant so getting back to what are the ways
where we can reduce her tone in the blut one is using somatostatin
analogues sander statin land Rio tide to prevent the release of serotonin the
blood the other is to block the hormone which makes this harm this hormone the
block the enzyme which makes this hormone and this new class drug is
called Zermelo the literal said at this drug was evaluated in large Phase three
international trial called telestar trial and there were three arms in this
trial the placebo group and to varying doses of Zermelo group 250 milligrams
tid and 500 milligram tid and what we were able to show in this trial was by
blocking this critical rate-limiting enzyme you can actually reduce the
certain introduction and urinary 5HIAA was a biomarker used to prove that point
this translated it into better control of carcinoid syndrome diarrhea as you
can see the black is the placebo arm and blue in the grey green are the the
treatment arms and the stool frequency is lower and the treatment group based
on these findings FDA approved this for carcinoid syndrome diarrhea which was not
controlled by somatostatin analogues to in summary serotonin or productions
driver carcinoid syndrome serotonin plays a major role in development of carcinoid
heart disease misandric fibrosis pulmonary to hypertension among various other
issues it also has demonstrated the effects on
tumor growth and it’s very critical to control serotonin to not only improve
the quality of life but to also improve the progression-free survival very
briefly in last two slides i would like to touch on the other functional
syndrome very rarely neuroendocrine tumors
especially pancreas can secrete a hormone called VIP very active
intestinal peptide and can give terrible diarrhea these are also somewhat treated
in the same way like carcinoid syndrome with help of somatostatin analogues
gastronome –is can present with bad GI ulcers o’donnell ulcers gastric ulcers
and they are treated with PP eyes sometimes we have to add h2 blockers
zantac and pan stoppers all you guys have heard about these agents and it
really works well ACTH the the Cushing’s syndrome we often
start them on ketoconazole it’s an antifungal drug but but really works
well in blocking this hormone production while we work with our surgeons in in in
debulking the tumors or taking the adrenals out and then very rarely
insulinoma pancreatic neuroendocrine tumors subtype they can produce excess
amount of insulin and cause really critical low blood sugars I’ve had
patients who needed to be on continuous dextrose or glucose infusion because we
weren’t able to control their sugars in the tumors and they are treated with a
dioxide and the way we treat these tumors the non function during the
consumer is just a quick slide on it can can cause as I mentioned bone pain and
they are treated with the PRRT if the disease is quite systemic and if there
are just few spots or oligo metastatic disease can consider radiation abdominal
pain some of my colleagues will be talking about some other interventions
which we can use to control or debug these tumors to control some of the
symptoms with that I would like to conclude thank you so much you