Introduction to NETs, Jennifer Chan MD, MPH, Dana-Farber

Introduction to NETs, Jennifer Chan MD, MPH, Dana-Farber

October 31, 2019 0 By Jose Scott


Thanks, Jim for that really kind
introduction. And I also want to thank Elyse Gellerman and NETRF for
sponsoring this event. iI follows as you just heard the two-day NANETS
conference which is what was a really wonderful meeting where hundreds of
people came together to discuss the care of patients with neuroendocrine tumors,
where we’re moving with research in the field ,and it’s really very nice to
continue that dialogue with you, So I also want to thank you for joining us
here today. I’m gonna focus my talk on just a very broad overview of
neuroendocrine tumors I think it’s always just like with everything
important to lay the foundation to help us understand perhaps some of the
following talks about treatment of neuroendocrine tumors and research into neuroendocrine tumors that we’ll dive deeper into. What I’ll be discussing so the
outline for my talk is to focus on really what are neuroendocrine
neoplasms or abnormal growths and what makes them unique? What are the key
features of neuroendocrine tumors that guide our management? And some of these factors include where the primary tumor– started some of the pathological
features. That I’ll go into in detail and whether or not these tumors are
secreting hormones, ie what is the functional status of the tumor and then
I’ll end with a brief overview of treatment options for neuroendocrine
tumors. So I’m going to start first with some words about the history of neuroendocrine tumors.This concept of neuroendocrine tumor dates back to 1907
when a German pathologist Dr. Oberndorfer first described these very special
tumors that he called carcinoid tumors because he noted that they had slowed
somewhat indolent and what he thought at the time to be benign behavior and this
terminology later developed into what people were calling carcinoid tumors.
Over the years we’ve recognized that neuroendocrine tumors are much more
complicated and that they’re much more heterogeneous. They do arise from
cells throughout the divert diffuse neuroendocrine tumor system and they’re
called neuroendocrine because they receive neuronal input just like nerves
and they also can secrete hormones just like endocrine cells, but they’re not
always benign they can grow abnormally and they can also spread which defines
them as malignancies but compared with other types of cancers
they can pursue a course that is sometimes more indolent or slow growing
than other types of cancers they’re also notable for their ability to secrete
hormones that can in some patients lead to very characteristic symptoms and and
syndromes one of the other really important features of neuroendocrine
tumors is the presence of what are called somatostatin receptors and
somatostatin is a hormone that we all have that is a master hormone that helps
to regulate the endocrine system and also hormone secretion and what we’ve
realized is that these somatostatin receptors are present on the vast
majority over 80% of most neuroendocrine tumors and that really can be leveraged
for imaging and finding neuroendocrine tumors as well as for treatment as I’ll
go into a little bit later and as you all know from some of the other speakers
in the conference I do want to point out that this terminology can be very
confusing even to medical professionals and I’m sure also to patients and
caregivers because you’ll hear them these neuroendocrine tumors referred to as
carcinoid neuroendocrine tumor and neuro endocrine carcinoma .and There is some
overlap but it there are also important distinctions. I do want to note that this
terminology carcinoid is falling out of favor because as I mentioned to you
although initially they were called carcinoid because they were felt to be
carcinoma-like. not necessarily malignant. We do realize now that they can grow and
they can spread so most of at least in most organ systems these neuroendocrine
tumors were no longer calling carcinoid tumors they’re really referring to them
as either neuro endocrine tumor neuron tern carcinoma and I’ll go into that
distinction in a little bit you know we will still use the word carcinoid in
some instances there are some neuroendocrine tumors
that’s still just by definition are called carcinoid the most important
example of that is lung neuroendocrine tumors which are still based on the
pathologic classifications distinguished between carcinoid and atypical carcinoid
and we also will still call some of the hormone syndromes most classically
carcinoid syndrome that’s a defined syndrome and based on hormone secretion I want to next focus on some of the
really important features of neuro endocrine tumors that I think are
important to understand and that really do influence management and helps us to
understand the biology of the cancer and these are kind of I have bucketed into
four main categories one is you know what is the primary tumor site where did
the tumor originate and most commonly we distinguish between neuroendocrine
tumors that start in the pancreas versus neuroendocrine tumors that start and
other sites including the GI tract the lung and the thymus the next important
feature really is the stage how extensive is the disease is it still
localized or has it spread somewhere else in the body the other important
feature is really the pathology what we are seeing in a biopsy and I’ll again go
into more detail but grade and differentiation are the key elements to
focus on finally what we also refer to as the functional status is important to
understand this is really a clinical diagnosis based on whether patients have
symptoms that are related to the hormones that the tumors are secreting
so I’ll delve into more detail to each of each of these starting first with the
primary site of neuroendocrine tumors and they really can originate anywhere
in the body the neuringer current system is present in all organ systems so we do
see neuroendocrine tumors originating in multiple organs most commonly in the
small intestine and the lung and in the pancreas
classically neuroendocrine tumors were classified based on where they started
in relation to the embryologic gut development there’s a tube that begins
to differentiate into various organs and the foregut is gives rise to organs
including the assignments the lung the esophagus and the upper small intestine
and the stomach the mid gut gives rise to the small intestine in the first
portion of the colon and the hindgut gives rise to kind of the lower part
called the distal colon and and the rectum we still will distinguish
neuroendocrine tumors based on on where they start with with these distinctions
of poor gut mid gun hind gut and it really does matter where these tumors
start and the most important reason it matters is because that the biology of
neuroendocrine tumors varies based on where it starts
you know when scientists have done a sequencing analysis of neuroendocrine
tumors starting with the small intestine compared to pancreas we’re finding very
different genetic alterations we also see that even stage 4 stage
neuroendocrine tumors that start in some organs for instance the small intestine
behave in a slower growing fashion than other neuroendocrine tumors for instance
that may start in the pancreas or the lung and also most importantly the
treatment sensitivity also varies depending on where the primary tumor
originated pathology is also really important as I mentioned and one of the
key elements that pathologists will comment when they look at comment on
when they look at it a biopsy is it’s something that we call differentiation
and differentiation is what they are what they’re referring to is how similar
or dissimilar neuroendocrine tumors appear compared to their normal neuro
endocrine cell counterparts and what I’ve shown on this slide is an example
on the left of what pathologists see is a well differentiated neuroendocrine
tumor in contrast on the right side to a poorly differentiated neuroendocrine
carcinoma and the well differentiated neuroendocrine tumors look more similar
just by morphology or appearance compared to the poorly differentiated
your endocrine carcinomas pathologists also will use stains to help them
identify not just by appearance stains to help them identify that these
are originating from neuroendocrine cells the most common stains that are
used are for neuroendocrine markers including chromogranin and synaptophysin. So those are things that we look for in our pathology reports the
differentiation and the presence of these markers. Grade is also commented on by the pathology and that’s different than differentiation. Grade is
really a measure of proliferation the numbers of cells that appear to be
dividing or or growing and the pathologist will assess grade based on
under the microscope the numbers of cells that are in what we call mitosis
in the process of division and also as stain for something that’s called ki67
which highlights the stains the highlights the cells that are that are
proliferating and neuroendocrine tumors have been divided into
low-grade tumors, intermediate grade tumors ,and high-grade tumors. and They
have a very different growth rate and and biology based on the grade. I’m gonna
highlight and I don’t expect you to take notes on this but I’m going to highlight
some of the features that are included in a pathology report. The pathologist
will tell us about the differentiation status and then even divided within that
tell us the grade so we make distinctions between well differentiated
neuroendocrine tumors that are low intermediate and high grade and poorly
differentiated neuroendocrine carcinomas which are high grade and also by
appearance more poorly differentiated as I mentioned to you the longer in
different tumors they they follow a similar principle the pathologists are
looking at morphology and they’re also looking at measures of proliferation .So
the pathologists again they will assess grade by looking at the mitotic count
and other factors that tell us about growth so these I think are for us very
important elements to recognize. when we first meet patients is you know what is
the pathology because that also helps us to understand perhaps how things may
behave in the future and also how we might be able to best treat these tumors.
Stage, as I mentioned to you is based on the extent of disease at the
time of diagnosis. You know has the tumor spread far from the primary tumor– or is
it contained and localized — and this helps us to know whether or not the
tumor can or should be removed with surgery. The stages determined, based
on radiology scans, that include CT scans that are done with multiphasic
protocols so that the radiologists can take pictures at different time points.
MRI is also another imaging modality that we use to assess and to find
neuroendocrine tumors. Nuclear imaging has become a very important part of the
assessment of neuroendocrine tumors and as I mentioned to you neuroendocrine
tumors have somatostatin receptors on them. In the majority of cases, so we can,
the nuclear medicine doctors can radio label these somatostatin analogs, that
bind to those receptors. You can image and see the tumors with these
nuclear imaging techniques. More recently, we’ve been using gallium 68 dotatate
PET/CT scan. This really has, in most cases, replaced what had been used in the
past with octreotide scan. Another type of nuclear imaging test is an FDG PET
scan. That’s a more , I think, a traditional type of PET scan, that really
is looking at metabolic activity because many of the lower grade neuroendocrine
tumors are not growing or proliferating much. The FDG-PET scan may not show those tumors in the higher grade tumors which are growing more quickly
can show up on the FDG-pet scans so what I’ve shown here is just a few examples
of the imaging that we use for part of the staging. A CT scan on the left. MRI
in the middle. And the nuclear imaging Gallium 68 dotatate PET CT scan on the right. What you can see is that each imaging modality uses a different
technique to find the tumors the CT scan and the MRI is you know. Just to
orient you, these pictures are taken as if somebody is lying on a table. And and
these pictures are taken with sections. And the radiologist looks at each
section to look for areas that might be tumor. So what we’re seeing on on the
minute can you go back one oh this way so what you can see on the left side is
these darker areas, in this is the liver you can see darker areas that represent
the tumor in the middle is an example of an MRI from a patient where you can see
smaller areas of disease that are in the liver and on the on the gallium 68 dotatate PET CT scan we’re imaging is looking at a patient face on and what
we’re seeing are darker areas that represent their new neuroendocrine tumor
because they’ve taken up the imaging tracer the gallium 68 dotatate. So when
we look at these scans we do restage disease. And divide tumors based on their
extent. Localized disease has not spread beyond the region of the primary tumor.
Liver predominant metastatic disease: the patient may have a tumor that has spread
but has spread only or primarily to the liver. And then there are cases where the
disease has spread more widely. And the way that we think about an approach– the
management of patients–really depends on whether it has spread and how it has
spread. And I think what you’ll hear from some of our other speakers are the
surgical approaches that can be taken for localized disease or liver
predominant disease. The right interventional radiology techniques that
also can be used for liver of predominant disease. When there’s
more widely metastatic disease we often will be thinking about strategies that
will treat the entire body with what we call systemic therapies– that are given
intravenously or orally. The other important element I think to think about
for patients is what we call the functional status. This really refers
to we use the term functional to refer to whether or not patients have any
symptoms related to hormone secretion.So functional tumors are tumors where
patients with functional tumors have symptoms that are related to the hormone
secretion .And in most cases what we see actually are non-functional tumors where
patients have no symptoms related to hormone secretion. The most classic
example of a functional neuroendocrine r tumor is what we call the classical
carcinoid syndrome. About 20 to 30 percent of patients with small intestine
or endocrine tumors have this classic carcinoid syndrome related to secretion
of a hormone, formulas including serotonin and other peptides and the
secretion of these hormones can lead to many manifestations including flushing
symptoms, where patients will experience a warmth or redness. Diarrhea longer
term. The elevation of serotonin and other hormones can lead to complications
where there’s fibrosis of the heart valve- – where carcinoid heart disease may
be present or fibrosis in the abdomen in the mesentery.
So other neuroendocrine tumors that arise in the pancreas can can secrete
different hormones and what I’ve listed on this slide are the other hormones
that are associated with pancreatic neuroendocrine tumors that include
insulin and due to the excess of insulin there may be symptoms of low blood sugar
gastrin which is a hormone that stimulates the production of acid so
patients may experience symptoms related to ulcer disease vasoactive intestinal
peptide is a hormone that can cause diarrhea. So I think it’s important for
us as physicians to understand what types of symptoms the patients are
experiencing .So that we can be able to assess whether or not any of these
hormones might be secreted. What’s also I think interesting to note is that
depending on where they form, where the tumor started, various hormones are
secreted.Some of the neuroendocrine tumors secrete another hormone that’s
called ACTH which can lead to cortisol excess, which also causes very different
symptoms, compared to what we see with pancreatic neuroendocrine tumors or
small bowel. And tumors with the classic carcinoid syndrome, a lot of
questions come up, about , you know, testing. For these hormones, we will check for
hormorones ,depending on symptoms that patients may be experiencing. And , again,
depending, for instance there may be symptoms of low blood sugar. We may be able to check for hormones, including insulin. And similarly when
there are other symptoms that may suggest acid production, we can check for
hormones like gastrin. And if patients are experiencing bowel movement
difficulties or diarrhea, we can check for hormones like vasoactive intestinal
peptide. So again the the assessment of these hormones really is dependent on
this symptoms that patients may be
experiencing. Serotonin which is secreted by some neuroendocrine tumors to cause that classic carcinoid syndrome can be measured by can be measured by checking
the breakdown product 5 HIAA that is excreted in the urine. I would say that
controversy exists regarding the or in pancreatic polypeptide these types
of hormones can be made and secreted by neuron-specific enolase but they
don’t typically cause symptoms and have the the use of these markers as part of
the follow-up I think is something that’s debated. So the management
principles for patients include resection of localized or limited
metastatic disease. And for patients who have more advanced disease, our goals
really are to control the symptoms that might be related to hormone secretion. if
they’re present and also to control the growth of disease, I think it’s important
to recognize that this is a multidisciplinary team approach. That
there are many people who are involved in making the decisions about care and
that can include medical oncologists, gastroenterologist, surgeons, nurses,
radiation oncologists. Every patient has a different need and I think every
patient has a different team that’s involved in the care of their patients. So I want to start by just giving a
basic overview of the options to control the advanced of well-differentiated, control
the growth of advanced well- differentiated neuroendocrine tumors and
the major categories, include surgery to remove localized disease or limited
spread of disease. For patients who have liver predominant disease, we can treat
with liver-directed therapy that include ablation or embolization is
where things are injected into the liver. And later in the after later in the
morning you’ll heal from dr. Solon about liver-directed therapies. Peptide
receptor radionuclide therapy is a newer modality in the United States- – to treat
advanced neuroendocrine tumors.That really takes advantage of the
somatostatin receptor. And later in the of nuclear imaging test is an FDG PET
scan. That’s a more , I think, radionuclide therapy. And there also
are medical therapies that are used to treat patients with advanced disease,
that include somatostatin analogues molecular targeted therapies, and
chemotherapy. So I wanted to give everybody a basic overview of these
categories of therapy so somatostatin analogues are agents that bind to this
amount of statin receptors that are present on the neuroendocrine tumors.
And this figure is a diagram of a cell that has receptors on its surface. And
these receptors are important for integrating signals that help the cells
to react to either grow or secrete hormones. The somatostatin receptors are
present on the neuroendocrine tumors and somatostatin analogs including
octreotide and lanreotide can bind to those receptors and these agents are
used as a therapy for patients because they can improve carcinoid syndrome by
decreasing hormone secretion. And they’ve also been shown to slow the growth of GI
and pancreatic neuroendocrine tumors. Peptide receptor radionuclide therapy is
a form of therapy where these somatostatin analogs are labeled with a
radionuclide that can then find its way to the tumor and emit a tumoricidal
doses of radiation so lutetium 177 is one such radionuclide that emits beta
and gamma radiation and lutetium 177 dotatate was approved last year to treat
patients with advanced GI and pancreatic neuroendocrine tumors that were growing
after somatostatin analog therapy molecular targeted agents are a class of
medications that also are used to treat neuroendocrine tumors. And what this
figure shows again is a cancer cell that has various receptors and some of these
receptors target some of these receptors are involved in the signaling that
drives cell growth and cell proliferation. And they there are agents
that can bind those receptors to block that signaling pathway to then block
these processes that are responsible for the growth and spread
of of disease and also the growth of blood vessels that support this process
of growth and spread so I wanted to focus on one targeted agent called
everolimus, which is approved for neuro endocrine tumors. And everolimus is an
inhibitor of the mTOR pathway. mTOR signaling is an important pathway that
drives growth of neuro endocrine tumors. And everolimus, by blocking this pathway,
has been shown to slow growth of pancreatic neuroendocrine tumors as well
as non-functional gastrointestinal and lung neuroendocrine tumors. So this is
also an option that we will consider for patients. The other approach to treating
cancer is to block this process. That’s called angiogenesis, which is the
formation of new blood vessels that are needed to support the growth and spread
of cancer. This process of angiogenesis is driven by growth factors that bind to
receptors–VEGF–or vascular endothelial growth factors. One such growth factor
that binds this receptor and that signals growth of blood vessels– there
are medications that are called tyrosine kinase inhibitors- – that can inhibit this
receptor to slow down this process.There have been multiple tyrosine kinase
inhibitors that have been studied for neuroendocrine tumors. And this is, I
know it’s a confusing figure , but it lists many of the tyrosine kinase
inhibitors that have been studied for neuro endocrine tumors and the receptors
that they block. They all to some degree block this VEGF receptor, but block
other receptors that are involved in in growth we’ve seen in clinical trials.
That one of the tyrosine kinase of nuclear imaging test is an FDG PET
scan. That’s a more , I think, there also have been some recent
clinical trials that have shown that another tyrosine kinase inhibitor pazopanib can slow growth of non-pancreatic neuroendocrine tumors. And just last week, we heard that another trial another phase 3 trial that was
conducted in China of a tyrosine kinase inhibitor called sorafenib
also slowed the growth of nonpancreatic neuroendocrine tumors there are other
trials that are going on evaluating other tyrosine kinases inhibitor is
called cabozantinib and axitinib so you may hear about these agents. Also in
the future cytotoxic chemotherapy is what many people think of when they
think about cancer therapies. They are active in some types of neuroendocrine cancers. Chemotherapy with these types of agents that we call “alkylating agents”
that damage the DNA to prevent growth appear more active in pancreatic
neuroendocrine tumors. And the alkylating agents that have been used in pancreatic neuroendocrine tumors include streptozocin and temozolomide. A regimen that we commonly use is capecitabine and temozolomide which
is effective in patients with pancreatic neuroendocrine tumors. How active these
cytotoxic chemotherapy are for patients with other types of neuroendocrine tumors? Particularly small intestine neuroendocrine tumor hasn’t been as well
studied but it looks like cytotoxic chemotherapy may not be as active in
small bowel neuroendocrine tumors as compared to pancreatic neuroendocrine
tumors. So I know I gave you a very broad overview of the different treatments. And
I think sometimes one of the harder questions that we ask is …well what type
of treatment? And I think that’s again where it becomes very important to
involve multiple disciplines in that decision. And also you know as we make
these decisions we consider various factors that are related to patients.
You know how symptomatic they are from their cancer, whether it be from the
cancer and where it is, or whether it’s from hormones that are present. We also
think about other medical conditions that patients may have as we make our
decisions. Some of the disease-related factors are the ones that I had
mentioned to you about grading of the cancer and the pathology of the cancer.
And I think over time we begin to appreciate how fast or how slow growing
cancers are and that helps us and when we might want to start
treatment I think what you’ll hear from some of our other speakers is you know
one important thing is to think about you know is this a cancer that we can
remove with surgery or is this something that has spread beyond the point where
surgery is going to be helpful we look at patterns of spread for instance liver
dominant disease or whether it’s more widespread that might trigger us to use
a more systemic approach and then the hormone issue is functional and
non-functional tumors also drive whether or not we need to focus on hormone
control starting oftentimes with those somatostatin analogs we also are very
focused on what are what is our outcome are we looking to shrink the cancer or
are we able to stabilize growth where shrinkage is not quite as important so
again just I want to highlight and just let everybody know that there this is an
evolving field and treatment choices really must be individualized for each
patient we don’t yet have any data that tells us that one treatment is better
than the other treatment we have a growing number of agents that we can can
consider but we really need to take into account some of the factors that I
mentioned as we make our decision I want to spend just a few minutes on some of
the more rare neuroendocrine tumors because I think they’re also important
to talk about and some patients in the audience may have some of these more
rarer and Krynn tumors so poorly differentiated neuroendocrine carcinomas
as opposed to the neuro endocrine tumors that I focused on are in most cases more
aggressive than the well differentiated neuroendocrine tumors they’re not
usually associated with hormone syndromes and our treatment is very
different because of this biology we more commonly will start with
chemotherapy with platinum agents and etoposide to treat the poorly
differentiated neuroendocrine carcinomas there’s a lot of research going into
other types of therapy that may be useful for patients with poorly
differentiated neuroendocrine arcinomas and there’s a lot of interest now in
immunotherapy. Pheochromocytoma paraganglioma is another rare form of
neuroendocrine tumor that’s derived from nerve cells in the
sympathetic or parasympathetic para ganglia the adrenal medulla is part of the
sympathetic nervous system these tumors are often benign but what makes them
unique is their ability to secrete hormones these catecholamines and meta
nephrons that can lead to symptoms and medical complications and what I’ve
listed on this slide is a number of symptoms that patients with
pheochromocytoma and paraganglioma can experience related to this hormone
excess including headaches palpitations diaphoresis high blood pressure
particularly so our approach to management of pheochromocytoma and
paraganglioma is to resect these tumors and it’s really important before surgery
to make sure that the hormone effects are well blocked with alpha blockers and
if needed calcium channel blockers or beta blockers for patients have more
advanced disease our goals are still to control the effects of these hormones to
block the effects of the catecholamines and we also want to if needed try to
control the growth of the disease peptide receptor radionuclide therapy is
emerging for the treatment of advanced compared pheochromocytoma and
paraganglioma particularly with the recent approval of
a iobenguane i -131 which is a radiolabeled agent that is incorporated
into the pheochromocytoma paraganglioma cells to exhibit to observe a tumorcidal
effect. There also is activity of chemotherapy and there’s less data but
sometimes we will use somatostatin analogues to treat pheochromocytoma
paraganglioma there also are reports of activity of the tyrosine kinase
inhibitors that I mentioned to you for pheochromocytoma paraganglioma but this
also is a an area of ongoing research so I think some of the challenging
questions and future directions are related to appropriate sequence of
therapies and really how can we better personalized therapy for patients in
addition to what I mentioned you that are based on disease and in patient
related factor we are actively studying immunotherapy
and what the role of the immunotherapy might be for neuro endocrine neoplasms
we haven’t seen at least a single agent therapy as much activity of
immunotherapy for the well-differentiated neuroendocrine
tumors we’re starting to begin to look at combinations of immunotherapy and
immunotherapy with other agents as potentially a way to treat
neuroendocrine tumors but this really is an area of active investigation I want
to end by pointing out that the incidence of neuro endocrine tumors is
on the rise in the United States this is a figure from the cancer registries in
the United States the seer database that shows over the last decade or two the
incidence of neuron to consumers is rising across all sites throughout the
lung and in the GI tract but what this database also shows us is that patients
are living longer patients have better survival for neuroendocrine tumors now
compared to even 2000 2004 and I think that what we what we think is going on
is that as we are understanding this disease better as we’re doing more
research to understand the biology of treatment as we’re developing new
therapies we’ll be able to extend the lives of patients so you’ll notice that
the improved outcomes for patients really does coincide with when we began
to notice and when we began to have availability of some of the newer
therapies that I mentioned so there’s active research that’s ongoing and we’re
hoping to be able to build on this to extend the lives and to extend the
quality of life for our patients so with that I want to thank you thank you for
attending and thanks for your attention END