Center for GI Cancers CME Webinar Series 2025 • 3 / 3 Skip navigation Search Create Avatar image Center for GI Cancers CME Webinar Series: Neuroendocrine Cancer

Transcript

• 00:00Really, it's a pleasure to
• 00:01be here tonight. My name
• 00:02is Pamela Coons, and I'm
• 00:03a GI medical oncologist
• 00:05and the chief of GI
• 00:07medical oncology
• 00:08here at Yale Cancer Center
• 00:10and Smilow Cancer Hospital.
• 00:12So, as I just mentioned,
• 00:13we are
• 00:15rounding out the four part
• 00:17CME webinar series for the
• 00:19center for GI cancers following
• 00:21the GI oncology urine review,
• 00:23then colorectal cancer and gastroesophageal
• 00:25cancer. And tonight,
• 00:27we are talking about neuroendocrine
• 00:29cancers.
• 00:31It's my pleasure to introduce
• 00:33my colleagues this evening.
• 00:35So first off, I will
• 00:37be talking about just NETS
• 00:38one zero one and some
• 00:40systemic treatment.
• 00:41Doctor David Klemstra is a
• 00:43professor of pathology,
• 00:44and he will be talking
• 00:45about NET pathology.
• 00:48Doctor John Kuntzmann is an
• 00:50assistant professor of surgery and
• 00:51surgical oncology,
• 00:53and he will be discussing
• 00:54the
• 00:56primary
• 00:57and metastatic disease. And doctor
• 01:00Gabriella Spilberg is an assistant
• 01:02professor of radiology and biomedical
• 01:04engineering and nuclear medicine, and
• 01:06we'll talk about theranostics.
• 01:08We'll each talk for about
• 01:09fifteen minutes, and then we'll
• 01:10have a thirty minute q
• 01:12and a.
• 01:15Alright. So to kick off,
• 01:16I'm gonna do an introductory
• 01:18just around language and nomenclature
• 01:20of NETs
• 01:21and some discussion around systemic
• 01:23treatment.
• 01:25These are my disclosures.
• 01:29And this is the outline.
• 01:30So I'll talk briefly about
• 01:31epidemiology and nomenclature,
• 01:33characteristics that impact how we
• 01:35think about treatment,
• 01:36and then discuss treatments for
• 01:38tumor control. I'll give an
• 01:39overview, but then I'll also
• 01:40talk about some of our
• 01:41newest treatments in the last
• 01:42couple of years.
• 01:44So this is a slide
• 01:45I'd love to use because
• 01:46I think it really shows
• 01:48how much progress we've made
• 01:50in the last couple of
• 01:51decades.
• 01:52So until the late nineteen
• 01:54eighties, we only had two
• 01:56available therapies. Streptazosin
• 01:58was FDA approved for pancreatic
• 01:59NETs, and octreotide
• 02:01was approved for hormone control.
• 02:04And then we had almost
• 02:06nothing for about
• 02:08twenty years. And then starting
• 02:10in twenty eleven, we had
• 02:12this explosion
• 02:13of available systemic treatments.
• 02:16That's that's below the timeline.
• 02:18And then above the timeline,
• 02:20we had advances in imaging.
• 02:22And we'll talk about all
• 02:23of those things this this
• 02:24evening.
• 02:26So many of you, I'm
• 02:27sure, have heard the word
• 02:29carcinoid, which means cancer like.
• 02:31This term was coined by
• 02:32a German pathologist, doctor Orban
• 02:34Dorfer, in the early nineteen
• 02:35hundreds. And while this was
• 02:37a really important contribution to
• 02:39the field,
• 02:40it also was a bit
• 02:41misleading.
• 02:42So he initially described these
• 02:44tumors as small and multifocal
• 02:47with undifferentiated
• 02:48cellular formations
• 02:50that they had well defined
• 02:51borders, had no metastatic potential
• 02:53and were slow growing and
• 02:54harmless. And it was for
• 02:56almost a hundred years after
• 02:58this
• 02:58that,
• 02:59for a very long time,
• 03:01these were actually not even
• 03:02considered cancers.
• 03:04It was really in the
• 03:05late,
• 03:06nineteen nineties, early two thousands
• 03:08that they were described as
• 03:09cancers and captured in the
• 03:10SEER database as cancers.
• 03:12And, so that that does
• 03:14make some epidemiologic studies trickier.
• 03:18So in terms of epidemiology,
• 03:20both incidence and prevalence, on
• 03:22the left is a figure
• 03:23of incidence. So the incidence
• 03:25or number diagnosed per year
• 03:27is actually low,
• 03:28but rising. So that is
• 03:30the the yellow line in
• 03:32comparison to the blue line,
• 03:33which is the incidence of
• 03:34all malignant neoplasms.
• 03:36So the incidence of NETs
• 03:38at present is about eight
• 03:39to ten per hundred thousand,
• 03:41but has increased pretty dramatically
• 03:43over the last thirty years
• 03:45thought to be in large
• 03:46part due to better diagnostics.
• 03:49However,
• 03:50that is probably not enough
• 03:51to describe,
• 03:53to exclusively
• 03:55describe the reasons for the
• 03:57increase.
• 03:58Prevalence is the number of
• 03:59patients alive, and really NETs
• 04:01have higher prevalence than previously
• 04:03appreciated.
• 04:04NET prevalence exceeds that of
• 04:05stomach and pancreatic adenocarcinoma
• 04:08combined. So really a much
• 04:09bigger public health problem. And
• 04:11in fact, NETs at present
• 04:12are the second most common
• 04:14GI malignancy.
• 04:18Recently, a new version of
• 04:19the AJCC guidelines came out.
• 04:21This is version
• 04:22nine. And we are starting
• 04:24to see better data around
• 04:26overall survival. And I thought
• 04:27just juxtaposing these was really
• 04:29important to show you that
• 04:30the five year overall survival
• 04:32for pancreatic NETs,
• 04:35for metastatic pancreatic NETs is
• 04:37about six to seven years,
• 04:38and for metastatic small bowel
• 04:40NETs is eight to ten
• 04:41years.
• 04:42It it can differ, as
• 04:44you can see, by pathologic
• 04:45stage.
• 04:46But I think that we've
• 04:47really made significant advances in
• 04:49treating patients with metastatic disease
• 04:51such that they live for
• 04:52years, and these are really
• 04:54metastatic NETs is really more
• 04:56of a chronic condition in
• 04:57chronic cancer.
• 04:59NETs are epithelial neoplasms that
• 05:01are derived from nirnapine cells
• 05:03throughout the body. Most grow
• 05:04slowly in comparison with their
• 05:06adenocarcinoma
• 05:07counterparts.
• 05:08The majority are sporadic with
• 05:09about ten percent or less
• 05:11associated with familial syndromes.
• 05:13And really pathognomonic for the
• 05:15disease is the presence of
• 05:16somatostatin
• 05:17receptors.
• 05:18Eighty to ninety percent of
• 05:19NETs overexpress somatostatin receptor type
• 05:21two.
• 05:23The diagnostic workup includes
• 05:26really at the foundation
• 05:28cross sectional imaging. That is
• 05:29the primary tool that we
• 05:31monitor these patients with,
• 05:33Either a multiphasic CT and
• 05:35that multiphasic
• 05:36is really critical.
• 05:38We highly recommend arterial phase,
• 05:41imaging as part of that.
• 05:42An MRI is also acceptable.
• 05:45And then somatostatin receptor imaging
• 05:47with either gallium sixty eight
• 05:48DOTAPET or copper sixty four,
• 05:50which doctor Spilberg will will
• 05:51talk about later,
• 05:52has also become quite important.
• 05:54So the somatostatin receptor based
• 05:56imaging is often avid in
• 05:57low grade disease,
• 05:59but not avid in high
• 06:00grade. And the opposite is
• 06:02true for f eighteen FDG
• 06:04PET. It's avid in high
• 06:05grade and not in low
• 06:06grade.
• 06:08Tissue diagnosis, we have some
• 06:09minimum data elements.
• 06:11We like to see doctor
• 06:12Klimstra will be talking about
• 06:14this, in detail, so I
• 06:15will not be going over
• 06:16this.
• 06:17And then hormone and tumor
• 06:19markers, we sometimes measure twenty
• 06:21four hour urine and plasma
• 06:22five five HI. I'm I've
• 06:23really pretty much pivoted using
• 06:25the plasma test. It's much
• 06:27easier for patients.
• 06:29And there are some specific
• 06:30peptides and amines like glucagon,
• 06:33insulin, gastrin.
• 06:35And and I've really stopped
• 06:37checking chromogranin a. So I
• 06:38I,
• 06:39say here resist the temptation
• 06:41to order chromogranin a. I
• 06:42find that it is,
• 06:44quite variable. It often leads
• 06:46to more anxiety than it
• 06:47is helpful both for the
• 06:48physician and for the patient.
• 06:50I don't find it a
• 06:51useful biomarker.
• 06:54So there are, in my
• 06:55mind, a number of characteristics
• 06:57that that help,
• 06:59me decide how to treat
• 07:01the patient in front of
• 07:02me. They include functional status,
• 07:05so whether or not a
• 07:06patient has symptoms of of
• 07:07a measurable hormone,
• 07:09primary site stage,
• 07:11volume of disease,
• 07:13degree of differentiation,
• 07:15the WHO grade, the somatostatin
• 07:17receptor status,
• 07:19germline and somatic mutations,
• 07:21sex, gender, race, and social
• 07:22determinants of health. I'm only
• 07:24gonna focus on a few
• 07:25of these, but I'm really
• 07:26gonna focus primarily on on
• 07:28how we select the treatment.
• 07:30So treatment for
• 07:32tumor control for NETs. I'm
• 07:33really gonna focus on just
• 07:35the neuroendocrine
• 07:36tumors. I'm not gonna talk
• 07:38about poorly differentiated neuroendocrine carcinomas
• 07:40tonight just for the sake
• 07:41of time. So these four
• 07:43buckets are somatostatin analogs,
• 07:45targeted therapies,
• 07:47cytotoxic
• 07:48chemotherapy,
• 07:49and radioligand therapy.
• 07:52So doctor Spielberg will talk
• 07:53about radioligand therapy. I will
• 07:55not include that in in
• 07:56my talk.
• 07:58So the
• 07:59overall
• 08:00gap net treatment approach includes
• 08:03surgical surgical debulking.
• 08:05If possible, we resect the
• 08:06primary and even sometimes metastatic
• 08:09disease.
• 08:10For pancreatic NETs less than
• 08:11two centimeters, we can also
• 08:12consider observation, and this is
• 08:14adapted from the NCCN guidelines.
• 08:16I will let doctor Kuntzmann
• 08:17focus on talking about surgery,
• 08:18both for primary and METs.
• 08:20If a patient has unresectable
• 08:22metastatic
• 08:23and low tumor burden disease,
• 08:24we often observe
• 08:26or use a somatostatin analog
• 08:28as first line treatment.
• 08:29If they have unresectable
• 08:31metastatic disease and have symptoms
• 08:33for their from their primary
• 08:34tumor.
• 08:36Again, doctor Kuntzmann will talk
• 08:37about indications for resection of
• 08:39the primary tumor.
• 08:40And then if patients have
• 08:41unresectable metastatic or clinically
• 08:44significant
• 08:45tumor burden, we will think
• 08:47about SSA as first line
• 08:48or other systemic treatment options.
• 08:51And those options, again, as
• 08:52as seen in that timeline,
• 08:53have really
• 08:55expanded over the last decade.
• 08:57I've separated it into small
• 08:59bowel NET and pancreatic NET.
• 09:00There are some slight differences,
• 09:02although there is some overlap.
• 09:05The optimal sequence of therapies
• 09:07is currently unknown,
• 09:10and we are starting to
• 09:11see
• 09:12more clinical trials emerge that
• 09:14compare active agent to active
• 09:16agent. So we will start
• 09:17learning a little bit more
• 09:18about sequence
• 09:19and,
• 09:21sort of comparisons of survival
• 09:22and response rates as we
• 09:24get data from those studies.
• 09:26So I'm gonna briefly review
• 09:28some of our FDA approved
• 09:29agents and the studies that
• 09:31led to those.
• 09:33So we we know that
• 09:34somatostatin analogs have an anticancer
• 09:37effect or anti proliferative effect
• 09:39on the basis of the
• 09:40PROMID and the CLARINET studies.
• 09:42The CLARINET study led to
• 09:44the FDA approval of lanreotide
• 09:46for tumor control in twenty
• 09:48fourteen on the basis of
• 09:49a prolonged progression free survival.
• 09:52PFS is the primary
• 09:54endpoint for most neuroendocrine tumor
• 09:56studies mostly because
• 09:58OS is going to be
• 09:59impractical given that NETs,
• 10:01have a much longer overall
• 10:03survival. Patients have often gone
• 10:05to get subsequent therapies. So
• 10:07overall survival ends up being
• 10:09a really impractical endpoint.
• 10:13Somatostatin analogs do not shrink
• 10:15NETs, so I think that's
• 10:16another very important point. The
• 10:18response rate is in the
• 10:19single digits.
• 10:20Side effects include nausea, diarrhea,
• 10:23gallstones,
• 10:25and hyperglycemia.
• 10:29Everolimus is also FDA approved
• 10:31really across the board for
• 10:33pancreatic NET, GI, and lung
• 10:36NET. There was a series
• 10:37of studies called the radiant
• 10:39trials.
• 10:40So RADIENT three and RADIENT
• 10:42four were the key trials
• 10:44that led to FDA approval
• 10:45in the respective primary sites.
• 10:47So RADIENT three was for
• 10:49pancreatic NET. RADIENT four was
• 10:51for GI and Lung NET.
• 10:53And you can see here
• 10:54that the median PFS is
• 10:55actually very similar in those
• 10:56studies,
• 10:57with an absolute difference of
• 10:59about,
• 11:00five to six months for
• 11:01both of these.
• 11:03Treatment outcomes,
• 11:05also,
• 11:06this agent does not yield
• 11:07shrinkage,
• 11:08single digit response rates, but
• 11:11prolongs progression free survival. Side
• 11:13effects, this is a more
• 11:14difficult
• 11:15treatment than somatostatin analog, so
• 11:17it causes hyperglycemia,
• 11:19fatigue,
• 11:20stomatitis,
• 11:21rash, pneumonitis, and diarrhea.
• 11:23So these were approved,
• 11:25in twenty eleven.
• 11:29Sunitinib
• 11:30is FDA approved for pancreatic
• 11:32NETs.
• 11:33Again, very similar PFS data
• 11:35compared to Everlimus.
• 11:37So this was a sunitinib
• 11:38versus placebo study in pancreatic
• 11:41NET. Medium PFS was eleven
• 11:42months versus,
• 11:44excuse me, versus five months.
• 11:46This I've sort of given
• 11:47the these, trials
• 11:50presenting to you in a
• 11:51way that they become increasingly
• 11:53difficult more difficult in terms
• 11:54of side effects. So sunitinib
• 11:57can cause hypertension, fatigue, diarrhea,
• 12:00nausea, vomiting, and rash.
• 12:03So the newest tyrosine kinase
• 12:05inhibitor that was just FDA
• 12:07approved in April of twenty
• 12:09five, so just last month,
• 12:11is cabozantinib.
• 12:12Cabozantinib
• 12:13has slightly different targets than
• 12:15sunitinib, most notably CNET.
• 12:18This was a,
• 12:20a sort of two cohort,
• 12:23study. So they had a
• 12:24pancreatic NET study and an
• 12:26extra pancreatic NET study. So
• 12:27in the extra pancreatic NET
• 12:29cohort, which is the,
• 12:30Kaplan Meier curve that you're
• 12:31looking at here, we saw
• 12:33a prolongation of PFS
• 12:35for cabozantinib
• 12:36versus placebo.
• 12:37The response rate was single
• 12:39digits four percent.
• 12:41For the pancreatic NET cohort,
• 12:43I saw a slightly longer
• 12:45median PFS, and the response
• 12:47rate was actually higher. It
• 12:48was eighteen percent.
• 12:50So this is now FDA
• 12:51approved for adults and pediatric
• 12:53patients with lung,
• 12:55GI, pancreas, and unknown primary
• 12:57NET,
• 12:58because end of March.
• 13:04So in terms of chemotherapy,
• 13:07capecitabine
• 13:08temozolomide
• 13:09is used very commonly in
• 13:10pancreatic NET on the basis
• 13:12of the ECOG ACRAN twenty
• 13:13two eleven study.
• 13:15And
• 13:16this, was a study I
• 13:17had the opportunity to lead.
• 13:19It demonstrated
• 13:20a benefit of the combination
• 13:22arm compared
• 13:24to temozolomide
• 13:25alone. And also a really
• 13:26key takeaway is that this
• 13:28does in fact yield tumor
• 13:29shrinkage. So about a forty
• 13:31percent response rate for the
• 13:32combination arm.
• 13:34Pretty well tolerated, but can
• 13:35cause cytopenias,
• 13:37fatigue, diarrhea, nausea, vomiting, and
• 13:39hand foot syndrome.
• 13:42One key takeaway from this,
• 13:44I'm gonna focus in the
• 13:45figure on the right, is
• 13:46that I had mentioned response
• 13:47rate is high in both
• 13:48arms.
• 13:49The study was not designed
• 13:51to detect a difference in
• 13:52response rate, but this is
• 13:54for a patient population who
• 13:55is in need of objective
• 13:57shrinkage.
• 13:58Another takeaway is that I
• 13:59do not generally use this
• 14:01for patients with small bowel
• 14:02nets.
• 14:04So as we're thinking about
• 14:05selecting treatments, it's really critical
• 14:07to think about patient characteristics,
• 14:10pay the patient in front
• 14:11of you. What other comorbidities
• 14:13do they have? Treatment outcomes
• 14:14do you need? Is stability
• 14:16gonna be sufficient, or do
• 14:17you really need a response
• 14:18if a patient has symptoms
• 14:20from tumor bulk or from
• 14:21hormones?
• 14:22And then as we think
• 14:23about our buckets
• 14:25of peptide receptor radionuclide therapy,
• 14:27somatostatin analogs,
• 14:29targeted therapies, and cytotoxic chemotherapies,
• 14:32the you can weigh these
• 14:34different variables.
• 14:37So trials to watch.
• 14:39I'm not gonna go through
• 14:39these in detail, but I
• 14:40want you to have these
• 14:41available
• 14:42afterwards. The the our presentations
• 14:44are being recorded tonight. So
• 14:46really exciting that we're starting
• 14:47to see we have an
• 14:48adjuvant study in pancreatic NET
• 14:50of CAPTEM.
• 14:52There's a study looking at,
• 14:54more frequent dosing of octreotide
• 14:57to see if that is
• 14:58something that can help slow
• 14:59growth. And then for metastatic
• 15:01paragangliomide
• 15:02pheo,
• 15:03temozolomide versus temozolomide plus olaparib,
• 15:05which is a PARP inhibitor.
• 15:08So take home points. I
• 15:09hope I've shown you that
• 15:10NETs are not that rare.
• 15:11They are deserving of high
• 15:13quality basic translational clinical research
• 15:15efforts.
• 15:16We have many tools in
• 15:17the toolbox,
• 15:19that include a range of
• 15:21classes of therapy, SSAs, radioligand,
• 15:23targeted, and chemotherapies.
• 15:26However, there's no known optimal
• 15:28sequence. And really that tailoring
• 15:30of treatment for every patient
• 15:31requires a careful balance of
• 15:33patient and treatment characteristics.
• 15:35And I think the last
• 15:36takeaway is a perfect segue
• 15:37into passing the baton to
• 15:38my partners is that multidisciplinary
• 15:40care and coordination is really
• 15:42essential in this disease.
• 15:44So, so thank you. I
• 15:45will I will pause here,
• 15:48and I will pass the
• 15:50baton.
• 15:51So the next speaker up
• 15:52is doctor Klimstra.
• 15:56Thanks, Pam. Just bringing up
• 15:58my
• 15:59slides.
• 16:01So,
• 16:03as Doctor. Coons said, a
• 16:05perfect segue is to talk
• 16:06take a step back
• 16:08a little bit and talk
• 16:09about how do we establish
• 16:11the diagnosis
• 16:12of
• 16:13gastroenter or pancreatic
• 16:15neuroendocrine tumors. It's a mouthful
• 16:17GepNets or GepNens
• 16:18depending on what you're speaking
• 16:20of.
• 16:21These are my disclosures.
• 16:24So neuroendocrine
• 16:26tumors have classic histologic features
• 16:28that are typically well recognized.
• 16:32They've been described for
• 16:34over a hundred years.
• 16:37But they're actually very diverse.
• 16:39They can arise throughout the
• 16:41body. We're really focused below
• 16:42the diaphragm here, but of
• 16:44course the lung thymus
• 16:46scan, other sites are also
• 16:48common. And microscopically, we refer
• 16:50to this growth patterns with
• 16:52nests and ribbons as being
• 16:54organoid.
• 16:55And the nuclei are also
• 16:56very
• 16:58characteristic.
• 16:59But in general, we prove
• 17:00the diagnosis using immunohistochemistry
• 17:03for markers of neuroendocrine differentiation
• 17:05and we'll talk about that
• 17:06a little more minute.
• 17:07I think probably the most
• 17:08important takeaway
• 17:09from
• 17:10what I'm going to say
• 17:11is the fact that neuroendocrine
• 17:13neoplasms
• 17:14can be either well differentiated
• 17:16or poorly differentiated. And these
• 17:18are really
• 17:19very, very different
• 17:21categories.
• 17:22Differentiation of course refers to
• 17:24the resemblance of neoplastic cells
• 17:26to their normal counterparts. So
• 17:27for instance, this is a
• 17:28pancreatic islet and this is
• 17:30a pancreatic neuroendocrine tumor. And
• 17:32you can see in this
• 17:33well differentiated
• 17:35tumor, it looks very much
• 17:36like the normal islets. And
• 17:38they strongly express markers that
• 17:40are found in in in
• 17:42normal neuroendocrine cells like chromogranium
• 17:44and cementifazin.
• 17:46But well differentiated and poorly
• 17:48differentiated neuroendocrine neoplasms,
• 17:50although they share neuroendocrine differentiation
• 17:52are really different. And I
• 17:54can't overemphasize
• 17:55this.
• 17:56They can on occasion be
• 17:58difficult for us to distinguish.
• 18:00Sometimes they share some histologic
• 18:03features. But these are really
• 18:04fundamentally different. They arise from
• 18:06different cells.
• 18:07They have a different relationship
• 18:08to non neuroendocrine neoplasia like
• 18:10adenocarcinoma
• 18:12or squamous cell carcinoma.
• 18:14They're genetically
• 18:15different and they're dramatically different
• 18:17in terms of their aggressiveness
• 18:19and their treatment.
• 18:21And just to give you
• 18:22some examples of this, you
• 18:24know you look at well
• 18:25differentiated neuroendocrine tumors, they tend
• 18:27to be associated with MEN1,
• 18:29whether differentiated or not.
• 18:32There can be precursor lesions
• 18:33in the endocrine lineage in
• 18:35the well differentiated but not
• 18:36poorly.
• 18:37On the contrary, the non
• 18:39neuroendocrine precursors like dysplasia
• 18:42can be associated with a
• 18:43poorly differentiated neuroendocrine neoplasm.
• 18:47The important point at the
• 18:49bottom is that they never
• 18:50co occur. So the well
• 18:51differentiated ones stay well differentiated
• 18:53ones and the poorly differentiated
• 18:55are poorly and they aren't
• 18:56mixed together.
• 18:57This is just an example
• 18:59from the lung but similar
• 19:00conclusions
• 19:01exist for any anatomic site.
• 19:03They're very different genomic alterations.
• 19:06The top two are quite
• 19:07characteristic of poorly differentiated neuroendocrine
• 19:09carcinomas. RB,
• 19:11and p fifty three are
• 19:12commonly mutated.
• 19:14And MEN for instance is
• 19:16mutated in the well differentiated
• 19:17but not poorly.
• 19:19So,
• 19:21really try to keep in
• 19:23mind that when someone
• 19:25uses the term well differentiated,
• 19:26they're talking about a completely
• 19:28different
• 19:29beast than a poorly differentiated
• 19:31neuroendocrine neoplasm.
• 19:33Terminology
• 19:34in this area has been
• 19:35a problem for years and
• 19:37we were able to standardize
• 19:38this
• 19:39for most anatomic sites. Certainly
• 19:42south of the diaphragm it's
• 19:43standardized. The lung people
• 19:45are still a little
• 19:47unhappy with this and prefer
• 19:49to use the term carcinoid
• 19:51for the well differentiated tumors.
• 19:54But generically we use the
• 19:56term neoplasm to refer to
• 19:58both well and poorly differentiated.
• 20:00The term
• 20:02term term tumor means well
• 20:04differentiated.
• 20:06The term carcinoma
• 20:07means poorly differentiated.
• 20:10And that can be either
• 20:11small cell carcinoma or large
• 20:13cell neuroendocrine carcinoma.
• 20:15There are also rare,
• 20:17entities that are mixed,
• 20:19a component of both neuroendocrine
• 20:20and non neuroendocrine. And we
• 20:22really don't have time to
• 20:23get into these, but you
• 20:24may see,
• 20:25occasional reports of these
• 20:28mixed variants.
• 20:30Now how do we recognize
• 20:31that we're dealing with a
• 20:32neuroendocrine tumor?
• 20:34In the well differentiated category,
• 20:36it's really not
• 20:37a big challenge. These organoid
• 20:39patterns, you can see the
• 20:40ribbons
• 20:41in the top left or
• 20:42the nest in the bottom
• 20:44left, quite typical. The nuclei
• 20:46are quite typical.
• 20:48The poorly differentiated
• 20:50carcinomas are a little different
• 20:51though. They tend to have
• 20:52a very poorly differentiated morphology.
• 20:55There are some features that
• 20:56we equate with neuroendocrine differentiation,
• 20:59such as a nesting pattern,
• 21:01a certain pattern to the
• 21:03chromatin.
• 21:04But these require some additional
• 21:06evidence to prove that they're
• 21:08neuroendocrine.
• 21:09And that is found in
• 21:10the in the form of
• 21:11immunistic chemical staining.
• 21:14This is a longer list
• 21:15than you need, because there
• 21:16are many markers that have
• 21:18been
• 21:19used in the past or
• 21:20that have recently been developed.
• 21:22But the three highlighted ones,
• 21:23chromogranin,
• 21:24a,
• 21:25synaptophysin,
• 21:27and insulinoma
• 21:28associated protein or I n
• 21:30s m one are the
• 21:31three that are currently
• 21:33accepted as
• 21:34both sensitive and specific
• 21:36for neuroendocrine differentiation.
• 21:39Now
• 21:41when you're talking about a
• 21:42well differentiated neuroendocrine tumor,
• 21:45almost all of them are
• 21:46positive for these markers when
• 21:47used in combination,
• 21:49chromogran and synaptophys and stain
• 21:51ninety five percent.
• 21:53Certain
• 21:54other nonneuroendocrine
• 21:55neoplasms
• 21:56do stain predictably for these
• 21:58that we have to know
• 21:59about. And occasionally you can
• 22:01have idiosyncratic staining of other
• 22:02neoplasms, so they're not a
• 22:04hundred percent specific, but they're
• 22:05they're very reliable.
• 22:07In fact, some pathologists question
• 22:09whether it's truly necessary to
• 22:11stain every obvious neuroendocrine tumor
• 22:14for these markers. I think
• 22:15it tends to make people
• 22:17more comfortable to see that
• 22:18this has been done just
• 22:19to make absolutely sure.
• 22:21But there are some that
• 22:22are just so prototypical
• 22:23you don't you don't honestly
• 22:24need it.
• 22:26That is not the case
• 22:27for the poorly differentiated.
• 22:30Small cell neuroendocrine carcinoma has
• 22:32a very classic morphologic
• 22:33finding, and you can consider
• 22:35making this diagnosis without immunohistochemical
• 22:38support as long as you've
• 22:39ruled out other things.
• 22:41But large cell neuroendocrine carcinoma
• 22:43absolutely has to have
• 22:45immunohistochemical
• 22:46staining to prove that it's
• 22:47neuroendocrine.
• 22:48And there can be some
• 22:49debate about
• 22:51how strong or how diffusely
• 22:52positive it should be. I
• 22:53mean if you get a
• 22:54stain like this chromogranon and
• 22:56when it's it's quite compelling.
• 22:59But the WHO
• 23:00now is saying that you
• 23:01should have two of those
• 23:02three markers
• 23:03positive to verify this diagnosis.
• 23:08One side point I'd like
• 23:09to make is you have
• 23:10to be careful with immunohistochemistry.
• 23:12So
• 23:13adenocarcinomas
• 23:15can also have neuroendocrine differentiation.
• 23:17It can come in the
• 23:18form of scattered positive cells
• 23:20like you see in this
• 23:22adenocarcinoma
• 23:23with a few cells labeling,
• 23:25or it can actually be
• 23:27more extensive
• 23:28and and just detect it
• 23:30incidentally.
• 23:30And it really
• 23:32the prognostic
• 23:33import of this kind of
• 23:35finding is really not clear.
• 23:37We don't believe it's prognostically
• 23:39relevant. These are still adenocarcinomas.
• 23:41And so be a little
• 23:42bit careful about asking a
• 23:44pathologist to do neuroendocrine markers
• 23:46on something they're confident is
• 23:48not a neuroendocrine tumor, because
• 23:49you might like what you
• 23:51find.
• 23:54Now the other critically important
• 23:56thing is grading neuroendocrine neoplasms.
• 23:59Grading is something we've implemented
• 24:00in the last fifteen or
• 24:02twenty years,
• 24:03and it's based
• 24:05entirely or largely on the
• 24:07proliferative rate measured by mitotic
• 24:09counting or the k sixty
• 24:11seven immunohistochemical
• 24:12stain.
• 24:13The well differentiated
• 24:15tumors can be either grade
• 24:17one, grade two, or grade
• 24:18three
• 24:19depending upon the rate of
• 24:21proliferation.
• 24:22Whereas the neuroendocrine carcinomas are
• 24:24by definition grade three all
• 24:25the time.
• 24:27Grading generally correlates very well
• 24:29with prognosis, and this is
• 24:30one of many studies showing
• 24:32this. It's quite a dramatic
• 24:33difference
• 24:34in in in behavior based
• 24:36on the grade.
• 24:37But another important feature to
• 24:39keep in mind is that
• 24:40the grade of neuroendocrine tumors
• 24:42is dynamic.
• 24:44It can vary regionally within
• 24:46a neuroendocrine tumor.
• 24:48It can vary between different
• 24:49sites of disease. For instance,
• 24:51a primary versus a metastasis
• 24:52or two different metastases.
• 24:54And it can even change
• 24:56over the course of disease.
• 24:57So if you have a
• 24:58patient whose disease has been
• 24:59progressing slowly
• 25:01and suddenly it starts to
• 25:02grow more rapidly, it's likely
• 25:04that it has become higher
• 25:05grade.
• 25:06And this argues that we
• 25:07should really be assessing the
• 25:08grade every time we have
• 25:10a tissue sample
• 25:11of a neuroendocrine tumor.
• 25:14The criteria for this,
• 25:16you know, again, throughout the
• 25:18body, there's a little variability
• 25:19in how we do this,
• 25:20but the GI in pancreas
• 25:22has been standardized. And this
• 25:24was
• 25:25twenty nineteen
• 25:27classification.
• 25:28It was just
• 25:30reassessed by the WHO and
• 25:32they haven't really changed it
• 25:33at all.
• 25:34And so you can see
• 25:35the the proliferative rate that
• 25:37distinguishes the three grades of
• 25:39neuroendocrine tumors,
• 25:42both by mitotic rate and
• 25:44key sixty seven.
• 25:45And then you can also
• 25:46see the higher proliferative rate
• 25:48that characterizes
• 25:49the neuroendocrine carcinomas.
• 25:52I would draw your attention
• 25:53to the fact that the
• 25:54proliferative rate threshold for neuroendocrine
• 25:57carcinoma is exactly the same
• 25:59as it is for g
• 26:00three nets.
• 26:01And so the distinction of
• 26:02these two has suddenly become
• 26:04a bit of a challenge
• 26:05for us, and we'll come
• 26:06back to that in a
• 26:07second.
• 26:08But this is what the
• 26:09mitotic figures look like in
• 26:10a in a intermediate grade
• 26:12neuroendocrine tumor. There are a
• 26:13few of them.
• 26:16It's probably easier to assess
• 26:18key sixty seven to be
• 26:19honest.
• 26:20And this has been pretty
• 26:22standardized.
• 26:22You see examples of low
• 26:24grade, intermediate grade, and high
• 26:25grade with a highly variable
• 26:26number of cells with nuclear
• 26:28staining.
• 26:30There are lots of ways
• 26:30to do this. The way
• 26:32we do it is we
• 26:32actually take a photograph
• 26:34of the hot spot, the
• 26:35highest labeling area, and then
• 26:37count the positive cells versus
• 26:39the negative cells, and you
• 26:40can get an actual number,
• 26:42sixty one positive out of
• 26:43fourteen hundred and twenty one
• 26:45cells counted. And this should
• 26:47be included in all pathology
• 26:48reports on neuroendocrine tumors.
• 26:52Now since we've been using
• 26:54this, there's been some feedback
• 26:56about this grading scheme.
• 26:58And in particular, the g
• 27:00two category may be overly
• 27:02broad. You know, you have
• 27:03a three percent is g
• 27:05two, but also nineteen percent
• 27:06is g two. And many
• 27:07people have observed that those
• 27:09two tumors don't behave the
• 27:11same.
• 27:12There have been some proposals
• 27:13to raise that three percent
• 27:15cut point.
• 27:17That's not really gained any
• 27:18traction.
• 27:19A more appealing proposal is
• 27:21to divide g two into
• 27:23a and g two b
• 27:25based on ten percent.
• 27:27So g two a being
• 27:29three to ten and g
• 27:30two b being ten to
• 27:32twenty.
• 27:33And there's actually a nice
• 27:35paper that just came out
• 27:36in an archive
• 27:40from the Hopkins group looking
• 27:41at forty years of pancreatic
• 27:43neuroendocrine tumors. And you can
• 27:45see with this grading scheme
• 27:46the the dramatic difference in
• 27:48outcome between G2a and G2b.
• 27:51So I suspect that this
• 27:52will work its way into
• 27:53new proposals.
• 27:57So we have the concept
• 27:58of a neuroendocrine tumor
• 28:00being a low grade,
• 28:02tumor that can undergo grade
• 28:04progression
• 28:05to be high grade.
• 28:07And the concept
• 28:08of poorly differentiated neuroendocrine carcinoma
• 28:11being a carcinoma from the
• 28:13get go being high grade
• 28:16uh-uh throughout its course.
• 28:18Both of these pathways though
• 28:20give rise
• 28:21to high grade neuroendocrine neoplasms.
• 28:24And in fact, here we
• 28:25see an example
• 28:27of
• 28:28a intermediate grade pancreatic neuroendocrine
• 28:31tumor that has progressed within
• 28:33the primary tumor. It has
• 28:35at the lower right you
• 28:36can see the
• 28:37the intermediate grade areas and
• 28:38in the upper right a
• 28:39very high grade area. And
• 28:41if we look at the
• 28:42key sixty seven, it's nearly
• 28:44a hundred percent in this
• 28:46high grade area.
• 28:47Which creates some problems because
• 28:49if you didn't know about
• 28:50the low grade area, you
• 28:51would think this was a
• 28:52neuroendocrine carcinoma.
• 28:54And indeed what we've found
• 28:56now is that there's an
• 28:57overlap
• 28:58in the K sixty seven
• 28:59between the well differentiated NETs
• 29:02and the poorly differentiated neuroendocrine
• 29:04carcinomas.
• 29:05And we have this range
• 29:06of K sixty seven between
• 29:08around thirty to seventy where
• 29:10both can occur.
• 29:12And so how are we
• 29:13gonna tell these apart?
• 29:15Well there can be some
• 29:16clinical clues.
• 29:18For instance, if the patient
• 29:19had a lower grade
• 29:21NET, then the high grade
• 29:22tumor is also a NET.
• 29:24If it's octreotide
• 29:26or one of the other
• 29:27somatostatin
• 29:28based imaging scans positive, it's
• 29:30probably well differentiated
• 29:32NET. If it's FDG PET
• 29:34positive, it's probably a poorly
• 29:36differentiated
• 29:37carcinoma.
• 29:38And then by morphology, we
• 29:40can also look to see,
• 29:41is there a lower grade
• 29:42component like I just showed
• 29:43you? Is there a non
• 29:45neuroendocrine component like adenocarcinoma,
• 29:47which would mean that the
• 29:49neuroendocrine
• 29:50is
• 29:51poorly differentiated?
• 29:53And then there are molecular
• 29:54clues.
• 29:56This is for pancreas, but
• 29:57the same thing is true
• 29:58for other anatomic sites. There
• 30:00are different types of mutations
• 30:01in the well differentiated and
• 30:03poorly differentiated,
• 30:04and this persists
• 30:06in general as the tumors
• 30:07become higher grade.
• 30:08So if you have a
• 30:09g three net
• 30:11that lacks RB and p
• 30:13fifty three, that's reassuring that
• 30:15it's still a net. If
• 30:17it has those mutations,
• 30:19it probably is a poorly
• 30:20differentiated neuroendocrine carcinoma.
• 30:23So this can be done
• 30:24now to help classify these
• 30:26high grade tumors which hopefully
• 30:27will point to appropriate therapy.
• 30:31So to summarize what we've
• 30:32discussed,
• 30:33important points here is that
• 30:35neuroendocrine neoplasms as a general
• 30:37category can be either poorly
• 30:38different I'm sorry, well differentiated
• 30:40NETs
• 30:41or poorly differentiated
• 30:43neuroendocrine
• 30:44carcinomas.
• 30:46The neuroendocrine differentiation
• 30:47should be demonstrated by immuno
• 30:49labeling.
• 30:51Inappropriate pathological
• 30:53context, meaning don't stain things
• 30:54that don't look like neuroendocrine
• 30:56tumors in the first place.
• 30:59Grading
• 31:00is based on a three
• 31:02tier scheme, perhaps with subgrades
• 31:04for g two based on
• 31:05the t sixty seven and
• 31:07the lactamics.
• 31:08Whereas,
• 31:09neuroendocrine carcinomas
• 31:11are hard to read by
• 31:12definition.
• 31:13The grade can be a
• 31:14dynamic feature of NETs, so
• 31:16you have to keep track
• 31:17of it as these tumors
• 31:18progress.
• 31:19And finally, we have some
• 31:20ways to tell g three
• 31:22NETs from
• 31:23neuroendocrine carcinomas, but they can
• 31:25be quite challenging.
• 31:27So with that, I will,
• 31:29stop and pass the, pass
• 31:31the baton to our next
• 31:33speaker.
• 31:34Great. Thanks, doctor Klimstra.
• 31:37We'll have doctor Kuntzmann go
• 31:39next.
• 31:44Good evening, everybody.
• 31:52All coming through?
• 31:58Pam, you're muted, but you
• 31:59looked like you said yes.
• 32:00Yes. Sorry about that.
• 32:02No problem.
• 32:04Alright. Good evening, everybody. My
• 32:05name is John Kunstmann. I'm
• 32:06one of the surgical oncologists
• 32:07at Yale.
• 32:09And, you know, I co
• 32:10lead the neuroendocrine tumor from
• 32:12a program here with doctor
• 32:14Coons from a surgeon's perspective.
• 32:16So there'd be a few
• 32:17things that I'll repeat that
• 32:18are particularly pertinent to the
• 32:19surgical management
• 32:21that, the excellent pathologic and
• 32:23general medical overview,
• 32:25already presented.
• 32:28But we'll try and move
• 32:28along fairly quickly.
• 32:30For my portion of the
• 32:32discussion,
• 32:32I really wanna convey what
• 32:34are the indications for surgery,
• 32:36and kind of emphasizing that
• 32:38each case really does need
• 32:39an individualized approach,
• 32:41and what surgeries we can
• 32:43do. We're kinda stick again
• 32:45in the interest of time
• 32:46to pancreatic,
• 32:48and intestinal neuroendocrine tumors,
• 32:51and, skip over neuroendocrine carcinomas
• 32:54and some of the higher
• 32:54grade lesions,
• 32:57for which surgery has a
• 32:58pretty minimal role anyways,
• 33:01and then also briefly talk
• 33:02about metastatic disease.
• 33:04So, again, just to reiterate,
• 33:05I'm gonna start with pancreatic
• 33:07neuroendocrine tumors.
• 33:09From a peanut standpoint, again,
• 33:11you know, historically, many were
• 33:13diagnosed because of hormone oversecretion.
• 33:16Those hormones that,
• 33:18are oversecreted by functional tumors
• 33:20can correlate with more or
• 33:21less aggressive disease.
• 33:23But nowadays,
• 33:24many are found in the
• 33:26most are found in the
• 33:27nonfunctional
• 33:28setting,
• 33:29and up to half the
• 33:30diagnoses are completely incidental,
• 33:32usually imaging findings. When they
• 33:34are symptomatic,
• 33:36generally, it's larger tumors, and
• 33:38it's caused those symptoms are
• 33:39caused by it pushing on
• 33:40something,
• 33:42GI tract or bile ducts
• 33:44or something like that that
• 33:46leads to the presentation.
• 33:49You know, staging, again, already
• 33:50nicely summarized,
• 33:52by doctor Koons. But, you
• 33:53know,
• 33:54the biggest thing from a
• 33:55surgeon's perspective, of course,
• 33:58is understanding whether it's localized
• 34:00or metastatic disease.
• 34:02Regardless of stage, there are
• 34:04a number of options that
• 34:05exist as already discussed, and
• 34:07surgery is appropriate, in some
• 34:08cases, a stage four disease.
• 34:09But that,
• 34:11surgical
• 34:12treatment generally,
• 34:14the initial approach is gonna
• 34:15be surgery only in localized
• 34:17disease.
• 34:18For localized pancreatic or endocrine
• 34:20tumor surgery is the primary
• 34:21treatment modality.
• 34:23As, you know, general rules,
• 34:25functional peanuts,
• 34:27are almost all good surgical
• 34:29candidates simply because,
• 34:31oversecretion of hormones leads to,
• 34:33you know, syndromic disease.
• 34:37And nonfunctional
• 34:38peanuts that are causing some
• 34:39of those compressive symptoms like
• 34:41jaundice or,
• 34:43gastric outlet obstruction, etcetera.
• 34:45We'll talk a little bit
• 34:47down the road,
• 34:48as I progress for locally
• 34:50advanced tumors,
• 34:51that could be considered unresectable.
• 34:54As briefly mentioned, you know,
• 34:55that that definition is changing.
• 34:57I think both
• 34:59improvements
• 35:00in surgical techniques, new approaches
• 35:02we've devised to operating in
• 35:04the case of nonmetastatic,
• 35:06especially pancreatic neuroendocrine tumors, has
• 35:08changed the definition of what's
• 35:09unresectable.
• 35:10Moreover, we now have effective
• 35:12systemic agents that can downstage
• 35:14some of these patients,
• 35:16to
• 35:16cases.
• 35:18I'm just gonna briefly mention,
• 35:19you know, peanuts that are
• 35:20associated with genetic syndromes most
• 35:22commonly, MEN1, but of course,
• 35:24others like tuberous sclerosis, etcetera.
• 35:27You know, in those cases,
• 35:28it's truly
• 35:29a multidisciplinary
• 35:30disease where decisions on when
• 35:32to operate have to take
• 35:33into account a number of
• 35:34other factors like patient age,
• 35:36their endocrinology,
• 35:38status,
• 35:39and what the future expectations
• 35:41are.
• 35:43So, again, talking about totally
• 35:45incidental
• 35:46peanuts, which is what we
• 35:47see most often nowadays,
• 35:50as nicely summarized by doctor
• 35:52Klimstra, we wanna know as
• 35:53much as we can about
• 35:54how aggressive
• 35:55that disease is from a
• 35:56pathologic standpoint, k sixty seven
• 35:58being particularly important.
• 36:00But I'd also like to
• 36:01highlight regional spread.
• 36:03You know, these are frequently
• 36:05lymphotropic
• 36:06tumors.
• 36:07And then, of course, the
• 36:08tumor size relates to its
• 36:09resectability.
• 36:11Even for small low key
• 36:13sixty seven peanuts,
• 36:14they all have the potential
• 36:16to grow and spread. It's
• 36:17just some are are very
• 36:18unlikely to do so.
• 36:20One of the frequent things
• 36:21that occurs in in my
• 36:23clinic is a patient will
• 36:24come to us and, you
• 36:25know, they have a peanut,
• 36:26and
• 36:28they've been told that they
• 36:30do not have cancer,
• 36:32you know, which is always
• 36:33difficult to walk that back.
• 36:34And I and I totally
• 36:35understand
• 36:36the fact that they have
• 36:37a pancreatic lesion and it's
• 36:39not adenocarcinoma.
• 36:40It's a neuroendocrine tumor, obviously,
• 36:42that sets a completely different
• 36:43conversation.
• 36:46But oftentimes, we do have
• 36:47to characterize to, you know,
• 36:49recharacterize these lesions to patients
• 36:51if they've gotten the notion
• 36:52that, you know, there's not
• 36:53much to worry about.
• 36:55That being said, you know,
• 36:57as I alluded to, there
• 36:58are a number of tumors
• 36:59that are
• 37:01so unlikely to spread that
• 37:02observation
• 37:03is a potential management strategy.
• 37:05So this has been floating
• 37:07about for about ten or
• 37:08fifteen years now,
• 37:09looking at a few studies.
• 37:10You know, one of the
• 37:11earliest studies came out of
• 37:12the clinic, you know, Mayo
• 37:13Clinic fifteen years ago, and
• 37:16that observed that over a
• 37:17long period of time,
• 37:19patients with small asymptomatic p
• 37:21nets that were nonfunctional
• 37:23had the same survivorship as
• 37:24patients that underwent an initial
• 37:25resection.
• 37:27This study was contradicted by
• 37:29a study out of Duke
• 37:31that suggested patients that were
• 37:33observed
• 37:34did much worse.
• 37:36That being said, that was
• 37:37a database study. It was
• 37:38retrospective. It was subject to
• 37:39a lot of selection bias.
• 37:42You know, a study performed
• 37:43here at Yale about the
• 37:44same time,
• 37:46it did show that patients
• 37:47with small neuroendocrine tumors that
• 37:49were observed that later underwent
• 37:50resection
• 37:51did have a very, very
• 37:52favorable ten year survival.
• 37:54Although some did have, you
• 37:56know, regional spread at the
• 37:57time of resection.
• 37:59And then a large study
• 38:00also out of, MSK
• 38:02showed that if patients are
• 38:04watched well, you know, about
• 38:05a quarter of them will
• 38:06convert to resection over a
• 38:07five year period. But, again,
• 38:09the survival is the same.
• 38:12Now what this boils down
• 38:14to, and there's been a
• 38:14number of other studies over
• 38:16the years that, mostly fall
• 38:17on the side that there
• 38:18is a population in whom
• 38:19it's safe to avoid surgery
• 38:21in.
• 38:22So the answer, I think,
• 38:23to the question posed here
• 38:25that some peanuts may be
• 38:26safe to observe is yes.
• 38:28Who are those candidates? Again,
• 38:30has to be nonfunctioning tumor,
• 38:31has to be asymptomatic.
• 38:34You know, this is a
• 38:34little controversial, but essentially,
• 38:37we here at Yale really
• 38:38believe that if there's already
• 38:39some evidence of regional spread
• 38:41to lymph node involvement,
• 38:43regardless of any other characteristic
• 38:45that's an indication for surgery,
• 38:47we need to understand that
• 38:48it's well differentiated,
• 38:50preferably small. The incidence of
• 38:52both regional and metastatic spread
• 38:54starts to rise precipitously over
• 38:56two centimeters.
• 38:57And then I think something
• 38:58we often forget about but
• 39:00is critically important, is the
• 39:01patient has to be amenable
• 39:03to follow-up.
• 39:04If this is somebody who
• 39:05either
• 39:06through, you know, anxiety will
• 39:08be unable to tolerate a
• 39:10surveillance based strategy,
• 39:12that's a genuine symptom as
• 39:13well, and sometimes that is
• 39:14an indication for surgery.
• 39:16Also, if it's a patient
• 39:17that's not going to comply
• 39:18with serial examinations
• 39:20and follow-up,
• 39:21you know, that may tilt
• 39:22you towards surgery,
• 39:24at an earlier phase.
• 39:26So if we've made the
• 39:27decision to go to surgery,
• 39:29what are our goals? Obviously,
• 39:30we wanna maximize the local
• 39:32control with a margin negative
• 39:33resection.
• 39:35Regional lymphadenectomy
• 39:36is considered standard of care.
• 39:37We wanna improve and prolong
• 39:39people's survivorship,
• 39:40and then hopefully improve their
• 39:42quality of life, particularly in
• 39:43the case of hormonal syndrome
• 39:45or in metastatic disease.
• 39:49Secondary, but almost as important
• 39:50is we wanna minimize the
• 39:52complications and the morbidity of
• 39:54having a pancreatic resection.
• 39:56So
• 39:56in the short term, you
• 39:57know, that generally consists of
• 39:59infection related complications or pancreatic
• 40:01fistula.
• 40:02But in the long term,
• 40:03you know, having some of
• 40:05the pancreas resected can lead
• 40:06to diabetes or exocrine insufficiency.
• 40:08So, you know, a big
• 40:09part of our pancreatic surgery
• 40:11program here is the multidisciplinary
• 40:13care from both,
• 40:14nutritionists
• 40:15and also,
• 40:17the endocrine team. So
• 40:19surgical approach and what kind
• 40:21of procedure we do is
• 40:22really dictated by what lymph
• 40:23nodes need to be retrieved,
• 40:24where is the tumor, and
• 40:26what's the patient's tolerance for
• 40:28an operation.
• 40:30You know, less is oftentimes
• 40:31more with regards to surgery,
• 40:33but in this case,
• 40:34the tumor itself generally tells
• 40:36us what the right operation
• 40:37to do.
• 40:39You know, enucleation
• 40:40is a wonderful parenchymal sparing
• 40:42technique.
• 40:43The issues with enucleation
• 40:45are a higher rate
• 40:47of pancreatic fistula and no
• 40:48lymph node retrieval, but it's
• 40:50the ideal operation for more
• 40:51indolent tumors.
• 40:53Frequently, you know, this is
• 40:54for insulinoma.
• 40:56You can see a case
• 40:56there that we did a
• 40:57few years ago. Really nicely
• 40:57circumscribed tumor. We don't need
• 40:58large margins. You know, this
• 40:58is a
• 41:00curative tumor. We don't need
• 41:02large margins. You know, this
• 41:03is a curative operation for
• 41:05most patients with insulinoma.
• 41:09For non insulinomas, essentially, where
• 41:11enucleation is not a good
• 41:13approach.
• 41:14Again, the tumor location is
• 41:15key.
• 41:16Tumors located in the pancreatic
• 41:18head oftentimes undergo Whipple procedure.
• 41:20Tumors located in the neck
• 41:22or body oftentimes undergo a
• 41:23distal pancreatectomy.
• 41:25I'm oversimplifying
• 41:26there. We do do a
• 41:27central pancreatectomy
• 41:29in some patients for tumors
• 41:30that are really directly in
• 41:31the neck. That's a good
• 41:33parenchymal sparing approach in many
• 41:34patients.
• 41:35Also, splenic preservation is a
• 41:37possibility if we think the
• 41:39chance for lymph node spread
• 41:40is quite low.
• 41:43You know, many patients and
• 41:45many referring providers
• 41:47still remember that old adage
• 41:48you may have heard in
• 41:49medical school about, you know,
• 41:51how awful pancreatic surgery is.
• 41:52You know, that is not
• 41:53true anymore.
• 41:54Pancreatic surgery is very safe,
• 41:56especially in large volume experience
• 41:58centers,
• 41:59and improperly
• 42:01selected patients.
• 42:02There's a very linear
• 42:04relationship between volume and experience
• 42:07with regards to surgical outcomes
• 42:08and quality.
• 42:11Some operations, that's very surgeon
• 42:13dependent.
• 42:14For a pancreatectomy,
• 42:15it is institution dependent
• 42:17because there's much more than
• 42:18just surgical expertise that goes
• 42:20into outcomes for this. Anesthesia,
• 42:22ICU care, interventional radiology,
• 42:24pathology, medical oncology colleagues,
• 42:27all all critical.
• 42:29Just to,
• 42:30look at at our numbers
• 42:31here at Yale, you know,
• 42:32we do almost a hundred
• 42:33pancreatectomies
• 42:34a year.
• 42:36Many of these are done
• 42:36in a minimally invasive fashion.
• 42:39I'm just putting up some
• 42:40some statistics
• 42:41here and how they relate
• 42:42to us. You know, at
• 42:43Yale,
• 42:44our mortality
• 42:46is much lower than the
• 42:47national average. Our complication rate
• 42:49is better than the ninetieth
• 42:50percentile nationally for most of
• 42:52the morbidity
• 42:53that occurs, and our length
• 42:54of stay is also better
• 42:55than the national average.
• 42:57So I think we do
• 42:58it quite well here. Just
• 42:59to discuss briefly, you know,
• 43:01for a distal pancreatectomy,
• 43:03again, some tumors, mainly those
• 43:05that are locally advanced
• 43:07with vascular involvement,
• 43:09we still perform through an
• 43:10open approach,
• 43:11but more often, it's a
• 43:12minimally invasive approach, either laparoscopic
• 43:15or robot assisted.
• 43:17The decision to perform a
• 43:18splenectomy is on a case
• 43:19by case basis.
• 43:21That being said, for most
• 43:22of these tumors, since we
• 43:24wait to perform the operation,
• 43:26in other words, we observe
• 43:27tumors that are,
• 43:29less worrisome and less likely
• 43:31to spread, many times by
• 43:32the time they do go
• 43:33to surgery for a PNET,
• 43:36splenectomy is indicated.
• 43:38And as I mentioned, central
• 43:39pancreatectomies
• 43:40are a good option for
• 43:41some patients if we're trying
• 43:42to maximize parenchymal preservation.
• 43:45I couldn't resist. I had
• 43:46to put one or two
• 43:47surgical photos. You know, here's
• 43:48a a video,
• 43:50of a distal pancreatectomy
• 43:51being done laparoscopically,
• 43:54somewhat sped up. We're entering
• 43:56the lesser sac here. The
• 43:57stomach's being lifted up. You
• 43:59can see the tumor right
• 44:00there with the white arrow
• 44:01on it,
• 44:02you know, kind of pointing
• 44:03to the tumor in the
• 44:04mid body.
• 44:06We're retracting some areas around
• 44:08the pancreas, moving all of
• 44:09the stomach, colon, retroperitoneum
• 44:11out of our way.
• 44:13We're creating that tunnel underneath
• 44:15to mobilize the pancreas itself.
• 44:17You can see here's the
• 44:18pink, the splenic artery being
• 44:20divided after it's dissected.
• 44:22We then do the same
• 44:23thing with the splenic vein.
• 44:25In this case, both are
• 44:26being divided with surgical staplers,
• 44:28and then we divide the
• 44:29pancreas itself,
• 44:31and remove the specimen and
• 44:32send it off to doctor
• 44:33Klimstra and his pals to,
• 44:35to examine.
• 44:38Anyways, there it's retrieved in
• 44:39the in the specimen bag.
• 44:41So with regards to splenic
• 44:42preservation,
• 44:44we here do not perform
• 44:48splenic preservation without preserving,
• 44:51both the inflow and outflow.
• 44:53It is possible to be
• 44:54done without that, but this
• 44:56is how we do it
• 44:56at Yale. The outcomes are
• 44:58so much better if you
• 44:59do it that way. You
• 45:00can see the anatomy there
• 45:01and how it looks after
• 45:02a minimally invasive,
• 45:03spleen preserving,
• 45:05distal pancreatectomy.
• 45:07So just to summarize,
• 45:10you know, what are the
• 45:11goals from a peanut standpoint?
• 45:12Obviously, we wanna control the
• 45:14disease, and we wanna have
• 45:15minimal,
• 45:16morbidity.
• 45:17The operations to remove the
• 45:19peanut is really driven by
• 45:20the tumor itself, and the
• 45:21choice of operation
• 45:23kind of is dictated by
• 45:24the location of the tumor.
• 45:25And the outcomes,
• 45:27are excellent when done in
• 45:28high volume centers.
• 45:30Switching gears to surgery for
• 45:32enteric or intestinal neuroendocrine tumors,
• 45:35You know, I'm really gonna
• 45:36focus on midgut tumors. Not
• 45:38only are they quite common,
• 45:40you know, stomach neuroendocrine tumors
• 45:41are a little bit of
• 45:43a
• 45:44topic of discussion to themselves.
• 45:46But as pointed out, and
• 45:47I'm not gonna belabor the
• 45:48point, the incidence is rising.
• 45:50You know, mid gut tumors,
• 45:53that are neuroendocrine
• 45:54differentiation are the most common
• 45:56small bowel tumors for at
• 45:57least twenty five years now,
• 45:58and these patients do sometimes
• 46:00present with abdominal pain oftentimes
• 46:03due to obstruction.
• 46:04You
• 46:05know, that's either from the
• 46:06primary tumor or a reaction
• 46:08to a mesenteric
• 46:09MET,
• 46:10of the neuroendocrine tumor that's
• 46:12causing an obstruction.
• 46:13There's an OR photo here.
• 46:14Again, just to be warned,
• 46:16here's an intussusception
• 46:17that's occurring in the small
• 46:18bowel,
• 46:20secondary to the primary neuroendocrine
• 46:22tumor.
• 46:23And you can see why
• 46:23that would cause a a
• 46:24bowel obstruction.
• 46:26The remainder are diagnosed incidentally.
• 46:28Now, again, these are very
• 46:29lymphotropic tumors, so oftentimes the
• 46:32way they're diagnosed, because the
• 46:33primary tumors are quite small,
• 46:36is a regional metastasis to
• 46:37the mesentery,
• 46:39which can grow to be
• 46:40quite large and be calcified
• 46:41and stand out on a
• 46:42scan even if it's a
• 46:43completely incidental finding.
• 46:45Same goals with regards to
• 46:47staging. Oftentimes, biopsies are not
• 46:49possible,
• 46:50but, frankly, oftentimes, they're not
• 46:52necessary.
• 46:53It is helpful if you
• 46:55suspect a neuroendocrine carcinoma.
• 46:57As mentioned by doctor Klimster,
• 46:59the role for surgery in
• 46:59those is is fairly limited.
• 47:02But a good high quality
• 47:04cross sectional imaging scan is
• 47:05critical to determine resectability
• 47:07and the degree of spread.
• 47:10You know, this is a
• 47:11scan of a patient of
• 47:12mine that was discovered incidentally
• 47:14where you can see just
• 47:15a small mesenteric
• 47:16nodule.
• 47:18This was performed on a
• 47:19CAT scan
• 47:20well before diagnosis,
• 47:22but over time, you know,
• 47:23looking back with retrospect, that
• 47:25was there, but it wasn't
• 47:26called. And then over time,
• 47:27it progressed into this large
• 47:28mesenteric mass with calcification.
• 47:32You know? And and when
• 47:34she got to me, this
• 47:34is how it looked,
• 47:36some years later. We were
• 47:37able to resect her, you
• 47:39know, doing very well at
• 47:40this point. That being said,
• 47:42oncologic goals, very similar in
• 47:44the pancreas. You know? We
• 47:45wanna clear the primary tumor.
• 47:48We have to keep in
• 47:48mind that a third of
• 47:49these cases have multifocal disease.
• 47:53So if a minimally invasive
• 47:54approach is thought to be
• 47:55appropriate, one thing we crucially
• 47:57must do as neuroendocrine
• 47:59surgeons
• 48:00is look at the entire
• 48:01bowel.
• 48:02That's possible in a minimally
• 48:04invasive way, you know, with
• 48:05some of the techniques we
• 48:06have now.
• 48:07But we always have to
• 48:08look for that multifocal disease,
• 48:09and then we have to
• 48:10be very mindful of removing
• 48:12the entire mesenteric nodal packet,
• 48:15not just the big calcified
• 48:16nodule, but all of the
• 48:17lymph nodes in the area
• 48:18because they are possible sites
• 48:20of of persistent disease.
• 48:22In particular,
• 48:24many of these patients that
• 48:25present with bowel obstructions, both
• 48:27primarily and recurrent,
• 48:29an operation can really improve
• 48:30their quality of life even
• 48:32if it's not curative.
• 48:34With regards to minimizing morbidity,
• 48:36the
• 48:37length of gut that remains
• 48:39is the critically important,
• 48:43step in these operations, especially
• 48:45in patients that have had
• 48:46multiple operations.
• 48:48You know, personally, I have
• 48:49been the surgeon for a
• 48:50patient who was their eleventh
• 48:51operation,
• 48:53after ten operations at other
• 48:55institutions.
• 48:57In those cases, you know,
• 48:58length of guts, ischemia become
• 49:01really, really important,
• 49:02factors in term in terms
• 49:04of planning the surgery.
• 49:05All of these patients, I
• 49:06think, should get a cholecystectomy
• 49:08because many of them will
• 49:09get a somatostatin analog at
• 49:11some point during their during
• 49:13the course of their care.
• 49:15Again, a few surgical photos
• 49:17just to give you a
• 49:18quick heads up, not to
• 49:19surprise you.
• 49:20Here's a case with multifocal
• 49:22tumors marked with the blue
• 49:24arrows on the left so
• 49:25you can see what I'm
• 49:26talking about. You know, many
• 49:27of these are not visible
• 49:28on imaging.
• 49:30That's getting better now, thanks
• 49:32to doctor Spilberg and the
• 49:33functional imaging they can perform.
• 49:35Here you can see a
• 49:36number of nodules in the
• 49:37mesentery on the right. Again,
• 49:39if you don't
• 49:40look for them, you won't
• 49:41find them.
• 49:42And so that entire mesenteric
• 49:44packet needs to be removed
• 49:45to clear this disease.
• 49:47You know, here's that picture
• 49:48again just to show you
• 49:49what it looks like after
• 49:51clearing all of those vessels.
• 49:54Never mind. Photo went away,
• 49:56so we'll just move along.
• 49:58I wanna touch briefly on
• 50:00surgery and metastatic disease.
• 50:03Again, the indications for that
• 50:05from a cancer directed standpoint.
• 50:08For patients with large volume
• 50:10disease and hormonal oversecretion, whether
• 50:12that's pancreatic
• 50:13or from an intestinal neuroendocrine
• 50:15tumor,
• 50:17debulking that disease can sometimes
• 50:19improve their quality of life
• 50:21by reducing hormone oversecretion.
• 50:24With regards to actual tumor
• 50:26control,
• 50:27debulking seems to have a
• 50:30survivorship
• 50:31benefit.
• 50:32The degree of debulking necessary
• 50:34and the amount of survivorship
• 50:36improvement
• 50:37is highly variable depending on
• 50:39the study that is read.
• 50:40Generally, we prefer to debulk
• 50:42at least eighty to ninety
• 50:43percent, but seventy percent is
• 50:45sort of considered the limit
• 50:47lower limit of what might
• 50:48be helpful.
• 50:50It is important to note
• 50:51that especially in well differentiated,
• 50:53grade one or grade two
• 50:55disease,
• 50:56you can operate on people
• 50:57from a metastatic standpoint with
• 50:59curative intent if you can
• 51:00clear all of the disease.
• 51:03There are also situations where
• 51:05palliation is very important,
• 51:06either for obstruction,
• 51:08biliary bypasses, etcetera.
• 51:10Lower grades will do better,
• 51:12but this always needs to
• 51:14be a decision taken with
• 51:15the entire team.
• 51:18So just deliver a section.
• 51:20Just to summarize,
• 51:21again,
• 51:22a theme of my entire
• 51:23talk is that decisions for
• 51:24surgery really need to happen
• 51:25with the entire team.
• 51:27Patients with resected tumors do
• 51:29very, very well both in
• 51:31pancreatic and small bowel neuroendocrine
• 51:33tumors. With small bowel disease,
• 51:35it's oftentimes better to go
• 51:36in a little earlier rather
• 51:37than a little later,
• 51:39because it reduces later complications.
• 51:42I I think future directions
• 51:44that we're really excited about,
• 51:45I think, you know, Pam
• 51:46alluded to this a little
• 51:47bit. You know, neoadjuvant approaches,
• 51:49there's a number of trials
• 51:50that are now investigating this,
• 51:52both cytotoxic therapies
• 51:54and PRRT.
• 51:55Really, really, really exciting, from
• 51:57a surgical perspective.
• 51:59Also, the molecular
• 52:00guidance that we can get
• 52:02from some of the new
• 52:02pathologic and genetic testings,
• 52:05and we're looking forward to
• 52:06when we can sometimes use
• 52:07these technologies in the operating
• 52:09room too.
• 52:10So I'll stop there. These
• 52:11are my partners as well
• 52:12as a number of folks
• 52:13that have done research in
• 52:14the NET area or surgical
• 52:16oncology area.
• 52:17And I'm happy to stay
• 52:18on for questions at the
• 52:20end.
• 52:22Thank you, John. That was
• 52:24great.
• 52:25So okay. Doctor Spilberg is
• 52:27gonna help us wrap up
• 52:28here with her talk on
• 52:30theranostics.
• 52:40One second.
• 52:44Is it on presentation
• 52:46mode? Yes. Looks great.
• 52:48Thanks.
• 52:50Good evening. Thank you so
• 52:51much for the kind invitation
• 52:53to be here tonight.
• 52:55Thanks everyone for,
• 52:58coming to watch this. I'm
• 53:00gonna talk about net ternostics
• 53:02and,
• 53:03this is really the work
• 53:04of
• 53:05an entire net team together,
• 53:09to make some of these
• 53:10work.
• 53:11With that I have no
• 53:12relevant
• 53:13disclosures.
• 53:14So theranostics
• 53:15is the contraction of two
• 53:17words therapy and diagnostics
• 53:20which use diagnostics.
• 53:22And why is imaging so
• 53:24important?
• 53:25We can only treat what
• 53:27we can see. If you
• 53:28just looked at this,
• 53:30chest c t and looked
• 53:32at the bone structures,
• 53:34If I was reading this,
• 53:35I would have read this
• 53:36as normal.
• 53:38However, this patient had a
• 53:40DOTATATE PET CT
• 53:42and you can see that
• 53:44all these black areas and
• 53:46these
• 53:47areas of increased color in
• 53:49the spine here are areas
• 53:51of metastatic
• 53:52disease.
• 53:53So without this type of
• 53:55technique there is no way
• 53:56you would really see these
• 53:58lesions.
• 54:00Sometimes
• 54:01MRI can,
• 54:03depict these but not always
• 54:05this is routinely done or
• 54:07sometimes the alterations are so
• 54:10diffused that even on MRI
• 54:12sometimes
• 54:13is difficult. So really images
• 54:15imaging drives management and that's
• 54:17why
• 54:18this is so important when
• 54:19we talk ternostics.
• 54:21And why is it challenging
• 54:23to image nets?
• 54:25Nets are a bucket. They're
• 54:27a very heterogeneous
• 54:29group.
• 54:29And then the imaging presentation
• 54:31will
• 54:33go along with that. So
• 54:34it's not a single imaging
• 54:36presentation.
• 54:37It's not a single appearance.
• 54:39And also sometimes the tumor
• 54:41sizes are very small,
• 54:43which are below the resolution
• 54:45of some modalities.
• 54:46And it really requires
• 54:48integration
• 54:49of multimodality
• 54:50imaging, meaning whoever is interpreting
• 54:53the study
• 54:54needs to understand
• 54:55all the imaging done previously
• 54:58and up to that point
• 54:59and make a history
• 55:01of all the findings together.
• 55:04So not always that comes
• 55:06together
• 55:07in,
• 55:09in a very easy way.
• 55:11So it really creates a
• 55:13challenge to bringing things all
• 55:14together
• 55:16to make these diagnosis
• 55:17and interpretations.
• 55:20Types of imaging modalities,
• 55:22we talk we talk generally
• 55:24about
• 55:26CT,
• 55:27MRI, and ultrasound
• 55:29as conventional or anatomic imaging,
• 55:32which is a type of
• 55:33imaging where we're looking for
• 55:34the morphology
• 55:35appear or the appearance of
• 55:38the organs and
• 55:40structures
• 55:41or we talk about molecular
• 55:43imaging,
• 55:44which
• 55:45primarily we're talking about PET
• 55:46CT
• 55:47and maybe MIBG scintigraphy,
• 55:51which is,
• 55:53less than nowadays for
• 55:56NETs, however, sometimes can be
• 55:57useful.
• 55:58And when we talk about
• 56:00molecular
• 56:00imaging,
• 56:01predominantly,
• 56:02we're talking about PET.
• 56:04PET is positive on emission
• 56:06tomography,
• 56:07and this is the
• 56:09PET image. It's a black
• 56:10and white low resolution image.
• 56:12And at the same time,
• 56:14we acquire a CT.
• 56:16And the PET image is
• 56:18overlaid over the CT and
• 56:20creates this color coded image
• 56:22here
• 56:23that people like looking.
• 56:25And I think it makes
• 56:26it easier to understand
• 56:28what these,
• 56:30two datasets
• 56:31mean together. But we're really,
• 56:34when we're interpreting
• 56:36these, we're looking at two
• 56:38datasets and the superposition
• 56:40of them to really understand
• 56:42what's happening.
• 56:43And then molecular imaging is
• 56:45really about
• 56:47look into the small details
• 56:51of what is happening at
• 56:52the molecular and cellular level.
• 56:54What are the processes
• 56:56which are happening
• 56:58in,
• 56:59a very specific location?
• 57:01And there are different strategies
• 57:04for molecular imaging.
• 57:07Odor,
• 57:08which was initially
• 57:10how molecular imaging was
• 57:14started,
• 57:15we did metabolic metabolism
• 57:18assessment
• 57:18with a glucose
• 57:20analog,
• 57:21FDG.
• 57:22And then
• 57:23for and then a little
• 57:25after,
• 57:26somatostatin
• 57:27receptor
• 57:28expression
• 57:29became also a target for
• 57:31imaging. And because NETs
• 57:33overexpress
• 57:34somatostatin
• 57:37receptors,
• 57:37most commonly type two,
• 57:40this is a good target
• 57:42for imaging these
• 57:45tumors.
• 57:46So when we're talking about
• 57:48this assessment,
• 57:50we have a couple of
• 57:52tracers or radio traces,
• 57:54radionuclides.
• 57:56These are very similar words
• 57:57that are
• 57:59almost interchangeably
• 58:00used.
• 58:02So you have a target,
• 58:05you have a peptide, you
• 58:06have a linker that links
• 58:08these two.
• 58:09And
• 58:11when you look here, the
• 58:13radionuclide
• 58:14can be exchanged
• 58:15into an imaging version or
• 58:17a treatment version.
• 58:19And that's why
• 58:21theranostics
• 58:22is so
• 58:24impressive because for the first
• 58:25time, you're really
• 58:27imaging the exact location where
• 58:29you're delivering your drug. You
• 58:31know
• 58:32the place that you image
• 58:35is the exact same place
• 58:37that you deliver
• 58:38your
• 58:39treatment.
• 58:40So when you're looking at
• 58:42assessment for more aggressive
• 58:44tumors,
• 58:46they typically lose the somatostatin
• 58:48receptor expression,
• 58:50and they become more hypermetabolic,
• 58:53and they're better assessed with
• 58:55FTG.
• 58:57FDG.
• 58:58And for example, in this
• 59:00case here, this is the
• 59:01same patient,
• 59:03and this is an FDG
• 59:05PET and this is a
• 59:06DOTATATE, which is a somatostatin
• 59:08targeted
• 59:09PET.
• 59:10And when you're looking at
• 59:12these,
• 59:13these are basically
• 59:14images of in vivo
• 59:17expression
• 59:18of somatostatin
• 59:19receptors.
• 59:20And this is the only
• 59:22way you can actually
• 59:24image the entire disease burden
• 59:27without having to biopsy every
• 59:29single site.
• 59:30The you're imaging the heterogeneity
• 59:33of the tumor
• 59:34with,
• 59:36inside the patient without having
• 59:38to ever
• 59:40really sample
• 59:41these locations. So when you're
• 59:43doing
• 59:44what we call dual PET
• 59:46or multiplex
• 59:47PET, you're really evaluating
• 59:50the
• 59:52the extension of disease and
• 59:54the heterogeneity
• 59:56of,
• 59:58that disease.
• 01:00:01So again, when you're doing
• 01:00:03targeted therapy, you really want
• 01:00:05to make sure that you're
• 01:00:06treating
• 01:00:07a target
• 01:00:08that it's really the drive
• 01:00:10of the progression. Because as
• 01:00:12nets are very heterogeneous,
• 01:00:14you really want to treat
• 01:00:16whatever is
• 01:00:19problematic
• 01:00:19for the patient
• 01:00:21and,
• 01:00:22what's really going to be
• 01:00:24the fastest growing
• 01:00:26side of the disease. So
• 01:00:28how do you evaluate the
• 01:00:29presence of a target without
• 01:00:31sample bias from biopsies? Because
• 01:00:33if you biopsy
• 01:00:35and you have a sample
• 01:00:36bias, how can you understand
• 01:00:39that you're really treating
• 01:00:41the problem of the patient?
• 01:00:42And that's why the PET
• 01:00:43is so important.
• 01:00:46So when we're treating these
• 01:00:48patients, once we identify
• 01:00:50the target,
• 01:00:52the same molecule, the same
• 01:00:54ligand, and the same linker
• 01:00:56are used, and we just
• 01:00:57change the radionuclide.
• 01:00:59And currently, we use a
• 01:01:04radioactive
• 01:01:05particle called lutetium one seventy
• 01:01:07seven, which is a beta
• 01:01:08emitter.
• 01:01:09And the beta emission causes
• 01:01:11single strand DNA damage.
• 01:01:14And when the cell tries
• 01:01:16to replicate, it can't, so
• 01:01:17it dies.
• 01:01:19So that's basically how this
• 01:01:21treatment work.
• 01:01:22So
• 01:01:23the
• 01:01:24approach
• 01:01:25of getting to these treatments
• 01:01:27is really multidisciplinary
• 01:01:29for every single patient.
• 01:01:31We review patients on tumor
• 01:01:32board every week because it's
• 01:01:34really about bringing all the
• 01:01:36information together in the same
• 01:01:38place
• 01:01:39and having everyone
• 01:01:41on the same page.
• 01:01:42Patient selection is critical because
• 01:01:45if you don't have the
• 01:01:46target as the drive of
• 01:01:48the progression,
• 01:01:49then it's pointless to treat
• 01:01:51a specific patient.
• 01:01:53And this is very important
• 01:01:56to understand.
• 01:01:57Once the drug finds the
• 01:01:59target, it binds to the
• 01:02:01cell surface
• 01:02:02and it's internalized.
• 01:02:04And then that's when the
• 01:02:05bad emission happens and it
• 01:02:07causes single strand DNA damage.
• 01:02:10And when we're using this
• 01:02:12type of therapy, we're doing
• 01:02:13four cycles
• 01:02:15approximately
• 01:02:16eight weeks apart and the
• 01:02:18dose of two hundred millicuries
• 01:02:20is fixed
• 01:02:21in general.
• 01:02:23And again, this has emerged
• 01:02:26as a new image, a
• 01:02:27new treatment modality
• 01:02:29just like chemotherapy,
• 01:02:31brachytherapy.
• 01:02:32We're really talking about this
• 01:02:34as a new paradigm.
• 01:02:37So this a patient we
• 01:02:38treated this was the initial
• 01:02:40scan
• 01:02:41then the patient progressed as
• 01:02:43you can see all these
• 01:02:44little dots here in the
• 01:02:45liver
• 01:02:46and here in the protonium
• 01:02:48these are implants
• 01:02:49and then this is when
• 01:02:51we started treating the patient
• 01:02:53and this is
• 01:02:54was at the end of
• 01:02:55treatment.
• 01:02:58Beta
• 01:02:58emission is not
• 01:03:00curative.
• 01:03:01We always have
• 01:03:04we always expect to
• 01:03:07hold progression.
• 01:03:09But there's a lot of,
• 01:03:11research and work being done
• 01:03:13into other types of particles
• 01:03:15or combination therapies
• 01:03:17to
• 01:03:20optimize that.
• 01:03:22And then this is another
• 01:03:24case which I think it's
• 01:03:25interesting. This is a patient
• 01:03:26who had a
• 01:03:28high grade mixed s inner
• 01:03:30cell neuroendocrine carcinoma of the
• 01:03:30pancreas and this is an
• 01:03:30fdg PET and you see
• 01:03:30that
• 01:03:31neuroendocrine carcinoma of the pancreas
• 01:03:33and this is an f
• 01:03:34d g PET and you
• 01:03:35see that the pancreatic lesion
• 01:03:37is hot and then there
• 01:03:39was a growing liver lesion
• 01:03:40on the MRI
• 01:03:42and a DOTATATE was obtained.
• 01:03:44And in the DOTATATE, you
• 01:03:46can see that this lesion
• 01:03:47is cold. There's relative photopenia,
• 01:03:50which means this is high
• 01:03:52grade. There is no point
• 01:03:53in treating this patient
• 01:03:55with,
• 01:03:57radioligand
• 01:03:57therapy as there is no
• 01:03:59binding
• 01:04:00of this in this location.
• 01:04:02This patient went on to
• 01:04:04let have a hepatectomy,
• 01:04:05a left hepatectomy.
• 01:04:07And it's really,
• 01:04:10about
• 01:04:11the
• 01:04:13imaging and the histology. Right?
• 01:04:15The high grade
• 01:04:17generates relative photopenia because of
• 01:04:20the loss of the somatostatin
• 01:04:22receptors. And this patient is
• 01:04:24really better staged with FDGPAT.
• 01:04:27And this patient would never
• 01:04:28be a good candidate for
• 01:04:31lutetium dota date.
• 01:04:33And when we're doing these
• 01:04:34treatments these are highly complex
• 01:04:37so that
• 01:04:38you have an idea this
• 01:04:39is an infusion suite
• 01:04:41because of the high radioactivity.
• 01:04:43All the floors are covered.
• 01:04:45The bathrooms are enclosed in
• 01:04:47the infusion suite
• 01:04:49where there's higher,
• 01:04:50chance of leaking and contamination.
• 01:04:53The floors are all
• 01:04:55extra covered. They are in
• 01:04:57the end of a day
• 01:04:58all essay then evaluated
• 01:05:00for contaminations
• 01:05:01and things like that.
• 01:05:03And this is,
• 01:05:04done for each single patient.
• 01:05:06So there's prep before
• 01:05:09then there's cleaning after,
• 01:05:11each infusion.
• 01:05:13So
• 01:05:14take home points
• 01:05:16for imaging.
• 01:05:18When we're assessing
• 01:05:20patients with well differentiated
• 01:05:22net somatostatin
• 01:05:23receptor
• 01:05:25targeted
• 01:05:26PET is a great
• 01:05:28exam.
• 01:05:30I did not mention
• 01:05:32extend too much into the
• 01:05:33SUVs
• 01:05:35but I wanted to make
• 01:05:36sure that this
• 01:05:38went out because this is
• 01:05:39a very
• 01:05:42common factor of confusion. The
• 01:05:44SUV max, which is a
• 01:05:47semi quantitative
• 01:05:48measurement
• 01:05:49that we use in PET
• 01:05:51when we use an FDG
• 01:05:52for metabolic imaging
• 01:05:54has a meaning,
• 01:05:56which is very different when
• 01:05:57we're looking at density of
• 01:05:59expression of a receptor.
• 01:06:01So because there are variations,
• 01:06:04physiological
• 01:06:05variations between time points,
• 01:06:07changes in s u v
• 01:06:09max for dota data or
• 01:06:11for somatostatin
• 01:06:12targeted
• 01:06:14receptor
• 01:06:14pad between time points are
• 01:06:16unreliable
• 01:06:17for any assessment of response.
• 01:06:21F d g is usually
• 01:06:23great
• 01:06:23for high grade nets
• 01:06:26and to look for heterogeneity
• 01:06:28and
• 01:06:29the imaging modalities
• 01:06:31are always complementary.
• 01:06:33The liver should always be
• 01:06:34evaluated
• 01:06:35separately, especially when you don't
• 01:06:37see a CT correlate
• 01:06:39on the pet or an
• 01:06:41an non contrast CT.
• 01:06:43You should never measure
• 01:06:45the amount of uptake or
• 01:06:47the size of the uptake
• 01:06:48because that's a window setting.
• 01:06:51So if you cannot really
• 01:06:53measure, you need a
• 01:06:55multiphasic
• 01:06:56study,
• 01:06:57either CT or MRI to
• 01:06:59really characterize
• 01:07:00these lesions.
• 01:07:02Otherwise, you're
• 01:07:03not really evaluating
• 01:07:05changes over time. That's really
• 01:07:07key
• 01:07:08and then for treatment you
• 01:07:09really need a multi disciplinary
• 01:07:11team as this is so
• 01:07:13sub specialized
• 01:07:15and things are so individualized
• 01:07:18for each patient
• 01:07:19and again the patient selection
• 01:07:21is really critical
• 01:07:22for identifying
• 01:07:24the patients who are most
• 01:07:26likely to have a response
• 01:07:28as this is an image
• 01:07:29guided therapy this is really
• 01:07:31key.
• 01:07:33And then things that are
• 01:07:35coming down the pipe is
• 01:07:37new types of particles with
• 01:07:40alpha emission or alpha plus
• 01:07:42beta
• 01:07:43combinations
• 01:07:44or synergistic
• 01:07:45approaches with immunotherapy,
• 01:07:47targeted the therapy,
• 01:07:49new targets and new binding
• 01:07:52mechanisms,
• 01:07:53antibodies,
• 01:07:54small molecules,
• 01:07:55and new imaging technology.
• 01:07:57The imaging technologies
• 01:07:59has really advanced with something
• 01:08:01called total body PET
• 01:08:03where you acquire head to
• 01:08:05toe
• 01:08:07simultaneously
• 01:08:08instead of having to acquire
• 01:08:10pieces of the patient at
• 01:08:12the time and that generates
• 01:08:14a much higher resolution,
• 01:08:16faster acquisition and lower radiation.
• 01:08:19Multiplex
• 01:08:20imaging when you're imaging multiple
• 01:08:23targets like FDG
• 01:08:25and,
• 01:08:26for metabolism
• 01:08:28and,
• 01:08:29dote and,
• 01:08:31somatostatin
• 01:08:33targeting
• 01:08:34for
• 01:08:35receptor
• 01:08:36and then personalized those symmetry
• 01:08:39who currently deliver these therapies
• 01:08:41as standard,
• 01:08:43those, but,
• 01:08:45there's a lot of work
• 01:08:46ongoing and to understanding those
• 01:08:48effect.
• 01:08:49So
• 01:08:51thank you very much.
• 01:08:54Thank you, doctor Spielberg.
• 01:08:56Alright. Well, I'll ask my
• 01:08:58my
• 01:09:00co presenters to put on
• 01:09:01their camera, and, we'll certainly
• 01:09:04take some questions. Maybe I'll
• 01:09:06I'll kick us all off.
• 01:09:08So,
• 01:09:09maybe I'll start with doctor
• 01:09:10Klimstra.
• 01:09:12So is there such thing
• 01:09:13as grade evolution in neuroendocrine
• 01:09:16tumors?
• 01:09:16I get patients will ask,
• 01:09:18can my grade change over
• 01:09:19time?
• 01:09:20I know that this has
• 01:09:21been sort of an evolving
• 01:09:22field.
• 01:09:24Definitely. Yeah. There definitely is.
• 01:09:26And and we didn't use
• 01:09:27to understand that partly because
• 01:09:29we didn't see the tumors
• 01:09:30at different time points.
• 01:09:32But but now we do.
• 01:09:34And at Yale, we actually
• 01:09:35rebiopsy these,
• 01:09:37when they start growing. And
• 01:09:39I think,
• 01:09:40you know, doctor Spielberg just
• 01:09:42mentioned the the possibility of
• 01:09:43even,
• 01:09:44acquiring FDG positivity. I think,
• 01:09:47you know,
• 01:09:48we we can we see
• 01:09:49some that go all the
• 01:09:51way from g one to
• 01:09:52g three, and it wouldn't
• 01:09:53shock me if if those
• 01:09:55highly proliferative tumors had,
• 01:09:57an FTG
• 01:09:58positive appearance.
• 01:10:00Yep. Thank you.
• 01:10:03Doctor Kunstman,
• 01:10:05question for you. So we
• 01:10:06have shared a number of
• 01:10:08patients,
• 01:10:09for per I'll give an
• 01:10:10example of a patient with
• 01:10:11a metastatic
• 01:10:12small bowel net who maybe
• 01:10:13still has their primary in
• 01:10:15place.
• 01:10:16When would you like to
• 01:10:17see those patients for consideration
• 01:10:19of resection of their primary?
• 01:10:21Like, when when is it
• 01:10:22too late?
• 01:10:24When do you think, like,
• 01:10:25a surgical referral is appropriate?
• 01:10:29Well, I don't think it's
• 01:10:30ever too late.
• 01:10:31You know, it may not
• 01:10:32be the right decision
• 01:10:34at that point in their
• 01:10:35care.
• 01:10:38But, you know, I think
• 01:10:39one of the things
• 01:10:40that I was hoping to
• 01:10:42convey
• 01:10:43is that for all of
• 01:10:44these patients
• 01:10:45from the get go, a
• 01:10:46multidisciplinary
• 01:10:48approach is really, really important.
• 01:10:51You know, I think
• 01:10:53from a surgeon's standpoint,
• 01:10:55obviously, we want to do
• 01:10:57the right operation.
• 01:10:58But as just alluded to
• 01:11:00by doctor Klimstra, you know,
• 01:11:02many of these patients have
• 01:11:03courses measured in the decades
• 01:11:04now.
• 01:11:06You know,
• 01:11:08each operation gets a little
• 01:11:09bit more challenging
• 01:11:10for
• 01:11:11variety of reasons,
• 01:11:13even in the minimally invasive
• 01:11:14era. So I think it's
• 01:11:15really important to have a
• 01:11:17surgeon involved quite early even
• 01:11:19in the metastatic setting.
• 01:11:22You know, oftentimes, you know,
• 01:11:24just to use your example,
• 01:11:25we we agree, but sometimes
• 01:11:27we don't. And and, you
• 01:11:28know, I think we value
• 01:11:29that diversity,
• 01:11:31of opinions in managing these
• 01:11:32patients because it it can
• 01:11:34be a little bit complicated,
• 01:11:35and it can go on
• 01:11:36again for many, many, many
• 01:11:37years.
• 01:11:38And you have to be
• 01:11:39very thoughtful about when you're
• 01:11:40gonna pull the trigger on
• 01:11:41an operation.
• 01:11:43I certainly prefer to see
• 01:11:45patients
• 01:11:46right away.
• 01:11:48You know, obviously, I can
• 01:11:49only speak for myself, but,
• 01:11:51you know, coming to see
• 01:11:52a surgical oncologist,
• 01:11:54at least at Yale, is
• 01:11:55not like going to the
• 01:11:55barber. You're not going to
• 01:11:57get a haircut.
• 01:11:58You know?
• 01:12:00There are many patients I
• 01:12:01see, and the answer is
• 01:12:03no. It's not right or
• 01:12:04no. Not yet.
• 01:12:05But that being said, I
• 01:12:06think we can't weigh in
• 01:12:07if we're not part of
• 01:12:08the conversation. So so I
• 01:12:09do think an early referral
• 01:12:11is a great idea.
• 01:12:12Generally, patients like that as
• 01:12:14well so they can hear
• 01:12:15maybe about what's coming down
• 01:12:16the pike.
• 01:12:18Yep. Yep. Totally agree.
• 01:12:20Doctor Spielberg,
• 01:12:21what are you most excited
• 01:12:23about in the treatment area
• 01:12:25of theranostics?
• 01:12:27I think that,
• 01:12:30dosimetry
• 01:12:31has not been fully
• 01:12:34used at its
• 01:12:37potential.
• 01:12:38I think we currently do
• 01:12:40standard dosing for all patients
• 01:12:42and I think define those
• 01:12:44symmetry for the audience?
• 01:12:46Sorry. So those symmetry, basically,
• 01:12:48you calculate the burden of
• 01:12:50disease that the patient has.
• 01:12:53And one of the ways
• 01:12:54you can do it is
• 01:12:55you deliver
• 01:12:56one cycle and then you
• 01:12:58image at multiple
• 01:13:00time points after
• 01:13:02you image the drug itself.
• 01:13:05The drug itself
• 01:13:06after you treat
• 01:13:08has gamma emission and you
• 01:13:10can image that.
• 01:13:12So it can actually
• 01:13:13image
• 01:13:14the drug at its target
• 01:13:17and then calculate
• 01:13:20how does that,
• 01:13:22what's the overall burden of
• 01:13:23the patient
• 01:13:25and how does that,
• 01:13:27leave the patient.
• 01:13:28And these things help us
• 01:13:30understand
• 01:13:32what is the patient's own
• 01:13:33kinetics because we have an
• 01:13:35idea from trials of what
• 01:13:37is
• 01:13:38in in general, but all
• 01:13:40patients are different.
• 01:13:42So their renal function, their
• 01:13:44liver function.
• 01:13:45And I think once we
• 01:13:46understand that, we can optimize
• 01:13:49the doses
• 01:13:50to
• 01:13:51more
• 01:13:53give a higher dose upfront
• 01:13:55or a lower dose to
• 01:13:56certain patients,
• 01:13:58which is going to be
• 01:13:59helpful
• 01:14:00into
• 01:14:01optimizing this therapy into,
• 01:14:04more,
• 01:14:07specific for each
• 01:14:09scenario.
• 01:14:11Yep. No. I I agree.
• 01:14:12I'm looking forward to that
• 01:14:13also in terms of tailoring
• 01:14:15treatments.
• 01:14:16I'll maybe mention something that
• 01:14:18I think about in terms
• 01:14:19of systemic treatment.
• 01:14:21You know, I think as
• 01:14:22our patients do better and
• 01:14:24live longer,
• 01:14:25we also wanna be thinking
• 01:14:26about side effects and thinking
• 01:14:28about kind of risk benefit
• 01:14:29ratio.
• 01:14:30For our patients with pancreatic
• 01:14:32neuroendocrine tumors, many of them
• 01:14:34will receive
• 01:14:35both an alkylating agent like
• 01:14:37temozolomide
• 01:14:38and will go on to
• 01:14:39receive,
• 01:14:41lutetium dotatate,
• 01:14:43both of which carry some
• 01:14:44risk
• 01:14:45for secondary myelodysplastic
• 01:14:47syndrome.
• 01:14:48I get asked this both
• 01:14:49by patients and by treating
• 01:14:51physicians of sort of how
• 01:14:53how real is that risk.
• 01:14:54I think both independently
• 01:14:56carry about a two to
• 01:14:57three percent risk.
• 01:14:59But,
• 01:15:01sequentially and cumulatively, that risk
• 01:15:03may actually be higher, and
• 01:15:04I think we really need
• 01:15:05better predictors of that
• 01:15:07of who may be at
• 01:15:08risk for that. I don't
• 01:15:09know, Gabby, if you have
• 01:15:10any thoughts on that.
• 01:15:12Yeah. No. I definitely agree.
• 01:15:14I think we currently don't
• 01:15:16have
• 01:15:17a great
• 01:15:18biomarker
• 01:15:19that predicts who are the
• 01:15:21patients at higher risk,
• 01:15:23and we probably should be
• 01:15:25starting to look to look
• 01:15:26at genetics
• 01:15:28to see
• 01:15:29patients who have some alteration
• 01:15:31or something
• 01:15:32that could make them
• 01:15:35more likely for that. And
• 01:15:37even though they don't have
• 01:15:38any symptoms or any,
• 01:15:41exhibit any changes yet, the
• 01:15:42sequential link for those specific
• 01:15:44patients may be more
• 01:15:46risky,
• 01:15:47and I don't think we
• 01:15:48have that data. I think
• 01:15:50that's definitely to come.
• 01:15:52Great.
• 01:15:52Well, I'll ask our audience
• 01:15:54to pose us questions. But
• 01:15:55if in the absence of
• 01:15:56those, I'll do one round
• 01:15:57of sort of a final
• 01:15:59forward thinking question for everybody.
• 01:16:01Maybe we'll go kind of
• 01:16:02in the same order that
• 01:16:03we, gave presentations.
• 01:16:05So,
• 01:16:06so doctor Klimstra,
• 01:16:08are you what what either
• 01:16:10are you hopeful for in
• 01:16:11the field or if there's
• 01:16:12an unanswered question you'd be
• 01:16:14really excited to look at?
• 01:16:16Yeah. That's a it's a
• 01:16:17great question.
• 01:16:19You know, the and we've
• 01:16:20talked about this privately. I
• 01:16:21think one of the,
• 01:16:23great advances that you showed
• 01:16:25in your talk is the,
• 01:16:27plethora of different therapeutic options
• 01:16:29that now exist,
• 01:16:30particularly for pancreas, but for
• 01:16:32for all NETs.
• 01:16:34And, you know, most of
• 01:16:35these patients will receive multiple
• 01:16:37different agents over the course
• 01:16:38of their disease.
• 01:16:40And it remains an open
• 01:16:41question how to,
• 01:16:44strategize
• 01:16:46and how to stage these,
• 01:16:48based on what patients are
• 01:16:50likely to respond to.
• 01:16:51Unfortunately, we really don't have
• 01:16:53great biomarkers
• 01:16:54for these agents. Even some
• 01:16:56of the somewhat targeted agents
• 01:16:58where you could intuit a
• 01:16:59biomarker,
• 01:17:00it hasn't been developed to
• 01:17:02the point where it's clinically
• 01:17:03useful. So for me,
• 01:17:05what would be an exciting
• 01:17:06problem to address is to
• 01:17:08identify
• 01:17:09therapeutic,
• 01:17:10biomarkers that we can test,
• 01:17:12in the tumor tissue by
• 01:17:14genetic sequencing or immunohistochemistry
• 01:17:16or even
• 01:17:18AI.
• 01:17:19Sounds good. Alright. Doctor Kunstman,
• 01:17:22on to you. Same question.
• 01:17:24Yeah. I mean, I'm very
• 01:17:26excited about the availability of
• 01:17:29the neoadjuvant approach for these
• 01:17:30tumors.
• 01:17:32You know, if we can
• 01:17:33clear these patients surgically of
• 01:17:35their disease to r zero,
• 01:17:37they do incredibly well.
• 01:17:40You know,
• 01:17:41even for particularly
• 01:17:44innovative surgeons, there are just
• 01:17:46tumors that we need cytoreduction
• 01:17:48to enable that to happen.
• 01:17:51You know,
• 01:17:52and and I think
• 01:17:54in the future, in the
• 01:17:55next, you know, in the
• 01:17:56present and in the next
• 01:17:57few years in particular,
• 01:17:59we're gonna have the opportunity
• 01:18:01to offer curative approaches to
• 01:18:03patients that in the past
• 01:18:04we never would have considered
• 01:18:05it.
• 01:18:07You know, I think part
• 01:18:09of that,
• 01:18:11one of the downsides is
• 01:18:12that means there's increasing complexity
• 01:18:14because there's such heterogeneity both
• 01:18:16in these tumors and the
• 01:18:17therapeutic options. It creates some
• 01:18:19some challenges because
• 01:18:21sequencing of treatments really matters,
• 01:18:24in these patients.
• 01:18:25But I think that's really
• 01:18:27exciting because a lot of
• 01:18:28patients, we sort of had
• 01:18:29to relegate them to chronic
• 01:18:30disease status.
• 01:18:32We might be able to
• 01:18:32offer a curative option with
• 01:18:34a combination
• 01:18:35of of treatments, both they're
• 01:18:36anoxic, surgical, medical, cytotoxic, etcetera.
• 01:18:41Yep. Yep. Totally agree. Alright.
• 01:18:43Doctor Spielberg.
• 01:18:46I think,
• 01:18:47the combination
• 01:18:49approaches
• 01:18:50either with
• 01:18:51different particles
• 01:18:53or different drugs and moving
• 01:18:55from a palliative,
• 01:18:58setting into a curative setting.
• 01:19:01I think when we talk
• 01:19:02about other types of,
• 01:19:05radiation particles, we may be
• 01:19:07able to get different effects.
• 01:19:11And then,
• 01:19:13as we move into this
• 01:19:14field, hopefully, we'll get into
• 01:19:17curative
• 01:19:18rather than just palliation, which
• 01:19:20is really the goal.
• 01:19:22Yep.
• 01:19:23Well, I wanna thank all
• 01:19:25of you for,
• 01:19:26joining me this evening for
• 01:19:27a really great
• 01:19:29great presentations and great discussion.
• 01:19:31I share your enthusiasm
• 01:19:32about the future, and I'm
• 01:19:34really excited about the questions
• 01:19:35that we can ask together.
• 01:19:37So,
• 01:19:38thank you to the audience
• 01:19:39for listening tonight,
• 01:19:41and,
• 01:19:42we will see you next
• 01:19:43time. Thanks, everybody.