Center for GI Cancers CME Series: Rare Gastrointestinal Cancers

Name: Center for GI Cancers CME Series: Rare Gastrointestinal Cancers
Uploaded: 2026-02-25T13:46:22.22Z
Duration: 1 h 28 min 4 s
Description: Moderated by Raghav Sundar, MD, PhD Presenters: Thejal Srikumar, MD Associate Professor of Medicine (Medical Oncology and Hematology) Kiran Turaga, MD, MPH Professor of Surgery (Oncology) and Chief of Surgical Oncology Stephen Lattanzi, MD Assistant Professor of Medicine (Medical Oncology and Hematology)

February 25, 2026

Moderated by Raghav Sundar, MD, PhD

Presenters:

Thejal Srikumar, MD

Associate Professor of Medicine (Medical Oncology and Hematology)

Kiran Turaga, MD, MPH

Professor of Surgery (Oncology) and Chief of Surgical Oncology

Stephen Lattanzi, MD

Assistant Professor of Medicine (Medical Oncology and Hematology)

Information

ID: 13872
To Cite: DCA Citation Guide

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00:00Alright. Let's get
00:01started. Good eve good evening,
00:03everyone, and thank you for
00:04joining us for,
00:06the Center of GI Cancer,
00:07the CME webinar series,
00:10at the
00:11for the Gastroenterology
00:12Cancer segment. I'm Raghav Sundar.
00:15I'm a GI medical oncologist
00:16and leader of the Gastroesophageal
00:18Cancer Program.
00:23These are my disclosures.
00:26So for the past few
00:27months, the Center for GI
00:28Cancers have had a webinar
00:30series. This is part three
00:31of this webinar series. In
00:33February, we had a GI
00:35oncology year in review.
00:37And in March with for
00:38Colorectal Cancer Awareness Month, we
00:40had the colorectal,
00:42series. And this month, we're
00:44gonna do Gastroesophageal
00:45Cancers as a part of
00:47the Gastroesophageal
00:48Cancer Awareness Month. And we
00:50have I'm I'm pleased to
00:51be joined by three fantastic
00:53speakers,
00:54who will be talking to
00:55us about different aspects of
00:56the multimodal discipline
00:58discipline of,
01:01gastroesophageal cancers.
01:02So I have, professor Dan
01:04Boffa,
01:05who's a professor of surgery
01:06from thoracic oncology,
01:08who'll be talking to us
01:09about,
01:10surgical updates.
01:12I have,
01:13doctor Kevin Du, who's an
01:14associate professor from radiation oncology,
01:16who'll be updating us on
01:18the latest in radiation oncology
01:20for gastroesophageal
01:22cancers.
01:23And I also have, Doctor.
01:24Joanna Gibson, who's an associate
01:25professor of pathology, who'll be
01:27talking to us in the
01:28latest in the biomarkers of
01:29gastroesophageal
01:30cancers.
01:31And to get things started
01:32off, we'll start with Doctor.
01:34Gibson sharing with us a
01:35little bit about,
01:37what's up and new in,
01:39the pathology space for gastroesophageal
01:41cancers. Doctor Gibson, please.
01:44Thank you.
01:51So,
01:52as you can see, I
01:53went with a green background
01:55because it's spring, and I
01:56was inspired.
01:57So it's not a diss
01:59at Yale.
02:00The Yale blue is wonderful,
02:01but I thought this was
02:03appropriate.
02:04So,
02:05I have no disclosures.
02:07So just a broad, review
02:09on the role of pathology
02:10in GJ,
02:11adenocarcinomas.
02:13Obviously, pathology,
02:15does,
02:16the tissue confirmation of the
02:18diagnosis
02:19by looking at biopsies.
02:21We help with, staging once
02:23a resection has occurred by
02:24reviewing
02:25the extent of the tumor
02:26and and, lymph nodes.
02:29We also assess metastases
02:30in a in a lot
02:31of different ways.
02:33And the main thing,
02:35that we sort of also
02:36contribute to that has impact
02:37on how patients are treated
02:39is
02:40biomarker assessment. And in particular,
02:42I'm going to talk about
02:44the IHC biomarkers.
02:46So
02:48at, Yale, we perform
02:50IHC biomarkers
02:52at reflux,
02:53at diagnosis through a reflux
02:55pathway. So reflux meaning that
02:57we do it whenever we,
03:00have a diagnosis of a
03:01gastroesophageal
03:02adenocarcinoma.
03:04And whether that's primary at
03:05the site or metastatic,
03:07if that's what the diagnosis
03:09is, we will perform all
03:10four of these biomarkers,
03:13at whatever time of the
03:15diagnosis. And one of the
03:16reasons why is because,
03:18the percent of patients that
03:20present with stage three zero
03:21four disease at the time
03:22of diagnosis is pretty high,
03:24you know, gets into seventy
03:25percent or so for GJ
03:27cancers. And,
03:29and it it is helpful
03:31to have these biomarkers
03:32upfront so so patients can
03:34be triaged to the right
03:35treatment option.
03:37And while we perform IHC,
03:39we do use other techniques
03:40if necessary,
03:42for,
03:43assessment of
03:46confirmation or or other biomarkers
03:48as well. And those are
03:50through a, you know, slightly
03:51different pathway.
03:53So I'm just gonna go
03:53through each of these.
03:55The initial ones, I'll just
03:57kind of, walk through in
03:58an abridged way. So mismatch
04:00repair deficiency
04:01is the biomarker that I
04:02kinda like to say,
04:04has double duty,
04:06because it, it is used
04:07for a couple of different
04:09clinical contexts. The biological basis
04:11for targeted therapy is immunotherapy
04:13targeting
04:14PD one, PD l one
04:15pathway.
04:17And that's thought to occur
04:18because
04:19tumors with mismatch repair deficiency
04:22or MSI status
04:24have
04:25high
04:27tumor antigen,
04:28and can activate,
04:30the immune system. And so
04:32by using PDL one inhibition,
04:34we can sort of target,
04:35tumor cells for
04:38immune mediated,
04:40destruction.
04:41And, mismatch repair deficiency
04:43is predominantly
04:44tested using,
04:46IHC.
04:48But we do have other
04:49techniques that can also detect
04:50it. But MMR IHC
04:52is a widely available technique
04:55that most laboratories have,
04:57and we're able and it's
04:59fairly easy and reproducible.
05:02So it's,
05:03and it's fast. So we're
05:05able to do that, and
05:07that's one of the reasons
05:08why we start with that
05:08one.
05:10And then, you know, how
05:12often I'm just gonna move
05:14one of the panels
05:16up to my other screen
05:17here. Excuse me for just
05:19one moment.
05:22And,
05:25how how often is, MMRD
05:27found in esophageal,
05:29and gastric cancers? It's not
05:30very common. In one study,
05:33from
05:34twenty sixteen, they found seven
05:35percent. I recently
05:37reviewed a Yale cohort,
05:40from twenty eighteen to,
05:42twenty twenty four, and we
05:44found about eleven percent in
05:45stomach cancer and
05:47a lot less in esophageal
05:48GJ cancers. But it is
05:50an important biomarker,
05:52that we need to identify
05:53because it does have this
05:55targeted
05:55targeted therapy
05:57option.
05:59Another
06:00biomarker is HER2, and that's
06:02the old reliable biomarker. And
06:04the basis for targeted therapy
06:06is that,
06:07some tumor cells will have
06:09overexpression of HER2
06:11on their surface, and,
06:13this can be targeted
06:15using antibodies
06:17or antibody drug conjugates.
06:21And, again, we use a
06:22method of IHC.
06:24That's the main method of
06:26finding
06:27this
06:31biomarker
06:32on tumor cells. And in
06:34terms of how often we
06:36see it, probably seen in
06:38about,
06:41fifty to sixty percent of,
06:44GJ cancers. Kind of depends
06:45on which study you read,
06:46what cohort.
06:48It's been, this has been
06:49a biomarker that has been
06:51in practice for a number
06:52of years, and you can
06:53you can see that the
06:55use of, this biomarker,
06:57expression
06:58testing has increased from, you
07:00know, ten, fifteen years ago
07:02to,
07:04more recently.
07:06And so we have a
07:08IHC component, and we will
07:10perform FISH testing if, the
07:12IHC shows a two plus
07:14pattern. And the exciting thing
07:16about HER2 is that even
07:17though it's been around for
07:18a long time and we've
07:19been able to target it
07:20using monoclonal antibodies,
07:23now there is,
07:24newer,
07:25data coming out that,
07:27the
07:28antibody conjugates
07:30can use can be also
07:31used,
07:32in even, patients that have
07:34HER2 low,
07:36one plus or two plus
07:37findings.
07:38So it it is something
07:39that is going to be
07:40able to be expanded to
07:42other, patients.
07:45PDL one. I wish I
07:46could stop talking about PDL
07:48one.
07:49This is the problem child
07:50for the IHC biomarkers.
07:52The biological basis for targeted
07:54therapy is the same.
07:55It's very similar to MMR
07:58where, blockade of the PDL
08:00one, PD one pathway can,
08:05activate,
08:06the immune system to eliminate
08:08tumor cells.
08:09We use the, PDL one
08:14twenty two c three,
08:15antibody, which is the FDA
08:17approved,
08:18method.
08:19And,
08:20we perform what's called the
08:22CPS or combined positive,
08:24score. So that's the total
08:25number of PDL one staining
08:27cells in a tumor section
08:28that includes tumor cells, mononuclear
08:30inflammatory cells over the total
08:32number of tumor cells times
08:34one hundred.
08:35And,
08:36the problem is that,
08:40the FDA approved assay is
08:44is, the positivity cutoff is
08:46determined to be CPS greater
08:47than one.
08:49But in trials,
08:50in certain trials, CPS greater
08:52than five was actually,
08:54much more, reliable
08:56and,
08:57effective.
08:58And so
08:59it's it's difficult. And the
09:01CPS score of one,
09:03is quite subtle, and there
09:05have been umpteen number of
09:06studies showing that pathologists
09:08are really not very good
09:09at being reproducible,
09:11across,
09:12pathologists. And one of the
09:14most recent papers on that
09:15is from our group,
09:17David Rem and Sujian Zhang
09:18group who are, our pathologists
09:21here who've looked at that.
09:23It is more reliable at
09:24the higher cutoffs. So, you
09:25know, CPS of five or
09:27more is probably more reliable
09:28as a result.
09:29And that could explain this
09:31this variability,
09:32could explain some of the
09:33lack of efficacy,
09:35for,
09:36trials
09:37in this setting.
09:39So claudan eighteen is the
09:41new kid on the block,
09:42and I'm going to
09:44talk about this in a
09:44little bit more detail. So,
09:47basically, claudan eighteen is a
09:50protein,
09:51that's a transmembrane protein that,
09:53forms the tight junction
09:56between cells. And normally, in
09:57the normal tissues, it's expressed,
09:59and you can see that
10:00it's in the tight junctions
10:01between the epithelial cells. But
10:03once, cancer cell,
10:09is, you know, goes through
10:10carcinogenesis,
10:11becomes a cancer cell, the
10:12claudin eighteen, can be retained
10:14on the surface of those
10:15cells, and it is also
10:16exposed because the tumor cells
10:18no longer stick to each
10:19other in the same way
10:20as native epithelial cells.
10:23And,
10:25and then looking at more
10:27detail at the protein,
10:28there's a loop, with a
10:30couple of binding sites where
10:32antibodies can be, used to
10:34target that particular,
10:37protein.
10:40And,
10:40in terms of,
10:42what do we know about
10:43expression of claudine eighteen point
10:45two in esophagus or,
10:47GJ cancers?
10:49And,
10:51based on a in one
10:53study, based on a positivity
10:54of, greater than seventy five
10:56percent two plus or three
10:58plus expression,
10:59we find positivity in about
11:00thirty eight percent of, of
11:02cancers. And you can kind
11:03of see that, this high,
11:05positivity
11:06here.
11:08And,
11:09this was the cutoff that
11:11was used for the study
11:12to look at, zolventuximab,
11:15which is the the main
11:17antibody that's targeting this pathway.
11:19But there are other novel,
11:21antibodies
11:22that,
11:24and antibody,
11:25drug conjugates that could potentially
11:28be useful to target lower
11:30level expression
11:31of this particular biomarker.
11:33So if you include those,
11:35then you're you're adding a
11:36lot more,
11:37patients to the possibility of
11:39getting targeted treatment.
11:41And I just I have
11:42a summary here of all
11:42the phase two and three
11:44clinical trials from one of
11:45the recent reviews
11:46for anybody who's interested in
11:48more detail.
11:49And so what do we
11:50do at Yale for claudine
11:52eighteen point two?
11:53So we, again, use the
11:55FDA approved,
11:57assay,
11:58which is the forty three
11:59dash fourteen a,
12:01antibody.
12:03And,
12:05we, when we report the
12:06results of our claudan eighteen
12:08staining, we report it in
12:11categories.
12:12So greater than seventy five
12:14percent
12:16positivity, fifty to seventy five,
12:18twenty to forty nine, one
12:20to nineteen, and zero percent.
12:21And that's because we wanna
12:23be ready for those newer,
12:26antibody drug conjugates
12:28and bispecific antibodies to see,
12:31if these patients would benefit
12:33from those in the future.
12:36And, again, you can kind
12:37of see what the spectrum
12:38of staining is.
12:40It's a relatively
12:43easy antibody,
12:44to read. And then we
12:46always look for our normal
12:47controls in the background,
12:48mucosa.
12:50Okay. So that's the basically,
12:52the end of my talk.
12:53I've described all four of
12:54these biomarkers
12:56and,
12:57what they're targeting
12:58and how we assess them.
13:01And,
13:02this is already out of
13:03date because we do have
13:05a emerging predictive biomarker, FGF
13:08r two b that's coming
13:09up.
13:10And, we are getting ready
13:12to have that IHC testing
13:14method, brought on board for
13:16us. So this is just
13:17stay tuned
13:18about this in the future.
13:21And so here I have
13:22a summary table for anyone
13:23who's interested.
13:25So,
13:26again, we have our four
13:28IHC biomarkers that we are
13:30performing as a reflex workflow
13:32so that we're providing this,
13:34information
13:35at diagnosis
13:37and,
13:39for, you know, the the
13:40various, uses,
13:43clinically and just, you know,
13:45again, just the summary chart
13:47of all the information I
13:48talked about today. And I'll
13:49stop there, and I'm happy
13:51to take any questions. And
13:52I I apologize if I
13:53went a little too long.
13:56Let's see. Thanks. That was
13:57good. Doctor Gibson, that was
13:58a great talk. I can,
14:00may I encourage
14:02the viewers, listeners to,
14:05put in any questions that
14:05you have into the chat
14:07or into the q and
14:07a box, and we'll try
14:09and do them,
14:10either now or at the
14:12end of the the session
14:13when after all after all
14:14four of us speak because
14:16I think it'll be quite
14:16helpful to have a multidisciplinary
14:18discussion
14:19at the end of all
14:20the chats.
14:22If there are no emerging
14:23questions, maybe we'll move on
14:25to, doctor Baufa, who's gonna
14:27give us an update from
14:28the surgical perspective.
14:38Hi there. Thank you very
14:40much. Dan Boffa. I'm one
14:41of the,
14:42thoracic surgeons,
14:44here at Yale. And I'm
14:45just gonna talk
14:47briefly about, a couple of
14:50aspects of the surgical management
14:52of esophageal
14:52cancer.
14:55So,
14:57may I have a couple
14:59of disclosures?
15:01This is what people think
15:02about,
15:03when we mention an esophageectomy
15:06for esophageal cancer, that it's
15:08a extremely dangerous thing,
15:10to deal with an extremely
15:12dangerous problem.
15:14And,
15:14hopefully, I can convince you
15:16at at some level that
15:17it's become infinitely safer,
15:20and,
15:21the recovery
15:23is,
15:24is much different now with
15:25minimally invasive,
15:26approaches.
15:28But I do think it's
15:28an important question.
15:30And
15:31and
15:32do we need to do
15:33an esophagectomy
15:35in everyone? And I think
15:36that some of the most
15:37exciting,
15:39trial data that's been coming
15:41through
15:42is looking at things,
15:44that maybe we,
15:45can be more selective in
15:47how we
15:48apply some of the traditional
15:50treatments as well as, some
15:52of the the newer treatments.
15:53So
15:55this I'm gonna focus on
15:57the the Saino trial, which
15:59is a phase three,
16:01trial,
16:02that looked at,
16:05selecting people
16:06to not go
16:08on to surgery after receiving,
16:11the cross regimen of induction,
16:14chemoradiation.
16:17Before that, though,
16:19you have to know that
16:20the person has experienced a
16:22complete clinical response. And so
16:25there there was a trial
16:26before the trial, which is
16:27the presaino trial, which was
16:30looking at, could you tell
16:32if people had been cleared
16:34of their disease
16:37after receiving CROS. Because if
16:39you couldn't do that, then
16:40there's,
16:41no point in,
16:43the trial, which is taking
16:45people who appear to have
16:46been cleared of their disease
16:48and,
16:49selectively
16:50watching them to see if
16:52the the cancer came back
16:53and deferring esophagectomy
16:55to only those people where
16:56the cancer came back. And
16:57so this was the trial
16:59to determine, could you
17:01detect people that were free
17:03of residual disease? This was
17:05done in the Netherlands. Again,
17:06it was after the CROS
17:08regimen.
17:09The
17:12the
17:13four to six weeks after
17:15the completion of the chemo
17:16radiation, they underwent an endoscopy.
17:18And,
17:20if,
17:21they, was there was viable
17:23cancer,
17:24they did a PET scan
17:25and an esophagectomy
17:27right away.
17:28If they didn't see vital
17:29any viable cancer, they did
17:30a second endoscopy,
17:33an ultrasound, a PET scan,
17:35and then everybody got an
17:37esophageectomy,
17:39after the, the second evaluation.
17:43So there were about two
17:44hundred and twenty patients. This
17:46was done
17:48a few years ago. They
17:49were mostly adenocarcinomas,
17:51and they wanted to see
17:53that of the people who
17:55had cancer still in them,
17:58what was the proportion of
17:59them that had a negative
18:03clinical assessment?
18:04And they called those false
18:06negatives.
18:08And so they started by
18:09just doing biopsies
18:10the way they routinely do
18:12biopsies.
18:13And they,
18:15they had a a false
18:16negative rate
18:18of about thirty percent. So
18:20then they started doing a
18:21byte on byte, which just
18:22basically means,
18:24that they took a byte
18:26and then went back to
18:27the same area and bit
18:29in the same area again,
18:30which gets a little bit
18:31deeper.
18:33Using this, they found, the
18:35false negative rate, again,
18:37meaning negative results in people
18:40who still had at least
18:42ten percent,
18:43of their residual cancer.
18:46So it improved from thirty
18:48percent to seventeen percent. And
18:49when they added FNA of
18:51nodes that were bigger than
18:52five millimeters,
18:53it went down to ten
18:54percent. So
18:56ten percent of the patients
18:57who had
19:00residual cancer,
19:01which they defined as greater
19:03than ten percent residual cancer,
19:05had a false negative.
19:07And so this is a
19:09table by group and the
19:10TRG,
19:12at the top here, this
19:13is their different categories of
19:15residual disease. And so if
19:17you were a TGR one,
19:19you had a complete pathologic
19:20response,
19:22or you had one to
19:23ten percent viable cancer,
19:28or greater than ten percent
19:29but less than fifty,
19:30or greater than fifty percent.
19:32These are the categories that
19:33they
19:34code their viable cancer.
19:36And this is what the
19:38study was designed to look
19:39at, just these patients
19:41who had more than ten
19:43percent viable cancer,
19:45and they found,
19:46that there was a ten
19:47percent false negative rate.
19:50But they didn't really look
19:51at the people with one
19:52to ten percent residual cancer.
19:54And I would argue that
19:55patients probably care about that,
19:58that that if you're really
20:00looking to see who's been
20:01rendered disease free, you'd wanna
20:03know any living disease.
20:06But what's funny about this
20:07is
20:09this the way this was
20:10set up was to say,
20:11how well does the test
20:13perform?
20:14So given
20:15residual cancer,
20:17is the test coming up
20:19with a positive or negative
20:20result? Well, patients don't think
20:22that way. They don't care
20:23about
20:24scenarios and how the test
20:26performs. They wanna know about
20:27test results and what does
20:28it mean.
20:30So if a test says
20:31no cancer, what is the
20:33chance that you actually have
20:34cancer? That's the false negative
20:36rate,
20:37that really matters most to
20:40patients, and that points to
20:41negative and positive predictive value.
20:43And so when you look
20:44at all the people who
20:45had a negative test result,
20:48and granted that this was
20:49published saying there's a ten
20:50percent false negative rate to
20:52this presano
20:53trial. But if you actually
20:54looked at everybody who had
20:56a negative test result,
20:58there were twenty nine,
20:59negative test results.
21:01They the patient still had
21:02cancer fifty five percent of
21:03the time. And so
21:05that's just an important number
21:06to keep in the back
21:07of your head that a
21:08negative,
21:09Sano level evaluation,
21:13there's viable cancer half the
21:15time.
21:17So now to talk about
21:18the Sano trial.
21:20So, this is a really
21:22nice trial
21:23done,
21:24again, in the Netherlands.
21:26Twelve high volume
21:28centers, and it was it's
21:29a recent trial,
21:31similar to presano,
21:34mostly adeno, and about twenty
21:36five percent squamous. And, again,
21:38it's the CROS regimen.
21:40And they use something called
21:41a stepped wedge clustered randomization,
21:44which basically means the patients
21:46aren't randomized.
21:48The twelve hospitals,
21:49they only do one or
21:51the other,
21:52and what they do evolves
21:55over time. So everybody that
21:56goes to each hospital gets
21:59the same,
22:00form of treatment, either
22:02cross then surgery or cross,
22:05versus active surveillance.
22:07And every three months,
22:09hospitals
22:10switch from
22:12being a surgery,
22:14performing center
22:15to one that does surveillance.
22:16So anybody who signs up
22:18for this trial, they know
22:19what they're getting,
22:20because of the hospital that
22:22they go to. And then
22:23eventually, all the hospitals were
22:25doing active surveillance. So with
22:27the start of the trial,
22:28every hospital, all twelve hospitals
22:30were doing surgery,
22:32cross then surgery.
22:33And then
22:35every three months,
22:36two hospitals were randomly
22:39assigned to take all their
22:41patients
22:42subsequent to that and do
22:44active surveillance.
22:45And so, eventually,
22:46more and more of the
22:47hospitals became active surveillance,
22:50until all of them were
22:52active surveillance. And so it
22:54was designed as a two
22:55year overall survival from the
22:57from the time that they
22:58determine a complete clinical response.
23:01And it's non inferiority, which
23:03means that,
23:04they picked a margin.
23:06They said fifteen percent. So
23:08if the difference in two
23:10year survival between
23:12surgery
23:13as, following cross or
23:16active surveillance,
23:17if they were within fifteen
23:19percentage points of each other,
23:21it was not inferior. And
23:22it actually it's the
23:24upper boundary of the confidence
23:25interval by that that's not
23:27critical.
23:29So they screened about eleven
23:31hundred patients. And interestingly,
23:33about twenty five percent of
23:34all the people they screened
23:37did not wanna participate this.
23:39And and I think that's
23:39just important
23:41to sort of understand the
23:42appetite. Again, this is not
23:44randomized. They they would know
23:45what they're getting up front,
23:47but they were not interested
23:49in in, participating
23:51in this. So there were
23:52about seven hundred and sixty
23:54that underwent that
23:56first evaluation,
23:58which,
23:59was an upper endoscopy,
24:02and,
24:03an ultrasound.
24:06The at that first evaluation,
24:08thirty six percent were found
24:10to have cancer in the
24:11esophagus. So people got their
24:13chemotherapy and radiation.
24:15They had a six week,
24:17at the six weeks after
24:19the chemotherapy and radiation, they
24:20got an upper endoscopy.
24:22Just over a third of
24:23them, they still had viable
24:25cancer in the esophagus. And
24:27those that did not
24:29went on to the twelve
24:30week clinical evaluation, which is
24:32a little bit more involved,
24:34which was upper endoscopy,
24:36ultrasound, and a PET scan.
24:38And of the people that
24:39underwent that second clinical evaluation,
24:42another third were found to
24:44have live viable cancer,
24:47but forty of them,
24:49actually sorry. Forty, forty of
24:50them actually had systemic metastases
24:53that they were
24:55found between their screening
24:57and this twelve week clinical
24:58evaluation.
25:00But they deemed thirty five
25:01percent
25:03had a complete clinical response,
25:07from this this,
25:08group.
25:10And from this,
25:12a hundred and eleven underwent
25:13standard surgery.
25:15A hundred and ninety eight
25:16underwent active surveillance. The numbers
25:18don't completely match up because
25:19they actually brought in some
25:20of the presano
25:21patients.
25:23And so this was the
25:24clinical
25:25response assessment. So six weeks
25:27after induction therapy,
25:29this was the four bite
25:30on bite biopsies.
25:32And if they didn't see
25:33any cancer, they went ongoing,
25:35observation. And then at twelve
25:37weeks, they added a PET
25:38scan
25:39and the EUS.
25:41And if there were no
25:42tumor cells at the twelve
25:43weeks,
25:44they were deemed a complete,
25:46clinical responder.
25:49And, if you were getting
25:51active surveillance,
25:53then
25:54in year one, you got,
25:57the the biopsy, the bite
25:58on bite biopsies, the EUS,
26:00and the PET scan every
26:01three months. Year two is
26:03every four months. Year three,
26:04every six months.
26:06And then after,
26:07the third year, it was
26:08annually.
26:10And when you look at
26:11overall survival, this was their
26:12endpoint.
26:14Seventy four percent of the
26:16active surveillance,
26:17patients were alive at two
26:18years, and seventy one percent
26:20of the standard surgery patients
26:22were alive. And so this
26:24is encouraging
26:25that there are people who
26:26can be actively surveyed.
26:29But I think the real
26:30interesting is is how you
26:32know, what happened in, to
26:34these different patients as they
26:36went along. And so if
26:38you divide all the patients
26:40up into an and put
26:41them into the a, into
26:42the the pie chart, you
26:44can get rid of the
26:45people who were excluded for
26:47sort of technical reasons.
26:50Fifty five percent of patients
26:53had before they could get
26:54randomized or before they were,
26:57made it to the point
26:58of being,
27:00assigned to one of the,
27:02two groups,
27:03they had viable cancer. About
27:05a third at each checkpoint,
27:08and then five percent had
27:09mets,
27:11systemic mets during this evaluation.
27:14And then if you look
27:15at the groups that underwent,
27:18either the active surveillance or
27:20the standard surgery,
27:22it's a much smaller subset.
27:24And if we really focus
27:26on the active surveillance group,
27:28which is about a quarter
27:29of the patients that started
27:31all of this,
27:32and break them down,
27:35you can see that
27:37about four percent of them
27:38developed
27:39METs,
27:40systemic metastases,
27:41why they were while they
27:42were undergoing active surveillance.
27:46Local only failure means they
27:48found the cancer in the
27:49esophagus, but nowhere else.
27:51That happened twelve percent of
27:53the time.
27:54Ten percent of them went
27:55on to surgery, while two
27:56percent did not.
27:58And then eight percent,
28:00of patients,
28:01there was no cancer in
28:03the two years of observation.
28:05They had no cancer no
28:06return of cancer. And if
28:08we just look at the
28:09people who underwent active surveillance
28:12and just look at that
28:13subset,
28:14So forty two percent of
28:15patients underwent surgery,
28:18eventually,
28:20as for a median about
28:21six months.
28:23About seventeen percent of the
28:24people that underwent active surveillance
28:26developed metastases,
28:28and seven percent developed local
28:30only failure. Cancer came back
28:32in the esophagus,
28:34but they opted not to
28:35have surgery.
28:36So I think this is
28:37kind of an interesting perspective
28:39of things. So the first
28:40thing is if these people
28:41waited
28:43six months,
28:44were there any downside to
28:46waiting? Because why not just
28:47do this for everybody if
28:48there's no downside
28:50to waiting?
28:51Even if it's a very
28:53small percentage of patients that
28:54can avoid surgery,
28:56Why not? And so the
28:58concern is that if you
28:59wait longer, people can develop
29:01metastases that they otherwise would
29:04not have. And so
29:05there was a difference,
29:07that was not statistically significant,
29:09but a but a trend
29:10for a difference at thirty
29:11months,
29:13difference in the,
29:15the rate of distant metastases,
29:18forty three percent for the
29:19surveillance
29:20group, and thirty four percent
29:22for the standard surgery. This
29:23was not statistically significant, but
29:25it is a
29:27it it's approaching
29:28significance in in my mind.
29:31And if you look at
29:32the disease free survival,
29:34there is no difference in
29:36the
29:37period that was observed. But
29:38if you look, they are
29:40starting to separate after two
29:42years. You are starting to
29:43see
29:44a bit more,
29:46of a disease free survival
29:48trend,
29:49in the people that had
29:50surgery.
29:51And so
29:53in sort of putting this
29:54together, forty five percent of
29:56people, if you do the
29:57SANO protocol,
29:59give CROS,
30:01and then,
30:03do these,
30:04serial endoscopies,
30:06six weeks and twelve weeks,
30:08you're gonna find a complete
30:09clinical response in about forty
30:11five percent of people,
30:12but two thirds of them
30:14actually still have cancer.
30:16And about sixteen percent of
30:18people seem to be
30:20disease free
30:21after cross
30:23only. So if you just
30:24give people chemoradiation,
30:26predominantly adenocarcinoma,
30:28about sixteen percent of people
30:30are alive and disease free
30:32at two years. So it's
30:34not a huge number, but
30:35it is the it is
30:36a number,
30:38a reasonable number.
30:39And so,
30:41you know, again, because,
30:43of people with persistent cancer,
30:45people that develop metastases, people
30:47who have recurrent cancer who
30:48were once cleared,
30:51that's sort of the impact.
30:52So we're you're really deferring
30:54treatment
30:55for the possibility that people
30:57have been cured with their
30:58nonsurgical
30:59approach.
31:01And this is not terribly
31:02different from what we would
31:04see we saw in the
31:05German trial with chemo radiation
31:08alone.
31:10The French trial was a
31:11little bit, better
31:13in terms of, survival. But
31:15sixteen percent cure rate,
31:18is not,
31:19is is it you know,
31:20sixteen to twenty percent, I
31:22think, is a reasonable
31:23expectation
31:24for nonsurgically managed, particularly adenocarcinoma.
31:29But there were people that
31:30surgery is unlikely to help,
31:32people that develop metastases, and
31:34there were some people that
31:35were cured. And when you
31:37add all of those up,
31:39you know, there is probably
31:40a twenty, twenty five percent,
31:44if not a few more
31:45that surgery is really not
31:46helping. And the question is,
31:48can you figure this out?
31:49If you knew this ahead
31:50of time, who could who
31:51was cured by nonsurgical
31:53treatment and who was just
31:55incurable,
31:56that would be very helpful.
31:57And I think this is
31:58where the most exciting research
32:00is coming because this is
32:01going to happen in our
32:02lifetime,
32:03perhaps with cell free DNA,
32:07probably not with circulating tumor
32:09cells, which was some of
32:10my research, unfortunately.
32:12But I think AI looking
32:14at using AI to look
32:16at a lot of,
32:18either radiomics
32:19or
32:22micrographs.
32:24I do think there's enormous
32:26potential
32:27to understand what's going on
32:29with our cancers and our
32:30treatment,
32:32so that we can much
32:33more accurately assess things. And
32:35so just to close,
32:37again, coming back to the
32:39the horrors of what is
32:40an esophagectomy,
32:43I I just think it's
32:44a different era. I think
32:46esophagectomies
32:47can be done safely. I
32:49think people can return to
32:50their quality of life
32:52as, as an expectation.
32:55But I do think this
32:56is a Henry Ford quote.
32:57Whether you think it can
32:58be done or you do
32:59not,
33:00you are probably right. I
33:02think that
33:04there
33:05it is not a given
33:06that,
33:07that your surgery is gonna
33:08be done in a way
33:09that's gonna leave you highly
33:11functional.
33:12I think Connecticut,
33:14is blessed to have
33:17a a number of talented,
33:19teams, that perform esophageal cancer.
33:23We are a three star
33:24program for the Society of
33:25Thoracic Surgeons, but I can
33:26tell you we've trained,
33:28a lot of people in
33:29the state, and we are
33:30not the only,
33:31we're not the only group
33:32that does this, well.
33:34So
33:35thank you,
33:36very much.
33:39Thanks very much, doctor Buffet,
33:41for reinforcing the importance of
33:43surgery in in this very
33:45difficult to treat, tumor type.
33:49No questions? Okay. Next, we
33:51move on to doctor Du.
33:52He's gonna talk to us
33:53about the advances in radiation
33:55oncology.
33:59Okay. Hello, everyone.
34:01I'm just going to share
34:03my slides here.
34:06And,
34:07are you seeing my presentation
34:09page?
34:10I think you need to
34:11swap it, Kevin. Okay. Got
34:13it. Sorry.
34:26Let's,
34:34There you go.
34:36Okay.
34:37So my name is Kevin
34:38Du, and, I'm
34:40one of the
34:41radiation oncologists
34:43in the department of therapeutic
34:45radiology,
34:46here at Yale and, also
34:48medical director of the Trumbull
34:49Radiation Oncology Center at the
34:51Park Avenue,
34:52Medical Center.
34:54So
34:55it's really nice to, spend
34:56some time here talking with
34:58you about,
34:59radiation treatment for esophageal cancer.
35:02And, for unfortunately, I have
35:04no disclosures.
35:06The
35:07modern radiation therapy, I just
35:10a word,
35:11to give you my thoughts
35:12is really, I think, you
35:13know, all about trying to
35:15use
35:16radiation biology,
35:18advances in physics and computing
35:20technology
35:21to really
35:22improve our therapeutic index. And,
35:25there's been a lot of
35:26really incredible advances in radiation
35:29in the past twenty years.
35:31And, really, ultimately, you know,
35:33the the kind of the
35:35the holy grail for for
35:36radiation is really how can
35:37we improve functional
35:39preservation, organ preservation,
35:42and how can we improve
35:44pathologic complete response and cure
35:47more patients with radiation.
35:49And,
35:50so for esophageal cancer, this
35:51has actually been looked at
35:53really quite a bit in,
35:55in in the past, forty
35:57years or so.
35:58And, just to kind of,
36:01give
36:02a basic overview, everyone, I
36:04I I think, may may
36:06be familiar with this, but
36:07we have two different types
36:09of esophageal cancers. And and,
36:11really, in the modern era
36:12of esophageal cancer treatment, we
36:14approach each one differently in
36:16terms of how we think
36:17about radiation. So,
36:19squamous cell cancers and adenocarcinomas
36:22being the two histologies.
36:24And then we also think
36:25when we think about considerations
36:27of radiation,
36:28what the look where the
36:29location of the cancer is.
36:30Is it in the upper
36:31cervical esophagus,
36:33the middle thoracic, or lower
36:35thoracic
36:36locations,
36:38and how that might affect
36:41radiation decision making?
36:43And, over the years, you
36:45know, we've used a lot
36:46of different regimens. But as,
36:49this panel shows, we've really
36:52focused a lot in the
36:53United States and,
36:55and Europe
36:56in terms of looking at
36:58combination of chemotherapy,
37:00radiation, and surgery.
37:02And,
37:03since the nineteen eighties, there
37:04have been many clinical trials
37:06looking at this,
37:07and this is all kind
37:08of put together in some
37:10nice meta analysis a few
37:12years ago,
37:13showing really, you know, kind
37:15of in this as we
37:16look down the this, the
37:18the unity line here that
37:20many of these trials with
37:21chemoradiation
37:23before rate, surgery
37:25suggest a benefit, but not
37:27necessarily a statistically significant benefit.
37:30But when you combine all
37:31of them together, there is
37:32something that suggests favoring chemoradiation
37:35for esophageal cancers.
37:37And very similarly, for chemotherapy
37:39without radiation,
37:41also,
37:42crossing unity. But then when
37:43you put them all together,
37:45potentially suggesting,
37:47although just touching unity,
37:49favoring chemotherapy. And so despite,
37:52I would say, maybe about
37:53twenty years of clinical trial
37:54work,
37:55the question still remained,
37:58really, you know, what what
37:59is it is anything better
38:01than surgery alone? And, this
38:03is where,
38:05the cross trial really,
38:07changed
38:08was it was,
38:09changed the paradigm,
38:11when it was published. And,
38:13and this is looking at,
38:15carboxyl
38:16chemotherapy
38:17with radiation
38:18prior to surgery,
38:20compared to surgery alone. And
38:21there was an overall survival
38:23benefit,
38:23using new adjuvant chemoradiation
38:26compared to surgery alone.
38:28When you break out squamous
38:30cell cancers and adenocarcinomas,
38:32really,
38:33it became very clear that
38:35the survival benefit for the
38:37CROS trial is really driven
38:38by, the squamous cell cancer
38:41subset and and not as
38:42much by the adenocarcinoma
38:45esophageal cancers.
38:47And, really interestingly,
38:50you know, carboxyl
38:52did not seem to affect,
38:54distant recurrence
38:55rates. That is, that even
38:57though this combination of chemotherapy
38:59radiation
39:00was
39:01better,
39:02at at reducing local regional
39:05recurrence,
39:06that,
39:08it it really didn't seem
39:09to decrease the rate of
39:10distant metastatic disease. So,
39:13ultimately, the conclusion from the
39:14CROS trial,
39:16my takeaway is that it
39:18it's a really good regimen
39:20probably for squamous cell cancers,
39:22but we probably can do
39:24better for adenocarcinomas.
39:28And
39:29there's been a lot of
39:30trials since then reported about
39:32effective chemotherapy
39:33for adenocarcinomas.
39:35And, looking at more
39:37aggressive
39:39chemotherapies,
39:41it does seem that chemotherapy
39:44may be equivalent or better
39:46than chemoradiation
39:47in the setting of surgical
39:48resections for adenocarcinomas.
39:50And I'm just going to
39:51focus on one of those
39:52trials, the ISOPEC trial, which
39:54made a big
39:55splash this year, very high
39:57impact, high profile publication.
40:00And, this,
40:01was run looking at randomizing
40:05perioperative
40:06FLOT chemotherapy,
40:08compared to the cross regimen
40:10of carboxyl
40:11and and radiation,
40:13for adenocarcinomas.
40:15And, it showed that the
40:17survival was improved
40:19with,
40:20perioperative
40:20chemotherapy
40:21flot,
40:22compared to the CROS regimen,
40:25with a really impressive five
40:27year overall survival rates.
40:29And,
40:30even,
40:31in adenocarcinomas,
40:33with, aggressive chemotherapy, FLOT regimen,
40:37an improved pathologic complete response
40:39rate compared to the CROS
40:40regimen.
40:41And so
40:43the ISOPEG trial really showed
40:44us, I think, that FLOT
40:46chemotherapy,
40:48is,
40:48really the appropriate regimen for,
40:51esophageal adenocarcinomas
40:53and, probably more effective in
40:55carboxyl.
40:57The question though is is
40:59really this idea
41:00of with more effective chemotherapy,
41:03you know, can,
41:05radiation
41:06still add
41:09to to to the benefit
41:10of neoadjuvant therapy before surgery
41:14when you're using FLOT chemotherapy
41:16instead of carboxyl
41:18chemotherapy?
41:19And, this is a little
41:21bit of an older trial,
41:22but
41:24I like this trial because
41:25this trial kinda compared
41:27in a,
41:29roundabout way,
41:31chemo
41:32FOLFOX chemotherapy
41:33to carboxyl,
41:35both with, radiation treatment.
41:38And this is a, adaptive
41:40trial. So patients were randomized
41:43to either FOLFOX or cobrataxol.
41:46And then if they responded
41:47to one or the other
41:48chemotherapy,
41:50they then continued on that
41:51chemotherapy
41:53with,
41:54radiation. If they were resistant
41:56to that chemotherapy, they actually
41:57switched over to the other
41:59type of chemotherapy together with
42:01radiation.
42:02And, the five year old
42:04overall survival here was about
42:05fifty three percent. This is
42:07a phase two trial randomized
42:08trial, so a smaller trial
42:10than than, or phase three
42:12trial. But still,
42:13five year overall survival of
42:15fifty three page percent, which
42:16is about similar to the
42:18winning arm of isopec. And
42:19then also the PCR rates
42:22for the, folks who responded
42:24to FOLFOX chemotherapy
42:26was, significantly higher,
42:29at twenty six percent.
42:31So, you know,
42:33I I think that, again,
42:34this is kind of comparing
42:36two trials, which you're not
42:37really supposed to do. But,
42:39you know, it kinda gives
42:40you a a suggestion that
42:41maybe
42:42FOLFOX based or five f
42:44u based, excuse me, multi
42:46agent chemotherapy
42:49is the way to go
42:50with a favorable
42:52five year overall survival
42:54and, that the path CR
42:56rate,
42:57may be
42:58improved
42:59still even in the setting
43:00of five of even five
43:02of few based chemotherapy,
43:04you know, with with a
43:05more favorable path CR rate
43:07with the addition of radiation.
43:10And where this is important
43:11is is really this idea
43:13that,
43:15doctor Boffa just really, went
43:17through in a lot of
43:18detail, which is that there's
43:19this kind of attractive
43:23concept of saying, okay. For
43:24folks who have a complete
43:26pathologic risk or a complete
43:27clinical response to chemoradiation,
43:30can we avoid surgery?
43:32And, so the SANSO trial
43:33is one example of that
43:35trial. There's others.
43:37And,
43:38interestingly enough, you know, they
43:40did look at the global
43:41quality of life,
43:43in the Sano trial,
43:44which did improve in the
43:46short term, but, seemed to
43:48level out
43:49in the long term. And
43:50so that was kind of
43:51an interesting finding where,
43:53despite patients really,
43:55probably,
43:56preferring
43:57to avoid
43:58surgery
43:59that, their quality of life
44:00may actually improve given enough
44:02time after surgery.
44:04And, you know, speaking of
44:05quality of life,
44:07this has been looked at
44:08out of from the Netherlands.
44:09And,
44:10you know, I think the
44:11idea here is that with
44:13chemoradiation
44:16across the board, maybe about
44:18twenty to thirty percent pathologic
44:20complete response rates across most
44:21studies.
44:23That
44:24the
44:25again, the holy grail is
44:26really to try to figure
44:27out, is there any way
44:29that we can, really accurately
44:31assess pathologic complete response rates?
44:34Is there any way that
44:35we can,
44:36increase the the number of
44:38patients that achieve this pathologic
44:40complete response rate? But,
44:42this is a nice demonstration
44:44that patients prefer organ preservation.
44:47You know? And, actually, they
44:48considered organ preservation as the
44:50second most important factor after
44:52overall survival
44:54and, even would accept a
44:55a trade off in survival
44:57for significant probability of organ
44:59preservation. And so, again, this
45:01is something where there's a
45:03real need here
45:05to improve
45:06our results with chemoradiation,
45:08and and try to make
45:09this a more realistic feasible
45:12option for patients.
45:14So,
45:15in summary,
45:16just the Yale approach to
45:18chemoradiation,
45:19you know, based on off
45:20the CROS trial,
45:22the squamous cell cancers really
45:24had the, the best outcomes
45:26there of any
45:28preoperative,
45:29trial for squamous cells. So,
45:32squamous cell cancers, we're following
45:34at this point the cross
45:35regimen.
45:36For adenocarcinomas,
45:38it's clear that FLOT chemotherapy
45:40is is probably the best
45:42chemotherapy
45:43regimen.
45:44And, we may actually add
45:45in radiation,
45:47on top of that depending
45:48on,
45:49on on certain risk factors.
45:52So patients who are at
45:54high risk who are high
45:55risk surgical candidates, who are,
45:57maybe unlikely to ever get
45:59to surgery because of comorbidities
46:01or, or or age or,
46:04high risk of metastatic disease.
46:07You know, these are probably
46:08patients that,
46:09may be better served with
46:11chemoradiation,
46:13bulky cancers where there may
46:15be a risk of positive
46:16margins with surgery,
46:17and extensive lymphadenopathy
46:19where radiation may help to
46:20cover the,
46:21nodal basins.
46:24And then as a as
46:25a as a final
46:27two minute,
46:28one minute, two minute,
46:33notes that,
46:35you know, at Yale, we
46:36do have some,
46:38newer things coming down the
46:39line for esophageal cancer.
46:42And,
46:43one approach which,
46:45again, is
46:46getting more traction is this
46:47idea of treating,
46:49limited metastatic disease
46:51with curative
46:53intent. And,
46:54this
46:55is this is,
46:57the SABRE COMET trial, which
46:58looked at metastatic
47:00cancer patients,
47:01a small trial, one to
47:03five metastatic lesions,
47:05with standard of care,
47:07palliation
47:08versus
47:10standard of care with,
47:12SBRT
47:13showing a survival benefit,
47:15with the addition of local
47:16therapy with high dose ablative
47:19radiation.
47:20And,
47:22a series from MD Anderson
47:24for esophageal
47:25gastric cancers looking at a
47:26similar concept,
47:28patients getting systemic therapy with
47:30an excellent response,
47:31and then consolidation surgery or
47:33radiation. And, you know, kind
47:35of intriguingly,
47:36even up to,
47:38ten years,
47:40about a twenty percent survival
47:41in this highly selected
47:43single institution
47:44retrospective study.
47:46But, certainly suggested that maybe
47:48in some patients, there can
47:49be long term survival
47:51with, consolidative,
47:53radiation.
47:54And so at Yale, we
47:56have this trial,
47:57through,
47:58open at this point,
48:00which is open through the
48:01ECOG group, looking at this
48:03concept of consolidative radiation in
48:05patients with oligometastatic
48:07HER2 negative esophageal or gastric
48:09cancer,
48:10patients with less than five
48:12metastatic lesions,
48:14and at least stable disease
48:15with first line systemic therapy
48:17and then continuing
48:19on to,
48:20radiation treatment to all of
48:22the metastatic sites.
48:24And,
48:25you know, we're this is,
48:26this is
48:28an international trial and open
48:30now for enrollment.
48:32And then, finally, just because,
48:34you can't have
48:35radiation a radiation talk without
48:37some something with new technology,
48:40just a
48:42note that
48:44that Yale is is going
48:46to be opening Connecticut's first
48:48proton center,
48:49and this should be opening
48:50up toward the end of,
48:52next year,
48:54in Wallingford, Connecticut.
48:56And, protons are really attractive,
48:59and,
49:00you know, cutting edge radiation
49:02technology.
49:04And the advantage of protons
49:06is that, where X rays
49:08go through your body and
49:09no matter how carefully we
49:11aim,
49:12x rays at the esophagus,
49:14there's always this low dose
49:16spread of radiation to the
49:17lungs and heart,
49:19that protons,
49:20stop. And so,
49:22you can see in this
49:23example of a proton plan
49:25delivering dose to the rate
49:26to the to the primary
49:28tumor,
49:29but really sparing a lot
49:30more lung from this low
49:31dose and very importantly, sparing
49:33a lot more hearts. And
49:34we know that,
49:36survival is actually improved,
49:38the the less heart dose
49:40we we, we deliver. And,
49:43that that's a that's a
49:44big risk with esophageal cancer.
49:46So,
49:48this is, something we're looking
49:50forward to and and, again,
49:52will be a big benefit,
49:54you know, for our patients
49:55here in Connecticut.
49:56So, thank you. I apologize
49:58for going
49:59over, and,
50:01I'll
50:02turn it back to,
50:04doctor Sundar.
50:07Thanks. Thanks, Kevin. That was
50:09really fantastic, and,
50:11looking forward to having a
50:12multidisciplinary,
50:13discussion on some of the
50:14cases,
50:16after this.
50:17I'm gonna give the last,
50:19planned talk.
50:30Right.
50:31And so for the last
50:33part, I'm gonna cover,
50:34updates,
50:35over the last year in
50:36systemic therapies,
50:38mainly covering the three main
50:40components of, HER2 targeted therapies,
50:43as Doctor. Gibson talked about,
50:44GLAADIN eighteen point two, as
50:46well as, some immunotherapy updates
50:48as well.
50:51And this has been one
50:52of the most exciting aspects
50:53of gastroesophageal
50:54cancers is that in terms
50:56of just putative therapeutic targets,
50:58we can see that this
50:59entire space has really
51:01exploded over the past few
51:02years. We have multiple different
51:04drugs that are coming into
51:05the space. And
51:07by,
51:08improving
51:09systemic control as well as
51:10response rates to primary tumors,
51:12the idea is in combination,
51:14as you can see, with
51:15radiation as well as surgery,
51:16the goal is to try
51:17and be able to cure
51:19a lot much larger number
51:20of patients who are suffering
51:22from gastroesophageal
51:23cancer than what we could
51:24in the past.
51:28So in the HER2 space,
51:29we know that,
51:31the data from
51:32keynote eight eleven, which looked
51:34at patients with,
51:36advanced unresectable gastrosophageal
51:38cancers that were HER2 positive,
51:41newly diagnosed. And upfront, they
51:43were randomized
51:44to receive either chemotherapy
51:46in combination of trastuzumab, which
51:48has been the Toga regimen,
51:50which we have been giving
51:51patients for the past ten
51:52plus years,
51:54to also then receive
51:57pembrolizumab.
51:58And this trial had early
51:59results that read out a
52:00couple of years ago. And,
52:03we know that there was
52:04a progression free survival benefit
52:06for the addition of pembrolizumab
52:09to the Toga regimen with
52:10chemotherapy and trastuzumab.
52:12And this has been now
52:13the standard of care for
52:14patients over the past couple
52:16of years, where if you're
52:18HER2 positive,
52:19the addition of pembrolizumab,
52:21has demonstrated survival benefit.
52:23Last year, we actually saw
52:25the overall survival,
52:27results that was presented by
52:28Doctor Janjie Guyan and, also
52:31published in the New England
52:32Journal of Medicine. And there
52:33continues to be
52:35a clear separation of the
52:36curves and a survival benefit
52:38for the addition of pembrolizumab.
52:41This is the long one
52:42of the longest overall survivals
52:44we've seen at twenty months
52:46for patients who received pembrolizumab
52:48compared to sixteen point eight
52:50months for those that received
52:51placebo
52:52with a very nice hazard
52:53ratio zero point eight zero.
52:55And,
52:56however, one of the things
52:58to note about this trial
52:59is the fact that,
53:01there was clearly a
53:03lack of benefit
53:04of the addition of pembrolizumab
53:06for those that had a
53:07PD L1,
53:08CPS score of less than
53:10one. And in this group
53:11of patients, actually,
53:13the survival was poorer
53:15for the patients that received
53:16the pembrolizumab con considered compared
53:18to standard of care, and
53:20that led the FDA to
53:21actually update
53:23the indication for the role
53:24of pembrolizumab
53:25and restricted only to patients
53:28that are tumors that had,
53:31both a co expression of
53:32HER2 as well as PDL1.
53:35And so now in terms
53:36of the HER2,
53:38positive gastroesophageal
53:39cancers,
53:41and gastroesophageal
53:42adenocarcinomas
53:43for frontline treatment, the recommendation
53:45is in combination with the
53:46platinum and fluoropyrimidine
53:48doublet is to look at
53:50the PDL one score. And
53:52the PDL one CPS is
53:53less than one, then the
53:55recommendation is only for the
53:56addition of trastuzumab.
53:58But if the PDL one
53:59CPS is one or greater,
54:00then the recommendation is to
54:02add trastuzumab
54:03with a PD one blockade
54:05with pembrolizumab,
54:06and that's kind of what
54:08we now follow as a
54:09standard of care for HER2
54:11positive gastroesophageal
54:12cancers.
54:15Switching gears a little bit,
54:17we know that, trastuzumab
54:19deruxtecan, which is antibody drug
54:21conjugate,
54:22before two HER2,
54:24demonstrated
54:25a survival benefit
54:26compared to,
54:28physician's choice of chemotherapy in
54:30the Destiny Gastric o one
54:31study.
54:32And this actually led to
54:33the approval
54:34of trastuzumab, deruxtecan
54:36about,
54:38four years ago now
54:39for,
54:41patients that had progressed on
54:42frontline treatment with trastuzumab
54:45and,
54:47then
54:48were treated with trastuzumab deruxtecan,
54:50which is the antibody drug
54:52conjugate.
54:55The the initial data that
54:57was presented in, Destiny Gastric
54:59o one was purely generated
55:00from an Asian study. And
55:02this is why we had
55:04the SNE gastric o four
55:05study that, was a randomized
55:07phase three trial, specifically in
55:09the second line setting for,
55:12patients that have progressed on
55:13frontline treatment with trazuzumab
55:15based,
55:16treatments.
55:17And
55:18importantly in this study, all
55:20patients had a rebiopsy
55:22of
55:22the tumors and confirmed HER2
55:25positivity before they were randomized.
55:27And they were randomized to
55:28receive either trastuzumab,
55:30duraxtecan,
55:31or paclitaxel
55:32and ramosirumab.
55:34And,
55:36this actually had a press
55:37release that announced that this
55:39study met its primary endpoint
55:41for overall survival, suggesting
55:44that trastuzumab, durax deacon has
55:46not did
55:48demonstrate an overall survival benefit
55:50over paclitaxel and ramosirumab,
55:52and this is actually going
55:53to be presented,
55:54as an oral abstract at
55:55ASCO in a couple of
55:57months.
55:58And we're looking forward to
55:59hear these data, and this
56:01will be practice
56:02reaffirming in the United States
56:03where we are very often
56:05using trastuzumab, deruxtecan. In second
56:07line, one of the take
56:08home messages from this trial
56:10would be,
56:11the the concept of potentially
56:12looking to rebiopsy
56:14patients and confirm the HER2
56:15positivity
56:16status before treating these patients
56:18with,
56:19another HER2 targeted therapy.
56:22We also saw very early
56:24data from Destiny Gastric O3
56:26where they were trying to
56:27bring trastuzumab deruxtecan
56:28into frontline
56:30in combination with five,
56:31five FU chemotherapy
56:33and pembrolizumab.
56:35And,
56:36these data were actually presented,
56:38late last year, by doctor
56:40Janjigin at,
56:42ESMO,
56:43where there was actually very
56:44promising,
56:45waterfall plots that we saw
56:47of the combination of trastuzumab,
56:49daroxetecan
56:50with chemotherapy with five f
56:52u and pembrolizumab.
56:54And you can see,
56:55almost all the patients responded
56:57to treatment with a progression
56:59free survival of about ten
57:00months.
57:01One of the concerns about
57:03the ethnic gastric o three
57:04was,
57:05the higher dose of trastuzumab
57:07derazecan with six point four
57:08milligrams per kilogram actually had
57:10quite a lot of toxicities.
57:12And so they actually opened
57:13a second cohort with a
57:15lower dose of five point
57:16four milligrams per kilogram of,
57:18atrazuzumab deruxtecan.
57:20And this had very similar
57:22sort of response rates and
57:23survival,
57:24but had much, much lower
57:25toxicities.
57:27And this is what has
57:28now translated into the DESTINY
57:30gastric o five trial, which
57:32is looking at frontline HER2
57:34positive gastric cancer and randomizing
57:36patients to receive TDXD
57:39chemotherapy and pembrolizumab
57:41versus the toga versus the
57:42keynote eight eleven regimen with,
57:45chemotherapy,
57:46trastuzumab, and pembrolizumab.
57:48And this trial is actually
57:50opening at Yale very soon.
57:54Next, switching gears. Doctor Gibson
57:56spoke about claudine eighteen point
57:58two.
57:59This is a normal protein
58:00that's expressed, tight junction protein
58:02that's seen in,
58:04normal gastric mucosa.
58:06But,
58:07in cancer cells, the the
58:09the claudin eighteen the tumor
58:10cells lose the polarity
58:12that leads to an overexpression
58:13of claudin eighteen point two
58:15on surface,
58:16and zolbituximab
58:17is a monoclonal antibody that
58:18binds to claudin eighteen point
58:20two.
58:22A couple of years ago
58:24now, we saw,
58:25two randomized phase three trials,
58:27the SPOTLIGHT and GLO trials.
58:29Both trials looked at the
58:30combination of chemotherapy.
58:32SPOTLIGHT looked at FOLFOX,
58:34while,
58:35GLO looked at KPOXX
58:37with or without zolpidemap
58:38in patients that had an
58:40overexpression of claudine eighteen point
58:42two, which doctor Gibson explained
58:44was in more than seventy
58:45five percent of the tumor
58:46cells. And in both trials,
58:49there was an overall survival
58:50benefit for the addition of
58:52zolpituximab
58:53two chemotherapy
58:54with an overall survival benefit
58:56improvement of about three months
58:57in both trials and a
58:58hazards ratio of zero point
59:00seven five.
59:01There was also a very
59:02clear improvement in progression free
59:04survival that was matched on
59:05both trials. And this led
59:07to the approval of zolbituximab
59:09in,
59:10the United States. The FDA
59:12approved it in October last
59:13year. And so,
59:15most patients that have an
59:16expression of claudoin eighteen point
59:18two can be offered zolbituximab
59:20in combination with chemotherapy.
59:24Interestingly, in both trials, there
59:26was no improvement in objective
59:27response rates to the addition
59:29of zolpidemab.
59:30So although there was a
59:31survival improvement, there was no
59:33objective response rate improvement,
59:36with,
59:36in as you can see
59:37in spotlight, it was sixty
59:39point seven in the zolbituximab
59:40arm and sixty two
59:42percent in the placebo arm.
59:45One of the problems with,
59:48zolbituximab
59:49is that because
59:50the claudine eighteen point two
59:51is expressed in the normal
59:53gastric mucosa
59:54is that there is quite
59:55a lot of nausea and
59:57vomiting that these patients express,
59:59these patients face, and the
01:00:01nausea and vomiting is very
01:00:02often
01:00:04maximum in the first couple
01:00:05of cycles
01:00:06of
01:00:08treatment with zolbituximab.
01:00:10And,
01:00:11for the medical oncologist listening
01:00:13to this talk, one would
01:00:14say, hey.
01:00:15We know how to deal
01:00:16with, high dose chemotherapy and
01:00:19nausea and vomiting, and this
01:00:20is not something that we
01:00:21need to be taught again.
01:00:22But the truth is that
01:00:23the nausea and vomiting for
01:00:24zolbituximab
01:00:25is so unique that they
01:00:26actually had to have a
01:00:27consensus guidelines
01:00:29for the management of the
01:00:30nausea and vomiting with zolpidemaximab.
01:00:32This was a consensus guideline
01:00:33just published a couple of
01:00:34months ago, and the recommendation
01:00:36is actually for using a
01:00:38highly hematogenic regimen with an
01:00:40NK1 inhibitor,
01:00:42five HT3 inhibitor,
01:00:44dexamethasone,
01:00:44as well as olanzapine
01:00:46with other recommendations of triplet
01:00:48anti nausea, vomiting,
01:00:50regimens as well. But at
01:00:51Yale, we have actually adopted
01:00:53the four drug regimen for
01:00:54the treatment of patients receiving
01:00:56sorbituximab,
01:00:58And the nausea and vomiting
01:00:59has definitely been a lot
01:01:00more manageable
01:01:01with this regimen.
01:01:07Again, a couple of months
01:01:08ago, we also saw the
01:01:09results for joint analysis of
01:01:11both the Spotlight and Lou.
01:01:12Again reinforcing this idea that
01:01:14the addition of zolbituximab
01:01:16to chemotherapy
01:01:17was beneficial
01:01:18with a very nice hazards
01:01:19ratio of zero point seven
01:01:20seven for overall survival.
01:01:22And this was published in
01:01:23the New England of General
01:01:24Medicine,
01:01:25a couple of months ago.
01:01:28One of the things that
01:01:29are unique with gastric esophageal
01:01:31cancers is the fact that
01:01:32a lot of the biomarkers
01:01:34that we use are not
01:01:35oncogene drivers, and therefore are
01:01:37not uniquely
01:01:38present in each tumor. And
01:01:40there is a lot of
01:01:41overlap in the coexpression
01:01:43of these biomarkers in tumors.
01:01:45This means that there could
01:01:46be patients that have or
01:01:47tumors that have expression of
01:01:49both PD L1 and claudin,
01:01:50claudin and HER2. And there's
01:01:52a lot of because a
01:01:53lot of the targeted therapies
01:01:55are combined with chemotherapy in
01:01:57the frontline,
01:01:58there's a lot of confusion
01:01:59on whether,
01:02:00patients who have coexpression of
01:02:02both Claudin and PDL one,
01:02:03for example, should receive either
01:02:05immunotherapy
01:02:06or Claudin targeted therapies in
01:02:08frontline.
01:02:09And to actually answer this
01:02:11question, we are the the
01:02:12Lucerne trial is looking at
01:02:14both HER2 positive and PDL1
01:02:16positive metastatic gastrosophageal
01:02:18cancers and randomizing these patients
01:02:20who receive chemotherapy and pembrolizumab
01:02:23with or without zolbituximab.
01:02:25And this is another trial
01:02:26that's gonna be opening up
01:02:27at Yale soon for patients
01:02:28that have both expression of
01:02:30HER2 and, not HER2. Sorry.
01:02:32Of PDL one and claudin.
01:02:35This is an error. Sorry.
01:02:40And, of course,
01:02:41all of us are familiar
01:02:42with the idea of of,
01:02:45immunotherapy in combination with,
01:02:47chemotherapy
01:02:49for frontline treatment of metastatic,
01:02:51gastric, esophageal cancers. We have
01:02:52multiple different clinical trials with
01:02:54pembrolizumab,
01:02:55nivolumab, tislelizumab,
01:02:57all FDA approved for frontline
01:02:59treatment,
01:03:00in combination with chemotherapy.
01:03:03There's a lot of controversy
01:03:05around the PDL one cutoff.
01:03:06And as doctor Gibson mentioned,
01:03:08we are not going to
01:03:09go into that rabbit hole
01:03:10today. But the idea is
01:03:11that,
01:03:12the general principle is that
01:03:14for PD L1 experiencing tumors,
01:03:16that the addition of immunotherapy
01:03:18to chemotherapy in frontline
01:03:20is, considered standard of care.
01:03:23One of the questions is,
01:03:25is there a role for
01:03:25the continuation of immunotherapy
01:03:28into second line? And here
01:03:29we have the PARAMUNE study,
01:03:31which is looking at adding
01:03:33nivolumab
01:03:33to a second line regimen
01:03:35of paclitaxel and ramasirumab
01:03:37for tumors that have a
01:03:39PD L1 CPS score of
01:03:40one or greater.
01:03:42And this study is also
01:03:43gonna be opening,
01:03:45at Yale soon.
01:03:49And lastly, moving into the
01:03:51earlier phase of resectable gastroesophageal
01:03:53cancer space,
01:03:55we have had the CheckMate
01:03:56five seventy seven study that
01:03:58looked at patients that had
01:03:59undergone chemoradiation
01:04:00and surgery, and then,
01:04:02did not for those who
01:04:04had not achieved a pathological
01:04:05complete response were randomized to
01:04:07either receive nivolumab or placebo.
01:04:10And this study had a
01:04:11disease free survival benefit, and
01:04:12this has been something that
01:04:13we have been offering our
01:04:14patients.
01:04:15But,
01:04:18in a couple of months,
01:04:19we are going to see
01:04:19the overall survival data that
01:04:21are going to be presented
01:04:22at ASCO.
01:04:23And we are looking forward
01:04:24to see whether the overall
01:04:25survival will be positive for
01:04:26this important trial.
01:04:29We also saw data from
01:04:30KEYNOTE-five eighty five that looked
01:04:32at the addition of pembrolizumab
01:04:34two chemotherapy in the perioperative
01:04:36setting followed by surgery. And
01:04:38this was actually a negative
01:04:39trial where,
01:04:41although there was an event
01:04:43event free survival benefit, this
01:04:45did not achieve statistical significance
01:04:47and the overall survival benefit
01:04:49was not
01:04:50positive
01:04:51for the addition of pembrolizumab
01:04:53two chemotherapy.
01:04:55However, we also saw data
01:04:57from the MATAHONE study that
01:04:58was a more cleanly designed,
01:05:01single endpoint study and with
01:05:03a more consistent chemotherapy
01:05:05backbone with FLOT,
01:05:06and in this study, patients
01:05:08with FLOT were, come were
01:05:10randomized to either receive durvalumab
01:05:13or placebo and then underwent
01:05:15surgery and then either continue
01:05:17with durvalumab and FLOT. And
01:05:19this study, we saw earlier
01:05:20data,
01:05:21looking at an improvement in
01:05:22pathological
01:05:23complete response of nineteen percent
01:05:25versus seven percent. But, at
01:05:28ASCO this year, we are
01:05:29gonna see, as a plenary
01:05:31session, the event free survival,
01:05:33of Matterhorn,
01:05:34and the press release announced
01:05:36that this had achieved its
01:05:37primary endpoint and is a
01:05:38positive study. So this is
01:05:39definitely gonna be practice changing,
01:05:41and very likely patients are
01:05:43going to start going to
01:05:44be offered,
01:05:46FLOT in combination with dorvelumab,
01:05:48or resectable gastroesophageal
01:05:50adenocarcinomas.
01:05:53And we are going to
01:05:54have multiple on the background
01:05:55of that, we are going
01:05:56to have multiple perioperative chemotherapy
01:05:58plus, novel therapeutic trials that
01:06:01are opening up at Yale
01:06:02in the next,
01:06:03few months.
01:06:05At the end of the
01:06:06day, from a systemic therapy
01:06:08perspective,
01:06:09I think Doctor. Gibson will
01:06:10also agree that we should
01:06:11be testing all our biomarkers
01:06:13upfront for HER2 PDL1 claudine
01:06:15as well as mismatch repair
01:06:17deficiency.
01:06:18We know that addition of
01:06:19pembrolizumab
01:06:19two chemotherapy and HER2 positive,
01:06:22tumors
01:06:23are beneficial except in PD
01:06:25L1 negative tumors.
01:06:26The addition of zolbituximab
01:06:28is important,
01:06:29for patients that are claudan
01:06:31eighteen point two positive,
01:06:32but, the management of toxicities
01:06:34will be key.
01:06:37Darvelumab in combination with FLOT
01:06:39is likely to be practice
01:06:40changing in the next few
01:06:41months. And we have multiple
01:06:43trial options for patients with
01:06:44gastrointestinal cancers across the entire
01:06:46network.
01:06:48And, with that, I'm going
01:06:49to, end my talk.
01:06:58We do have a a
01:07:00a few more minutes for
01:07:00question and answers. I encourage
01:07:02folks to, drop in questions
01:07:04into the,
01:07:05either into the chat or
01:07:06into the q and a
01:07:07box.
01:07:09In the meanwhile,
01:07:10we we have,
01:07:12one of our,
01:07:13attendees who's,
01:07:15actually an esophageal cancer survivor
01:07:16who's gone through the entire
01:07:18journey of chemoradiation
01:07:20as well as surgery,
01:07:21and perhaps we could give
01:07:24miss
01:07:24Deepika
01:07:25a chance to talk. Emily,
01:07:27do you think we could
01:07:29see if we could get
01:07:29Deepika,
01:07:31speaking right, or is she
01:07:32already a panelist with us?
01:07:38Okay. I think Deepika has
01:07:40speaking.
01:07:42Deepika, can you hear us?
01:07:43Yeah. I can hear you,
01:07:44but am I audible?
01:07:47Hi. Thanks for thanks for
01:07:49joining the call and, for,
01:07:52dialing in dialing in. Like
01:07:53to share Let's share with
01:07:55us
01:07:55a
01:07:56little
01:07:57bit.
01:07:58Yeah. Am am I audible?
01:08:01Yeah. It's a little bit
01:08:02faint, but, maybe you could
01:08:05Hey. Into the mic, please.
01:08:07Yeah. I am sorry for
01:08:09that,
01:08:10for the voice thing because
01:08:13one more. Hello. Am I
01:08:15am I audible now?
01:08:17Yeah. Please go ahead. It'll
01:08:18be it'll be great to
01:08:19hear your, journey,
01:08:21through this entire
01:08:24Okay. Process.
01:08:26I I I'm sorry. I'm
01:08:28sorry about my voice. So
01:08:30hello, everyone. I'm Deepika Karki.
01:08:32I'm currently
01:08:34a research fellow at Mayo
01:08:35Clinic,
01:08:36Jacksonville, Florida.
01:08:38And as of today, I
01:08:39am four years cancer free.
01:08:42I was diagnosed with esophageal
01:08:44cancer
01:08:45when I was,
01:08:46twenty five years old,
01:08:48which is four years ago,
01:08:50and I was diagnosed on
01:08:51the in the initial stages.
01:08:55It was a squamous cancer,
01:08:57and it was it was
01:08:58located thirty eight centimeters from
01:09:00the incisors.
01:09:02It was fifteen centimeters long,
01:09:04and it was two millimeters
01:09:06thickness.
01:09:07So I had multiple rounds
01:09:09of chemotherapy,
01:09:11radiotherapy
01:09:12followed by resection of my
01:09:13esophagus.
01:09:15And
01:09:16post resection,
01:09:18one of the complications that
01:09:19I'm facing is
01:09:21the paralysis of my right
01:09:22vocal cord. Hence, my voice
01:09:25is very hoarse, and I'm
01:09:27sorry for that.
01:09:28But, yeah, it was a
01:09:29great talk, and, you know,
01:09:31it's really nice to see
01:09:32all the
01:09:33developments that has been happening
01:09:35in this field.
01:09:37I'm from Nepal originally,
01:09:39so all my treatment was
01:09:41done there, and it does
01:09:43not have as many resources
01:09:45as that was stocked in
01:09:47this
01:09:48amazing webinar today. But, yeah,
01:09:51just wanted to share it
01:09:52with all of you.
01:09:56Thanks, Deepika. It's it's really
01:09:58great to have, a success
01:10:00story and it's very difficult
01:10:01to, treat tumor type, and,
01:10:03it's great to see you,
01:10:06talk so proudly about your
01:10:08illness and share so greatly
01:10:09about the journey that you've
01:10:10gone through.
01:10:11Yeah. So a few points,
01:10:13that I wanted to talk
01:10:14about after listening to
01:10:16all the wonderful speakers was
01:10:17that, we didn't talk a
01:10:19lot about radiation pneumonitis,
01:10:21and that's something that I
01:10:23live with.
01:10:24And, you know, and, also,
01:10:26currently, I'm working on this
01:10:27project that is kind of
01:10:28looking at the
01:10:30cognitive function in patients,
01:10:32who are die who are
01:10:33diagnosed with cancer, you know,
01:10:35in their adolescent period at
01:10:37a very young age.
01:10:39So I actually did a
01:10:40case report on myself
01:10:42that I'm more than happy
01:10:43to share with the team.
01:10:44And I feel like if
01:10:45we could have more trials
01:10:47targeting on, like, young,
01:10:49you know, young patient cohort
01:10:52group
01:10:52because we mainly talk about
01:10:54therapies for elderly or, you
01:10:56know, young pediatric patients.
01:10:58But we don't have a
01:10:59lot of trials that kind
01:11:01of look at a major
01:11:02chunk, you know, of that
01:11:04particular
01:11:05patient population, and we talked
01:11:07about quality of life too.
01:11:09So my voice is something
01:11:10that I kind of have
01:11:11to explain on an everyday
01:11:13basis.
01:11:14So that's that. And I
01:11:16was initially
01:11:17I had dumping syndrome,
01:11:19which was very bad. And
01:11:21even now, I sometimes have
01:11:23posterior hypertension
01:11:25and hypoglycemia.
01:11:27So those are some of
01:11:28the quality of life barriers
01:11:30for me.
01:11:31And, yeah, just something that
01:11:33I wanted to share about
01:11:34with the team, with the
01:11:35prospects of maybe
01:11:38maybe, like, more amazing projects
01:11:40that might just come up
01:11:41in the future.
01:11:45Thanks, Deepika. I think you
01:11:46bring up some very, very
01:11:47good points, and maybe we
01:11:48could use this as the
01:11:49starting point for some of
01:11:50the discussions that we wanted
01:11:51to have. And I think
01:11:52both doctor Balfa and doctor
01:11:54Nus spoke,
01:11:55about this point that
01:11:57we need to correctly select
01:11:59the folks that may
01:12:00benefit from radiation and also
01:12:02be spared from radiation and
01:12:04similarly benefit from,
01:12:06surgery and be spared from
01:12:07surgery. And this brings up
01:12:09this point that,
01:12:10all all the patients that
01:12:11are treated at Yale are
01:12:12discussing a multidisciplinary
01:12:14tumor board. Very often,
01:12:16the four of us are
01:12:17on those tumor boards discussing
01:12:18who would be the right
01:12:19patients to get the right
01:12:20sort of treatments.
01:12:22And,
01:12:22we are reaching a point
01:12:24where we are,
01:12:26getting to a more personalized
01:12:28sort of treatment
01:12:29using biomarkers and other sort
01:12:31of strategies to decide on
01:12:32which patients should be benefiting
01:12:34from which aspects of the
01:12:36various therapies that we have
01:12:37available.
01:12:39But maybe it would be
01:12:39nice to hear from, doctor
01:12:41Du and doctor Boffa a
01:12:42little bit on the the
01:12:43thoughts that we go through
01:12:44when we decide on these,
01:12:47cases on whether we should
01:12:48be offering radiation as well
01:12:50as offering surgery.
01:12:54Sure.
01:12:55You know, Deepika, thank you
01:12:57for sharing your
01:13:00your cancer journey. And it
01:13:02you know, I think that
01:13:03it's important that overall survival
01:13:06is not,
01:13:08everything
01:13:08and that that we really
01:13:10have to look at,
01:13:12quality of life. And,
01:13:15I think that the
01:13:17one of the things that
01:13:18that I I do think
01:13:19we do really well here
01:13:21is when things don't go
01:13:23the way that we would
01:13:24love them to go,
01:13:26to, you know,
01:13:28have ways to mitigate
01:13:30complications of treatment. And so,
01:13:33whether it's a recurrent nerve
01:13:35issue and medializing
01:13:37cords or,
01:13:38you know, having, like, a
01:13:39world class ENT team,
01:13:43or,
01:13:44really a great pulmonary team.
01:13:46But but I think your
01:13:47your points are are really
01:13:49well taken. And and I,
01:13:50you know, I
01:13:51I I think I never
01:13:53ever talk anybody into an
01:13:55esophageectomy
01:13:56because it really is a
01:13:57trade off. It's an investment.
01:13:59It's and I'm sure you
01:14:00could attest. It's a it's
01:14:01a it's a tremendous recovery,
01:14:05and that trade off has
01:14:06to be meaningful.
01:14:08The potential gains in survival
01:14:10have to be,
01:14:11meaningful. And and this is
01:14:13a you know, I've had
01:14:14several patients in their late
01:14:16twenties,
01:14:18and,
01:14:19but but a lot of
01:14:20our patients are in their
01:14:22eighties and are facing this.
01:14:23So you have both ends
01:14:25of the spectrum and trying
01:14:26to really
01:14:27be transparent
01:14:29about
01:14:30what is the potential,
01:14:32to gain
01:14:33from,
01:14:34each modality of treatment,
01:14:37including
01:14:38systemic treatment and radiation and
01:14:40surgery,
01:14:42and what is the likelihood
01:14:44of experiencing an event that
01:14:46degrades
01:14:47quality of life?
01:14:52Yeah. I'll I'll follow,
01:14:54doctor Boffa's radiation
01:14:57generally
01:14:58follows surgery, but, the,
01:15:00this is something where,
01:15:02miss Karki,
01:15:04you know, this is really,
01:15:05an amazing story, and thank
01:15:07you so much for sharing.
01:15:08Congratulations
01:15:09on on your fourth anniversary
01:15:11of of of being cancer
01:15:13free.
01:15:14It's really amazing.
01:15:15I I share,
01:15:18a lot of what you
01:15:19say where, you know, I
01:15:20when I walk in and
01:15:21talk to, patients in the
01:15:24room,
01:15:25I I do try to
01:15:27really
01:15:28take into account and try
01:15:30to figure out what the
01:15:31right treatment is for them.
01:15:33Radiation is a difficult treatment.
01:15:35It's a it's a lengthy
01:15:36treatment.
01:15:37You know, there's a lot
01:15:39of,
01:15:40side effects that are associated
01:15:42with radiation to the esophagus.
01:15:45And,
01:15:46and and, and so it
01:15:47really is not, the the
01:15:49right treatment for everybody.
01:15:51However,
01:15:52you know, in overall, we
01:15:54try to assemble a treatment
01:15:55package that is,
01:15:57that combines the best
01:16:01chances of success
01:16:03together with trying to figure
01:16:05out what's best for the
01:16:06patient's quality of life
01:16:08going forward.
01:16:09We need better treatments. That's
01:16:11for sure.
01:16:12So that's where the research
01:16:14that,
01:16:15doctor Raghav is, Sundar is
01:16:17talking about are so important,
01:16:19novel novel therapies.
01:16:21You know, proton therapy,
01:16:23I'm really sorry to hear
01:16:25that your your lungs were
01:16:26impacted by the treatments.
01:16:28You know, I think that's
01:16:29a big advantage of newer
01:16:32radiation
01:16:33therapies like proton therapy, which,
01:16:35you know, patients don't have
01:16:38may have only limited access
01:16:40to. You know, protons are
01:16:41not everywhere.
01:16:43And but,
01:16:44but, has been demonstrated really
01:16:46to reduce the dose to
01:16:48the to the lungs and
01:16:49the heart as as I
01:16:51was
01:16:51showing earlier.
01:16:53But,
01:16:55that being said, I'm so
01:16:56glad that you're
01:16:58doing well after treatment and,
01:17:01you know, and and at
01:17:03a at a great place
01:17:05down in Florida,
01:17:07you know, pursuing pursuing things
01:17:09that are important to you.
01:17:10Thank you for sharing.
01:17:13Thanks,
01:17:14doctor Du. I I have
01:17:16a question to doctor Gibson
01:17:18as well as to, Deepika
01:17:19because,
01:17:21if, Deepika, you shared your
01:17:23your your case report with
01:17:25us, and you actually achieved
01:17:26a pathological complete response.
01:17:28So my question is,
01:17:32to to Deepika will be
01:17:34at that point where you
01:17:36had to make the judgment
01:17:37call, you would have been
01:17:39peri clinical complete response. And
01:17:41so the decision to still
01:17:43go ahead with surgery to
01:17:44be really sure that you
01:17:45have no disease left behind,
01:17:47I wanna hear your thoughts
01:17:48on the journey. And separately
01:17:50to, doctor Gibson is,
01:17:52how much of discordance do
01:17:54you see
01:17:55between CCR and PCR? Because
01:17:57that's always gonna be this
01:17:58judgment call when we try
01:18:00to head down this nonoperative
01:18:01route. And
01:18:04do we always need to
01:18:06get PCR for us to
01:18:07be confident that we've gotten
01:18:09rid of everything, or is
01:18:10CCR good enough? I mean,
01:18:11doctor Buffa spoke a little
01:18:12bit about it, but I'd
01:18:13like to hear your thoughts
01:18:14on this. Maybe we'll hear
01:18:15doctor Gibson's thoughts as and
01:18:17then listen to what Deepika
01:18:19had to think about. Sure.
01:18:22Yeah. I also wanna say
01:18:23thank you to, to Deepika
01:18:25for sharing her story. I
01:18:26think it's,
01:18:27it's incredible to hear these,
01:18:30these real life experiences,
01:18:32and it really paints a
01:18:34picture of of what people
01:18:36go through
01:18:37when I sign that report,
01:18:39that there's, you know, cancer
01:18:41found.
01:18:43I think for
01:18:45you know, I I
01:18:47it's actually a really good
01:18:48question, you know, clinical,
01:18:50complete clinical response versus complete
01:18:52pathological response.
01:18:55I actually
01:18:57don't have a study on
01:18:59the off the top of
01:19:00my head that, sort of
01:19:01looked into that. We are
01:19:03not following that as a,
01:19:07as a
01:19:09metric,
01:19:09at Yale that I know
01:19:10of unless doctor Baffa has
01:19:12something that,
01:19:14his group, is doing. So
01:19:16I actually think it would
01:19:17be,
01:19:18interesting to, you know, look
01:19:19into that a little bit
01:19:20more.
01:19:24I I will I will
01:19:25say that complete pathological response
01:19:27is not a simple,
01:19:31concept. I think,
01:19:33I would encourage anybody who
01:19:35reads papers that evaluate that
01:19:37to understand how exactly
01:19:40the esophagus
01:19:41resections were,
01:19:43examined.
01:19:44And when we examine post
01:19:46treatment esophagectomy
01:19:47specimen,
01:19:49we have a protocol where
01:19:50we examine the entire tumor
01:19:52bed histologically,
01:19:54and that can sometimes be
01:19:56really difficult to tell. So
01:19:57we end up submitting, you
01:19:58know, the entire area where
01:20:00the tumor might have been,
01:20:02if we can't identify,
01:20:04a a good tumor bed.
01:20:05So we're, you know, doing
01:20:06a complete assessment
01:20:08of that,
01:20:10of the tumor site.
01:20:12And I would say there's
01:20:14not,
01:20:17you know, depending on where
01:20:18you practice,
01:20:19that might be different.
01:20:21There might be different approaches
01:20:22of how pathology is assessed.
01:20:25And so I think
01:20:27before you sort of look
01:20:28at a paper and look
01:20:29at the pathologic complete response
01:20:31data, understanding
01:20:32what the protocol was to
01:20:34examine the esophagus is an
01:20:35extremely
01:20:36important exercise,
01:20:38because if they did not
01:20:39examine the entire tumor bed,
01:20:43you know, they might have
01:20:44missed that residual bit of
01:20:45cancer that was in there.
01:20:47And we see that. We
01:20:48see that. We we will
01:20:49submit an entire tumor bed,
01:20:50you know, let's say a
01:20:52three centimeter scar at, you
01:20:54know, above the g junction.
01:20:56We'll submit that, examine that
01:20:57in, you know, fifteen, twenty
01:20:59blocks, and there'll be cancer
01:21:00on one or two of
01:21:01them
01:21:03and not the rest. And
01:21:04so you really could miss
01:21:05it if you're not doing
01:21:06a complete pathologic response. So
01:21:07that's my one cautionary tale
01:21:09about that
01:21:10and data about that.
01:21:12But, yeah, I I don't
01:21:14I don't know the data
01:21:15offhand comparing
01:21:16the clinical versus pathological response.
01:21:19So that's something I would
01:21:20need to
01:21:21look into a little bit
01:21:22more.
01:21:23And I don't know if
01:21:24anybody else has,
01:21:27insight into that. I bet
01:21:28I'm sure Dan has some
01:21:29insight or, Kevin, I see
01:21:30you unmuted as well. I
01:21:32think you can flip a
01:21:33coin
01:21:34with a a complete response,
01:21:36and,
01:21:37and that'll be about as
01:21:39good as any,
01:21:40anything.
01:21:42To Dan's point, I think
01:21:44we we absolutely need better
01:21:46ways of assessing,
01:21:48such as circulating,
01:21:50you know, blood test, tumor
01:21:52markers, or, you know, even
01:21:54AI approaches.
01:21:56That's really the the most
01:21:57important question
01:21:59with chemoradiation
01:22:00and,
01:22:01these days, I think, and
01:22:03something which could really
01:22:06revolutionize
01:22:07the the field, I think,
01:22:08and really improve our patient
01:22:09care.
01:22:11Yeah. I I agree with
01:22:12that. It's it's about there's
01:22:14about a fifty percent false
01:22:16negative rate to the clinical
01:22:18evaluation. That is really what
01:22:20presaino showed. That's what,
01:22:23we'd found,
01:22:25when
01:22:26I was in Cleveland, and
01:22:28it's it's a pretty consistent,
01:22:30thing.
01:22:31But we know that not
01:22:32every pathologic
01:22:34complete responder is cured.
01:22:36So it's it's,
01:22:39but but the
01:22:40Joanna, that's a really interesting
01:22:42point that I didn't really
01:22:43think about is how,
01:22:46the processing does you know,
01:22:47I you know, you're
01:22:50nobody likes to look for
01:22:51things they don't wanna find.
01:22:53And,
01:22:54you know, it it's,
01:22:56it is interesting to know
01:22:58understand the different processing. That
01:22:59would be an interesting study
01:23:00is to sort of look
01:23:02at complete pathologic responders,
01:23:05have different centers look at
01:23:07the same things to see
01:23:08if there's concordance in that.
01:23:10But I think just looking
01:23:11at the protocols and sort
01:23:12of understanding how people are
01:23:14assessing
01:23:14that,
01:23:16that point, I think, would
01:23:17be interesting. Yep.
01:23:22And just on that note,
01:23:24you can see that a
01:23:25new study is forming at
01:23:26the end of this
01:23:28with
01:23:29this group.
01:23:30But I I mean, I
01:23:31also want to highlight the
01:23:32fact that we are very,
01:23:33very dependent on the pathologist
01:23:35for our decision making. So
01:23:37we're very grateful to having
01:23:38a very strong and collaborative
01:23:40pathology team at Yale that
01:23:42helps us make a lot
01:23:43of these decisions downstream.
01:23:45Deepika, are you unmuted? Can
01:23:47you share your thoughts on
01:23:49going for
01:23:50surgery? Hello?
01:23:52Is he here? Yeah. Yeah.
01:23:53I'm
01:23:54so sorry. I always do
01:23:55the voice test before I
01:23:56speak.
01:23:57So, yeah, as as for
01:23:59me, it was like after
01:24:00I finished
01:24:01my treatment with chemo and
01:24:03radio, my
01:24:04surgeon, he performed an endoscopy
01:24:07on me.
01:24:08And on that, he found
01:24:09a polyp.
01:24:10And I was actually, like,
01:24:11clinically well ever since my
01:24:13first
01:24:14dose, like, my first session
01:24:15of chemotherapy. So there was,
01:24:17like, never a question of
01:24:19not being a clinical responder.
01:24:21But when he found that
01:24:22polypony
01:24:23follow-up endoscopy
01:24:25and considering my age, like,
01:24:27he kind of
01:24:28counseled me and my family
01:24:30for his of a check
01:24:30to me. And,
01:24:32yeah, that's I think how
01:24:33I how I, like, cave
01:24:35into it.
01:24:36And that being said, I
01:24:37think the initial months were
01:24:39definitely very hard because
01:24:41I couldn't eat and,
01:24:43you know, I had dumping
01:24:44syndrome, and it was very
01:24:45hard.
01:24:46But right now,
01:24:48like, years down the line,
01:24:49I'm able to
01:24:51have a full meal and
01:24:53I'm much better.
01:24:54And just the fact that
01:24:56my parents and my family,
01:24:58we're all kind of, you
01:25:00know, happy that the main
01:25:02source
01:25:02of where the lesion was
01:25:04is gone from my body.
01:25:06So I think that's one
01:25:07sense of, like,
01:25:08relief that me and my
01:25:09family have.
01:25:11And my follow-up PET scans
01:25:12have also come out all
01:25:14clean.
01:25:15So I guess that also
01:25:17kind of helped me and
01:25:18my family make that judgment
01:25:20about
01:25:21to go or not with
01:25:23the suffragectomy.
01:25:24So, yeah, I think that
01:25:25really helped.
01:25:27Thanks, Deepika. This is really
01:25:29nice to hear your journey
01:25:30and, glad to hear that
01:25:31you recovered.
01:25:33I think part of the
01:25:35decision to do to operate
01:25:36would have also been that
01:25:37you were diagnosed at a
01:25:38very young age, and I
01:25:39think most people
01:25:41to to Gibson's point, most
01:25:42people wouldn't want to risk
01:25:44leaving any tumor behind. So
01:25:46that's great.
01:25:47I have a couple of
01:25:48questions on the chat. I
01:25:49think both I'll try and
01:25:50address.
01:25:51So one question is the
01:25:52question of looking at the
01:25:54addition of trastuzumab
01:25:55with FLOT for HER2 positive,
01:25:58adenocarcinoma.
01:25:59So we actually have the
01:26:00innovation trial that looked at
01:26:02this,
01:26:03with both trastuzumab as well
01:26:05as pertuzumab, not with FLOT,
01:26:06but with older chemotherapy regimens,
01:26:08which was negative.
01:26:10And so that study,
01:26:13didn't show any benefit in
01:26:14the addition of HER2 in
01:26:15the perioperative setting. And so
01:26:17we need to be careful
01:26:19about extrapolating data from the
01:26:20metastatic setting and moving it
01:26:22into the perioperative setting without
01:26:24having clinical trials support some
01:26:26of these data?
01:26:27The other question was any
01:26:28chance of improving on CROS?
01:26:31That part actually, the truth
01:26:32is, at least at Yale,
01:26:34we all firmly believe that
01:26:35CROS was not the best
01:26:36regimen from a chemo radiation
01:26:38perspective
01:26:39for adenocarcinomas,
01:26:41specifically
01:26:42for squamous cell cancers is
01:26:44a different story, and we
01:26:45think carboxyl in combination with
01:26:47radiation is beneficial.
01:26:50Importantly, the CROS regimen has
01:26:52a much lower dose of
01:26:53radiation with just forty one
01:26:55point four grammes, which is
01:26:56very different from a more
01:26:57definitive dose of radiation, which
01:26:59is fifty point four grammes.
01:27:00And the carbotaxol is at
01:27:01very low doses of chemotherapy,
01:27:03which is, fifty milligrams or
01:27:05kilogram of, paclitaxel weekly for
01:27:08five cycles and one point
01:27:09five,
01:27:11AUC of carboplactin,
01:27:12five for five cycles, which
01:27:14typically is not good enough
01:27:15for systemic control. And so
01:27:17most of the regimens that
01:27:18we use would have much
01:27:19higher doses of chemotherapy,
01:27:22with chemoRAS either using FOLFOX,
01:27:24like the CAOGB eight zero
01:27:26eight zero three regimen, or
01:27:27just having FLOT as a
01:27:29chemotherapy with,
01:27:31five FU oxaliplatin
01:27:32as well as docetaxel,
01:27:34to improve the perioperative outcomes.
01:27:36And this is an area
01:27:37of a lot of controversy
01:27:38and a lot of research,
01:27:41that people are people are
01:27:42working on.
01:27:44We are at the top
01:27:44of the hour, so I'm
01:27:45gonna take a chance take
01:27:46this opportunity to thank everyone
01:27:48for joining us today. Take
01:27:49this opportunity to have, have
01:27:52my fantastic panelists joining me
01:27:53and giving great talks, and,
01:27:56thank you very much for
01:27:57joining us today, and have
01:27:58a great evening.