Center for GI Cancers CME Webinar Series: Colorectal Cancer

Name: Center for GI Cancers CME Webinar Series: Colorectal Cancer
Uploaded: 2025-07-01T14:57:44.0733333Z
Duration: 1 h 6 min 12 s
Description: March 27, 2025 Presentations by Drs. Michael Cecchini and Haddon Pantel

July 01, 2025

March 27, 2025

Presentations by Drs. Michael Cecchini and Haddon Pantel

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ID: 13270
To Cite: DCA Citation Guide

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00:00Hello. My name is, Michael
00:02Giacchini. I'm an associate professor
00:04of medicine at the Yale
00:05School of Medicine.
00:07I'm a medical oncologist in
00:08the Yale Cancer Center.
00:10I'm co director of the
00:11colorectal cancer program and co
00:13director of the GI
00:14clinical research team here at
00:16Yale.
00:18I'm here with my colleague,
00:19doctor Pantel,
00:20one of our colorectal surgeons.
00:21I'll let him introduce himself.
00:24Thank you, Mike. My name
00:25is Hadden Pantel. I'm a
00:27colorectal surgeon also here at
00:29Yale.
00:30And, I just wanna thank
00:31everyone for taking time this
00:33evening to,
00:34hopefully learn some helpful things
00:36about, colon cancer and rectal
00:38cancer.
00:39So we'll be doing the
00:41Yale,
00:42CME for colorectal cancer for
00:43twenty twenty four, twenty twenty
00:45five.
00:46Originally, this is gonna be
00:47a three part session with
00:49myself, doctor Jacqueline Gaddy, and
00:51doctor Pantel, but this will
00:52be just doctor just the
00:53two of us,
00:54doctor Pantel and myself, this
00:56evening.
00:57We're gonna start with,
01:00my presentation.
01:01Doctor Pantel will moderate some
01:03questions,
01:04and then, the role will
01:05reverse. He'll present, and I'll
01:07I'll moderate some questions for
01:08him.
01:09We're we'll have, no more
01:11than a max of, an
01:12hour presentation,
01:14which will
01:15therefore give plenty of time
01:16for questions. This session will
01:17certainly not go any longer
01:19than one and a half
01:20hours. We'll we'll, frankly, probably
01:21be more along the hour
01:23mark.
01:24Please put your questions into
01:25the chat. Some questions may
01:27be answered directly by, response
01:30in the chat, but we'll
01:30try and,
01:31field the questions, to the
01:33presenter.
01:34If the question seems pertinent
01:35at the time of presentation,
01:36you may see doctor Pantel
01:38and myself interrupt each other
01:39to answer the relevant question
01:40at that time. Otherwise, we'll
01:42probably save some of these
01:43questions for the end of
01:44the presentation.
01:46So
01:47thank you so much. Let
01:48me get my presentation up
01:49right here.
01:54Alright. So,
01:56again, this is, our twenty
01:58twenty four, twenty twenty five
02:00ELCME for colorectal cancer, and
02:02thank you so much for
02:03joining us this evening.
02:05Here are my disclosures,
02:08and here's an outline for
02:09what I'm gonna talk about
02:10today. So We're still we're
02:11still really gonna Can you
02:12guys can I think your
02:13slides are gonna be pulled
02:14up?
02:16Oh, I'm sorry. I'm not
02:17sharing, am I?
02:20Good call there,
02:24Ed.
02:35That better? That looks perfect.
02:38That's actually a spec up
02:39there.
02:41Wouldn't be,
02:42wouldn't be, a presentation without
02:44a few technical difficulties, and,
02:46I'm not the chief technology
02:48officer here or anything.
02:49So,
02:50so this is, the twenty
02:52twenty four twenty twenty four
02:54twenty twenty five Yale CME
02:55for colorectal cancer. My disclosures
02:57again.
03:00And here's an outline for
03:01what I'm gonna discuss this
03:02evening.
03:04I'm gonna talk about,
03:05biomarker updates from the the
03:07past year. I'm gonna talk
03:09about,
03:11BRAFV six hundred e, obviously,
03:12a very important biomarker for
03:14our disease and some
03:16treatment. KRAS and HER2, we've
03:18got some updates there as
03:19well, some approvals in the
03:21last year with, you know,
03:22these,
03:23biomarkers.
03:24We'll talk about mismatch repair
03:26deficient,
03:27microsatellite instability, high disease. It's
03:29always a very important topic,
03:31and we have some very
03:31recent updates that I think
03:32are important.
03:34We have updates in ctDNA
03:36with the five year follow-up
03:37from the DYNAMIC study. We
03:39have the Altair results that
03:40tell us a little bit
03:41about what we can and
03:42can't do, perhaps with persistently
03:44positive circulating tumor DNA. We
03:46have a recent approval for
03:47anal cancer with retinphemimab
03:49that that we'll be discussing
03:50as well.
03:52Excuse me, not approval. We
03:53have a recent guideline change
03:54with retinphemimab.
03:57So how do we apply
03:58the biomarkers in twenty twenty
04:00five for,
04:01colorectal cancer?
04:03These are the biomarkers really
04:05that as as I see
04:06them at this point in
04:07time. We have KRAS,
04:10which is a sort of
04:11a negative biomarker for most
04:12patients in the first line
04:13setting. What we can't use,
04:15we can't use drugs like
04:16panetumumab
04:17and stuximab.
04:18We have KRAS g twelve
04:19c, our one actionable
04:21KRAS mutation that we can
04:22target with drugs.
04:24I'll come back to BRAF
04:25in a second. We have
04:27some rare fusions. Of course,
04:28we have TMB high, which
04:29is relatively rare, but microsatellite
04:31instability high, and we have
04:32HER2 amplified, maybe four percent
04:34of these patients, four percent,
04:35five percent each of these.
04:38So, again, we've we've done
04:40a good job, I think,
04:41over the last several decades
04:42of carving up this type
04:43of cancer into different molecular
04:45subtypes,
04:46but there's a lot of
04:47work to do in this
04:48maroon color, which has no
04:49biomarker, and the blue color,
04:51we're still,
04:52not able to really target
04:54most of these variants of
04:55KRAS. Although, that really may
04:56be changing with some of
04:57the new PANRAS inhibitors that
04:59we have in the clinic,
05:00which I could really think
05:01that could change dramatically how
05:03we think about this disease.
05:05But what about this subtype,
05:06the BRAF v600E,
05:08nine percent of metastatic colorectal
05:09cancer, one of the most
05:11aggressive molecular subtypes of the
05:13drug of the disease. We've
05:15used encorafinib, BRAF inhibitor with
05:17cetuximab
05:18as second line therapy for
05:20several years,
05:21since that was published in
05:22the New England Journal of
05:23Medicine
05:24as second line therapy. But
05:25first line key first line
05:27therapy has largely been chemotherapy.
05:29Olflox, Fulfirinox,
05:31plus appropriate biologic, which would
05:32generally be bevacizumab.
05:35What about moving things up
05:36to an earlier alliance? So
05:37that is what the breakwater
05:39study tried to do.
05:41This was just presented two
05:43two months ago at our,
05:44on our meeting ASCO GI.
05:46And this is this is
05:47a practice change in study.
05:49So this took patients that
05:51were,
05:54of appropriate age, had measurable
05:56disease,
05:57had and had never received
05:59any prior treatment for their
06:00metastatic disease, and, of course,
06:01had BRAF v six hundred
06:03e mutations,
06:04a class one mutation in
06:06BRAF. The BRAF protein functioning
06:08as a monomer to stimulate
06:10tumor growth as as an,
06:12oncogene.
06:14And,
06:16randomized patients in a one
06:17to one to one fashion
06:19are encorafenib and cetuximab,
06:21BRAF inhibitor and cetuximab,
06:23BRAF inhibitor
06:24plus cetuximab plus chemo plus
06:26FOLFOX six,
06:29versus standard of care options,
06:31FOLFOX, FOLFIREX, etcetera.
06:34This arm and craftsmanship of
06:35cetuximab,
06:36you can see that numerically
06:38smaller and that's because it
06:39closed earlier,
06:40and these are really the
06:41the arms that move forward
06:42for comparison here. The study
06:44was looking at progression free
06:46survival and overall response rate
06:47as a dual primary endpoint
06:49by Bicker by blinded review.
06:51And, of course, overall survival
06:53is a key secondary endpoint,
06:54which would kick in automatically
06:55depending on the response rate
06:57seen. So this is the
06:58way they built their study.
07:00Again, dual primary endpoints.
07:02If, overall
07:03response rate,
07:05was significant, then, then OS
07:08would be triggered for an
07:09interim analysis. And as we'll
07:11get to, this is exactly
07:12what happened given the higher
07:13response rate.
07:14This was a balanced,
07:16study. Again,
07:18chemotherapy plus engraftment, cetuximab versus
07:20standard of care. Most of
07:22these patients had right sided
07:24tumors, which is what we
07:24would expect for this disease,
07:26certainly a worse prognosis for
07:28this,
07:29this subtype of colorectal cancer
07:31and frankly the worst molecular
07:32subtype in terms of prognosis.
07:35Two thirds of patients are
07:36more or less had liver
07:37metastases in this study.
07:39And again,
07:40we're we're quite advanced overall.
07:42This is the response rate
07:44that we saw, so sixty
07:45point nine percent, so sixty
07:46one percent essentially
07:48with this FOLFOX and graphonamocetuximab
07:50versus forty percent with the
07:52standard pair of of chemotherapy
07:53alone.
07:54So certainly,
07:56a substantial improvement in response
07:59rate. When we look at
08:00duration of response, also very
08:01impressive. More than six month
08:03duration of response, forty six
08:05percent with with with the
08:07investigational arm versus only fifteen
08:09percent of the chemotherapy arm,
08:11so improving durability of these
08:13responses. Still have a ways
08:14to go, though. As you
08:15can see that that the
08:16year mark, this does drop
08:17back down to fifteen percent.
08:19So that's great. It's important
08:21to get responses, but this
08:22is really what matters. Are
08:23we making our when we,
08:26intensify chemotherapy,
08:27are we just seeing responses
08:29but survival is ending up
08:30the same?
08:31This was the overall survival
08:33that we saw.
08:35This is an interim analysis
08:36and even though you see
08:37a very impressive hazard ratio,
08:39point four seven and a
08:40low p value at this
08:42interim
08:43analysis, it was you know,
08:44very strict in terms of
08:45statistical design. This actually technically
08:48does not achieve statistical significance,
08:50but it is an interim
08:51analysis.
08:52Obviously, this is a very
08:53promising first step,
08:55and,
08:56the response rate and,
08:59it speaks for itself as
09:00well. And based on this,
09:02there was there was an
09:04approval granted for this in
09:05the frontline setting.
09:07When we look at the
09:07subgroup analysis, this is what
09:09we saw. So you can
09:10see this to the right
09:12of this line favors
09:13the encorafenib, stuximab with FOLFOX.
09:15So another way of putting
09:17it is base basically, all
09:18subgroups seem to benefit from
09:20this. And where does this
09:21land?
09:22Even though this was just
09:23presented in January, we've already
09:25got it now into our
09:26national guidelines.
09:27So So for BRAFV600E
09:29mutation positive, encorafenib
09:31with appropriate biologic, which would
09:33be an EGFR inhibitor plus
09:34FOLFOX, has become the standard
09:36of care. Of course, there
09:37may be patients you think
09:38can tolerate this,
09:40and and
09:41those patients could still get
09:43full thoughts if they had
09:44some contraindication to nacorafenib, vesituximab,
09:47or pematumumab,
09:48or something like that. But
09:49I do think the majority
09:50of patients will be getting
09:51this regimen going forward.
09:55So
09:56that was BRAFV six hundred
09:58d, this slice of the
09:59pie.
10:00What other slices of this
10:01pie have we made an
10:02impact on in the last
10:03year?
10:04So KRAS g twelve c
10:05has certainly been an evolving
10:07story over the last few
10:08years, but there was there
10:09were two approvals with KRAS
10:11g twelve c in the
10:12last year that I wanna
10:13highlight.
10:14Adagracin,
10:15KRAS g twelve c inhibitor,
10:17and sotorasib
10:19were both granted FDA approval
10:20for advanced CRC this this
10:22past year. You know, these
10:23have been in guidelines for
10:24a little bit. Many of
10:25us may have been familiar
10:26with their use from managing
10:28lung cancer, but now,
10:30a full FDA approval for
10:32sotorasib
10:32and, again, accelerated approval for
10:34adagracib.
10:36Both of those agents available.
10:37I think this is a
10:39a very important
10:41breakthrough in the management of
10:43colorectal cancer is is is
10:45targeting these, molecular subtypes. Again,
10:48personalized
10:49medicine, getting the right drug
10:50to the right patient at
10:51the right time.
10:52So this is
10:54some data from the sotorasib
10:55study. You can see here
10:57that, sotorasib and pantetumumab,
11:00was better than standard of
11:01care for advanced patients. Again,
11:03this is advanced patients.
11:05There are studies going on
11:06to move this this therapy
11:08up into an earlier line
11:09of therapy.
11:10When, we look at the
11:11median progression free survival for
11:13advanced patients that have progressed
11:14on biflopyrimidine,
11:16oxaplatin or in a T
11:17can, etcetera, then the median
11:18progression free survival with the
11:20standard of care arm was
11:21two months. That's the time
11:22of the scan, right? That's
11:23the time of scan. We
11:24We scan every eight weeks.
11:25So basically, standard of care
11:27doing very little for these
11:28patients, whereas the investigational arm,
11:30had a PFS of five
11:31point six two months. I
11:33think we still have a
11:34ways to go to to
11:35to prolong that.
11:37Moreover, I think moving these
11:38drugs up earlier on in
11:39the line of treatment, which
11:40is under active investigation,
11:42will,
11:44will,
11:45make an a a better
11:46impact. Make giving these drugs
11:48earlier in somebody's treatment course,
11:49I think we'll we'll get
11:50more effectiveness from them. But,
11:52certainly, this now is a,
11:54a reasonable option for our
11:56patients essentially in the third
11:57line setting that are about
11:58there or I prefer the
12:00term five floor pyramid in
12:01refractory setting.
12:03So some of the data
12:04from AdaGradsson, the other g
12:05twelve c inhibitor, you can
12:07see this is from the
12:08New England Journal paper that,
12:10that supported its approval. You
12:12can see, in this waterfall
12:14plot, the majority of these
12:15bars going down indicating cytoreduction
12:17and about, half of them
12:19crossing
12:20the the thirty percent threshold
12:22of partial response. You can
12:23see, again, similar PFS, similar
12:26OS for a very advanced
12:27patient population.
12:29So I think these numbers
12:30can only improve,
12:32as we make these options
12:33available earlier in the course
12:34of treatment for our patients,
12:36which hopefully future studies will
12:38show.
12:39So what do we also
12:40see? We also saw on
12:41our NCCN guidelines that KRAS
12:43g twelve c mutation positive
12:44patients,
12:46should be receiving sororacin or
12:47adagracin
12:48with, appropriate,
12:51biologic therapy, eGFR, and,
12:55either could be appropriate.
12:57What about HER2NU? We saw
12:59some updates at ASCO in
13:00June of this past year
13:01from the MOUNTAINER study. This
13:03is actually the final update
13:04from this study. I'll just
13:05highlight it in a couple
13:06of slides because, again, it
13:08is, speaking to this theme
13:09of of of biomarker,
13:12by of of these rare
13:13biomarkers for colorectal cancer that
13:15are highly
13:16highly actionable.
13:18So this,
13:19was a study,
13:21that evaluated patients that are
13:23were essentially,
13:25on their third line of
13:26treatment for colorectal cancer. So,
13:28again, prior,
13:30five flirapyrmidine
13:31refractory essentially here. Then we're
13:32getting a small molecule tucatinib
13:35with antibody trastuzumab,
13:36HERD and HER2.
13:38And this was,
13:40really the arm that was
13:41investigated. You can see forty
13:43one plus forty five in
13:44over eighty patients.
13:46Per FDA requirements, they were
13:47required to look at TUKAT
13:49and monotherapy to really determine
13:51determine separation of components.
13:53But these were the arms
13:54that biologically really made the
13:56most sense, frankly,
13:57and,
13:59were were reused as the
14:01main efficacy analysis to to
14:03look at the effectiveness of
14:04the drug.
14:05So what were the final
14:06outcomes from the study? We
14:07can we can see here
14:09that Doctor. Strickler presented this
14:11at ASCO in June a
14:12response rate of thirty nine
14:14percent, so close to forty
14:15percent response rate.
14:18Durable response is fifteen point
14:20two months, median progression free
14:21survival, eight point one months,
14:23median overall survival, twenty four
14:25months. This is for patients
14:27in the third line setting.
14:29These are numbers that we
14:30would typically expect to see
14:31in the first line setting.
14:32So very promising targeted therapy
14:34for patients.
14:35May main side effect of
14:37the combination being diarrhea to
14:38watch out for,
14:40but, overall, thought to be
14:42a good alternative to the
14:43chemotherapy options these patients have
14:46in these later lines. Whether
14:47or not this will translate
14:48to moving it up earlier
14:49is being evaluated in, additional
14:51studies including first line study
14:53now.
14:54But, this has now become
14:56the, really the standard of
14:58care for HER2
14:59positive disease,
15:01in the refractory setting.
15:04One other very important biomarker
15:06is mismatch repair deficiency, and
15:08this is a biomarker that
15:09comes up very regularly in
15:11our conferences and very regularly
15:13in my discussions with patients
15:14because of the the impact
15:16immunotherapy could have on these
15:18patients,
15:20which we've we've we've known.
15:21Right? We've known keynote one
15:23seventy seven,
15:24immunotherapy is better than chemotherapy.
15:27Pembrolizumab,
15:29in blue here, showing the
15:30prolonged progression free survival compared
15:32to chemotherapy.
15:34The,
15:36immune check on inhibitors like
15:37pembrolizumab, nivolumab, glumab have been
15:39used in the factory setting
15:40for some time, but moving
15:41them up into the first
15:42line was what one seventy
15:44seven did for the first
15:45time,
15:46and it showed an impressive
15:48PFS benefit. Because of their
15:49use later, the the OS
15:51benefit has not been,
15:53shown or reported yet, and
15:55I think will likely take
15:56a long time,
15:57to see to see that.
16:00Hazard ratio, so pembrolizumab protein
16:02works better in in all
16:04subtypes.
16:06But what's new what's new
16:08is Checkmate h w.
16:10This is a story that
16:11the has been evolving for
16:12a couple of years for
16:13this trial because it's a
16:15three arm trial. And what
16:16do we see first?
16:17We saw,
16:19the nivo arm presented,
16:21and now what we're seeing
16:23is the nivoipi arm,
16:25versus,
16:27versus,
16:28chemotherapy.
16:30At first, we saw the
16:32the,
16:33the nivo ipi arm versus
16:35chemotherapy. Excuse me. And then
16:36now we're seeing nivo versus
16:38ipi nivo, which is really
16:39the comparison we wanted to
16:40see all the whole time.
16:42We already knew that immunotherapy
16:43should be not chemotherapy from
16:45keynote one seventy seven.
16:47So we saw this last
16:48step GISCO.
16:50So this
16:51is important
16:52data to have, but but
16:53in many ways, this isn't,
16:56this isn't necessarily changing the
16:58paradigm,
16:59completely. So this was ipinivo,
17:02dual immune checkpoint blockade,
17:03versus nivolumab,
17:05excuse me, versus chemotherapy,
17:08alone.
17:09And you can see very
17:11big separation of these curves
17:12here. Not even reached medium
17:14pressure free survival.
17:17Very impressive durability.
17:19Ipinivo
17:20clearly outperforming chemotherapy
17:22here. But, again, what we
17:23need to see is is
17:24two main immune checkpoint better
17:26inhibitors really better than one
17:27because it could be potentially
17:28more toxic. So, that's what
17:29we that's what we got
17:31to see this year at
17:32at GISCO in twenty twenty
17:34five. We saw NivoIPI
17:36versus IPI.
17:37This is first line therapy
17:39for mismatch repair deficient tumors.
17:41Moreover,
17:43central confirmation
17:44was done for mismatch repair
17:46steps which is really important,
17:48and wasn't done in t
17:49note one seventy seven.
17:51So ipinivo
17:52did though demonstrate improved PFS
17:54compared to nivolumab.
17:56This This was simultaneously published
17:58in The Lancet, so this
17:59is the reference from The
17:59Lancet. If we look at
18:01the central confirmation of microcecal
18:03instability high where we can
18:04be darn certain that the
18:06tumor is truly mismatch repair
18:08deficient,
18:09This is a kind of
18:10separation we can we see
18:11here. So, again, chemotherapy that
18:13those curves were down here,
18:14but, we are collecting very
18:16clear separation that ipinivo
18:18has a as an improved
18:19PFS. You can see highly
18:20statistically significant, has your ratio
18:22of sixty two,
18:24And the
18:25whole monomonee centrally confirm,
18:27subset of patients,
18:29it's very similar numbers. So
18:30it does seem that ipinivo
18:31will be better than nivolumab.
18:33What about in the subgroup
18:34analysis when we look just
18:36about all subgroups,
18:38were were favored using the
18:39dual immune checkpoint block blockade?
18:42What about response rate?
18:44Well, if we just look
18:45at the, oh, the the
18:47the number of overall response
18:48rate, you see it's seventy
18:49one versus fifty eight percent
18:51with two immune checkpoint inhibitors
18:52versus one immune checkpoint inhibitors.
18:54Notably, this is way higher
18:56response rate than we saw
18:57with, in keynote one seventy
18:58seven and pembrolizumab.
18:59Again, that may have some
19:00things to do with the
19:01central confirmation,
19:03mismatch repair status testing,
19:06or there could be other
19:07other reasons for that. So
19:08higher response rate, better progression
19:10free survival.
19:11What about toxicities?
19:12Not unexpected to see more
19:14toxicities with Duo immune checkpoint
19:16blockade. With the dose of
19:18ipi we use now, Certainly,
19:19these are more much more
19:20manageable.
19:22And I think when you
19:22really just look at the
19:23totality of grade three of
19:24VersaVent's twenty two versus fourteen
19:26percent,
19:27is,
19:28is different, but, is is
19:30not dramatically different. And I
19:32think many of these we've
19:33become able to manage effectively.
19:35But, frankly, there are some
19:37patients that will be left
19:38with lifelong,
19:42endocrine
19:43disorders,
19:44and that needs to be
19:45taken into account.
19:46So at the end of
19:47the day, though, I think
19:48ipnivo is,
19:50become standard of care for
19:52a lot of patients with
19:53first first line mismatch repair
19:55deficient tumors. I think for
19:56patients that you're more worried
19:58about toxicities
19:59or that have lower burdens
20:00of disease, it's not unreasonable
20:02to think about the single
20:03agent and IPD one if
20:04you're concerned about toxicity.
20:07But, APNivo is what I
20:09am using in
20:11the majority of my practice
20:12for patients first line with
20:13this disease now
20:14given that very dramatic durability
20:16of the curve.
20:17So what's my summary for
20:19the approach to biomarkers in
20:20twenty twenty five?
20:22Your FE six hundred d,
20:23what what changed?
20:25What changed is now we
20:26use fofloxacin, carafenib, zetuximab as
20:28first line. K. RS g
20:30twelve c. What changed? Well,
20:31now we have these approved.
20:32Now they're FDA approved.
20:35There's not just just data.
20:36There's approval
20:37behind them. So for flow
20:39of permeating refractory CRC with
20:41the appropriate eGFR inhibitor given
20:43alongside,
20:44Whether or not we get
20:45to start,
20:46considering that in the first
20:47line setting will depend on
20:48how some of these other
20:49trials read out. Tucatinib and
20:51trastuzumab
20:52is the only HER2 directed
20:53therapy
20:55FDA approved for
20:57for
20:59HER2 positive colorectal cancer. Although
21:01there are other agents, trastuzumab,
21:04lepatent and trastuzumab,
21:07DS,
21:08eighty two zero one a,
21:09that that can be considered
21:11for,
21:12considered as well. But this
21:14is the FDA group regimen.
21:15This is what I use
21:15in the majority of my
21:16patients, the first HER2 directed
21:18therapy.
21:19Although,
21:20trastuzumab
21:21drugs, TCAN, yeah, is is
21:22certainly something I use, if
21:24there's a KRAS mutation present
21:26or if
21:27like, in addition to the
21:28HER2 or if, patients are
21:31too congestive in refractory.
21:33And then now what changed
21:34with deficient mismatch repair? I
21:36think ipi, limumab, and nivolumab
21:38as first line therapy has
21:39become my standard,
21:41except in circumstances where I
21:43think that toxicity is my
21:44major concern
21:46and,
21:46and maybe disease burden is
21:48lower.
21:50So I'm gonna pivot now
21:51to,
21:52localized disease.
21:55I'm not gonna talk as
21:56much about localized disease in
21:58the management about around the
22:00perioperative setting, but I'm gonna
22:01talk about,
22:03what we do with that,
22:04some of some of the
22:05biomarkers for adjuvant therapy.
22:07So we've seen,
22:09the dynamic study presented at
22:11ASCO a couple of times.
22:12It's
22:12been published in the New
22:14England Journal of Medicine initially
22:15at the two year mark,
22:17and then now this is
22:18the five year follow-up from
22:20the DYNAMICS study. And so
22:21the DYNAMICS study sought to
22:23evaluate patients with stage two
22:25colorectal cancer
22:27and evaluated for the presence
22:28or absence of circulating tumor
22:30DNA.
22:31And if patients had positive
22:33circulating tumor DNA,
22:35they were deemed high risk
22:37and and,
22:38and given adjuvant therapy. And
22:40if patients didn't have circulating
22:41tumor DNA,
22:43then,
22:44then they when they were
22:45not, so given therapy.
22:50So this is the the
22:51kind of the breakdown of
22:52patients,
22:54and and adjuvant therapy could
22:55be by the way, it
22:56could be well, I guess,
22:58we have it here. It
22:59could be,
23:00just oxaliplatin
23:02it's,
23:03just floropyrimidine
23:04or it could be,
23:06oxaliplatin
23:07oxaliplatin based chemo.
23:09When you look at these
23:10numbers, they look low because
23:11why? The majority of patients
23:12who you test for ctDNA
23:14will be negative, even the
23:15ones that relapse.
23:17So,
23:20about twenty percent of these
23:21patients were mismatch repair deficient.
23:23And And, again, you can
23:24see very few, well, fifteen
23:26ish percent were t four
23:27disease. So the majority of
23:28these, patients would be t
23:30three n zero, so earlier
23:31stage
23:32t earlier stage two tumors.
23:35And what do we see?
23:35We saw, well, look, if
23:36if you look at the
23:37ctDNA guided management versus the
23:39standard management,
23:42so in the blue line,
23:43if you're positive, you got
23:44adjuvant therapy. If you're negative,
23:46you didn't. And if you're
23:47in the red line, we
23:48we did the standard management,
23:49so the typical histopathologic
23:51risk factors.
23:54You can see very little
23:55difference in overall survival,
23:57although arguably, maybe five year
23:59overall survival is,
24:01not even long enough for
24:02stage two disease.
24:04But what about when we
24:05start to look at cancer
24:06specific survival?
24:08Again, not much difference.
24:09And looking about recurrence free
24:11survival, again, not much difference
24:13with CTD guided management versus
24:15standard management.
24:17If not much different, then
24:18why use it? The whole
24:19this was all predicated on,
24:21trying to use less oxaliplatin,
24:23less neuropathy, less chemotherapy, less
24:25complications from chemotherapy
24:27with CTD,
24:28DNA guided management.
24:32But I think that when
24:33you start to look at
24:34some of the details of
24:36the subgroups, it's important to
24:37know who this is a
24:38good strategy for and who
24:39this
24:40is not as good of
24:41a strategy for. So,
24:44there are patients that are
24:45gonna have high risk features
24:47that may be ctDNA
24:48negative.
24:49And what should trump what?
24:51Should ctDNA
24:52negative negativity trump t four
24:55status,
24:56other high risk histopathological features?
24:59I would argue it should
25:00not trump p four status,
25:01and this curve,
25:02is part of my my
25:03thinking on this.
25:05This is a similar curve
25:06that that was presented in
25:08the two year follow-up as
25:10well. For patients that are
25:11CT
25:12that are negative, everybody on
25:13this slide here has is
25:15CT
25:16DNA negative.
25:17But if your t four
25:19if you have a t
25:19four tumor and you're
25:21negative, you still have a
25:23close to a twenty percent
25:25risk of recurrence.
25:27And I I don't think
25:29that, that's, justifiable
25:31to kind of omit,
25:33chemotherapy based on this alone.
25:35Again, this is a share
25:36an opportunity for shared decision
25:38making with patients,
25:40but,
25:40I I worry that the
25:41negative predictive value in t
25:43four disease,
25:44is not as good as
25:45it could be.
25:48This was another important piece
25:50of data, I think, that
25:52many of us were in
25:53and,
25:54excited to see, at GISCO,
25:57was, well, what about what
25:58else about ctDNA can we,
26:00can we do differently in
26:01twenty twenty five? This was
26:03a study that took patients
26:05after chemotherapy,
26:07after the surgery, I guess,
26:09first, and then after adjuvant
26:11chemotherapy.
26:12And And it evaluated patients
26:13that were positive, either right
26:15after that chemotherapy finished or
26:17when they were minimally residual
26:19disease positive when that they
26:21had a ctDNA recurrence, and
26:23tried to say, can I
26:24cure more patients
26:27by giving additional systemic therapy?
26:30So patients had cured of
26:31resection. Could have been stage
26:33four. Could have been cured
26:34of liver metastatic resection or
26:35could have been a root
26:36section of that stage two
26:38tumor, stage three tumor.
26:40They got the chemotherapy for
26:42three months, six months, whatever
26:43it was, and then they
26:45got a c tDNA positive
26:47that could have been
26:48it two months later
26:50or eight you know, eleven
26:51months later.
26:53If they had that positivity,
26:54they were randomized one to
26:55one to control
26:57arm of placebo
26:59versus experimental arm of,
27:02trifluridin to bristle,
27:05and,
27:06followed for three years.
27:09And the main endpoint was
27:11looking at disease free survival.
27:12And so what do we
27:14see? We
27:15so this is, again, placebo
27:17in red,
27:19investigational arm in blue,
27:22a hazard ratio point seven
27:23nine that was not statistically
27:25significant for disease free survival,
27:27but treating these persistently
27:29positive,
27:30tumors,
27:31with additional systemic therapy. When
27:33looking only at the patients
27:34with stage four disease,
27:37the hazard ratio was was
27:39a bit better and the
27:40p value also a a
27:41bit better.
27:43But when certainly, when looking
27:44at all patients, there didn't
27:46seem to be as much
27:46of a benefit.
27:48And, again, this is disease
27:50free survival, and you can
27:51see,
27:52at,
27:53as as the curve as
27:55as time goes on, the
27:56curves do get closer and
27:57closer to, unfortunately, zero. So
27:59what I think we're mostly
28:00just delaying recurrences in those
28:02set settings
28:03rather than,
28:04rather than enhancing cure.
28:07So the summary, I think,
28:08now for ctDNA
28:09is still incredibly prognostic,
28:12in the adjuvant setting. For
28:14patients with t four stage
28:15two colorectal cancer, I to
28:17me, recurrent risk remains high
28:19even if even in the
28:20ctDNA
28:21negativity setting.
28:23So, I would argue that
28:24the negative predictive value is
28:26not not not sufficient to
28:29recommend widespread use,
28:31to omit therapy.
28:33Additional studies going on in
28:35that space,
28:36some of them here.
28:38We don't have really any
28:39data to support treating patients
28:41with persistently positive ctDNA after
28:44adjuvant therapy. So that's, with
28:46additional systemic therapy. So for
28:47somebody that has minimally residual
28:50disease positivity,
28:51I after chemotherapy,
28:53I would not recommend giving
28:55that patient additional chemotherapy.
28:58If there's a treadmill, that's
28:59one thing, but I wouldn't
29:00do with any of the
29:01standard agents.
29:03And so I'm gonna I'm
29:05gonna finish with,
29:06a a quick discussion about
29:08anal cancer.
29:10So the podium,
29:11the podium study,
29:13I think that this is
29:14a a very important study
29:15for a a disease that,
29:19has not seen as much
29:20development as we would like
29:21over the last,
29:23decade.
29:25Evaluating patients with,
29:27metastatic,
29:28so no prior treatment for
29:29metastatic disease, all the way
29:31to those,
29:32neoadjuvant therapy and relapse
29:35with carboplatin,
29:36plus retin filumab,
29:38anti p one,
29:39and,
29:41versus placebo plus carboplacam,
29:43craglitaxel.
29:45And,
29:45the,
29:47the the the trial's
29:49primary endpoint was PFS, but
29:51also, of course, looking at
29:52overall survival.
29:53So, it was a well,
29:55well designed study.
29:58We use a very reasonable
29:59size. This is a hard
30:00study to do in this
30:01subtype of the disease,
30:03as many of these patients
30:04are cured. But those that
30:06are not cured have a
30:07very poor survival, and, it's
30:09a rare cancer to begin
30:10with.
30:12So we saw it was
30:13primarily,
30:15primarily a female population, primarily
30:17white.
30:18So that gives us some
30:19questions about generalizability.
30:23And then patients,
30:25a lot of about a
30:25third of patients with both
30:26arms had metastatic disease, very
30:28low rates of HIV positivity.
30:30Again,
30:31these are raising questions about
30:33generalizability.
30:34Most patients had some PD
30:35L1 expression. So what did
30:37we see for progression free
30:38survival?
30:39We saw nine point three
30:40versus seven point four months.
30:42So you see there is
30:42some separation of these curves
30:44here. This is statistically significant.
30:45A hazard ratio of point
30:46six three. This looks great.
30:48Definitely suggest that rifapilimumab
30:51is playing a role,
30:52in the improvement here. And
30:54when we look at overall
30:55survival, you can see, again,
30:57twenty nine point two months
30:58with the,
30:59immunotherapy
31:00added on to the carboplatin
31:02versus twenty three months with
31:03the chemotherapy alone.
31:05Hazard ratio, point seven. P
31:06value, less than point o
31:08five. Although, because this was
31:09an interim
31:11look at the,
31:13at the overall survival, this
31:15doesn't technically meet statistical significance.
31:17But, again, this is interim.
31:19I think many of us
31:20expect this to,
31:22hold over time and and
31:24gain statistical significance.
31:27This made it as a
31:28category
31:29two b, so,
31:31a recommendation as first line
31:32therapy. I think when the
31:33overall survival data is mature,
31:35as long as it supports
31:36its use, I would expect
31:38this this recommendation to become
31:40a bit firmer. But at
31:41the moment, it is a
31:42category two b,
31:45for first line therapy.
31:47So I'm gonna end here.
31:50So I just wanted to
31:51quickly summarize and unpack some
31:53of the the,
31:54points we discussed. And BRAFV600
31:57e now has a, a
31:59new approval and a new
32:00strategy for first line treatment
32:02with Foflox, engraft, and ipincetuximab,
32:04the standard of care for
32:06metastatic disease,
32:08as the initial therapy now.
32:10Ipilimumab
32:11and nivolumab should be considered,
32:12I think, for the majority
32:13of patients as initial therapy,
32:16added for mismatch repair deficient
32:18disease,
32:19adagrasimstuximab,
32:20seracipentumab,
32:22both acceptable regimens for refractory
32:24g twelve c mutated tumors.
32:26And I think while ctDNA
32:28is very promising,
32:30its negative predictive value,
32:32is is not sufficient for
32:34me to use it as
32:35a as a a a
32:37tool to omit,
32:39adjuvant therapy for patients with
32:41PT four disease,
32:43where recurrent rates still are
32:45around twenty percent.
32:47And I'm very encouraged by
32:48the data with retinolumab.
32:50I'm I'm looking forward to
32:52the overall survival, hopefully, at
32:53a future congress.
32:56I will
32:57stop here, and we can
32:59we can discuss any questions
33:01that
33:03hadn't you ended up come
33:05through or that you wanna
33:06ask, and then I will
33:07pass the baton over to
33:08you for your presentation.
33:09Alright. I'm gonna start with
33:11an audience question that I
33:12might have my own. So,
33:13question from the audience. First,
33:15they said amazing presentation.
33:17So
33:18agree completely.
33:19The question was, do you
33:20see any prospect of vaccines
33:22for treatment in colorectal cancer
33:23in the future?
33:25Yeah. What a great question.
33:28So I,
33:30as I mentioned, co direct
33:31our colorectal cancer program
33:33and treat patients with standard
33:34of care treatments. But I
33:36also am a phase one
33:37investigator here at Yale. So
33:38I,
33:40have been involved in a
33:41number of vaccine trials
33:43and,
33:44certainly follow this literature.
33:47I I do think that
33:48the promise of vaccines
33:50is is is very solid.
33:53The
33:54problem thus far has really
33:56been how we've studied vaccine
33:58based therapies.
34:00I think the paradigm
34:02of drug development has been
34:03to study drugs in the
34:04advanced setting first, make sure
34:06you see a signal,
34:07and then hopefully move them
34:08up earlier.
34:09But vaccines, I think, maybe
34:11it's certainly different.
34:13And maybe arguably, that should
34:15all be different. But but
34:16vaccines, I think, we're probably
34:18not setting ourselves up for
34:19success in terms of their
34:21effectiveness
34:22in the treatment refractory setting
34:24and where the immune system
34:25is a lot more dysfunctional
34:26or tumor burden is very
34:28high.
34:29Probably as a rule for
34:31immunotherapy, but but I think
34:32vaccines may be even more
34:33extreme example of that.
34:35And so I we've seen
34:37data in pancreas cancer,
34:39another cancer with, I arguably,
34:41a very high unmet need
34:43like colorectal cancer
34:45that a vaccine in the
34:46adjuvant setting when there is
34:47no visible cancer,
34:49showed promise in a small
34:50subset of patients because that's
34:51all that was studied.
34:53And we've seen some of
34:54that data actually for colorectal
34:56cancer too. There's a Nature
34:57Medicine paper with a KRAS
34:59vaccine
35:01that,
35:03I I think looks promising
35:04for patients that had liver
35:05metastases resected then didn't have
35:07any evidence of disease. So,
35:09again, the authors of that
35:10study was published in,
35:12it was nature it was
35:13one of the nature journals,
35:15that looked at it in
35:16a minimal the the authors
35:17looked at it in the
35:18minimal residual disease setting, but
35:20after a metastectomy, and they
35:21showed certainly showed impressive signals
35:24of potential success, and I
35:25hope that work will continue.
35:27So I do I do
35:28think there is a role
35:29for vaccines.
35:30I think we need to
35:30be smart about how we
35:31use them, and it's it's
35:33it's moving these types of
35:34therapies up earlier in,
35:36in the in the treatment
35:37paradigm
35:38even even for their early
35:39development.
35:41So yeah.
35:44Alright. Well,
35:45I I completely agree with
35:47the previous
35:49person about,
35:50great presentation.
35:53In in disclosure, we I
35:54asked I asked doctor Keeney.
35:55I said, do you have
35:56any questions you want me
35:57to ask? And he said,
35:57no. I'm gonna be on
35:58my toes. He'll be set
35:59to be ready for anything.
36:00So,
36:01just a little bit about
36:02detail. I really liked what
36:03you talked about, the DYNAMIC
36:04study.
36:06You said that,
36:07where did those T4 patients
36:09recur? I wonder if you
36:10think that the T4 patients
36:11were much more likely to
36:12recur as peritoneal based disease
36:14as opposed to nodal or
36:15liver metastases,
36:17and maybe that's why circulating
36:19tumor DNA was not so
36:20effective in picking it up.
36:22Can you explain on it?
36:24Site specific,
36:25utility for ctDNA, you know,
36:27perineal versus more hematologic or
36:29lymphatic?
36:31Yeah. No. That's a great
36:32question.
36:33I think the
36:35unfortunately, we don't have the
36:36data from the paper. If
36:37it's in there, I would
36:38have to look in the
36:38supplementary
36:39for where the recurrence was
36:41though. But you do bring
36:42up some good points. Well,
36:43so first of all, one
36:44of the points is unfortunately
36:46t four disease
36:48is incredibly prognostic. Obviously, lymph
36:50node status is two,
36:51but we know that stage
36:53three a tumors have a
36:54better survival, frankly, than T4
36:56tumors that are just stage
36:57two. So,
36:59so that's a very important
37:00prognostic
37:01marker just for relapsed anywhere.
37:04But as you point out,
37:05are there different areas of
37:06the body
37:07that recurrence is more likely
37:09to be detected by circulating
37:10tumor DNA? And the answer
37:11is certainly yes.
37:13Makes sense if there's hematogenous
37:15spread,
37:17a blood based test may
37:18be better picking that up.
37:20So peritoneal disease is a
37:21a little bit of a
37:22blind spot, I would say,
37:23for for circulating tumor DNA.
37:25Now that does not mean
37:26you cannot have a positive
37:27result for peritoneal disease, but
37:30certainly it seems like you're
37:31less likely to have that
37:32compared to a liver metastases
37:34or a lung metastases or
37:35something like that. I think
37:36liver metastases
37:37are probably the strongest
37:40correlation to having a a
37:41positive ctDNA.
37:48Alright.
37:49Well,
37:50please put your additional questions
37:52through the chat. We'll have
37:53some time for kind of
37:54both of us to answer
37:55them at the end. But
37:56now I'm gonna pass the
37:57baton over to doctor Hatten
37:59Pintell to do his his
38:00presentation.
38:01Alright. Tough act to follow.
38:04Hopefully, I think I'll be
38:05around the twenty minute mark,
38:06and we should be,
38:08hopefully done around,
38:10seven. So I'm gonna just
38:11share my screen here.
38:15Let's
38:16see.
38:24Alright. Does that look okay
38:26just before I get started?
38:29It does. Yes. Okay. Alright.
38:32So thank you everyone for
38:33your time this this evening,
38:35and,
38:36hopefully, this just, generates some
38:38questions and and, hopefully, some
38:40answers as well. So I'm
38:41Hadden Pantel. I'm a colorectal
38:43surgeon here.
38:45These are my disclosures.
38:48Before I start into a
38:49little bit of the education
38:50part, I actually just wanna
38:51start with a call to
38:52action.
38:53So as as, hopefully, some
38:55of you guys know,
38:56March is Colorectal Cancer Awareness
38:59Month.
39:00And,
39:02I've sort of started thinking
39:03about that a fair amount.
39:04I actually started thinking about
39:05this even back when I
39:06was a fellow. I, you
39:07know, I it's most people
39:09are probably aware October is,
39:11Breast Cancer Awareness Month. I
39:13think, one is a high
39:15prevalence of disease, but Breast
39:17Cancer Awareness Month, has these
39:19very high profile,
39:21public health campaigns supported by
39:23the NFL,
39:24Major League Baseball.
39:26There's a lot of,
39:28industry and marketing tie ins
39:29with pink ribbons and wearing
39:32pink and things like that.
39:34So it's been, you know,
39:36a very highly visible,
39:38you know, public health awareness
39:40campaign.
39:43You know, how have we
39:44done?
39:45So two thousand one is
39:47when March was,
39:48designated as Colorectal Cancer Awareness
39:51Month. That was under, Bill
39:52Clinton.
39:53And,
39:55since that time, you know,
39:56there's been a lot of
39:57things to raise,
39:59awareness.
40:00I think there's a lot
40:01of things about it. Instead
40:02of pink, they picked blue.
40:04I'm not sure how blue
40:05is the colon, but
40:07unless we arrived at blue.
40:09And and so there's been
40:10a lot of push to
40:11sort of promote our own
40:13month, and and here we
40:14are. I think this this
40:15event itself is probably a
40:16sort of a tie in
40:17from that.
40:18And and so,
40:20it just kinda got me
40:21wondering,
40:22is this public campaign helpful?
40:25How does it do? Here's
40:26information from our our own
40:28institution,
40:30with with our own doctor
40:31Giacchini here,
40:32talking about, one, public interest.
40:35And then sort of I
40:36I sort of started wondering,
40:38well, we get people talking,
40:39but what do we do?
40:41I feel, a lot of
40:42times in medicine as as
40:43a surgeon specifically,
40:44there's a lot of, you
40:45know, writing notes and saying
40:47things and having conferences, but
40:48what are we actually doing
40:49for our patients? And that's
40:51really what I want this
40:52sort of call to action
40:53to be and really sort
40:54of what got me wondering
40:55about this.
40:57So
40:58when,
40:59whenever you have a question,
41:00what do you do? You
41:01Google it. This is a
41:03really interesting website. It's Google
41:05Trends. If if anyone wants
41:06to look this up, they
41:07can. This is a screenshot
41:08from it last night. You
41:10know, this is what people
41:11are looking at.
41:13So you can get pretty
41:14good data. This actually goes
41:16back quite far, and you
41:17and you can,
41:18use
41:20this search terms, but also
41:21related search terms to build
41:23on on, like, concepts and
41:24things like that. And so,
41:28you know, I looked at
41:29specifically
41:30colon cancer. This actually has
41:32data from the United States,
41:33but also I looked at
41:34data from the UK or
41:35bowel cancer,
41:37and a and a bunch
41:38of other words. As you
41:39can see, we've got
41:41the search interest or popularity.
41:43It's a scale of zero
41:44to a hundred,
41:45and then this is the
41:46data by month. And if
41:48you look at the blue
41:49squares, I use blue because
41:50blue is March for colon
41:51cancer awareness month, you can
41:53see here that there's these
41:54peaks. And, actually, if you
41:56when we looked at this
41:57data, we we fed it
41:58with a sinusoidal model looking
42:00at, is it quarterly? Is
42:01there a lag?
42:04Is it every you know,
42:05should this the cycle, be
42:07every twelve months? And and,
42:08in fact, this data does
42:10fit that that model. So
42:11you do see a peak.
42:13I think you can see
42:14it just with your eye.
42:15I don't think you need
42:15the statistics behind it,
42:17but but they are relevant
42:18to what's coming later.
42:20But, I think you can
42:21see that
42:22if you look at has
42:24March as colorectal care
42:26sorry. Sorry. Colorectal cancer awareness
42:28month been successful,
42:30if you look at Google
42:31search data,
42:33whether it's perfect or not,
42:35I think the answer is
42:36yes. We've got people interested
42:38in this concept.
42:41But now where I was
42:42talking about sort of the
42:43rubber meets the road or
42:45the scope meets the patient,
42:46so to speak,
42:48how has that
42:50public interest been leveraged into
42:52actually improving upon screening? What
42:54have we done for our
42:55patients?
42:56So
42:58in order to sort of
42:58dive into that, the more,
43:00functional end of things,
43:02utilize looking at
43:04rates of endoscopy
43:06across the United States across
43:08a a large endoscopy data
43:09set.
43:11This represents both community and
43:13academic centers,
43:14pretty much every region in
43:16the United States.
43:18And what we looked at
43:20specifically because there's obviously
43:21variation. Right? Some people,
43:24take vacation in July and
43:25August. That's very common.
43:27Some types of people try
43:28and get a lot of
43:29scopes in, you know, in
43:31in December and November
43:33because they wanna get things
43:34done or procedures done before
43:36the end of the year
43:37when their insurance before their
43:38deductible sort of resets.
43:40So what we decided to
43:41look at in this dataset
43:43is what is how many
43:44endoscopists were scoping at that
43:46time and what percentage of
43:47their colonoscopies
43:48were done for screening.
43:51The reason I mentioned about
43:53all that sinusoidal model and
43:54everything like that is I
43:56don't think you guys need
43:57the statistics here to see
43:59there is no peak. There
44:00there is no annual,
44:03you know, increase in percentage
44:05of screening scopes done in
44:07this data set,
44:09every March. And, also, we
44:10did try and fit the
44:11model to see, well, is
44:12there a shift or a
44:13delay. Right? Because you may
44:14expect that you see someone
44:16wearing blue, and you think
44:17maybe I should get screened
44:18for colon cancer, and you
44:20get your Cologuard. And then,
44:21you know, certain time later,
44:23you know, it comes back
44:24positive and then you get
44:25scope. So,
44:27this this model does fit
44:29for that sort of time
44:30delay. We sort of set
44:30it in different different, frequencies
44:33or or different, cycles, and
44:35also shifting it back across
44:37basically every month.
44:38The bottom line is that
44:40really we don't see any
44:41effect for the impact on
44:43screening endoscopy.
44:45So
44:46getting back to my original
44:48sort of call to action
44:49or call to arms for
44:51for any health care providers
44:53or anyone who may be
44:54listening to this either right
44:56now or or just virtually
44:58later on in another date,
44:59when I think about what
45:01impact National Colon Cancer Awareness
45:02Month has had, I think
45:04we are being very successful
45:06in getting
45:07people,
45:08patients,
45:09interested or aware in what
45:11colon cancer is, what rectal
45:13cancer is. I think that
45:15is made aware by sorry.
45:17That's that to me is
45:18is evident by the search
45:20data. But where I think
45:21we as a health care
45:22community can do better for
45:24our patients is actually leveraging
45:26that awareness
45:27into something meaningful.
45:29And because
45:31from the the the endoscopy
45:33data, I don't think we're
45:34there yet,
45:36because, you know, I'd hope
45:38to see some increase in
45:39rate of endoscopy
45:40or something
45:42moving forward. So my conclusion
45:44from all this, really, I
45:45think,
45:46for us, we've done it
45:47I mean, I said stop
45:48talking, start acting. I don't
45:50quite mean that. I think
45:51keep talking. Great. We've been
45:53successful there. But now I
45:55think it's things about start
45:56acting. So it's great to
45:58wear blue. It's great to
45:59have all these things, but
46:00I think there's other things
46:01we could be doing.
46:02Increasing access to endoscopy, things
46:04like opening our endoscopy
46:06suites on the weekend or
46:07focusing on other screening methods
46:10at that time of year
46:11to, you know, potentially get
46:12things out.
46:14Alright. I'm gonna get off
46:15my soapbox and then,
46:18hopefully talk about something
46:20else. So,
46:22I'm gonna talk a little
46:23bit about the cyclic nature
46:24of something,
46:25and that's specifically about
46:27local excision of rectal cancer.
46:30I think a lot of
46:30times in in medicine, we
46:32have these we started one
46:33way, we changed, and we
46:35came back all the way
46:36around. I think of, I'm
46:37a surgeon, but I do
46:38endoscopy. I operate you know?
46:40So
46:40I think about bowel preps
46:42during
46:43colorectal surgery.
46:44It was initially nothing.
46:46Then started with both antibiotic
46:48and mechanical prep.
46:49Then it went to just
46:50mechanical.
46:52Nothing.
46:53Mechanical and lo and behold,
46:54we're back there to a
46:55Nichols Condon prep, you know,
46:57with
46:58antibiotics and mechanical prep. So
46:59I think a lot of
47:00things in medicine are cyclic
47:02as we get more and
47:03more data.
47:05And so I'm gonna really
47:06be talking about that sort
47:07of cycle,
47:09in regards to, rectal cancer,
47:13specifically local excision. So,
47:15we're gonna start in the
47:16past. We're gonna start, around
47:17the thirteen hundreds. So this
47:19is around the hundred year
47:20war.
47:21And this is John Arden.
47:23He was considered England's first
47:25surgeon,
47:26but the thing that's germane
47:28to this
47:29is that he is the
47:30first person to describe or
47:31at least actually to write
47:32down
47:33the,
47:35diagnosis of rectal cancer. So
47:37back at this time, obviously,
47:38there was a lot of
47:39infectious colitis, a lot of
47:40infectious problems.
47:42And so oftentimes, it was
47:43hard to differentiate,
47:46between dysentery or or or
47:48something else and a malignancy.
47:50And so he's the first
47:51person to really describe actually
47:53doing a rectal exam
47:55for the diagnosis.
47:57And, you know, he said
47:58that you should do on
48:00exam, you should find something
48:01hard as a stone.
48:04And so he was basically
48:05able to make that correlation
48:07that the blood, the mucus,
48:09the urgency,
48:11was not all infectious ideology
48:13like dysentery, but was in
48:14fact,
48:15a malignancy. So first diagnosis
48:18then, that's what we started
48:19at. I'm not sure they
48:20had gloves back then.
48:22This is my I I
48:23I don't speak much Latin.
48:24Here's his original Latin text
48:26on this.
48:28So that was initial diagnosis.
48:30So we're going, you know,
48:31thirteen hundreds, and now,
48:33sort of where we at
48:34now. I think most of
48:35us know sort of the
48:37initial treatment,
48:39CT, chest, abdomen, pelvis, you
48:40know, our sort of rule
48:42out metastatic disease.
48:43And then for local staging,
48:46MRI, pelvis with and without
48:48contrast, we we also use
48:49ultrasound gel in the lumen,
48:51which can give you sort
48:52of I I have here
48:53what we call nice ability
48:55for bread slicing, making sure
48:57that as the slices of
48:58the MRI are coming through,
48:59that we're being
49:01perpendicular to the rectum and
49:02that we're really able to
49:03get nice heights and measurements
49:05between the levator plate and
49:06the pelvic floor and the
49:08tumor.
49:09And so I think most
49:11of us know about our
49:12CT or MRIs.
49:14Yes. I do think that
49:15there is still a a
49:16place for endorectal ultrasound.
49:18It's obviously it this this
49:20is a picture actually out
49:21of our textbook. We, as
49:22surgeons, are still tested on
49:23this. These pictures still appear
49:25on our exams,
49:26but I do think it's
49:27also germane because I'm gonna
49:29be talking about local excision,
49:31other in places where it
49:32should or maybe shouldn't be
49:33done or or where we're
49:34going with it. And so
49:35I do think it's important
49:36to highlight that
49:38one of the advantages of
49:39endorectal ultrasound is having the
49:41probe directly on the mass
49:43can help differentiate between a
49:44t one and a t
49:45tumor, and maybe help differentiate
49:47between who is a candidate
49:49for local excision and who's
49:50not. And then, of course,
49:51CEA complete colonoscopy,
49:54but also digital rectal exam.
49:55So,
49:56yes, we have all of
49:58these tests and all of
49:59these high, you know,
50:01high pollutant things, but we're
50:02still also going back to,
50:04you know, the thirteen hundreds.
50:06And and I do think
50:07it's very important to have
50:08a good exam.
50:10If you're a surgeon or
50:11a radiation oncologist prior to
50:13treatment,
50:14is this fixed to the
50:16anorectal ring? Is this a
50:17t four lesion involving the
50:18sphincters and the pelvic floor?
50:20What is the relationship like
50:21anterior to the posterior wall,
50:23the vagina, or the prostate?
50:24So,
50:25I do you know, MRI
50:27is is excellent for things
50:28like that,
50:29but it's a single snapshot
50:31in time. So a dynamic
50:33physical exam
50:34can also give information, which
50:36I which I think is
50:37absolutely quintessential
50:38for the patient and for
50:39for planning and treatment.
50:42Okay. So we've sort of
50:43talked about historical
50:46diagnosis,
50:48where we're at now, and
50:49then what about historical,
50:51resection?
50:52And, actually, when I initially
50:53made this slide, I said
50:54historical resection, and then I
50:55said historical local excision. And
50:57the the thing is that,
50:59at at the time of
51:00the initial so now we're
51:01five hundred years later. It
51:03took five hundred years from
51:04figuring out the diagnosis to
51:05now someone attempting to try
51:06and treat this.
51:08But really local excision
51:10for,
51:11the first
51:12about
51:13fifty to a hundred years
51:14was really the only way
51:16of treatment.
51:17So, this is Jacques Lisfranc,
51:19who did the first,
51:21excision,
51:23in Paris.
51:24This was through a peritoneal
51:25approach,
51:27and, really, it was only
51:28used for distal tumors.
51:30Essentially, the patient this was
51:31done without anesthetic. The patient
51:33would bear down. They would
51:34do a pull through and
51:35a and a local excision.
51:37And, really, that was the
51:39only option at that time.
51:44And as you can see,
51:45the the outcomes were were
51:47quite poor.
51:50Excuse me.
51:52Very high operative mortality
51:56and very high local recurrence
51:58rates too. I'm gonna skip
52:00back from that. Sorry.
52:02And really a lot of
52:03the mortality was due to
52:05again, they were not able
52:06to if you entered the
52:07peritoneal cavity, that was considered
52:08a technical error in your
52:10operation, and then the patients
52:11usually would succumb to complications
52:13like peritonitis.
52:14So really this is just
52:15operating or treating distal third
52:18tumors.
52:19So that's sort of the
52:21early stages of local excision.
52:23There were some people. So
52:25Liz Frank had a a
52:26disciple,
52:27who sort of advocated for
52:29resection of the coccyxin block
52:30for better exposure, and so
52:32there were cert were some
52:33improvements for local excision.
52:35But really things did not
52:37change much. This is a
52:38a picture from our most
52:40recent textbook
52:41about what transanal excision was.
52:43So I have this recent
52:44history.
52:47Again, this
52:48is operating through through an
52:49anoscope,
52:51showing an excision here and
52:52then a closure.
52:53So a little different from
52:54that picture, but but actually
52:56probably not that much different.
52:58And, you know, our our
52:59current recommendations,
53:01just like I was talking
53:02about, before,
53:04are for
53:06really just favorable t one
53:08cancers,
53:08really things that are just
53:10confined to the submucosa.
53:12Because, you know, in this
53:13situation, you're not gonna be
53:14sampling any mesorectal lymph nodes.
53:17And so anything that's gonna
53:19put you at risk for
53:19that, whether it's lymph vascular
53:21invasion, poor differentiation,
53:23tumor budding, or something that's
53:24just technically challenging to excise,
53:27those are folks who, you
53:28know, should be being considered
53:30for proctectomy.
53:32At least based on these
53:33recommendations, I'll talk to you
53:34a little bit. We're gonna
53:35talk a little bit more
53:36about that, but I don't
53:37wanna totally tip my hand.
53:39So here's the outcomes.
53:41This is a, you know,
53:41case series starting from ninety
53:43nine to two thousand three.
53:45The interesting thing about this
53:46is it does include some
53:47t two disease, and and
53:48you can see recurrence rates
53:50are quite high.
53:52Survival rates are are lower.
53:55Some of this is a
53:55little bit selection bias because
53:57these t two patients,
53:59we even even, you know,
54:00not back then, but even
54:01this time people knew that
54:02probably should be doing proctectomy
54:04or TME.
54:05But so some of the
54:06selection bias may be the
54:07folks with a little larger
54:08or deeper tumors
54:09maybe were less, fit, and
54:11so we're maybe more likely
54:12to undergo transanal excision.
54:14But you can see, recurrence
54:16rates, like I said, high,
54:19for these t twos. And
54:20and even for the t
54:21ones,
54:22survival is low.
54:25And, again,
54:28moving forward, I'm just, trying
54:29to make sure we stay
54:30on time.
54:31I'm gonna talk about, you
54:32know, additional advances. Right? Because
54:34like I said, this picture
54:36doesn't look that much different
54:37from that picture.
54:39So here we are now,
54:40I guess, in maybe, in
54:42twenty ten. I consider that
54:44modern time, so maybe I'm
54:45getting old,
54:47with using better visualization,
54:49for transanal excision. So now
54:51we're talking about, what's called
54:53TAMUS or transanal minimally invasive
54:55surgery.
54:57Mike, can you see the
54:58is this is the video
54:59coming through?
55:01Yes. It is. Okay. Good.
55:03Alright. Sorry.
55:05So you can see here,
55:07so,
55:08showing you some views now
55:09from so this is the
55:10setup of the case and
55:11then showing some views here
55:12for resection.
55:13You can see the visualization
55:15is is much,
55:16is much better. So we're
55:18able to clearly see the
55:19tumor, and we're able to
55:20clearly mark out a nice
55:22circumferential margin,
55:24and ensure. So a much
55:26different and better view from
55:27what we're saying. It's the
55:28it's base it is the
55:29same technique
55:31as was shown or sorry,
55:32the same principle
55:33as was shown in those
55:34other slides, but maybe with
55:36easier technique,
55:38and an easier visualization.
55:40And then as you can
55:41see
55:44I think I'm just going
55:45in circles. Here we go.
55:47You can see, though, the
55:47same same exact concepts
55:50of resection all the way
55:51through.
55:52You can see some fat
55:54here.
55:56But the visualization,
55:58you stop it when you
55:59get into bleeding, of course.
56:01And then I think one
56:02of the additional advantages
56:04is then,
56:06ease of of in block
56:07and complete resection so that
56:09we can formally assess,
56:11the depth of invasion.
56:13So which I think is
56:14one of the advantages of
56:15of this type of technique
56:16is we can get a
56:18nice corked out fully complete
56:20specimen,
56:21which is helpful for our
56:22pathologists.
56:23And then closure, which I
56:24do for hemostatic hemostasis. Excuse
56:26me. But you certainly,
56:28do not have have to
56:29do for tamus.
56:31Though, again, I I do
56:32think it's, helpful for closure
56:34and somewhat for symptoms.
56:37Okay.
56:38So I've been talking about
56:39local excision,
56:41all of this,
56:42but but but isn't this
56:44a little bit of ancient
56:45history? Right? Aren't we still
56:47now even more modern?
56:48Aren't we into the paradigm
56:50of, total neoadjuvant therapy and
56:53watch and wait?
56:54Right? So when we talk
56:55about
56:57local excision, really, it's just
56:58reserved for the patients with
57:00the earliest of disease with
57:01just favorable t one tumors.
57:04But, unfortunately,
57:06that's just a small percentage
57:07of patients.
57:08And so what about people
57:09with locally advanced disease? I
57:11showed on those earlier things,
57:12even with t four disease,
57:14the outcomes were poor. Sorry.
57:15With t two disease, I
57:16I apologize. With t two
57:17disease, the outcomes were poor.
57:19So how how would this
57:20ever be something that's applied
57:22to,
57:24you know, more bulky disease?
57:26And, you know, in the
57:27age of for locally advanced
57:29tumors, either a consolidation approach
57:31with with chemoradiation
57:33followed by chemotherapy or an
57:34induction approach where the the
57:36paradigm is flipped, we still
57:38have to check for response.
57:39Right? How do we tell
57:41if folks still have disease?
57:44How do we, one, assess
57:45if they still have residual
57:46disease?
57:47And two, what do we
57:48do if it's equivocal?
57:50I was hoping that doctor
57:51Giacchini was actually gonna do
57:52a little bit of of
57:53I'm not gonna talk about
57:54circulating tumor DNA here. I
57:56was hoping he would, but,
57:57we don't quite we're not
57:58we're quite that coordinated.
58:00Okay? So talking about watch
58:02and wait, I'm just gonna
58:03really briefly touch on so
58:04we can keep moving. But,
58:06really, first series published in
58:07two thousand four,
58:10and really what the definition
58:11is, tumor bed replaced by
58:12scar or normal mucosa
58:15on clinical and endoscopic
58:17exam. And I think that
58:18the the,
58:20most important
58:22thing is really the the
58:23feel as as over an
58:25endoscopic
58:26evaluation,
58:27but there are other adjuncts
58:28for this.
58:31Complete clinical response is not
58:32always predictive of pathologic complete
58:34response, and that's really the
58:35hard part. Just because it
58:37looks like something is either
58:39there or not
58:40does not always mean that
58:42it's the same thing.
58:44So, you know,
58:46like anything in medicine, we
58:47always on the side of
58:48sensitivity and not specificity.
58:50So we can certainly
58:51tolerate situations where,
58:54we think that the person,
58:55still has residual disease,
58:57but they've off actually had
58:59a pathologic complete response, and
59:01we tell that on proctectomy.
59:03But the harder situation and
59:04the one that we really
59:05don't tolerate
59:06is when we think there's
59:07a complete clinical response,
59:09but there's not. And that's
59:10where we sort of have
59:11to talk about close surveillance.
59:14So, how do you tell?
59:16There's a couple things that
59:18you can get to.
59:20Full I'm I put this
59:21a little bit out of
59:22order, but, really, your clinical
59:23assessment
59:24can entail MRI.
59:26I've got some features here
59:28that we do, but also
59:30digital rectal exam and full
59:31thickness local excision. So now
59:33again, we're getting all the
59:34way back to it.
59:36The problem
59:39is that it can be
59:40equivocal. So
59:42things like MRI,
59:44exam and endoscopy,
59:46low sensitivity and specificity,
59:49depending on, again, a lot
59:50of a lot of,
59:52observer bias or or, inner,
59:55inner observer
59:57variability.
59:58But, again, you can see
59:59here this complete response. Okay.
01:00:01I think we can all
01:00:02agree this person can be
01:00:03well, not all. I think
01:00:04you'd feel I would feel
01:00:05comfortable with the watch and
01:00:06wait approach for that.
01:00:08What about the, you know,
01:00:10incomplete, obviously residual tumor? I
01:00:12think we can say, okay,
01:00:14going towards proctectomy or, you
01:00:16know, doing TME,
01:00:18but what about this sort
01:00:19of in between person?
01:00:21Endoscopy can be challenging.
01:00:24The the and the findings
01:00:25can be hard.
01:00:26There's a lot of false
01:00:28positives and false negatives. So
01:00:29then
01:00:31talking about resection of the
01:00:32tumor booked, tumor bed or
01:00:34resection of residual disease. I
01:00:36think of this as a
01:00:37diagnostic tool at this point
01:00:38in time.
01:00:39There is ongoing studies to
01:00:41see if this is therapeutic,
01:00:42meaning are you debulking that
01:00:44last or getting rid of
01:00:45that last amount,
01:00:47But it has the ability
01:00:48really to upstage or adequately,
01:00:51assess for residual disease,
01:00:53more so than maybe endoscopic
01:00:55biopsies
01:00:56or,
01:00:57MRI.
01:00:59So sorry. I went a
01:01:00little bit over time.
01:01:02But, again, to get back
01:01:03to sort of the past
01:01:04and the present, I think
01:01:05that, yes, we've started with
01:01:06this very crude, though accurate,
01:01:09way of telling what what's
01:01:10going on. We have this,
01:01:13very complicated treatment paradigm for
01:01:15rectal cancer, and this doesn't
01:01:16even include metastatic disease, which
01:01:19which can even be more.
01:01:21But I think, ultimately, when
01:01:22we're thinking about these folks
01:01:23in this watch and wait
01:01:24setting, I still think there
01:01:25is a place for, obviously,
01:01:26the exam, but even things
01:01:27like,
01:01:28transanal excision in that,
01:01:32near complete response,
01:01:34group.
01:01:35And with that, I'm open
01:01:36to any questions we may
01:01:38have,
01:01:39and and thank you everyone
01:01:40for their time. I'm gonna
01:01:41stop sharing.
01:01:42Thank you, Hadden.
01:01:45Can you talk a little
01:01:46bit about the the timing
01:01:48of surgery after radiation for
01:01:50rectal cancer and
01:01:51what what the practice is
01:01:53at Yale?
01:01:54Yeah. I think that's a
01:01:55great question, and
01:01:58I think you must have
01:01:59heard me arguing with Jeremy
01:02:00on tumor board.
01:02:01Yeah. So I think it's
01:02:02it's a really important,
01:02:04point because we know that
01:02:06one of the major impacts
01:02:08on
01:02:10on,
01:02:11tumor regression is time
01:02:13between radiation and assessing response.
01:02:16And we know that the
01:02:17more time you wait,
01:02:19oftentimes,
01:02:20you're gonna see more response
01:02:22from radiation.
01:02:24And I I kind of
01:02:25alluded to that a little
01:02:26earlier
01:02:28about, induction I I talked
01:02:29about induction,
01:02:32total neoadjuvant therapy versus consolidation.
01:02:35And and so if you
01:02:36look at, like, the
01:02:38the the which we have
01:02:39there,
01:02:41a lot of people will
01:02:42say, well, if you look
01:02:44at the,
01:02:45and and this is in
01:02:46the conclusions, I I believe.
01:02:47If you look at the,
01:02:50the,
01:02:51consolidation folks, so radiation chemo
01:02:54radiation,
01:02:55FOLFOX, assess risk clinical response.
01:02:57If you look at that
01:02:58group, they have a higher
01:03:00rate of organ preservation
01:03:01and a higher rate of,
01:03:03CCR,
01:03:05compared to the induction folks,
01:03:07the chemo and then the
01:03:08radiation.
01:03:09And to me, I just
01:03:10think that's a little bit
01:03:11of comparing apples to oranges
01:03:13because in that in that
01:03:15first group, in the,
01:03:18consolidation folks, the time between
01:03:19completion of radiation
01:03:21and assessing response
01:03:22is long. It's like about
01:03:24three months.
01:03:25And if you look at
01:03:26the induction TNT folks, it's
01:03:28like eight. It's I sorry.
01:03:29It's no. It's like one.
01:03:30So I think that that
01:03:32can make it challenging.
01:03:34Our current practice here actually
01:03:36does depend. I think we
01:03:37do have a a patient
01:03:39specific approach.
01:03:41But,
01:03:43currently, we I usually try
01:03:45and assess response
01:03:46as far out as possible
01:03:48with also the caveat that
01:03:49they we we tend to
01:03:51try and plan intervention about
01:03:53ten weeks,
01:03:55after completion of radiation.
01:03:57But there's also the
01:03:59the legit this is a
01:04:00great thing on paper. Okay.
01:04:01Well, let's check it week
01:04:03eight after you know, two
01:04:04two months after completion. And
01:04:06then if there's still disease
01:04:14I guess we've lost hat
01:04:15in there.
01:04:17But, as he mentioned, our
01:04:19general practice is to do
01:04:20the the radiation at at
01:04:22at about the the excuse
01:04:23me. Do the surgery at
01:04:24the at the twelve week
01:04:26mark
01:04:26after radiation. So I'll finish
01:04:28kind of his thoughts there.
01:04:30And typically doing the the
01:04:32MRI
01:04:33eight, nine, ten weeks after
01:04:35that radiation
01:04:36as well as with flexible
01:04:37sick endoscopy around that time.
01:04:41Well, I wanna thank everybody
01:04:43for joining this evening for
01:04:45our Yale,
01:04:47continuing medical education for colorectal
01:04:49cancer,
01:04:50for twenty twenty four, twenty
01:04:51five. I hope you learned
01:04:53something.
01:04:54You can please feel free
01:04:55to email me at michael
01:04:56dot chiquini at e l
01:04:57dot e d u or
01:04:59hadden dot pentel at e
01:05:00l dot e d u.
01:05:01If you want to back,
01:05:02Mike. Sorry. Sorry. I wasn't
01:05:04sure if you're coming back.
01:05:05So I I had a
01:05:05I had a technical error.
01:05:06I'm sorry.
01:05:07So, so, anyway, the the
01:05:09the point I was gonna
01:05:09say is that that that's
01:05:10great, and that that really
01:05:11makes the most sense. But,
01:05:12also, logistically, someone said, well,
01:05:13I have to plan. You
01:05:14know? You're gonna be planning
01:05:15an operation. I'm gonna need
01:05:17to take time off of
01:05:18work.
01:05:19What about letting my family
01:05:20know? What about arranging for
01:05:21childcare or other things or
01:05:22transportation?
01:05:24And so sometimes it it
01:05:25can be logistically hard,
01:05:27to to do that.
01:05:30I do yeah. So that
01:05:31those are sort of my
01:05:32thoughts.
01:05:33Absolutely.
01:05:34Alright. Sorry. Alright.
01:05:36No. All good. Well, I
01:05:37kind of was in the
01:05:38in the beginning stages at
01:05:39the end,
01:05:41of of ending the the
01:05:43CME. But, again, thank you,
01:05:44doctor Pantel.
01:05:46This was a fantastic presentation,
01:05:48fantastic discussion. Thank you to
01:05:50all our attendees,
01:05:52for,
01:05:53for the questions.
01:05:55Please feel free to email
01:05:57either of us. Our
01:05:59names and, emails are on
01:06:01the website, but it's pretty
01:06:02simple at e l. It's
01:06:03first name dot last name
01:06:04at e l dot edu.
01:06:06We'd be happy to answer
01:06:07additional questions.
01:06:08Thank you so much. Have
01:06:09a great night here, everyone.
01:06:11Thanks.