Evolving Multidisciplinary Management of Colorectal Liver Metastases

September 23, 2020

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Kevin Billingsley, MD, MBA, FACS, David Madoff, MD and Michael Cecchini, MD

Yale Cancer Center Grand Rounds | September 22, 2020

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00:00Agenda welcome everyone to Cancer
00:03Center grand rounds and really
00:05pleased to have three various themed
00:08colleagues presenting and I, you know,
00:12I think if there's one particular theme
00:15that I think emerges among many from
00:19today's forum is that we have what's
00:23really great is the number of talented
00:26people across multiple disciplines.
00:28Who are making progress on pivotal questions
00:32in cancer care in Cancer Research,
00:34and I think today's forum is just you
00:37know one very clear of many examples
00:40of three individuals doing great work,
00:42each coming from it from a different
00:45discipline but working together towards
00:47really making a difference for patients
00:49for the field and and obviously advancing
00:52our research and educational agenda.
00:54And I I would, I'll do.
00:57I'd like to do is really.
00:59Introduce one of our speakers and ask him
01:02to then introduce the other colleague.
01:05So let me introduce Kevin Billingslea,
01:07who I think frankly in the past.
01:10I guess nine months or so really
01:13needs no introduction.
01:14Kevin, as many of you know,
01:17joined us in in or about January.
01:20As our chief medical officer for the Yale
01:23Cancer Center and Smilow Cancer Hospital.
01:26And is also a professor in
01:28the Department of surgery.
01:30Kevin is responsible for our
01:33clinical enterprise,
01:33working with our leaders in
01:36nursing and other disciplines,
01:37and has really done an extraordinary
01:40job and certainly working.
01:42You know,
01:43arriving here and nothing less stepping
01:45into the frying pan with Kovid.
01:48And really the need to work
01:51collaboratively across so many
01:53people to execute on what was heroic.
01:56An extraordinary response on so many parts.
01:59Kevin,
01:59beyond his success as our
02:02chief medical officer,
02:03is an international leader in
02:05the clinical care and research
02:08of patients with a paddle,
02:10biliary cancers,
02:11as well as gastrointestinal ligatures.
02:13Legacies before joining us here,
02:15Kevin was a professor at Oregon
02:18Health and Science University
02:20where he was the medical director
02:23of the Knight Cancer Institute and
02:25the chief of surgical oncology,
02:28and Kevin is going to.
02:30Take over with our discussion of
02:32evolving multidisciplinary management
02:33of colorectal liver metastases,
02:35and I'll let Kevin take over and
02:38introduce the other great faculty,
02:40Kevin, thank you.
02:42Charlie,
02:43thanks, thank you so much for that
02:46really gracious introduction.
02:48I'm thrilled to be here.
02:50We're going to do kind of A tag
02:53team screen sharing here and let me
02:54see if I can get going with that.
03:10OK, is that working for folks?
03:12I I only see you Kevin. OK.
03:37There you go. Got
03:47it, how about that OK? Well, you
03:55know it's as Charlie alluded to.
03:57I've had the pleasure of spending much of my
04:00career as hepatobiliary surgical oncologist.
04:03And you know, I will share that one of
04:06the most gratifying aspects of my time
04:09in surgical oncology is participating
04:12and witnessing the dramatic advances
04:14that we have had in the multidisciplinary
04:18care of patients with colorectal liver
04:22metastases and one of the things that
04:24I was most excited about is I prepared
04:27for my transition to the ill Cancer
04:30Center in Smilow.
04:32Cancer Hospital was the
04:34fact that we truly have.
04:36Kind of.
04:37We essentially have a world class
04:39team of experts across disciplines
04:42who are contributing to the care
04:45of this unique group of patients.
04:49And we have all of the elements here and I
04:53want to with that as a jumping off point.
04:58Introduce my two partners in this
05:01multidisciplinary grand rounds.
05:02Doctor Michael Cicchini is a.
05:05A seasoned veteran of Yale,
05:07he's a graduate of the Albert
05:10Einstein School of Medicine,
05:12came here to New Haven for residency,
05:15stayed on for fellowship,
05:17and has just continued to rocket
05:20to prominence from there.
05:22Michael profited as many of our
05:24fellows have from the mentorship
05:27and guidance of doctor Jill Lacey,
05:30who is as most of you know,
05:33the Dean of our GI medical Oncologist.
05:36Michael has carved out a really unique
05:39spot for himself and our organization,
05:42an increasingly across the country.
05:44In a mix of traditional clinical
05:46research and GI medical oncology
05:48as well as phase one clinical trial
05:51work and drug development.
05:53So delighted to have him with me
05:56today and as a clinical partner.
05:59Next,
06:00doctor David made off is a relatively
06:04recent addition to the Yale team.
06:06When I was preparing for my move here,
06:10he was one of the most one of the
06:14people that I was most excited
06:18to partner with.
06:19David,
06:20his essentially written the book
06:23on portal vein, embolization, and.
06:25And optimization of the hepatic
06:28remnant for in preparation for
06:30complex hepatobiliary surgery,
06:32he spent much there earlier part of
06:35his career at the MD Anderson Cancer Center,
06:39then transitioned back here to the
06:41East Coast where he's at Cornell
06:44for a number of years and then more
06:47recently we've been fortunate to
06:49recruit him as the vice chair for
06:53clinical research and the section
06:56chief of Interventional radiology.
06:58And I will say kind of quickly.
07:01Is this side note one of the things
07:04that I enjoy most about caring for
07:07patients with colorectal liver metastases?
07:09Is that it really is a team sport.
07:13This multidisciplinary grand rounds
07:14does highlight a number of us who are
07:18involved from surgery, medical oncology,
07:20Interventional radiology.
07:21I do feel little remiss in not
07:24having some other folks on a panel
07:26who were important contributors
07:27such as radiation oncology.
07:29And other disciplines,
07:31but I know we'll have other opportunities.
07:34So this is a very comprehensive field.
07:37We're not going to cover everything today.
07:40Our goal is a team is to kind of give
07:44you some broad brush overviews
07:46of developments and high points.
07:49I will be talking.
07:50I'll be giving an overview and talking
07:53about some surgical strategies mainly
07:55focusing on patients with advanced disease.
07:58Doctor made off will be talking about
08:01his real area of world class expertise.
08:05Which is various techniques to optimize the
08:08liver remnant to support complex resection.
08:11Role of Interventional radiology
08:13and Michael will be updating us on
08:17the numerous advances and systemic
08:19chemotherapy for the disease.
08:21Well, the idea of resecting colorectal
08:24liver metastases is not new.
08:27You know surgeons have been
08:29doing this for 40 plus years.
08:32What is exciting is the developments
08:35that have been made in the safety
08:39of these operations.
08:40The number and variety of technical
08:43approaches and the slow but steady
08:46increase in long-term survival that
08:49patients enjoy after these procedures.
08:52Why would we focus on aggressive
08:55liver directed therapy for this
08:57patient with liver metastases?
08:59Well,
08:59as many of you understand,
09:02the liver disease in metastatic
09:04colorectal cancer often serves as
09:07as the main source of Morbidity
09:09and mortality and affect the driver
09:12demise for folks with this disease.
09:15And this occurs through a number of pathways.
09:18Patients with bulky disease can
09:21experience liver failure more commonly.
09:23They suffer from progressive biliary
09:26obstruction which is understandable,
09:28untreatable,
09:28and once this occurs an they're jaundice,
09:32it is very difficult to.
09:35Provide ongoing effective
09:36systemic chemotherapy,
09:38and it leads to kind of a downhill spiral.
09:43The good news is that from multiple currents.
09:48Case series we know that complete
09:51resection of colorectal liver metastases
09:54patients can enjoy up to and sometimes
09:57more of 50% five year survival rate,
10:00yet, there remain significant challenges.
10:02Roughly,
10:02only 20% of patients with this
10:05disease process are resectable at
10:07the time that presentation,
10:09and even with aggressive surgical
10:12therapy recurrence,
10:13remains frustratingly high.
10:14Often you know 80% at about
10:17the five year mark.
10:19I don't want to steal doctor
10:22Cecchini's Thunder here,
10:23and I apologize for stepping on his turf,
10:27but no self respecting surgical
10:29oncologist would talk about progress
10:32in this area without some mention of
10:35the groundbreaking advances that have
10:37been made in systemic chemotherapy.
10:39I think this timeline kind of
10:42tells the story.
10:43We've gone from the 5F U era,
10:46which was the case for many years is.
10:50Really,
10:51the only chemotherapeutic option
10:53in this disease with a 12 to 14
10:57month median survival to our current
10:59modern regiments with Folfox,
11:02Folfiri and increasingly triplet
11:04chemotherapy or patients even
11:06without surgery,
11:07are enjoying survival of 29 plus months so.
11:12As much as we have,
11:14surgeons congratulate ourselves
11:15on our technical wizardry of big
11:18piece of the progress in the
11:21background is effective chemotherapy.
11:23So this is what I is, a surgical oncologist.
11:27Love to see a patient with
11:29easily resectable disease,
11:31limited number of tumors,
11:33one maybe two tumors that are
11:35peripherally placed not in close
11:37proximity to major vascular structures,
11:40and these folks are amenable to
11:42an atomic or segmental resection.
11:44The surgical options for manageing
11:47folks like this are manifold.
11:49They can be treated well within
11:51traditional open operation. Lapre Scopic.
11:54Liver resection is now in the mainstream,
11:57and increasingly we're used
11:59utilizing the robotic platform
12:01to address some of these tumors.
12:04Now more commonly,
12:05what we see particularly at
12:07large academic medical centers,
12:09such as we work in our patients who have
12:13advanced colorectal liver metastases.
12:15These are patients with multi focal disease.
12:18Often the diseases bilateral on
12:20both sides of the liver and often
12:23their bulky lesions which are in
12:26close proximity to major vascular
12:28structures or portal pedicles.
12:30So I'm going to share the story of
12:33a 48 year old woman who I treated
12:37in Portland about eight years ago.
12:40She presented with bulky,
12:41complex liver disease,
12:43Anna sigmoid non obstructed
12:45sigmoid primary cancer in place.
12:47So not to dwell on too many
12:50liver technicalities,
12:51but she had a high central liver
12:53lesion in close proximity to the
12:55vena cava sitting right under the
12:58confluence of the three hepatic veins.
13:00Should an additional bulky lesion
13:03in segment for the liver sitting
13:05in proximity to one of the pedicles
13:08in the in the middle hepatic vein?
13:11And then she had another bulky
13:13lesion in segment five and six
13:15on the right side of the liver.
13:18So this is a perfect segue into the
13:20need for multidisciplinary multi
13:23disciplinary strategies to address
13:25patients like this with advanced
13:29colorectal liver metastases.
13:31And I'm going to talk today in my
13:35section about 3 strategies to to
13:38approach this group of patients,
13:41all requiring the integration
13:43of multiple disciplines.
13:46Probably the most common is what we
13:49described is conversion chemotherapy,
13:52which involves the upfront utilization
13:55of multiagent chemotherapy.
13:57Usually oxaliplatin based to downstage
14:00tumors within the range of respectability.
14:04Another approach that is increasingly
14:06used at high volume centers around the
14:09world is what we call staged habit ectomy.
14:12This is breaking the surgical
14:14treatment up into two sessions
14:16with an intervening procedure
14:17called portal vein embolization,
14:19which leads to optimization of
14:21growth of the plant hepatic remnant.
14:24And then the last topic I will
14:27touch on briefly is something that
14:29many of us around the world are
14:31starting to do which is complex
14:34parenchymal sparing receptions,
14:36which allow simultaneous resection
14:38of multiple sites of disease.
14:41So the patient I described did
14:42go on to have eight cycles of
14:45Folfox with bevacizumab Avastin,
14:47and she was in the subset of patients
14:50who enjoyed a stunning response.
14:52As you can see,
14:54the central lesion shrunk dramatically.
14:56You can start to see some width on the Ivy,
15:00see a little more space around
15:02the dip attic veins.
15:04This lesion is now shrunk
15:06away from the left portal.
15:08Pedicle involves the caudate lobe of
15:10the liver which is a bit of a tricky
15:14place to operate but now has good clearances.
15:17The left pedicle segment for
15:19lesion significantly smaller and
15:20the right side liver lesion,
15:22also smaller.
15:23This allowed us to take her to the
15:25operating room and one operative setting.
15:29Treat her with a left hip.
15:30It ectomy a caudate lobe resection segment
15:336 or section in a sigmoid colectomy.
15:36This was her diseases that appeared
15:39in the operating room, stomach,
15:41liver, Gallbladder, and the caudate.
15:44Lesion shrunken in partially calcified.
15:47The segment 56 lesion again nice response
15:50partially calcified and what she wound
15:53up with his complex bilateral resection,
15:55but with plenty of good healthy liver
15:58remnant left and I know everyone
16:01reports their greatest success.
16:03What happened with this lady is
16:05she had a single side of recurrent
16:08disease about two years after that we
16:11treated with a little wedge resection
16:14and she is disease free at last.
16:17Follow up about 8 years out.
16:20So what we've learned over the
16:22years in the French are really led
16:25the way in this is that patients
16:28can enjoy even after chemotherapy.
16:30Conversion can enjoy a very high
16:33rate of long-term survival.
16:35This is data from Renee.
16:37A damn now presented years ago,
16:39but makes the point.
16:41They looked at their subset of
16:43patients from their entire spectrum
16:45of liver metastases who are respected
16:48after conversion chemotherapy.
16:50And although this group of patients
16:53who were converted to Resectable
16:55did not enjoy the survival that
16:58the primary population did,
17:0033% five year survival in a subset of
17:05patients extending out into the eight
17:07to 10 year mark as my patient did.
17:11I'd only just you.
17:13While I was there, my partner,
17:16Sky Mayo and I took a kind of
17:19a new is old or old.
17:22Is new approach to kind of
17:24optimizing this approach.
17:25We started a hepatic
17:27arterial infusion program.
17:28As many of you know,
17:31this involves the placement of a
17:33chemotherapy pump in a catheter
17:35into the hepatic artery to deliver
17:38focus chemotherapy with the
17:40aim of converting patients.
17:41It's a complex operation involves
17:44dissection of the hepatic artery
17:46placement at the pump in a subcutaneous
17:49pocket with installation of FDR.
17:51We did this in combination with
17:54systemic chemotherapy with Folfox.
17:56I'm just going to quickly report these
17:59results we placed about 27 pumps.
18:02At this time we analyze data.
18:05We looked at the 1st 20.
18:07Two of these pumps, all.
18:09A subset for unresectable disease.
18:15Many of these were high risk disease,
18:1836% with the K Ras mutant.
18:20All had synchronous disease.
18:22All had multiple liver lesions.
18:24The point relate relative to this talk
18:28that I'd like to point out is that.
18:31Of the 13 patients that we were
18:34aiming to convert to respectability,
18:37a subset we were able to eventually
18:39get to the operating room with
18:42very extensive bilateral disease,
18:44so this is yet another kind of
18:47regional chemotherapy strategy to
18:48convert patients to Resectable.
18:50Another approach that is done
18:52throughout the world that is
18:55facilitated by David's work is
18:57a two stage HEPA tech to me.
18:59This is for patients with complex.
19:02Lateral disease,
19:03they go to the operating room in one
19:05session and either have reception of
19:08the left liver disease or ablation.
19:10Then they go on to portal vein embolization,
19:13which leads to hypertrophy of
19:14the left liver and the
19:16remainder of the disease is
19:18respected in a second operation.
19:20And this is a strategy that allows
19:23us to treat what can be otherwise
19:28completely unrespectable disease.
19:30So series from around the world to
19:32demonstrate that even for patients
19:34with advanced bilateral disease,
19:36if we can complete the two stage resection,
19:39we can provide patients with
19:41excellent long-term survival.
19:42There is always going to be a subset
19:44of patients who dropped out due to
19:47progression between the operations
19:49or in the course of therapy.
19:51And unfortunately,
19:52those folks don't do well,
19:54but this is a great strategy to
19:56get patients to the operating room.
20:00One of the things that I in a
20:02number of other surgeons that
20:04started to do in recent years,
20:06is exploit the concept of
20:08the R1 Vascular margin.
20:10This is related to the fact that there
20:13is going to be a subset of patients
20:15like this who have bulky tumors and
20:18the diseases in close proximity to
20:20a major vein or poorly pedicle.
20:22But it is possible if you can get a
20:25wide resection margin on the rest
20:27of it and get a very narrow margin
20:30that's positive only on the vein to
20:33get excellent local Disease Control
20:35in that part of the liver and still
20:38preserve significant liver parenchyma.
20:40My Friend Doctor Guido Tort
20:42Caelian Milano has been kind of
20:44the primary proponent of this,
20:46and I think that this is a strategy
20:49that is gaining traction and many
20:52HP be centers around the world.
20:55Guido and his team have reported their
20:58experience and one of the things that
21:01I think his striking is that patients
21:04who have you compare their survival.
21:07When you compare R0 resection with R1
21:10resection from the liver parenchyma,
21:13there's clearly decrement in survival.
21:15However,
21:16the group that have an R1 margin
21:19only on a vessel have a survival.
21:22It is virtually identical to
21:25those that are R0 resection.
21:27I think that this is a great example
21:30of a theme that we see across surgical
21:34oncology and multiple diseases breast cancer.
21:37The most notable here where we
21:39overtime have gone to a multi modality
21:42approach involving chemotherapy,
21:44radiation and much more limited
21:46surgery going from radical mastectomy
21:48to breast conservation.
21:50Now moving towards even eliminate ING the
21:53axle airy component of breast cancer surgery.
21:56Same in head and neck.
21:58Laryngeal preservation,
21:59possibly preservation of the
22:01rectum in Rectal carcinomas.
22:03Sarcomas off ajil cancer.
22:05The theme is consistent
22:07throughout integration.
22:08Multi modality therapy allows
22:10a more conservative operation,
22:11and I think we're getting there
22:15and liver cancer.
22:16This was one of my cases from Portland,
22:19not a great picture,
22:20but a patient who I took care of.
22:22You had multifocal disease in the
22:24upper part of the right side of
22:26the liver and left liver requiring
22:28reception down on to the hepatic
22:30veins and right point medical.
22:31Kind of a wedge resection on the left side,
22:34all able to do this in a single operation.
22:37The greatest thing about this
22:39is that all of these
22:41strategies do require multidisciplinary care.
22:44An integration, as I take off my
22:47surgeon hat and put on my CMO hat,
22:50all of these strategies come together
22:52in the fact that our aim at the
22:56Yale Cancer Center through both our
22:58care signature effort as well as
23:01our multidisciplinary disease teams,
23:03is to create a wrap around set
23:06of services for our patients.
23:08As I mentioned, it's not just liver
23:11surgery and medical oncology.
23:13An Interventional radiology.
23:14We need to coordinate care for
23:16many of these patients,
23:18including radiation therapy.
23:19Image Ng, including nuclear medicine.
23:22Of course, oncology, nursing,
23:23pathology, social work,
23:25our colleagues in colorectal cancer
23:27surgery need to be involved in genetics,
23:30and I think that's the promise.
23:32An fun of what we're doing,
23:35so I'd like to hand off now
23:38to doctor made off.
23:40Thank you David.
23:43I guess I need
23:44to stop my screen. Share
23:46my screen here.
23:48And.
23:57OK, so can you can
24:01you will hear me.
24:06Yes, we can hear you. So what I would
24:09first like to thank Charlie and Kevin,
24:11as well as my for giving me the
24:13opportunity today to speak at the
24:15El Cancer Center grand rounds.
24:17As you may recall,
24:18I didn't discuss this topic of
24:20liver regeneration in last December,
24:22but today I will be focusing on how
24:24these techniques relate to optimizing
24:25the anticipated future liver remnant
24:27prior to resection in patients,
24:29really with only colorectal liver metastases.
24:31Very happy to be here in terms of the
24:34fact that this is, like Kevin said,
24:36this is really in my life's.
24:38Work and passion and having the
24:41opportunity is for me very, very nice.
24:46So. As you just heard from Kevin,
24:50there have been tremendous
24:51advances and Pat ability.
24:53Every surgical techniques,
24:54such that death is now considered rare.
24:56However,
24:56complications such as fluid retention,
24:58Cola stasis,
24:59an impaired synthetic function still
25:00contribute to prolong recovery times.
25:02An extended hospital stays.
25:03This is particularly true
25:05instead of an extent,
25:06but did have a tech to me where 5 or
25:08more per node segments are removed,
25:11and in fact,
25:12as you can see,
25:13the mortality in this setting
25:15can approach 8 to 10%.
25:18This can be seen from this French study.
25:20There is direct correlation between
25:22the number of overall complications
25:25and the size of the liver remnant,
25:27and this is not in regards to the
25:29severity of the overall complications,
25:31but really only the complication rate.
25:34So at this time there's really
25:36no limit to how smaller liver in.
25:47In order to reduce the morbidity of Petra
25:51section at least 20% mushrooming in patients
25:54with normal underlying liver that is.
25:56For example, patients that have colon
25:58cancer Mets to the liver without ever
26:02having touch chemotherapy 30% in injured
26:04liver such as those that have had extensive
26:07chemotherapy or Seattle hepatitis and
26:1040% in those with underlying cirrhosis.
26:12So there's many preoperative strategies
26:15to prepare the liver for resection and.
26:18These include Portland Embolization,
26:19which was briefly discussed
26:21by Kevin radiation lobectomy.
26:23There's an apps procedure that will
26:25get into briefly and also something
26:28called liberties deprivation.
26:30Support and embolization is
26:32the original strategy,
26:33first described by professional recruiters
26:35group from the University of Tokyo in 1990.
26:37It's been used to redirect portal blood
26:40flow to the future liver remnant or FLR,
26:42and by doing so,
26:44initiate hypertrophy of the non embolized
26:46segments and by doing this we can reduce
26:48the number of overall perioperative
26:50complications and increase the pool
26:52of potential surgical candidates who
26:54have what we call marginal anticipated
26:56future liver remnant volumes.
26:57Please note that the goal is really
26:59not to improve the overall survival
27:01after resection is compared to
27:03those that did not require PV.
27:05It's just really to achieve similar
27:08survival rates to those patients
27:10who want to undergo surgery.
27:12It did not actually require
27:14PV an ultimate until recently.
27:16The general consensus was the PV was the
27:19standard of care at most had ability,
27:21every centers worldwide or safe
27:23and effective generate generation
27:25or generation of the FLR.
27:27It's now been over a decade since
27:30the first meta analysis of usefulness
27:32of PV was published,
27:33and in this study they would do 37
27:36publications with over 1000 patients
27:38and found a previous states with a
27:40low mortality and morbidity rate.
27:42Further,
27:4285% of the patients were able to
27:44get their proposed surgery.
27:46However,
27:46as you can see down here is that
27:49there was a substantial group of
27:51patients that were not respected
27:53and this was due mostly to disease
27:55progression or insufficient.
27:56I purchased it.
27:59I stated previously the goal of PV
28:01in the setting of colorectal cancer
28:04is to get similar survival rates to
28:06those patients who do not require PV.
28:09Here we see two actually French
28:11studies and pretty old.
28:13There actually showed where
28:14these outcomes were born out.
28:17Now PV E not only causes the
28:19Liberty purchase fee,
28:20but it also results in improved
28:22function of the FLR and this has
28:24been shown by nuclear medicine
28:26studies with alobar function shifted
28:28from the embolized than an embolism
28:30for after tbe further in patients
28:32with Hilar Cholangio Carcinoma,
28:33who had biliary drainage catheters more
28:35bile is produced in the non embolized
28:38bourbon in the embolized liver and Lastly.
28:40We can see that less alterations in liver
28:43function tests after resection occur
28:45following PV even knows in which P VE.
28:48Was not performed.
28:49So for decades CT has been the
28:51cornerstone for surgical planning and
28:53when assessing the FL are we do our
28:57calculations based only on the size of
28:59the liver. Remaining siti does directly
29:01measure the future liver remnant and the
29:04total liver volume is not actually measured,
29:06but rather it's estimated from
29:08the Association between the
29:09liver and patient size.
29:11And this is based on body waiting patients,
29:14body surface area or a larger
29:16patient would need a large deliver.
29:18Smaller patient may need a smaller liver.
29:20The FL R2 total estimated liver volume
29:23ratio can then allow for uniform comparison.
29:25Adefa lower volume parts of resection,
29:27whether or not PVE was performed.
29:29And this is the formula which is
29:31based on a linear regression equation
29:33from over 500 Western adults.
29:35It's critical to understand the
29:37denominator does not change on the pre
29:40and post CT scans because it is an estimate.
29:42One must realize that PV E does cause
29:45atrophy of the emboli segments that
29:47there have been cases where the total
29:49liver volume is directly measured.
29:51And went down after PV E.
29:53Therefore,
29:54even if the numerator is unchanged, the FL,
29:57our percentage may inadvertently increase,
29:59giving once a false sense of
30:01belief that hypertrophy did occur.
30:03And unfortunately patients have died
30:05after surgery when this happens.
30:07So if we look at this patient with
30:10colorectal liver metastases here
30:12we see approximately 4 weeks later
30:15that the FLR grew from 17 to 30%
30:18or degree of hypertrophy of 13%.
30:20This patient also had.
30:21Kinetic growth rate of 3.5%,
30:23which is a good indicator and this
30:26will be discussed in much more
30:28detail in a little bit.
30:32In recent years,
30:32there's actually been controversy as
30:34to be appropriate limit for resection,
30:36and this may depend on the institution
30:39and the formula being used.
30:40In Europe, for example, therapies
30:42uses the cut off for the need for pbe.
30:45That said, we showed during my time at MD
30:47Anderson there statistically significant
30:49differences in outcome, whether it
30:51be from liver insufficiency or death.
30:53If you have less than percent, FL are,
30:56however, no differences were found.
30:57Once you had more than 20%
30:59of your FL are remaining.
31:02And further,
31:03we wanted to see the impact of
31:05PV in the patient population
31:07in this patient population.
31:08We found that in those patients
31:10that had at least 20%,
31:12meaning that they already either
31:14had 20% not requiring PV or had 20%,
31:17and in those days we did it
31:19with a higher environment to see
31:21if there was any difference,
31:23and we compared them to those patients
31:25who had less than 20% and actually had
31:28at least 20% and did not require PV,
31:31E and compared them to those also that.
31:34And did not have 20% and needed PV E.
31:37And we found that as long as the
31:39patient after PV at least 20%
31:42of the future liver remnant,
31:43it really was no difference in
31:47what happened after resection.
31:49So we talked about the brief
31:50hypertrophy a little earlier.
31:52So what is the degree of purchasing?
31:54Well,
31:54it's the post PV efl R minus the pre
31:56PV EOFLR which gives you a dynamic
31:58measure of liver regeneration and
32:00this is important because there
32:02is an amount of high purchase that
32:04is necessary to review.
32:05If you have complications in our study
32:07published in MD Anderson in 2007,
32:09you can see that those patients
32:11that have more than 5% degree if I
32:13purchase he had significantly less
32:15complications that had more than 5% FL.
32:17So here we have a tale of two rivers,
32:21one patient with Cirrhosis,
32:22and HTC who underwent a right
32:25hip attacked me,
32:26the other with colorectal liver
32:27metastases and only had 5% steatosis
32:30who underwent an extended right.
32:31He protected me here.
32:33We see that the cirrhotic patient
32:35had excellent hypertrophy,
32:36while the other patient had only 1% growth.
32:39Interesting Lee, the cirrhotic patient,
32:41did well after surgery,
32:42while the patient that had the
32:44normal liver or what we thought was
32:47a pretty normal liver actually.
32:49Died after their reception.
32:50Therefore,
32:51if we see that you can use these
32:53numbers to see that patients that
32:55have at least 20% FLR and at least 5%
32:59degree of hypertrophy had a zero percent,
33:0190 day mortality.
33:02And like I said,
33:04this information can be used when
33:06trying to understand whether a
33:08patient should be indicated for
33:09their reception after PV.
33:11So now that we know the floor cut
33:14off numbers that is 20% for normal liver,
33:1630% for injured liver from chemotherapy and.
33:1940% for Cirrhosis,
33:20and we know that if I purchased the 5%,
33:23is this enough to really be able
33:25to predict which
33:26patients should have their surgeries?
33:28So we now know that we've had
33:31purchase fees based on the timing
33:33of the image Ng and that a true
33:35assessment of the epilogue growth is
33:38difficult to compare among patients.
33:40Therefore, we developed a new variable
33:42called the kinetic growth rate or KJR,
33:45which is the degree of hypertrophy
33:47over the time elapsed from
33:49PV E in the number of weeks.
33:52So here we see three patients
33:54with colorectal liver metastases,
33:55each with a degree of hypertrophy,
33:57well within the amount needed for successful,
34:00safer section.
34:01However, the patient on the bottom actually
34:03died from liver failure after section,
34:05so we went back and reviewed the cases
34:08and found that the time for the first 2
34:11patients with 35 days to get these results,
34:13while we found that the patient had died,
34:16it actually occurred in 70 days.
34:18So when we went back and calculated
34:20the kinetic growth rate,
34:22the patient that I had only
34:241 zero point 3% per week,
34:26while the other two had
34:29much higher growth rates.
34:31Therefore, when assessing patients
34:32which should have surgery,
34:34we found that in order to really be safe,
34:38that we really need 2% per week.
34:41That led to know hepatic
34:43insufficiency or 90 day mortality.
34:46So,
34:46is Kevin stated earlier we can now
34:48extend the boundaries for safer section
34:50by using advanced surgical strategies
34:52such as the two stage protecting
34:54me like for this pain titlebar,
34:56colon article, living metastases,
34:58patient first had systemic
34:59chemotherapy with excellent response,
35:00then had surgery to clear
35:02the left lateral liver.
35:03The FL,
35:04our volumes were calculated
35:05to be 16% of PV was performed,
35:08and then FLR was then found to be 26%.
35:11So the definitive resection
35:13was then performed.
35:14So to assess the benefit of
35:16the two stage separate ectomy,
35:18we reviewed patients who had
35:20invented the advanced strategy
35:21with extended pack resection and
35:23compared those those that did not
35:25have tumor in their FL are therefore
35:27not really needing second stage.
35:28Our results had shown that there
35:30was no difference in overall and
35:32disease free survival in those
35:34patients that required the two stage
35:36protect me as compared with those
35:38that only required the one stage.
35:40And as Kevin showed from our study from
35:43MD Anderson in a really highly selected.
35:45And she cohort who did complete
35:47the second stage.
35:48We were able to achieve a
35:5060% five year survival,
35:51which is really considered amazing.
35:53Anything about a decade ago given to
35:56buy Alobar nature of the disease.
35:59However,
35:59there is some concerns regarding team
36:01be one of the major concerns is the
36:04potential drop out of up to 35% of
36:06patients due to an insufficient FL
36:08are or or tumor progression within
36:10the four to six week waiting period
36:13from the TV to the definitive resection.
36:15Therefore,
36:16other approaches are needed.
36:18So one.
36:18Issue that has been entertained
36:21has been that PV can lead to
36:24expedited tumor growth,
36:25so to that end the recent
36:27data supports that we
36:28can use chemotherapy during the
36:29waiting period and also can be used
36:32within the postoperative period
36:33which at one time was thought to
36:35maybe limit for generation. However,
36:37that has not borne out to be the case.
36:40So there are other alternative
36:42approaches that we can use.
36:44It is Interventional radiologist.
36:46This is a case.
36:47This is a study that was performed
36:49from Korea where TV did not leave
36:52the sufficient regeneration.
36:54Anna Korean group found that
36:55later performing right,
36:56having bane embolization in
36:58addition to the PV is shown here
37:01actually result in better outcomes.
37:03We've also used something
37:05called radiation lobectomy.
37:06This is done by the Transarterial Bar
37:09Administration of Y-90 microparticles.
37:11She's now an established means
37:13of providing local tumor control
37:15within the liver.
37:16That said,
37:17there was an unintended phenomenon
37:19of contralateral liver I8 and seven
37:21in several retrospective studies.
37:23Contralateral hypertrophy?
37:24A curd from 21 to 47%,
37:26and therefore this has been suggested
37:29as an alternative to PV with the
37:32benefit of local tumor control.
37:33And the test of time.
37:36So we had talked about this earlier,
37:38but nuclear medicine is showing
37:41improved liver function after PV E
37:43in this small study of 13 patients,
37:45with some being colorectal liver
37:47metastases who underwent some
37:49nuclear medicine scintigraphy.
37:50They showed that using radiation
37:52lobectomy actually can cause
37:54changes in regional liver function,
37:56and this correlated with the functional
37:58liver absorbed doses from Y-90
38:01and pack and then in 2014 a group
38:03from France compared 141 patients
38:05who underwent right PV with third.
38:0835 patients who underwent radiation
38:10lobectomy at two centers that were
38:12matched for criterion known to
38:15influence liver regeneration after PVD.
38:17The radiation was performed if the authors
38:19found the case would be challenging,
38:21provid PB and to be honest,
38:23I'm not sure why this would be,
38:26but when they match the patients they found
38:28significantly more hypertrophy after PV.
38:30They concluded that while the hyper
38:32chicken radiation lobectomy substantial
38:33and doesn't minimize tumor progression,
38:35PV can induce significantly greater,
38:36and I purchased the in radiation
38:38lobectomy with these therapeutic doses.
38:40So how do you decide if you should
38:42use PV or radiation lobectomy?
38:44The decision should be based
38:46on achievement intent,
38:47such as.
38:48Is the patient a candidate for section
38:50now and what is the plan resection if
38:52the reception should be done now you
38:55should just go ahead and perform the P PE.
38:57You also need to know what type of
38:59malignancy patient has and whether the
39:01patient has underlying liver disease.
39:03Cases where patients have bottle
39:05bar colorectal metastases that
39:06require a Tuesday check.
39:08Her protect me.
39:08There is likely really no
39:10role for radiation lobectomy,
39:11as you can see,
39:12I'm personally not in favor of the
39:15radiation lobectomy in this approach,
39:17as you would really need to do 190 of
39:19both lobes and it seems appropriate
39:21in the setting of HTC with cirrhosis.
39:24But I don't think it really is
39:26appropriate in the setting of
39:28colorectal liver metastasis.
39:30Another approach is Alps,
39:31which is short for associating liver
39:33partition and portal vein ligation.
39:35This approach was proposed to
39:36replace pbe with two surgeries.
39:38He performed interactive right
39:39portal vein ligation followed
39:41by completely divest arising.
39:42Segment four of the liver and
39:44at the same session is surgeon
39:46clears the floor of tumor.
39:48The patient is then closed with
39:50the tumor bearing liver in place,
39:52while the FLL rapidly have Portuguese
39:54and then the Sturgeon returns within
39:567 to 10 days for a second laparotomy
39:58to complete the definitive resection.
40:00And early reports actually
40:01showed very strong tumor growth.
40:03I mean, fellow growth and was believed to
40:06have a lower risk for tumor progression.
40:09That being said,
40:10when comparing PV 2 apps that were
40:12the massive infest or hypertrophy
40:14in the Alps Group,
40:15but it came at a much higher cost
40:18of major complications and death.
40:20Interestingly,
40:21while the kinetic growth rate
40:22was found to be higher electron
40:25microscopy studies from Japan showed
40:27that the hepatocytes were not mature
40:29and not really able to handle the
40:31increased blood flow to the FL are.
40:33Therefore,
40:34it was shown that it is not simply
40:36regenerating the liver rapidly,
40:38but also in a way that allows
40:40the hepatocytes maturan function
40:41appropriately so interesting.
40:43Lee,
40:43a systematic review and meta
40:45analysis for colorectal liver
40:46metastases was performed,
40:47confirming the findings of the faster
40:49kinetic growth rate with Alps.
40:51But with the increased morbidity
40:53and mortality.
40:53So for this reason numerous
40:55modifications have been proposed,
40:57many of which negated distinct advantages
40:59of why Alps was proposed in the 1st place.
41:02And Lastly,
41:03I want to show a new procedure,
41:05one that we will now be using it Yale,
41:09while while I already showed sequential
41:11PV into Patty being embolization,
41:13Liberty is deprivation is performing PV.
41:15And how do you been embolization
41:17in a single session?
41:18The goal is to shorten and optimize
41:21the phase of liver preparation.
41:23Or surgery without the
41:24aggressive nature of Alps,
41:26and in this early
41:27feasibility study from 2016,
41:28the procedure was found to be safe
41:31and feasible in a small patient
41:33cohort of only seven patients,
41:35and then the same group then added
41:37embolization of the middle of having pain
41:39to the right hepatic vein embolization,
41:41and they found that by doing so
41:43they can get safe and provide the
41:46most marketing rapid elevation in
41:48hypertrophy and liver function.
41:49Unprecedented for an IR procedure,
41:51and just soon Kevin and I will
41:53be the Copia eyes.
41:55Or yell prospective clinical trial.
41:57Looking at Libertines deprivation
41:58called Dragon One and Dragon 2
42:00dragon one is a feasibility study,
42:02and Dragon 2 actually will compare it
42:05to the standard of care which is PV.
42:08So in conclusion,
42:09liver regeneration is critical to
42:11managing colorectal liver metastases,
42:12and, as I hope to have shown,
42:15there are numerous strategies
42:16that can regenerate the liver,
42:18either percutaneously or by surgical means.
42:20Currently,
42:21the understanding of Liberal generation
42:22in this area is really at its infancy.
42:25Any apples opportunities do
42:27exist for research,
42:27so I'm looking forward to
42:29working with your team and
42:31looking forward working with
42:32Kevin on this dragon study and
42:34thank you for your attention.
42:36Thank you David, that was awesome.
42:44Thanks bikini.
42:49Kevin David, can you stop
42:51sharing? OK, stop the sharing here, yeah?
42:56Alright, so I'm Michael Cicchini.
42:59I'm a medical Oncologist and
43:02I'm going to talk about the chemotherapy
43:06in the Peri operative management of these
43:10liver metastases for colorectal cancer.
43:14So first I'm going to talk
43:18about the molecular profiling.
43:20That's important to decide.
43:22Chemotherapy agents as well as sightedness,
43:25which is not truly molecular
43:27profiling but certainly hasn't
43:29impacted the chemotherapy selection.
43:31The two types of patients we encounter,
43:34the unrespectable patiently up respectable
43:37biologics and then some of the damage
43:41our agents can do that can complicate
43:43the role of complicated surgery so.
43:46Molecular profiling for colorectal cancer.
43:48What information do I really need to
43:50know to make a chemotherapy decision?
43:52Wrap the grass in the raft status
43:54are very important and they have
43:56been so for some time mismatch
43:58repair status microsatellite status,
44:00which is analogous to that and
44:02then the sightedness has become
44:04increasingly important for determining
44:05determining which biologic to use.
44:07So the origin of the primary tumor was at
44:10a left sided tumor or right sided tumors.
44:13So to remind ourselves why Rasen
44:15rap status is so important.
44:17We need to go back to the EGFR pathway.
44:20So EGFR here in this purple
44:22is upstream of crowds.
44:24B RAF MEK Erk.
44:25So in our ask mutated cancer
44:27or at mutated cancer.
44:29This is this pathways constituently activated
44:31below the level of the ship receptor.
44:34We have drugs syntax Mammon,
44:36Panitumumab two monoclonal antibodies
44:37to target EGFR receptor that we add on
44:40to chemotherapy, so they're effective.
44:42If this pathway is not constituent active,
44:45blow it.
44:46So in a rash wild.
44:47I porra filetype we add on
44:52Panitumumab Humanized Monoclonal
44:54Antibody an and or so or sucks Mad A.
44:58A chimeric antibody,
44:59but for the patients that are
45:02mutated in rats,
45:02we have to take a different approach.
45:05So bad this is mab.
45:07Kevin talked about a little bit
45:09to monoclonal monoclonal antibody
45:10against veg that Jeff Vascular
45:12endothelial growth factor,
45:13and that's also added on to chemotherapy
45:15be Rapids become important just
45:17in the last couple of years.
45:19Now we have targeted agents for
45:21that and Grafton if insta tox mad,
45:24but for the Intents and purposes
45:26of this stock graph is used as
45:28a negative prognostic.
45:29Mutation and most of those
45:31patients are not can be included
45:32in the consideration of surgery.
45:34So why is the mismatch repair
45:36status so important?
45:37So to answer that,
45:39we first have to remember what
45:40mismatch repair proteins do.
45:42So Emily age 1:00 PM S 2 Ms H2, and six.
45:46These are the four most most clinically
45:48relevant mismatch repair proteins.
45:50Their function is to follow
45:51the DNA polymerase machine DNA
45:53polymerase machinery along as it
45:55undoubtedly makes some mistakes.
45:56It fixed these these single base mismatches,
45:59which are most prevalent in these areas,
46:01called microsatellites,
46:02which are dynamically Titan tribe
46:04nucleotide repeats across the genome.
46:05You can imagine this DNA machinery.
46:07It's really caught up on
46:09all this repetitive DNA.
46:10Lots of mistakes are made so
46:12we know when these are lost.
46:13Tumors have very high tumor
46:15mutational burden that which leads
46:16to a lot of Neoantigens.
46:18We've known for some time that these
46:19are some of the most sensitive cancers
46:21to immunostimulatory therapies such
46:23as anti PD one and four therapies.
46:25So they've been approved in the refractory
46:27setting for you for a few years but
46:30only recently just a few months ago.
46:32Did we get to see their activity
46:34in the first line setting?
46:35You can see very dramatic separation
46:37of these two curves here.
46:39Green being Pember Lizum app,
46:40purple being the chemo arm for a first line.
46:43Microsatellite instability.
46:43High collector cancer.
46:44I mean if we look at the two year mark here,
46:47you're seeing 48% of patients that
46:49are microsatellite instability,
46:50higher progression, free and alive.
46:52At at two years versus only 19% with chemo.
46:54But for today's top,
46:55what's really important to look?
46:57Actually look at this part
46:58of the curve on the far left,
47:01because that's where anybody
47:02that's going to surgery would be.
47:04Maybe early on in their treatment journey
47:06and you can actually see Pembroke behavior.
47:09A bit more inferior to chemotherapy.
47:11In this setting in a very rapid drop off,
47:14even with Pam bro,
47:16which obviously has a tail on this curve.
47:18So immunotherapy in the new edge
47:20of insteading for somebody that's
47:22initially resectable, for example,
47:23is definitely not ready for prime time.
47:26And I think future directions will
47:28certainly be chemo immunotherapy,
47:29and hopefully will negate some
47:31of the early drop off.
47:32Why is sightedness important?
47:34So we've known for some time
47:36that high and got the left sided
47:38Colon is a different embryologic.
47:40Origin in the right right colon so
47:42hindgut for left and got for right.
47:44Right sided tumors generally worse prognosis,
47:46more methylated tumors,
47:47higher beer after some degree.
47:49Higher crass and left side it more
47:51than more traditional APC mutations
47:53in TP 53 mutations and we know
47:55that even if your rash wild type,
47:57it matters whether or not you
47:59respond to a EGFR antibodies such
48:01as anti tumor map or cetuximab.
48:03So it's really the rash wildtype left
48:05sided tumors that we're thinking about
48:07using these drugs in the first line setting.
48:10And even if rash while typing right
48:12sided data SIM it at this is a
48:15map should still be considered.
48:17So what are the drugs that we have
48:20at our disposal to help these
48:22patients so full Fox?
48:24We've probably all heard full box,
48:26full fury, full Fox series.
48:28And when we use in pancreatic cancer here,
48:31full fear knocks,
48:32but they're slightly different approaches.
48:34So what is folfox?
48:35So five fluoro uracil,
48:37which is patented by Charlie Heidelberger.
48:39I think in 1957 and is still
48:41around and going strong.
48:43Is a family space inhibitor so
48:45you don't have time to look
48:47around for rapidly dividing cells.
48:49Luca born potentiates the activity
48:51of five FU.
48:52It's a vitamin that we give
48:54along with the chemotherapy.
48:55Oxaliplatin is the oxen in full box,
48:58and that's in platinum agent that causes
49:00DNA addicts and ultimately results in
49:02double stranded breaks and are in Attican,
49:05which is the IRI. In full fury is.
49:08Ultimately converted into its active form.
49:09About summarize, one inhibitor,
49:11SN 38 and ultimately also end
49:12result is double stranded breaks,
49:14so these are the main agents we have.
49:16We started out again with just
49:185F U and this is about what we
49:21were doing back in the early 90s,
49:23so we had about a median survival of 12
49:25year for patients with mosaic answer.
49:27When we started to have doublet
49:29chemotherapy's in full box and full theory,
49:31we move this out about the two year mark.
49:34Now we're really between the two and three,
49:36or mark or median overall survival.
49:38For most, for most of our active trials
49:41with colorectal cancer with folfox theory,
49:43the triple combination that's a bit more
49:45toxic and reserved for younger patients
49:48is about a 32 month median survival,
49:50so we have to ask ourselves at tumor board,
49:53what does this patient have it with?
49:55Cash pathway to cure?
49:56So what our main goals with chemotherapy?
49:59We've heard a little bit
50:01about conversion therapy,
50:02so converting the unrespectable
50:03patient to a respectable patient.
50:05If we have a patient that's upfront,
50:07resectable chemotherapy can still be
50:08useful to reduce the surgical complexity.
50:11Eradicate micrometastatic disease,
50:12which is also hopefully doing for
50:14the unrespectable patient and then
50:15also assess the biology of the
50:17aggressiveness of the disease.
50:19Is somebody actually getting a
50:20response through chemotherapy,
50:21or they just rapidly progressing?
50:23That's not a patient you want
50:25to surgery anyway,
50:26and if we know that even in the best
50:28of circumstances the patients never
50:30going to get to a surgical option
50:33that the treatment is prolonging life,
50:35hopefully by controlling disease in
50:37improving tumor related symptoms,
50:38so we should think about this as two groups,
50:41the unrespectable patient.
50:42And the resectable patients.
50:43So the upfront receptable patient and
50:45just there's no right way to integrate
50:48chemotherapy into these patients.
50:50By the way,
50:51different centers take different approaches,
50:53but there's more nuanced than
50:55just this slide.
50:56But when to consider a front reception?
50:59Generally, for fewer liver metastasis,
51:00chemotherapy response?
51:01Not really.
51:02The surgeon doesn't really think
51:04chemotherapy response is going to
51:06lower the complexity of the operation.
51:08But when do we do it when there's more
51:11than four suspicious knodel involvement?
51:13My Liberty disease.
51:14But again, there's more nuanced to this,
51:16so we have to we have to take everything.
51:19Every aspect of the patient into account.
51:21Do they have a lot of other comorbidities?
51:24Where if they if they are not
51:26tolerating chemotherapy well,
51:26we're expecting significant increase
51:28in liver liver damage,
51:29which could complicate in operation?
51:30Is there reason to suspect that
51:32they have particularly aggressive
51:34disease and you want to give him the
51:36tincture of time on chemotherapy to
51:38make sure they're not just rapidly
51:39progressing and you're going to put
51:41them through an unnecessary operation?
51:43Did they recently received full Fox for?
51:45For management of primary primary,
51:48so could a slight response results
51:52in maybe converting an
51:54open reception to a laprascopic reception.
51:59So what, what chemotherapy do
52:00we typically use? So again,
52:02these are patients that could be respected,
52:04most likely, so full Fox,
52:05a doublet chemotherapy,
52:06perhaps with the biologic bevacizumab
52:07panitumumab receptors amount,
52:08but the important part is to limit the
52:10number of chemo cycles as much as possible.
52:13These patients that can get to surgery
52:15quickly and should get to surgery quickly,
52:17and we want to do as little
52:18damage is possible to the to
52:20the liver without chemotherapy.
52:22So we should image patients early and
52:23as soon as thought as soon as feasible.
52:26These patients should be taken into surgery.
52:28We generally plan to do six
52:30months total of chemotherapy.
52:31But the rest would be reserved for later.
52:33So what about the unresectable patient?
52:34Now this patient can't get this
52:36surgery without a response,
52:37so it's a different.
52:38It's a different approach,
52:39so we talked a little bit about
52:41what is undetectable.
52:42But so,
52:43how likely is this understandable
52:44patient going to get going to
52:46be able to get an operation?
52:47Perhaps as high as a third 1/3
52:49of the time that we will get
52:51enough cited reduction to convert
52:52this patient to respectable?
52:54But what regiment is best?
52:55Again, if you look at guidelines,
52:57both guidelines are very so.
52:58The guidelines don't really
52:59take much of a stand.
53:01They say Folfox Folfiri Anna tumor map.
53:03But this is a mad.
53:04They kind of leave it up to the
53:07treating oncologists asthma.
53:08On the other hand,
53:09takes a more dogmatic approach.
53:10It says full flux is the recommendation
53:12or for unresectable metastases.
53:14Considerable Fox series,
53:15so that's that's the approach
53:16that we would take here,
53:18predominantly in the United States
53:19that most most centers would do.
53:21But certainly here at Yale
53:23for the younger fit patients,
53:24we would be for an unrespectable patient.
53:26We would do full foxy reefer.
53:28This is a map, but for our upfront,
53:30resectable patients we would
53:32again just be doing a doublet.
53:33So I'm going to skip through
53:35this in the interest of time,
53:37especially since Kevin showed
53:39some of the slides are ready.
53:41So what about our biologics?
53:42So this is another level of nuance.
53:45Again, to do our chemotherapy here.
53:47So we have.
53:48We have agents such as bad.
53:50This is a map which is a vascular
53:52endothelial growth factor antibody
53:53against speculative growth factor,
53:55which is created by the tumors and
53:57stimulates blood vessel growth.
53:58Because the tumor needs
54:00increased vascularity,
54:00so we know that bevacizumab
54:02increases response rates,
54:03but it can potentially increase
54:05perioperative complications.
54:05We see vascular events such as
54:07such as arterial thrombi, Venus,
54:09thrombi, on occasion perforations,
54:11but the big concern is wound healing,
54:13so we generally would hold
54:15bevacizumab within six weeks
54:16prior to any server dream.
54:18There is some data that supports it
54:20up to four weeks prior to surgery,
54:23but but the concern is how you
54:25when you hold it preoperatively.
54:28So this is actually been looked at.
54:30The addition of bevacizumab in systemic
54:32therapy for unresectable liver metastasis.
54:34So we have a cohort of patients
54:36here split up into two groups.
54:38These are all kras mutated
54:40patients or patients that are
54:42perfect fit for bevacizumab.
54:43So full blocks plus bevacizumab
54:45in arm a in Folfox alone.
54:47In R&B you can see that the reception,
54:50the rate of R0 Resection complete resection,
54:5222 verses about 6% without
54:54the berbasis matters so very,
54:56very big difference about
54:57getting to surgery there.
54:58What about progression free survival 9 1/2
55:01months median versus about 5 1/2 months
55:03median favoring Bevis is maben blue here.
55:05Same thing with overall survival.
55:07Less less striking difference
55:08about 25 versus 20 months.
55:10Both are statistically significant.
55:11So bad this is a map should be used
55:14in the Peri operative management with
55:16Folfox 4 correct meeting liver metastases.
55:18What about the EGFR antibody face?
55:20These are highly effective therapies for
55:22patients that are crashed while type.
55:24You think you think we see a
55:26similar a similar story here.
55:28In fact, we're.
55:29In exact opposite, so again,
55:31we have two groups here.
55:34This is a new epoch study,
55:36split into chemotherapy,
55:38perioperatively before and
55:39after surgery with cetuximab,
55:41an without stuck some,
55:42and so without cytoxan map is here in blue.
55:46Progression free survival curve
55:47here so you can see the red group
55:50chemotherapy plastic doing inferior
55:51to the chemotherapy alone group.
55:53Same thing with overall survival.
55:55What's really interesting?
55:56If you look at these curves,
55:58these are these are the Times of surgery,
56:00so this curve have not separated.
56:02They separate later.
56:04An obvious explanation to this
56:05oh would be an awesome app.
56:07Is creating some increase in
56:09perioperative complications?
56:09But that's not the case and the fact
56:12that the changes in progression free
56:14and overall survival happened later
56:16again speaks to. They did that.
56:18It's not an actual increase
56:19in proper complications.
56:21Frankly,
56:21I haven't seen any good explanation
56:23for why this we're seeing these
56:25these these confusing results,
56:27but I think we should proceed with
56:29caution when using our bodies
56:31in the perioperative setting.
56:32I think a lot of my colleagues
56:35have not bought into this,
56:37and I again uncertain on the
56:39rest of the biological rationale
56:41of why we're seeing this,
56:42but it's a very striking
56:44overall survival difference.
56:45It's almost three years.
56:47Median overall survival
56:48difference without the antibody.
56:49So chemotherapy associated
56:50liver diseases will close on
56:52South are drugs can do damage.
56:54That's why the name that our approach is to
56:57limit the number of cycles when feasible,
56:59so Oxaliplatin,
57:00cut static sinusoidal abnormalities.
57:01You can see the dilations here in
57:03light of these sinusoids that directly
57:05from oxide Platt and you can see
57:07nodular regenerative hyperplasia.
57:09This, like lighter pink nodule here.
57:11Crowding out the more healthy
57:13liver tissue here,
57:14which creates noncirrhotic portal
57:15hypertension, both from Oxaliplatin,
57:17where Uniti Concuss.
57:18Seattle hepatitis so fatty fatty
57:19infiltration and inflammation of the liver.
57:21Here very severe case,
57:22and the less of your case.
57:24But frankly there shouldn't be fact.
57:25Neither of these images.
57:27So in in conclusion,
57:29we took the talked about the
57:30importance of molecular results.
57:31Those are things that need to be
57:33sent on every patient so that the
57:35medical oncologist can know what
57:37treatment approach should be done.
57:38The role of sightedness,
57:39our approach to the unrespectable
57:41in the upfront respectable,
57:42and some of the damage our agents can do.
57:45Thank you so much.
57:49Michael, thank you for high speed yet
57:54incredibly comprehensive overview of
57:58rapidly evolving and complicated field and.
58:03David, I want to thank you as well.
58:07Given the time, I don't think we have much
58:11leftover for discussion, I would just.
58:14Close by saying that this is an
58:18incredibly exciting field to work in,
58:21I think the overview that my partners
58:25have given gives the audience a
58:28sense of the enormous complexity yet
58:31opportunity involved for our patients.
58:34And I think for all of us who work together,
58:37it is yet another call.
58:39For an extraordinary level of teamwork,
58:42integration, communication,
58:43all of these clinical services have to be
58:48linked together by meticulous communication
58:50between us is clinicians as well as
58:54our nurses and administrative Staffs.
58:56As we kind of navigate care
59:00throughout a very complex system.
59:03Charlie, anything to add.
59:04Oh, I just want to thank David,
59:07Michael and Kevin for really
59:09just a brilliant discussion.
59:10And thank you for your leadership,
59:12your collaboration and building a
59:14team around a pivotal area of care,
59:17research and thanks everyone for joining
59:19us and think giving us a lot to think
59:23about and really exciting progress.