Evolving Multidisciplinary Management of Colorectal Liver Metastases

Transcript

• 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.