Hepatocellular Carcinoma – From Screening to Treatment: Current Practice, Pearls, and Puzzles

February 01, 2023

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Yale Cancer Center Grand Rounds | January 31, 2023

Presentation by: Dr. Tamar Taddei

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00:00Instead, it is for me a great pleasure
00:04to introduce Doctor Tamar Kali,
00:07who is now Professor of Internal Medicine
00:09and the Department of Internal Medicine,
00:12but also the Chief of Gas and Technology
00:15and the VA Connecticut healthcare system.
00:17And this is not a small place, in fact she.
00:22Is there after Harold Kahn,
00:24Roberta Grossman and Lupica sits house so
00:28she has a great legacy to uphold and we.
00:32Certainly, sure.
00:34She'll do even even better in the VA system.
00:38She directs the cancer program and also has
00:42been very active in the VA system at large.
00:46Where she. Ryan, Sir.
00:51Some very important multicenter trial
00:53among them some already famous like
00:56the vocal other on the statins will
01:00soon be available and and and also a
01:04new recent very large grant on the
01:08use of abbreviated MRI to screen for
01:11liver cancer and this is another great.
01:14I could give it to you.
01:15She is a great mentor for a number of hours.
01:22Fellows and trainee and and I like
01:25to think that she has been a trainee
01:28here for many, many years and we
01:31were pleased to see her growth.
01:33So in a way, she is the witness
01:37of the Yale education system.
01:39And how Michelangelo used to say,
01:42after she stopped sculpturing the Moses,
01:47he said, why don't you talk?
01:50Well, our masterpieces talk,
01:52and here I can give you some
01:55metadata on the episode casino.
02:00Thanks so much Mario for the introduction.
02:03So Mario actually has been my clinical
02:06mentor for going on a couple decades now,
02:08not quite yet, a couple decades, but.
02:11He actually started the first tumor
02:14conference for HCC at Yale and I was
02:17part of that conference as a trainee.
02:19And actually what I learned from him,
02:20I took to the VA.
02:21So we have a a really nice network
02:24of regional tumor boards which
02:25have been incredibly fruitful.
02:27So I'm going to talk about a lot today.
02:29I'm hoping to really impart what's
02:31going on in current practice and pearls,
02:34but mostly a lot of puzzles.
02:36So if you come away with more questions
02:37than answers, that's the objective.
02:39There are a lot of questions right now in HC.
02:41And I'm going to talk a little
02:43bit about the work we've been
02:44doing both at Yale and the VA.
02:46I have no disclosures other
02:48than I'm not an oncologist,
02:49I'm a hepatologist and so I may
02:51use acronyms you don't understand.
02:53I'm hoping I will explain them all,
02:56but if you have questions,
02:57by all means, don't hesitate.
02:59So my objectives are for you to
03:01understand the present state
03:03really of biomarkers and potential
03:05emerging biomarkers in HCC,
03:06to understand the importance of
03:08multidisciplinary management of HTC
03:09and key stakeholders and decision
03:11making and to learn about new
03:13therapeutics and treatment paradigms.
03:15But mostly I think what I'm trying
03:17to impart is just how complex this
03:19landscape has become and how essential
03:21it is for us to work together
03:23both clinically and at the bench.
03:25So HTC as you know is a global
03:28health problem.
03:28This is a map of the world showing
03:30the sort of different degrees
03:32of blame for certain underlying
03:35etiologies of chronic liver disease.
03:37In the West it's been predominantly
03:40hepatitis C,
03:41in the east predominantly hepatitis B.
03:43But what's really important here
03:45is to note the prevalence of fatty
03:48liver disease or non alcoholic
03:50steatohepatitis related liver disease
03:51as well as alcohol and the pandemic
03:54has brought to light a lot of issues.
03:56Regarding alcohol and a lot of
03:58sex disparities and alcohol and I
04:00think we're going to be seeing HC's
04:02related to really the synergies of
04:04things like metabolic syndrome,
04:06alcohol etcetera.
04:07So the epidemiology is definitely shifting.
04:10Viral hepatitis will always be a
04:11major issue and until we can you
04:13know essentially do the right public
04:15health thing globally,
04:16we're still going to have happy
04:19you know related HCC.
04:21So HTC is a leading cause of liver
04:23related and cancer related mortality.
04:25So there are sort of competing
04:27risks of death.
04:28When you think about HTC,
04:30you want to think about the person's
04:31liver disease as potentially
04:32a competition to their cancer
04:34related mortality.
04:35It is the leading cause of death
04:37in cirrhosis and 1/3 of patients
04:39will with cirrhosis will develop
04:40HCC over their lifetime.
04:42And you can see that it claims
04:44upwards of almost a million deaths.
04:46By 2025,
04:47we think globally will have
04:49a million deaths
04:50related to liver cancer.
04:51And chronic liver disease is really
04:54a prerequisite in 90% of the cases.
04:56But how much fibrosis is still
04:58an issue that we're studying.
05:01And we've seen a market incidence
05:04increase in HCC in the US from 1990
05:08to 2020 at a threefold increase.
05:12A lot of that was due to hepatitis
05:13C but the issue is that even
05:15though things are kind of steadying
05:16from hepatitis C and our ability
05:18to treat and cure hepatitis C,
05:20the fatty liver disease epidemic.
05:22Sort of the next wave.
05:25So who should get surveillance?
05:26We recommend liver ultrasound and
05:28AFP every six months in all patients
05:31with cirrhosis and patients with
05:33chronic hepatitis B and that's
05:35regardless of cirrhosis.
05:36And the way that we image people
05:38is essentially with an ultrasound
05:40they should have an an AFP.
05:42But if they have an elevated AFP even
05:44if they're ultrasound shows nothing or
05:45if they have something focal on ultrasound,
05:48we then go to dynamic contrast
05:51enhanced imaging with a CT or MRI.
05:54But there are some Gray areas here,
05:56sorry,
05:56this didn't convey well the first line
05:58of that says hepatitis C with a cure,
06:01but without pre-existing
06:02cirrhosis prior to their cure,
06:05non-alcoholic fatty liver
06:07disease without cirrhosis.
06:08So these are folks who we really
06:10don't have biomarkers for.
06:11They don't fall into the cirrhosis
06:13category and many of them are
06:15being diagnosed with HC and they
06:17shouldn't have and aren't in a
06:20screening or or surveillance program.
06:22We know that liver cancer
06:24surveillance saves lives.
06:25I'm going to actually use the
06:27term screening and surveillance
06:28kind of interchangeably here,
06:29understanding that we're looking
06:30at an at risk population.
06:32Those are people with cirrhosis.
06:33So it's really surveillance.
06:34But I think a lot of people are
06:37used to the term screening,
06:38meaning that they don't have
06:39a pre-existing cancer.
06:40And so you're going to screen for a cancer.
06:43Just know that when it comes
06:44time to discuss the trial that
06:46I'm going to be discussing,
06:47we have to call it screening because
06:49that's just what they made us call it.
06:50But surveillance is really the proper term.
06:52So this is a nice,
06:54nice graphic of a big meta analysis
06:56that looked at almost 150,000
06:58patients and showed that really the
07:01benefits of surveillance are manifold.
07:03So we can detect cancer early,
07:06we can offer curative therapy and
07:09we can improve overall survival.
07:11There are some sort of data free
07:13zones here in terms of the harms
07:14of screening and these are things
07:16that need to be studied in this
07:18population and those harms are
07:19many different types of harms,
07:21financial, physical, etcetera.
07:24So surveillance is advised by
07:26all GI liver societies and NCCN,
07:28but ASCO and the preventative Services
07:31Task Force don't advise surveillance
07:32and until there is a mandate for this,
07:35it's not going to be taken up
07:37widely by primary care providers
07:39and this remains a major issue.
07:41So surveillance rates are poor.
07:43So this is actually a private
07:45sector study that looked
07:46at a a cohort of hepatitis
07:48C cirrhosis patients.
07:49So they really should have been in a
07:51surveillance program and only about
07:531/4 we're getting every six month.
07:55Ultrasound. So this is pretty abysmal.
07:57I mean, if you look at sort
07:59of longer surveillance rates,
08:01maybe every year somebody's
08:02remembering to do this,
08:04but it's more haphazard than
08:06actually being done regularly.
08:08Now VA data looks a little bit better.
08:11We're at about 44% and we do have
08:13a lot of different ways to get our
08:16primary care docs to order ultrasounds.
08:19But I think what's really important is
08:21if you compare this to places in Europe
08:23where surveillance rates approach 65%,
08:25for example in the UK or in Japan
08:27where there is high as 75%,
08:29we're really,
08:30we have a long way to move this needle.
08:33And we really only see the
08:35tip of the iceberg.
08:36So in addition to low uptake of surveillance,
08:38many patients are unaware of
08:40their risk of developing HCC.
08:42And that's due to the silent nature of
08:44cirrhosis and the lack of awareness of
08:46the disease among primary care providers.
08:47And primary care providers now are
08:49really burdened by so many things
08:51they have to think about that liver
08:53disease is pretty low on the list.
08:55Now we know that linkage to liver
08:57cancer care starts with identifying
08:58cirrhosis and starting surveillance.
09:00But again,
09:01primary care providers desperately need
09:03to be educated to even suspect cirrhosis
09:05and surveillance really needs a mandate.
09:07I don't think this is going to
09:09be done until we actually prove
09:11that surveillance saves lives,
09:12and that probably has to be
09:14done in a randomized trial.
09:16So at risk populations that I talked
09:18about before are changing with the
09:20Natural History of liver disease.
09:21So in the US,
09:23we are widely treating hepatitis
09:24CI would say in the VA we've
09:27treated almost 75% to 80% of our
09:29patients with hepatitis C Some
09:32160,000 veterans have been treated.
09:34And so this actually gives us a
09:36unique group in which to study
09:38post SVR sustained viral response
09:40risk of HCC and we've seen that
09:43risk go down significantly,
09:44however, if there's significant.
09:45Fibrosis stage three to four,
09:47they're still at pretty high risk
09:49of developing HCC in their lifetime,
09:51but we are not seeing that it's
09:53cost effective to do ultrasound
09:54in patients without cirrhosis.
09:56So the question is,
09:57are there other biomarkers we
09:58could be looking at?
10:00Noncirrhotic Naphill DI think is
10:01keeping us all up at night because
10:03up to 1/3 of fatty liver disease
10:06related HCC occurs in the absence
10:08of cirrhosis and these people
10:09are usually diagnosed late.
10:11But if you think about the 70 million
10:14Americans who probably have NAFLD.
10:16There it's really not cost effective
10:18to order an ultrasound for them.
10:19So again we need biomarkers and imaging
10:22really is, is not the way to go.
10:24So we're looking at risk stratification
10:27tools to identify those at highest
10:30risk and then surveillance now
10:32in clinical practice
10:33is done on a case by case basis.
10:35So this leads to the next problem
10:37which is that HTC is diagnosed late.
10:40So this is SEER data from 2012 to 2018
10:44which shows that you know really in
10:46the majority of cases it's diagnosed
10:48late with either regional lymph
10:50node spread or distant metastases.
10:51And we know that when HTC is diagnosed late,
10:54survival goes down.
10:55So five year relative survival
10:58and localized disease is 36.1%
11:00much better than it's ever been.
11:02But overall five year relative
11:03survival is about 21. Percent.
11:05We've moved the needle a little.
11:06It was about 18% in the last big sear.
11:11Cohort that they looked at.
11:13So how do we identify opportunities
11:16for directed education and outreach?
11:18This is work that's essentially a
11:20it's a mentorship of Doctor Strauss
11:22Tabasco with Doctor Mezzacappa,
11:25one of our fellows.
11:26I'm looking at tumor registry and US
11:29Census data specific to Connecticut and
11:31we're working with the Department of.
11:34Public health in Connecticut.
11:35So this is geolocalization or hotspotting.
11:38And this approach we took to really
11:40kind of see where our case is most
11:42dense in the state and then what
11:44are some of the associations to the
11:46case rate and the stage diagnosis.
11:49And interestingly,
11:50we found not only this wide variation in
11:52cumulative incidence of HCC by ZIP code,
11:55but also strong associations
11:56between Community level,
11:58poverty and education and
12:00the HTC case density.
12:02So really you could do this
12:04anywhere in the country.
12:05That I've taken you kind
12:06of from global to local,
12:08and I'm sure that Doctor Shaw,
12:09Sebasco and Doctor Mezzacappa will
12:11think about interventions in the
12:14community that we can actually
12:16improve our outreach and surveillance.
12:18So getting back to this conundrum
12:20with ultrasound,
12:21so ultrasound is what we use in the
12:23present state for HCC surveillance,
12:25but we know that it lacks sensitivity
12:27for early stage detection and
12:29this has always been a problem.
12:30And it's also a problem of geography.
12:32In Europe,
12:33usually physicians do the
12:35ultrasound in the States, text do.
12:37The ultrasound body habitus is
12:39very different geographically.
12:40We have pretty large body habitus.
12:43And generally what you can see
12:44here is that while ultrasound may
12:46be OK for diagnosis at any stage.
12:48It's really pretty poor for
12:50diagnosis at early stage.
12:52And no matter what stage you're looking at,
12:53MRI really is the gold standard.
12:55The question is can you use
12:57something like an MRI to screen?
12:59And that's sort of a question
13:02that begs asking,
13:03so can we move the needle on early
13:06detection so we can do ultrasound, CT or Mr.
13:09These are the pros and cons.
13:10You know,
13:11clearly we can look at things like
13:14developments and other cancers.
13:16So for example in Europe.
13:19They use contrast enhanced ultrasound.
13:21I don't think that's ever going to
13:23really take off here in the states for
13:25many reasons like lung cancer where
13:27you can use low dose chest CT for example,
13:30could you do low dose liver CT?
13:33Probably not because of the kind of
13:35resolution that you need to see liver cancer.
13:38But abbreviated MRI with shorter imaging
13:40times actually may be promising.
13:43And when I say shorter imaging times,
13:44right now it takes about 45
13:46minutes to do a liver MRI.
13:47With abbreviated MRI you can get
13:48a person on and off the table.
13:50In about 10-15 minutes.
13:52So this is something that we want to study.
13:56And I think the VA is really the perfect
13:58and probably the only place to study it.
14:01So cirrhosis is highly prevalent and MRI
14:03is really readily available at the VA
14:05and cirrhosis is quite common in the VA.
14:08The reasons for that is we have a 5
14:10fold higher incidence of hepatitis C,
14:11which again is mostly now cured.
14:13We have very high prevalence of
14:15alcohol use disorder and very high
14:18prevalence of metabolic comorbidities.
14:19In addition, we have an aging population.
14:21And as you all know,
14:22cancer is a disease of aging.
14:25So it's really the right mix of patients.
14:28We are the largest healthcare provider
14:30for liver disease in the nation
14:32and we're a closed system that can
14:33really look at our own metrics.
14:35So our electronic health record
14:37has been curated for research by
14:39the corporate data warehouse where
14:41we can really have wonderful,
14:42very rich data that spans 20 years.
14:47We also have operational sort
14:49of on the patient facing side,
14:51population health dashboards to identify
14:53patients in need of surveillance.
14:55We have clinical reminders that alert
14:57primary care providers to perform HC
15:00surveillance and we've made a lot of
15:02innovations with care coordination
15:03and navigation with online tracking
15:05tools that help us follow the patient
15:07through the continuum of care.
15:09And again,
15:09MRI is really readily available and
15:11we don't have to prior authorize
15:13anything in the VA.
15:15Not nice.
15:16So so we can do this study in the VA.
15:22So the question is will earlier detection
15:24with abbreviated MRI actually result
15:26in a cancer related mortality benefit
15:28and this is what we want to find out.
15:30So our study called the premium study
15:32which I'll get to is a VA cooperative
15:35studies program funded study.
15:36So the CSP actually funds very large
15:38scale trials only when they're super
15:40convinced that we're going to be asking
15:42fundamental questions that could change pack.
15:45Practice and they provide a dedicated
15:47coordinating Center for handling
15:49the trial across many centers.
15:51And we actually designed a study with
15:53a non screening arm which took a lot of
15:57convincing because gastroenterologists
15:58and hepatologists consider a non
16:00screening arm unethical and actually
16:02many other trials have tried this
16:04in patients simply wouldn't enroll.
16:07So the other issue is that we
16:10really do think that ultrasound
16:12is at this point insensitive.
16:14Enough that it's actually
16:16not a bad comparator,
16:18since it's standard of care anyway.
16:21So this is the study.
16:22It's called preventing liver
16:24cancer mortality through imaging
16:25with ultrasound versus MRI.
16:27And it's a randomized controlled
16:28trial of standard of care
16:30ultrasound plus AFP versus
16:32abbreviated MRI plus AFP every six
16:34months in patients with cirrhosis
16:35who have a high risk of HCC.
16:38And some might say, well, geez,
16:39why are you starting there?
16:41You know, there's so many people
16:42who have so many variable risks,
16:44why are you starting there?
16:45And I think we have to start
16:47here because surveillance even
16:49in cirrhosis has poor uptight.
16:50Poor uptake and a lot of debate still
16:53around it outside of the liver world.
16:56So I think this is the right population.
16:58This is the abbreviated MRI protocol
17:00if any of you are interested.
17:01It really has all the sequences to
17:05diagnose HCC and the room time as
17:07I said is about 10 to 15 minutes.
17:09So we're essentially taking a
17:11diagnostic exam, shortening it,
17:13still keeping the diagnostic sequences
17:15and using it as a screening exam.
17:17Our primary outcome is cumulative
17:19HTC related mortality.
17:21The study and which is your age
17:23for the surveillance portion and
17:25we're powered to detect a reduction
17:27in HCC related mortality of 35%.
17:29Of course,
17:30we're going to be following any incident
17:32HCC through the life of the study as well.
17:35So our study setting is 47
17:37VA medical centers with high
17:38numbers of cirrhosis patients.
17:40According to those population
17:42health dashboards,
17:43they have to have adequate
17:45MRI capacity and access to a
17:47multidisciplinary liver tumor board
17:49for state-of-the-art treatment of HCC,
17:50which is a tall order.
17:52It's one thing to diagnose a bunch of HCC,
17:54but if you're not treating it correctly,
17:56that would really influence the study.
17:58So every center has to agree that they
18:00will send their patient to a tumor
18:02board and that they have access to care.
18:05The VA is very serious about trying to
18:08enroll veterans all over the country.
18:10So they have these network of dedicated
18:12enrollment sites that we're working
18:14with and giving priority to the study.
18:16Our total sample size is 4700 patients,
18:192350 per arm and the duration is
18:219 years and it's eight years in
18:23the surveillance and then nine
18:25years for data analytics.
18:26And what's interesting here is if you
18:28think about the burden to each center,
18:30we're basically asking them to enroll about
18:33100 patients over the enrollment period.
18:35Which is the first three years of the
18:37study and essentially they're going to
18:39be performing 100 extra abbreviated MRI.
18:42So you know,
18:42those people would have had an
18:44ultrasound every six months.
18:45They're getting an abbreviated MRI.
18:46It's not a huge ask.
18:48It's actually fairly tenable for a
18:51larger center that has a functioning MRI.
18:54So this is just the,
18:55what the study is going to look
18:57like in terms of enrollment is
18:59for the first three years and
19:01then everybody is you know in a
19:03surveillance pattern through year
19:05eight and then we analyze the data.
19:07And this is just a schematic of our
19:09hypothesis and the difference between
19:11abbreviated MRI and ultrasound.
19:13So we hope that we're going
19:15to detect cancer at
19:16earlier stages, offer more curative therapy,
19:19reduce HC related mortality
19:21and if this is true,
19:23then abbreviated MRI will be widely adopted,
19:26MRI's are becoming cheaper.
19:28So the hope is that this study will also
19:30dovetail with technological advances
19:32that make MRI within reach for patients.
19:35And again you can see that
19:37we're really hoping to.
19:38Capitalize on the sensitivity of of MRI.
19:42So we will have a large
19:44bio and image repository.
19:46So we're going to be collecting
19:47blood every six months from patients
19:49when they come in for their imaging.
19:50That's going to be shipped to the A
19:53central biorepository for processing.
19:54We're collecting all the digital
19:56files for ultrasound abbreviated MRI.
19:59And so there are many possibilities
20:01for collaboration on biomarkers,
20:02both blood and imaging.
20:03And imaging is actually very important.
20:05There may be much that we learn from
20:07MRI's that has nothing to do with.
20:08Answer and the CSP is actually
20:11really nice at encouraging spin-off
20:13studies and in collaborating with
20:16other centers like NIH for example.
20:19So I talked about a biorepository.
20:21I think one of the biggest questions that
20:24the reviewers had for this grant was,
20:26well, hey,
20:27what if something happens where
20:28you can just screen for HTC,
20:30you know,
20:31based on some blood test and I
20:32it is a real threat.
20:34I don't think it's necessarily going to
20:35come to pass in the life of the study,
20:37but it is something that we felt
20:39that a biorepository would be
20:41very useful to validate in a
20:43pretty heterogeneous population.
20:45And one can argue, well,
20:46the VA how heterogeneous is it?
20:48It's a bunch of.
20:49Then, but the truth is,
20:50is that it's actually quite heterogeneous
20:53in terms of ethnicity and background.
20:55So you can see here the present
20:57state of biomarker development
20:59development for early detection.
21:01There are four FDA approved biomarkers
21:03on this list here there's AFP,
21:06AFP, L3,
21:07DCP and GALAD and their DRN
21:10phase of validation.
21:11So really AFP is hit prime time.
21:13I don't think many of us use
21:15FPL 3 DCP or Gallatin practice,
21:18but you can see.
21:19As you go down this list,
21:20you're starting to have multiple different
21:22factors play into your algorithm.
21:24So you're you're never going to find a
21:26Holy Grail in HC of like 1 great protein,
21:29one great marker.
21:29It's always going to be a mix
21:31of different things,
21:32clinical you know proteins etcetera.
21:35So we're getting much more into
21:38sort of this algorithmic type
21:40approach to biomarker development.
21:43Liquid biopsy,
21:44I think has been very encouraging.
21:45In other cancers,
21:46it's certainly encouraging an HTC,
21:48but it requires cross validation
21:50and better precision.
21:52I would say that detecting early
21:54HCC is difficult actually.
21:56Where these biomarkers may be most
21:59important is in detecting recurrence, Umm.
22:01So there's a lot of work going on here.
22:04But I think for early detection,
22:06liquid biopsy isn't yet ready for prime time.
22:09There's a lot of things that are
22:11very intriguing in liquid biopsy.
22:13So it's not.
22:13Just circulating tumor cells,
22:15it's things like extracellular vesicles,
22:18you know, circulating free
22:20DNA and methylated DNA.
22:22So there's a lot to learn here and
22:24a lot of platforms on which we can
22:26kind of look at different things
22:28from the blood that we collect.
22:30So even with the best of intentions of
22:33trying to think about different populations,
22:37I can bring you down to the microscopic
22:39level and tell you that not only are
22:41our populations heterogeneous in terms
22:42of their ideology of liver disease,
22:44but the cancer itself is
22:46really heterogeneous.
22:47And there can be intratumoral heterogeneity,
22:50intratumoral heterogeneity.
22:51And so this actually
22:53becomes very complicated.
22:55And all of this is HC under the microscope.
22:57So you can see just how
22:59different some of these patterns.
23:00Yeah. So again,
23:03there's intratumoral heterogeneity,
23:05intratumoral heterogeneity
23:06and this is really, you know,
23:08obviously interpatient heterogeneity,
23:09which I've discussed.
23:10But then there's a lot going on
23:13in terms of components of tumor
23:15heterogeneity in the liver.
23:16So the liver is a complicated organ
23:19where there's a lot of innate immune
23:21suppression because actually the
23:23liver is what screens for foreign
23:25pathogens in your diet, right,
23:26and all the things that you're seeing.
23:28So these cancers grow up in a in a fairly.
23:31Immune suppressed environment.
23:32So it's a little bit different
23:34than the milieu of other organs.
23:35So there really is a lot to consider
23:38in terms of how to study this.
23:40And teasing out oncogenic pathways
23:41from the pathways that are already
23:43upregulated from hepatic injury
23:45and repair is very complex.
23:47And I think we all like to think linearly,
23:49but it doesn't really work here.
23:51So these are all the things that
23:53are associated with the paddock
23:55inflammation and fibrosis,
23:56some of them individually,
23:57some of them synergistically,
23:58some of them lumped together like metabolic,
24:01obesity, Nash and diabetes,
24:02which are all interrelated.
24:04And we like to think that all of these
24:06start this cascade that goes stepwise
24:08from inflammation and fibrosis to advanced.
24:10Fibrosis and cirrhosis to HCC,
24:12but it really doesn't happen that way.
24:14And we know that 20 to 30% of HTC
24:17and hepatitis B NAFLD and HIV
24:19arises in the absence of cirrhosis.
24:21So we can't really,
24:23although it's very tempting,
24:24we can't really think linearly here.
24:26We have to think about different hits when
24:28in the lifetime these hits are happening,
24:30what are the exposures,
24:32the persons involved with,
24:33etcetera.
24:34So there's a lot really to consider and I
24:36think these stepwise schematics are great
24:38if you're learning about the disease.
24:40So once you've learned about their disease,
24:42you realize just how complicated it is.
24:45So one of the things we're looking
24:47at in the VA and this is again
24:48work in the vocal cohort,
24:50which is a big virtual cohort of
24:52130,000 patients with cirrhosis.
24:54And the VA over these past 20 years
24:58is some of the effects of blood
25:00glucose control and some hypothesis
25:02around blood glucose control.
25:04And we actually found quite
25:07antithetically that sustained
25:08blood glucose
25:09control actually increases your risk for HTC.
25:13Why is that? It's because of
25:14the Tropic effective insulin.
25:15So we have to actually look at the
25:18pharmacoepidemiology of these patients
25:19when they were started on insulin,
25:22when in the course of their
25:23diabetes and their liver disease
25:24they were started on insulin,
25:26what other drugs they received etcetera.
25:29So this is really just to show you
25:31the robustness of the associations
25:33you can look at in the VA,
25:35but that you can't stop there.
25:36Actually there's a whole lot more
25:38that has to be done both in terms
25:40of looking at the richness of
25:42the pharmaco epidemiological data
25:43but also then mechanistically.
25:45So this is really nice.
25:46To be able to kind of take a really
25:48like 30,000 foot view and say what
25:50are all the things that now we need to
25:52study based on what we found is what
25:54we didn't expect quite a paradox here.
25:57So HTC is clinically complicated
25:59because it's unique among cancers.
26:02And this is where I think
26:03oncologists sometimes say, oh,
26:04you know, you hepatologists,
26:05you always want to stand out,
26:06be unique, right.
26:07There's nothing unique about this,
26:09but it really is unique.
26:11So it's one patient with two diseases
26:13and cirrhosis leads to multifocal
26:15liver cancer because of the field
26:17effect and very high recurrence rates.
26:19It also really has complicated
26:21treatment and trial design and it
26:23is a a cancer that's something of
26:25an anathema to oncologist because
26:27you guys like tissue.
26:28And we can diagnose this by imaging alone.
26:30And actually that's where I
26:32think our field has misstepped.
26:34I think we actually put ourselves
26:35way behind without getting biopsies
26:37for so many years.
26:38It is the only solid organ malignancy
26:40for which transplantation offers a cure,
26:42which puts the onus on us to
26:44make sure that we're sending the
26:46right people for transplant.
26:47But surgeons love to push the envelope.
26:50They should push the envelope and we're
26:52really beginning to push the envelope,
26:54meaning that people who we thought had
26:56disease way outside bounds are having.
26:58Remarkable complete responses
27:00on immunotherapies and coming
27:02back to transplant,
27:04which is very weird and very
27:07frightening for many of us.
27:08But their early responses look really good.
27:11So I think we're going to see a lot
27:12of stage migration with the newer
27:14therapies and we're going to have to be very,
27:16very careful in how we treat these people.
27:19And I think the adage of just because
27:21you can do it doesn't mean you should
27:23do it is something we have to take
27:25very seriously as as this landscape
27:27changes in terms of treatment.
27:30So the treatment of HCC up until now
27:32has followed a very linear pathway
27:34from early to advanced disease.
27:36So hepatology surgery,
27:37both surgical oncology and transplant
27:39surgery and interventional radiology have
27:42really dominated early stage disease.
27:44And oncology is usually consulted
27:46only in diffuse infiltrative
27:48intermediate stage disease or in
27:50advanced disease with vascular
27:51invasion or extrahepatic Mets.
27:53And that's really unfortunate for
27:55the oncologist because sometimes
27:56they're really referred to you
27:57too late and they're too sick.
27:59The treatment and had you brought your
28:02expertise to the table earlier on,
28:04it probably would have
28:05actually been really good.
28:06So I think oncology now feels very
28:09much welcome at the table because
28:10we do have so many new treatments.
28:13But also the lack of that expertise
28:15for so long because we really
28:17didn't have good systemic therapies,
28:19I think really detracted from
28:21our development as a field.
28:23So the advent of new therapies is
28:25definitely changing this paradigm,
28:27not only the timing of specialty involvement.
28:29But also the types of specialists involved,
28:31for example,
28:32SBRT now has a place in the
28:35arsenal for HCC management.
28:36So this is not for you to memorize,
28:39but the staging classification that we use
28:42called the BCLC staging classification.
28:45And the things that I just want to
28:46draw your attention to is that really
28:48we have to think about the patient
28:50and their functional status first
28:52in terms of their liver function.
28:54So this is really what drives our
28:56initial decision making before
28:58we even begin to count tumor.
29:00Or think about tumor burden and then
29:02tumor burden is actually looked at across,
29:05you know very early, early,
29:06intermediate and advanced stages.
29:09And then we have treatments
29:11ascribed to those different stages
29:13with a expected survival,
29:15which I have to say has gone up
29:18significantly in the last 10 years.
29:20You know,
29:20essentially it used to be 3 months for
29:22advanced stage and now we're looking at,
29:25you know, over two years,
29:26over 2.5 years for taste.
29:28I mean,
29:29these are quite big differences
29:31than 10 years ago.
29:32What's new about this classification
29:34is everything below this blue bar,
29:37so essentially before I go
29:38below the blue bar.
29:40I just want to say that they've now
29:42separated out intermediate stage
29:43disease because we know that diffuse
29:45infiltrative HCC is a different actor,
29:47especially when it's by low bar,
29:49you really can't approach it locally.
29:52But we've now put in successful
29:55downstaging again moving back towards
29:57a curative or transplant effort.
29:59And then the stage migration is a
30:02theme that's really being played
30:04out both by surgical oncologists
30:06and transplant surgeons.
30:08And then we have now up to three.
30:10Kinds of systemic therapy when we
30:12only had one line for 10 years.
30:14So in the last five years,
30:16we've seen a lot of change.
30:18And that's really why multidisciplinary
30:20care is essential.
30:21So we really have to define our endpoints.
30:24So we want to improve survival.
30:26Everybody wants to improve survival,
30:27but survival is relative to the
30:29liver disease.
30:29So you really don't want to offer
30:31a treatment that's going to hasten
30:33somebody's death from liver failure.
30:34And that is a very,
30:35very tough decision that requires
30:37a lot of thought.
30:38You really need to know your patients,
30:39you need to know their markers,
30:41you need to know them well.
30:42Proper risk assessment and obviously
30:44proper patient selection is key
30:46to any surgeon. You know,
30:47surgeon doesn't want to be surprised.
30:49There are. There are standards
30:50that have to be set and there's,
30:53as I've mentioned, a lot of Gray areas,
30:55but there's also a lot of
30:57variations among disciplines.
30:58For example,
30:59surgical oncologists approach surgery
31:01very differently than transplant surgeons.
31:03And there's variations among
31:05programs and regions.
31:06And especially when it comes
31:07to liver transplantation,
31:08there's significant variation.
31:09So our job as a group of people who
31:13take care of these patients in a
31:16multidisciplinary way is to identify
31:18the optimal candidates for treatment.
31:20Identify contraindications and then
31:22consider them across the continuum,
31:25weavering patients back to
31:26tumor board all the time.
31:27And I would argue that every single
31:30recurrence and every single new
31:32tumor has to be brought to tumor
31:34board because you will forget that
31:36patient and you will miss their
31:38opportunity for something that
31:39could really prolong your life.
31:41So tumor board for liver cancer
31:43I think is absolutely necessary.
31:45You can't take care of these patients alone.
31:47You don't want the onus of all that
31:49decision making falling on one person.
31:51And this graphic is from a paper
31:54written by Doctor Jaffe here at Yale
31:57really kind of describing this playbook.
32:00You know,
32:01essentially the hepatologist is quarterback.
32:02Usually these folks come through us
32:04and then we bring them to tumor board.
32:06But there are a lot of different
32:07referral lines and we've seen
32:08people coming through oncology,
32:10coming through interventional radiology.
32:11The most important thing is that
32:13you discuss that patient before you
32:15treat them and that really should be
32:17the norm because there are always
32:18new ideas and if you don't discuss,
32:20you won't.
32:21You won't think about, you know,
32:23what could be a potential, you know,
32:25better therapy.
32:26Remember that tumor boards actually
32:28serve a lot of purposes.
32:30They are accredited.
32:31They have to have mandatory attendance
32:33from certain disciplines.
32:34They have a liaison to the tumor
32:36registrar so they can actually pick
32:38up cases and report them early.
32:39They provide an objective
32:41forum for discussion and that
32:42they really should be that,
32:44an objective form for
32:45discussion where everybody,
32:46everybody's opinion matters.
32:48They should foster trial
32:49enrollment and they do.
32:50There are many studies that have
32:52shown that and they really help to set
32:54institutional guidelines in Gray areas,
32:56of which we have many.
32:57They're also a really
32:58important thing for trainees.
32:59So the one thing I loved most as a Med
33:01student was multidisciplinary team reward.
33:03So it's no, you know,
33:05strange thing that I ended
33:07up running tumor boards.
33:08So our tumor boards in the VA are regional.
33:12So I run a big Southern New England
33:15regional tumor board that takes
33:16care of Vermont and Providence,
33:18also Rhode Island, Vermont,
33:20Massachusetts,
33:21Connecticut.
33:21This is actually a study of about
33:254000 patients across the VA.
33:27And what we found in this study
33:29was that seeing a hepatologist
33:31actually was associated with
33:33a 30% mortality reduction,
33:35but it wasn't associated
33:36with higher odds of
33:38receiving active therapy.
33:39So what does that mean?
33:40That means we're actually carefully
33:42deciding who can get therapy and
33:44who should not get therapy because
33:46we know that palliative care in
33:48hepatology can prolong life in liver
33:50cancer and in in stage liver disease.
33:52It's knowing who's the right person for
33:54that palliative therapy versus who's
33:56the right person to get treatment.
33:58And very encouragingly to me because
33:59you know tumor board is a labor
34:02of love and very labor intensive,
34:03multidisciplinary tumor boards also
34:05were associated with lower mortality.
34:08So this study was very heartening.
34:12So we have many options for local
34:13regional therapy and early and
34:15intermediate stage disease, Umm.
34:17So this is the part of the BCLC
34:19classification from very early
34:21to intermediate stage.
34:22And we have liver resection and liver
34:25transplantation not for the faint of heart.
34:27You need to have really good liver
34:28function for a liver resection.
34:30Liver transplantation is wonderful
34:31because it cures the underlying
34:33cirrhosis and the liver cancer,
34:34but it's not for everyone and there
34:36are very strict criteria for who
34:38can and can't get transplanted.
34:39Local regional therapies abound.
34:41And ablation now can be given thermally,
34:45can be given chemically and also with SBRT.
34:49So there's emerging data to suggest
34:51that SBRT and small lesions does have
34:54ablative and curative properties
34:56for palliative intent.
34:58So this is moving more towards
35:00intermediate stage B disease.
35:01There are transarterial therapies,
35:04chemoembolization and eitrem or
35:06why 90 treatment and then SBRT.
35:10So these therapies are supposed to prolong.
35:12By about 2 1/2 years,
35:14which is pretty considerable and
35:15people have pretty good quality
35:17of life with these therapies.
35:18The one thing is that these transarterial
35:20therapies do take out a penumbra of
35:22functioning liver and so you really
35:24have to think about their liver function.
35:26Same with ablation,
35:27but less so.
35:27Ablation is usually pretty targeted.
35:31So this actually is data that's
35:33going to be published as part of
35:35the ASLD guide guidance for HCC.
35:37And what I can tell you is that
35:39in in considering this guidance,
35:41the way that we interpret CT's and
35:44MRI's in patients with cirrhosis is
35:47very standard because the reason that
35:48we can make this diagnosis without
35:50a biopsy is that these tumors look
35:53very characteristic on imaging.
35:55And this has guided our field for
35:56a long time and for a long time we
35:59actually argued against doing biopsy because.
36:01They feared tumor seeding especially
36:03in the transplant patient.
36:04But really tumor seeding is very,
36:06very rare and nowadays we have
36:08better technology and the way we
36:10do biopsies and so it's,
36:11it's quite rare and good hands.
36:13And So what we've tried to do is explain
36:15that biopsy actually may be very important,
36:18especially when you're not entirely
36:20certain because some therapies can be
36:22offered and you may lose your window.
36:24So now we actually recommend
36:26biopsy and lyrids 4, probable HCC,
36:29lyrids 5, you certainly can.
36:31Biopsy when they're deaf,
36:32quote,
36:32UN quote,
36:33definitely HTC and lyrids
36:35malignancy means you can't
36:36really determine if it's an HTC.
36:39So biopsy was always the norm there.
36:41And then if you have tumor in vain,
36:43you may be able to biopsy to do Umm,
36:46you know, testing,
36:47for example, a tumor profiling.
36:48So I think we'd like to see more and
36:51more biopsies being done and being done
36:53rationally across the continuum of care,
36:55but this guidance is at least an opening
36:58to try to get people to think about it.
37:00So now the choice of systemic therapies,
37:03these are people who have either
37:05that diffuse infiltrative,
37:06extensive by lobar liver involvement,
37:08they're called.
37:09Intermediate stage or advanced
37:11stage when they have tumor that
37:14goes outside the liver or tumor
37:16that's in the lymph nodes or veins.
37:19So we have a lot of new therapies and
37:22here you can see trials that have been,
37:25these are FDA approved drugs,
37:26their superiority trials,
37:28non inferiority trials in phase two trials.
37:31I'm not going to go into this
37:33because I think this audience
37:34understands how these agents work,
37:36but what I can tell you is that we have.
37:39Had an onslaught of agents and
37:41really a very short period of time.
37:44So just like we used to get dizzy when
37:46we had all the new hep C therapies.
37:48And I used to say to myself, oh,
37:49thank God, I'm not a virologist now.
37:51I'm like, oh gosh, thank God,
37:53I'm not an oncologist,
37:54but it's really not true.
37:55I think we actually,
37:56we actually understand these
37:57agents very well.
37:58And I think those of us who do
38:01immune therapies like for example,
38:02inflammatory bowel disease or transplant,
38:05we're actually pretty savvy with
38:07using immune therapies, so.
38:09We understand this language,
38:11we understand the side effect
38:12profiles and we're very happy that
38:14there are a lot of different agents.
38:15I think the question is, you know,
38:17where and when do we use these
38:19agents and in whom,
38:20and we're not really sure yet.
38:22So you can see that just in
38:25the last five years,
38:26we've had eight new sort
38:28of regimens come to market.
38:30What I do want to show on this
38:31slide is that in the sharp trial,
38:33the overall survival in that population
38:37in the placebo arm was 7.9 months and
38:41the sorafenib arm was 10.7 months.
38:43So that's median overall survival.
38:45And flash forward now to 2022
38:48and you can see that for all the
38:51verses sorafenib trials.
38:52The survival is actually quite a bit longer.
38:55We're looking at about anywhere
38:56from 12 to 14 months.
38:57So we've definitely moved the
38:59needle on probably patient selection
39:01and other things you know,
39:03getting used to using these drugs etcetera.
39:05So I think what you've seen is actually.
39:08The field and the Natural History
39:10of the field moving as well and you
39:11can't really take that for granted.
39:13I think it's an important thing
39:14that people don't talk about much,
39:15but getting used to using TI's in
39:17patients with liver disease was
39:19pretty difficult. All right.
39:20So here's our current paradigm.
39:22It's based on clinical characteristics.
39:24So we look at advanced stage HCC,
39:26either BCLC or intermediate stage B with,
39:29you know, those caveats as I mentioned.
39:32We want to think about
39:34contraindications for immune therapy,
39:35which is something we didn't think
39:37about until these drugs came to market.
39:39So what kind of autoimmune
39:40disorders does a patient have?
39:42Might they be going for liver transplant?
39:44Should we check with the liver transplant
39:46Center if there if they would be OK with
39:49transplanting a person who received an
39:50immune checkpoint inhibitor and then we
39:52actually have to think about other things.
39:54So right now the first line choice
39:58is atezolizumab and bevacizumab.
40:00Bevacizumab is a VEGF inhibitor
40:02with a higher risk of bleeding.
40:04And so in the in brave 150 trial
40:05which is what brought this to market,
40:07they did an EGD.
40:09Within six months of the patients
40:11going on this regimen,
40:12not a great real-world thing.
40:14It's really hard to get all
40:15these people in for an EGD.
40:16The problem is,
40:17what if they actually find varices
40:18and there was no stigmata of bleeding?
40:20Then what do we do?
40:21And actually,
40:22the trial said that they were treated
40:25according to institutional norms,
40:27which is a big Gray area.
40:28But my thought is if they don't
40:29have stigmata of bleeding,
40:31try the drug,
40:31make sure you tell the person there's
40:33a higher risk of bleeding and,
40:35you know, don't bother banding them and
40:37putting off their therapy for months.
40:39That's kind of ridiculous.
40:40So there's now a lot of real
40:42world OHS that came out of these
40:44trials as as always happens,
40:46but we have to think about these things.
40:48So Ateso,
40:49Bev is the first line choice for our
40:52patients if they can have these drugs.
40:56Tremelimumab and durvalumab just
40:57came on the market and then there
40:59are a lot of people who can't
41:01have immune checkpoint inhibitors
41:02and they can still get TI.
41:04The areas that are sort of dashed and
41:06Gray are sort of entirely data free zones.
41:09So these areas here if you can.
41:11My cursor,
41:11which I don't think you can.
41:13So what happens if they got an immune
41:16checkpoint inhibitor in for in frontline,
41:18you know, can they go back to a TKI.
41:20So these are things we're not
41:21entirely sure of.
41:22So there's a lot of room to
41:26study these things.
41:28What's important is what we're missing,
41:30which is that all of these trials
41:31are done in child Pugh a patients.
41:33So these are well compensated patients.
41:35They look fine.
41:36They don't have any complications
41:37of their liver disease and actually
41:39a lot of our patients have
41:40complications of liver disease when
41:42they're diagnosed with their HCC.
41:43So we want agents that can help
41:46with Child Pugh B patients.
41:47These are patients who you know
41:50may have a low albumin.
41:52They may have, you know,
41:53prolonged INR,
41:54they may have trace societies
41:55that's controlled with diuretics,
41:57for example.
41:58So as part of our recommendations we really
42:01think that well selected child pubby
42:04patients should be offered either
42:07TI's which have been studied in them
42:09or single agent anti PD one or anti
42:11PDL 1 immune checkpoint inhibitors
42:12combination therapies really haven't
42:14been looked at in these patients.
42:16So I think we have to treat
42:19those patients carefully.
42:20So I think one of the problems
42:22that we have with understanding
42:23the data around immune checkpoint
42:26inhibitors is how variable the.
42:28The. Predictability of responses.
42:30So these are people who had a partial
42:33response and a goal triangle and you
42:35can see it's all over the map and
42:37there are people who have really,
42:39really long ongoing responses until
42:42they then develop progressive disease.
42:45So all of the arrows are people who were
42:48still alive after 72 months towards that end.
42:50And then all of the, Umm, you know,
42:53blocks where they end show where
42:55they progressed and and passed away.
42:57But I mean,
42:58I think that the interesting thing here is.
43:00Well, who are these people who can
43:02have this 72 month long response?
43:04So this that data was from the keynote
43:07224 trial which was pembrolizumab
43:09after progression of disease with
43:11sorafenib and I think this is what
43:12really got a lot of us thinking.
43:14But more recent data that comes
43:16out of the in brave 150 At's above
43:19trial really shows us the landscape
43:21of the immune profiles of these
43:23patients and the fact that the ratio
43:26of T regulatory to effector T cells
43:28really matters in terms of survival,
43:31especially with immune checkpoint inhibitors.
43:33So I think this is definitely
43:35getting towards the more personalized
43:37approach and how to figure out who
43:40should get these drugs,
43:41Umm,
43:42some of the interesting things that
43:43have been published lately.
43:44And the GI world or liver world is
43:47this paper that looks at you know
43:50essentially frontline PD1 inhibition
43:52or PD1 treatment compared to receiving
43:55a PD1 as a second line or third line.
43:58So here you can see that if you
44:00start with PD one and first line,
44:02it's more likely that you're going
44:03to have a complete remission or a
44:05partial response as opposed to if
44:07you start in second line and third
44:09line when you're more likely to have
44:11stable disease or progression of disease.
44:13So this was a pretty small trial
44:14and there were.
44:15Issues in terms of the timing of biopsies
44:18and the timing of duration of disease.
44:21But what you can see is that
44:23clearly over overall survival
44:25and progression free survival and
44:27frontline anti PD one therapy for
44:30HCC is really quite impressive.
44:32What is even more interesting about
44:34this paper which just came out was
44:37really that they were able to take
44:39and develop sort of a a signature and
44:42the signature this is basically a.
44:45Interferon antigen presenting signature
44:47they called it if interferon AP
44:50essentially and what you can see is
44:53that people who had the signature
44:55obviously they had increased CD4
44:58memory activated T cells and M1
45:00macrophages and plasma cells in the
45:02tumor microenvironment. They responded.
45:04The non responders really had
45:06significantly higher you know T regulatory
45:09cells in the tumor microenvironment.
45:11So I think we're getting more and more
45:14into personalization but obviously.
45:15These trials had big data repositories
45:17and they're just still reporting,
45:19so I think the next couple of
45:21years will be very interesting.
45:23So I think bottom line is we
45:24need to collectively strive
45:25for a personalized approach,
45:27whether we're looking at population
45:28health or looking at the patients biology.
45:31And so this is kind of where we were.
45:33I think we're moving more towards
45:35the tailored approach.
45:36But you can see when you kind of throw
45:39all of these populations together,
45:42give them a treatment,
45:43you get a 20% response and that's great
45:45and we can show that and that's wonderful.
45:48But the real question is who are these
45:49people who are going to respond or not
45:51going to respond and how can we actually?
45:53Properly categorize them so that
45:55they can get the treatment that
45:56they need and this is really what
45:58we're doing you know all throughout
46:00our clinical and research lives.
46:02So what are the most pressing
46:04clinical and research related needs?
46:05I think access to care for
46:07prevention and screening is #1.
46:09A lot of liver disease actually is something
46:12that is modifiable early diagnosis.
46:15So imaging of course liquid biopsy tissue
46:19we need clinical blood based imaging
46:21and tissue biomarkers for detection,
46:23prognosis and.
46:24Response to treatment,
46:25I don't think it's going to be
46:26one or the other.
46:27I think it's going to be all of them.
46:29And the mechanisms of pathogenesis
46:31and tumor behavior really are
46:33still in many ways unknown.
46:35We're working on it,
46:35but we have a lot of questions.
46:37The order and timing of treatments
46:40and sequential classification
46:41is really important.
46:42So revised tumor staging,
46:43we really have to start getting into
46:45it and we have to do it for stage
46:47migration and stage shift and we really
46:50need to deliver value based care.
46:51These patients need to be taken
46:53care of in a multidisciplinary.
46:55Environment where they really
46:56feel that the whole team is there
46:58for them and that they're the
46:59Most Valuable Player on the team.
47:01So my key takeaways,
47:02the epidemiology of HC is shifting.
47:04Fatty liver disease is a big new
47:06kid on the block, no pun intended.
47:08That was terrible. I'm sorry.
47:10We need, we need to embrace complexity,
47:13technology and team based care
47:14and science to offer our patients
47:16the best possible outcome.
47:18So really when we break down
47:20silos across care and science,
47:22we actually do the best science.
47:25They really need a
47:26multidisciplinary approach.
47:27It's the mainstay for complex
47:28decision making and I think people
47:29always feel better when they're
47:31part of a collective and really
47:32come up with a good plan of care.
47:34We should really push the envelope.
47:36It's important to push the envelope,
47:38most ideally in a clinical trial setting.
47:41And the surge in large scale
47:43observational and omic data
47:44should help inform large prospective
47:46trials as well as all the analytical
47:49platforms we have for these data.
47:51And systemic therapy options continue
47:53to grow for advanced HCC patients.
47:55But now is the time that we should
47:57stop looking at that 20% response
47:59and actually figuring out who we
48:01should treat when and with what.
48:03We definitely need a better understanding
48:05of when to introduce systemic therapies
48:07and there are 150 ongoing clinical trials
48:10that are going to reshape the field.
48:12In terms of adjuvant, neoadjuvant,
48:14the game is just beginning.
48:16So I really want to thank a lot of people,
48:19really most importantly Amy Justice,
48:22who really mentored me for the virtual
48:24cohort at the VA and through a lot of the
48:27work we've been doing on HIV associated HC,
48:29Dave Kaplan, who's my Co,
48:31Pi in the vocal study,
48:32Georgianna Who's my Co
48:33chair of the premium trial,
48:35Mario who's mentored me for probably more
48:38years than he'd like to think about,
48:40Catherine Mezzacappa provided me with this.
48:42Sides of her preliminary work and she
48:44just received a liver pilot grant,
48:46which is wonderful for her Rajni meta,
48:49from the rapid case ascertainment
48:51resource for the Cancer Center,
48:53who's really been my right hand now for
48:54well over a decade and many, many more,
48:57but most importantly my patients.
48:58So thank you.
49:07Yes.
49:10The light.
49:14So one of the things that I
49:16think about is we do see this,
49:17as you point out, looming.
49:22Epidemic with Don alcohol.
49:26It is exciting to think about surveillance
49:29and seed interventions in the.
49:31Anti violence phase,
49:32but we actually have an enormous
49:35capacity for risk reduction
49:37in fatty liver disease.
49:39Do you have any interventions in
49:41the planning stages for that and
49:44need any prospective studies?
49:47I don't have studies of my own.
49:50I can tell you that I'm pretty active
49:52with the American Liver Foundation.
49:54That does a lot around educating the populace
49:58about all of these sort of lifestyle,
50:02you know, and preventative measures.
50:04I think we have to start with our
50:07children and I really wish that there
50:10was a way that we could actually have
50:13pediatricians and hepatologists, you know,
50:15kind of come together and maybe maybe.
50:17Maybe it's the best thing for
50:19pediatric hepatologists to figure out
50:21how to educate children about food,
50:23food shortage, healthy eating, exercise.
50:25So, you know, pharmaceuticals,
50:27they're sexy and there's a lot of money.
50:30And there's really not so much
50:32money for preventive medicine and
50:34especially for these food deserts,
50:36which actually beg a much larger question
50:38of the social determinants of health.
50:41So it's a great question.
50:43It's a huge, you know,
50:45bite to take off and chew.
50:47And I haven't gone there.
50:48But it does,
50:48it does trouble me.
50:49I mean it troubles me that you know
50:51that the disparity of resource put
50:53in One Direction versus the other.
50:58Question.
51:02I don't understand.
51:04What's your DNA? Endoscopies.
51:11So we yeah. Oh, sorry.
51:16If you can call back attention and
51:18you've got valuable. Doesn't need, right?
51:24So suppose that.
51:31Yes. Patient has
51:34significant potential.
51:38What are you going to do?
51:39Nothing, right? So you you you
51:40did a meaningless test, right?
51:44Just before the treatment,
51:45which is not indicated,
51:46is outside with the guy, right?
51:50What do you do?
51:53Right. So um. We do the endoscopy because I,
51:57I I'm working on oncology at the VA,
52:00but it's not they really want the endoscopy
52:03if there are no stigmata of bleeding,
52:06I do not band. And I say,
52:08hey look there's portal hypertension here,
52:10there's some variances, right,
52:12the patients on carvedilol and
52:14they're like OK, at least you know,
52:15at least we know what we're getting into.
52:16So the patient could bleed.
52:18I said the patient could bleed from
52:20gastritis like what's you know.
52:21So, so I think what we'd like to
52:23do and I think what we can do.
52:26In the next year or two is sort of more
52:28phase four kind of what's the real
52:30world experience because I'm sure that
52:32in the VA system people are getting a
52:35Tiso Bev without a prior EGD because
52:38not all centers are big enough etcetera,
52:40etcetera.
52:40So, so we actually have some designs
52:42on doing that sort of study.
52:46Yeah.
52:49Yeah, they've come to us,
52:50Mario, for the data. Yeah.
52:56Yes, Tommy?
53:06Umm.
53:26Um, so I would say that from my experience,
53:31the uptake in atisa above has
53:33really only been, you know,
53:35it had a slope of uptake 2122.
53:40O I'm not sure that I can
53:42answer that question.
53:43What I can say is we're seeing much
53:45more advanced disease at presentation
53:47because people didn't come in for
53:49imaging and that is really heartbreaking,
53:52very heartbreaking.
53:53So you know, you got people who
53:55really haven't come to the VA in
53:57three years and then they come in and
53:59they have you know multifocal disease
54:00everywhere and some of them are young.
54:03So it's that's pretty awful.
54:05But I don't think I've,
54:06I I've have enough experience over
54:09the atisa Bev.
54:10FDA approval to say that there's
54:12been any difference?
54:14Are you thinking just about immune
54:15regulation post COVID or?
54:20Hmm. OK.
54:26Right.
54:35Hmm. That's an interesting thought.
54:39I mean, I can tell you our our rates of
54:41alcoholic hepatitis are skyrocketing,
54:43and they're skyrocketing among young people.
54:45So there is definitely a lot of
54:48psychological burden from the pandemic, so.
54:52Umm. Yeah.
54:56OK. Sorry, I fell down on the job here.
54:59OK. So one of the questions was,
55:02as you mentioned, some oncologists are
55:04reluctant to use atisa Bev of smaller
55:07large varices or even hemorrhoids.
55:09Any suggestions how to convince them to use
55:12this regimen without banding? So I mean,
55:14I think thanks for that question, Simona.
55:16I think it's really basically saying,
55:19you know, we've got this,
55:20if the person bleeds were here,
55:22they know how to reach us,
55:23we know how to reach them.
55:24You know, we're available, if anything.
55:27Thumbs up.
55:28You know, Yale is a center of
55:29excellence in terms of hepatology care.
55:31So is West Haven.
55:32We know how to ban people if they bleed.
55:35I think it's it's really honestly getting
55:37them used to using the combination
55:38and not seeing a lot of bleeding.
55:40And I think it's just going
55:42to be tincture of time.
55:44Laura Morrison asked,
55:45can you please share your latest
55:47innovations and Co management of these
55:49patients with palliative care at the VA,
55:51the palliative care role in tumor board.
55:53We see many opportunities for
55:55expanding this collaboration at SMILO.
55:57Our palliative care fellows always
55:58appreciate the different model
56:00at the VA that's very lovely.
56:02Thanks Laura.
56:02So yes,
56:03we are Co localized with palliative care,
56:06so they come to our clinics.
56:07We have a clinical trial that's
56:10enrolling patients and we it's a
56:12clustered randomized controlled.
56:13Trial of standard of care,
56:15palliative care intervention versus
56:17hepatology trained palliative care.
56:20So our palliative care docs,
56:21we are randomized to the
56:23palliative care intervention.
56:24So it's the standard of care palliative
56:26care consultant and having them at
56:28tumor board and in clinic is wonderful.
56:30So all of our end stage
56:32liver disease patients,
56:32all of our multifocal HTC's,
56:34they all see palliative care from the get go.
56:37So it's not like this awkward
56:39handoff where you're like OK now
56:40you're really sick and you need
56:42to see the palliative care doctor.
56:44It's it's from the beginning
56:45we say we work together.
56:47Palliative care is a layer of support.
56:48They're here to really think
56:50about other things.
56:51You may not be having any symptoms now,
56:53but they're going to help you get
56:54your logistics straightened out
56:55or they're going to help you get
56:56help into the home if you need it,
56:57or they're going to think about the
56:59things that really matter to you while
57:00we're focusing on your organ here,
57:02you know what I mean?
57:03So I think we all tend to be very
57:05myopic in specialty care where we just
57:07focus on the organ that we're thinking
57:09about and like rarely do we say,
57:11so you know,
57:11what are your goals like?
57:12What's really important to you?
57:14How do you want the next few
57:15months to unfold?
57:16Because I think a lot of us
57:17are afraid of the Pandora's box
57:19that's going to open because then
57:20we actually may have to connect
57:22with another human being.
57:23And palliative care is wonderful
57:25because they teach us like
57:26I have learned so much from palliative care,
57:29how to open a conversation,
57:31how to ask difficult questions,
57:32how to know when I'm over my head.
57:35So I would say that most of us at
57:36the VA really know how to deliver,
57:38you know, primary palliative care.
57:40And we rely on palliative care
57:43for specialty palliative care,
57:44which is really.
57:45What their experts in and we're
57:47hoping that we can impart that
57:48kind of training nationally.
57:50So that's going to be the results
57:51of that study which is funded by
57:54PECORI and which is basically a it's
57:56a multi center private NBA study
57:58that's at the PI's Victor Navarro
58:01out of Jefferson in Philadelphia.
58:03Thanks Laura.
58:06I think that's it. Any other questions?