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

Transcript

• 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?