Safety and Effectiveness of Care Across Networks that Form Around Top-Ranked Hospitals and Challenges in Brain Metastases Management

Transcript

• 00:00Posed for today.
• 00:01We have two talks, one from Doctor Boffa
• 00:04and then the second from doctor Chang.
• 00:07Doctor Boffa will go first.
• 00:09Let me make a brief introduction of Dan.
• 00:12Doctor Boffa is a professor of
• 00:14thoracic surgery and division
• 00:15chief of thoracic surgery.
• 00:17Newly appointed in recent months.
• 00:19Congratulations who received his
• 00:20medical degree from the University
• 00:22of Chicago's Pritzker School of
• 00:24Medicine and completed residency
• 00:25at New York Presbyterian Hospital
• 00:27Weill Cornell Medical Center and
• 00:29his fellowship at Cleveland Clinic.
• 00:31Dan specializes in oesophageal
• 00:33and lung cancer.
• 00:35Achalasia gastroesophageal reflux disease,
• 00:37Adel hernia,
• 00:37oesophageal diverticula
• 00:38am and hyper hydrosis.
• 00:40All things you don't want to have
• 00:42as a highly skilled looking doctor
• 00:45Barber performs the majority of his
• 00:48surgeries with minimally invasive procedures.
• 00:51Committed to increasing the
• 00:52survival rate of cancer patients,
• 00:54doctor Boffa has focused his clinical
• 00:56research on the prevention of tumor
• 00:58metastases and the early detection of
• 01:00lung cancer and on a personal note,
• 01:02I've just been thrilled to be working
• 01:04with Dan for almost a decade now.
• 01:06Here,
• 01:06as we've taken an already great
• 01:08top and made it even better,
• 01:10so Dan, so happy to have you today.
• 01:12The floor
• 01:13is yours alright. Thank you very much.
• 01:16So I have one disclosure.
• 01:18I have a couple of disclaimers.
• 01:20For the interest of time I'm going to present
• 01:23some data without much in the way of methods.
• 01:27I'm happy to go over anything
• 01:30afterwards and I'll even make a pretty
• 01:33egregious statement without any data.
• 01:36And I also have a disclaimer.
• 01:37This is a very emotional topic, and it's
• 01:40one that is fraught in quite a bit of.
• 01:45It makes people quite uncomfortable,
• 01:46and so I just want to give you that as
• 01:50a as a heads up. So surgical safety?
• 01:53Why is this even important?
• 01:55Why is this worth talking about?
• 01:58Um? So I'm going to give you what I
• 02:02think is a mind blowing perspective.
• 02:05So surgical deaths occur in
• 02:07patients who are likely to be cured
• 02:10because that's who we operate on.
• 02:13Had they not died,
• 02:14they would have lived a long time.
• 02:17Therefore, when you,
• 02:19when a surgical patient dies,
• 02:21they forfeit a considerable
• 02:23amount of survival.
• 02:25So if you look at survivorship that's lossed
• 02:29each year from cancer surgery mortality's,
• 02:32it's a big number,
• 02:34even though there's only thousand patients
• 02:37that have died from surgical mortality's,
• 02:40they would have lived
• 02:42many years collectively,
• 02:44in fact.
• 02:45It is,
• 02:45it is very similar to what you
• 02:48would see if you took all stage
• 02:51four patients and stop giving
• 02:54chemotherapy to three out of four.
• 02:57An I can go into detail about how
• 02:59we came up with these numbers,
• 03:01but it's a huge amount of
• 03:02survivorship that's lawston,
• 03:03so this is just giving some perspective.
• 03:06So cancer surgery outcomes are quite
• 03:09variable and they vary based on
• 03:12factors related to patients surgeons.
• 03:14But they also very relating to
• 03:17variables that relate to the hospital.
• 03:19So this is a classic study birkmaier
• 03:22put out almost 20 years ago where
• 03:25he showed that as you increase the
• 03:29surgical volume at a hospital,
• 03:31the mortality decreases.
• 03:34The numbers at the extremes
• 03:36are quite different.
• 03:37The going from a 20% chance of
• 03:40dying from your surgery to 8%
• 03:42and this is 30 day mortality.
• 03:4490 day mortality is generally
• 03:46twice these numbers,
• 03:47so it's a huge amount of variability.
• 03:50So the question is how does a
• 03:53patient pick the best hospital?
• 03:55Well, one way is to use mainstream media,
• 03:59an US news and World Report is probably
• 04:02the most common that people talk about,
• 04:05and that patients engaged when
• 04:07they're making these decisions.
• 04:09And there's some data that actually it
• 04:12is a pretty reliable way to find a safe,
• 04:16high quality hospital.
• 04:19The IT does create a unique situation though.
• 04:23The hospital name is associated with the
• 04:27hospital's reputation for quality and safety.
• 04:30That becomes their brand.
• 04:33Top ranked hospitals have a strong brand.
• 04:36These top ranked hospitals have been
• 04:39increasingly forming affiliations with
• 04:41hospitals and communities and during
• 04:43those affiliations they share that brand.
• 04:45So here's an example.
• 04:47Here's Hellman's Pella Clinic.
• 04:49I made this up.
• 04:50It's famous, it's trusted,
• 04:53it's respected in its top ranked.
• 04:56It, there's Middlebury Hospital,
• 04:57which is a hospital in the community.
• 04:59I made this up as well.
• 05:03And they form an affiliation,
• 05:05and then Asterix is the affiliation.
• 05:08Could be part ownership.
• 05:09It can be just a monetary based relationship,
• 05:13but there's a whole range
• 05:15of affiliation means,
• 05:17but during that affiliation,
• 05:19the Middlebury adopts the brand of Hellman,
• 05:22Pella Clinic, and the question is,
• 05:24what does that mean?
• 05:26So the first question is what
• 05:29would he patients think of that?
• 05:33Well, we conducted a survey.
• 05:35This is a public survey,
• 05:37so it's not patients.
• 05:38It's the general population we use GfK,
• 05:41which allows you to conduct
• 05:43nationally representative surveys.
• 05:47And we had a study that
• 05:49looked at 1000 patients.
• 05:50We had a response rate of
• 05:53just under 60% and we asked.
• 05:55We asked people what do you think
• 05:57the likelihood of dying from surgery
• 06:00when you consider a top ranked
• 06:02hospital or a hospital in the
• 06:05community that is affiliated with a
• 06:07top ranked hospital and we describe
• 06:09this as a complex cancer operation.
• 06:12So of the thousand patients. Um?
• 06:16Just over 1/4 felt that you were
• 06:19more likely to die at an affiliate
• 06:22versus the top ranked hospital.
• 06:244% felt you actually more likely
• 06:26to die at the top dranked hospital.
• 06:29But 69% felt that it was the same
• 06:31that the safety was the same at
• 06:34a top ranked hospital and the
• 06:36affiliate that shares its brand.
• 06:41The so once this affiliation has formed,
• 06:44once you add the name of the
• 06:46hospital to the hospital community,
• 06:4869% of people think the safety is the same.
• 06:51That's very different to when
• 06:53they don't have the brand to
• 06:55hospitals that are not affiliated.
• 06:5785% of people preferred and be cared for.
• 07:00The top ranked hospital.
• 07:01When you actually talk about
• 07:03the effectiveness of care,
• 07:05how often patients would be cured of cancer,
• 07:08half the respondents thought that the safety
• 07:11and the effectiveness of care is the same.
• 07:13At top ranked hospitals and the community
• 07:17hospitals or hospitals in the community
• 07:20that share the top ranked brand.
• 07:22And we wanted to know is this true?
• 07:25So we started with a study
• 07:27in Medicare patients,
• 07:28so these are people over the age of 65
• 07:31and we looked in the Medicare database
• 07:33and we looked at top ranked hospitals
• 07:36and those were hospitals that had been
• 07:39ranked at least once between 2012 and 16,
• 07:42and because some hospitals come
• 07:44in and out of the top ranked.
• 07:48Cohort you end up with 59 hospitals,
• 07:50so we started with 59 hospitals.
• 07:53We used the American Hospital
• 07:55Association survey to look to see
• 07:57if they had an affiliation recorded
• 08:00and that was 640 hospitals.
• 08:02But then we did an Internet search
• 08:04and looked for hospitals that were
• 08:06actually hospitals in the community,
• 08:09the affiliates that were advertising
• 08:11that affiliation in their brand presence,
• 08:13something that the public and patients
• 08:15would see just for our nomenclature,
• 08:18we call the top ranked hospitals parents.
• 08:21And the affiliates children?
• 08:22It's it's just.
• 08:24It makes it easier to talk about.
• 08:26We don't imply maturity or seniority
• 08:28or anything like that.
• 08:30It's just helps us conceptualize.
• 08:32And I will use that terminology
• 08:34a little bit later.
• 08:36So we looked at complex cancer surgery and
• 08:39these were the procedures we looked at.
• 08:42There were 17,000 patients that
• 08:44had surgery at top ranked hospitals
• 08:46and 12,000 affiliates.
• 08:47Other than a little bit difference
• 08:50in the age,
• 08:51most of the associated demographics
• 08:53were actually pretty similar.
• 08:54When you looked at the case mix,
• 08:57meaning,
• 08:57what types of procedures the
• 08:59affiliates were doing compared
• 09:01to the top ranked hospitals,
• 09:03you see that most of the surgeries
• 09:05were colectomies at affiliates so 60.
• 09:083% of all the complex surgeries
• 09:11they were doing were colon based.
• 09:14Where is the top ranked hospitals
• 09:16that was just a third and when
• 09:19you look at Whipples,
• 09:20Whipples made up a very small percentage
• 09:22of what was happening at affiliates,
• 09:24but a reasonable percentage of what
• 09:27happened at top ranked hospitals.
• 09:29And there is a sense of
• 09:31regionalization within these networks,
• 09:33so again,
• 09:33the previous slides were looking
• 09:35at it from the affiliate or the
• 09:38top ranked hospitals standpoint.
• 09:39But if you look at the type of
• 09:42surgery and say where are all
• 09:44of the colectomies being done,
• 09:46what's the split for all colectomies?
• 09:48More than half of all colectomies
• 09:51are happening at affiliates,
• 09:52whereas for Whipples only 18% of
• 09:54Whipples are happening in affiliates.
• 09:56So it does seem that the more
• 09:59dangerous operations in this.
• 10:00Mix are happening at the top ranked
• 10:03hospital as appeared the affiliates.
• 10:05So the the code words are very different.
• 10:08Affiliate hospitals are smaller,
• 10:09so if you look at the
• 10:11beds it's 200 versus 700.
• 10:13If you look at other things that have been
• 10:16associated other attributes that have been
• 10:19associated with quality that you affiliates.
• 10:22There's a big difference there for
• 10:23Commission on cancer accreditation.
• 10:25The affiliates are less likely.
• 10:26They are far less likely to be a teaching
• 10:30hospital in the annual volume is much lower.
• 10:33If you look at the use of minimally
• 10:37invasive techniques and leapfrog standards.
• 10:40It's far and away.
• 10:42Favors the top ranked hospital,
• 10:44so we looked at 90 day mortality
• 10:46and we looked at.
• 10:48We first use an aggregate approach which
• 10:50meaning we took all the patients that
• 10:53had surgery at the top ranked hospitals
• 10:55and we compared him to all the patients
• 10:58who had surgery at the affiliates.
• 11:01And the dark blue bars are the
• 11:03top ranked hospital and the
• 11:05lighter ones are the affiliates.
• 11:08The different procedures are on the X axis,
• 11:11and a taller bar means a
• 11:13higher 90 day mortality.
• 11:15And for everything the
• 11:17affiliate has a taller bar.
• 11:20When you look at it in an adjusted way,
• 11:23this is a logistic regression.
• 11:25Looking at 90 day mortality and it's
• 11:28listed here for each of the procedures.
• 11:31But when you look at all the procedures,
• 11:34its mortality was 1.4 times
• 11:36higher and affiliate hospital
• 11:38versus the top ranked hospital.
• 11:40We did not include in our adjustment
• 11:42hospital factors because patients
• 11:44don't consider those typically
• 11:46when they are making decisions,
• 11:48they look at a top ranked hospital.
• 11:50They look at the brand.
• 11:53They're not looking at teaching status
• 11:56or ciocie accreditation or annual volume.
• 11:59We now looked at a family approach
• 12:01where we took each parent and
• 12:03looked at all of their children.
• 12:06So we took one top ranked
• 12:08hospital and compared it to all
• 12:11of their affiliates combined.
• 12:13And we use the standardized mortality ratio,
• 12:15which is similar to what CMS uses
• 12:18to create its star rating system.
• 12:21Here the Orange of the top ranked
• 12:24hospitals and the blue are the
• 12:27affiliates collectively and
• 12:28anything to the right screen.
• 12:31Right means it's less safe
• 12:33than anything to its left.
• 12:35So here you can see the orange dots
• 12:39seem to be to the left and the
• 12:42blue dots seem to be right saying
• 12:45showing there's a higher adjusted
• 12:48mortality at the affiliates.
• 12:50And when you look at all of them combined.
• 12:5583% of the time the blue bars were
• 12:59to the right of the orange bars,
• 13:03so 83% of the time the affiliates
• 13:06were less safe than the specific
• 13:09top ranked hospital.
• 13:11So in summary,
• 13:12the chance of dying from complex surgery
• 13:15an affiliate is about 40% higher
• 13:17than it is at the top ranked hospital.
• 13:20An 83% of the time.
• 13:22So it's not just a couple
• 13:24of top ranked hospitals
• 13:26that are the issue,
• 13:27and we've done sensitivity analysis.
• 13:29Looking at does it matter where
• 13:31in the top 50 you fall we have
• 13:34adjusted for things like volume
• 13:36and hospital attributes and it does
• 13:39not eliminate this differential.
• 13:41So we wanted to look at
• 13:43this in a different way.
• 13:45We looked in the National Cancer
• 13:47database because this allowed us to
• 13:49look at all ages an with a lot more
• 13:52patients and better staging information.
• 13:54For those of you that aren't familiar
• 13:56with the National Cancer database,
• 13:58it's it contributing to the National
• 14:01Cancer database is compulsory
• 14:02for all COC accredited hospitals.
• 14:04It ends up capturing about 70% of the
• 14:07cancer care in the United States.
• 14:10So we looked between 2012 and 16.
• 14:14We expanded the number of.
• 14:18Cancers that we were looking at and
• 14:21we ended up with 120,000 patients,
• 14:2380,000 at top ranked hospitals
• 14:25and 40,000 affiliates.
• 14:27This is again unadjusted mortality,
• 14:29so the the blue bars are the affiliates.
• 14:32The orange bars at the top
• 14:35ranked in for every one of them.
• 14:37The Blue Bar is taller,
• 14:39meaning there's a higher unadjusted
• 14:42mortality at the affiliates.
• 14:44When you look at a 90 day mortality
• 14:47in an adjusted model,
• 14:48the odds ratio of 90 day mortality
• 14:51was actually 1.7 times higher.
• 14:53So your 70 * 70% more likely to
• 14:56die from your cancer surgery at
• 14:58an affiliate hospital compared
• 15:00to the top ranked hospital.
• 15:03We wanted to look at long-term
• 15:06survival as well.
• 15:07So if you look at Unadjusted Stage 3,
• 15:10colon cancer,
• 15:11the red line is the top ranked
• 15:14hospital survival.
• 15:15The blue line is the affiliate survival,
• 15:18and so this is just for Stage 3 colon cancer.
• 15:22It's significant for Stage 1,
• 15:24two and three colon cancer.
• 15:27We also looked at lung cancer,
• 15:29and we really only did those two cancer
• 15:33types because in this in this way,
• 15:36because the numbers were low.
• 15:38The for the other cancer types,
• 15:41so we just looked at stage stratified,
• 15:44colon and lung and it was significantly
• 15:46higher at the top ranked hospital versus
• 15:50the affiliate after cancer surgery.
• 15:52And we landmark these outside
• 15:54the 90 day mortality.
• 15:56So it wasn't just that you were
• 15:59having fewer surgical deaths,
• 16:01even of if you just looked at people
• 16:04that survived their cancer surgery.
• 16:06The survival was higher.
• 16:10We also looked at this in an adjusted way.
• 16:14We use gamma models and time ratios,
• 16:17so a time ratio just means relative to
• 16:20the survival at the top ranked hospital.
• 16:23So this is the plot of the adjusted survival.
• 16:27So anything to the left of the
• 16:30yellow line means that they had less
• 16:33survival that affiliates had less
• 16:35survival than top ranked hospitals.
• 16:38So overall, all of the procedures.
• 16:41The survival was less at the affiliates
• 16:44versus the top ranked hospitals,
• 16:46so overall the after surgery the
• 16:50patients at affiliate hospitals only
• 16:52lived about 3/4 as long as patients
• 16:56that had surgery at top ranked hospitals.
• 16:59So in that that data was
• 17:02adjusted for volume as
• 17:04well and it did not change the
• 17:07significance of the findings.
• 17:10So the summary of that this research
• 17:12is that the public believes that brand
• 17:16sharing equals quality sharing that
• 17:19surgical mortality is 1.7 times higher.
• 17:22If you have surgery at a affiliative,
• 17:25a top ranked hospital compared to
• 17:28the actual top ranked hospital.
• 17:31And that the survival is shorter
• 17:33at the affiliate compared to
• 17:35the actual top ranked hospital.
• 17:37So affiliation does not in and
• 17:39of itself equal care equality,
• 17:42despite the fact that that a large
• 17:45proportion of the public believes it does.
• 17:49So is this the problem or is
• 17:52this the solution?
• 17:54So we actually believe that the network
• 17:57infrastructure can be leveraged to be the
• 18:01solution to a lot of the gaps in cancer care.
• 18:05And it really provides three key things.
• 18:08Connectivity,
• 18:09accountability and ability.
• 18:11So from the connectivity standpoint,
• 18:14if you look at the current cancer surgery
• 18:17market share a lot of hospitals have a piece
• 18:21of the pie and they're totally disconnected,
• 18:25and it's very difficult
• 18:27to share best practices.
• 18:29The there's privacy issues.
• 18:31There's competition among the hospitals.
• 18:33There's the lack of compatibility
• 18:35between their systems,
• 18:37so as a result,
• 18:39it's very difficult to
• 18:40do quality improvement.
• 18:42Across these hospitals.
• 18:43But you gotta keep in mind that
• 18:46there's a connection between the top
• 18:49ranked hospitals and their affiliates.
• 18:52That eliminates these barriers.
• 18:54It turns out that the these networks
• 18:57around the top ranked hospitals,
• 19:00they have a huge piece of the pie.
• 19:03It's not a one out of three complex
• 19:06surgeries actually happens within
• 19:08these networks and every year
• 19:10their market share is increasing,
• 19:13so it's eliminating the barriers that
• 19:15prevent a lot of quality improvement
• 19:17within These Top Rank networks.
• 19:20And they are major players in
• 19:23the complex cancer surgery.
• 19:24Domain. Accountability.
• 19:28So for instance Yale.
• 19:30I has multiple sites within
• 19:33the state and we have.
• 19:35These are multiple affiliates and all of
• 19:38the networks around top ranked hospitals
• 19:41have a similar map of different states.
• 19:44They are comprised of
• 19:46very different hospitals.
• 19:48And the temptation is to identify with
• 19:51one of the hospitals that people at each
• 19:56of their hospitals feel that they had.
• 20:00Dentify with their hospital,
• 20:03but the reality is.
• 20:05The network is our identity and we have
• 20:08to embrace that and the we should have
• 20:12one set of expectations an for safety,
• 20:14effectiveness,
• 20:15timeliness and the patient experience should
• 20:18be the same across the entire network.
• 20:21And there are bodies that are
• 20:23starting to look at networks as
• 20:26individual entities to be accredited.
• 20:29So while I think there's a,
• 20:31there's a moral obligation to match
• 20:34outcomes and care with public expectations.
• 20:37There's likely going to become some
• 20:40oversight that will look at how
• 20:43well in the way in which care is
• 20:46delivered across these networks.
• 20:49The last is the ability the
• 20:51giving hospitals the ability
• 20:53to provide excellent care,
• 20:55so excellent care is
• 20:57comprised of three domains.
• 20:59First is infrastructure which
• 21:01are the resources in the support.
• 21:04And for this quite simply,
• 21:06the scenario has to match
• 21:07the hospital environment.
• 21:08If the hospital is not equipped to care
• 21:10for big surgery and the complications of
• 21:13that surgery or stem cell transplants,
• 21:15that's not where it should take
• 21:17place within the network.
• 21:19But there are other opportunities,
• 21:20so regionalization within a
• 21:22network I think is important.
• 21:24Process needs to be lead to consistent
• 21:27outcomes, but it also needs to be
• 21:30adaptable to the individual nuances.
• 21:33And I think the best way to think
• 21:35of process is to think of the user.
• 21:37So from the patient's perspective,
• 21:39and there's no better user perspective
• 21:41in my opinion than the users of Amazon.
• 21:44It's single access.
• 21:45It feels like it's one big store,
• 21:47although it's a whole bunch of
• 21:49different stores in different
• 21:50structures that are participating,
• 21:52it feels like it's close to home,
• 21:55but it's almost never close
• 21:56to where you live,
• 21:58and it does allow for the public
• 22:00to make an informed choice,
• 22:02and I think that's important is to
• 22:04allow people to have a choice that
• 22:07where they want to be cared for,
• 22:09and be informed as to the implications.
• 22:13Great network,
• 22:14feels like a great team and that
• 22:17includes not just surgeons but medical
• 22:20oncology and radiation oncology,
• 22:23but also the nurses and the technicians
• 22:26and the therapists you have to.
• 22:29You have to expand by programs.
• 22:32It's not just a Ala carte
• 22:35expansion through affiliation.
• 22:36You really have to program
• 22:39build throughout a network.
• 22:42And finally, Clinical Excellence.
• 22:43In my opinion,
• 22:44Clinical Excellence in staff
• 22:46is comprised of three things.
• 22:48The knowledge, skill, and judgment.
• 22:51And you need to have experts.
• 22:53So here is an example of experts.
• 22:56This is the division of thoracic
• 22:58surgery at Yale.
• 22:59But you have to keep in mind that
• 23:02there are experts out of outside of
• 23:04New Haven and we have to recognize
• 23:07and partner with these experts
• 23:09and and give them what they need
• 23:12to be clinically successful.
• 23:14And we can't just have physician experts.
• 23:17It's gotta be experts at every
• 23:20every touch point with patients,
• 23:22there has to be content expertise
• 23:26across the domain.
• 23:27Process may be our signature.
• 23:30But excellent people are our
• 23:32margin and we have to give people
• 23:35what they need to be successful.
• 23:37So when you think of a network.
• 23:41We have to take great care patients.
• 23:43There's no doubt,
• 23:43but we also have to be a great place to work.
• 23:47Every decision we make,
• 23:48we have to think about what are
• 23:50the implication on our patients
• 23:52and our ability to provide care.
• 23:54But we also have to think of
• 23:56the implications on the people
• 23:57who are working here,
• 23:58because if it were not,
• 24:00these two things simultaneously,
• 24:02it's not a sustainable model.
• 24:04I thank you and I'd be happy to
• 24:07take questions for 2.5 minutes.
• 24:10Thanks Dan, that certainly was
• 24:12stimulating and brings up a lot of issues.
• 24:15Let me ask the first question
• 24:17as questions are coming in so
• 24:19it's sort of a two parter one.
• 24:21When you operate at Bridgeport
• 24:23or at New London,
• 24:25is that an affiliation or is that as
• 24:27if you're operating at the same center?
• 24:31So the we have the same
• 24:34expectations for outcomes,
• 24:36but the people that are involved in
• 24:39the care are we have any Mace who
• 24:43is spends time at both campuses,
• 24:46spends time at tumor board at
• 24:49this campus and uses a lot of the
• 24:53shared infrastructure so that the
• 24:56intake process is driven through.
• 24:59Here the Park Ave.
• 25:01Cure model is the same care
• 25:04model as it is in New Haven,
• 25:07so different people,
• 25:09but people that are tightly integrated
• 25:12into the New Haven infrastructure
• 25:14so that we believe we we deliver
• 25:17a very similar level of care.
• 25:19We just don't do the same things there.
• 25:23There are complex cases,
• 25:25we just don't do there.
• 25:28Thanks, I'm hurting.
• 25:29Chow asks from the VA.
• 25:31Is it possible that patients who
• 25:32ended up going to the community
• 25:35hospitals had fewer resources,
• 25:36an worse socioeconomic status?
• 25:38And that was the reason for the difference?
• 25:42The so when you adjust for so the
• 25:47NCD has income by zipcode, but the.
• 25:53When you look at when you just for race,
• 25:59adjust for income.
• 26:01Adjust for education.
• 26:03These factors still exist,
• 26:05so I think that those are certainly
• 26:09things that influence choice and.
• 26:13We have a lot of research in a
• 26:16separate vein as to why patients
• 26:19choose the hospital that they do
• 26:22an in a separate survey looked at
• 26:25barriers to traveling for safer care
• 26:28because it's pretty well known that
• 26:30people prefer safer environments,
• 26:32but they have barriers that cannot
• 26:35that prevent them from coming.
• 26:37We found that about,
• 26:38I think it was about 75% of
• 26:42people that wanted to come.
• 26:44Two, the flagship in a hypothetical model,
• 26:47had a barrier.
• 26:48The interesting thing is when
• 26:50we looked at facilitators,
• 26:52it was almost always a low cost facilitator,
• 26:56meaning it was a ride or it
• 26:59was a night to stay or parking,
• 27:02or but it wasn't a huge thing that
• 27:06was keeping them from being able to.
• 27:10Jetta come we are our new line
• 27:13of investigation is looking on
• 27:16the impact of Medicaid expansion
• 27:18on cancer care and so.
• 27:20I think that's also ties into that,
• 27:22so we should have more for you on
• 27:25that front. In the future we
• 27:26have time for one more question.
• 27:28The questioner asks this time of affiliation
• 27:30overtime lead to improved outcome.
• 27:32Also for the Children's Hospital and I'll
• 27:33just add you showed a slide where you
• 27:36compared expertise at the main center and
• 27:38then you showed care center physicians.
• 27:40But you were showing surgeons in one picture
• 27:42and medical oncologists in the other.
• 27:44So is this hold for all disciplines
• 27:45or is this just for surgery? Little
• 27:48confusing. I think it I think that. So.
• 27:52I will say TuneIn on Friday to surgery
• 27:55grand rounds where I have an hour and
• 27:58I'm going to go into a lot of this.
• 28:01But I one trick is to answer the
• 28:03question you have the answer to.
• 28:05So I'm going to show you very quickly.
• 28:08We had 144 affiliations that took
• 28:10place during our study period.
• 28:12We look the year before and after just to
• 28:14see does affiliation make things better,
• 28:16but top bar the dark one is pre affiliation.
• 28:19The lighter one is after affiliation.
• 28:22So and then these are just the affiliates.
• 28:25And then we also look at non
• 28:27affiliates and see what happened.
• 28:30So if you look at the hospital beds
• 28:32they got a little bit smaller.
• 28:35If you look at the OC accreditation
• 28:37they got they picked up more of the
• 28:41affiliates gained accreditation,
• 28:42but you also saw an effect like
• 28:44that in the non affiliates.
• 28:47When you look at the number of complex
• 28:50surgeries the affiliates got busier after.
• 28:53Affiliation,
• 28:53and that didn't happen in the non affiliates,
• 28:56so the the affiliation increased
• 28:59their market share.
• 29:00But if you look at 90 day mortality
• 29:03before and after affiliation,
• 29:05there's a big drop,
• 29:07so the affiliates got safer
• 29:09after affiliation,
• 29:10so that was really encouraging unfortunately,
• 29:13however.
• 29:13And the non affiliates also
• 29:15dropped during that time period.
• 29:18And when you look in a difference
• 29:20in difference model,
• 29:21there actually really the
• 29:23change overtime is very similar.
• 29:25We could find no effect that
• 29:27affiliation made hospitals better.
• 29:28It seems that the top ranked hospitals
• 29:31choose to affiliate with better hospitals,
• 29:33so affiliates are better than non affiliates.
• 29:36But the active affiliation in these 144
• 29:38hospitals did not make anything better.
• 29:41OK,
• 29:41well,
• 29:41that will have
• 29:43to be the last word.
• 29:45Certainly we need to come to some more of
• 29:47your lectures and talk about this more,
• 29:50but you know, certainly this is vitally
• 29:52important for patients and physicians
• 29:54like to understand these data.
• 29:56Thank you, Dan. Thank you.
• 29:57OK, well we have a second talk today and.
• 30:00I'm also a colleague and friend,
• 30:03Veronica Chang,
• 30:03Professor of neurosurgery who's going
• 30:05to talk to us about challenges in
• 30:08brain cancer metastases management.
• 30:10I have a little blurb here also
• 30:12from Renee for her.
• 30:14If I can get it up here.
• 30:17Doctor Chang is a professor of
• 30:19neurosurgery and radiation oncology
• 30:21and director of stereotactic
• 30:22radiosurgery and the Gamma Knife Center.
• 30:25She received her medical degree from
• 30:27the University of WA and completed her
• 30:30residency at Yale School of Medicine.
• 30:32Her fellowship at Johns Hopkins.
• 30:35Veronica leads in a row surgical arm of
• 30:38the brain metastasis program at Yale.
• 30:40This is a program that's comprised of
• 30:43Multidisciplinary Physicians in the
• 30:45specialty areas of medical oncology,
• 30:47radiation oncology, neurosurgery,
• 30:48radiology, pathology, neurooncology.
• 30:49This is the nationally ranked unique
• 30:52program specifically dedicated to
• 30:54coordinating clinical management of
• 30:55patients with brain metastases as
• 30:57well as the performance of brain
• 30:59science of science, basic science,
• 31:01translation and clinical trials.
• 31:02She's an active member of our long sport.
• 31:06Saronic it's a pleasure to have you here.
• 31:07Today we started a few minutes late
• 31:09so I won't cut you short at the end.
• 31:11We'll make sure we have time for
• 31:13questions as well. The floor is yours.
• 31:15OK thanks Ray. How? Sorry, hang on a second.
• 31:33OK, does that look alright?
• 31:37OK, so thank you Roy for that introduction.
• 31:43That was very kind so. I'm going to.
• 31:48My talk is going to be a little
• 31:50bit different than dance today.
• 31:52That's not at all that
• 31:54would be uncomfortable.
• 31:55And before I start,
• 31:58these are my disclosures.
• 32:01So as you all know,
• 32:02brain tester sees code about 20 to 40%
• 32:05of patients with metastatic cancer.
• 32:09And so you can see on the left back when
• 32:11I started treating brain metastases,
• 32:13we only thought that a few types of
• 32:17cancer really went to the brain.
• 32:19This is obviously changed over the years,
• 32:22and so you can see on the right now
• 32:24that pretty much almost any cancer
• 32:26type can go to the brain because while
• 32:29about 10% of brain metastases can be
• 32:32found at initial diagnosis of cancer,
• 32:34by far the vast majority,
• 32:36so 90% developed later in the course of
• 32:38cancer and as patients are living longer,
• 32:41I think the brain metastasis
• 32:43problem is becoming more prevalent.
• 32:46And so over the last two decades,
• 32:48then significant changes have occurred
• 32:49in the management of brain metastases.
• 32:51And while there have been an increasing
• 32:53number of successes in treatment and
• 32:55want to concentrate today on some
• 32:56of the challenges that have arisen
• 32:58from these changes in paradigm.
• 33:00And so the biggest change in brain
• 33:03metastasis management has been the
• 33:05move from whole brain radiation
• 33:06therapy with or without surgery,
• 33:08which was supported by the petrol studies
• 33:11in the 1980s to the incorporation of
• 33:13brain radiosurgery first as salvage,
• 33:16then for a few lesions as first line
• 33:18treatment and then for radiosurgery
• 33:20to pretty much everything and now to
• 33:23a combination of CNS penetrating drugs
• 33:27in combination with radiosurgery.
• 33:29And I know that many of you are
• 33:30familiar with radiosurgery.
• 33:31But for those of you who are not,
• 33:33gamma knife is the machine that
• 33:35we use here at our institution for
• 33:37the delivery of brain radiosurgery.
• 33:39For the majority of our patients,
• 33:41gamma knife still requires the
• 33:43application of an immobilizing
• 33:44headframe that then it allows the
• 33:46placement of each metastasis in the
• 33:48into the middle of the radiation beams,
• 33:50which enables the delivery of a
• 33:53very accurately targeted high dose
• 33:54of radiation in a single day to
• 33:56single fraction to target lesions
• 33:58almost anywhere in the brain.
• 34:03And also sorry. And so,
• 34:07with all our radiosurgery capable machines,
• 34:09how about we now also have
• 34:11mask based capability?
• 34:13And so, while accuracy of treatment
• 34:15and long treatment tolerability
• 34:17is still best in the frame,
• 34:18the mask is further extent expanded.
• 34:21Our capability to treat
• 34:22patients like this one.
• 34:24And so this is a 64 year old lady who was
• 34:26just recently diagnosed with lung cancer.
• 34:28Some of you may remember her.
• 34:30And this patient would previously have
• 34:32had whole brain radiation therapy because
• 34:34of the large number and size of lesions.
• 34:37Today what we can do is break the
• 34:39radiosurgery up into three to five days.
• 34:41So on the first day,
• 34:43the frame is applied and all the
• 34:45smaller lesions are treated so you can
• 34:47see that there's quite a few lesions
• 34:49that are less than 3 centimeters in diameter,
• 34:51and all of these are treated in
• 34:53single fraction as they would be
• 34:55for most of their other patients.
• 34:57Then a plan is made for the larger
• 35:00lesions in the first of three or five
• 35:02fractions can be administered in the frame,
• 35:04and the patient comes back for 204
• 35:07more treatments than performed in
• 35:09the mask to only the larger lesions.
• 35:11And so it's gotten very complicated
• 35:13from a planning standpoint,
• 35:14but this often allows us to avoid
• 35:17whole radiation therapy altogether.
• 35:18And it means that radiation can be
• 35:21completed usually within a week.
• 35:23And so this may seem a little
• 35:25crazy on our part,
• 35:27but parallel to our institutional practice,
• 35:29the national use of radiosurgery
• 35:30has grown exponentially as well
• 35:32as you can see from these grants
• 35:34from the National Cancer database.
• 35:36So on the left,
• 35:37obviously is what we used to do before,
• 35:40and then on the right you can see
• 35:42that not only is ready yesterday
• 35:43being used as first line treatment
• 35:46for patients living longer,
• 35:47and often undergoing second and
• 35:49third treatments with radiosurgery,
• 35:50and so its use is escalated
• 35:52or around the country.
• 35:57And so not only then do we
• 35:59increasingly see treatment plans
• 36:00that look like this one on the left,
• 36:02where the blue dots are the first treatment,
• 36:05yellow dots, the second treatment,
• 36:07and so each time the patient
• 36:08comes is more lesions treated,
• 36:10but to the right you can see in every
• 36:12increasing number of radiosurgery capable
• 36:14machines being developed, and so on.
• 36:16The top is the cyber knife,
• 36:18which was the first iteration outside
• 36:20the gamma knife in the middle of picture
• 36:22is Linux based radiosurgery machines.
• 36:24So they look very much like our standard.
• 36:27Radiation machines then on
• 36:28the bottom is the ZAP.
• 36:30Which is the newest self shielded
• 36:33machine that you might start
• 36:35seeing coming on the market?
• 36:36And so the question arises then,
• 36:39as radiosurgery becomes
• 36:41increasingly available.
• 36:43Many lesions is too many
• 36:45to treat with radiosurgery.
• 36:47And so,
• 36:48based on survival literature which
• 36:51we're realizing now is not great for us,
• 36:53large popularity population data
• 36:55suggests that there is no upper limit
• 36:58to when to consider radiosurgery
• 37:00since there are groups that that
• 37:02show that median overall survival
• 37:04durations can be in the order of 18
• 37:07to 20 months in patients with greater
• 37:10than 30 metastases treated at one sitting.
• 37:15From the neurocognition outcome standpoint,
• 37:17which is where we'd like to be without data,
• 37:20there is no guidance here,
• 37:22since the largest randomized
• 37:23study involved only patients with
• 37:25one to three brain metastases,
• 37:27and this study only showed that whole brain
• 37:31radiation therapy was bad for cognition.
• 37:34And so the only data that we have
• 37:37to go on is this small study that
• 37:39was done which tried to correlate
• 37:42the number of lesions with how much
• 37:45dose the whole brain might achieve
• 37:47received in a single day of treatment.
• 37:50And so we believe that for greyhole rain
• 37:52dose, which is marked on the left axis
• 37:55correlates probably about 25 lesions,
• 37:57which is the current our current
• 38:00upper limit of safety.
• 38:02Unfortunately,
• 38:03there's very little other data to guide us,
• 38:05and so it's important not only to
• 38:08remember that number of lesions treated
• 38:10needs to be taken in context of patient
• 38:12expected survival and cognitive reserve.
• 38:15But also,
• 38:15patient ability to tolerate,
• 38:17delete the treatment and so
• 38:19treat in 25 lesions,
• 38:20translates into three hours of
• 38:22physics planning while the patient
• 38:24sits and waits with the headframe
• 38:26on and then an additional three
• 38:28more hours of having one's head
• 38:30locked in the machine for treatment,
• 38:32making it a 7 to 8 hour
• 38:34minimum treatment day.
• 38:35And obviously the time is spent is
• 38:37worth it if the results are good, but.
• 38:42It's not for everybody.
• 38:45So for many patients who still
• 38:47live less than a year after
• 38:49diagnosis of brain metastases,
• 38:51though radiosurgery still
• 38:52remains the first line treatment.
• 38:55And so on the bottom you can see
• 38:57here a volume change overtime graph
• 38:59that we published quite a while ago,
• 39:01now showing that if you live only nine
• 39:03months there is that initial shrinkage
• 39:05of the radiosurgery treated lesion.
• 39:07As you can see all the way to the left
• 39:10of the graph and then the volume remains
• 39:12stable over the course of your lifetime.
• 39:15If however, you live longer than that,
• 39:18then there is an increasing chance that
• 39:20you could run into this phenomenon
• 39:23that you see around the 12 to 18 month
• 39:26mark where the lesions start to grow,
• 39:29and so as radiosurgery has become
• 39:31more popular. Nationally.
• 39:32The rate of this phenomenon
• 39:34has significantly increased,
• 39:35and so this is a phenomenon that
• 39:37is unique to radiosurgery,
• 39:39does not occur after a whole
• 39:42brain radiation alone.
• 39:44And and it's becoming
• 39:47increasingly problematic.
• 39:48And so when we first
• 39:50encountered this phenomenon,
• 39:50it was assumed that regrowth was due to tour,
• 39:53'cause that's what it was when things
• 39:55regrew after horn radiation therapy.
• 39:57But in fact,
• 39:58we know now that 50% of
• 39:59radio graphic regrowth.
• 40:01Can be due to post high dose radiation,
• 40:04inflammatory phenomenon
• 40:05known as radiation necrosis,
• 40:07which you can see on the right,
• 40:10and so is images show perivascular
• 40:12and intra parenchymal T cell
• 40:15infiltration associated with the
• 40:17standard necrosis and Astra Cytosis
• 40:20and Vascular Highlanders issue
• 40:22that you see following radiation.
• 40:24While we do not really understand
• 40:26the pathophysiology still behind the
• 40:28development of radiation necrosis clinically,
• 40:30we have relied on experience
• 40:32that suggests that if disease
• 40:34is progressing in the body,
• 40:36then regrowth in the brain
• 40:38is likely to be tumor.
• 40:40On the other hand,
• 40:42what we've learned is that patients
• 40:44who are doing well in the body and
• 40:46have been successfully treated
• 40:48with immunotherapy or have received
• 40:50repeat radiation for presumed tumor,
• 40:52regrowing in the brain and more
• 40:55likely to develop radiation necrosis.
• 40:58Unfortunately,
• 40:58even with these clinical predictors
• 41:00were not always right,
• 41:01and so we turned to image Ng
• 41:04to try to help us.
• 41:06And over the years,
• 41:07many imaging sequences have been proposed,
• 41:09including those listed here.
• 41:11The latest favorite is more
• 41:13profusion and so to the right is
• 41:15an example of how wrong we can
• 41:18still be with these images though.
• 41:20So this is a patient who had his right
• 41:23temporal and then right cerebellar
• 41:25lesion treated nine months ago.
• 41:27The lesion started to regrow
• 41:29an on Mr Perfusion.
• 41:30Blue areas are considered low blood
• 41:32flow whereas green to red areas are
• 41:34considered higher blood flow and
• 41:35so where there's less blood flow,
• 41:37we think it's less likely to be to Moran.
• 41:40More blood flow more likely to be tumor.
• 41:43So the right temporal lesion was
• 41:45red's tumor and the right cerebellar
• 41:47lesion was read as radiation necrosis.
• 41:50Both lesions ultimately needed
• 41:52resection for symptomatology,
• 41:53and in fact,
• 41:54the pathology was the exact opposite.
• 41:57And so unfortunately today the
• 42:00gold standard for differentiation
• 42:02differentiating tumor from radiation
• 42:04across this remains surgical.
• 42:06One imaging modality that has
• 42:07been reported to be more helpful
• 42:09in Europe is amono acid pet.
• 42:11The traditional amino acid compound
• 42:13that has been most studied and used,
• 42:15his radio labeled methionine,
• 42:16which unfortunately has a very
• 42:18short half life and his therefore
• 42:21being too expensive to make and
• 42:23use here in the United States.
• 42:24A much more stable compound,
• 42:26however, has recently come on the
• 42:27market called flu sick living,
• 42:29and so I just wanted to introduce
• 42:31you to a new image Ng trial
• 42:33that we're starting here.
• 42:34So pursue is a phase 2B trial which
• 42:37is currently open for any brain
• 42:39metastasis patient with lesions
• 42:41regrowing after radiosurgery.
• 42:43Its purpose is to gather preliminary
• 42:46data to help define the image in
• 42:49cutoff values for classic luvene pet
• 42:51by correlating preoperative imaging
• 42:53with post craniotomy pathology.
• 42:56Once these image in cut offs
• 42:58have been defined though,
• 42:59then we'll be opening revelate,
• 43:01which will be a phase three
• 43:02study to determine the efficacy
• 43:04of flu sick Lavigne Pat.
• 43:05In different shading,
• 43:07tumor from radiation necrosis.
• 43:08For this study,
• 43:09both patients undergoing craniotomy
• 43:10and laser thermal coagulation,
• 43:12which will talk about a little bit later,
• 43:15will be eligible,
• 43:16and so hopefully you'll be seeing this
• 43:18study coming around and will be able
• 43:20to move closer towards obtaining a
• 43:22noninvasive method of differentiating
• 43:24tumor from radiation process.
• 43:28So the next challenge is what to do
• 43:31once we workout, whether the lesion is
• 43:34regrowing tumor or radiation necrosis.
• 43:36What's interesting over the years is that
• 43:39management options for radiation necrosis
• 43:42have become more available than tumor.
• 43:45And so these are the options available.
• 43:48Obviously for radiation necrosis
• 43:49it's possible just to observe the
• 43:51lesions because some of these lesions
• 43:53will resolve on their own.
• 43:55We've learned though, as I said before,
• 43:57that radiation necrosis tends to occur
• 43:59in patients tends to occur more often
• 44:02in patients receiving immunotherapy.
• 44:04And so stopping immunotherapy as an option,
• 44:07and certainly avoiding reradiation,
• 44:10is probably one of the biggest
• 44:13ways of avoiding making this worse.
• 44:16There are many medical therapies
• 44:18that have been tried.
• 44:19The only one that has been demonstrated
• 44:21to be efficacious's purpose is
• 44:23a map in a randomized trial.
• 44:25But what we've also learned is that surgical
• 44:28management has been very effective,
• 44:30and so back in the day we only
• 44:32had craniotomy available.
• 44:33But if you completely remove a
• 44:36radiation across this lesion,
• 44:37then resolution is is rapid.
• 44:40Not everybody wants a craniotomy though,
• 44:42and so over the last five or six
• 44:44years we've developed a technique
• 44:47called laser thermal coagulation.
• 44:49Shorten does lit,
• 44:50which is helped us with with this population.
• 44:54And so again,
• 44:55for those who are not familiar letters is
• 44:58a minimally invasive stereotactic procedure.
• 45:00So through the same smaller 5
• 45:02millimeter stab incision in the skin,
• 45:04we can introduce a biopsy needle
• 45:05through the skull into the lesion,
• 45:07take a bite,
• 45:08and then take out the needle and through
• 45:11the same hole we can introduce the laser,
• 45:14which is what you can see on the left.
• 45:17Patient then gets introduced
• 45:19into the MRI machine.
• 45:21Um and we check to make sure that the
• 45:24laser is inside the middle of the lesion.
• 45:26We then turn the laser on and you can
• 45:29see the yellow lines around the lesion.
• 45:32Those are the lines are the heat lines
• 45:34that allow us to know when to stop.
• 45:37Turn off the laser.
• 45:40And so this is an example of how
• 45:42radiation necrosis works best,
• 45:43and so to the left you can see a patient
• 45:46who had in fact 23 lesions treated
• 45:49with radiosurgery of all of them.
• 45:51Though this was the only lesion in the
• 45:53right basal ganglia that became a problem.
• 45:55So it started to regrow,
• 45:57was associated with a lot of adima around it.
• 46:00We went ahead and treated this lesion.
• 46:04And you can see that the incision
• 46:06is only a couple staples.
• 46:08Long patient was able to go
• 46:10home first day after surgery.
• 46:12They were able to come off steroids
• 46:14in a week and you can see in
• 46:17two weeks how quickly.
• 46:18Even though the lesion size
• 46:20itself is not decreased,
• 46:22that the edema has gotten
• 46:23better by six weeks.
• 46:25Obviously good resolution and so so
• 46:27the nice thing is we haven't had to
• 46:30do craniotomies for these lesions,
• 46:31which are obviously significantly morbid.
• 46:34And have been able to offer
• 46:36one additional option.
• 46:39Home and so how we decide which option
• 46:43to treat with with for radiation
• 46:46necrosis still remains highly variable.
• 46:49So we went back and looked at our
• 46:52institutional experience to try
• 46:53and work out if we could start to
• 46:55standardize how we choose what we do.
• 46:58So the first study we did looked
• 47:01at craniotomy versus lit.
• 47:03So what we learned was that both
• 47:06tools are pretty good at taking
• 47:08care of radiation necrosis.
• 47:10What it appears though,
• 47:12is that symptom resolution and
• 47:14ability to wean off steroids
• 47:16may be better with craniotomy.
• 47:18But what we realized also was
• 47:20that the lesion volume was larger
• 47:23in our craniotomy patients.
• 47:25And so when we took out all
• 47:27the lesions that were greater
• 47:29than 3 centimeters in diameter,
• 47:32and what you can see all the way to
• 47:36the left is that is that in fact,
• 47:39the two surgical tools,
• 47:41litton craniotomy basically
• 47:42become comperable in Efficacy.
• 47:44And really what becomes a?
• 47:47Decider for how well things work is
• 47:49whether or not the lesion is radiation,
• 47:52necrosis,
• 47:53or tumor,
• 47:53and so from this we started first
• 47:56of all to try and detect lesions
• 47:59when they're small so that we can
• 48:01take advantage of the minimally
• 48:03invasive technique of lit,
• 48:05rather than having to condemn
• 48:07the patient to craniotomy.
• 48:10But obviously,
• 48:10if the lesion is larger than
• 48:123 centimeters then craniotomy
• 48:14is still effective.
• 48:17Um? The what we did next was then can
• 48:22try and compare use of lit to Aston.
• 48:26And what you can see here is
• 48:29that we actually have two very
• 48:32different populations being chosen
• 48:34for the two different treatments.
• 48:38So lit patients tending to be a little bit
• 48:41better functionally, and not only that,
• 48:44but the time from radiosurgery tool.
• 48:47It tends to be significantly longer
• 48:49than for those getting bear versus man.
• 48:52So for whatever reason,
• 48:54patients who have lesions that are
• 48:56regrowing early after radiosurgery a are
• 48:59tend to be getting drug more frequently.
• 49:04In addition to that,
• 49:05when we look at local lesional control,
• 49:07what we also see is 2 very different
• 49:09patterns of response, again making the
• 49:11two treatments very hard to compare.
• 49:14If we start with the graph on the right,
• 49:17the graph shows 3D volume change overtime
• 49:19again and you can see that the black
• 49:22line which is the business, is a Medline.
• 49:25There's a relatively rapid decrease in
• 49:27lesion size in response to Adbaston,
• 49:29but this response ultimately
• 49:31does not last forever.
• 49:33In addition, on the left you can
• 49:35see based on the runner criterion,
• 49:37that while a 15% a subset of patients
• 49:39had an excellent response to Avastin,
• 49:42showing a CR both at three and six months,
• 49:45the majority of patients only have disease
• 49:48stabilization and then progression.
• 49:50In comparison, after lit,
• 49:51there is the expected increase in lesion
• 49:54volume from the surgical procedure itself,
• 49:56but then a good long term
• 49:59volumetric response.
• 50:00You Irano this is less easy to
• 50:03interpret because much of the
• 50:04volume change were large enough to
• 50:06result in a progression of disease.
• 50:09Reading early on that then resolved
• 50:11to stable disease by six months.
• 50:14And so ultimately,
• 50:15local control was significantly
• 50:16better at six months and beyond
• 50:18for laser compared to Avastin.
• 50:20But obviously if you have a large lesion
• 50:23with Mass Effect relatively early on,
• 50:25that can't be surgically
• 50:27respected than Avastin.
• 50:28Now clearly plays a role.
• 50:32Lastly, from a multi institutional
• 50:34study of lit, we learned that
• 50:35complete ablation of a radiation
• 50:37across this lesion results in better
• 50:39local control than partial ablation.
• 50:40They can see in the first 2
• 50:42lines of the table to the left,
• 50:44and so the smaller the lesion at
• 50:46the time of lit, the more likely
• 50:49it will resolve post operatively.
• 50:51And so this last point is you can
• 50:53see also applies to regrowing
• 50:54tumor which is the bottom two
• 50:56rows of the table to the left.
• 50:58And for this reason we have started
• 51:00advocating for lit much earlier
• 51:02in the course of these patients.
• 51:04Whether we think it's radiation,
• 51:05necrosis, or tumor.
• 51:08To the right,
• 51:10the study also underscores one
• 51:12more problem in brain metastasis
• 51:14management and that is that
• 51:17regrowing tumor both in the local
• 51:19control as well as survival.
• 51:21Data is a much bigger problem to
• 51:25manage the radiation necrosis.
• 51:27And so this brings us to,
• 51:29kind of how we offer radiation dosing here.
• 51:32And so while we would prefer that our
• 51:34patients not get either complication,
• 51:37if we had to pick one complication,
• 51:39radiation necrosis would be the
• 51:41preferable one because we seem to have
• 51:43better treatment options available.
• 51:47Alright, and so for the last few
• 51:50minutes I wanted to move away from
• 51:52surgery and radiation and talk a little
• 51:55bit about work that we've been doing.
• 51:57Looking at recurrent tumors.
• 51:59So recurrent tumor being the most
• 52:01difficult of the problems that we manage.
• 52:03Unfortunately more radiation and surgery
• 52:05is usually morbid for the patient,
• 52:07and so is there a way that we look
• 52:10at changing systemic therapy to
• 52:12be more effective in the brain?
• 52:15And so I want to thank doctor Hertz and
• 52:19the support group for the opportunity
• 52:22to participate in the lung score.
• 52:25And credit for the work that I'm
• 52:26about to present goes mostly to my
• 52:28collaborators Don Wayne and pathology
• 52:30and Abby Patel and radiation oncology
• 52:32and they labs for hosting us,
• 52:34but also to Stephanie Chokers.
• 52:35One of our star neurosurgery residents
• 52:38who is really the force behind
• 52:40getting a lot of this work done.
• 52:43And so as background,
• 52:44the two proposed mechanisms for CNS failure,
• 52:48particularly,
• 52:48we've been looking at lung cancers with
• 52:51targetable mutations or either that drug
• 52:54penetration into the CNS remains low,
• 52:56and so compared with the
• 52:58systemic concentrations,
• 52:59tolerance can developed in the
• 53:02central nervous system overtime.
• 53:04Or the second mechanism is that
• 53:06as shown by Priscilla breast,
• 53:08you know through the whole exome
• 53:11sequencing data that she's presented
• 53:13before that clinically actionable
• 53:15gene alterations can be present
• 53:17in brain metastases.
• 53:19That would that may not be
• 53:21found in the primary tumor.
• 53:22Brain metastasis tissue,
• 53:23however,
• 53:24is often difficult to obtain and
• 53:26so we propose that perhaps by
• 53:28looking at cell free DNA in the CSF,
• 53:29we may be able to better study
• 53:32CNS tumor mutations.
• 53:34So we started a CSF biorepository
• 53:36in 2017 and have been collecting
• 53:39time matched CSF blood and brain
• 53:42metastasis tissue where possible.
• 53:44Things slow down a little bit with kovid,
• 53:47but we have over 100 samples down.
• 53:49This is a breakdown of their pathologies.
• 53:52And this is the gene panel
• 53:53that we've been using,
• 53:54which we recognize it would
• 53:55be a little bit limited,
• 53:56but we had to start it somewhere.
• 53:59And so this is a little bit of a busy slide,
• 54:02but what you can see is that we've
• 54:04been successful at finding tumor
• 54:05DNA in the CSF in about 2/3 of
• 54:07our patients with purely intra
• 54:09parenchymal brain metastasis.
• 54:10So not left a meningeal disease,
• 54:12although the amount of DNA
• 54:14has been highly variable.
• 54:16In addition,
• 54:17in the table on the left to the
• 54:19top you can see that while tumor
• 54:22DNA was also detectable in the
• 54:24blood of many of our patients,
• 54:26with interpretable brain metastases,
• 54:28neither patient with cytology
• 54:30proven leptomeningeal disease
• 54:31had tumor DNA in their plasma.
• 54:33And so when we broke down our
• 54:35population into patients with no stable
• 54:38or progressing systemic disease,
• 54:39you can see that plasma DNA tends
• 54:41actually to be more reflective
• 54:43of extracranial disease than
• 54:45intra cranial disease.
• 54:46And Lastly to the right,
• 54:48when matching mutations found in
• 54:50CSF plasma and brain metastasis
• 54:52tissue, it appears in fact that tumor DNA
• 54:55in the CSF matches the brain metastasis
• 54:58much better than plasma circulating DNA.
• 55:02And so it seems that tumor DNA found
• 55:04in the CSF may be a better way to
• 55:07study brain metastases. Mutation.
• 55:08We need to collect obviously more
• 55:11samples and so will be coming to you
• 55:13all to try and get these samples,
• 55:15but we're hoping that if the data is in
• 55:18fact validated that will be able to UCSF,
• 55:20perhaps as a way to inform changes
• 55:23in their systemic therapy options
• 55:24for current brain metastases.
• 55:26Thank you very much and I'm
• 55:28happy to take questions.
• 55:30Thanks Veronica, that was wonderful.
• 55:32We do have time for questions
• 55:34as the questions come in.
• 55:36Just wanna remind everyone that we
• 55:37have our ask a review on October 23rd.
• 55:40This year we're doing it virtually from 821.
• 55:45So tell us a little bit more about how
• 55:48you get the CSF from the patients.
• 55:50These are lumbar punctures that are
• 55:52done on patients identified from
• 55:54the clinics. So yeah,
• 55:55so we actually have a variety so I can
• 55:58just go back here for a second so we
• 56:01have a variety of points where we can.
• 56:03We can get CSF so the biggest one
• 56:05is mostly been from craniotomy so
• 56:07we try and identify a site where
• 56:09we can get CSF that's distant.
• 56:12Then the lesion that we're about
• 56:13to respect and we get the CSF
• 56:16before we reset the lesion.
• 56:17So hopefully there's no.
• 56:19Contamination,
• 56:19but Yes the other places,
• 56:21so one is on the wards and so I think
• 56:24if there's any concern in patients
• 56:26for leptomeningeal disease and we're
• 56:29getting a diagnostic lumbar puncture,
• 56:31then it would be nice to
• 56:34get CSF at that time.
• 56:36And then the last mechanism is one
• 56:38that's a little bit unique and has
• 56:41provided a little bit of a challenge also.
• 56:43So patients who are actually getting
• 56:45re biopsy as part of kind of the
• 56:48lung protocols for progression of
• 56:50disease if they also have progression
• 56:52in their central nervous system.
• 56:54So untreated brain metastases that
• 56:56we've been asking those patients at the
• 56:59time of their broad to have a lumbar
• 57:01puncture performed to get CSF as well,
• 57:03and so those are kind of the
• 57:06three opportunities that we have.
• 57:08And then yes,
• 57:09and then obviously in the clinic,
• 57:11if we're seeing patients that need
• 57:12number of functions for clinical reasons,
• 57:14right?
• 57:14We
• 57:14do have a question someone asks,
• 57:16they say thank you for your wonderful
• 57:18program and all your help with
• 57:19brain metastases over the years.
• 57:20Is there a limit to the number of metastases
• 57:23that you can use gamma knife for?
• 57:26Yeah, so I think it goes back to,
• 57:29you know, kind of what we
• 57:31think patients can tolerate.
• 57:33So gamma knife.
• 57:34Obviously there is no limit.
• 57:36The planning system allows us to treat,
• 57:39I think over. Over 100 lesions
• 57:41now within the planning system,
• 57:44so logistically it's it's not
• 57:46impossible to do that.
• 57:47As I had said though,
• 57:49I think to treat 25 lesions is hard
• 57:52enough for a patient in a single day,
• 57:56and certainly those are 25
• 57:58lesions that are easy to plan and.
• 58:02And relatively easy to treat.
• 58:04I think for those patients
• 58:06who have larger lesions and
• 58:08lesions in more complex areas.
• 58:10Such as up against the.
• 58:13The brain stem or the
• 58:14optic nerves or whatever.
• 58:16Then you know the the planning
• 58:17and the treatment for those
• 58:19lesions takes even longer,
• 58:20so we are our radiation oncologists
• 58:22are trying to keep the cap at 25
• 58:25because we had shown that the whole
• 58:27brain dose is about four Gray.
• 58:29But in addition to that it's
• 58:31about as long as a patient can
• 58:33tolerate 7 or 8 hours with with us.
• 58:35It's not so fun with us down the basement.
• 58:38That's great
• 58:39in the final question from someone
• 58:41who's obviously been watching
• 58:43the entire day. They they ask.
• 58:46Are you doing the gamma knife at
• 58:48sites outside of Cedar Street or is
• 58:50it all being done at the main center?
• 58:53And are there plans to expand
• 58:54this around Connecticut?
• 58:56So, so the Gamma Knife Machine Percy.
• 59:01There's only one of those
• 59:04here in Connecticut.
• 59:05The Certificate of need.
• 59:07It's difficult to get more
• 59:09than one in our little state,
• 59:12but brain radiosurgery,
• 59:13which can be done either with gamma
• 59:16knife or mlynek based techniques.
• 59:19There's actually 11 centers around the around
• 59:22the state that are that are capable of it.
• 59:26With linac based radiosurgery, though,
• 59:28this software is not capable really of
• 59:31treating more than 10 lesions at a time,
• 59:34and once you've exceeded 10 total,
• 59:36whether it be all at one time
• 59:38or over several treatments,
• 59:40then it gets really difficult
• 59:42to take into account what's been
• 59:44treated before as versus what
• 59:46needs to be treated going forward,
• 59:48and it's the reason why the multiple
• 59:51metastases always end up here,
• 59:53and so I think,
• 59:55as Doctor Boffa was saying before.
• 59:57You know it is the reason why
• 59:59we are the referrals.
• 01:00:01I'm not sure that there's enough volume
• 01:00:04necessarily to grow around the state,
• 01:00:06and it's very expensive and time consuming.
• 01:00:10You know, treatment so.
• 01:00:12It's hard to cultivate elsewhere.
• 01:00:14I know,
• 01:00:14I know. I said last question,
• 01:00:16but I can't not ask Doctor Sklar's question.
• 01:00:20Jeff, thank you. He has.
• 01:00:21How do you propose to UCSF DNA in
• 01:00:24patients with multiple lesions?
• 01:00:25For example, your patient who had both
• 01:00:28tumor necrosis and regrowth of tumor?
• 01:00:31So.
• 01:00:35So it's interesting, I don't.
• 01:00:37I think that finding so we
• 01:00:39don't have a marker necessarily
• 01:00:42for radiation Necrosis Persay.
• 01:00:45What I think that we care about is,
• 01:00:48is there regrowing tumor and so I
• 01:00:50think that if we find mutational
• 01:00:52DNA first of all we don't.
• 01:00:54We don't 100% know that it
• 01:00:56correlates with active disease yet,
• 01:00:57but if we're able to demonstrate that
• 01:00:59then we need to be concerned that we're
• 01:01:02not just treating radiation to process
• 01:01:04and I think that's really the issue.
• 01:01:07Great, well, I think that we are at
• 01:01:09time and actually a few minutes over,
• 01:01:11but no one needs to walk back to
• 01:01:13their office. So I figured I could
• 01:01:14get a few more minutes in there.
• 01:01:16Thank you, Veronica, that was wonderful.
• 01:01:18Thank you, Dan.
• 01:01:19Thank you to the organizers Renee and the
• 01:01:21team and we'll see you back next week.
• 01:01:23It's been a pleasure moderating today. Have a
• 01:01:25good day. Everyone. Thank you.