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

October 21, 2020

Yale Cancer Center Grand Rounds | October 13, 2020

Daniel Boffa, MD and Veronica Chiang, MD, FAANS

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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.