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Hello and welcome to Noon Conference, hosted by Modality

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Noon Conference connects the global radiology community

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through free live educational webinars that are accessible

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for all and is an opportunity

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to learn alongside top radiologists

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from the around the world.

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Today we are honored to welcome Dr.

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Lacey Macintosh for a lecture entitled,

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resist 1.1 Principles, pearls and Pitfalls.

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Dr. McIntosh is an associate professor

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of radiology at UMass Medical Schools

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and specializes in cancer and molecular imaging.

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She currently serves as the associate program director

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of Diagnostic Radiology Residency and Chief of Oncology

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and Molecular Imaging at UMass Memorial Medical Center.

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She loves teaching and working with residents.

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At the end of the lecture, please join her in a q

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and a session where she will address questions you may

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have on today's topic.

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Please remember to use that q

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and a feature to submit your questions so we can get to

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as many as we can before our time is up.

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With that, we are ready to begin today's lecture.

0:59

Dr. McIntosh, please take it from here.

1:02

Great. Thank you, Ashley,

1:03

and thanks for inviting me to speak on this topic.

1:06

Um, so today, as she mentioned,

1:07

we're gonna talk about recess 1.1 principles,

1:10

pearls and pitfalls.

1:12

Um, I do some consulting for clinical trial reads

1:15

and curriculum content creation.

1:19

Um, so the objectives of this lecture are to

1:22

increase overall familiarity

1:23

with Resus 1.1 response assessment criteria, um,

1:26

to really understand the concepts behind this, uh,

1:29

and to integrate the principles into clinical care when, uh,

1:33

we're reading studies on cancer patients.

1:37

So the purpose of Resus, like why do we have these, uh,

1:41

tumor response assessment criteria?

1:43

And the goal is that we really want to determine if

1:46

and how well an anti-cancer agent works.

1:49

Um, and the goal with these is to have these designed

1:52

to be the most accurate way

1:54

to capture the treatment response.

1:57

Um, so Resus 1.1 is probably the most popular

2:00

and the one that people are most familiar with,

2:02

but it's, um, and it's often

2:04

but not always the most appropriate, uh,

2:07

response assessment criteria for a particular cancer

2:10

or a particular drug.

2:12

Um, and like many of these assessment criteria,

2:15

this has evolved over time.

2:18

Once people start using it, they find, um, you know, uh,

2:22

gaps or holes and ways to improve it.

2:25

So the current, the most, um, current iteration

2:28

that we use is this recess 1.1 over here on the right.

2:33

Now, as I mentioned, resist is not the only assessment

2:36

criteria, but it's one of many.

2:38

Um, I listed here a table

2:39

that shows some other response criteria.

2:41

For example, these ones are used in, uh,

2:43

renal cell carcinoma,

2:45

but other ones that you may have heard of might be choi, um,

2:48

immune related response criteria, mass criteria, um,

2:53

lugano is one that's used for lymphoma.

2:55

So, um, if we have time at the end, I'll, I'll sort

2:58

of touch on some of these as well,

3:00

but reist is just one of, of many,

3:02

but it's probably the most commonly used for solid tumors.

3:07

Um, so we must acknowledge like, yes, the goal

3:09

of looking at these assessment criteria is to find a way to

3:14

quantify something that's very qualitative, right?

3:17

Looking at imaging. Um,

3:18

and so we do that by measuring things and describing things,

3:21

but, uh, we must acknowledge

3:23

that not all disease is really amenable to being measured.

3:26

Um, and so there are other, you know, systems that we use

3:30

to try and assess, um, tumor volumes

3:33

and tumor burden, um, even when they can't be measured.

3:37

So I just wanted to mention this one.

3:38

This is the peritoneal carcinomatosis index.

3:41

And so, um, this is another way that people sort of use to

3:45

quantify how much peritoneal disease there is.

3:47

As, as you guys know, it can be very difficult to measure,

3:49

but, um, this is achieved by splitting the abdomen,

3:53

abdomen up into these, um, different sections,

3:56

and then providing a score based on

3:58

how much disease you see in each area.

4:02

Alright, so Resis 1.1.

4:05

Um, most radiologists I think are aware of this

4:07

and have heard about it, but, um, you know,

4:10

we aren't really using this at the workstation on patients

4:13

every day unless you're participating in, um, you know,

4:17

assessing patients who are on clinical trials.

4:20

Um, but, you know, many

4:21

of us are reading cancer studies at the workstation

4:23

and not really using recess in a formal way.

4:26

Um, these are used in clinical trials.

4:29

They, you know, follow a very strict sort of, um,

4:34

guideline of how they're done.

4:35

And, um, you know,

4:37

imaging is done on a very particular schedule.

4:40

So when, when this is used in the setting

4:42

of a clinical trial, it's very formal.

4:44

Um, you know,

4:46

even though you're not using at the workstation,

4:48

I think it's a really important thing for radiologists

4:50

to be aware of, because

4:52

what we're doing at the workstation is really based off of,

4:54

um, of resist.

4:56

Uh, we're doing it in a little bit different way.

4:58

We're combining it with clinical factors.

5:00

We have a lot more information about, you know,

5:02

what's going on with the patient.

5:03

We have notes from the me, the electronic medical record

5:06

that we can sort of integrate.

5:07

We have tumor markers, all those sorts of things.

5:09

But, you know,

5:11

performing actual formal resus reads at the workstation

5:15

can be challenging, right?

5:16

Um, patients travel around for care and outside,

5:20

or baseline imaging may not be available,

5:22

especially if you work at a, a referral center

5:24

where patients are coming from other places.

5:27

Um, as I mentioned,

5:28

the imaging is done on a pretty strict schedule time-wise,

5:32

um, and it's, you know, designed to assess, uh,

5:35

treatment at certain intervals.

5:37

And, um, as we all know for various reasons,

5:41

patient preference

5:42

or, uh, you know, patient, um,

5:47

on a patients that we need to scan, um, at our centers

5:50

and, you know, contrast, availability, all of these things,

5:53

um, you know, it's not always possible

5:56

to get patients' imaged on a certain timeline in the,

5:59

in the practical clinical setting.

6:01

Um, you know, and finally, time, it takes time

6:03

to do these formal, um, these formal assessments.

6:07

And we all know that time is not in surplus, um,

6:10

for us radiologists these days.

6:12

But, um,

6:13

and as I mentioned, not, uh,

6:16

resus isn't used in all cancer types.

6:18

Um, and we will talk about some of these at the end

6:20

of the presentation, but lymphoma, just on gle, um,

6:25

mesothelioma are just a few examples where

6:27

Resus doesn't really, um, isn't the best

6:30

and most accurate way to capture tumor burden and response.

6:35

So this is an overview table,

6:37

and we're gonna sort of dive into all

6:38

of these things in the next part of the lecture.

6:41

But, um, the top part sort of talks about how we define

6:45

and select disease that we're going to track over time.

6:49

Um, so we look at targets

6:51

and we, these can be non nodal, like a tumor,

6:55

a liver met a lung lesion, um,

6:57

and those are gonna be measured in your long axis.

7:00

Uh, in order to qualify as a target, it has

7:02

to be one centimeter or greater.

7:04

Um, these can also be lymph nodes, which, um, these need

7:07

to be, uh, these need to measure 1.5 centimeters

7:11

or greater in the shortest axis.

7:13

Um, and these are measured routinely on the axial,

7:16

that's the convention is measuring in the axial plane.

7:19

So, um, we just give one

7:21

to measure one dimensional measurements here.

7:24

Um, thing for disease that are, are not targets, um,

7:27

these are things that are either non-measurable

7:30

or, um, in excess of your target lesions.

7:34

Um, the nodes can be a little bit smaller,

7:36

but the short axis must still be greater

7:38

than one centimeter.

7:39

Um, and then we, we formally follow up to five lesions total

7:44

and two lesions max per organ.

7:47

Lymph nodes globally count as one organ,

7:49

so you can only measure

7:51

and follow two, uh, target lymph nodes,

7:54

even if they're from different parts of the body.

7:57

Um, and then we calculate a sum of the target diameters.

8:02

Um, and so we, we create an assessment based on sort

8:07

of what's going on with our targets and our non-arts,

8:09

and then we track these over time.

8:11

So the bottom part of the graph

8:13

or the table shows, um, then we assign, you know,

8:17

these different response categories to, uh, each time point.

8:21

And so, um, you know, the ideal situation is

8:24

that we see a complete response

8:25

where we have a disappearance of all disease,

8:27

and lymph nodes don't really

8:29

disappear when they're involved.

8:30

So they, we just require those to normalize,

8:33

and that's defined as having a short axis

8:35

of one centimeter or less.

8:37

Um, when we see a 30%

8:39

or more decrease in the sum of diameters compared

8:42

to baseline, um, that's considered a partial response.

8:46

And then I'm gonna skip down to progressive disease.

8:49

This is a 20%

8:50

or greater increase in the sum of diameters compared

8:52

to the Nader or where disease looked the best.

8:54

And I, I've got a slide on this later.

8:56

Um, and this must be an absolute increase

8:58

of five millimeters or greater.

9:00

You don't wanna be calling progression on a lymph node

9:02

that's increased in, you know, two or three millimeters.

9:05

And then stable disease is, um, really sort of a catchall

9:09

that, um, encompasses anything that falls

9:11

between a PR and a pd.

9:14

Um, so the, the language is really sort of particular, um,

9:20

you know, uh, stable disease can really allow

9:22

for quite a bit of improvement

9:24

and quite, you know, a, a bit of, uh, worsening as well

9:27

and still be considered stable disease.

9:29

So that's something to sort of be aware of.

9:34

Alright, a general workflow

9:36

for a patient in a clinical trial

9:37

that's being assessed on by Resus.

9:40

1.1 is, you know, determination of eligibility.

9:43

Um, this is usually done by CT MRI can also be used.

9:47

Some of the, um, you know, they,

9:50

the language in Resus 1.1 talks about the role

9:53

of chest x-ray, but honestly, in modern day cancer imaging,

9:56

there really isn't much of a role for chest x-ray.

9:59

Um, PET can also be used as a substitute or an adjunct.

10:03

Um, but CT is really preferred where you can do, um,

10:06

measurements on the axial plane.

10:08

That can be done, um,

10:09

sequentially the same way on subsequent, um, studies.

10:14

So targets are then chosen,

10:16

and we'll talk about this in the next couple slides,

10:18

and we calculate the sum of the diameters, um,

10:21

and then we identify non-arts

10:23

and sort of describe those, uh, create a report

10:26

and then, um,

10:28

patients are followed up at subsequent time points.

10:30

And this can be different from study, from trial to trial.

10:35

So principles, all disease must be accounted

10:38

for on your baseline scan.

10:39

Um, so you're gonna go through

10:41

and select your appropriate targets

10:42

and like we said, up to five targets, two max per organ.

10:46

And then everything else is gonna be a non-target.

10:49

Um, and you can follow these individually or in groups.

10:52

Um, I tend to be a grouper.

10:54

An example of this would be if you had, you know,

10:57

10 liver metastases, you would maybe select the two largest

11:01

and easiest to reliably measure,

11:03

and you'll use those as targets.

11:04

And then you must have a group of non-target,

11:07

or you must have non-arts

11:09

to follow the remaining liver lesions.

11:10

And so I would probably create a group that was, you know,

11:14

non-target number, whatever it is,

11:16

and say remaining liver lesions,

11:18

and then you follow those as a group.

11:20

Um, it's important to classify all

11:23

of your disease at baseline, um,

11:25

because as you follow it, you, you need to be able

11:28

to formally track everything.

11:30

So in the example that I gave,

11:32

if you have multiple liver lesions, only two

11:34

of which are targets, if one of the ones

11:36

that has not been designated as a target starts to grow

11:39

or progress, you can't really call that new disease.

11:42

That's not accurate.

11:44

Um, it's really,

11:45

it would be progression in off target disease.

11:48

So, um, you just need to make sure

11:50

that everything is classified either as a target

11:52

or non-target, um,

11:53

that you've determined represents disease at baseline.

11:58

Um, so when selecting your targets, you usually wanna go

12:01

for the largest lesions

12:03

and ones that like really represent your disease.

12:06

Um, however, uh, if these are not really amenable

12:09

to measurement or they, um, are not, you know, going

12:14

to be reliably measured between from study to study,

12:17

you know, bowel lesions can be really difficult.

12:19

You can imagine on axial plane,

12:21

a bowel lesion may look very different, um,

12:24

from study to study.

12:25

So that's sort of the judgment call of the reader.

12:28

Um, but usually you wanna do the largest, easiest

12:31

and most reliable to measure at subsequent time points.

12:34

Um, and then as I mentioned, you're going

12:36

to either report the long axis if it's a non nodal lesion

12:40

or the short axis if it's, uh, a mal, a lymph node

12:43

that you believe to be malignant.

12:45

Um, and then nodes that are,

12:49

we see this all the time clinically, right, like nodes

12:51

that are less than 10 millimeters.

12:53

We definitely see these nodes that are involved, especially

12:56

with, you know, things like rectal cancer

12:58

or, um, you know, lesions that we see on PET

13:02

that are FDG avid and clearly involved,

13:04

but don't quite meet this.

13:05

And so that's another differentiation of, you know,

13:08

doing this, uh, using Resus versus like your clinical reads.

13:12

Um, the point of Resus is to track and measure

13:16

and to, you know, quantify disease volumes, uh,

13:19

or disease, um, diameters

13:20

and sort of look at, uh, levels of improvements.

13:23

So you may have to ignore lesions that you, um, you know,

13:27

you suspect could be involved,

13:29

but if they're not really, if they don't fall into this

13:31

trackable category, you have to just sort of let them go.

13:34

Um, that's not really the goal of, of recess is

13:37

to catch everything,

13:38

but it's to catch everything that's, um, you know,

13:40

obviously disease and trackable.

13:45

So some considerations.

13:47

If you have a lesion that has a hypervascular rim, you want

13:50

to include that in your measurement.

13:53

Um, bony disease is generally not appropriate as a target.

13:58

Um, and the reason for that is

13:59

because we're tracking size over time, right?

14:01

And if you have a, a bone lesion, um, you know,

14:06

and you're measuring it, bone lesions when they heal,

14:08

often become more sclerotic

14:10

and they don't necessarily disappear.

14:11

So you can imagine that even if your bone lesion like

14:14

totally heals, you're not gonna have,

14:15

you're not gonna have a significant change

14:18

in the size of it.

14:19

And so Resus isn't really gonna capture that response.

14:22

So if your lesion has a significant soft tissue component,

14:25

your bone lesion does, you can select that as a target.

14:29

Um, but anything

14:31

that's really bone based should be a non-target lesion

14:34

and not, not be considered target.

14:38

So after you've selected your targets, you're gonna

14:40

classify everything else, um, as non-arts.

14:43

And so these may be, you know, just whatever is in excess

14:46

of your targets, but also things that aren't suited

14:48

for exact measurements but can be followed.

14:50

So things like effusion, ascites, um, lepto ingal disease,

14:55

lymphangitis involvement of the skin or the lung.

14:58

Here's an example here

15:00

of lymphatic carcinomatosis of the lung.

15:02

We have some ascites.

15:03

We've got sclerotic bone or some sort of mixed lytic

15:06

and sclerotic bone disease here.

15:08

And so you're gonna categorize that baseline

15:10

that this is just like present.

15:11

You wouldn't really categorize it as absent

15:13

'cause you wouldn't be listing it as as a lesion.

15:16

So it's just at baseline,

15:17

it's given the designation of present.

15:20

Um, other things

15:21

that might be appropriate non-arts are lesions

15:24

that have been ablated or radiated.

15:26

Um, and yeah, that's just something to sort of think about.

15:30

Generally, you're not supposed to ch

15:32

to choose these as targets.

15:33

Um, some clinical trials have exceptions and allow for that.

15:37

Um, you know,

15:39

especially if it's like the only site of disease as well.

15:43

So at baseline, you're gonna calculate your sum

15:45

of diameters using the long axis for non nodal lesions

15:48

and the short axis for nodal lesions.

15:50

Here's an example here.

15:52

Um, we've got multiple liver lesions

15:54

and we've selected two that we're measuring in the longest,

15:57

um, diameter on the axial plane.

15:59

Um, we've got a lymph node here, um,

16:02

which is being measured in the short axis,

16:04

and then a peritoneal mass, uh,

16:07

or two peritoneal masses here in the

16:09

pericolic gutter and pelvis.

16:10

And so you'd, um, get the measurements from all

16:13

of these and add them up.

16:15

So some places use like a, a chart like this

16:18

where you can sort of put everything in, um, you need

16:21

to provide series and image numbers for reference as well.

16:26

Um, and then you're gonna calculate your sum of diameters,

16:29

you're gonna talk about your non-target lesions,

16:31

and then any other findings that may be, you know, sort

16:34

of present or contributory or just incidental.

16:37

Um, your baseline report, you know,

16:39

is gonna include normal things like the modality

16:41

and the parameters, use slice thickness, all of that.

16:45

Um, you're gonna talk about your target lesions with ser

16:48

with series and image numbers, um,

16:50

and then non-target lesions as we mentioned,

16:53

and incidental findings.

16:54

Uh, and then you're gonna come up with a conclusion.

16:59

So moving up for, into follow up, um,

17:03

you wanna make sure sort of,

17:04

you wanna do your quality assessment to start like,

17:06

you know, is this follow-up study technically

17:09

comparable to the prior.

17:11

Um, you know, as I mentioned, we really like

17:12

to do CT versus ct.

17:15

We really prefer contrast CT and contrast ct,

17:18

but as you guys know, patients can't always get contrast

17:21

and you know, sometimes they get other

17:22

imaging for other reasons.

17:24

So that's again,

17:25

a judgment call on the reader if the subsequent imaging is

17:29

an appropriate and, um, you know, comparable study to use,

17:33

um, if it's a,

17:35

an appropriate substitute for adequate assessment.

17:39

And then you're gonna go through your targets

17:41

and you're gonna calculate the sums

17:43

of diameters on your new study.

17:45

Um, you wanna continue to measure lymph nodes even if they,

17:48

when they drop below one centimeter

17:50

and they're considered normal, um, you still want

17:53

to document, you know, those single

17:56

millimeter uh, measurements.

17:57

And the reason is that you don't want to, uh, if

18:00

that lymph nodes begins to en enlarge again,

18:02

and, you know, say it goes up

18:04

to like 12 millimeters short axis, if you've documented that

18:07

as a zero previously, that's going

18:09

to overstate the progression versus if it went from nine

18:12

millimeters to 12 millimeters.

18:14

Um, and you can have a complete response even if your sum

18:18

of diameters isn't zero, if you have nodal lesions, um,

18:22

you're gonna assess your nont targets

18:24

and you're gonna say, you know, are they present?

18:27

Are they absent? Are they present with progression?

18:29

Have they worsened? Um,

18:31

and then of course you're gonna look

18:32

for any new sites of disease.

18:34

So here's some examples here where, um, we had some lesions

18:39

that, you know, are very, very small to begin with,

18:41

and then on follow up they're getting bigger.

18:43

So you're gonna measure those.

18:45

Um, and then new liver lesions here on the bottom study.

18:51

Uh, and then here on the right we can see we've got,

18:55

you wanna measure these in the same as

18:57

as much in like a similar manner, a reproducible manner.

19:01

Um, that may not always be possible if

19:04

where the long axis is changed, uh, has changed,

19:08

but you really want to try to do that.

19:10

So this is a lung lesion that's decreased in size,

19:13

another one in the right lung.

19:15

And then, um, you can see there's like a little bit

19:17

of a change in orientation of the SubCal lymph node,

19:20

but you're still sort of in the spirit

19:21

of measuring it in the same short axis there

19:26

sometimes lesions, um, split or merge.

19:30

Um, and so we have, you know, sort

19:32

of accommodations to figure that out.

19:34

If your lesion has split into two lesions, it, you know,

19:36

turns out it was a conglomerate to begin with

19:38

or for whatever reason, it's splits.

19:40

You basically treat these two lesions as one lesion

19:44

and you, um, you add their, their diameters together

19:48

to be able to compare it to the prior.

19:50

Um, and then same thing when lesions sort

19:53

of become confluent.

19:54

Um, you treat those, that group of lesions as

19:57

as a single one, and you try to, you know,

19:59

make the measurements as comparable as possible.

20:02

Um, sometimes like non nodal lesions will become too small

20:05

to measure if they're like, you know, 1, 2, 3 millimeters

20:09

and those are given an arbitrary

20:11

measurement of five millimeters.

20:13

Um, some other things that can happen with certain drugs

20:16

as you can see cavitation.

20:17

Um, and that can be a little bit, you know, difficult

20:20

to document and figure out like,

20:22

how do we measure this, right?

20:24

And we'll talk about this later,

20:25

but that, that is something that's a little bit

20:27

of a pitfall for reis, right?

20:29

Because the overall size

20:30

of this lesion hasn't really changed.

20:32

But, um, you can certainly see

20:33

that there's less tumor there.

20:36

Um, here's an example of a lesion

20:38

that's maybe become too small to measure.

20:40

It's just sort of like a scar.

20:44

And then when you're following up your non-arts, um,

20:47

you're often not measuring.

20:48

I mean you can if they're measurable lesions

20:50

and you can sort of look at that and track that,

20:52

but you're not really calculating anything based on

20:55

non-target measurements.

20:57

Um, you're really just giving more

20:59

of a qualitative assessment.

21:00

Um, has this resolved or normalized?

21:02

If it's a node, is it present

21:04

or is it present with progression?

21:07

Um, and so present really has like a,

21:10

does some heavy lifting here

21:11

because, you know, it can improve without resolving

21:15

or it can slightly increase in size

21:17

without really progressing.

21:19

And that all sort of just falls in that present category.

21:23

So here's what, you know, a, a table may look like for, um,

21:27

you know, your baseline

21:28

and your subsequent assessments where you're going

21:31

to document your sizes of your targets, the image numbers,

21:34

your sums of diameters,

21:35

and you're gonna do that at each time point

21:37

and measure those and, um, compare those.

21:39

And you're gonna look for decreased, uh,

21:41

percent decrease in the, um, sum, sum

21:44

of diameters from baseline or an increase from the Nader.

21:47

Um, these are non-applicable at baseline obviously,

21:50

because you're not calculating a change,

21:52

but you'll have these filled in,

21:53

in the subsequent time points.

21:55

Um, non-target lesions, again, it's qualitative.

21:58

You're just sort of talking about are they still there?

22:00

Are they, you know,

22:02

are they worse meeting progression or have they resolved?

22:05

And then presence or absence of new lesions.

22:08

And then again, other findings.

22:11

So just walk you through like an example here.

22:14

Um, this is a patient with metastatic colon cancer

22:16

with liver lesions.

22:17

These two studies on,

22:19

or these two images on top are from the baseline.

22:21

So you can see we have a lesion measuring 4.6 centimeters

22:24

and another one measuring 5.4 centimeters.

22:26

So our sum of diameters here is 10 centimeters on follow-up,

22:30

the lesions decrease in size to three three and two seven.

22:34

Um, and so those add up to six centimeters.

22:36

So when we calculate the, the percentage difference in, um,

22:41

in the sums of diameters,

22:42

we're getting a 40% decrease, right?

22:45

So that's gonna fall into this partial response category

22:47

of 30% or greater decrease in the sum of diameters

22:50

for baseline sum from baseline sum diameters.

22:53

So it seems pretty straightforward, right?

22:56

Of course, not all cases are straightforward like that,

22:59

but this is a, a good example when

23:00

you're sort of just learning.

23:03

Um, so targets are assessed

23:05

with these four categories that we've talked about.

23:07

Um, you know, I'll just review them again quickly.

23:11

Uh, complete response or crs disappearance of all lesions

23:15

and lymph nodes normalized.

23:17

Um, partial response is a 30% or more decrease.

23:21

Uh, progressive disease is a 20% or more increase, um,

23:25

or any new disease.

23:26

And then stable disease is really just like everything in

23:29

between PR and PD for your non targets.

23:33

We aren't going to be calculating these percentages

23:35

'cause we're not measuring things, right?

23:36

So the categories here are a little bit different.

23:38

We have a cr which is just like disappearance of e

23:41

of everything and normalized lymph nodes.

23:44

Um, PD is, uh, they use this term

23:47

of unequivocal progression, um, or, you know, new disease.

23:52

And so there's a little bit

23:53

of wiggle room here if something's like increased a little

23:56

bit and that's the judgment of the reader, like,

23:58

do you think that this is like unequivocal progression

24:01

or do you feel that it's equivocal?

24:04

Um, and so again, it's,

24:06

it's a qualitative assessment for you as a reader.

24:10

And then there's this category, instead of having PR

24:12

and sd, we have this non cr, non pd.

24:15

And so it's just basically a catchall of like anything

24:18

that falls in between these two.

24:20

So we have our assessments for targets,

24:23

we have our assessments for non-arts,

24:25

and then we have to sort of harmonize those

24:27

to give a global assessment.

24:29

And so you can see here you have whatever you've given your

24:33

target listed here,

24:34

whatever you've given your non-target listed here,

24:37

are there any new lesions?

24:38

And what's your overall response?

24:40

So an example

24:41

of this may be if your target lesions have gone away,

24:44

but your non-target disease is sort

24:46

of in this in-between category where it's not gone

24:49

but it hasn't progressed, you don't have any new lesions.

24:51

And so sort of the harmonization of this,

24:54

the targets carry a little bit more weight is gonna be, uh,

24:57

this is gonna be graded in overall partial response.

25:01

Um, you can see here that anything that has new lesions

25:04

or involves PD at any, you know, sort

25:07

of assessment is gonna result in pd.

25:13

So I mentioned this earlier when we're talking about partial

25:17

response, this is always gonna be

25:19

calculated in reference to the baseline.

25:22

Um, whereas progressive disease is gonna be in reference

25:25

to the Nader or the lowest point

25:27

or basically where the disease looked the best.

25:30

Um, and so this is kind

25:31

of a graphical representation of that.

25:33

So here's our baseline at the yellow arrow.

25:35

We can see over weeks that this disease has decreased,

25:39

this sum of diameters has really dropped

25:41

and we're down to like, you know,

25:42

a 40% improvement, which meets pr.

25:46

Um, this, you know, sort of stays where it is for the next,

25:49

uh, couple of time points.

25:50

And then we start to see disease grow and take off

25:53

and unfortunately hit the progressive disease.

25:57

So you can see that if you compared like this sum

26:00

of diameters to the baseline,

26:03

this is actually gonna look like a partial response, right?

26:06

But that would be incorrect

26:07

'cause you have to compare this to

26:09

where disease looked best.

26:10

And so, you know, disease improved

26:12

and then it started to, um, take off.

26:14

And then you do that calculation here.

26:17

So that's why you compare to the Nader.

26:19

Um, and here's like a pictorial example of that

26:22

where we have baseline, you know,

26:23

this large left lung lesion, which, uh, decreases in size

26:27

but then starts to progress by week 54.

26:32

So this is, you know, kind of, uh, you know,

26:36

what are the applications of these results

26:39

and what do we do with this res resus 1.1 categorization

26:43

and information that we get.

26:45

Um, so a lot of, uh, a lot

26:48

of the time we categorize objective responders

26:51

as patients who've resulted in a CR

26:53

or IPR, um, complete response or partial response,

26:56

and we put people in the stable disease

26:59

and progressive disease as non-responders.

27:02

Um, and so patients who progress, we can use this

27:05

to determine progression-free survival

27:07

or time to progression.

27:09

And for patients in the, um, you know, objective responders,

27:13

we can calculate overall response rates.

27:16

Um, so here's some examples of this.

27:18

Here's a time to progression.

27:20

You can see baseline, we've got, you know,

27:22

a significant improvement.

27:23

We meet pr and then we're at PR

27:27

until this like 54 week time point

27:30

where we've got this increase in, um, the sum

27:33

of diameters from the Nader.

27:34

So this is how we would calculate the time

27:37

to progression being 54 weeks from the time of like,

27:40

you know, improvement to the time

27:42

of the first documented progression.

27:46

Duration of response would be once we hit, uh, the PR

27:49

category, it's how long you stay there,

27:51

which we hope is either indefinite or ends in a cr.

27:54

But you know, in this case, unfortunately,

27:56

patient progressed again.

27:58

And so this is the same, the same case,

28:00

but the duration of response is this calculation here from

28:04

when the first time that we hit PR

28:06

to the first documented, um, pd.

28:12

So limitations of resist.

28:13

Uh, like I said, this can be really tricky if you don't

28:16

have targets, right?

28:18

If you're, if the majority

28:19

of your disease is non-measurable.

28:21

So things like ovarian cancer, um,

28:23

primary peritoneal disease, um, you know,

28:26

you may not have things that are easily trackable.

28:29

Um, other things like

28:31

that have poor measurement reproducibility.

28:33

So mesothelioma doesn't really grow in a

28:37

spherical mass like fashion.

28:39

It kind of grows in a rind, um, a rined morphology.

28:43

So we have different ways to measure that.

28:45

A modified, uh, system that we use,

28:48

masses that persist after therapy.

28:50

So we see this all the time with lymphoma, right?

28:53

Um, we can have lymph, no masses that we see by pet, uh,

28:57

undergo a complete metabolic response,

28:59

but we still have residual tissue there, right?

29:02

So, um, if you are just looking at size

29:05

and you're not really looking at the metabolic activity

29:08

of lymphoma, you may not be capturing like, you know,

29:11

your response as as accurately.

29:14

Um, so sometimes it's certain types

29:17

of disease like the three we just talked about,

29:19

but sometimes it's also the therapy.

29:21

Um, traditional chemotherapies are cytotoxic

29:25

and they act directly to kill cells, um,

29:28

to kill cancer cells.

29:30

Um, and so those should demonstrate responses

29:33

with a decrease in size.

29:35

But some of the newer targeted therapies,

29:37

particularly like the tyrosine kinase inhibitors

29:40

that target like vgf, E-G-F-R-A-L-K,

29:45

those are more cytostatic

29:46

and they're designed to sort of, sort of shut down cellular

29:50

proliferation and they're not really acting

29:52

with like direct cell killing.

29:54

Um, and so their responses may be less pronounced

29:59

and a little bit more of like disease stabilization

30:02

and more like modest decreases in size.

30:06

Um, so if you're really just only focused on size,

30:08

you might sort of be missing, um, these other

30:13

responses if you're, if you're dealing

30:14

with cytostatic drugs.

30:16

Um, so we'll go through some examples of these.

30:19

But, um, you know, gist, uh, metastatic gist is a,

30:22

a disease known to, um, when it's treated with Gleevec

30:26

to really have changes in density that may be more, um,

30:29

noticeable or, um, sort of pronounced than changes in size.

30:35

Um, you can have intratumoral hemorrhage with certain drugs,

30:39

uh, you know, as a part of their treatment response.

30:42

And you can imagine that may not lead

30:43

to a shrink in size of a tumor.

30:45

It might actually lead to a slight, uh, increase in size.

30:49

And then as we touched on

30:50

before, cavitations of lung lesions, cavitation is, um, uh,

30:54

an important feature that we see with like bevacizumab

30:57

or Avastin treatment, um, especially in in lung lesions.

31:03

So as I mentioned, mesothelioma has a nons

31:06

spherical growth pattern.

31:08

And so like how do you measure something

31:09

that's growing in like a hollow like cylinder sort of.

31:13

Um, and so we have a modified Resus 1.1,

31:17

which we basically like, uh, pick certain levels

31:21

and we measure in a perpendicular access to the chest wall,

31:25

um, and we do it at certain places

31:27

and we try to reproduce that at each time point.

31:32

As I mentioned with cavitation,

31:33

this is a metastatic colon cancer patient, um,

31:37

who's being treated with Avastin

31:38

and at baseline has a seven millimeter nodule.

31:41

Um, you can see at the six week follow up

31:43

that the lesions actually increased in its overall diameter

31:47

to 1.5 centimeters,

31:48

but there's, you know, it's mostly containing air

31:52

and there's less of this, uh, enhancing

31:55

or, you know, solid tumor tissue there.

31:58

So if you were, um, evaluating this with recess 1.1,

32:02

you're gonna call this a PD

32:04

because this is more doubled in,

32:05

more than doubled in size when in fact this is like a really

32:08

nice response that we're seeing here.

32:12

Um, like I mentioned with, uh, gist, that's naive

32:16

to any tyrosine kin kinase inhibitor.

32:19

So Imatinib or Gleevec is sort

32:21

of the most commonly used drug here.

32:23

Density is really important

32:24

because part of the treatment response here is OID

32:27

degeneration, um, hemorrhage necrosis, sort

32:30

of liquefaction of the tumor.

32:32

Um, and so what we notice with these lesions are is

32:36

that they dramatically drop in density.

32:38

Um, they might actually appear larger

32:41

or easier to see, um, especially in the liver.

32:44

And so you really wanna be careful

32:46

that you're not misinterpreting those changes

32:49

for progressive disease.

32:50

Um, you can use PET ct, uh, FDG PET CT in cases where it's,

32:55

you know, not really clear,

32:56

but treated lesions should really be NFDG negative if

32:59

they're, you know, filled with all of this, uh, material

33:02

and not enhancing tumor.

33:05

So here's some, uh, examples of this.

33:07

This is metastatic just to the liver, oops, sorry.

33:11

Where you can see we have, um,

33:13

this lesion in the right low measuring 2.8 centimeters

33:17

and then the left lo measuring 1.7 centimeters on baseline,

33:20

so a sum of diameters of 4.5 centimeters.

33:23

Um, on follow-up you can see that this is increased

33:26

to three nine and two nine here, um, which would be,

33:30

you know, a 6.8 centimeters sum of diameters.

33:32

And so this is gonna be a 50% increase, which would classify

33:37

as a progressive disease.

33:38

But if you look more closely, the density

33:41

of these lesions are, you know, sort of slightly hypo dense

33:45

or hypo enhancing to background liver on the baseline.

33:48

And then when you look on the follow-up, the,

33:50

the density is really dropped here.

33:52

We definitely have like a significant fluid component

33:55

and there is still some enhancing tumor here,

33:58

but the amount of tumor tissue compared

34:00

to baseline has decreased.

34:01

You can sort of see the same thing going on in

34:03

this lesion in the left lobe.

34:04

There's now like a significant

34:06

component of it that's not tumor.

34:08

Um, and these also have intratumoral hemorrhage

34:11

and so you sort of don't know is what I'm seeing blood

34:14

or tumor or OID degeneration.

34:16

So here's um, MR post contrast of, uh,

34:21

of these, of this patient.

34:23

Um, this size is pre and post contrast.

34:25

And so you can see that this is T one hyperintense material

34:27

in here, probably blood

34:29

or pro nastious material, um, um, which is not enhancing.

34:32

So in fact, this is really an excellent response to therapy.

34:36

So you can see where reist like doesn't really cut it

34:39

for assessing or capturing response

34:42

of these drugs in these particular malignancies.

34:47

Um, so in response to that, there's been development

34:50

of the choi and modified CHO criteria.

34:53

Um, it's not really the topic for today's,

34:55

so I'm not gonna dive too much into it,

34:57

but I just wanted to make you guys aware of it.

34:59

But you can see it uses a similar response, um, as, uh,

35:03

categories of CRPR, uh, SD and pd.

35:07

Um, and there is some certain, you know, overlap

35:09

of like a CRS disappearance

35:11

of all lesions with no new lesions.

35:13

But, um, there's sort of different thresholds

35:16

for the changes in size.

35:18

And there's also this allowance for decreases in, um,

35:21

in tumor attenuation, um, measured in hounde units.

35:25

So you really need CT for these.

35:27

Um, they also have some clinical criteria

35:31

as well incorporated.

35:32

But, um, yeah, one, one thing you also wanna look out

35:37

for in these is these can develop intratumoral nodules.

35:41

Um, you know, they can develop or increase in size.

35:44

And so you can imagine if the overall size

35:46

of the lesion isn't changing, you could sort

35:49

of miss a progression if you're not

35:50

looking for these nodules.

35:53

These are more tied to changes in character

35:55

of the tumor rather than just size.

35:57

So, um, here's an example of this.

35:59

This is like a post-treatment metastatic gist to liver,

36:02

and you can see these like very low density cystic looking,

36:07

um, lesions, which are, you know, just treated disease.

36:10

And then on follow-up you can see the development

36:12

of these little intratumoral nodules

36:14

that the arrows are pointing at.

36:16

Um, and then at a subsequent time point they've like

36:19

significantly increased.

36:20

Um, and we've confirmed with pet CT over here

36:23

that these are in fact active and viable tumor.

36:26

So, um, you know, Reeses really focuses heavily on size,

36:31

but size isn't always the whole story.

36:34

So this is a really, I think, an important concept

36:37

to integrate at the workstation, right?

36:39

Um, we can all sit there and look at, at lesions

36:42

and say, you know, same, bigger, smaller, no significant,

36:45

you know, changes or whatever,

36:47

but you really have to go beyond that

36:48

and also look at the character of, of the lesions

36:52

and you know, especially when you're dealing

36:54

with certain histologies and,

36:56

and certain drugs that are being used.

37:00

Here's another example.

37:01

This is metastatic renal cell carcinoma.

37:03

This patient's on sorafenib, um,

37:06

which is a tyrosine kinase inhibitor.

37:07

A little clue is anything

37:08

that ends in an IB is probably a tyrosine kinase

37:11

or kinase inhibitor.

37:12

And one of these like targeted, um, psychos static drugs.

37:17

Uh, but on first glance you see on your baseline we've got

37:21

some, you know, nasty looking hypo enhancing lesions

37:24

with a hyper enhancing rim.

37:27

Um, you can see several of these

37:29

and then on follow up, I think, you know,

37:31

your first instinct might say like, wow,

37:33

there's so many more lesions.

37:35

This is, this is progression, right?

37:37

But when you actually look at the character

37:39

of these lesions, you know, this dominant one here in the

37:41

left lobe, we've lost our hyper enhancing rim.

37:44

The density's really decreased.

37:45

There is still like an internal septation,

37:47

but there's not that same enhancing, um,

37:50

hypo enhancing tumor in there.

37:53

Um, and then, you know, we sort of see same story going on

37:56

with this other segment four lesion.

37:58

And you know, this one here on the

38:00

right that's partially visualized.

38:01

And then when you look at these ones along the periphery

38:04

of the right lobe, when you, in, in retrospect, you can see

38:07

that these are actually here,

38:08

but they're just sort of iso to slightly hyper

38:11

to slightly hypo enhancing on the baseline.

38:14

And so you are appreciating and seeing more lesions.

38:18

But the reason for that is because the density has dropped.

38:20

And so this is actually a response in

38:23

previously occult lesions.

38:25

So this is another, you know, thing to just be aware of,

38:28

especially at the workstation is, you know,

38:31

are you actually seeing new lesions

38:33

or are is this response in lesions

38:35

that were difficult to see before?

38:40

So again, this is that table I showed you

38:42

before with the various assessment, um, response criteria

38:46

and mass is one that's used in renal cell carcinoma

38:49

and it doesn't use the same categories as the rest of them.

38:52

It has more of like a favorable response, uh,

38:55

an intermediate response

38:56

and an unfavorable response with, you know,

38:59

different thresholds, uh, for size,

39:01

but it also accounts for decreased attenuation.

39:04

So just another one to sort of be on the radar.

39:08

Another class of drugs that we, um,

39:10

are using in clinical trials

39:12

and in clinical practice are immune checkpoint, respo, uh,

39:15

immune checkpoint inhibitors.

39:17

Um, and these have really, um, sort of different, uh,

39:22

and can be very atypical response patterns, um,

39:25

particularly early in the course of treatment.

39:28

Um, and so we've created, you know,

39:30

a separate response criteria to address tumors

39:33

that are treated with these drugs.

39:34

And so you can see there's different thresholds for the, um,

39:37

changes in size.

39:39

These are done in bi-directional measurements.

39:41

And the real key differentiation here is that we require,

39:46

um, that response can mimic pd

39:49

that's called pseudoprogression.

39:50

I'll show you some examples of this in a minute.

39:53

Um, and that we need reassessment on scans

39:55

that are at least four weeks apart to really sort

39:57

of be certain about what we're seeing.

40:00

So I'll show you just quickly, there's four patterns

40:03

that we've observed with immune

40:04

checkpoint re um, inhibitors.

40:06

And you know, one is what we expect to see with, you know,

40:09

most other drugs is a decrease in size

40:12

or, um, you know, a resolution of a finding.

40:15

So this chest wall lesion in a malignant melanoma has, um,

40:20

you know, certainly decreased in size here over time.

40:23

Uh, another pattern we can see is long periods

40:26

of just basically stabilization.

40:29

Sometimes this is followed by, uh,

40:31

an eventual decline in the term tumor burden.

40:34

Um, this is another metastatic melanoma case.

40:39

Um, and then, uh, patterns three

40:41

and four are ones showing pseudoprogression.

40:43

So here you can see at again, metastatic melanoma.

40:47

We've got this axillary lymph node,

40:48

which at the first time point

40:50

significantly increases in size.

40:51

This is like more than doubled.

40:53

This is probably four times its original size.

40:56

Um, I don't know if you can appreciate here,

40:58

there's a little bit of a drop in density

40:59

and a slight decrease in size at time 0.3.

41:02

And then we have like kind

41:04

of a dramatic decrease in size shrinkage to almost,

41:07

you know, near complete response by time 0.6.

41:11

Um, and so what this is is a delayed tumor response, right?

41:15

We have a known site of disease

41:17

that gets worse before it gets better.

41:20

Um, this is thought to reflect like there's,

41:23

there's two things that we believe this represents.

41:27

So number one is that it takes time

41:29

to train the immune system, um,

41:31

to fight these particular malignancies

41:34

using these particular drugs.

41:36

And so there is actually true growth that occurs

41:39

before the immune killing sort of kicks in

41:41

and takes care of disease.

41:43

The other thing is when you have immune infiltration

41:45

of sites of disease, you can have some edema

41:47

and some swelling that will make lesions, you know,

41:49

get a little bit bigger and look worse

41:51

before they, um, start to improve and, and respond.

41:54

We have biopsies showing both of these scenarios.

41:58

Um, so here's another one.

42:00

This is again, metastatic melanoma to the ally.

42:02

You can see it definitely gets worse.

42:04

We've got a drop in density, which doesn't always happen,

42:06

but in this case it does.

42:08

And then we've got an eventual decline in the size.

42:13

Uh, this is a really interesting case.

42:14

So we've got metastatic melanoma to the muscles

42:17

and soft tissues of the lower extremities on both sides.

42:20

Um, and you can see at time 0.1,

42:22

we definitely have an increase in, you know,

42:24

abnormal tissue in, on both sides,

42:26

but dramatically so on the right.

42:28

So by recess you're gonna call this, um, progression even

42:33

by choi criteria or mass criteria.

42:35

This has not demonstrated a significant decrease in density.

42:39

In fact, areas are looking more dense and more enhancing.

42:41

So you're gonna call progression here as well,

42:44

um, with those criteria.

42:45

And then we can see at time 0.3 everything is gone,

42:48

which is just sort of incredible.

42:50

Um, so that's why sort of the extra time points, um,

42:55

especially early on in treatment are required

42:57

to really determine what sort of response is happening.

43:01

Here's another one of Hodgkin lymphoma.

43:03

You can see there's quite a bit of disease at baseline.

43:05

I'll draw your attention to this dominant mesenteric mass,

43:08

which, um, you know, over time points two

43:11

and three continues to get bigger.

43:13

Um, we've got some sort

43:14

of mixed response going on in the chest.

43:16

Some of these lesions are looking a little bit better.

43:19

Um, but by, you know, time 0.4

43:21

and time 0.5, we've got like a complete response.

43:24

Um, so this can be really, really tricky.

43:27

Pseudoprogression, I don't want you

43:28

to walk away thinking this is like the most common thing

43:30

that we see, but it's um, it's documented in like, you know,

43:34

three to 10% of cases.

43:36

So most of the time when you see progression,

43:38

it's gonna be true progression,

43:39

but if you're in the first like 12 to 15 weeks of treatment,

43:42

you really should consider pseudoprogression as well.

43:45

This is just a graphical representation of the two, um,

43:48

things we talked about, actual tumor growth before response

43:52

and you know, just immune infiltration

43:53

and swelling before response.

43:56

Um, the fourth and final pattern is where we see

43:58

what we think is new disease.

44:00

And this is really just pseudoprogression in

44:02

previous like micro metastases that just we weren't able

44:06

to visualize yet, but it's the same sort of scenario.

44:09

Here's some more examples of, um, pseudoprogression.

44:12

So we can see normal looking bone.

44:14

Here we are very early week eight, uh,

44:17

we see a new lytic lesion, which then by week 17 has healed.

44:21

Um, we see no lymphadenopathy here,

44:24

new lymphadenopathy in the pelvis,

44:25

and then an improvement, um, normal looking bone mixed, uh,

44:30

or mostly lytic, you know, nasty looking disease here,

44:34

which then eventually heals.

44:35

So the pseudoprogression is really something to be aware

44:38

of early on in treatment.

44:40

So again, the response pattern that we use to determine, um,

44:45

you know, if a drug is working

44:47

or if disease is progressing depends on both what kind

44:51

of disease it is, but also what kind of drugs we're using.

44:54

So those are things I like

44:55

to know when I'm reading cancer cases, you know,

44:57

what's the histology, what drug are they on,

44:59

and how long they've been on it

45:01

because it can sort of tell you which principles should we

45:03

be using to assess response

45:05

and what sort of atypical pattern should we be expecting.

45:09

Um, this is a really great resource.

45:11

This is like one of my homepage

45:12

that I use the National Cancer Institute,

45:15

um, drug dictionary.

45:16

You can like search any drug

45:18

'cause it's impossible to memorize all of them.

45:20

Um, and it will tell you like a very sort of succinct, um,

45:24

you know, mechanism of action that can clue you into,

45:27

you know, what, what type of drug

45:29

and what category it falls in, which will help you determine

45:31

what kind of response you're looking for.

45:34

Here are my references and I'm happy to take any questions.

45:38

Um, I know this was a very dense topic, so, uh,

45:41

appreciate all of your attention and interest.

45:47

Well thank you so much Dr.

45:48

Macintosh for that awesome lecture.

45:52

We will open the floor for some questions,

45:54

so if you've got them, go ahead

45:56

and stick that in the q and a box.

46:00

Oh, let's see, q and a, sorry.

46:02

No worries. Role of

46:04

and brain tumors post radiosurgery response.

46:07

So yeah, sorry, I did not mention this,

46:09

but, um, we have different response criteria for,

46:12

for neuro-oncology.

46:14

So recess isn't really used uh, for, for brain tumors.

46:18

This is mostly recess is used for solid tumors, um,

46:21

and mostly sort of in the, in the body.

46:24

Um, you know, outside of neuro

46:29

are you able to change target lesions and recess criteria?

46:33

Say post-treatment, there is new disease for follow-up.

46:36

So no recess is really inflexible.

46:38

Um, which is why it's very important

46:40

to get the baseline right.

46:42

Um, you aren't able to change targets, you sort

46:45

of have to follow them forever.

46:47

Um, and that's why you also wanna make sure

46:49

that you're catching all disease

46:51

and using them as um, you know, either targets

46:55

or non-arts because you wanna be able to follow what happens

46:59

and track what happens with the non-arts.

47:01

And then any new disease,

47:03

of course you give it a categorization of like new lesion,

47:06

that's sort of like a third category.

47:10

Alright, when target lesions decrease

47:12

or are completely gone,

47:14

but non-target lesions appear,

47:17

is it considered a progression?

47:19

So anything that appears would not be a non-target,

47:23

that would be considered a new lesion.

47:25

And yes, that would be progression.

47:27

Anytime there's new, um, disease is progression.

47:32

Let's see, for lymph node measurement,

47:33

do you measure the short axis

47:35

or the long axis to determine the sum of diameters?

47:39

Um, so for lymph nodes, you uh, you measure

47:42

and report the short axis, um,

47:44

and that's what gets calculated in your sum of diameters.

47:49

Alright, looks like it takes familiarity

47:51

and experience to get used to how each

47:53

and every tumor behaves and respond.

47:55

Do you have a table for patterns based on your personal case

47:58

experience to make it easy to remember

48:00

and categorize new patient cases?

48:03

Um, you're absolutely right.

48:05

Um, it does take lots of familiarity

48:08

and experience and practice.

48:10

Um, you know,

48:12

and I would say it's actually even more important in

48:14

clinical practice than it is.

48:15

Um, you know, in the clinical trials they basically tell you

48:18

what to use, um,

48:20

and you know, that's determined

48:21

by whoever's designing the clinical trial.

48:23

And so, um,

48:24

sometimes they actually have you use more than one response

48:27

criteria and you're sort of doing different measurements

48:29

because they're not sure which one is gonna categorize it,

48:32

um, categorize it best.

48:35

But, um, yeah, I sort of, I just think about what,

48:40

what disease looks like, um, how it grows,

48:44

how it responds, um,

48:46

and that might be different based on which type of,

48:49

you know, drug is being used to treat it.

48:52

So I don't,

48:53

but that would be a really good idea for a publication

48:55

to sort of, um, try to categorize those and,

48:59

and figure out, you know, a workflow

49:02

or an algorithm of like what to be thinking about

49:04

with different cancers and different drugs.

49:07

Thanks for the idea.

49:10

Um, is there any problem if I do like a pseudo reist,

49:15

sometimes we don't have the first study of the patient

49:17

to check the target lesions.

49:19

How can we report that?

49:21

So reist is like a formal reist read is only really

49:26

required in the setting of a clinical trial where you would,

49:29

you would have to have all of those things.

49:31

Um, sometimes trials give like an allowance

49:34

for like if a baseline is missing then you know,

49:36

this is exactly how you would document it.

49:39

Um, but in clinical practice, if you don't have a baseline,

49:44

I mean there's not really much you can do.

49:46

Uh, you can only see what you say or, or say

49:50

or talk about what you see.

49:52

Um, and so you can certainly compare subsequent studies

49:56

to the earliest one that you have available.

49:58

But, um, I wouldn't,

50:00

I wouldn't be doing anything formal about like

50:02

targets or non-arts.

50:03

It's just sort of like a clinical read would be very,

50:07

you know, you can certainly measure things

50:08

and talk about things, but I wouldn't be giving like a,

50:11

a formal recess report on that.

50:12

I would just sort of be like your usual clinical report.

50:16

Okay. Um, cervical chain nodes are also short axis.

50:21

Um, yes, the nodes are measured the

50:23

same no matter where they are.

50:24

And like I said, it's important to remember that the, um,

50:28

lymph nodes are globally one organ

50:30

and so you can only choose two of those

50:32

with reist if you have a lymph node predominant

50:35

disease like lymphoma.

50:37

We don't use reist in, in lymphoma at all.

50:39

We have a separate one called Luo, um,

50:42

which is very pet heavy,

50:43

but there is like, you know, CT only criteria as well

50:46

and those are actually measured in long and short axis

50:49

and we use both of those in a calculation

50:52

of a sum of diameters.

50:53

So lymphoma is a totally different story.

50:57

Alright, how would you differentiate

50:58

and report a visually new lesion

51:00

that's pseudoprogression versus true progression?

51:03

So, um, in trials you basically would report it

51:07

as a new lesion, but you can flag it as something

51:10

that you think is pseudoprogression

51:11

and you can sort of look at the subsequent time point

51:14

and you know, you might need that subsequent, you need

51:16

that subsequent time point to determine if it's progression,

51:20

uh, versus pseudoprogression for a clinical read.

51:23

Um, I will, you know, an example of a read

51:26

that I would give is I would say there's slight in,

51:29

you know, there's increase in size

51:30

of the right liver lesion.

51:33

Um, you know, given the

51:36

short time intervals since initiation of treatment,

51:39

this could represent progression versus pseudoprogression

51:43

recommend a follow-up exam in no less than four weeks.

51:47

That's sort of how I would phrase it, is that you have

51:49

to list both in the differential if you, you know,

51:52

if both are in the differential

51:53

and then request a subsequent time point.

51:55

And then that's sort of where you,

51:57

you the pseudoprogression versus true progression is always

52:00

something that's made in retrospect.

52:01

You can't tell at the time point times

52:03

that I think more about pseudoprogression are when I see a

52:07

mixed response if, if you know, something's getting worse,

52:10

but then I also see things that are getting better that sort

52:12

of makes me think more about

52:14

pseudoprogression than true progression.

52:17

Um, when the size of the lesion increases,

52:20

how can we suggest pseudoprogression

52:22

rather than progression?

52:23

Oh God, I just answered that one.

52:25

Um, you can't always, a lot of times you have

52:27

to give both in the differential,

52:28

but again, if there's a mixed response, it, you know,

52:31

might make me lean one way a little bit more than another.

52:34

All right. PD assessed based on Nader,

52:37

but what if we do not have the Nader any surrogate?

52:40

Basically you have to just work with what you have

52:42

and you figure out, you know,

52:44

however long the patient's been on this particular drug

52:46

or treatment regimen, what is the time point

52:48

where their disease look best?

52:50

And then you have to sort of base it on that.

52:54

Is there an automated program

52:55

for calculating status in reus 1.1?

52:59

Um, there are, and actually quite a few PAC systems, um,

53:03

have, uh, you know, programs built right in to be able

53:06

to do this, you just have to sort of like,

53:08

you do the measurements and the um, the numbers get imported

53:11

and also the calculations of the changes.

53:14

Um, and most of the clinical trial, uh,

53:18

like there are programs like Mint is one, um, that's used.

53:22

Biore is another that, um, you basically do the measurements

53:27

and they get, uh, automatically inputted

53:29

and managed, um, like that.

53:31

So yeah, there is automation,

53:32

which makes things a lot easier.

53:35

Alright, new brain metastasis is always pd.

53:39

Yes, any new site of disease

53:40

and, um, sometimes that happens where, you know,

53:44

a trial may only have chest, abdomen, pelvis imaging

53:47

and then suddenly at a time point you get a brain Mr thrown

53:51

in there that has like a new lesion, especially

53:53

with something like lung cancer.

53:55

And that would trigger a pd even if it's like you can sort

53:58

of assume that it's a new lesion even if you don't have, um,

54:02

priors based on, you know, clinical presentation

54:04

or, or whatever.

54:07

Um, okay. Do you use Resus in breast cancer?

54:11

So yes.

54:13

Resus can be used in, um, in, in metastatic breast cancer

54:16

that requires chemotherapy.

54:18

Um, we're starting to see, you know,

54:20

there's like different drugs

54:21

that are being used in breast cancer

54:22

and even those immune checkpoint inhibitors are being used.

54:25

So it, it does also depend on the particular drug.

54:28

But yes, you can use Resus 1.1 in breast cancer. Okay.

54:33

I've had cases where pseudoprogression progress for one

54:36

to three years, would these lesions be called

54:39

pseudoprogression versus progression for the one

54:41

to three years of scans?

54:43

So probably not at that point.

54:45

I really think about pseudoprogression in the first

54:47

12 to 15 weeks.

54:49

It has been documented out to like, you know,

54:51

40 or 50 weeks.

54:53

Um, but I think that's really the

54:54

exception rather than the rule.

54:56

Um, if something is progressing at one to three years,

55:00

it's probably true progression

55:02

because the disease has either mutated

55:04

or for whatever reason is not

55:05

responding to the drug anymore.

55:07

So at that time point, I think it would be safe to,

55:10

you know, definitely call that true progression.

55:13

What is a Nader?

55:15

So a nader is just the word that we use

55:17

to describe the time point where disease looks the best

55:21

or has the greatest response.

55:23

Um, and so that might be the first time point

55:27

or it might take several time points to get there.

55:29

Um, if you have progression right away, uh,

55:31

like at your first time point,

55:32

then you don't really have a Nader

55:34

because you just have your baseline.

55:37

Alright. Non-target bone lesions, any new is pd? Yes.

55:42

Any new lesion, um, is pd, no, nothing

55:46

that's new is gonna be classified

55:48

as a target or a non-target.

55:49

It's just simply going to be called a new lesion.

55:55

You got 'em all? Alright,

55:58

that was excellent. Thank

56:01

You guys. And those are some

56:02

really great questions.

56:03

There's always interest in pseudoprogression

56:06

and sort of how to, how to parse that out.

56:10

It's, um, it's a, a really tricky thing, right?

56:12

Because it looks exactly like progression

56:14

and it, it feels funny to put in your differential.

56:16

Like this could be pseudoprogression, which is a response,

56:20

you know, gonna eventually be a response

56:21

or this could be progression.

56:23

And so it's like they're sort of opposites

56:24

and it, it feels funny to put those in your differential,

56:27

but, um, with these drugs they just, they can be very

56:31

challenging and, uh, have unexpected, you know,

56:35

response patterns that um, you just really need more time

56:38

to figure out what's going on.

56:40

Oh, a couple more questions came in.

56:42

Oh, if you wanna go for it. Yeah.

56:45

If we have a target lesion

56:46

with cavitation in follow-up study,

56:48

should we still measure it in the long axis,

56:50

include it in the sum of diameters,

56:51

and just additionally report the change of morphology.

56:54

So yes, in a 1.1 formal read in a clinical trial,

56:59

you would still measure it.

57:01

Um, and you can certainly leave comments, um,

57:05

about the change in morphology.

57:07

In a clinical read, I would like absolutely lead

57:10

with the change in morphology

57:12

and I would, in my impression call it a response,

57:15

even if the size is unchanged

57:17

or even slightly bigger, uh, in a patient with lung cancer

57:21

and brain metastases on the baseline exam, non-target,

57:25

which disappeared by the second

57:27

and third follow-up, will the reappearance

57:30

of the brain lesion by the fourth be classified

57:32

as pd if target lesions are pr?

57:35

So this can be trial specific.

57:37

Um, if you feel

57:39

that the lesion has like fully disappeared,

57:43

you can't detect it on, you know, any, any part

57:47

of your imaging, then you know,

57:49

the reappearance would be considered, like it would be,

57:52

you would have to document it as a new lesion

57:54

because once you've documented a target lesion as resolving,

57:58

um, you can't really resurrect it or bring it back.

58:00

So it would have to be classified as new lesions.

58:04

Um, sometimes for like pet studies, uh, pet clinical trials,

58:09

if you have something that like the metabolic

58:12

avidity resolves,

58:14

but then it that comes back, that's more likely

58:17

to be classified as like a, a local recurrence of a target.

58:21

Um, and,

58:22

and not like a new lesion, it's just that, you know,

58:25

the avidity got so low that we weren't really able

58:27

to appreciate it, um, you know,

58:29

with micrometastatic disease or whatever.

58:31

So it's kind of trial specific.

58:34

Um, and it could, it could go either way,

58:37

but if you have cleared a target

58:39

or even non-target lesion, if you've said

58:41

that it's completely resolved

58:42

and you truly believe that, then

58:45

that would be considered new disease.

58:49

Let's see. Do you have any experience

58:51

of post radiosurgery changes on CT in hepatocellular cancer?

58:56

Like change in enhancement patterns?

58:58

Yeah, that's a little bit outside of the scope

59:00

of this lecture,

59:01

but um, yes, you can certainly have like, you know,

59:06

changes in the enhancement patterns

59:08

of hepatocellular carcinomas after radiation

59:11

and changes of like the surrounding parenchyma

59:13

and changes that do suggest recurrence.

59:16

Um, particularly like, you know, new

59:18

or increasing areas of, um, nodular

59:21

or peripheral enhancement like at the, at the margins

59:24

of the lesion or the treatment field.

59:27

Alright. Can you repeat the time you use to guide yourself,

59:31

uh, to think it might be pseudoprogression versus

59:34

progression since the SAR of treatment?

59:35

Yeah, it's usually in the first 12 to 15 weeks is

59:38

where pseudoprogression is most commonly seen.

59:42

Um, you know, if we were at like 16 or 17 weeks

59:45

and the patient's like,

59:47

and another part of progression in pseudoprogression is also

59:49

how is the patient doing?

59:51

Um, sometimes we have oncologists come in

59:53

and they say like, man, this, this study was read

59:56

as like worsening, but the patient's doing great.

59:58

They feel awesome. You know, that might sort of also that

60:03

that can sort of help figure out, okay,

60:05

should they stay the course, should they keep doing the

60:07

treatment and you know, re-image

60:08

and, you know, give them the benefit of the doubt

60:10

that this could be pseudoprogression.

60:12

If that's the case at like, you know, 16, 17 weeks,

60:14

I'll still certainly consider that it's not like a hard

60:17

and fast at 12 to 15,

60:18

but that's sort

60:19

of the most common time period in which this occurs.

60:24

Um, can we consider the volume

60:25

of a lesion rather than the short axis?

60:27

So yeah, a lot.

60:28

There's actually like, you know, many people that feel

60:31

that volume of lesions is uh, superior to, um, you know,

60:36

looking at unidimensional

60:37

or bi dimensional measurements, um, that it's more,

60:41

you know, able to capture changes a little bit better.

60:44

Um, that's not what's used in Resus 1.1.

60:47

And a big part of that I think is just

60:49

because what, what is available to us

60:51

as radiologists, right?

60:53

Not everybody has like vol volume tree available to them.

60:57

And we can also see differences across platforms, you know,

61:00

between volume tree,

61:01

but again, like, you know, by dimensional, uh,

61:05

or manual measurements are certainly not, uh,

61:08

always reproducible.

61:09

We have inter observer and inter observer variability.

61:12

So, um, no system is perfect.

61:15

Some people do really like volume

61:17

and there are some assessment criteria

61:18

that use tumor volumes,

61:19

but for resis 1.1, it's really just, uh, a manual

61:25

single dimension measurement.

61:29

Okay. I think that was all of 'em. I

61:31

Think, I think you got it all.

61:34

Thank you so much.

61:36

Yeah, thank you guys. Thanks for your attention.

61:38

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61:40

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61:44

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