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Imaging Response Criteria Training for PCWG-Modified

RECIST 1.1

Transcript

1. Introduction

Notes:

Hello, and welcome to this training on PCWG-Modified RECIST 1.1., the response criteria we use in our

prostate cancer clinical trials. My name is Greg Goldmacher. I am head of Clinical Imaging for Merck

Research Laboratories.


1.2 Why this Course?

Notes:

So, why are you taking this course? Well, the Prostate Cancer Working Group, or PCWG response criteria

version 3, was published in February 2016, and the bone scan rules from that publication have been

incorporated into our prostate cancer clinical trials. Therefore, if you are involved in one of our prostate

cancer clinical trials, you need to understand these rules.

Now, these rules sit on top of or are a modification of RECIST 1.1, the response evaluation criteria in solid

tumors. We’ll have a brief review of RECIST 1.1 as part of this course, but you really need to have a

thorough working knowledge of RECIST 1.1. So, if you need a refresher on RECIST 1.1 first, please go and

study the appropriate materials, and then come back and pick it up here.


1.3 Learning Objectives

Notes:

At the end of this course, you should be able to explain how the process of PCWG-Modified RECIST 1.1

assessment works, you should be able to describe the response categories for bone lesions and some of

the critical concepts associated with that response assessment, and you should know how to put the soft

tissue assessment and the bone lesion assessment together to produce an overall response for each visit.


1.4 Outline

Notes:

So, here’s what we’re going to talk about. First, we’ll go through the assessment of response and soft tissue,

which you’ll notice looks a whole lot like RECIST 1.1. We’ll then talk about how to assess response in bone

and go through some examples and exercises for bone response assessment, and then we’ll talk about how

to put the soft tissue assessment and the bone lesion response assessment together to give you an overall

response for each assessment.


1.5 Overall Response Assessment

Notes:

So first a big picture overview. The response assessment overall is a combination of soft tissue assessment

per RECIST 1.1 and the bone lesion response assessment using the rules of PCWG. And together those

combine to produce what we are calling PCWG-Modified RECIST 1.1.


1.6 Two Lesion Assessments

Notes:

So the soft tissue’s assessment will basically look just like RECIST 1.1. You will follow target and non-target

lesions and look for new soft tissue lesions to produce an overall soft tissue response.

Bone lesions in these trials will not be followed by RECIST 1.1. They will be assessed only on the bone scan

and will be recorded only as bone lesions. And the case reports forms will allow you to differentiate between

soft tissue lesions and bone lesions. As you will see, the assessments are purely qualitative, so there are no

measurements of bone lesions.


2. Soft Tissue Response: RECIST 1.1

Notes:

Let’s start with a review of soft tissue response assessment, which is basically RECIST 1.1.


2.2 Baseline – Soft Tissue Target Lesions

Notes:

So, we start off at baseline by identifying all the malignant lesions in the soft tissue. Then those lesions are

classified into those that are measurable and non-measurable.

To be measurable, a non-nodal lesion has to be at least 10 mm in longest diameter and the lymph node has

to be at least 15 mm in short axis. In addition, remember that a good measurable lesion has to have

reproducible measurements. From among the measurable lesions, we then select the target lesions.

Measurable lesions are what we can measure, target lesions are what we actually do measure. You can

select up to 10 target lesions total, up to five per organ. The published version of RECIST 1.1 says up to five

total, but we allow a broader sampling in our trials. Remember the paired organs, such as the lungs, are

considered one organ, and all lymph nodes, collectively, are considered one organ.

And then of course all lesions that are not selected as target, whether they are measurable or non-

measurable, are followed qualitatively as non-target. Remember that once a lesion is selected as target, it is

always target for the remainder of the trial, and once non-target, always non-target.


2.3 Baseline - Document Soft Tissue Non-Target Lesions

Notes:

Non-target lesions are everything else that you are sure is a tumor but that you did not select as a target.

That means all non-measurable lesions in soft tissue including lesions which are too small or those that do

not lend themselves well to reproducible measurements, such as those that are poorly bordered or spread

along surfaces or are in locations that can move, especially those relative to the slice plane. Fluid collections,

such as ascites, if they are known to be malignant, can also be followed as non-target lesions. We ask that

all brain lesions are followed as non-target and of course all measurable lesions aside from those you chose

as target lesions.

Now for the PCWG-Modified RECIST criteria, lesions in the bone, even if they have a soft tissue component,

are not followed by RECIST 1.1 rules, and are followed only by PCWG and only by bone scan. Of course,

bone lesions from prostate cancer are typically sclerotic and typically do not have soft tissue components.

To make documenting all disease at baseline not too labor intensive, you can document multiple non-target

lesions in a single organ as a single entry in the case report form. So, for example, if there are numerous

small lung nodules, that can be one non-target lesion.


2.4 Calculation of Soft Tissue Response

Notes:

Now on to response.

For soft tissue target lesions, you find them, measure them, add up the diameters, and then compare the

sum of diameters to baseline and nadir to classify the target response.

Non-target lesions are assessed collectively as either all gone (CR), still there (Non-CR / Non-PD), or

showing dramatic worsening such that even if the target lesions were responding, you would still say the

treatment has failed. That is unequivocal progression or PD for non-target lesions.

And then for new lesions, either they are definitely present (Yes) or you are uncertain, or they are not

present. If you are uncertain, if a new lesion is so small you are unsure if it’s really there, you follow it out

and if it becomes unequivocal later on, you can retrospectively go back and call the new lesion at the time it

was first seen.

Once we have assessed all three of these components, we combine them into an overall soft tissue

response for a visit.


2.5 Soft Tissue Response

Notes:

So for the soft tissue response, if either the target lesions or the non-target lesions show progression, or if

there are new lesions, the overall response is PD.

The overall response is CR if all the lesions disappear.

If the target lesions disappear but the non-target lesions do not definitively disappear, the overall response is

PR.

If the target lesions show PR, SD, or NE, unless the non-target or new lesion force you to call progression,

the response if whatever the target lesions show.

Now, if there weren’t any target lesions at baseline, there is no target lesion response, it’s non-applicable,

and the response is driven entirely by the non-target lesions. So if the target lesions were not there and the

non-target lesions are still present, you can have an overall response of non-CR / non-PD.

Finally, if there weren’t any soft tissue lesions at all at baseline, that is there is neither an applicable target

lesion or non-target lesion response and there are no new lesions, we have this Overall Response category

of NED, which stands for no evidence of disease.


3. Bone Response: PCWG

Notes:

So, that was soft tissue response. Now let’s talk about response in the bone.


3.2 Bone Response Categories

Notes:

For the purpose of these criteria, the response in the bone is assessed by nuclear medicine bone scan, not

by CT or MRI. CT or MRI can be used as correlative and anatomical information to help you decide whether

a bone scan finding is really a lesion not, but the assessment really is based on the nuclear medicine bone

scan.

Now, the core assessment to be made on the bone scan whether or not it shows progressive disease, or PD.

PD is present if there are at least two new bone lesions which are not due to flare, which we will discuss

more in a moment, and are persistent. Note that enlargement of lesions that were already present at

baseline does not constitute progression. Progression assessment is really driven by new lesions. So, if

there are at least two new bone lesions not flaring and persistent, that is called PD.

If there is any bone disease present, new or existing, but the conditions for PD have not been met, that is

called non-PD, and when two new bone lesions are first observed, whether they are thought to be possibly

flared or not, that is initially called PDu, or PD unconfirmed. Based on the next bone scan, you go back and

update the PDu either to PD or to non-PD. So, you should never have PDu as the response if there is any

later bone scan available. The only time you would have a response of PDu is if that is the last available

bone scan.

We also have a bone response category of NED or no evidence of disease if there are no bone lesions on

the scan at all. That could be either if there were some present at baseline and they have completely

disappeared or if there have never been any bone lesions on the scan to start with.

Finally, if the bone scan is entirely missing or is of such poor quality it cannot be assessed, then the bone

response is NE, or non-evaluable.


3.3 What is Flare?

Notes:

Now let’s talk about this phenomenon of tumor flare. Remember that what you see on a bone scan is not

actually a tumor but bone rebuilding where a tumor has broken it down. That means that early on in the

course of effective treatment, where the tumor is dying, bone rebuilding at the site of that dying tumor can

appear as a new lesion. In reality, of course, the lesions is not new, it was present at baseline, and what

you’re seeing is actually a favorable treatment response.

So in this example, you can see on the initial bone scan there are lesions present in the spine and the ribs.

Then, early on in treatment, you can see what appear to be new lesions in the skull, the ribs, and the pelvis.

And then, with further treatment, these lesions resolve. So for the purposes of these criteria, we define the

flare window as the first 12 weeks following initiation of therapy. And any lesions that appear during this time

are regarded as being highly suspicious for flare, rather than true, new lesions.


3.4 Bone PD

Notes:

So again, progression in the bone is defined as at least two new bone lesions, which are not due to flare and

which are persistent. So, if you see at least two new bone lesions on a scan within the flare window, that is

considered PD unconfirmed. If the next bone scan outside the flare window shows at least two additional

new lesions, then that initial scan that showed the new lesions is considered progression.

However, if the next scan outside the flare window does not show at least two additional new bone lesions,

then whatever new lesions appeared during the flare window are considered equivalent to baseline lesions,

and on later scans, they are not counted when you are counting up new lesions. This is known as the 2+2

rule. You need at least two new lesions within the flare window and at least two additional new lesions on

the next scan outside the flare window to call progression within the flare window.

Now, outside the window, all you need is two new bone lesions. They do not need to appear on the same

visit, so if you had a new lesion at Week 36 and another new bone lesion at Week 48, that would be

considered PD at the time the second new bone lesion appeared, but these lesions do have to be persistent.

That is, you need to get another bone scan to make sure they don’t disappear because bon scans are prone

to various kinds of false positives. So, when the conditions for PD outside the flare window are met, you still

call that PDu initially and then at the time of the next scan you update it to either PD or non-PD.


4. Case Examples

Notes:

Let’s look at some case examples to illustrate these rules and how they are applied. In all of these examples,

we will presume a trial that has bone scans performed every nine weeks.


4.2 Example 1

Notes:

So here’s the first case showing a series of bones scans, and the dots on the scans represent new lesions.

So whatever lesions were present at baseline we’re basically ignoring, all we’re looking at are the new

lesions as shown by the dots. Is there progression in this case, and at what week does it happen? Please

pause here and think about your answer before we proceed.

The scans show two new lesions that appear at Week 18 outside the window. This is the timepoint of

progression. Of course, initially this would have been called PDu at Week 18, and then after seeing the scan

at Week 27, you would update the response at Week 18 to PD.


4.3 Example 2

Notes:

Here is case number two. Again, new lesions are represented by the dots on the bone scan. Please think

about whether there is progression and at what point it occurs. Pause at this time and think about your

answer before we continue.

Okay, so here two new lesions have appeared at Week 27, again outside the flare window. All the lesions

have appeared outside the flare window. So, again at Week 27, this would initially be called PDu, and then

once at Week 36 you see that those lesions persist, you would update Week 27 to PD.


4.4 Example 3

Notes:

Okay, here’s the third case. Again, the dots represent new lesions. Pause and think about whether there’s

progression here and at what timepoint.

Okay, so here the new lesion appears within the flare window at Week 9. Remember that any lesions that

appear during the flare window, unless they meet the 2+2 rule and are confirmed as progression within the

flare window, are regarded as flare phenomena and don’t contribute to lesion counts later. So now excluding

that lesion, one lesion appears at Week 27, and an additional new lesion at Week 36, and then those new

lesions persist, so this is progression at Week 36, where you have two new lesions that are confirmed as

persistent by the Week 48 scan.


4.5 Example 4

Notes:

Here is case number four. Again, the dots represent new lesions. Please pause at this point and think about

whether there has been PD and at what time before we proceed.

So here, two new lesions have appeared at Week 9 within the flare window. These are followed by two

additional lesions at Week 18. This is an example of the 2+2 rule being met, so progression here is

confirmed at Week 9. Again, initially would be called PDu, but then once you see the Week 18 scan,

progression is at Week 9.


4.6 Example 5

Notes:

Case number five. Again, the dots represent new lesions. Think about whether there has been progression

here, pause to come up with your answer, and then we’ll continue.

So, note that three new lesions appear at Week 9. This would be called PDu. However, there are not at least

two additional new lesions at Week 18, there is only one more new lesions. So Week 9 would be updated to

non-PD. Those three lesions would be ignored moving forward. They do not count toward the new lesions

and since there is only one new lesion that counts which is at Week 18 and persists at Week 27, the

conditions for PD are never met, so this is non-PD at every visit.


4.7 Example 6

Notes:

Case number six. Again, the dots are new lesions. Think about whether there has been progression, and, if

so, when. Pause, come up with your answer, and let’s continue.

Here we see two new lesions at Week 9, so we call that PDu. At Week 18, there are no additional new

lesions, so Week 9 is updated to non-PDu, and those two lesions do not count toward the new lesions

moving forward. Now, a new lesion appears at Week 27 and an additional new lesion at Week 36, so that

would again be called PDu, because there are now two new lesions. And then Week 48 shows those to be

persistent, so this is PD at Week 36.


4.8 Example 7

Notes:

Case number seven. Again, the dots represent new lesions. Please think about whether there has been

progression and when. Pause, come up with your answer, and then we’ll continue.

So this is a tricky case. There are two new lesions at Week 9. They would be called PDu. When we look at

Week 18, there are two other new lesions that have appeared. However, the lesions at Week 9 have

disappeared. They are not persistent so they were not new lesions. That visit would be updated to non-PD.

Now, there are two new lesions at Week 18, and this is outside the flare window, so this would be called

PDu. And then Week 27 confirms these two new lesions are persistent, and so Week 18 is the timepoint of

progression.


4.9 Example 8

Notes:

Now, this final case is something I’m showing you as an example rather than as a problem for you to solve.

It represents an unusual situation called a superscan. This happens when there are so many lesions

throughout the skeleton that they fuse together, and the bone scan can actually appear nearly normal. Here

at baseline, you can see there are numerous focal lesions. Then, at Week 9, it becomes harder to see

discrete lesions, and at Week 18, the bone uptake is a bit patchy, but could almost be mistaken for a normal

uptake patter. However, there is reduced uptake in the soft tissues, and in particular, you don’t even see

uptake in the kidneys, which should normally be seen. It takes a bit of an experienced eye to recognize this

pattern, and I hope you work closely with your colleagues in the nuclear medicine and radiology

departments, who will pick up on this. If a superscan occurs, we consider this progression and do not require

confirmation.


5. Combined Response

Notes:

So, we’ve talked about assessing response in soft tissue using RECIST 1.1 rules and in the bone using the

Prostate Cancer Working Group rules. Now, let’s put these together in the overall PCWG-Modified RECIST

1.1 response.


5.2 Overall Combined Response (PCWG Modified RECIST 1.1)

Notes:

So here is the table that shows you how to combine soft tissue response and the results from the bone scan.

So, first of all, notice that PD always wins. That is, if you have PD in the soft tissues or in the bones, it’s

called PD. If you have PDu on the bone scan, that is entered as PDu overall, unless of course soft tissue

results show PD, and then PD wins.

If the bone scans shows anything other than PD, the soft tissue response dominates, so if you have stable

disease on soft tissue and anything except progression on the bone scan, it’s going to be stable disease in

the overall assessment. The exception is if the bone scan is entirely missing or was not done and there were

bone lesions present at baseline, then the other overall assessment would be called non-evaluable.

If the soft tissue response is CR and lesions are still present on the bone scan, then they affect the overall

result in the same way that non-target lesions do in RECIST 1.1. That is, if target lesions were present at

baseline and they are gone but there are still lesions in the bone scan, that’s called a PR, and if there were

no target lesions at baseline, then the overall response is called non-CR/ non-PD.

To have a CR overall, of course, you would need a CR in the soft tissues and no bone lesions present on

the bone scan.

And finally, if there were never any soft tissues disease to start with, that is the soft tissue response is NED,

then the overall assessment is driven entirely by the bone scan result.


5.3 Resource - Imaging Educational Materials

Notes:

Now, there’s a resource I want to mention to you, and that is the Merck Imaging Tip Sheet. We have a tip

sheet on RECIST 1.1 and we also have a tip sheet on PCWG-Modified RECIST 1.1. These tip sheets

provide information on these rules, on lesion assessments, and basic information on how to enter the

responses in the case report form. And the examples that we’ve gone through are provided in the tip sheet.

These tip sheets can be provided to sites. Also, as another resource for sites, we’ll have CLMS courses on

RECIST 1.1 and on PCWG-Modified RECIST 1.1, which parallel the myLearning courses on the same

information. A CRA can assign these courses to site staff to complete.


5.4 Conclusions

Notes:

So here’s what we talked about. We talked about how to assess soft tissue response essentially using

RECIST 1.1 rules. We’ve talked about how to assess response in bone using the Prostate Cancer Working

Group rules as applied to bone scan with the key concept being that progression requires two new lesions

that are persistent and are not the result of flare and you combine the soft tissue and bone responses to

come up with the overall combined response by PCWG-Modified RECIST 1.1.

Thank you for your attention.

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