Transcript
Dr. De Ridder: Good morning, dear colleagues. In the next 15 minutes, I'm going to present to you some tools for the clinical evaluation of neurocognitive assessments.
So over the last decades, as illustrated by the previous speakers, we have shift from Whole brain radiotherapy that treats the entire content of the cranial vault to uniform dose to a Stereotactic RadioSurgery for patients with a limited number of brain metastases.
Now, Whole brain radiotherapy may cause neurocognitive function decline because of diffuse injury, for instance, by the immunization or by encephalitis. While the Stereotactic RadioSurgery, on the other hand, may cause neurocognitive function decline because of an increased risk of intracranial progression, an increased risk of development of new metastasis.
And this is illustrated in these next slides. It's a paper published in 2007 in the "Red Journal." Now, you see the neurocognitive decline after SRS. On the Y-axis, you see the patients free from the decline, free from the case of Mini-Mental State Evaluation below 27, brought it against the time of radiation on the X-axis. And these investigators compared SRS alone, the grey curve, versus SRS and Whole brain combined, the blue curve. And we can see that the patients receiving only SRS had adverse neurocognitive outcome than the one receiving SRS and Whole brain radiotherapy. And this was explained by an increased risk of intracranial recurrence, so the development of new metastases, and this was at the time where routine MRI was not available for a lot of these patients and...
Man: Yeah, nonsense.
Dr. De Ridder: ... [inaudible 00:01:48.174] radiotherapy was not offered if patient developed new asymptomatic brain mets.
Note here that these investigators used Mini-Mental State Evaluation for neurocognition and is quite a good tool to investigate neurocognition. If you look, for instance, to the initial decline after Whole brain radiotherapy, you can see that this MMSE, this Mini-Mental State Evaluation does not reflect what we see in our daily patient population treated by Whole brain radiotherapy.
More recent trials are in favor of Stereotactic RadioSurgery. Here, you see the publication by Chang. So they use the Hopkins Verbal Learning Tests to evaluate neurocognition, and they also compared one group receiving Stereotactic RadioSurgery alone, another group receiving Stereotactic RadioSurgery plus Whole brain radiotherapy. And you look, for instance, the delayed recall in the Hopkins Verbal Learning Test, you see that after SRS and Whole brain, 52% of the patients show significant decline versus only 24% in the Stereotactic RadioSurgery alone. And this was also true for the late recall and the late recognition. Of course, SRS was mostly used in the treatment of one to four brain metastases.
What, now, if you treat multiple brain metastases? What, now, for instance, in this patient here that I have treated to a 12-ray metastases and that it's treated to the element system. If patient have multiple brain metastases that you treat by SRS, you are going, by definition, to radiate a larger volume of normal brain. These are the law of physics. And in addition, if patients have a larger number of metastases, a larger intracranial tumor load, statistically, they have a higher risk of developing new and multiple new metastases over time. So these are two arguments why patients that we treat by SRS for multiple brain mets have a potential neurocognitive outcome than the patient that we treat with one to four metastases.
And the question that we want to further investigate is very timely, and has SRS an advantage over Whole brain radiotherapy in the treatment of multiple brain metastases? And we've already seen in the previous talks that according to the part of the world where you are from, this custom may be a bit different.
Now, if you want to address this question with regard to neurocognition, you don't need to use one, two, like the Mini-Mental State Evaluation or like the Hopkins Verbal Learning Test. No, you need to look to the different domains in neurocognition. The first domain is verbal fluency. Second domain is learning and memory. Third domain is attention and information processing. The fourth domain is fine motor and speed. And the fifth domain is executive function, so meaning, the combination of at least two different tasks.
Let's take a look at the first domain, verbal fluency. This can be evaluated by a Controlled Oral Word Association test or COWA tests, and I invite you to participate to this test so I would invite you in the next minute to try to say as many words as possible starting with letter F, and our chairman will time your efforts.
Okay. I think we are not at one minute but most already stopped by saying words with letter F.
Second domain is learning and memory. And therefore, you can evaluate the direct and the late recall of the patients by the Hopkins Verbal Learning Tests. Take now a close look at these 12 words and try to remember them. And I want to know how is your immediate memory? Repeat now as many words as you can in yourself in any order from the previous 12 words. For the smart colleagues between us, this was not only a test of memory but also a test of observation because in the Hopkins Verbal Tests, you have three categories of four words. You have four music instruments, you have four vegetables, and you have four boats. So this may help you to technically remember the words.
A third category is attention and information processing. And this is assessed by a Symbol digit modality test. You receive a key where all symbols receive a number and you then receive different rows of symbols and you need to fill in the right number.
We then move to the fourth and the fifth domain, and I take them together because they can both be evaluated by a Trail making test. The first part is to evaluate fine motor and speed. And here, you have the patients to connect from 1 to 2 to 3 to 4 and so on. So I will try to do this test for you and hope I succeed in it. Okay. It takes...
And then we need to evaluate the executive functions and there, you have a more difficult Trail making test where you do not only need to go from 1 to 2 to 3 to 4, but where you also need to combine the number with the letter at the same position in the alphabet.
So I haven't chosen these four tests by [inaudible 00:07:50.840]. These are the tests of the Standardized testing battery. It has been published in "Lancet Oncology" in 2011 by an international task force on cancer and neurocognition. Of course, if we need to take these four tests, they are taken by paper and pencil and this is very labor-intensive. It is a one-on-one assessment. You need to have observation so you have a learning curve of the observators, and you need to pay them also a salary. And of course, all data is manually entered into a computer.
And because of this labor intensiveness, and because the reality of economics in healthcare, this cannot be done in many departments. That's why Brainlab decided to develop an app, the Cognition app. This is an app, of course, for neurocognitive testing. It's from iPad and it has a friendly interface. We will see some screenshots in a moment. Now, we are currently the first to test and use the app. And I must be honest that we are just using the app because it took us six months to get the app running together with Brainlab because it was on box in the iPad, some small box in the iPad program.
Here, you see, for instance, the verbal recall. So the Hopkins test can be done on the iPad and you can just say the words to the mic of your iPad. Here you see an example of the Trail making test that you can do on your touchscreen of the iPad. And here, for instance, you see an elegant Symbol-digit modality test where you can put the right number at the right symbol.
And of course, this is much quicker and much labor-intensive and much cheaper than the paper and pencil evaluation because you do not need observations. But, on the other hand, in the absence of observation, that this might perhaps not be that reliable because you don't know if a patient fails for the test or shows a decline, whether he just did it quickly without too much attention or whether he was really focused on it. And of course, it's done on an iPad so another possible pitfall, it requires some electronic device familiarity.
So we are currently testing the feasibility of cognition in a quite simple study design so we have a first group currently running of cognitive healthy patients. So we take patients with breast cancer without brain mets. And in charge of them, we take them twice a paper and pencil test, and twice the Cognition app, and so, thereby, we can evaluate accuracy and test-retest reliability.
In the second group of patients with brain metastasis, we will include 60 patients that take the Cognition app, a baseline before the start of radiotherapy and 1 to 3 months after the treatment. This is the endpoint, but of course, we'll do a longer follow-up of our patient. And this will be observed by a trained clinical neurologist and there'll be a quality survey, and this will be...then we will be capable to evaluate the compliance and the usability.
Now, before I want to thank you for your attention, I wonder how it is with your delayed memory. You can repeat perhaps as many words as you can remember from the Hopkins Verbal Learning Tests.
Well...
Chairman: Thank you.
So over the last decades, as illustrated by the previous speakers, we have shift from Whole brain radiotherapy that treats the entire content of the cranial vault to uniform dose to a Stereotactic RadioSurgery for patients with a limited number of brain metastases.
Now, Whole brain radiotherapy may cause neurocognitive function decline because of diffuse injury, for instance, by the immunization or by encephalitis. While the Stereotactic RadioSurgery, on the other hand, may cause neurocognitive function decline because of an increased risk of intracranial progression, an increased risk of development of new metastasis.
And this is illustrated in these next slides. It's a paper published in 2007 in the "Red Journal." Now, you see the neurocognitive decline after SRS. On the Y-axis, you see the patients free from the decline, free from the case of Mini-Mental State Evaluation below 27, brought it against the time of radiation on the X-axis. And these investigators compared SRS alone, the grey curve, versus SRS and Whole brain combined, the blue curve. And we can see that the patients receiving only SRS had adverse neurocognitive outcome than the one receiving SRS and Whole brain radiotherapy. And this was explained by an increased risk of intracranial recurrence, so the development of new metastases, and this was at the time where routine MRI was not available for a lot of these patients and...
Man: Yeah, nonsense.
Dr. De Ridder: ... [inaudible 00:01:48.174] radiotherapy was not offered if patient developed new asymptomatic brain mets.
Note here that these investigators used Mini-Mental State Evaluation for neurocognition and is quite a good tool to investigate neurocognition. If you look, for instance, to the initial decline after Whole brain radiotherapy, you can see that this MMSE, this Mini-Mental State Evaluation does not reflect what we see in our daily patient population treated by Whole brain radiotherapy.
More recent trials are in favor of Stereotactic RadioSurgery. Here, you see the publication by Chang. So they use the Hopkins Verbal Learning Tests to evaluate neurocognition, and they also compared one group receiving Stereotactic RadioSurgery alone, another group receiving Stereotactic RadioSurgery plus Whole brain radiotherapy. And you look, for instance, the delayed recall in the Hopkins Verbal Learning Test, you see that after SRS and Whole brain, 52% of the patients show significant decline versus only 24% in the Stereotactic RadioSurgery alone. And this was also true for the late recall and the late recognition. Of course, SRS was mostly used in the treatment of one to four brain metastases.
What, now, if you treat multiple brain metastases? What, now, for instance, in this patient here that I have treated to a 12-ray metastases and that it's treated to the element system. If patient have multiple brain metastases that you treat by SRS, you are going, by definition, to radiate a larger volume of normal brain. These are the law of physics. And in addition, if patients have a larger number of metastases, a larger intracranial tumor load, statistically, they have a higher risk of developing new and multiple new metastases over time. So these are two arguments why patients that we treat by SRS for multiple brain mets have a potential neurocognitive outcome than the patient that we treat with one to four metastases.
And the question that we want to further investigate is very timely, and has SRS an advantage over Whole brain radiotherapy in the treatment of multiple brain metastases? And we've already seen in the previous talks that according to the part of the world where you are from, this custom may be a bit different.
Now, if you want to address this question with regard to neurocognition, you don't need to use one, two, like the Mini-Mental State Evaluation or like the Hopkins Verbal Learning Test. No, you need to look to the different domains in neurocognition. The first domain is verbal fluency. Second domain is learning and memory. Third domain is attention and information processing. The fourth domain is fine motor and speed. And the fifth domain is executive function, so meaning, the combination of at least two different tasks.
Let's take a look at the first domain, verbal fluency. This can be evaluated by a Controlled Oral Word Association test or COWA tests, and I invite you to participate to this test so I would invite you in the next minute to try to say as many words as possible starting with letter F, and our chairman will time your efforts.
Okay. I think we are not at one minute but most already stopped by saying words with letter F.
Second domain is learning and memory. And therefore, you can evaluate the direct and the late recall of the patients by the Hopkins Verbal Learning Tests. Take now a close look at these 12 words and try to remember them. And I want to know how is your immediate memory? Repeat now as many words as you can in yourself in any order from the previous 12 words. For the smart colleagues between us, this was not only a test of memory but also a test of observation because in the Hopkins Verbal Tests, you have three categories of four words. You have four music instruments, you have four vegetables, and you have four boats. So this may help you to technically remember the words.
A third category is attention and information processing. And this is assessed by a Symbol digit modality test. You receive a key where all symbols receive a number and you then receive different rows of symbols and you need to fill in the right number.
We then move to the fourth and the fifth domain, and I take them together because they can both be evaluated by a Trail making test. The first part is to evaluate fine motor and speed. And here, you have the patients to connect from 1 to 2 to 3 to 4 and so on. So I will try to do this test for you and hope I succeed in it. Okay. It takes...
And then we need to evaluate the executive functions and there, you have a more difficult Trail making test where you do not only need to go from 1 to 2 to 3 to 4, but where you also need to combine the number with the letter at the same position in the alphabet.
So I haven't chosen these four tests by [inaudible 00:07:50.840]. These are the tests of the Standardized testing battery. It has been published in "Lancet Oncology" in 2011 by an international task force on cancer and neurocognition. Of course, if we need to take these four tests, they are taken by paper and pencil and this is very labor-intensive. It is a one-on-one assessment. You need to have observation so you have a learning curve of the observators, and you need to pay them also a salary. And of course, all data is manually entered into a computer.
And because of this labor intensiveness, and because the reality of economics in healthcare, this cannot be done in many departments. That's why Brainlab decided to develop an app, the Cognition app. This is an app, of course, for neurocognitive testing. It's from iPad and it has a friendly interface. We will see some screenshots in a moment. Now, we are currently the first to test and use the app. And I must be honest that we are just using the app because it took us six months to get the app running together with Brainlab because it was on box in the iPad, some small box in the iPad program.
Here, you see, for instance, the verbal recall. So the Hopkins test can be done on the iPad and you can just say the words to the mic of your iPad. Here you see an example of the Trail making test that you can do on your touchscreen of the iPad. And here, for instance, you see an elegant Symbol-digit modality test where you can put the right number at the right symbol.
And of course, this is much quicker and much labor-intensive and much cheaper than the paper and pencil evaluation because you do not need observations. But, on the other hand, in the absence of observation, that this might perhaps not be that reliable because you don't know if a patient fails for the test or shows a decline, whether he just did it quickly without too much attention or whether he was really focused on it. And of course, it's done on an iPad so another possible pitfall, it requires some electronic device familiarity.
So we are currently testing the feasibility of cognition in a quite simple study design so we have a first group currently running of cognitive healthy patients. So we take patients with breast cancer without brain mets. And in charge of them, we take them twice a paper and pencil test, and twice the Cognition app, and so, thereby, we can evaluate accuracy and test-retest reliability.
In the second group of patients with brain metastasis, we will include 60 patients that take the Cognition app, a baseline before the start of radiotherapy and 1 to 3 months after the treatment. This is the endpoint, but of course, we'll do a longer follow-up of our patient. And this will be observed by a trained clinical neurologist and there'll be a quality survey, and this will be...then we will be capable to evaluate the compliance and the usability.
Now, before I want to thank you for your attention, I wonder how it is with your delayed memory. You can repeat perhaps as many words as you can remember from the Hopkins Verbal Learning Tests.
Well...
Chairman: Thank you.