Host Dr. Davide Soldato and Dr. Shelia Garland discuss the JCO article "Randomized Controlled Trial of Virtually Delivered Cognitive Behavioral Therapy for Insomnia to Address Perceived Cancer-Related Cognitive Impairment in Cancer Survivors."

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato. I am a Medical Oncologist at Ospedale San Martino in Genoa, Italy. Today we are joined by JCO author Dr. Sheila Garland. She's a Professor of Psychology and Oncology at Memorial University, and she's the director at the Sleep, Health, and Wellness Lab and Senior Scientist at the Beatrice Hunter Cancer Research Institute. Dr. Garland will be discussing the article titled, "Randomized Controlled Trial of Virtually Delivered Cognitive Behavioral Therapy for Insomnia to Address Perceived Cancer-Related Cognitive Impairment in Cancer Survivors." Thank you for speaking with us, Dr. Garland.

Dr. Sheila Garland: Thank you so much for having me.

Dr. Davide Soldato: So, Dr. Garland, you designed a study that relied on cognitive behavioral therapy to treat insomnia, and then you assessed whether improvement in insomnia would be associated with an improvement in cancer related cognitive impairment. So I wanted to ask if you could give us a little bit of context and explain the rationale between these studies. So how common are these symptoms among cancer survivors, and why do we think that improving insomnia would also improve cognitive function?

Dr. Sheila Garland: Yeah, thank you very much. That's a really, really good question. And so cognitive behavior therapy for insomnia has been used to successfully treat insomnia in cancer survivors for quite some time. I think JCO was one of the first publishers to really demonstrate the potency of this intervention to improve insomnia. But as we know, patients will often present not just with insomnia, but insomnia comorbid with pain, fatigue, and very commonly cognitive impairment. If we take a look at the experimental research in sleep, we know that sleep quality and quantity is associated with very important cognitive functions. And so we've had clear sleep deprivation studies where if you're not able to successfully get sufficient quality or quantity of sleep, you're going to have impairments in attention and concentration and memory. So it really makes sense that if we're able to improve sleep in cancer survivors, that we're also able to address maybe some of the other concerns that they would have related to sleep. So this is an important clinical question for the patient's quality of life, but I also think it has important system implications where if we're looking at like resources and efficiency of allocating those resources, if we have an intervention that can treat multiple problems, that means that we can more effectively address lots of symptoms and use fewer resources in doing so. So that was the thought in designing this trial.

Dr. Davide Soldato: Thank you very much. That was very, very clear. So you spoke about the intervention that you implemented in the clinical trial. So I was wondering if you could give us a little bit of context. How long was the intervention? What were the main points addressed? Because you said that, in the end, we already have some data regarding cognitive behavioral therapy for treating insomnia. So I was wondering, did you personalize in any way, the program or the intervention to fit more to the cancer survivors population?

Dr. Sheila Garland: Yeah. So it is based on a protocol that has been well researched and has a great deal of evidence of efficacy. But we delivered this intervention over a course of seven weeks. So individuals had individual sessions with a trained therapist, and those sessions lasted about an hour and were over roughly about two months or so. Seven sessions over two months. And because they were delivered individually, there was some adaptation based on the clients' presenting problems. So while there's sort of a standard protocol, if the client is also presented with levels of fatigue or pain or anxiety or depression, the therapist was able to integrate those concepts into the therapy as well. There was nothing for cognitive impairment. So there was no additional intervention for cognitive impairment at all. We weren't doing any memory training or anything like that. So it was strictly the sleep and other symptoms looking at the impact of improving that on not only your perception of your cognitive abilities, but also on performance on a number of neuropsychological test measures.

Dr. Davide Soldato: So thank you very much for the detail. And I think that it's very interesting what you said, that the personalization of the intervention would also allow to treat some other symptoms that are distressing for cancer survivors. Like, for example, you mentioned fatigue or anxiety or depression. And I think that this goes back to the first point that you made about the intervention. So being able to treat different symptoms all at one in one single intervention, I think that that is a very intelligent use of resources and also to promote and implement, potentially some interventions that are beneficial for survivors of cancer on different domains and potentially different symptoms. So, going to the results a little bit, what did you observe regarding specifically insomnia with the intervention that you delivered?

Dr. Sheila Garland: Yeah, so, of course, we wanted to make sure that we were effective in targeting the primary outcome of what the trial was supposed to do, which was we were supposed to treat effectively, treat insomnia, and then determine whether treating that insomnia was related to improvements in cognition. So we were expecting that the intervention itself was going to be successful at improving insomnia, and we were. So we were able to not only demonstrate a statistically, but also a clinically meaningful improvement in insomnia severity. Usually that's measured by a change of about 8.4 on a measure called the insomnia severity index. And the change that we were able to produce was over 11 points. So it was clearly over the clinically meaningful change threshold.

Dr. Davide Soldato: Going back a little bit to the design of the study, this was a randomized clinical trial. And how did you allocate the participants of the study into which arms? And can you guide us a little bit in the study design?

Dr. Sheila Garland: Yes. A lot of thought went into the study design. We ultimately decided on having a waitlist randomized controlled trial, and this was because there is no other intervention for insomnia that has comparable efficacy. And we felt it would be unethical to not give people the standard treatment that we know works to treat insomnia. So that's where having them wait for a period of time and then receive the treatment was ultimately what we decided on. Overall, we were able to recruit 132 participants, and those were randomized into either receiving treatment immediately or receiving treatment after a two month waiting period.

Dr. Davide Soldato: So you mentioned that the intervention was actually very effective for treating insomnia. You reported an improvement in the insomnia severity index of almost 11 points. And as you mentioned, this is both clinically meaningful and it was also statistically significant. Did you see any improvement also on cognitive function, and how did you measure this outcome? Was it self reported, or did you also have some objective measure to see, for example, working memory or some other type of cognitive function?

Dr. Sheila Garland: Yeah. Also, a lot of thought went into choosing the primary outcome for this. And there's people who have argued compellingly that self reported cognitive function should be the primary target because we know, based on past research, that objective and subjective ratings of cognitive performance do not always correlate well with each other. And taking a very patient oriented approach, we wanted to make sure that we prioritized the patient's perception of their own function. We used one of the subscales of the functional assessment of cancer treatment cognition scale. So it was the Perceived Cognitive Impairment subscale that was what we used as our primary, but we also reported the two other subscales, which was the Perceived Cognitive Abilities and the Impact of Cognition on Quality of Life. We were able to not only discover that there were clinically significant improvements on all three of those subscales, but actually translated into, again, the clinically meaningful change threshold that's been established for the perceived cognitive impairment subscale is, I think it's around, like 5.9 points. So, using that cutoff, 75% of the participants in the trial reported clinically meaningful improvements in their perceived cognitive impairments, compared to just 43% of those participants in the wait list group. And we looked not only at the immediate intervention effects, but also on whether they were durable. So we had follow up assessments of both three months and six months after completing treatment, and the effects on insomnia, as well as the cognitive dimensions, they were maintained.

Dr. Davide Soldato: Thank you very much for this last remark, because I think that one of the worries I would say that we have when implementing this type of behavioral intervention is that in the end, the change that we produce and the behavioral change that we produce might be effective in the immediate time after completing the intervention. But frequently we sort of see the loss of this benefit that we produce with the intervention at later time points. And I think that this is very important that you also looked at the benefit that was maintained over time for the three and six months after the end of the intervention. And it's true that before we add some data regarding other types of behavioral intervention, for example, for weight loss or some other symptoms and other toxicity that we frequently target with this type of intervention, I was wondering, do you think that it's something specific to cognitive behavioral therapy and the specific symptoms that you were treating, so insomnia, that in the end, produced a durable and meaningful benefit over time?

Dr. Sheila Garland: So I do think that there's something really specific about this type of intervention. With insomnia, you're really changing the person's fear of not sleeping, and you're giving them tools to be able to both prevent the reocurrence of insomnia and also if the reocurrence should happen, they know what to do then to address it themselves. I was very curious about the impact that it might have long term. I actually wasn't sure whether it would have an effect immediately, considering that people do accumulate kind of a sleep debt after having insufficient sleep for a period of time. So I didn't know whether we would see anything immediately. I thought maybe we would need the long term follow ups to see some of the effect. But I guess maybe not surprisingly, at the end of the trial, thinking about when somebody has a good night's sleep, they're feeling the effects even the next day.

Dr. Davide Soldato: Thank you. That was very insightful. Regarding the duration of the intervention, because in the end, this was very short, because it was just seven sessions weekly, and usually also when we design or implement this kind of behavioral intervention, we frequently go for a longer period of time where the patient is subjected to this type of behavioral intervention. Frequently, we see around three, six months of intervention. And so I think it's really amazing the effect that you had on this specific symptom with such a short intervention. So I think that that is also something that speaks to the possibility of further implementing this type of intervention and this type of program for symptom control.

And going back a little bit to what was one of the main questions of the trial that you designed and the results of the article that you published, did you observe a mediating effect of the improvement of insomnia on the cognitive function? So, you said that insomnia improved, and so improved also your primary outcome, which was the scale of the FACT-Cog questionnaire. But did you see whether this improvement in cognitive function was really related and associated to the improvement that you observed in insomnia?

Dr. Sheila Garland: Yeah. So that was a very, very important question. We needed to first demonstrate that there was a relationship between the intervention and insomnia, and then there was a relationship between insomnia and cognition. And then we did some mediation analyses subsequent to determining both of those, and we found that the change in insomnia was a full mediator of the change in cognition. So we were able to say that it's not just time or it wasn't related to something else, that improving sleep did have this direct effect on the improvement that patients reported in their cognitive impairment.

Dr. Davide Soldato: We spoke a lot about the subjective improvement in cognitive performance. But you said that you also evaluated some specific and objective scale with, for example, I imagine some neuropsychological tests. Did you also observe some improvement for those specific tests, and did you observe the same amount of benefit or the same improvement, we could say, between the subjective and the objective weight of measuring cognitive function?

Dr. Sheila Garland: I think that's where the outcomes become a little less clear. So, we did measure performance based cognition at all of the time points, and we were very careful in selecting these measures. So we followed the guidance provided by the International Task Force on Cognition and Cancer. They had some very specific recommendations about how and what measures we use. So we made sure to use measures that were able to be repeated, so that had multiple forms, that had very identifiable ways to indicate improvements. So we used the Hopkins Verbal Learning Test to measure word recall, both immediately and delayed. We used measures to look at verbal fluency and working memory. Overall, we had six different specific aspects of cognition that we were looking at, immediate word recall, delayed word recall, word retention, verbal fluency, word recognition, and working memory. Some of those presented with a different pattern of change overall. So a little bit trickier to interpret than the person's perception of their own cognition.

Dr. Davide Soldato: That's very interesting because it's important to have this kind of objective assessment. But in the end, what we are really trying to target is a symptom that is distressing for cancer survivors. I'm not even sure that sometimes we need all of this detail, or at least that even if these outcomes that are more objectively measured, we do not observe the same amount of benefits. Still, if we are able to produce an improvement in the symptoms and the perception that the survivor or the individual or the patient, whoever we are trying to help in that specific moment and for those specific symptoms, reports an improvement, I think that is already very important. And I totally share the patient oriented approach that you followed in the study.

Going back a little bit to the population, because I think that this speaks a little bit also to potential avenues for further research. You included a population of cancer survivors who completed treatment at least six months before being enrolled in the trial. And relating to the population, I had two questions. So the first one is, do you think that you would have the same kind of results, so the same benefit, also among a population of patients who's in active treatment? And then the second one is a little bit more speculation, but do you think that we will arrive, or do you envision research where we kind of deliver this type of intervention in sort of a preventative way? So if we would be able to identify those patients who might later develop these types of symptoms, could we use this type of intervention sooner? So can we prevent these symptoms even before they appear? And could this be potentially associated also in a less symptoms developed over time and less need to treat these symptoms when they become more severe?

Dr. Sheila Garland: Those are two very, very good questions. The first one is regarding the population. You're right. These people were at least six months out of treatment, and we wanted to make sure that if there was any temporary disruption, that would have maybe been stabilized over that. But most of the people in this trial, and I will mention that we didn't focus on any specific cancer type or site. So this was really a heterogeneous group of cancer survivors, both male and female. The most prevalent diagnosis that we had was breast. But some of these people who were enrolled in the trial had advanced cancer, and as long as their cancer treatment, their regimen was stable, they were eligible to participate in the trial. So I think that's a very important point. If somebody is on a very intensive round of chemotherapy, it can be tricky to implement some of the more aggressive behavioral changes that can come with some of these insomnia treatments, because their level of wellness just isn't there. So during active treatment it can be challenging, but it is definitely not impossible. We would just tweak things a little bit to accommodate their physical well being at that time.

To your next question, though, this is where I think we really need to be going. Just like they've done in the area of, like, physical activity, trying to really strengthen people prior to treatment is the way to go. Because some of my other research looked at symptoms prospectively from the time of diagnosis over the first year, and it's roughly about half of people, at least, this was in my work with women with breast cancer, about half of women with breast cancer come into treatment with clinically significant sleep problems. So, a proportion of those people just continue to have sleep problems or even get worse after it. So there's definitely a role for that, sort of like rehabilitation, not only for maybe physical fitness to try and ward off fatigue, but also getting their sleep on track. I think people are really focused, especially in that early time, about like, "I want to eat right, I want to exercise," but I say it as many times as I possibly can, that you're not going to make healthy food choices, and you're not going to be getting out there and working out if you're not getting sufficient sleep. So we really need to have sleep there as the foundation and what supports all of those other healthy lifestyle behaviors that people are trying to change.

Dr. Davide Soldato: So sort of comprehensive intervention for people undergoing treatment where we kind of identify symptoms that are already there at the beginning, and we deliver some sort of intervention that can target a lot of those symptoms, maybe not all of them, but maybe improving also the way that treatment is perceived or the toxicity that they might develop over treatment.

Dr. Sheila Garland: And that's what I think. I think that if you're taking people who are already coming into treatment, that are looking after their health in ways that they can, they may be able to tolerate more aggressive treatments, they might be able to complete more rounds of chemotherapy, just getting them strong, going into treatment that way.

Dr. Davide Soldato: Also still focusing on that very patient oriented perspective that I think it's very important in general for oncologists and also for patients. I think that you were very wise in choosing an intervention that could be also delivered virtually, and this was one of the bases of the intervention. And regarding also the way the intervention was delivered, I had a question regarding the fact that this was actually an intervention that was delivered by professionals. But we also have some, maybe initial evidence, that suggests that some of this cognitive behavioral therapy can also be experienced, or at least the benefits can be obtained by the patients, even when it's self directed. So programs where patients are not actually interacting with a professional, but they are just following these types of programs. So do you think that there is room for both of those? And maybe should we suggest this type of self directed programs for all patients or all survivors and then just refer only those with a more significant or important symptom severity for the intervention with professionals? And this, I think, also goes to the discussion that we had at the very beginning about allocation of resources and ability also to tailor these types of interventions to the needs of different individuals.

Dr. Sheila Garland: I think that's really important to consider when looking at what's available for patients. They did a survey in the US of NCI Cancer Centers where they looked at the availability of CBT-I, and it was very low. I think around 20% or so of NCI Comprehensive Cancer Centers had the ability to refer to in-house CBT-I. If we had sort of a stepped care model like you're talking about, we may be able to more appropriately allocate people to the level of care that they need. A line of my research now is going into a specific app delivered cognitive behavior therapy for insomnia tailored to cancer survivors. And so looking at that very point, not everybody needs a provider, but I think that a self help manual or an app is also not going to work for everybody. So you're not going to completely take out the person. And depending on the complexity of the situation that the patient finds themselves in, they may really need that provider to consider all of the other factors. They might need it to encourage adherence or address maybe some of the barriers that would be getting in the way. So having different levels of care and being able to match people not only to the level of care, but also maybe by their preference. So, "I'd like to use an app." Great, we've got an app for you. Or "I'd like to see somebody." And I think matching it to people's preferences automatically encourages or enhances their engagement and their motivation to complete because they're getting what their preference would be.

Dr. Davide Soldato: And I think that at least if we could use a little bit more of these types of apps or tools or whatever we have out there, maybe we could increase at least that 20%. For example, if only 20% of NCI Cancer Centers, which are already places where care is delivered, probably with a higher attention to these types of symptoms for survivors compared, for example, to community hospitals or to smaller private clinics. So if we could at least have sort of a base and then refer only those that maybe have a higher need for a provider directed therapy or intervention, that maybe would also improve outcomes for a larger part of the population of survivors.

And one other thing that I wanted to ask you is, do you think, in your experience, because this was not really in the trial that you designed, but do you think that we also need cultural adaptation of these types of programs? Meaning, do we need to diversify based, for example, on ethnicity or level of education or, I don't know, just the background that the patient is experiencing?

Dr. Sheila Garland: Yeah, very, very good points. There are some studies currently being conducted out of the United States that have looked at cultural adaptations of CBT-I specifically. So there was a trial looking at CBT-I for African American women survivors of breast cancer, and also the Latinx population as well. From the results of those trials, it didn't necessarily improve the effects of intervention, but it improved the engagement, so people were less likely to drop out. So it wasn't always the content. It was how the content was presented. So people were able to visually see themselves more, they were able to relate more to the content in just the way it was presented, which made them go, "Oh, okay. This is why I should be here." And I think that that's part of the argument that I used for sort of adapting the cognitive behavior therapy for insomnia treatment that's being used in the general population, specifically to people who have had cancer, because people want to know, "All right. You know what? Is this safe for me to do? Will this work for me to do? How do I also do this when I have cancer related fatigue, or how do I do this when I also have pain?" So they want to know that, "Alright. This is right for me." That's probably, again, relating more to getting people and keeping people engaged with the treatment, maybe even convincing them to do it to begin with, talking about getting buy-in from important leaders in their community to say, "This is something that I would recommend or I would endorse." And those sort of community level endorsements maybe are just breaking down barriers to get people willing to engage with an evidence based treatment.

Dr. Davide Soldato: And I think especially with cognitive behavioral therapy, because I think that when we propose drugs for treating symptoms or, I don't know, intervention for losing weight or to be more physically engaged, well, the latter that I mentioned might be also a little bit more complicated, depending on the cultural context. But drugs are very easy to accept for the patients in most cases. But I think that cognitive behavioral therapy also has some type of cultural resistance, maybe among some of our patients and cancer survivors.

Dr. Sheila Garland: And I would also include oncologists in there as well. So, some of the treatment providers are not even exactly sure why would talking about this help. So I think separating it out, it's not just I'm going to talk about my sleep, it's that I'm going to engage with my sleep differently and breaking down maybe some of the stigma that, just because we're referring you to cognitive behavior therapy doesn't mean your problems are all in your head, but it means that there's ways that you can think about your sleep and ways that you can behave differently, which will reduce the things that are getting in the way of your sleep functioning the way that it should normally. I think when I talk to patients, and also when I do training with providers, I talk about how we can condition our bed to be associated with things other than sleep. So if we repeatedly snack in front of the tv, even though we've just had supper maybe a half an hour before, if we go and sit down in that chair that we always snack in, we're not hungry, but we find ourselves reaching for something to eat. The same thing can happen at night, where if you repeatedly pair your bed with things other than sleep, if you're thinking in bed, if you're planning, if you're worrying, if you're ruminating, if you know you're doing anything, if you're on your screen or you're watching tv or you're doing anything that's arousal producing, people can find that they're so tired, they're nodding off on the couch. They go up to bed, and all of a sudden, bang, they're wide awake and their mind is turning and they're thinking and they're like, "Why is this happening to me? I was just tired. I was so tired." People with insomnia can relate to that very easily. That, "Oh, okay. So there's this conditioned association between my bed and wakefulness. How do I get rid of that?" That's where what we think and what we do around our sleep, we can change to be able to make our bed someplace that is strongly associated with sleep and not all of those other activities.

Dr. Davide Soldato: Thank you for the remarks on oncologists and sometimes our resistance to accept this type of intervention. I think that this also speaks to the merit of the Journal of Clinical Oncology, which publishes high level evidence also on symptom management, and these types of interventions that are, in the end, effective for our patients.

So I think that this concludes our interview for today. Thank you again, Dr. Garland for joining us.

Dr. Sheila Garland: Thank you Dr. Soldato.

Dr. Davide Soldato: Dr. Garland, we appreciate you sharing more on your JCO article titled, "Randomized Controlled Trial of Virtually Delivered Cognitive Behavioral Therapy for Insomnia to Address Perceived Cancer-Related Cognitive Impairment in Cancer Survivors."

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