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Journal of Clinical Oncology recognizes that readers do not always have time to review an article in depth, and yet they still wish to understand how the results will influence their clinical practice or research. To address this need, we offer podcasts that will enhance the readership experience by presenting the key results of high-profile publications in a convenient audio format. Our podcasts are designed to place selected articles into a clinically useful perspective that is easy to listen to in the office or while on the road.

Life is busy, and it’s hard to get it all done during business hours! Journal of Clinical Oncology recognizes that you do not always have time to review an article in depth, and yet you wish to understand how the results will influence your clinical practice or research. JCO After Hours is a podcast intended to enhance the readership experience by presenting key results of high-profile publications in a convenient audio format, placing selected articles into a clinically useful perspective that you can listen to in the office or on the road.

Feb 1, 2022

Dr. Shannon Westin and Dr. Antonio Di Meglio discuss the issue of fatigue among cancer survivors.




Speaker 1: The guest on this podcast episode has no disclosures to declare.

Shannon Westin (Dr. Westin): Hello, everyone. And welcome to another episode of JCO After Hours. This is our podcast where we get in depth with different authors and experts about wonderful manuscripts that are being published in the Journal of Clinical Oncology. And today it is my great pleasure to be accompanied by Dr. Antonio Di Meglio, who is a Medical Oncologist and a Physician Scientist at the Breast Cancer Survivorship Research Program in Gustave Roussy in France. So welcome, Dr. Di Meglio.

Dr. Antonio Di Meglio (Dr. Di Meglio): Thank you so much for having me here today.

Dr. Westin: We're so excited to have you. We're going to be talking about your article, which is due to be published January 21, 2022, in the Journal of Clinical Oncology titled “The Development and Validation of a Predictive Model of Severe Fatigue After Breast Cancer Diagnosis: Toward a Personalized Framework in Survivorship Care.” And before we get started, I would just note that none of the guests have any relevant conflicts to disclose.

With that, let's get into it. I was so excited to read this paper because this such a critical problem for our patients. And I'm a gynecologic oncologist, but this goes across all—surgical, medical, any field that we could even think of. So why don't you start off by telling us what led you to explore the problem of cancer-related fatigue?

Dr. Di Meglio: Cancer related fatigue is one of the most troublesome and prevalent symptoms among cancer survivors and including breast cancer survivors. So several reports reported on the prevalence of cancer-related fatigue reporting up to 50% of patients in some studies with fatigue after cancer and the end of treatment. But what we know is that at least one in three cancer survivors experience fatigue symptoms at some point over time. In addition, we do know that fatigue is particularly distressing and impactful as it can impact on daily living and functioning and overall quality of life.

Also, there's an important impact on social function and return to work after cancer and adherence to oral therapies, especially in the age event setting in breast cancer survivors. Finally, we also know that fatigue is often inadequately addressed and often neglected because of lack of time, lack of resources. Definitely, we should do more in the clinic for our patients struggling with fatigue.

Dr. Westin: This is such an important issue. I think the elephant in the room here is how do we grade this and how do you advocate for a busy clinician in the clinic seeing 30, 40, 50 patients in a day. How do we really assess this? What's the best way to determine if somebody has cancer-related fatigue or is at risk?

Dr. Di Meglio: Thank you for this important point. In clinical research, we do have a number of instruments that we can use to grade fatigue, including the European Organization For Research and Treatment of Cancer, Quality of Life Questionnaires that are the questionnaires that we used in our study. These are instruments that our patient reported. So we really can hear patient voices and patient perspectives in terms of their own symptoms.

And some of the items that we use, for example, for cancer-related peak do not take much time to be asked also in a basic clinic. For example, we did use the EORTC QLQ Questionnaire C30 to score global fatigue. So we basically asked patient three questions: whether they needed to rest, they felt weak, or they felt tired, typical week. And these gave us the score of what we called global fatigue. There's also other instruments and companion models that we can use to assess more specifically dimensions of fatigue, including the physical, emotional, and cognitive dimension of fatigue.

It is true that in our busy day in clinics, this may not be easily implementable. But what I believe is that if we never ask patients the right questions, patients will never tell us the right answers that we can proactively use to address the symptoms. So even just assessing fatigue in a general way, asking whether their energy levels changed over the past weeks, if they know that any change that was related to the treatment or any tiredness that was not really related to their usual activities or that was impactful on daily activities, this should trigger clinicians to ask more and more and to find solutions for the problem. So just ask the questions, even though the assessment may not be comprehensive and extensive, but this can be very important and meaningful for the patients.

Dr. Westin: I think that's a really critical point because using validated instruments is obviously our aspirational goal and our attempted standard of care, but on a day in and day out clinic, it can be hard to have patients filling out a survey or something that may take a longer time. So I think that's a critical point is pull out these critical questions so that you can identify these issues and address them for your patient.

When we're talking about grading fatigue, say in the clinic, would you recommend maybe choosing one? How long do these types of assessments take? Is this something feasible for a busy oncologist in clinic?

Dr. Di Meglio: So definitely our study calls a little bit for the implementation of these instruments that are being used in mostly in clinical research over the past decades, also in the clinical practice. These are patient reported instruments that really can give us a sense of how impactful fatigue is in daily living and functionality. And when we grade fatigue using this instruments such as the EORTC scores, we can really capture fatigue that is defined as severe, meaning fatigue that really impacts on quality of life and needs to be absolutely addressed by clinicians and needs interventions urgently.

Dr. Westin: That makes a lot of sense. Why don't we get into a little bit more around your study using these specific instruments? Like what was the patient population? Run us through that.

Dr. Di Meglio: So this study was performed using CANTO data. CANTO is a longitudinal cohort of breast cancer survivors. Patients that were initially diagnosed with Stage 1, 2, and 3 breast cancer. It's a French cohort that enrolled patients across 26 centers in France starting in 2012. And at this point, the cohorts included over 10,000 patients, and this study was performed using a first split of the cohort for the development models that included around 6,000 patients overall, and then 3000 patients for the validation of these models.

So the availability of data of fatigue was really the driver of the patient population that we used for this study. So we used all available questionnaires of EORTC QLQ-C30 therapy, to which we assessed our primary outcome of interest, which was global fatigue. CANTO has a first assessment at baseline, that is a breast cancer diagnosis, meaning before the initiation of any cancer treatment. Meaning surgery, chemotherapy, radiation therapy, therapy of any type.

Then we perform longitudinal assessment at one year, two years, four years after diagnosis. There is a fifth assessment at five years after diagnosis for which data are not mature yet, but for the present study, we use data until four years after diagnosis. So our interest was to understand which are the risk factors for severe fatigue, primarily at two years after diagnosis. Then we also developed and validated models for severe fatigue at four years after diagnosis.

So our interest was to identify a population of patients that since diagnosis can be flagged as being at high risk of developing severe fatigue after diagnosis and of course after treatment for breast cancer. This is a population of early-stage breast cancer survivors. So I really want to highlight that these models were developed and validated for survivors that are free of cancer at the time of fatigue assessment. So whether they experience cancer recurrence, metastasis, second cancers, they exit cohort. So this is purely early stage survivors of breast cancer.

Dr. Westin: Thank you for that clarification. And I think it is important to really focus in on these populations because we are going to see differences in the occurrence of fatigue across patients that are actively receiving treatment in the continuum of recurrence or later in survivorship. So thank you for that clarification. I think that that really makes a lot of sense. And this is a population that's extremely large and very critical to our management. So why don't you tell us a little bit about what were some of the factors that you found to be associated with severe fatigue in your cohort?

Dr. Di Meglio: So our models allowed us to identify a number of factors that are risk factors for severe fatigue after breast cancer diagnosis. So first of all, the most consistent and the strongest factors that was identified as associated with post-treatment fatigue was pre-treatment fatigue. So patients that are already severely fatigued at diagnosis have much higher likelihood of reporting severe fatigue also years after diagnosis. This was identified as a risk factors also in previous literature as it may set stage for post-treatment fatigue because maybe there are biological disruptions or bio-behavioral disruptions that are already present at the moment of diagnosis.

So they keeping there and they put patients at higher risk of post-treatment fatigue. In addition to this, we found that clinical factors such as younger age was associated with high risk of fatigue after treatment. And there are also behavioral risk factors.  Patients that are current smokers at the time, active smokers at the time of the diagnosis, as well as patients with a higher body mass index. They are all at higher risk of persistent, severe fatigue after diagnosis.

Finally, we also identify concomitant symptom clusters that are associated with a higher risk of severe fatigue. And these include emotional distress and particularly anxiety, insomnia. So sleep disturbances and pain at the moment of diagnosis. These are the risk factors that emerged for the models of severe fatigue at year two after diagnosis. But when we look further in to the risk factors of fatigue at year four after diagnosis, we consistently identified premenopausal status that is very consistent with younger age and also received of hormonal therapy. So our assumption was that longer these patients are into hormonal therapy, the higher the risk of severe fatigue becomes. So even though our models at Tier 4 are to be considered exploratory, we believe that they give us an additional insight into which treatment related factors would be associated with higher risk of fatigue.

Dr. Westin: You'll have to forgive me because my knowledge of early breast cancer is very minimal. So for these patients, did any of them receive chemotherapy and was that at all relevant or is this a population that generally got maybe surgery and hormonal therapy?

Dr. Di Meglio: So in the population that we study and consistent with the stage distribution, over 50% of the patients received chemotherapy. Almost 80% and more received hormonal therapy. So we really investigated the impact of all treatment types on the risk of fatigue. And we did find a differential impact of different treat modalities on the risk of fatigue.  I liked this in the paper because this is Year 1 model while our main interest was Year 2 after diagnosis models. But we did find an impact of chemotherapy on the risk of fatigue at one year after diagnosis, meaning the closest time point that we have to the end of primary treatment, including chemotherapy. And this effect seems to produce over time, and we don't find it in models at Year 2 and Year 4 anymore. So it's less consistent and it's not confirmed invalidation models.

In contrast, the impact of hormonal therapy was much stronger at Tier 2 was confirmed at Tier 4. So this gives us the sense that the longer patients are on hormonal therapy, the higher risk of severe fatigue becomes for them. And this is also consistent with previous data from other literature. For example, Pat. A Ganz in The Mind-Body Study had demonstrated that hormonal therapy can delay the recovery from treatment-related symptoms that are usually associated with chemotherapy. And in a previous study using the CANTA cohort, we also had found an impact of hormonal therapy on the recovery of symptoms and functions that usually get better over time, for example, emotional function or future perspectives whose recovery seems to be delayed among patients that receive hormonal therapy.

Dr. Westin: Well, this is great, understanding who might be at risk and trying to identify these patients. I guess the natural question is next. Like what do we do? What are our available options to treat cancer-related fatigue or even prevent it?

Dr. Di Meglio: I think this is a great point and that definitely leads me to trying to understand and to explain what is the implementation of our models in clinic. So what we envision would be a clinical care setting where our models would aid clinicians to be more aware about the problem of fatigue and about ways that we have to better describe fatigue among our patients and better identify its risk factors. So let's imagine that we have an incoming new patient in our clinic and we assess the risk of severe fatigue in this patient after treatment. By assessing risk factors, we also assess fatigue at the moment of diagnosis. And we do know that in this analysis, we found that almost 25% of patients present already with severe fatigue diagnosis, and a patient like this needs to be already treated for the symptoms that he or she is reporting.

So we do have now available interventions to treat fatigue when it's already present. So first of all, increasing physical activity. We also have psychosocial interventions, including cognitive behavioral therapy and psychoeducational therapies that we know that work for cancer-related fatigue and some mind-body interventions, such as yoga demonstrated some activity for cancer-related fatigue.

Other approaches include mindfulness based approaches or acupuncture that can be offered to patients that already present with severe fatigue and diagnosis, particularly also the assessment of all concomitant conditions, such as nutritional imbalances should be performed in detail at the moment of diagnosis. In contrast, we might find a patient that doesn't have symptoms of severe fatigue at the moment of diagnosis, but definitely our models can increase the awareness of the risk factors and highlight a way to recognize symptoms that can hurl out the onset of fatigue and facilitate the management of risk factors and the referral to dedicated consultations or to dedicated specialists that can take care of such risk factors.

In fact, the majority of risk factors that we identified are modifiable, such as we can address as tobacco use. We can address overweight and obesity as well as we can address specific symptom clusters that usually come in conjunction with fatigue, sleep problems, pain, emotional distress. We do have interventions available for all these symptoms.

Of course, there is an important question there arises here, that is by addressing all three factors, is fatigue preventable at this point. I am not sure that we have the answer yet for this question at this point, but definitely by addressing risk factors, by addressing behavioral problems, we are addressing survivorship problems in a more comprehensive way. That is the direction in which survivorship care should probably go today. So as next steps, definitely we should look towards the implementation of risk models in clinical practice towards planning more meaningful prevention trials for problems such as cancer-related fatigue.

And in addition, I believe that cancer-related fatigue is just an example of very common and prevalent and distressing symptoms that are not often taken care of or sufficiently taken care of in the clinic. So this can serve as a case study, as a model to expand our no also of other symptoms and of other survivorship issues that our patients and survivors may face.

Dr. Westin: Well, I just want to commend you. These are really such exciting work, and I know it's something that will be implemented in the breast cancer community but also beyond. And I'm hoping that some of our other cancer-type survivorship experts are listening right now and getting inspired by your work. So we can look at this in other tumor types and really help implement this across the world. So thank you so much again for your amazing work. Thank you so much for taking the time to meet with me today, and best of luck in moving this forward.

Dr. Di Meglio: Thank you so much, Dr. Westin. It was great to be here with you today.

Dr. Westin: Thank you so much to all our listeners. We are always so grateful that you tune in and we can't wait to bring you discussion of our next manuscript. Have a great one.


Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.