Fatigue : What It Is, What It Is Not, Why It Happens and What Can We Do about It?

 Download Speaker Slides 

Fatigue : What It Is, What It Is Not, Why It Happens and What Can We Do about It?

Wednesday, May 3, 2023

Presenter: Grigory Syrkin MD, Memorial Sloan Kettering Cancer Center

Presentation is 48 minutes long with 10 minutes of Q & A.

Summary: Chronic fatigue after a stem cell transplant is common. It can persist for months, or even years. This video explains what contributes to transplant-related fatigue and describes exercise and mindfulness programs that are effective in reducing it.

Highlights:

• Transplant-related fatigue is NOT a character flaw or personal weakness eg. laziness or not working hard enough.
• Stimulant mediations have a very small effect (<10%) on transplant-related fatigue.
• Exercise and psychological interventions are the most effective tools for reducing transplant-related fatigue.

Key Points:

(01:58): Transplant-related fatigue is distressing because it doesn’t seem to go away.

(09:22): Cancer tends to shift even normal cells in the body into less efficient operation and contribute to fatigue.

(12:14): Chemotherapy impairs the work of our muscles and weakens them through several mechanisms.

(15:59): Fatigue occurs because cancer treatment undermines the cellular machinery of how we do things.

(17:31): Exercise and psychologic interventions are much better than stimulant medications for cancer-related fatigue

(21:05): Expending energy to exercise can actually reduce transplant-related fatigue.

(33:39): The best exercises for reducing transplant-related fatigue should have functional relevance and practical significance for improving quality of life.

(39:34): Exercise to reduce cancer-related fatigue should follow three simple rules to avoid pain and not completely deplete your energy level

(37:44): A modified, less intense version of interval training can be effective and safe for patients dealing with transplant-related fatigue. 

(39:34): Exercise to reduce cancer-related fatigue should follow three simple rules: If it hurts, don’t do it; don’t work too hard; and don’t do things you’ll regret.  

(44:50): Keeping track of exercise routines and holding oneself accountable can eventually produce significant improvements in overall fitness for cancer-related fatigue.

Transcript of Presentation:

(00:01): [Michala O’Brien]: Introduction. Welcome to the workshop, Fatigue: What It is, What It Is Not, Why It Happens, and What Can We Do About It. My name is Michala O’Brien, and I will be your moderator for this workshop.

(00:13): It's my pleasure to introduce today's speaker, Dr. Grisha Syrkin. Dr. Syrkin is a cancer rehabilitation physiatrist at Memorial Sloan Kettering Cancer Center. He helps patients figure out why they are having trouble performing certain tasks and then uses targeted exercise interventions, devices, and changes to their daily routine to help patients achieve their goals.

(00:36): Dr Syrkin sees patients through their entire cancer journey and tries to help them every step of the way. He occasionally prescribes medications for pain and other side effects with cancer treatment and works closely with oncologists to ensure that rehabilitation interventions are safe and effective. Please join me in welcoming Dr. Syrkin.

(01:06): [Dr. Grigory Syrkin]: Overview of Talk. Thank you very much for the soap box. Thank you very much for the introduction and we will begin. So, these are the learning objectives for today's presentation. We will talk about why fatigue happens, acutely and chronically, in the short term and in the long term before, during, and after stem cell transplant. We will talk a little bit about the difference between normal fatigue and fatigue experienced by patients who undergo a stem cell transplant. We'll talk a lot about energy conservation strategies and how to plan things and be able to complete tasks. We'll talk a lot about the role of exercise, sleep, and nutrition in managing fatigue. And then we'll briefly touch on the role of medications in managing fatigue.

(01:58): Transplant-related fatigue is distressing because it doesn’t seem to go away. So the transplant-related fatigue is a subset of cancer-related fatigue which is a very complicated phenomenon. And one of the most distressing things about it, from the patient's perspective, is that no matter what you do, it doesn't seem to go away. And even tiny little things that normally wouldn't be bothersome at all can be quite exhausting.

(02:20): From a physician's perspective, it's a very complex phenomenon because, as physicians, we like to measure things. And unfortunately, there is no good blood test or x-ray or any other kind of procedure that can accurately describe what fatigue is. So, a lot of the time, we have to rely on the patient's own perception of what is going on. And despite hundreds of studies, it's not truly 100% clear what the factors are that cause transplant and cancer-related fatigue. But most importantly, the net result of cancer-related fatigue and transplant-related fatigue is that patients have trouble making things happen.

(03:07): Fatigue can limit even simple activities. Now, if you think about what goes into making things happen, there's several steps that need to occur. First you have to decide what you want to do. Then, generally, you have to have some raw strength, sort of power burst typically called anaerobic power, to overcome initial inertia. So, think about getting out of bed in the morning, it can be quite a challenge. And then if the task that you need to accomplish requires multiple steps, you have to have some endurance to see things through to completion. And if it's a task that requires several hours, at some point, you will have to refuel, and you will have to rest, and then complete the cycle, and maintain focus.

(03:56): And I'm sure, as we all can appreciate, problems can happen along every step of the way. You can have a little chemo brain fog. You could have some weakness that really does make it difficult for you to get out of bed or take that first step. You can feel like you're out of gas and just don't have the endurance to walk 100 feet, let's say. And we do know that sometimes, patients don't have a good appetite, and there are all sorts of gastrointestinal issues in the transplant process that can make it hard to get [inaudible 00:04:34] in. And of course, sleep can also be disrupted which makes things hard.

(04:41): At the molecular level, all our activity depends on a single molecule known as ATP. Now, when we think about the most basic, down-to-the-molecular level mechanism that makes all of these things possible, it all boils down to one single molecule. That molecule is called adenosine triphosphate or ATP. It's a molecule that is responsible for running literally every single process, every single instant of observable work in the human body.

(05:12): So for example, thinking, neuro function, brain function is just a bunch of electricity running from one place to the next. And that electrical flow is accomplished by pumps which are run on ATP. When you try to lift something heavy, you need ATP to release energy and make the muscle contract. And when you have to go a long distance, you have to have a lot of ATP production to sustain work over a period of time. Anything longer than 20 seconds, you need some new ATP production.

(05:51): And so this energy coin, this ATP, is generated in the following fashion. This is very basic, but basically, the air that we breathe in and the food that we absorb gets transferred to the blood and then our heart pumps out the blood and oxygen and nutrients into every single tissue. And inside every single tissue, there is this cellular component called the mitochondrion or mitochondria. It's the part of a cell that is responsible for using the oxygen and fuel to make that ATP.

(06:30): The efficiency with which we create ATP can be measured in metabolic equivalents or METS. And so, this is where things become slightly more convenient for the physicians and the scientists because the efficiency of this process, the efficiency of using oxygen to burn energy, create ATP, and make more work, is actually something that we can objectively measure. And we measure this efficiency, this production, in what's called metabolic equivalents or METS.

(07:00): Everything we do has a certain metabolic cost we can measure as METS. And so one metabolic equivalent (MET) is the energy cost or oxygen consumption of doing nothing except laying down and breathing quietly. And from multiple experiments, we know that every single thing that we do has a certain metabolic cost.

(07:21): Maintaining physical independence requires about four and half METS. For example, making a bed is about three times as energy demanding as doing nothing. And going up a staircase requires almost five times the energy of doing nothing. And because of many studies which have been done over the years, we now know that for a person to maintain independence, and be able to do everything that they want, they have to be able to produce about four and a half METS. So, in other words, if you're unable to get to about four and a half times the energy expenditure/oxygen consumption, you will probably need help with at least something. You will no longer be independent.

(08:09): And so, to understand how this was figured out, we will travel a little bit back in time, almost 100 years ago. This distinguished-looking gentleman is Otto Warburg. He is a German physicist who received a 1931 Nobel Prize in medicine for his work on discovering the mechanisms by which cells are able to mint that energy coin. And this discovery is so significant that in oncology ,there is this term called the Warburg effect. The Warburg effect basically means that when patients develop cancer, somehow this energy coin mint becomes messed up. And what Otto Warburg figured out over 100 years ago is that cancer cells prefer to be very, very inefficient when trying to make those ATPs. They use a lot of glucose. And this is the reason why PET scans, where patients receive radioactively labeled glucose and then have a scan to see exactly where the cancer is, that's why these scans are so sensitive.

(09:22): Cancer tends to shift even normal cells in the body into less efficient operation and contribute to fatigue. And so one of the theories proposed over 100 years ago, and which is now gaining more and more traction in modern literature, is that when cancer progresses, it tries to shift the rest of the body, even normal cells, into a less-efficient mode. So even normal body parts start to lose their efficiency and begin burning more fuel and not generating a whole of those energy coins.

(09:49): So, under normal circumstances, when the conditions are right, a human cell can make up to 36 energy coins or 36 molecules of ATP out of one molecule of sugar, . But when cancer is present, that efficiency goes down to only two ATPs from one molecule of sugar. So, you can imagine that this change in how much energy can be produced can affect how a person functions.

(10:24): For physical work, going from point A to point B, most of the ATPs are, of course, used by muscle fibers. And I think it's important to know that there are several different types of fibers. So, for example, if you look at one muscle such as the bicep or the muscle that bends the arm, you can see under a microscope that there are different types of muscle fibers inside the belly of the muscle.

(10:53): So, there are type I fibers, which are typically redder because they are more endurance oriented. They can't generate a whole lot of force, but they're very, very fatigue-resistant, and they can do work for a very, very long time. Then we have hybrid fibers, type IIa or some of them are part IIa, part I. These are fibers that can do a lot of work and are also relatively fatigue resistant. They can work for quite some time. So, an analogy from the sports world would be type I is like a very long-distance runner who can run for 100 miles, 200 miles. And a type II fiber, type IIa fiber, would be someone who is a decathlete. They can jump. They can run fast but not very far.

(11:52): And then there's the last type of muscle fibers. There are type IIb or type IIx. These are muscle fibers that are exceptionally powerful. These are the fibers that allow people to do crazy things like deadlift 1,000 pounds, for example. These fibers have very, very little to no resistance to fatigue. So those are the do-it-once fibers.

(12:14): Chemotherapy impairs the work of our muscles and weakens them through several mechanisms. And so when attention is paid to how chemotherapy and other drugs used in cancer treatment affect muscle, it becomes clear that there are several mechanisms which impair the work of muscle. In some situations, it can be direct damage to the muscle fibers, and there appears to be preferential damage to specifically the power fibers. So it would be the muscle fibers that allow people to overcome the force of gravity and get out of bed in the morning. And it's also fairly common for patients to develop neuropathy. And when nerves suffer damage, the muscles which are supplied by those nerves, also get weaker.

(13:06): Now, we know from some animal studies that the damage to the muscle can persist a little bit longer and be more profound when injury happens, not just once but several days in a row. So, for example, it's not uncommon for patients to receive a chemotherapy regimen that have a muscle-toxic drug on day number one and then a different muscle-toxic drug on day number three or day number seven. So, it becomes a fairly challenging situation.

(13:40): Now, when these damaged mechanisms are looked at under the microscope at the molecular level, what we find is that the strength of muscle fibers definitely goes down, the endurance of the fibers goes down, and the work of the muscle becomes less efficient. Sometimes, muscle cells even die. And there's definitely a good amount of mitochondrial damage or messing up the energy production system of the muscle that goes on.

(14:15): So why I am saying all these potentially unpleasant and depressing things, is this. So, when we have cancer, cancer treatment can certainly create challenges. We also know that when we're not feeling so well and we're laying down to rest, that potentially complicates things a little bit.

(14:44): Simply lying in bed for long periods can also deplete muscle mass and muscle memory. So if you take a perfectly healthy fit individual who is in a space cadet training program, if you put them in bed for 24 hours, you will find the following things. If you keep them in bed for up to a week, they will lose about 5% loss of muscle strength and about 3% of muscle size. So that indicates that it's not just about the size. Something else also happens that impairs their performance. And that problem has to do with the loss of muscle memory, or the connections between the nerves and the muscles becoming slightly more frayed.

(15:27): We know that the larger leg and thigh muscles are the ones that seem to be affected first by this immobility. And to make things even more complicated, people can be more prone to lightheadedness and dizziness after as little as 24 hours of lying in bed. And so, what this all comes down to is that if you're tired, if you're undergoing cancer treatment, you're not moving a whole lot, chances are you may not start moving unless something happens.

(15:59): Fatigue occurs because cancer treatment undermines the cellular machinery of how we do things. And so oftentimes, when patients come to me with concerns of fatigue and inability to do things. They say things like, "Well, if I could just work a little bit harder, things would probably happen." Or "Doctor, I've been lazy recently", and I hope that I've been able to convince you all that the reason why this fatigue and inability to do things happens is not because someone is lazy or because they're not working hard enough. It's because cancer treatment undermines the cellular machinery and the very tools that we use to get things done and move through life on day-to-day basis.

(16:52): Stimulant medications for cancer-related fatigue are not very effective. Now, the idea that if you just stimulate people a little bit, give them caffeine or give them medications like the stimulant medications that are typically used for attention deficit hyperactivity disorder (ADHD), it turns out that the effect of those medications in cancer patients is very, very small, less than 10%. And what's more concerning to me is that these medications come with a risk as high as 30% of worsening someone's sleep habits. And as we know, sleep is very, very important.

(17:31): Exercise and psychologic interventions are much better than stimulant medications for cancer-related fatigue. The studies that looked at the use of stimulant medications for cancer-related fatigue concluded that the primary interventions for cancer-related fatigue should be exercise or some sort of psychologic intervention, or exercise plus a psychologic intervention, but definitely not stimulant drugs.

(17:55): Positive thinking psychology can significantly improve cancer-related fatigue. So speaking about mindset, it's easy to fall into the trap of trying to accept responsibility for everything that happened and be upset about things that maybe have not gone right. But it's also important that every day you can do something different. Every day, you can try something new. And there is a system in modern psychology called positive thinking psychology, which basically takes advantage of the fact that, if you keep track of good things and make those things feasible and palpable, like write a letter or write a little diary entry, and plan for good things and take stock of accomplishing those things, you'll actually feel better. And this has been tried recently in transplant recipients. And it was found that even though the effect of trying to keep a positive diary and write a little something once a week wasn't super large. It was still significant.

(19:19): Simple mindfulness exercises and conscious breathing has been shown to help maintain healthy cell counts in cancer patients. And in my mind, I always wonder "If you do something good for yourself only once a week and it leads to a positive outcome, would it lead to a better outcome if you tried to do this once a day? That's been studied. Patients who were undergoing a stem cell transplant were asked to do about half an hour of mindfulness exercise. They were asked to relax, lay in bed, and concentrate their thoughts on the lower belly and do some very gentle moving while laying down. They were also asked to do relaxation and breathing for 10 minutes, taking slow deep breaths in and slowly exhaling the deep breaths. They were then asked finish with 10-minute of gentle ankle rotation and brushing their hair and stroking their face and a nice gentle stretching of their arms and legs.

(20:34): It turned out that consistently doing something that's not demanding at all resulted in pretty interesting changes in their blood counts. So, these were the results from that mindfulness and conscious breathing study, which showed that patients who did these breathing and mindful interventions were able to maintain their cell counts. Whereas patients who did not had a significant drop in white cell counts for six weeks.

(21:05): Expending energy to exercise can actually reduce cancer-related fatigue. So now, switching gears a little bit and talking about the physical side of things, it may seem counterintuitive : if you're already short on energy coins, why would you want to spend more of those coins in an effort to get better? And so, one of the first studies that actually looked at trying to use exercise to make transplant patients feel better, now almost 30 years ago, did exactly that.

(21:36): This was a study of 20 transplant patients, 17 of whom had a donor transplant (allogeneic transplant) and three had a transplant with their own cells (autologous transplant). They were all fairly young. On average, these were 36-year-old Germans. They were 18 to 42 days post-transplant, and five days a week, they used the treadmill. And every week, the speed of the treadmill was increased a little bit. So, it turns out that even though these patients were doing something that was quite tiring five days a week, they managed to increase their speed and distance and, more importantly, suffered no effects from doing it. So, they definitely did not feel more tired, and most of them actually started to feel a little bit better.

(22:25): Virtually any moderate exercise can reduce fatigue and improve other symptoms in cancer patients. Now, one would say, "Well, walking on a treadmill under supervision of a German exercise physiologist is probably not very practical because not everyone has access to that." And it turns out that since that study, there' have been many, many, many different interventions that basically concluded that no matter what exercise you choose, as long as it's not super strenuous and as long as it's done more or less regularly even during treatment, even during transplant, there are no side effects. Patients definitely do feel better physically. They demonstrate objective improvements in endurance markers. They report better fatigue scores. And in some studies, it was found that patients who exercised had fewer days with nausea, and none of the exercises were extremely challenging. There are some studies that used stationary bikes, some just used walking in the hallway or going up and down stairs. Some used easily accessible things like resistance bands or stretching using hospital beds, hospital chairs.

(23:41): Patients receive benefits in reducing cancer-related fatigue even when they chose their own form of exercise without professional help. However, all of these interventions, of course, were done under supervision of either a physical therapist or rehab aid or some other health personnel. And so, the next question that you might ask is, "Well, it's okay to do exercise under supervision of a trained professional, but can you really exercise without supervision and be successful?" And it turns out that yes, in fact, you can.

(24:08): So this is a study that's almost 20 years old, which was an examination of 17 Floridians. On average, they were about 49 years old, and they were 16 months post-transplant. The majority of patients received their own cells (autologous transplant). There were four patients in that study who received donor cells (allogeneic transplant). They were basically instructed to exercise at least three times a week for at least 20 minutes. They were supposed to work out hard enough to make their heart rate go up, and they could observe their on the heart rate monitor that they wore.

(24:47): Patients were allowed to do what they wanted. They could either do some cycling or some walking. They could do some swimming, because in Florida, you have access to swimming. They could do exercise videotapes. And what was found in that investigation was that after 12 weeks, fatigue scores, and that would be the thin red line, the fatigue scores went down. But what was more impressive to me in that particular study, objectively measured aerobic fitness went up by about 15%.

(25:25): Exercise can even overcome the declining aerobic fitness that comes with age and make patients “younger.” Now, this is super, super important, and I cannot stress this enough. Aerobic fitness, or the ability of a human body to use oxygen to do work, declines at the rate of about 10% for every 10 years of life. So, if you are looking at a study or you're reading a report where they say, "Because of this intervention, aerobic fitness improved 15%," you could translate that into these patients just became 15 years younger.

(26:01): Now, if you're paying close attention to this chart, you will see that these patients weren't super fatigued when they started at the outset. So, their fatigue levels were about 4 out of 12, which is generally considered to be mild fatigue. And so, the next logical question becomes, "Well, it's easy to exercise when you are already not that fatigued, but what if your fatigue is quite severe? Will this work?" Well, it turns out that, yes, in fact, it will.

(26:34): Exercise can reduce severe fatigue to mild fatigue and the benefits appear to persist over time. So, this is a relatively small-sample study. It's also almost 20 years old at this point. And this investigation looked at 12 Canadian patients who were, on average, about 49 years old, and were about three years out from a donor cell transplant. So, these were allogeneic transplant recipients. Their exercise intervention was stationary biking three times a week.

(27:06): On Monday, they were instructed to do 20 minutes of easy pedaling with the effort of about 2 out of 10. (Zero is no effort at all;10 is all out, about-to-pass-out effort.) On Wednesday, they were instructed to cycle for about 15 minutes at moderate-to-high effort, so 6 out of 10 effort. And then on Friday they were instructed to cycle for 20 minutes at about 4 out of 10 effort.

(27:35): So, it's a relatively low-volume intervention, and it turns out that after 12 weeks, these patients demonstrated significant improvement in their fatigue scores. So, they were about 7 out of 12, which is a severe fatigue score. After 12 weeks, they were able to get those scores down to 3 out of 12. So, they went from severe fatigue to mild fatigue. And what was most interesting, those low-fatigue scores remained low even nine months after completing of the study. And as a nice bonus, when these patients' aerobic fitness was measured, it appeared that it improved 17% over the course of 12 weeks. So that's like saying these patients got 17 years younger after a three-month long intervention. It's pretty impressive, isn't it?

(28:34): So just to recap, so far, we've talked a lot about physical interventions or mental interventions. But what happens when you combine them?

(28:50): Combining physical and mental interventions for cancer-related fatigue can dramatically increase aerobic capacity and physical fitness. This is really, really interesting. So this is a study that came out last year. This is out of Australia. They looked at 21 patients who were about 56 years old on average. They were just over three years out after a donor transplant. These patients had six weeks of virtual coaching. So, they had a one-hour session during which a physiotherapist, or some other exercise professional, went over their exercise program, made sure that they were doing things right, and answered their questions. They also had a 60-minute mindfulness session led remotely. They were then instructed to engage in aerobic exercise for 20 to 30 minutes most days of the week. They were also instructed to do resistance bands workout using major muscle groups, anywhere from three to five times a week.

(29:51): At the completion of that three-month study, what they found was that these patients had a 27% gain in aerobic capacity and physical fitness. So that means effectively, these patients became 27 years younger, which I think is quite impressive. There are very few things that have that kind of effect.

(30:15): Nutritional assistance is also important in recovering from cancer treatment and reducing fatigue. switching gears and talking a little bit about how we can power all of these gains and what problems can occur... it's not uncommon for patients to develop mouth sores as they go through transplant. Their taste can be altered. Nausea happens almost universally during and after treatment. And patients can develop food intolerances from time to time. Unfortunately, in some cases, both the stomach which is the upper gastrointestinal tract and the lower intestine can be affected by graft-versus-host disease (GVHD) which makes it very hard to absorb nutrients.

(30:58): Now, I'm not a nutritionist, and it's very, very important to have someone available who can explain food choices and how you can help get enough calories and building blocks to move forward. But what's important is that even simple things. like keeping a bottle of water on hand to keep your mouth from being too dry and regularly brushing your teeth and having good access to a dental health professional can improve your ability to chew, eat and swallow.

(31:40): Insomnia is another challenge for cancer patients trying to minimize fatigue and maintain fitness. And as we remember from the getting-things-done diagram, after fueling up, it's important to rest. We do know that the prevalence of insomnia in transplant recipients can be quite high. Not surprisingly, it appears that the biggest problem are the hospitals themselves regardless of whether you are in Turkey or in Germany, if you are admitted to a hospital, insomnia levels can be quite high.

(32:14): When I do my hospital rounds, it becomes a running joke when I ask patients whether they slept well. The usual responses, "Have you ever tried sleeping well in a hospital?" That's quite challenging with all the bells and whistles and alarms going off.

(32:31): And even post hospital admission, patients can have persistent issues with having to use the bathroom at night. They can have persistent pain. They can have restless legs and things of that sort.

(32:48): There are things to do about difficulty sleeping at night, like making sure that most of your fluid consumption is during the first half of the day, so that less urine is produced during the night. Not drinking alcohol. Wearing compression stockings during the day and laying down with your feet elevated for about 20 minutes before you go to sleep. Using the restroom right before you go to sleep so you won't have to use the restroom as frequently during the night. And then certainly, when necessary, we can use things for restless leg syndrome or for neuropathy that could be interfering with sleep. So it's important to talk to your oncologist or supporting care specialist about that.

(33:39): The best exercises for reducing cancer-related fatigue should have functional relevance and practical significance for improving quality of life. Now, I know we talked a lot about different types of exercise. Certainly, the pandemic created challenges for people to access exercise spaces, gyms, and even physical therapy facilities. One of the things that we came up with, when trying to figure out how to get people to do things on their own time and without much access to equipment, was this CHEAP-O scheme.

When picking an intervention, we looked for things that cost nothing and have meaning. In other words, if we're going to do some exercise, it should be something that has functional relevance and practical significance to things that you do on a day-to-day basis. It should be an exercise that is easy and safe to do at home or if you're visiting someone. It's an exercise that is adaptable. If you're having a good day, you should be able to do it. If you're having a slightly worse day, you should still be able to do it, maybe with a slight modification. Ideally, you want an exercise that is portable, meaning you can do it anywhere. And it's an exercise that is outcome-friendly, meaning it's easy for you to track your progress because, as we know, what gets measured, gets managed.

(35:14): A simple exercise like repeatedly rising up out of a chair can bring significant benefits in reducing cancer-related fatigue. So of all things that have been tried with transplant recipients, the general population, and patients with other types of cancer, we decided that the simple act of getting up from a chair seemed to fit all of those buckets. Everyone has a chair. So, you definitely don't need any equipment for that except for something that's sturdy and won't fall apart. We know that this chair-rising intervention has been linked to many good things. We know that if you practice, it definitely gets better. We know that it correlates very well with fatigue scores in both breast cancer patients and in transplant recipients.

(36:06): And so interestingly, when we look at the complicated phenomenon like cancer-related fatigue, we know that if we change one factor in the patient's life, it can change the fatigue score a little bit. If we change two factors, it can change the fatigue score some more. And so in breast cancer patients, it was found that if you change their ability to do this chair-rise test, in other words, if you train people to get better at getting up from a chair, it explains about 50% of the change in their cancer-related fatigue score which I think is a pretty good evidence for this energy production basis for the cancer-related fatigue.

(36:58): When you try to do things for the purpose of exercise, you have to have a plan. You have to know when to do it, how much to do it, how much not to do it. And so, as I'm sure many of you have seen in the popular media and the news, interval training exercise is something that's touted every once in a while. It's the best thing since sliced bread. It's so effective, it's so efficient, anyone can do it. It's so well-published that there's even this New York Times Scientific Seven-Minute Workout application available for most smartphones.

(37:44): A modified, less intense version of interval training can be effective and safe for patients dealing with cancer-related fatigue.  So the basic underlying principle of interval training is that if you do something really, really, really hard and you take a tiny little break and you do something really, really, really, really hard again and take a tiny little break and do this in short cycles in a span of eight minutes, you're going to get some benefit. The trouble with high-intensity interval training is that even if you're a relatively healthy college-age person, it's really, really unpleasant, and it's actually really, really hard to do.

(38:17): So, you can imagine taking a person who is quite fatigued, and maybe not feeling so great, and asking them to do something that's really, really, really hard and unpleasant. It's probably not a very good strategic plan.

(38:36): So, doctors 40 years ago realized, "Well, you don't quite have to go really, really, really, really hard. And you can take much longer breaks between exercise sessions and you can still get pretty good effects." One of those professors is Dr. Katharina Meyer, who's a cardiologist in Switzerland. And she found that if you play a little bit with how hard you ask patients to work and how much rest you give them between those exercise sets, you can do safe and effective workout even with patients who have heart failure and even in patients who just underwent heart surgery. And since then, since the mid-80s, this approach has been tried in a variety of cancer patients, and it was found to be effective and safe when done under appropriate supervision.

(39:34): Exercise to reduce cancer-related fatigue should follow three simple rules: If it hurts, don’t do it; don’t work too hard; don’t do things you’ll regret.  So now we're talking about exercise that we would want all of you to implement in your daily life. So there are three rules you need to remember if you're starting some sort of exercise protocol. Rule number one is, if it hurts when you do it, don't do it. A little bit of mild discomfort is okay sometimes, not all the time. If there's a persistent problem, you need to talk to your healthcare specialist and try to figure out what the problem is.

(40:12): Second rule is don't work too hard. The effort when you do things should almost never come up higher than 6 out of 10 with 0 being no effort at all and 10 being absolute hardest all-out effort. In other words, even if you do some sort of physical activity as an exercise, you should feel a little bit tired when you're done, but you should have energy to do other things in your day like enjoy a nice meal with your family or go out for a walk later or read a book or something.

(40:43): And the last rule is don't do things you regret. So, for example, if you do something and then the next day you feel overly sore or uncomfortable, then that probably wasn't the right thing to do, or maybe not as much of it should have been done.

(40:55): Sit-to-stand training can be modified to fit individual capacities and be done almost anywhere. So, this is how I try to implement these principles with the sit-to-stand training. The first thing that we do after some questioning and physical examination, we use those fancy exam chairs that go up and down to figure out how high the chair should be for a patient to be comfortable and able to stand up without using their arms, using only legs. And then we see how many times a person can do this, get up and sit down in a span of 30 seconds. I instruct patients to maintain effort below 6 out of 10.

(41:40): And from doing this for years now, there's one time that someone said, "Yeah. This was a 7 out of 10 effort." So based on how many repetitions a person is able to do in those 30 seconds, we then decide how we're going to make this into a training program that they can do at home. So for patients who are able to do five repetitions in 30 seconds or less, or they need a really, really, really high chair because they have joint pain or because they have significant amount of weakness. We start practicing sit-to-stand twice a day, so these are the sunrise and sunset group. And for most people, their bed is much higher than the regular chair. So you do the sit-to-stands after you wake up, and you do the sit-to-stands before you go to bed.

(42:36): Patients who can do 6 to 10 repetitions in 30 seconds become the breakfast, lunch, and dinner group. And that's probably the vast majority of patients that I see in the clinic. So based on how many they do, we do three sets per day. And then patients who are more fit are able to do 10 or more sit-to-stands in 30 seconds, they become the true interval training group.

(43:06): In a sit-to-stand training program, the number and speed of repetitions can be progressively increased to regain fitness. So this would be an example of a sunrise to sunset training program. So, the patient is able to do three repetitions in 30 seconds. They will start with just one repetition on day one. They will do one sit-to-stand in the morning and one sit-to-stand in the evening. And then the next day, they will do one in the morning and two in the evening. And then the following day, they do two in the morning, two in the evening, and so on and so forth adding only one extra repetition for every day of training gradually building up to about 6 repetitions at a time.

(43:42): Then in the breakfast, lunch, and dinner group, the training looks something like this. So, let's say patient is able to do nine repetitions during the in-office test. So, then they are instructed to start with four repetitions for breakfast, four for lunch and four for dinner. And the following day just add one extra repetition to the last set of the day and continue until they get to about 6 repetition per set.

(44:10): And similarly, for patients who are more advanced and are able to do more than 10 repetitions or sets, we advance in the same manner except their exercise is done only in one five-minute session per day. So many patients are instructed to get a timer. And after they warm up a little bit, they walk around the room a little bit. They get the timer going. And when the minute begins, they do the set number of repetitions. And then when the second minute begins, they do it again, and so on and so forth for set three and set four and set five. This is quite condensed and very time efficient.

(44:50): Keeping track of exercise routines and holding oneself accountable can eventually produce significant improvements in overall fitness for cancer-related fatigue. And so, to underscore the importance of keeping track and holding yourself accountable, I'd like to share with you a couple of cases. So, this was a situation of a 61-year-old patient who was readmitted to the hospital with very severe stage IV graft-versus-host disease of his GI system about a month after a donor transplant. This patient was in the hospital for seven months, suffered multiple infections, lost essentially all the muscle, and had a recurrent issue with back and joint pain.

(45:25): And what you can see in these x-rays is someone who doesn't have very healthy joints. And in the words of one of our therapists, this person had the stiffest hips ever. However, this patient's goal to dance at a wedding about three months after hospital discharge. So, when they returned home, they created this very intense looking, very involved Excel spreadsheet where they tracked every step, every activity, different types of workouts. And eventually, this patient was, in fact, able to dance at a wedding three months after, which I thought was incredible. But this type of detail is overwhelming, and it's not for everybody.

(46:12): Even simple things, where you just pencil things down as you go along on a simple table, can actually be quite helpful and effective. So, these scribbles came courtesy of a patient who decided to practice sit-to-stands at home, and he was able to go from using a 28-inch high seat in May to using a regular seat, 22-inch seat, only two months later, and was able to increase his performance from three repetitions per workouts up to 14 repetitions.

(46:54): Transplant-related fatigue is a result of the treatment process and not a personal failing. Patients should start with whatever exercise they can do and gradually build up from there. And so, with that, I would like to reiterate that the fatigue that transplant recipients experience is not a personal weakness or a character flaw. Almost all of it is just the result of the cancer and the treatment process. It's important to start low or start where you can, proceed very, very slowly, and absolutely give yourself credit for every little thing that you're able to accomplish. Don't work too hard. Don't suffer too much pain. Try to stick to the routine. So make your bed, brush your teeth, stay hydrated, talk to your team, and try to get some rest which can require some changes like taking the TV out of your bedroom, for example. But it's a habit that will be very, very helpful.

(47:50): I did share some of the links to easily accessible, easily done and safe exercise videos. And with that, I welcome any questions, comments, or jokes.

Links:

Breathing Exercises: mskcc.org/cancer-care/patient-education/video/breathing-exercises

Chair exercises: mskcc.org/cancer-care/patient-education/chair-exercises-01

Beginner Bed Exercises mskcc.org/cancer-care/patient-education/beginner-bed-exercises-01

Intermediate Bed Exercises  mskcc.org/cancer-care/patient-education/intermediate-bed-exercises-01

Advanced Bed Exercises:  mskcc.org/cancer-care/patient-education/advanced-bed-exercises-01

Question and Answer Session

(48:06): [ Michala O’Brien]:Thank you, Dr. Syrkin, for this excellent presentation and those helpful videos. We'll now begin the Q&A session. Our first question is, can you discuss the best diet to combat fatigue? Are carbs okay?

(48:40): [Dr. Grigory Syrkin]: All right. So, I have to start by saying I am not a nutritionist, but carbs are definitely okay because carbs represent the most easily accessible form of energy that a person can absorb. And yeah, that's really it. Carbs are important for both short-term work and long-term work. And as I mentioned, there could be individual carb intolerances that develop during treatment. And it's very, very important to work with a nutritionist that can help you sort these issues out.

 From my experience working with excellent nutritionists, I will share with you that one of the most helpful pieces of advice that they give their patients is that when trying to figure out what works and what doesn't, it's very, very important to write things down. Just like it's important to track the number of repetitions and such, it's important to write down what you ate and when you ate it and how it affected you, so you can get a much better idea of what works for your body and what doesn't.

(49:52): [Michala O’Brien]: This question comes from a caregiver whose spouse is almost five months post-BMT. And when they're sleeping, how can you tell if his body needs rest or should I wake him up and take him for a walk?

(50:12): [Dr. Grigory Syrkin]: Right. So that is a great question. And so what I would say, in that situation, it's very important to try to figure out if this excess daytime sleepiness is the result of poor sleep at night. And if so, the first step would be to try to fix this disordered nocturnal sleep. Now, if sleeping at night is okay and this patient is still sleepy during the day, then what you do is you take advantage of those short periods when they are awake during the course of a day. Now, that is why I think short little exercise sessions like the sit-to-stands, for example, or just sitting in a chair doing some seated marches or doing some stretching or breathing can be so, so valuable because there is nothing in the exercise physiology world that says your exercise has to be done in one sitting, otherwise, it's not effective.

 It really is the total amount of physical activity that a person does in the course of a day that makes the difference. In fact, when scientists who study longevity look at which people do the best long term, it is those people who are not killing themselves in the gym one hour a day and then sit the rest of the day. It's basically people who try not to sit still. It's people who do a little bit of physical activity in little chunks spread out evenly throughout the course of a day. So, I would say if your loved one is sleepy most of the day, do take advantage of the times that they are not sleepy, because we do know that it's probably not a very safe idea to try to do exercise when you are about to fall asleep.

(52:16): [Michala O’Brien]: This person is two years out from transplant, and they haven't been exercising. They want to start exercising. How long would it take to get back to the original strength I had?

(52:28): [Dr. Grigory Syrkin]: Oh, it's impossible for me to answer this question because I don't know what the baseline is. But if I extrapolate from other patients that I take care of, I would say it depends on how active a person is before the transplant. Let's say they're highly active. Let's say they go to a boxing gym to do workouts, not necessarily to fight people, but just to be in that atmosphere and hit the punching bag a little bit and do some weights and do some skipping rope. It may take up to a year and a half to two years to get back to that kind of high-level activity.

(53:21): [Michala O’Brien]: This person is also about two and a half years from an allo transplant, and they get very fatigued in the later afternoon. Will this ever go away? Or it will be something that stays with you for a while?

(53:39): [Dr. Grigory Syrkin]: Well, so then my question will be, what have we tried to do to fix the situation? Is this an issue where maybe sleep is not as good during the night? Is this a situation where it's very easy for this person to get short of breath with tasks? Is this a physical fatigue phenomenon? Or is this more of an insufficient sleep mental fatigue phenomenon? And if the sleep is good and there's just not enough gas in the tank at the end of the day, then I would say it's probably a good idea to start implementing interventions targeted at getting more gas in the tank. So that would be aerobics and some resistance training.

(54:33): [Michala O’Brien]: Could you please address fatigue as it relates to low hemoglobin count and low pulmonary function test scores?

(54:41): [Dr. Grigory Syrkin]: Absolutely. Excellent questions. So, one thing that we do know is that patients can adapt to fairly significant insults when given enough time. So, for example, people who live at high altitudes become very efficient at extracting little oxygen from the air with whatever blood cells they have. And so I find that in my patients who are chronically anemic, for example, with hemoglobin so low that, in some situations, there would be a contraindication to exercise participation that over time, these low numbers really aren't that big of a factor. The patient's systems learn to be more efficient at oxygen extraction and using that oxygen to make ATPs and power cellular processes.

Now, pulmonary impairments are a little bit more challenging in the sense that there are different types of pulmonary impairments. Sometimes, patients can develop issues where it is hard for oxygen to be diffused from the air into the bloodstream. Those are tougher to deal with. But in the end, you can bypass pulmonary problems by improving peripheral adaptations. This is why cardiopulmonary rehabilitation or pulmonary rehabilitation is a recognized intervention. The gist of it is that patients who have lung problems or heart problems are trained, under supervision of a medical professional, to teach their muscles to be more effective, more efficient at using whatever oxygen is in the bloodstream to do the work and overcome fatigue and disability that way.

(56:46): [Michala O’Brien]: It looks like we're running out of time, so this will have to be our last question. Do you have any data on expected fatigue durations after CAR T-cell therapy?

(56:59): [Dr. Grigory Syrkin]: No. Off the top of my head, I do not know of any. The CAR T interventions are something new, and I’m sure we'll learn more about them in the next few years. But what I can tell you is that the training principles, as they relate to CAR T and donor cell transplant and autologous transplants are essentially the same. Exercise works if you do it, but you have to optimize things like sleep and nutrition to get the most out of it.

(57:35): [Michala O’Brien]: Closing. Thank you. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Syrkin for a very helpful presentation. And thank you, the audience, for your excellent questions. Please feel free to contact BMT InfoNet if we can help you in any way.

(57:55): [Dr. Grigory Syrkin]: Thank you very much for your time. I hope this was helpful.