Managing Fatigue

Chronic fatigue is common after transplant and is caused by many factors. Learn what you can do to improve it.

Speakers: Kenneth Miller MD, Tufts Medical Center; Christina Ferraro MSN, CNP,CMTCN, Cleveland Clinic

Recorded October 12, 2019 at the National GVHD Patient Summit

Presentation 40 minute, Q&A 20 minutes

Highlights of Presentation:

  • Fatigue is the most common complaint of long-term transplant survivors
  • Fatigue can be caused by many factors including poor sleep, chronic pain, poor nutrition, medical problems, medications, depression and/or anxiety
  • Exercise, targeted physical therapy, energy conservation devices and planning your day so you have energy for the things that bring you joy can help manage fatigue

Key Points

01:18 Cancer fatigue is a distressing, persistent sense of physical, emotional and/or cognitive tiredness or exhaustion not proportional to recent activity

05:12 Why patients and physician often don’t discuss fatigue

10:23 Fatigue can be caused by poor sleep, chronic pain, poor nutrition, medical problems, depression and/or anxiety: 

14:50 Medicines to treat nausea and vomiting, pain and/or cancer can cause fatigue 

15:29 There is higher incidence of fatigue after transplant in people over age 35, women and in people who got total body irradiation before transplant

17:22 When the brain senses certain types of inflammation, it programs the body to induce fatigue, sleep disturbance and depression:

22:55 Exercise and targeted physical therapy help reduce fatigue: 

26:40 Plan your day and use devices to conserve energy so you have it available for activities that are important to you during the day

29:11 Stimulants, used properly, can help with alertness and fatigue; anti-depressants do not: 

31:59 Eurgerics such a Provigil and Nuvigil are alertness-enhancing drugs that can help some people with fatigue: 

38:33 Preventive strategies you can take to help manage fatigue

Transcript of Presentation

00:00   My name is Kim Langer. I'll be the moderator for this afternoon's session and I'm excited to hear about what Dr. Miller and Ms. Ferraro have to tell us this afternoon about managing fatigue.

Please join me in welcoming Dr. Kenneth Miller and Ms. Christina Ferraro.

Dr. Miller is an Associate Chief Hematology/Oncology at Tufts Medical Center and a Professor of Medicine at Tufts University School of Medicine. His research focuses on developing transplant regimens that are associated with less toxicity and addressing the importance of maintaining quality of life.

Ms. Christina Ferraro is a BMT nurse practitioner at the Cleveland Clinic. She leads the Victor Fazio, MD BMT Cancer Survivorship Program and has experience seeing patients with GVHD, and patients in long-term follow up. She emphasizes patient empowerment, education and support. Please welcome Dr. Miller.

00:57  [Dr. Miller] Thank you very much. It's a pleasure to speak on a topic that's very dear to me on fatigue, and thanks Sue Stewart for inviting me again.

01:18  Fatigue is now recognized as a distinct medical entity that interferes with transplant survivors’ quality of life:  That's me. So, I need someone to help. I'm too tired. I'm more short of breath and it's characterized as I'm weary.

Well, I'll do it tomorrow. It can wait. I did too much yesterday, and we characterize that as exhaustion.

My back hurts. The medicines make me tired. My joints, legs and hands hurt, and we characterize that as lassitude.

I wake up tired, not refreshed, and I don't sleep well. And again, we use the term malaise for that.

My memory is not what it used to be. I have trouble concentrating. I am emotionally labile. And we characterize this as cognitive impairment.

But all this is really part of the spectrum of fatigue, and fatigue is now recognized as a distinct medical entity, and hopefully at the end of 45 minutes you'll understand more about it. But the most important thing, it really does interfere with the quality of life, of long-term survivors of transplant and survivors of chemotherapy.

01:18  Cancer fatigue is a distressing, persistent sense of physical, emotional and/or cognitive tiredness or exhaustion not proportional to recent activity:  So, what is cancer fatigue? And there's a definition supplied by the National Cancer Institute. It's a distressing persistent sense of physical, emotional and/or cognitive tiredness, three features, or exhaustion that is not proportional to recent activity and interferes with usual function. So, it's both physical, emotional and cognitive is now recognized as part of this overall concept of fatigue that happens when patients are cured, long-term survivors and following transplant.

What do patients complain of? "Oh, I feel so weak. I feel heavy. I'm tired. Every part of my body is tired. Oh, I lack motivation, interest in others. It's really typical. I have trouble sleeping at night." In fact, it's usually one of the first signs, either difficulty sleeping or hyper sleeping. "I'm too tired to think clearly." Patient say, "I used to work seven days a week. I used to have lots of interests. I used to socialize frequently. I used to go out. I used to be interested in sexual activities." All those are manifestations of fatigue when patients are cured of their disease.

03:50  Fatigue is the most common complaint of long-term transplant survivors:  In fact, it's the most common symptom associated with cancer long-term survivorship. These individuals who have cured been of their cancer, have received treatment, or a transplant. And when one looks at the data, what patients report, that almost 80% of patients report fatigue is the dominant symptom that they complain of long-term. Pain, well, a focus of great activity is only about 30%, and nausea is only about 15%. The fatigue is the most distressing symptom that patients complain of.

Moreover, the quality of life concerns in transplant survivors who are survivors for greater than one year following their either auto[logous] or allo[geneic] transplant, fatigue is again the major complaining symptom of close to 60% of patients. While they're concerned that they don't look like they did before the transplant because of either the treatments, or the medication they're on, or the lack of sexual desire is a big issue, and depression which very much follows fatigue, but it is really the fatigue that is the most distressing syndrome of patients who are out one year after the transplant, and theoretically past the period of where disease has the highest incidence of relapse.

05:12  Patients often don’t talk with their physicians about fatigue:  Do we tell physicians? Do patients talk about it? And there's been an evolution of this looking back in 1989 where fatigue was still an issue, but only about 15% of patients talked about it. Well, in '98, it went up, and in 2007, 80% of patients acknowledge that fatigue is a meaningful side effect of the therapy given to them.

Do you tell the doctor? Do our patients tell us that they have fatigue? Is this an issue that they bring up to us? And the answer would be no.

This survey was done where they asked two groups, they asked the physician and then asked the patient as they left the physician's office, "Did you talk to the physician about these issues?" And only 9% of physicians asked the patient about fatigue. Well, 80% of patients felt that they really had fatigue as being a major issue, it was just not addressed by the physician.

When they asked for the quality of life, "How do you feel after the transplant?" Only about 22% of physicians addressed that. Well, 33% of patients, almost a third, thought this was an important discussion that they should have with their physician ,but didn't.

So, where do patients, in fact, gather their information from? This is a bit of a distressing slide, but where do patients go to get information dealing with these important issues in their life? 27%, so about a quarter, speak to their physician. 21% present this office material or speak to the nurse practitioner or nurses about these issues. But most patients still use the Internet. And while the Internet is very good if you're ordering Chinese food and figuring out which is the best restaurant, as you know, the Internet is not a scientific source of information and is not, at least in the physicians hand, a reliable source of information, but is the major source where patients derive information about dealing with fatigue, tiredness and the post-transplant complications.

07:27  Why physicians don’t ask patients about their fatigue:  So, why don't physicians ask? They asked the same group of physicians about why you don't ask your patients about this important issue?

Well, it's not a big problem, they thought. The bigger problem is the disease, and the treatment, and what they've been through. More important issues to discuss. What medicine you're on, what your electrolytes are, what test I'm going to do. The physicians felt I have limited access to what I can do to fix it, therefore I'm not going to devote a great amount of time to it, therefore I don't ask.

And we are limited on how much time we do spend with patients. It's now this 15 to 20 minute interval. Electronic medical records have certainly changed how we relate to patients.

And the last is the physician says, "Well, I'm tired all the time too, so I sort of accept this as part of life." And that may be true.

08:24 Why patients don’t ask their physician about fatigue problems:  And the question is, now, why don't patients ask then? The same group of patients, they asked, "Why don't you ask the physician?" And some of the answers were similar.

One of them is they fear that fatigue was their first sign of relapse. So, if they bring this up again, are they telling the physician that my disease is relapsing, and there's a fear of that, and in most cases, it isn't. It's just fatigue. But patients are obviously and individuals are concerned by that.

Doctor really doesn't know how to fix it and the patients perceive that this is a topic that we, as physicians. don't know how to deal with well, or we have limited number of therapeutic interventions and if we can't fix it, why are we spending time on it?

There are more important issues to discuss, like the physician say. The treatment, graft versus host, the treatment of your disease, the complications of therapy and other illnesses.

And there's not enough time to discuss. Patients perceive that we really are limited in the amount of time we have for interactions. 15 to 20 minutes is not very long to discuss important issues with complicated patients.

And then the last is that patients inappropriately feel it's their fault. I'm just not doing enough and therefore that's why I'm tired. And hopefully at the end of this session, you'll realize that's not the case, but patients perceive it is their responsibility to do more and therefore feel less tired, to be more socially interactive, and do more with their family and friends.

10:01  There is a scoring system for fatigue:  There's now a scoring system, which has been developed for fatigue, from zero - which means patients have no fatigue - to 10, that's the worst fatigue that they can't do anything about. And physicians should use this, and as patients, you should tell your physician the same scoring system so it becomes part of your record. There are benefits for that, which I'll go through.

10:23  Fatigue can be caused by poor sleep, chronic pain, poor nutrition, medical problems, depression and/or anxiety:  And so, what do we know about it. Essentially fatigue is related to a lot of causes. One, sleep disturbances. If you don't sleep well, sleep hygiene is an important issue. Don't sleep whatever number of hours you need to be restful, well, the result is fatigue.

Chronic pain obviously can produce fatigue although it's associated with the medicines to treat chronic pain.

Poor nutrition. Loss of protein intake. Decreased caloric intake, or increase in just carbohydrates all contribute to fatigue.

And then there's the co-morbidities, which are fixable. Endocrinopathies, the thyroid being low, cardiac function, respiratory ailments, all these contribute to fatigue that should be looked into.

And then the last is the emotional component of the financial issues of going through a transplant or cancer therapy, which is meaningful. Anxiety associated with if the disease comes back and how it affects their family, and depression associated with their disease and their prior treatments. All these contribute to fatigue and therefore make it a much more complicated discussion in this 15 to 20 minutes we have to speak to our patients.

There are overlapping features between poor sleep, now characterized as sleep hygiene, that patients don't sleep as much as they should, don't get the required rest. That depression presents as fatigue and withdrawal, and it's treated with antidepressants.

But fatigue is really something different. And while they have overlapping features in this Venn diagram, they are meaningfully different. Fatigue is a separate distinct entity caused by separate biologic features that are distinctly different than patients who don't get adequate sleep, that are depressed about their illness. They may have all those features, but fatigue is something uniquely different.

12:30  Anemia, loss of muscle tone and weight, and loss of protein contribute to fatigue:  So, what are the contributing factors? Well, the easiest one is anemia. Patients who are profoundly anemic, their blood is low, don't have enough oxygen carrying capacity, may respond to red cell transfusions, and as you get older, their red cells need increases.

And then there's this new word, which is in the medical vocabulary called frailty, characterized somewhat as being frail. And that's where individuals lose muscle wasting or they're with protein loss. So, it's not just losing weight, but losing muscle. And characterizing an individual as being frail is not the same as they're thin or lost weight. It categorizes an individual who has this syndrome of their loss of muscle tone, muscle weight, and lost body protein.

Why this happens is very complex, and I'm going to talk more about this, but it has to do with ongoing inflammation associated either with the treatment, the disease, or features that we still don't understand. Inflammation from the prior therapy, in fact, stimulates the immune system, and this immune system tells the brain to feel fatigued and tired. The brain is responding to stimulation from parts of the body from this ongoing inflammation.

14:00  Lack of physical activity, poor sleep and depression can increase fatigue: There's a positive feedback loop from just feeling fatigued. If you're fatigued, you're less physically active, deconditioning, you lose muscle mass, you become frail, and therefore there's increased weakness which causes more fatigue.

Fatigue, you tend to nap during the day and therefore you have trouble nighttime sleeping, and daytime fatigue increases if you don't sleep well.

Fatigue, there's less participation in emotional favorable activities, and therefore individuals become depressed. And while aging and getting older is not a disease, loneliness associated with that is associated with multiple diseases. So, fatigue isolates patients from their family.

14:50 Medicines to treat nausea and vomiting, pain and/or cancer can cause fatigue:  Nausea and vomiting associated with the treatment or the medications results in fatigue. And often the medicines we use to control nausea and vomiting, while now being effective, are also associated with fatigue.

And then the medicines that we use on day to day basis, so the antiemetics, the opioids, and pain medications are all associated with the resulting side effect of fatigue.

And then obviously, the treatment of the cancer. The cancer drugs are associated with fatigue because they cause some muscle wasting and some last for hours.

15:29 There is higher incidence of fatigue after transplant in people over age 35, women and in people who got total body irradiation before transplant;  What are the studies that's associated with fatigue? The older you are, greater than 35, there's a higher incidence of fatigue after therapy. Same in the transplant community. Individuals over the age of 35 who undergo both types of transplant do have an increased incidence of fatigue.

The second point is somewhat unique. Usually females are much more resilient than males, but in the area of fatigue, the incidence of fatigue is much higher in females than it is in males. And while the males who write the article say it's because the females have a greater responsibility to take care of the males, but there's a meaningful difference, which is probably biologic.

It does correlate with sleep disturbance. So, patients who have poor sleep hygiene have an increase in fatigue. Patients who got total body radiation for their transplant have an increased incidence of fatigue.

16:30  In some cases, fatigue after transplant does not go away:  And the last point that is the most disconcerting, is that sometimes it doesn't go away. Many of us say, further out from the treatment of your cancer, further out from the treatment with the transplant, the less likely you have fatigue. And in some individuals it really does not improve because the mechanisms don't change.

Well, sleep disturbances are clear. If you have mild sleep disturbances, you have mild fatigue. Severe sleep disturbances, we have trouble sleeping, results in severe fatigue. And in fact, in some illnesses, the sleep disturbance - either not able to sleep or too much sleep - is the beginning of the onset of the development of chronic fatigue.

17:22  When the brain senses certain types of inflammation, it programs the body to induce fatigue, sleep disturbance and depression: Why does fatigue change? And I have to say in the last few years, there's been an enormous understanding or an enormous rethinking about what other mechanisms [cause] fatigue, and it's not just being tired. It is really activators as mediators of inflammation. While we may not recognize this, when one looks at the patient for mediators, they're increased, which signals the brain to promote ... and this is now the term, sickness behavior. The brain sense, by the ongoing inflammation, to produce a behavior that it programs the body to induce fatigue, disturbed sleep and depression. It is the inflammation that the brain senses to produce this sickness behavior, which is mediated by these inflammatory agents.

In fact, when one looks at the expression of the inflammatory genes, they increase in patients with fatigue and there's abnormalities of energy metabolism. So, muscle function is impaired, their energy requirement is increased because the brain is telling muscles to function improperly and because of the ongoing inflammation. So, there is a biologic correlate that we're beginning to understand to address what causes fatigue in individuals.

With the energy requirement of this abnormality, is energy metabolism. Muscles function abnormally when patients are fatigued. So, you're not just tired, but the muscles also function abnormal. The muscles therefore have increased energy need for the same amount of effort a patient who has fatigue on a biologic basis has to work harder than a normal individual.

19:12  Some factors that contribute to fatigue can are reversible:  Anemia does increase their oxygen requirement of tissues, poor nutrition, decrease protein intake, all contribute and are reversible in part by fatigue.

And immobility, and sedating medications. Again, it's a self fulfilling prophecy. Fatigue, you do less activity, you're less mobile, muscle strength decreases, and then medicines that we use that sedate them.

The GI tract is really very important. Obesity we now understand is a chronic inflammatory disease, and that's why patients with obesity have many chronic medical problems. That just being obese increases the background inflammation and is associated with an increased fatigue.

Same with poor protein intake, which interferes with the building of muscle and vital structures. Or diarrhea where you lose electrolytes. What's your diet like? What's your intake? Or patients with chronic fatigue frequently don't eat enough and therefore lose weight and lose muscle mass.

And then the same concept for fragility, where patients are frail and lose muscle mass and lose protein production. Poor oral intake is critical for the GI tract as a major energy source. And patients who lose weight on their ongoing therapy, in many cases is due to a GI effect, either they're eating the wrong foods or the wrong time. GI tract is critical in our evaluation of how we regulate energy.

21:00  Factors that physicians should use to asses a patient’s fatigue:   So, we have two measures with this that we think of fatigue differently, and it's not just being tired. And therefore the evaluation of the patient's fatigue, we need to think about in a broader sense. And there will be better studies to evaluate this.

So one is just simply energy. How much energy does it require a patient to walk 100 yards? We have this entity of looking at a six minute walk. How fast can they walk? Which really determines their overall energy output.

What's their mood? Depression is something separate from fatigue, but fatigue frequently causes depression and should be documented.

What's their intellectual capacity? People who were very cognitively functioning before they got sick, what happens after they get sick? You need to document and look at this.

What's their family life? Do they relate to family members like they did before? All need to be assumed that this is part of the same complex.

What's their sexual relationships with family members? Again, a manifestation of fatigue.

And what was their professional life? Have they gone back to work? Are they employed? Were they previously working and now they're not? All this is a manifestation of the fatigue that needs to be looked at and addressed.

And what did they do for their leisure activities? Are they avid sports fans of watching TV, or going to sports games, or interacting with family members, and they stopped doing that? It is a critical feature of ongoing fatigue.

So, it's not just the patient saying, "I'm tired," but it's this whole symptom complex that needs to be evaluated. All this obviously impacts the quality of life more than most of the other symptoms that patients have.

22:55  Exercise and targeted physical therapy help reduce fatigue:  One of the things that does work is exercise in most of these studies. Well, exercise seems to be good for almost everything. So, patients with fatigue or are after-treatment for their cancers or are post-transplant have physical deconditioning. Strength training is helpful. Adding weights to an exercise routine, putting pressures on, helping building muscle really does help and does help overcome fatigue.

Targeted physical therapy. Targeting the large muscle groups that will increase the benefit for the patient the most, it should be part of the physical activity.

This should be combined with cognitive behavioral therapy, that you should plan your day, you should use muscles that are strongest at certain parts of the day.

Aerobic is better than non-aerobic. Therefore, getting your heart rate up for a certain period of time helps. The party line of 150 minutes a week is unrealistic in most patients. The data would suggest that just 10 minutes every other day to start, starts building muscle and overcomes some of the negative impact of deconditioning. And supervised is better. So, if you have a trainer, or a TV program or someone who inspires you and says you have to do this every other day, the outcome for those patients who perform exercise to treat their fatigue is better. In fact, it's the only so far, effort consistently shown in prospective trials to help fatigue across the board.

Why does exercise help. Well, besides exercise being generally thought as being favorable, it does optimize function in multiple systems. Patients feel better, their heart feels better, they take deeper breaths, they open up small airways in their lungs. There's a change in muscle biochemistry if you do exercise, muscles respond better when you exercise them than when you sit on the couch and don't exercise. So, there's a biochemical mechanism associated with why exercise would work.

Oh, the other is it delays muscle fatigue. Stronger muscles, patients feel less tired, they're able to do more and therefore can do more exercise. There's also ... which is important, there's a decreased perception of fatigue and shortness of breath. And while patients' pulmonary function may not change, their perception of being short of breath or being tired does change. So,while you may not be able to see much change in the numbers, patients perceive that they are less tired and less fatigued, which is really a very important endpoint and outcome.

decreased depression and anxiety. Exercise has been used to treat both. It's an avenue to overcome both of these.

And there's cognitive behavior changes associated with exercise, that you're participating and making yourself better. So, there's a uplifting feeling that you're doing something for yourself, and that translates into improvement overall.

Cognitive Behavioral Therapy is the new term that applies across the board for this. What does this mean? What are the tactics? Well, it's targeted physical therapy. So, if your legs are tired, you want to target the muscles of your legs to make them stronger. If you feel that your arms are more tired, you're going to target your exercise for your arms. But you're also going to spare those muscles and not stress them out more even during the day. It's changing illness-related thinking in part. It's an adaptive approach.

26:40  Plan your day and use devices to conserve energy so you have it available for activities that are important to you during the day:  There's nothing wrong with using a wheelchair. My clinic is 200 yards from the elevator. I tell my patients, "There's nothing wrong with taking a wheelchair if [walking] makes you tired. You need to conserve your energy."

Chairlifts, so you don't have to climb up stairs, so you don't use energy when you don't need to.

Or oxygen at critical times when you feel more short-of-breath helps.

If you're in the supermarket, using a cart or sitting in a car, conserving your energy for things that are important in your life.

And even walking , itself, for a short period of time, is helpful to increasing muscle strength. So, it's the concept that I'm going to conserve my energy when I can conserve my energy so I can use energy and my muscles when I need to that's important in my quality of life.

Help yourself conserve energy. Use the wheelchair, use the cart, using the lift, using oxygen. These are motivating and encouraging patients, so you don't have to try to push yourself that far. You need to think of yourself as conserving your day.

You need to maintain social contacts. So even though you may now feel too tired to see your cousins, maintaining social contacts is really critical for overcoming fatigue and looking at cognitive behavioral changes.

But the key is the last line. You don't want to set yourself up to fail.

Sometimes you need to plan your day. If there's an important function, you don't have to do all the activities. And I structure my patients. I try not to book appointments on important days for patients, anniversaries, birthdays, they have an outing, you don't want energy to be used for things that are not going to bring joy to them or increase their quality of life. Patients need to plan their day, and you as a physician or health care provider, need to help patients to plan their day.

I do quote John Lennon is that, the reality leaves a lot to the imagination. How you're planning your day and what's important to you is [what] patients have to think and plan. They have to structure their days, so at their peak time they're doing things that are enjoyable.

29:11  Stimulants, used properly, can help with alertness and fatigue; anti-depressants do not:  There are drugs. There are alertness enhancing agents, the psychostimulants, and while there's some controversy about them, they do help given in a certain way.

Antidepressants have been used, thinking that patients are depressed. Most of the studies have shown these are really ineffective. Wellbutrin is better than other antidepressants since it has somewhat of a stimulatory effect, but most patients are really not depressed. So, the studies suggest there's very limited benefit for treating depression with antidepressants, or caffeine, drinking more coffee or a few espressos has very limited activity except you walk to the bathroom more frequently. And I do tell my patients when they got on the airplane, they should drink extra coffee so they get up and move to the bathroom. It avoids DVTs.

Stimulants do help, and the most commonly used would be Ritalin. And there are issues with stimulants. One, they are restricted. Physicians can only write a month at a time, they are somewhat regulated, but they do help.

When to take it is critical. And most of the studies tell patients to take it every day. And [that’s] inappropriate in this setting because your body gets used to these drugs. So, taking them before you do activities, before you exercise, before you go to family events is the most appropriate use.

They do have an addictive potential and one needs to be aware of that. The more you take the more you get used to them. But I advise my patients, in fact, to take it prior to activities, prior to doing their exercise, prior to family events that they want to participate in. So, if they need four hours of energy, taking two doses of Ritalin before that allows them participate in activities and allows them to do exercise.

But I caution them [against] trying to take this every day. Their body will get used to it and it won't be as effective. You want to take it in the morning, not at night because it'll keep you up. Studies suggests there is a benefit when you take it intermittently but not every day because your body will get used to it.

And there are side effects. Some people don't like the jitteriness that occurs with these medicines. There are a fair number of them and sometimes you need to adjust the dosing for the patient, and the timing, and which of the stimulants are you going to use.

Ritalin is the most widely used. It's short acting. It lasts about four to six hours, and I usually tell my patients, before you're going to do exercise, if you feel too tired to do it, you should take your Ritalin a half hour before and you'll be able to participate better.

31:59  Eurgerics such a Provigil and Nuvigil are alertness-enhancing drugs that can help some people with fatigue:  There are a number new drugs that also are non-stimulants, but they are alertness enhancing agents. They are eugerics which means good arousal drugs. And while they have some stimulant features, they're really not true stimulants.

This is what the pilots took flying to Iran and the war where it was an 18 hour flight. [They are] usually prescribed for patients who have sleep-wake disorders, or chronic fatigue syndrome, or who work night shift and day shifts, so they're not stimulated but they don't feel tired.

Because of this, they have a less addictive potential, but they do have some addictive potential. In some, it is a meaningful issue because they hang around for a long time. So, if you take two in the morning, patients may not start falling asleep until 2:00 in the morning. Again, there's the same feeling. If you take this every day, your body gets used to it.

It's not approved for cancer-related fatigue. Provigil was the first, which is now generic and therefore is less expensive. Nuvigil is the newer agent. There is concerns about once a day, the advantage of it, but the dosing for overcoming fatigue is not so clear. They're not addictive. They do have side effect profiles that patients don't like. Dry mouth, inability to sleep. And again, the same issues, you take it every day, they lose their effectiveness.  I tell my patients the same thing, if you will need more energy for a longer period of time, one or two of these agents may be beneficial. Again, it's on a patient to patient basis.

33:47  Make sure your doctor, uses in your medical record, the proper ICD code for cancer-related or transplant-related fatigue; it can affect which drugs insurance will approve for treatment as well a disability benefit:  Now there are ICD codes. Those that live in my world, this is an important change. So, there's a medical documented code associated with cancer-related or transplant-related fatigue. It helps you . And, therefore, a physician you’re seeing, you have to make sure they document the ICD code because it allows [your physician] to prescribe medicines for treating patients who have fatigue. It does help with getting certain disability benefits, because now it is recognized as a distinct medical illness. And it helps you obtain services and payments. So, by documenting the ICD code in the chart, patients have benefits that would otherwise not be available to them.

And with this, there are certain words that you need to tell your physician, so these are documented in the chart that coincide with the ICD codes: Diminished energy. Increased need to rest. Disproportionate recent activities. Complaints of generalized weakness or limb heaviness. Diminished concentration. Motivation is decreased. Hypersomnia. They sleep too much or don't sleep enough. Perceived struggle to overcoming activity. Marked emotional reactivity. I don't relate to my family members like I did before. Difficulty completing a task. Again this is something you should mention to your doctor. Perceived problems with short term memory and post exercise fatigue. These are all part of this ICD code, and these are keywords to tell your physician to document in the medical records to which insurance companies look for these words to give you that ICD code, and there are benefits associated with once this diagnosis is established.

35:45  A multi-disciplinary approach is needed to treat transplant-related fatigue:  The NCCN [National Comprehensive Cancer Network) has some standards now, recognizing fatigue as a distinct clinical problem and long-term survivors for treatment, and one that should be [treated with] a multidisciplinary approach. It's not just the physician, there should be a physical therapist, there should be a social worker, someone who's interested in exercise. OT [occupational therapy] is important to make sure the help is set up so you're not wasting energy, and same with physical therapy. So, there should be a multi-disciplinary approach, and if you're not getting that, you should ask for it because it's all part of this ICD code designation.

Part of it is you need to educate and train health professionals. In our clinic, there's a chart on every room. We're asking patients to grade their fatigue on a scale of zero to 10. So, we document it. But it's important to train healthcare professionals, physicians, nurse practitioners and nurses, that fatigue really does impact their quality of life and there are things you need to address that and document it. Fatigue and clinical health outcomes studies, the quality improvements of how institutions look, like how do they address fatigue.

Disability insurance so far has not covered fatigue, but there's a movement among us to say that a patient has fatigue, even though the symptoms may not be so specific, this should be covered by disability insurance much like any major illness would be.

And the next is that the rehabilitation should really begin prior to starting therapy. The patient starts demonstrating fatigue associated with the disease. Exercise starting before you begin treatment has been shown in some studies to meaningfully increase the outcome and decrease the incidence of fatigue.

So, what should you do? Well, you should talk to your healthcare provider. "Fatigue is a symptom I have," and quality of life it interferes with, and what can you or I do about this? You should ask for help. There are drugs that help, there are resources that help. Change your lifestyle adjustments. You should discuss medications as the fatigue continues. Will I benefit from Ritalin or one of the other drugs?

37:58  Structure exercise is better in reducing fatigue:  Structured exercise is better, therefore a trainer, a physical therapist coming to the house, telling you which exercise to do is better. She will review the sleep patterns. There really now is a science to sleep hygiene. Turning off the TV, turning off the computer, having the room dark. You need to train your mind that you go to sleep at a certain hour. And it does take time and planning to exercise all of these. So, you need to tell your healthcare provider that I understand this is not going to be done in a single visit.

38:33  Preventive strategies you can take to help manage fatigue:  What are the preventive strategies? One, scheduling your day is critical. Activities that are enjoyable, your activities should be focused around how you should save your energy. You need to plan your activities. Your patients and physician should not schedule three or four visits a day and expect patients to be able to perform as well at the end of the day as the beginning.

Oh, avoid medications. You know what? [Don’t} take your steroids in the evening if they'll keep you up and you won't sleep. Diuretics at night. Patients don't sleep. Going to the bathroom does not count as sleep. And you want to avoid daytime sedation. You want the patient to be awake during the day, taking data, sedating drugs at night.

It's difficult to catch up on lost sleep. One night not sleeping generally takes a patient two to three days. And the last one I show this slide, people get very upset. Hospitals are not a place to sleep. Oh, there's background noise. Why do you have to have your blood pressure at 4:00 in the morning? In reality, you don't. So, if somehow if you are put in the first room and they take your blood pressure at 4:00, you can request, "I don't want to be woken until 7:00 in the morning." If there's too much noise, hospitals are stressing being quiet time, and the quiet time should be at night. We don't need your blood drawn at 4:00 in the morning and waking up. Earplugs are very helpful if there's too much background noise.

Being admitted to the hospital, while we think it’s effective, for most patients, they just don't sleep and it takes them at least two to three days post discharge to catch up. Okay. Summary.

40:20  Summary of presentation:  Fatigue really is common and interferes with quality of life. 70 to 100% of patients who receive any kind of cancer therapy and survive and are doing well complain of persistent fatigue and it really does impact their quality of life. It can last months, two years after treatment ends, and the onset can be delayed six to 12 months after therapy.

Patients perceptions, their fatigue as their most distressing symptom complex. Not nausea, not pain, fatigue is really the most distressing and unfortunately, is rarely addressed by physicians and patients together. It is worse than nausea and vomiting. It is under-reported. It is under-diagnosed. And with having an ICD code, there's more therapies available, and therefore it's under-treated for most patients. It does affect, more than anything, the quality of life of a patient, which is why most patients underwent treatment to improve their quality of life.

And the last slide is I'm reminded of John Lennon's classic saying: “Life is what happens when you're busy making other plans". In the world of fatigue, you have to understand that life is most important, and you need to plan your day around that. While you may not be able to get rid of the fatigue, you can optimize your activities so quality of life is preserved through it. We can remember John Lennon for this classic line. Thank you.

Question and Answer Session

42:23 [Audience] Does high-dose chemotherapy cause fatigue:  Hi, Dr. Miller. I know you probably answered this already, but I'm going to have to have you do it again. Slow on the uptake. Do high doses of chemotherapy correlate with chronic fatigue GVHD symptoms?

 [Miller] So, the therapy itself, patients who are undergoing therapy usually complain of some component to fatigue, and some drugs more than others are associated with fatigue. So if you're on treatment, you say I'm really feeling very fatigued, you should address the physician. And while I gather it's somewhat reassuring to say that is a common side effect of the drug, and sometimes when the drug therapy ends, the fatigue gets better, in some patients, it's associated with ongoing inflammation, and therefore ongoing fatigue, once even the therapy is stopped and you're cured of the treatment, and that's the most disconcerting part.

I meet with patients after transplant, I don't ask them, "Do you have fatigue?" I ask, "How is your fatigue?" So, most patients feel fatigue after transplant, and then when you have GVHD and as the component afterwards, I think most patients also have some component of fatigue.

[audience] Yeah. Well, I guess what I'm hearing is that there's different chemotherapy drugs that we'll end up using to treat the illness. Do you find that-

Oh, this is a critical question. Yes. And most of us in this day and age, there are multiple regimens we can pick. And depending upon what your lifestyle is, If you're working full-time and [have] a busy schedule, you can tell your physician that that's my lifestyle and does this drug interfere with what I do and are there other choices? And in many instances, there are. They are not associated with increasing fatigue as their major side effect of the drug. Some drugs or regimens cause more fatigue than others, and acknowledging that to the patient is critical, and having the patient saying, "I anticipate continuing to work and maintain an active lifestyle."

44:53  [audience] Does higher dosages of chemotherapy correlate with more fatigue? Okay. I'm not sure I communicate [inaudible 00:45:01] example. Here I have a heavy dose of chemo given, stem cell transplant was done. And obviously, the fatigue we're discussing right now was associated with that. But a year and a half later, no more chemo, no more this, no more that, but we get the fatigue is still pretty intense. Is that generally because of heavier doses or chemo rather than lighter doses of chemo with that regimen?

[Miller] Extrapolating from what's known, the answer would be yes. That the higher doses of chemotherapy are associated with more tissue damage, ongoing inflammation is associated with more fatigue. The sad part about this is that in most trials, fatigue is not used as an endpoint of the study, so we don't know. And it's only now following, let's say, transplants from myeloma that patients are doing very well and fatigue is now becoming a meaningful issue in patients who are out five years from their auto transplant, something you have adorable response to your treatment, but now you're having ongoing fatigue. So, we perceive that the higher dose of chemotherapy, yes, but it's somewhat fatigue specific. And it's only recently that that has been added to one of the criteria for evaluating the responses.

Prior to this, fatigue was a low white blood count, heart failure, diarrhea, cough, shortness of breath was standard criteria. Fatigue was a little harder to characterize and so we had a scoring system and these features added to it, because it's not just fatigue. it's all these things, qualities that go with fatigue. So, we receive higher dose therapy is, yes, but it's not 100% that way.

47:08  [audience] What helps fatigue when you have GVHD, work full time, and maintain the household?  Hi. I have graft-versus-host disease and I am constantly tired. I work full-time still, because the first thing that I say to my doctor when I go to see him is, "I'm so tired. I'm exhausted." And his responses is it's graft-versus-host disease and there's nothing that they can do about that. But I'm working full-time, taking care of the household, have kids, have animals, but by the time I get home from work, I'm done, I'm done for the day. So, is there anything that you're aware of that can help me try to get some energy, try to wake up, try to do more?

 (Ms. Ferraro] It's a good question and I don't think anyone has the perfect answer. Everyone is a little individual. Dr. Miller did mention physical therapy, and I do send patients, even five years after transplant, who have chronic fatigue, to physical therapy, to figure out certain exercises, certain ways of getting exercise in to help with fatigue. It is not a quick fix. It is one of those long-term, unfortunately.

We also have a dietitian that I do recommend patients see, because sometimes what you eat can give you more fuel. Sometimes what you eat can take fuel away, because it's not a good nutritional base to try. Data and the studies out really show yoga does a great job at helping with fatigue, but once again, you work full-time, you have a family, where you going to fit it in? And that's always a good question.

When you look at what you can do in a day and you can pick four things, where does the exercise fit into those four things and where can you do it? And that's when asking for help at home helps. I don't know how old your kids are, but maybe they clean up after the pets and they have to start doing more and doing those things so that you can focus on taking that step for you. I had somebody recently tell me, "Only you can really take care of you." And it's a good point. We can't force you to do anything. Everybody needs to take that responsibility. And we as your health care providers, family members, need to support that for you and help you find the time to do those little things that over the course of many months will help you.

[Miller] And chronic GVH is the most difficult part to treat. And part of it is exercise does help, diet help. All these, not one thing helps, but acknowledging that this is part of the illness and that you need to set aside time for yourself.

And sometimes the work environment also can be structured to make that more doable. It is the most distressing symptom in most patients I have who have chronic graft-versus-host disease, and the worst part of is that most patients look fine. So, it looks like, "Well, why are you tired? You look well. You're not sick. You're cured of your disease."

But the fatigue is real. And each of these components that you do, not one helps, but all together, can alleviate. But you also have to do things to try to decrease energy output. [inaudible 00:50:56], family help, having certain times off, getting disability, making sure that this is acknowledged as a chronic medical problem and not just, "I'm tired because I don't like working," which isn't the case.

For most of us who treat GVH every day, is a problem that's very difficult to treat and it requires long-term vigilance, exercising every day, keeping your weight under control, changing how you sleep, having family members help, and sometimes having time off the mark, but acknowledging that this is part of the illness.

51:40 [audience] Does napping during the day help fatigue? Hi. I'm impressed that you work full time. I think that's pretty amazing. We at the Link get a lot of calls from patients who will ask about the napping thing, even just a 10 minute nap during the day and I'm not usually at a loss on that because I know that I can take a 10 minute nap and it helps tremendously, but I understand it would be different with cancer patients. So, I guess my question is, how do you handle the napping question?

[Miller] For me, patients who nap is helpful nap as long as it doesn't interfere with their sleeping at night. The worst is if you nap and I get rest and now I can't sleep at night. Sleep hygiene and not getting enough nighttime sleep, it does contribute to the ongoing fatigue. But the European countries, they go home in the middle of the day, put on pajamas and take a two hour nap. If you're in Spain, you can't get food from 3:00 to 5:00.

52:44  [audience]  Divide up time devoted non-stop to projects so you don’t end up with several days of chronic fatigue:  I sympathize with everybody that's going through the same thing I am with fatigue. But as part of your contributing factors, you say that the immune system tells the brain to feel tired. I want to give you an example of what I can and cannot do sometimes. I'm a project guy. You give me a project and I have to finish it. I do not get fatigued while I'm doing that. However, when I'm done, I might have to sit down for two days.

So, is my immune system ... The question comes in, is my brain telling me, at that point when I'm doing a project, I can do it through lunch, right up through suppertime, she hollers at me, my good caregiver, and then when I'm done, I get fatigued. But while I'm doing that particular activity, I'm great. I can do it forever. Is it just my brain telling me or am I really fatigue then too?

 [Miller] You're probably very focused ,and stimulating the brain in the right direction, but when you're done with that, the brain senses you're tired and that's the two days. You may want to divide your efforts and say, "Listen, even though I can spend all my time finishing my four hour project," I would advise my patients, if you can divide it into two hours so you don't have those two days of fatigue, you really need to plan your day on those activities.

Some of us are very driven, and therefore because of who we are, we'll not put down that pencil until we're done. You need to overcome that and realize life is different and dividing things over two days, there's nothing wrong with that, because otherwise your brain will sense it's really tired and all the cytokines which you've avoided will start making it tired. This is really a CNS [central nervous system] driven problem.

The advantage of understanding it is a CNS is], hopefully in the next few years, there will be directed therapies against these inflammatory agents rather than these nonspecific stimulants that just try to keep you awake at this [time]. You can try the stimulants afterwards, or my I usually tell patients, "Two hours is enough."

[audience] The one thing is I don't use any stimulants like that other than maybe some caffeine in the morning.

[Miller] You have to plan your day or else your body is telling you that in those four hours, you're stressing it too much.

55:42  [audience] Should I take antidepressants for depression if I am fatigued? Yes. You said something about antidepressants. Do you think that you should go off them? I've been on them since I think I was doing cancer treatments. So, I'm wondering is that something that's making me tired?

[Ms. Ferraro] I think that depends on why you went on antidepressants to begin with and-

[audience] Depression.

[Ms. Ferraro]  Yeah. I mean, if you're depressed and you come off of those antidepressants, your fatigue could actually get worse. Yes, one of the side effects of those medications can be fatigue, but the fatigue that happens with depression can be even more debilitating than the side effect of the drug. So you have to weigh your pros and cons, and that's something you can try and wean off of with the help of your physician and then also watch for signs of recurrent depression.

56:38  [audience] Adrenal insufficiency, caused by sterioids, can contribute to fatigue:  Hello. I hope I can describe this properly, but at times, I get so fatigued, I feel like I'm a bear hibernating, where you just go to sleep and you could sleep, sleep, sleep, whether it's day or night. And when I was being treated, they figured out it was ... they called it adrenal insufficiency. And with being on the steroids all the time, I guess our system, sometimes it burns out, sometimes it gets lazy. I guess mine is lazy. It has the potential to produce but it doesn't. Is that very common with us bone marrow transplant patients?

[Miller] Yes. That usually gets better. So, if you're on chronic steroids, your adrenal gland, which is producing the steroids, stops responding, and therefore needs replacement therapy, and sometimes chronic replacement therapy does help. At times, it gets better over time. The adrenal starts functioning. But this is not an uncommon problem because most patients are on long-term steroids and the adrenal shut off. It's an organ that all-of-a-sudden senses, "Oh, you have enough steroids on board, I don't have to work."

[Ms. Ferraro] That's like if you have sleep apnea or things like that, you want to rule out the physical potential cause of the fatigue, so adrenal insufficiency, checking thyroids, sleep studies, those things can help identify if there's a physical reason for the fatigue other than the inflammatory responses,.

[Miller] Yeah, all my patients, I check their thyroids every year, even though it's very subtle, because it's so commonly associated with chronic GVH. And adrenal insufficiency is not an uncommon problem especially with patients who've been on long-term steroids.

[Moderator] Well, thank Dr. Miller and Ms. Ferraro for their time and expertise and thank you audience for your excellent questions.

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