Carmen P. Escalante, M.D., F.A.C.P
Professor and Chair
General Internal Medicine
Ambulatory Treatment and Emergency Care
The University of Texas MD Anderson Cancer Center
Hello. My name is Carmen Escalante. I am the Professor and Chair of General Internal Medicine Ambulatory Treatment and Emergency Care at MD Anderson Cancer Center in Houston. Today, we will talk about cancer-related fatigue.
It is important to first define cancer-related fatigue. And I think the important concepts is that this is a persistent often subjective type of fatigue that is composed of multiple aspects, not only physical aspects, but emotional and especially cognitive tiredness. It is unrelieved by rest and it is out of proportion to recent activity. So these are some of the highlights that we think about when defining cancer-related fatigue.
It is a very common symptom - in fact, the most common symptom experienced by our cancer patients. The prevalence varies, and I think that variability is due to the numerous definitions that you find in the literature, but it is certainly most commonly near 90%. It is often very extreme in patients with advanced and metastatic disease. It is commonly associated with psychological disturbance and symptom distress and it may affect functional status and very commonly does.
Why do we often not hear of CRF, which I am going to refer to as cancer-related fatigue? Many patients are hesitant to report the fatigue because they want to receive their maximum cancer treatment, and they fear that if they complain about fatigue, the dose may be reduced. Also, they may believe that this is expected and that they should cope with it. Others do not want to be seen as complainers and many times patients may believe that this is either recurrent disease if they are without evidence of disease or that it may be advancing or progressive disease. And although we need to look for these types of activities, many times this is not the cause of the fatigue.
Why are healthcare providers often hesitant to discuss cancer-related fatigue? Well, we are always very busy and time constraints are something that we all have to deal with. But many times, we don't really understand fatigue that well, and there are limited treatment options and certainly this may impact, and it takes time often to discuss this symptom because there are no easy ways to address it as well as to measure it.
As far as pathophysiology, there are numerous hypotheses. The bottom line is we really don't understand what is causing fatigue. It is very interesting and we often -- and there is lots of research in trying to understand it. One of the more common hypothesis is that there is abnormal secretion of substances such as cytokines that may impair metabolism and certainly may impact fatigue. Another hypothesis may be related to energy metabolism and abnormalities in that aspect . And a third hypothesis may be decreased availability of metabolic substrates. The bottom line, though, is we really do not know at this point. Hopefully, over time, we will be able to better understand this and target our treatments to the pathophysiology that is appropriate.
There are many things that can impact fatigue -- cancer-related fatigue. And what we need to remember that this fatigue is related to the cancer or the cancer treatment. We do know that multiple treatments, and they are all listed, can impact fatigue. Patients that receive more than one treatment and certainly the more treatments tend to have more intense and more problems with fatigue. We do know that certain treatment effects, commonly anemia related to chemotherapy, can cause fatigue. And often the fatigue may be fluctuating depending upon the level of anemia. Hypothyroidism is very common, especially in our head and neck patients that may have radiation to the neck and the thyroid area, so we should be diligent about looking for those aspects. Renal dysfunction, which is a common side effect of many of our treatments, may be something that may impact and we certainly should be aware that this may be a complicating cause. There are other mechanisms and symptoms that are commonly associated with fatigue and very tightly correlated. Sleep disturbances: Many of the patients that have cancer-related fatigue also have sleep issues whether they are insomnia or hypersomnia and we will discuss those a little more as we go further. Pain is very commonly associated with fatigue as well as psychological factors such as depression and anxiety and obviously, nutritional aspects. Both patients with decreased nutrition, as well as our obese patients may have more difficulties with cancer-related fatigue. And the patients should be queried as to what they are eating and how much they are eating and their schedule of eating habits. Other comorbidities are very important. Cancer patients tend to be older. Older patients have other underlying diseases as well as cancer, and the condition of these diseases and control of these diseases are very important. Examples may include COPD, that commonly may be exacerbated, or uncontrolled diabetes, and these are things that should be looked for when patients complain about fatigue.
How do we approach patients with cancer related fatigue? Well, it is dependent upon the level of the fatigue and one easy query in a busy clinic may be to ask, on a scale of 0 to 10, with 0 no fatigue, and 10 the worst fatigue you can imagine, what is your fatigue today? For patients with very minimal fatigue, it should be education and certainly if they are going to have treatment, expectations of what the fatigue may be related to that treatment, and other general strategies to manage fatigue, and I will talk about those in a slide or two. And then those patients with moderate or severe fatigue should not only receive the same aspects as those with mild fatigue, but a primary evaluation.
So, general strategies for fatigue management will include the self-monitoring of fatigue level. Some patients are motivated enough to even do a diary, so that not only do you monitor the fatigue levels, but they should write the activities or things they are doing so that we may be able to develop a trend and know what time of day is their best portions. What activities are causing more fatigue or less fatigue, and then other things include energy conservation. These include setting priorities, pacing activities. I often have a discussion with the patient regarding delegation. Are there things that others can do that are not imperative that you have to do yourself? Another important aspect is scheduling activities, especially complex activities when there is most energy. So, if a patient describes that the mornings have more -- are more energetic for them with less fatigue than the afternoons, they should complete their most complex tasks in the morning compared to the afternoon. Other things such as labor saving devices may be helpful. These may include simple things, such as shower chairs or a stool for cooking, that may or may not include rollers, as well as for washing dishes. And suggestions such as these may be helpful for the patient. Also, at times, they may need to postpone nonessential activities. And I have discussions regarding napping and how much napping, what time of day, and sometimes limiting napping is helpful, so that it does not disrupt evening sleep, but gives them a burst of energy at times a day when necessary.
Other strategies also include a structured daily routine and having a weekly planner can be very helpful for the patient with outlining of each day's activity. And we are often very busy and many of us learn to multitask. Patients with cancer-related fatigue should try to focus on one activity at a time. Remembering that, it is not only physical fatigue often, but a cognitive aspect. And so sometimes the focus is very important on one thing that they are doing so that they can complete it before moving on to the next task. If they try multiple tasks, they may never complete any of the tasks. Distractions may be helpful including games, music, reading, and other things that take their mind off of focusing on the fatigue.
As far as those patients that have moderate or severe fatigue, they should also have a primary evaluation; and what does that encompass? First, it should be a focused history and this should include their current disease status and treatment, have they recurred or are they progressing? We should always think about, in my experience, many times, this is not the cause of the worsening of fatigue or initiation of fatigue. Reviewing medications or medication changes, and many of these patients are on numerous medications; and looking at all their prescriptions, not only the ones that we write and prescribe, but other over the counters and supplements including vitamins, herbals, and all these other medications that they may not have to take and often do not consider as medications. There often can be drug interactions with these medications and they should be considered.
An in-depth history regarding fatigue should be accomplished and that includes thinking about when did the fatigue begin? What is the pattern of the fatigue and the duration of the fatigue? Has it changed over time? Are there are other factors that either improve or worsen the fatigue? And does it affect the daily activities and the functioning, the ability to be independent? All these are important aspects that should be reviewed with the patient.
Considering other treatable causes as we previously discussed: pain, especially severe pain, is tightly correlated with fatigue and if the pain is improved, the fatigue may improve; as well as anxiety, depression, or other emotional distresses, anemia. And many times anemia is very easy to detect and may have been treated by the time you see the patient for fatigue. Sleep disturbances, not only insomnia, but obstructive sleep apnea may be a cause. Many times, it is not the quantity of sleep, but the quality of sleep. And so patients that have a lot of sleepiness, we should be very careful about asking them details about their sleep habits, snoring, napping, etc.
Nutritional assessment including weight: Have they gained or lost? Has the weight been stable? Have they had to buy new clothes because either the clothes are too tight or too big? And what type of things do they eat? How do they eat? Many times patients may not eat on a regular basis or may eat less than three meals a day, and understanding what they are taking in is very important. Activity is an essential query including what activities are they doing now compared to previous? What was their physical fitness level now versus before? Have they exercised in the past or they were able to continue to exercise if they have exercised in the past? Again, looking at the side effect profile of all their medications. An example, patients may have neuropathy from previous chemotherapy and may be on a drug to treat the neuropathy. These drugs are often very sedating and may affect their ability to do things, as well as their perception of fatigue. Patients with fluid or electrolyte imbalances, nausea, vomiting, and diarrhea may also be affected, so considering all these aspects on side effect profile of their medications.
As we previously touched upon, comorbidities are important. Whether the patient has an active infection certainly it will affect fatigue as well as them being febrile or afebrile. Underlying cardiac and other organ function, as outlined in this slide, can impact fatigue depending on the extent of the dysfunction. Endocrine dysfunction may be very common depending on the treatment. Menopausal state also is something that should be queried, especially in younger patients that may undergo early menopause secondary to their treatment.
So, what do we do about cancer related fatigue? Where there are two sets of interventions including non-pharmacologic interventions and pharmacologic interventions and we will briefly discuss both aspects.
In the non-pharmacologic interventions, these include activity enhancement or exercise. And this has the best evidence of all of the interventions for cancer-related fatigue. Others include psychosocial interventions, sleep therapy, and nutritional consultation, and I will describe each of those for you.
In the exercise category, this is a Category 1. And I also referred you to the National Comprehensive Cancer Networks Cancer-related Fatigue Guidelines. They have very detailed guidelines showing all of the aspects for cancer related fatigue. But the regime should be individualized, not all patients are the same. Consideration of the age of the patient and the gender, as well as what type of cancer is either present or has been treated. Does this impact your their ability to ambulate? What type of cancer therapy has been received or are they currently receiving therapy? And their physical fitness level, not only presently, but what was their level previously? Those patients that have higher levels of fitness and conditioning can start at a higher level of physical fitness than those that have never exercised even prior to their cancer treatment and diagnosis. The bottom line is we do not want a patient to overdue and hurt themselves either pulling a muscle or having angina. And certainly if the patient has another comorbidity that may impact their ability to exercise, that should be carefully considered and appropriate testing done. So that if they have significant risk factors for angina, a stress test, or other cardiac workup may be appropriate prior to prescribing an exercise regime. Patients may also consider this very difficult to understand and when they are describing fatigue and we are telling them to exercise as part of the intervention. So a careful discussion with the patient relating to the benefits of exercise not only for fatigue, but for cardiovascular aspects, weight control, emotional aspects related to relaxation and stress relief, may certainly be appropriate and encouraging for the patients, especially for those patients that may have never exercised previously.
There have been a number of exercise studies including patients that have been on active treatment as well as those that have completed treatments. There are a lots of design variability. Most of these studies are fairly small. A lot of the studies are related to breast cancer because it is a very common cancer and affects mostly women. There is also variability in the exercises prescribed, from aerobic exercises as listed, to a resistance training. And many of these studies have varied in the length of the study from short term of six weeks to as long as six months.
However, the bottom line is that in all these studies, regardless of the limitations, fatigue was decreased and functional quality or quality of life improved for those patients that had quality of life measured. Also, in those studies that looked at emotional distress and sleep disturbances, those also improved. So the evidence is there that exercise is a benefit and has the highest level of evidence of all the interventions for patients with cancer-related fatigue. And I firmly believe that for those patients that can exercise, we should try to get them moving. And the variability and how much they can exercise and the type of exercise obviously will change, depending upon the patient and should be customized to the patient.
A second type of non-pharmacologic intervention is psychosocial interventions or behavioral-type interventions and some of these are Category 1. There are numerous studies on cognitive behavioral therapy, stress management, relaxation, and support groups, and these may be helpful for the patient. For certain cognitive behavioral therapy, more resources may be necessary depending on the type of treatment needed and so that needs to be considered. But certainly if anxiety/stress is an issue, then some of these interventions may be very helpful for the patient.
Attention restoring therapy has been documented in the literature and what is this? Well, there has been some literature that shows that some patients have decreased ability to concentrate during a stressful situation and there have been studies that show things such as listening to birds or sitting in a very comforting garden, listening to nature sounds, may be helpful. And some of these patients that have undergone clinical trials with these interventions have shown improved concentration and problem-solving on neurocognitive testing and returned to work earlier than those that were in the control arm. So this may be helpful for some patients as far as cancer-related fatigue.
Sleep is a major issue in many of our patients and it goes along with the fatigue. And there maybe extreme disturbances from insomnia along the spectrum to hypersomnia. What are some effective sleep interventions that we may be able to try? Stimulus control or behavioral-type issues include things such as advising the patient to go to bed at a specific time and get up at a specific time, putting an alarm clock in place so they do not sleep later than usual, getting them on a schedule, avoiding caffeine late at night, and other stimulating evening activities may be helpful. Sleep restriction, meaning avoiding long or late afternoon naps that can interfere with nighttime sleep, limiting bedtime to sleep, so the patients that cannot sleep at night, but either cannot fall asleep or wake up and just cannot go back to sleep, advising to them to get up out of bed and do something that may be restful to help them get sleepy again and then go back to bed. The computer screens/TV screens tend to be stimulating, and so I often advise patients not to watch TV if they wake-up in the night, to do something more restful, listen to very relaxing music, read, or do something that may be helpful in getting them to feel sleepy again and then lying back in bed. Certainly, education and counseling on sleep hygiene is very helpful. Spending that time may be a wise investment. At times, patients need pharmacologic therapy for sleep and this may be necessary. Certainly, considering all their drugs, when making this choice, is necessary.
As far as nutritional aspects, educating patients about good nutrition, appropriate referral to a nutritionist or web sites, that may be helpful in educating them, especially those patients that may have underlying comorbidities that also impact such as: diabetes, hypertension, and heart failure. It may be appropriate if they have not visited with the nutritionist. Those patients that are very underweight or overweight certainly may benefit from a visit with a nutritionist. And at times we need pharmacologics to control other symptoms. Patients that are on active treatment commonly have nausea or diarrhea and other patients that have had treatments that promote malabsorption, may need other pharmacologics to help them cope with the side effects of those symptoms.
Another aspect is pharmacologic interventions and this would include stimulants, antidepressants, and steroids. These are three general classes and I will talk specifically about each. None of the pharmacologic interventions have a Category 1 of evidence.
The stimulants we commonly think about include methylphenidate, pemoline, modafinil, and now armodafinil, a newer one. Pemoline is really not used anymore. It has promoted hepatic dysfunction and has really never . . . the risks are much higher than the benefit of using this stimulant and the other stimulants are available and helpful, and so pemoline does not really need to be used, but I mention it because it is in the early literature for cancer-related fatigue. Methylphenidate is very common. It has been used for years in children with attention-deficit and hyperactivity disorders, and so we have a lot of experience. There is a short-acting methylphenidate that should be dosed twice daily, morning and around noontime. The doses may range from very low doses of 5 mg. in the morning and at noon to much higher doses. The most common side effect may be anxiety, certainly patients with for any of the stimulants that have uncontrolled hypertension or significant cardiac disease that must be considered. However, when you look at the literature of the stimulants as far as hypertension, in all of the literature that has been documented, it really only increases the blood pressure very small amounts from what has been documented in the literature, but certainly should be considered and patients should have well-controlled blood pressures prior to initiating this. Modafinil is a stimulant that is approved and commonly used for patients with narcolepsy or shift work disorders, as far as sleep. It is also a short-acting stimulant and should be dosed twice daily, generally in the morning and around noontime. Most of the stimulants are not dosed later in the evening because of the fear that it may interfere with nighttime sleepiness. Although there has been a study using methylphenidate that did dosing every two hours and seemed to be effective. And this was, of course, done with methylphenidate, not necessarily modafinil. Armodafinil is a once-a-day stimulant also used for narcolepsy and sleep disorders. The benefit is that it is a slow release, about a 12-hour span, and may replace the twice daily dosing, which some patients may like better. Methylphenidate also has a long acting once-a-day counterpart that can be used for those patients that prefer to have a once-a-day dosing. The stimulants have helped some patients and may need to be considered for patients that need a fatigue intervention more rapidly. They do work much more quickly than exercise, which may take several weeks to months to see a benefit. And, of course, it depends upon the level of the fatigue and the activities of the patients so that many times there are multiple interventions that are done and sometimes these interventions need to be staged depending upon what is going on with the patient.
Antidepressants have been used for cancer-related fatigue, but have shown only to be effective for those patients that have depression with fatigue. So that if the patient only has fatigue, we do not use an antidepressant alone. There has been a study with the selective serotonin-reuptake inhibitors looking at this aspect and certainly if the patient has depression, then they may be helpful. A secondary amine tricyclics in patients with fatigue and depression may be helpful for those patients that have sleep problems because they can promote sleep and should be taken in the evenings. There is a small study that has been done with bupropion. Bupropion tends to have a stimulant-type antidepressant effect and so this may be beneficial for some patients with significant fatigue and depression as well. Again, there is no Category 1 evidence for any of these -- this category.
Low-dose steroids have been used for cancer-related fatigue mostly in patients with advanced disease and in the latter stages of their treatment. Dexamethasone and prednisone have been used. Of course, because of the side effects in patients that have longer life spans, it may not be appropriate. And in these studies that have been done with steroids, the endpoint was not fatigue, but looking at muscular activity, muscular measurements. So fatigue may be a surrogate in these, and again, I think it may be considered in those patients near end of life that have significant fatigue that may be taking these drugs for shorter periods of time.
So, in summary, cancer-related fatigue is a very prevalent and significant issue for both our active cancer patients that are undergoing treatment, as well as our survivors or those patients that have completed treatment and are cancer free. The evaluation and treatment should consider multiple aspects and may require a multidisciplinary approach, as I have described. And certainly we should consider both pharmacologic and non-pharmacologic interventions, customizing the intervention depending upon the patient's abilities and needs. I do believe that there are continued opportunities in research. Presently, as I have described, there are multiple small studies for some interventions and minimal studies for other interventions. We do need well designed clinical trials for many of the pharmacologic agents and for the sleep dysfunction. And we certainly need to delve into more research looking at physiologic causes, because perhaps in the future, this may be the key to addressing fatigue and understanding fatigue and getting more target-related interventions for our patients. Thank you.
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