Exercise effects and fatigue in cancer patients

Author(s): Sravani Venkata Anjana Mudumbi, MD, Teresa Tang, MD

Originally published:07/17/2013

Last updated:09/19/2016

1. DISEASE/DISORDER:

Definition

Cancer related fatigue is defined as a “distressing, persistent, subjective sense of physical, emotional or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning”.1 CRF is differentiated by other types of fatigue in that it is not alleviated through rest. However, the assessment tools for CRF have not been universally agreed upon due to the highly personal and subjective nature of fatigue.

Etiology:

The etiology of CRF is multifactorial, and involves the interplay of physiological, biochemical, and psychological systems. From a biological standpoint, cancer itself as well as its associated treatments can cause elevated levels of pro-inflammatory cytokines, such as interleukin 6 and tumor necrosis factor, which have all been associated with CRF.2,3 In addition, associated comorbid and psychosocial factors, such as nausea, pain, depression, and poor sleep also play a major role.4,5

Epidemiology including risk factors and primary prevention:

With better screening methods and treatment options for cancer, more and more patients with cancer are living beyond the 5-year survival marker. It is estimated that there are more than 14 million Americans living with a diagnosis of cancer already.6 However, cancer survivors suffer from many side effects of treatments, which drastically affect quality of life.7

Fatigue has been increasingly recognized as a problem in cancer patients. It is one of the most common side effect in patients with cancer and is nearly universal in those undergoing cytotoxic chemotherapy, radiation therapy, bone marrow transplantation, or treatment with biologic response modifiers. Fatigue continues to be a chronic problem persisting months or even years after treatment has concluded in over two thirds of cancer survivors.8 Compared with other symptoms, such as pain or nausea, CRF is more distressing and often long lasting, with a strong impact on daily living and quality of life.9

CRF is most frequently reported in cancer survivors with sleep disturbance, pain, distress, depression, lymphedema, elevated body mass index (BMI), and low activity levels2. It is particularly prevalent among people with breast cancer, lymphoma, prostate, lung and advanced cancers. In general, CRF prevalence drops to about 25% among cancer survivors who have tumors not associated with CRF. In metastatic disease, the prevalence of cancer fatigue exceeds 75%.7

Patho-anatomy/physiology

Fatigue can be further described as being physical, affective, cognitive and psychological. Investigating causal relationship of CRF with specific physiologic mechanisms will remain difficult until it is better defined and clearly described.

Cancer fatigue is believed to be induced by the tumor itself, causing an increase in neutrophils, and inflammatory cytokines such as interleukin 6 and tumor necrosis factor. In a study of 46 terminally ill cancer patients (survival of 64.5 days), diagnosis of clinical fatigue strongly correlated with higher plasma IL-6 concentrations.10

Two years after successful primary therapy, fatigued breast cancer survivors were distinguished from non-fatigued survivors (n=50) by increased ex vivo monocyte production of interleukin (IL)-6 and tumor necrosis factor-α following lipopolysaccharide stimulation, elevated plasma IL-1ra and soluble IL-6 receptor (sIL-6R/CD126), decreased monocyte cell-surface IL-6R, and decreased frequencies of activated T lymphocytes and myeloid dendritic cells in peripheral blood.11 As cancer advances through stages, fatigue becomes more crippling, which corresponds with higher inflammatory markers compared with early stage disease in breast, ovarian and lung cancers.

One proposed mechanism in which these biological changes cause fatigue is through the suppression of the hypothalamic-pituitary-adrenal axis, causing a blunted cortisol response.2 In addition, elevated tumor necrosis factor has been shown to result in changes in skeletal muscle protein stores and/or metabolite concentration. This can lead to muscle wasting requiring patient to exert an unusually high amount of effort to generate adequate contractile force during exercise performance or during extended periods of sitting or standing.12

Cancer treatments, such as radiation, chemotherapy, and glucocorticoids, can also cause major biological changes that results in CRF. Animal models of lung and breast cancer have demonstrated an inflammatory response with corresponding fatiguing behavior while receiving chemotherapy. Ionizing radiation (even partial body exposure) often correlated with higher incidence of fatigue, and it is known to induce pronounced neuroinflammation and may be in part responsible for fatigue.

Comorbid and psychosocial factors, such as pain, nausea, depression, and poor sleep also contribute greatly to CRF.2 Depression often clusters with CRF which is also related to inflammatory markers such as TNF and interleukins.13-17

While none of these co morbidities, such as elevated BMI, uncontrolled diabetes mellitus, congestive heart failure, infection, anemia, hypothyroidism, inactivity, and lymphedema, have been shown to be etiological or to be contributing to the patho-physiology of CRF they should be evaluated and treated when possible, due to their influence on cardiovascular endurance.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

CRF fluctuates over the course of cancer treatment. CRF in patients receiving chemotherapy is commonly cyclic and worst when blood counts are lowest, in about 2 weeks; whereas, in patients receiving radiation therapy (RT), CRF peaks toward the end of therapy and decreases after radiation is completed. It is most common during active therapy, but persists for months or years after treatment. (There is need for further research on effect of fatigue on activity level which might influence decision for further anti-cancer treatments.)

Lack of exercise has been one of the most consistently identified risk factors for all cancer mortality, particularly for colorectal and breast.18-21 It has not yet been determined as to exactly how much and how intense of exercise should be performed to reduce the risk of cancer. Animal models have demonstrated that exercise can inhibit the incidence and progression of cancer in a variety of tumors. 22-27

Specific secondary or associated conditions and complications

Cancer prevalence increases with age, and is likely to be associated with more comorbidities that should be evaluated. Most frequent comorbidities are hypertension, diabetes mellitus, cardiovascular disease and arthritis. Anemia, thyroid dysfunction and depression are frequently part of the evaluation. Initial assessments must begin with a good comprehensive medical history, review of systems, and medications taken. Inadequate control of these should be corrected.

2. ESSENTIALS OF ASSESSMENT

History

When assessing a patient for CRF, it is important to keep in mind the two distinguishing characteristics of CRF: (1) symptoms of fatigue that are disproportional to the patient’s level of exertion and (2) are not relieved by rest or sleep. Use of open ended questions is important to help tease out these subtleties. A careful review of past medical history and review of systems should also be conducted to detect reversible sources of CRF, such as hypothyroidism, adrenal insufficiency, hypogonadism, poor nutrition, as well as address psychosocial factors such as insomnia and depression. A review of medications, with a focus on centrally acting medications that can cause fatigue, such as opioids, benzodiazepines, antihistamines and antiemetics, is also important.

There are multiple measures used to assess fatigue, including: Brief Fatigue Inventory, Cancer Fatigue Scale, Fatigue Symptom Inventory, Multidimensional Fatigue Inventory, Revised Piper Fatigue Scale, Revised Schwartz Cancer Fatigue Scale. However, there is no universally agreed-upon measure for CRF. The National Comprehensive Cancer Network (NCCN) has published guidelines for the evaluation and treatment of CRF. In this document there is a strong recommendation for asking all patients to verbally report their level of fatigue, usually on a numerical scale from 0-10. Fatigue is considered none/mild if it is rated 0-3; moderate at 4-6; and severe at 7-10. While this verbal numerical scale is quick and reliable, it is unidimensional. Therefore, it must be combined with careful history taking in order to identify contributing factors to generate a treatment plan.

Additional measures that are useful for both evaluation and outcome measures include the Functional Assessment of Cancer Therapy-Fatigue (FACT-F), MOS SF36, Fatigue Severity Scale, Human Activity Profile. The NCCN guidelines recommend that multidimensional fatigue measures are an assessment of function and life satisfaction and are included as a part of the routine surveillance of managing cancer survivors. Health care providers do not routinely assess patients for the presence of fatigue or seek to determine its contributors, resulting in inadequate or ineffective treatment and contributing to the high prevalence of CRF. Additional measures of sleep, such as the Pittsburgh Sleep Quality Index, and a dietary recall questionnaire may help identify other potential abnormalities.

Developing a routine checklist that includes comorbidities that contribute to fatigue, measures its severity, and treatment outcomes will systematize the approach and likely demonstrate improvement. Commitment to standardized measures (FACT-F, activity measures, etc) will provide an objective basis for designing and evaluating treatment. An example of a check list is given below:

Comorbidities to consider:

  1. Cardiovascular: valvular disorders, murmurs
  2. Pulmonary: COPD
  3. Hematology: anemia
  4. Gastrointestinal: poor nutrition
  5. Endocrine: hypothyroidism, hypogonadism, adrenal insufficiency
  6. Infectious Disease [ID]: urinary tract infection, pneumonia
  7. Psychiatric: insomnia, depression

Evaluation and follow up measure of fatigue:

  1. Verbal scale of 0-10 (with 10 being the most severe)
  2. Fatigue Severity Scale

Multi-dimensional Fatigue Inventory

Physical examination

A thorough physical examination should be performed to identify reversible or treatable contributors to fatigue. Special attention should be paid to the cardiac and pulmonary systems, as chemotherapy and radiation can cause cardiomyopathies or interstitial fibrosis. Fluid status should be observed, as well as examination of the oral cavity for signs of mucositis that could be preventing adequate nutrition. Manual muscle testing should also be performed to assess strength and distribution of weakness, to help further guide prescription of exercise therapies.

Functional assessment

A functional assessment enables the clinician to determine the impact of fatigue on activities of daily living (ADL). Traditionally, the Functional Assessment of Cancer Therapy-General (FACT-G)5 provides a good evaluation of ADLs. A standard instrumented ADL assessment is an important adjunct to functional evaluation. Some dynamic functional mobility testing that can be used to assess cardiovascular endurance in the setting of fatigue include AMPAQ, Get up and go, and 2 minute walk test.

Laboratory studies and imaging

Lab testing is done for comorbidities, and for contributing and reversible causes and should be tailored to the patient based upon history and physical exam findings. The following laboratory tests may be useful: hemoglobin, white blood cell count, thyroid function, fasting blood glucose, urine analysis, and vitamin levels. A chest x-ray may be useful if congestive heart failure or pneumonia are suspected.

Supplemental assessment tools

Environmental

One effective treatment of fatigue is assessing what the patient needs to do within his/her usual environment which includes home, work and avocational activities. A discussion about priorities is often helpful. Once this is established, the ability to assess which of these activities is particularly energy-draining and whether modifications can be undertaken to conserve energy. This may be through hiring help, enlisting friends/family, pacing oneself, and breaking up physically, emotionally and psychologically demanding activities into shorter periods. Occasionally rearranging one’s day to permit more to be done at the individual’s best time is useful. Sleep hygiene, going to bed at a regular time, taking short naps and awakening at a specific time may help to provide more refreshing sleep.6

Social role and social support system

CRF often disrupts usual home-work-life balance and specific activities. Family support for the patients, coordination of care, and consolidation of trips to various health providers is often beneficial. Support groups are often very helpful and many websites are available for information. Social networking and discussion of good cancer management programs are available.

Professional Issues

Cancer survivors are a rapidly growing patient population, living longer and better. CRF presents a challenge to patients wishing to lead a longer, more functional life. As such, its management is best approached from the perspective of the needs of people with chronic illness. A surveillance model using a multidisciplinary approach is recommended, enabling care coordination among oncologists, primary care physicians, oncology nurses and the rehabilitation team.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Management of fatigue is cause-specific when conditions known to cause fatigue can be identified and treated. When specific causes, such as infection, fluid and electrolyte imbalances, or cardiac dysfunction, cannot be identified and corrected, non-pharmacologic and pharmacologic treatment of the fatigue should be considered.7 NCCN guidelines emphasize interventions based on the patient’s clinical status: active cancer treatment, post treatment, and end of life. Education and counseling are central to the effective management of fatigue, as well as both non-pharmacologic and pharmacologic interventions.  Non-pharmacologic interventions may include a moderate exercise program to improve functional capacity and activity tolerance, restorative therapies to decrease cognitive alterations and improve mood state, and nutritional and sleep interventions for patients with disturbances in eating or sleeping. Pharmacologic therapy should be considered when non-pharmacologic interventions do not provide an improvement in fatigue and functioning. Pharmacologic therapy includes drugs such as systemic steroids, psychostimulants, and anti-depressants. Methylphenidate appears to be the most effective agent in the treatment of cancer-related fatigue.28  Two major systematic reviews concluded that methylphenidate showed a small but significant improvement in CRF over placebo in mixed tumor cancer patients with advanced disease but needs to be confirmed in a single, large RCT. All of these studies began with a lower dose of methylphenidate, such as 5mg daily, and titrated up to 20mg total dose per day, as according to patient symptoms and tolerance.29,30 More robust evidence also indicated that treatment of chemotherapy-induced anemia with erythropoietin has also led to improvement in fatigue in these patients. Unfortunately, erythropoetin has been associated with many adverse reactions, such as fatal thrombo-embolic events, and can no longer be recommended as a treatment option.30 When specific causes are present, such as mood disorders, sleep disturbance, infection, fluid and electrolyte imbalances, or cardiac dysfunction, they should also be identified and corrected.31

Education about fatigue should be offered to patients, especially before its onset, including reassuring the patient that fatigue is not an indication that the treatment is not working or that the disease is progressing. Daily self-monitoring through a log or diary should be encouraged, as they can provide information regarding peak energy periods. This can be used to plan activities accordingly and use energy conservation techniques.

Of the non-pharmacologic treatment options, physically based therapies and psychosocial interventions have the strongest evidence base.

a) Exercise: More evidence is now available on the benefits of exercise in decreasing CRF. The largest meta-analysis to date including 4881 patients with cancer during or after treatment found that exercise reduced CRF by a mean of 0.32 during and 0.38 following cancer therapy–aerobic exercise was the commonest method.32 A systematic review looking at 3816 participants found that moderate intensity exercise resulted in significant reduction of fatigue and increased walking endurance.33 Recommendations for an individualized exercise program should take into consideration the stage of cancer, patient’s age, psychosocial status, pain conditions. Treatment should start at a low intensity, gradually increasing as the individual’s aerobic capacity improves. Only rare and mild adverse events from exercise occur, including back, wrist, lower leg and rotator cuff injury; and they respond to usual treatments for soft tissue strain/overuse. The American College of Sports Medicine recently published guidelines regarding exercise in cancer patients and survivors. Generally, these patients do not need exercise tolerance testing prior to initiating an exercise program. However, additional screening is needed for those with peripheral neuropathies, musculoskeletal co-morbidities, wasting syndromes, increase risk of infection and fractures.

With regards to aerobic exercise, studies have shown that moderately intense aerobic exercise, as defined by 55-75% maximum heart rate, is effective in managing cancer related fatigue in early stage diagnosis. Modes of exercise include walking, or stationary cycling for those with ataxia or balance difficulties. Duration is typically 10-90 minutes, with a frequency of three to seven days a week. Recommendations for resistance exercise prescription include modes such as resistance bands, dumbbells, or fixed weight systems. Moderate to vigorous intensity (60-90% of one-repetition maximum) is suggested with two to four sets of exercises ranging from eight to 15 repetitions  performed. Frequency of resistance training should be three times a week.34 Overall, the American College of Sports Medicine (ACSM) recommends a total of 150 minutes of weekly moderate intensity exercise for this patient population.

According to ACSM guidelines, no cancer specific changes for aerobic exercises have to be made. However, specific resistance training adjustments should be made for various cancer diagnoses. For example, for patients with breast cancer, the first 16 sessions should be supervised. Very low resistance should be used initially, with close monitoring of lymphedema or arm and shoulder symptoms. Patients with breast cancer and prostate cancer are at high risk for fractures, as bony involvement is more prevalent in these populations. (Schmitz, American College of Sports Medicine Roundtable on Exercise Guidelines for Cancer Survivors, July 2010).

b) Psychosocial interventions: Patients should be counselled about coping with anxiety and depression, as they are commonly associated with fatigue. Interventions that have been shown to help can be grouped into three categories: cognitive behavioral therapy, psychoeducational therapies, and supportive expressive therapies.

c) Complementary approaches: There are a wide range of complementary therapies available for cancer-related fatigue, some of which include acupuncture, aromatherapy, adenosine triphosphate infusions, energy conservation and activity management, healing touch/therapeutic touch, hypnosis, lectin standardized mistletoe extract, levo-carnitine, massaged, mindfulness-based stress reduction, polarity therapy, relaxation, sleep promotion, support groups and Tibetan yoga. However, currently, there are insufficient data to recommend any specific modality for cancer fatigue.35

One of the most studied complementary therapies for CRF is acupuncture that is popular among cancer patients and some evidence suggests that it could potentially alleviate fatigue. A phase II uncontrolled study using acupuncture to treat post-chemotherapy fatigue by Vickers et al. has shown that acupuncture improved fatigue by 31.1%.36 Molassiotis et al. rigorously studied 47 cancer patients after chemotherapy in a randomized controlled trial with a 3-group design: acupuncture (n=15), acupressure (n=16) and sham acupressure (n=16).37 Improvements in fatigue were 36%, 19%, and 0.6%, respectively. Balk et al. compared effect of acupuncture on fatigue in cancer patients receiving a 6-week course of external radiation therapy with sham acupuncture and found that both true and sham acupuncture groups had improved fatigue, fatigue distress, quality of life, and depression from baseline to 10 weeks, but the differences between the groups were not statistically significant.38 A pilot randomized controlled trial of 30 women with fatigue following breast cancer treatment compared acupuncture with sham acupuncture and wait list controls found a significant reduction in fatigue for women receiving acupuncture compared with control after 2 weeks, and a significant improvement in well-being at 6 weeks for acupuncture compared with the sham and wait list control.39 Acupuncture treatment addresses patients with a wide range of diagnoses, defines patient groups by presentation rather than diagnosis, which may not employ placebos and may not be blinded. Although sham acupuncture is still an unresolved methodological issue in acupuncture clinical trials, future studies will be needed to compare real acupuncture with appropriate sham acupuncture to rule out a placebo effect of acupuncture and compare acupuncture with active control such as exercise or psycho-social interventions that have the strongest supporting evidence to better evaluate treatment-specific effects.

A large scale five-arm study, in which patients were prescribed: oral antioxidant supplementation plus medroxyprogesterone acetate; or megestrol acetate, eicosapentaenoic acid (EPA)-enriched nutritional supplement, carnitine; or thalidomide showed improved response with combination therapy over each in isolation, in terms of primary end points of lean body mass, resting energy expenditure and fatigue as well as inflammation, suggestive of a compound or synergistic effect when given simultaneously.40 Concerns with these medications include polypharmacy, adverse interactions, financial burden and compliance. Studies investigating effectiveness of vitamins and herbs show that multivitamin supplements and ginseng can improve fatigue.41 Concerns with many herbal remedies is possible interference with the enzymes and transporters utilized by chemotherapy due to which they can have potentially harmful interactions;42 these should be reviewed with all patients pursuing herbal treatments.

Coordination of care

Data exist for the value of adopting a surveillance model of care for breast cancer survivors. A multidisciplinary approach consisting of the primary care provider, oncologist, oncology nurse, social worker and rehabilitation professionals is recommended for these complex patients. For children, coordination with school officials and teachers may be important.

Patient & family education

Many websites offer information for patients and families that are frequently updated. Listed below are some of them. Support groups and community resources also offer information which is also available through the American Cancer Society (www.cancer.org) and The Wellness Community (www.thewellnesscommunity.org).

Self-management

Having good social support has been linked to better quality of life in cancer patients. With increasing social media and internet presence, several online workshops and programs targeting cancer patients have been created to provide additional education and support. A study of 352 cancer survivors enrolled in a 6 week online workshop addressing lifestyle changes such as diet, stress management, and exercise, showed improvements in insomnia, and engagement in more strenuous exercises.43,44 A 5-week web-based tool specifically targeted towards managing cancer fatigue has been studied in a small study involving 19 patients, and led to better self-understanding and management of cancer related fatigue.45,46

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

There have been numerous recent studies exploring immune pathways involved in cancer fatigue, as well as numerous nutritional supplements to address cancer related fatigue.

Immune modulators

There have been recent studies in the roll of the activation of the Toll-like receptor 2/4 radical cycle in fatigue, both in cancer patients and a variety of patients with chronic medical conditions. A better understanding of this pathway would be helpful in drug development.47 Studies of beta glucan have been shown to be helpful in augmenting endurance of physical activity levels in animal models via suggested immune mechanisms.48 One human trial of D-glucan showed decreased fatigue, but did not report statistical significance.49

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

Although the American College of Sports Medicine has provided basic guidelines for exercise in cancer patients, specific exercise protocols are unclear. In addition, better quality studies with higher power could be conducted for complementary therapies.

Educational materials for patients and families:

National Cancer Comprehensive Network: https://www.nccn.org/patients/resources/default.aspx

Eastern Cooperative Oncological Group (ECOG) in collaboration with American College of Radiology Imaging Network (ACRIN):
http://ecog-acrin.org/patients/resources

Center for Disease Control: www.cdc.gov/cancer/survivorship

Cancer Hope Network: www.cancerhopenetwork.org/

American Cancer Society (Cancer Survivor Network): www.csn.cancer.org

The Wellness Community www.thewellnesscommunity.org

Cancer Support Community www.cancersupportcommunity.org

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Original Version of the Topic:

Naomi Lynn H. Gerber, MD. Exercise effects and fatigue in cancer patients. Publication Date: 2013/07/17.

Author Disclosure

Sravani Venkata Anjana Mudumbi, MD
Nothing to Disclose

Teresa Tang, MD
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