Although fatigue is clearly prevalent in patients with cancer, it has been difficult to identify consistent correlates of fatigue in this patient population. The factors most often implicated have been the following:[1-9]
- Cancer treatment.
- Metabolic disturbances.
- Hormone deficiency or excess.
- Psychological distress.
- Physical deconditioning.
- Sleep disturbances.
- Excessive inactivity.
- Pulmonary impairment.
- Neuromuscular dysfunction.
- Pain and other symptoms.
- Proinflammatory cytokines.
- Nutritional deficiencies.
- Concomitant medical illness.
- Cardiac impairment.
The association of fatigue with the major cancer treatment modalities of surgery, chemotherapy, radiation therapy, and biologic response modifier therapy caused speculation that fatigue resulted from tissue damage or accumulation of the products of cell death. Interest in the effects of cancer treatment on the production of proinflammatory cytokines is based on recognition of the strong fatigue-inducing effect of some biologic response modifiers such as interferon-alpha and the finding of elevated levels of proinflammatory cytokines in people experiencing persistent fatigue following cancer treatment.[10,11]
Many people with cancer undergo surgery for diagnosis or treatment. Despite the high incidence of postoperative fatigue observed in clinical practice, little research exists that examines causes and correlates of postoperative fatigue in people with cancer. It is clear, however, that fatigue is a problem postsurgery that improves with time and is compounded by fatigue experienced from other cancer treatments.
Fatigue has long been associated with radiation exposure and is reported as being one of the most common and activity-limiting side effect of radiation therapy for cancer.[4,13] Most of the research describing the fatigue trajectory during radiation therapy has been conducted with women who have breast cancer and men who have prostate cancer.[13,14] Fatigue increases throughout radiation therapy, peaking around mid course; it remains at this level until radiation therapy is completed, improving somewhat during the 2 months after completion of treatment.[13-15] A study that investigated the trajectory of fatigue in men (n = 82) who were undergoing radiation therapy for prostate cancer found significant interindividual variability. The authors used hierarchical linear modeling, a highly sophisticated analytical method, to identify predictors for prolonged fatigue trajectories. Younger men with a high level of fatigue at radiation therapy initiation were at increased risk of higher levels of morning and evening fatigue during the course of radiation therapy. Additionally, level of depression at radiation therapy initiation predicted the level of morning fatigue during the course of radiation therapy.
A second study that included 73 women who were undergoing adjuvant radiation therapy for breast cancer found similar differences in the patterns and predictors of morning versus evening fatigue. Participants were recruited to the study at the time of their simulation visit and completed baseline questionnaires. Data were then collected on 2 subsequent days, in the morning and at bedtime, each week during radiation therapy; every 2 weeks for 2 months after radiation therapy; and once a month for 2 additional months thereafter. Fatigue was measured with the Lee Fatigue Scale. For the group as a whole, over the 25 weeks of data collection, morning fatigue decreased slightly during radiation therapy and was constant for 4 months afterwards, while evening fatigue increased through radiation therapy and then declined slightly after treatment. Evening fatigue was higher for those who:
- Were working.
- Had children at home.
- Had higher depression scores.
Morning fatigue was higher for those who:
- Had more trait anxiety.
- Were experiencing sleep disturbance.
- Were younger.
- Had lower body mass indices.
A number of research studies document the existence of a fatigue syndrome that is not specific to the disease type or radiation site and that demonstrates a gradual decline in fatigue in the patient after treatment is completed.[15,17-20] Some of these studies suggest, however, that not all patients return to pretreatment energy levels. Specific etiologic factors and correlates of fatigue associated with radiation therapy have not been identified. Risk factors for persistent low energy in cancer patients include older age, advanced disease, and combination-modality therapy.
Fatigue is a dose-limiting toxicity of treatment with a variety of biotherapeutic agents. Biotherapy exposes patients with cancer to exogenous and endogenous cytokines. Biotherapy-related fatigue usually occurs as part of a constellation of symptoms called flulike syndrome. This syndrome includes:
Mental fatigue and cognitive deficits have also been identified as biotherapy side effects. The type of biotherapeutic agent used may influence the type and pattern of fatigue experienced.
Treatment with chemotherapy is a predictor of fatigue and can be exacerbated by the coexistence of pain, depression, and/or anxiety.[Level of evidence: II] A longitudinal, descriptive study reported highest levels of fatigue at the midpoint of a patient’s chemotherapy cycles, with fatigue improving after treatment but not quite returning to baseline levels 30 days after the last treatment. In another longitudinal study of women with stage 0 to stage II breast cancer who received chemotherapy with or without radiation therapy (N = 103) versus radiation therapy alone (N = 102) versus a control group (N = 193), increases in fatigue were demonstrated 3 years posttreatment for the group that received chemotherapy with or without radiation therapy, compared with the two other groups. Mean scores for fatigue severity as measured by the Fatigue Symptom Inventory (range, 0–10) increased over the 3 years as follows:
- From 2.31 to 2.86 in the group that received chemotherapy with or without radiation.
- Only from 1.96 to 2.06 in the radiation therapy–alone group.
- Only from 2.20 to 2.22 in the noncancer control group.
There were statistically significant group-by-time effects for the group that received chemotherapy with or without radiation therapy. This increase in fatigue was not explained by hormone therapy and approached clinically meaningful values. It is not currently known what specific patient characteristics are associated with risk for long-term increased fatigue or more severe fatigue and who will experience fatigue resolution.
Evidence suggests that anemia may be a major factor in cancer-related fatigue (CRF) and quality of life in cancer patients.[28-30] Anemia can be related to the disease itself or caused by the therapy. Occasionally, anemia is simply a co-occurring medical finding that is related to neither the disease nor the therapy. Anemia is often a significant contributor to symptoms in persons with cancer. For individual patients, it can be difficult to discern the actual impact of anemia because there are often other problems that confound the ability to weigh the specific impact of anemia. The impact of anemia varies depending on factors such as:
- The rapidity of onset.
- Patient age.
- Plasma-volume status.
- The number and severity of comorbidities.
A retrospective review was conducted to understand the problem of anemia in patients undergoing radiation therapy. Anemia was prevalent in 48% of the patients initially, and increased to 57% of the patients during therapy. It was more common in women than men (64% vs. 51%); however, men with prostate cancer experienced the greatest increase in anemia during radiation therapy. In certain cancers, such as cancer of the cervix and cancer of the head and neck, anemia has been found to be a predictor of poor survival and diminished quality of life in patients undergoing radiation therapy.[33-36]
- Alteration in the body’s ability to process nutrients efficiently.
- Increase in the body’s energy requirements.
- Decrease in intake of energy sources.
Causes of nutritional alterations are listed in Table 1.
|Altered ability to process nutrients||Impaired glucose, lipid, and protein metabolism|
|Increased energy requirements||Tumor consumption of and competition for nutrients|
|Hypermetabolic state due to tumor growth|
|Decreased intake of energy sources||Anorexia|
Numerous factors related to the moods, beliefs, attitudes, and reactions to stressors of people with cancer can also contribute to the development of chronic fatigue. Anxiety and depression are the most common comorbid psychiatric disorders of CRF. Often, fatigue is the final common pathway for a range of physical and emotional etiologies.
Depression can be a comorbid, disabling syndrome that affects approximately 15% to 25% of persons with cancer. The presence of depression, as manifested by loss of interest, difficulty concentrating, lethargy, and feelings of hopelessness, can compound the physical causes for fatigue in these individuals and persist long past the time when physical causes have resolved.
Anxiety and fear associated with a cancer diagnosis, as well as its impact on the person’s physical, psychosocial, and financial well-being, are sources of emotional stress. Distress associated with the diagnosis of cancer alone may trigger fatigue. A study of 74 early-stage breast cancer patients with no history of affective disorder assessed various symptoms of adjustment approximately 2 weeks after diagnosis; about 45% noted moderate or high levels of fatigue. This fatigue may have been secondary to the increased cognitive strain of dealing with the diagnosis or to insomnia, reported as moderate to severe by about 60% of the patients. Therefore, fatigue may begin before treatment as a result of worry or other cognitive factors, both primary and secondary to insomnia. Various forms of treatment may compound this fatigue.
In cancer survivors, fatigue may also be increased above levels seen in the general population.[43,44] In testicular cancer survivors, anxiety and depression were predictive of fatigue, suggesting a possible role for psychiatric intervention in fatigue management. (Refer to the PDQ summaries on Depression and Adjustment to Cancer: Anxiety and Distress for more information.)
Psychologic and symptom distress have also been found to be significant predictors of fatigue.[46,47] In a study of 101 women about to undergo surgery for breast cancer, younger age, presurgery distress, and expectations about fatigue significantly predicted fatigue levels 1 week after surgery. In the regression model, age, distress and expectancy each uniquely contributed to fatigue, with distress and expectancy accounting for 25% of the variance.[Level of evidence: III] In a longitudinal study with women who had gynecologic cancer, symptom and psychologic distress significantly predicted fatigue before, during, and after treatment with chemotherapy, explaining up to 80% of the variance in fatigue scores after chemotherapy treatment.
Impairment in cognitive functioning, including decreased attention span and impaired perception and thinking, is commonly associated with fatigue.[48,49] Although fatigue and cognitive impairments are linked, the mechanism underlying this association is unclear. Mental demands inherent in the diagnosis and treatment of cancer have been well documented, but little is known about the concomitant problem of attention fatigue in people with cancer. Attention problems are common during and after cancer treatment. Some of the reported attention problems may be caused by the fatigue of directed attention.[50,51] Attention fatigue may be relieved by activities that promote rest and recovery of directed attention. Although sleep is necessary for relieving attention fatigue and restoring attention, it is insufficient when attention demands are high. Empirical literature suggests that the natural environment contains the properties for restoring directed attention and relieving attention fatigue.
Sleep Disorders and Inactivity
Causative or contributing factors in CRF may be:
- Disrupted sleep.
- Poor sleep hygiene.
- Decreased nighttime sleep or excessive daytime sleep.
Patients with less daytime activity and more nighttime awakenings were noted to consistently report higher levels of CRF. Those with lower peak-activity scores, as measured by wristwatch activity monitors, experienced higher levels of fatigue.
Sleep disorders clearly contribute to fatigue  and may differentially affect fatigue ratings, depending on the time of the rating. A study that evaluated fatigue in women undergoing radiation therapy for breast cancer found that sleep had a greater influence on morning fatigue values than on evening fatigue scores. In a similar study of men undergoing radiation therapy for prostate cancer, sleep contributed to both morning and evening fatigue levels. However, fatigue and sleep can also be distinct problems. One study that resulted in significant improvement in sleep with the use of cognitive behavioral therapy did not significantly affect fatigue.
Refer to the PDQ summary on Sleep Disorders for more information.
Medications other than chemotherapy may contribute to fatigue. Opioids used in the treatment of cancer-related pain are often associated with sedation, though the degree of sedation varies among individuals. Opioids are known to alter the normal function of the hypothalamic secretion of gonadotropin-releasing hormone.
Hypogonadism may be found in patients with advanced cancer and can contribute to fatigue during cancer treatment. One case-control study examined the effects of chronic oral opioid administration in survivors of cancer and, consistent with the research on intrathecal administration, found marked central hypogonadism among the opioid users with significant symptoms of sexual dysfunction, depression, and fatigue. One trial (NCT00965341) has studied whether testosterone replacement therapy affects fatigue in men with advanced cancer and low testosterone levels; results are pending.
Other medications—including tricyclic antidepressants, neuroleptics, beta blockers, benzodiazepines, and antihistamines—may produce side effects of sedation. In addition, concurrent medications such as analgesics, hypnotics, antidepressants, antiemetics, steroids, or anticonvulsants—many of which act on the central nervous system—can significantly compound the problem of fatigue. The coadministration of multiple drugs with varying side effects may compound fatigue symptoms.
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