Fatigue and dyspnea are two of the most common symptoms associated with
advanced cancer. Fatigue is also very commonly associated with cancer treatment
and occurs in up to 90% of patients undergoing chemotherapy. Both symptoms
have many possible underlying causes. In most patients, the etiology of
fatigue or dyspnea is multifactorial with many contributing interrelated abnormalities.
In a recent study of advanced cancer patients, fatigue was found to be
significantly correlated with the intensity of dyspnea. This chapter will discuss
the mechanisms, clinical features, assessment, and management of both of these
troublesome and often undertreated symptoms in cancer patients.
Fatigue has been defined as easy tiring and decreased capacity to maintain
performance. It results in physical and/or mental weariness following exertion
and is transient in most of us. In cancer patients, fatigue is often severe; has a
marked anticipatory component; and results in lack of energy, malaise, lethargy,
and diminished mental functioning that profoundly impairs quality of
life. It may be present early in the course of the illness, may be exacerbated by
treatments, and is present in almost all patients with advanced cancer.
The mechanisms of cancer-related fatigue are not well understood. Substances
produced by the tumor are postulated to induce fatigue. Blood from a fatigued
subject when injected into a rested subject has produced manifestations of fatigue.
The host production of cytokines in response to the tumor can also have
a direct fatigue-inducing effect. Muscular or neuromuscular junction abnormalities
are a possible cause of chemotherapy- or radiotherapy-induced fatigue.
In summary, fatigue is the result of many syndromes-not just one. Multiple
mechanisms are involved in causing fatigue in most patients with advanced
The causes of fatigue in an individual patient are often multiple with many
interrelated factors. Figure 1 summarizes the main contributors to fatigue in
Cancer cachexia results from a complex interaction of host and tumor
products. Host cytokines such as tumor necrosis factor, interleukin-1, and
interleukin-6 are capable of causing decreased food intake, loss of body weight,
a decrease in synthesis of both lipids and proteins, and increased lipolysis. Tumors
are also capable of producing lipolytic factors (lipolytic factor,
toxohormone L-2) and proteolytic by-products (proteolysis-inducing factor).
The metabolic abnormalities involved in the production of cachexia and the
loss of muscle mass resulting from progressive cachexia may cause profound
weakness and fatigue. However, many abnormalities described in Figure 1 are
capable of causing profound fatigue in the absence of significant weight loss.
has been shown to cause deconditioning and decreased endurance
to both exercise and normal activities of daily living. On the other hand, overexertion
is a frequent cause of fatigue in noncancer patients. It should also be
considered in younger cancer patients who are undergoing aggressive antineoplastic
treatments such as radiation therapy and chemotherapy and who are
nevertheless trying to maintain their social and professional activities.
In patients without cancer who present with fatigue, the
final diagnosis is psychological in almost 75% of patients (depression, anxiety,
and other psychological disorders). The frequency of major psychiatric disorders
in cancer patients is low. However, symptoms of psychological distress or
adjustment disorders with depressive or anxious moods are much more frequent.
Patients with an adjustment disorder or a major depressive disorder can
have fatigue as their most prevalent symptom.
related to advanced cancer or chemotherapy has been associated with
fatigue, and its treatment results in improvement of fatigue and quality of life in
Autonomic insufficiency is a frequent complication of advanced
cancer. Autonomic failure has also been documented in patients with a
subset of severe chronic fatigue syndrome. Although the association between
fatigue and autonomic dysfunction has not been established in cancer patients,
it should be suspected in patients with severe postural hypotension or other
signs of autonomic failure.
Research has shown that both intrathecal and systemic opioid
therapy, as well as cachexia and some antineoplastic therapies, can result in
hypogonadotropic hypogonadism. This can lead to fatigue, depression, and
Chemotherapy and radiotherapy
These treatments are common causes of fatigue
in cancer patients. Chemotherapy and radiotherapy for malignancy cause a
specific fatigue syndrome. Combined therapy with the two modalities appears
to cause worse fatigue than either modality given alone. The pattern of fatigue
reported by patients with cancer who receive myelosuppressive chemotherapy
is cyclical. It begins within the first few days after therapy is started, peaks
around the time of the WBC nadir, and diminishes in the week thereafter, only
to recur again with the next cycle of chemotherapy. Fatigue tends to worsen
with subsequent cycles of chemotherapy, which suggests a cumulative doserelated
toxic effect. Compared with women with no history of cancer, former
patients with breast cancer who had received adjuvant chemotherapy reported
more fatigue and worse quality of life due to this symptom. Similar results have
been noted in breast cancer patients who have been treated with high-dose
chemotherapy and autologous stem-cell support and in patients treated for lymphoma.
Radiation therapy tends to cause a different pattern of fatigue. It is often described
as a "wave" that starts abruptly within a few hours after treatment and
subsides shortly thereafter. Fatigue has been noted to decrease in the first
2 weeks after localized treatment for breast cancer but then to increase as radiation
therapy persists into week 4. It then decreases again 3 weeks after radiation
therapy ceases. The mechanism for fatigue in these situations is not well understood.
Surgery is another common cause of fatigue in patients with cancer. In addition,
commonly used medications such as opioids and hypnotics may cause
sedation and fatigue. Comorbid conditions not necessarily related to cancer
such as renal failure or congestive heart failure may coexist and contribute to
Fatigue is sometimes referred to as asthenia, tiredness, lack of energy, weakness,
and exhaustion. Not all these terms have the same meaning to all patient
populations. Moreover, different studies of fatigue and asthenia have looked at
different outcomes, ranging from physical performance to the purely subjective
Since fatigue is essentially a subjective sensation, it is by nature difficult to assess.
There is agreement that self-assessment should be the "gold standard."
Table 1 summarizes the four most common approaches to the assessment of
fatigue. The first category in Table 1 looks at the objective function that the
patient is capable of performing when subjected to a standard task. These functional
tasks have limited value in cancer care, however, as they are very difficult
for the advanced cancer patient to perform.
The second category in Table 1 attempts to assess the subjective effects of standard
The third category in Table 1 has been the most commonly used in oncology.
The two most common scales (ECOG [Eastern Cooperative Oncology
Group] and Karnofsky) consist of a physician's rating of the patient's functional
capabilities after a regular medical consult. A physiotherapist performs the
Edmonton Functional Assessment Tool and attempts to determine the functional
status, as well as all the obstacles to clinical performance in these patients.
The fourth category in Table 1 is the most relevant for both clinical management
and clinical trials in fatigue. Visual analog scales (VAS), numerical scales,
the Brief Fatigue Inventory, and the Piper Fatigue Self-Report Scale have been
validated. In addition, there are validated functional assessments in most QOL
(quality of life) questionnaires.
In addition to the assessment of the intensity of fatigue, the clinical assessment
of these patients requires clinicians to determine the impact of all factors on the
presence of fatigue.
To treat fatigue optimally, it is vital to identify and prioritize the different underlying
factors in each individual patient. A thorough history, including recent
treatment history, physical examination, and medication review, in addition
to simple laboratory investigations will help identify possible underlying
causes. Figure 2 outlines a therapeutic approach to fatigue management in cancer
patients. Whenever possible, an attempt should be made to treat these contributing
factors. It is impossible to determine at a given time, with certainty, if
one of these identified problems is a major contributor to fatigue or is simply a
coexisting problem in a given patient. Therefore, it is of great importance to
measure the intensity of fatigue and the patient's performance before and after
treating any contributing factor. If the level of fatigue does not improve after
correction of these abnormalities, it is clear then that further treatment will not
result in improvement in the future.
In patients with cancer treatment-related fatigue, it is very important to exclude
specific causes, such as hypothyroidism, hypogonadism, and anemia, and to consider
other potential adverse effects of treatment. If specific problems are identified.
they should be appropriately managed. For instance, patients with anemia
may experience symptomatic improvement with the administration of erythropoietic
therapy (epoetin alfa [Epogen, Procrit] and darbepoetin alfa(Drug information on darbepoetin alfa)
the dose and frequency interval that best fit the patient's need. Epoetin alfa(Drug information on epoetin alfa)
be administered weekly by subcutaneous injection; darbepoetin alfa has a longer
half-life, requiring less frequent dosing. Dosages and schedules of both agents
may be increased if necessary. (See section on "Dose and schedule of administration"
in chapter 40 for specific information about dosages and schedules.)
In most patients, there will be no identified reversible causes. A number of
effective pharmacologic and nonpharmacologic symptomatic treatments are
available for these patients.