Much of the information regarding interventions for fatigue relates either to healthy subjects or to persons in whom muscle fatigue is the primary etiology of the problem or fatigue is secondary to treatment-related anemia.[1,2][Level of evidence: II];[3,4] Without a determination of the causative mechanisms of fatigue in oncology patients, interventions must be directed to symptom management and emotional support. Although some recommendations for the management of fatigue in oncology patients have been made, these are theoretical or anecdotal in nature and in general have not been the focus of scientific evaluation.
Since the etiology and mechanisms regarding fatigue/asthenia in cancer patients are indeterminate, there is considerable variation in practice patterns regarding the management of this symptom. The focus of medical management is often directed at identifying specific and potentially reversible correlated symptoms, as in the following examples:
- Patients with fatigue and pain may have titration of pain medications.
- Patients with fatigue and anemia may receive a transfusion of packed red blood cells, nutritional interventions including iron-rich foods, supplemental iron or vitamins to correct an underlying deficiency, or injections of epoetin alfa.
- Patients with depressed mood and fatigue may be treated with antidepressants or psychostimulants.
It is often helpful to consider discontinuation of drugs that may be safely withheld. There is no agreed-upon approach for the evaluation and treatment of fatigue, but an increasing number of clinical trials are designed to address this issue in cancer patients.
One of the most popular categories of pharmacologic interventions evaluated for cancer-related fatigue (CRF) is psychostimulants (see Table 2). Psychostimulants are drugs that interact with neurotransmitters and receptors in the brain to increase cortical function. Different types of psychostimulants work through various mechanisms to produce activity in the brain consistent with short-term improvement in energy level and psychomotor activity. These medications may also improve mood, attention, and concentration in some populations. Psychostimulants on the market include the following:
Initial support for the hypothesis that psychostimulants may improve CRF arises largely from clinical anecdotal experiences. These medications are not approved by the U.S. Food and Drug Administration (FDA) for the treatment of CRF. However, preliminary evidence from randomized controlled studies [5,6,7] suggests that these medications might be helpful in a subpopulation of patients experiencing more severe fatigue. There are at least seven published randomized clinical trials evaluating psychostimulants for CRF: six with methylphenidate and one with modafinil. Only one of these randomized trials  has shown significant differences between the placebo group and methylphenidate group with respect to the outcome of fatigue.
The one study that demonstrated significant improvements over placebo for CRF used a mean dose of 27.7 mg of the D-isomer of methylphenidate as a study intervention. The population that benefited was women who had completed chemotherapy for breast or ovarian cancer. The study design incorporated a titration to effect, so some patients who may have benefited may have received more than 27.7 mg of the drug. Furthermore, 11% of participants on this trial withdrew because of adverse events, compared with 1% in the placebo arm. Conversely, an equally large randomized controlled trial randomly assigned patients with early and advanced disease, both on and off treatment, to receive 54 mg of a long-acting methylphenidate preparation equaling 27 mg of the D-isomer or a placebo; this trial found no differences between the two groups in any of the fatigue outcomes.[Level of evidence: I] There were significant differences between groups for nervousness and appetite loss, with the methylphenidate arm scoring worse on both of those side effects.