Cancer-Related Fatigue: Approach to Assessment and Management

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF,^75–77 but randomized controlled trials have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of nonpharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment.³⁷

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. Randomized controlled trials of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF.⁷⁸ Likewise, in an analysis of 5 randomized controlled trials, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo.⁷⁹ However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease.⁸⁰ Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically.⁸¹ In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner.⁸² However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment.⁸³ Also, other randomized controlled trials in patients undergoing adjuvant chemotherapy for breast cancer⁸⁴ and patients receiving radiation therapy for brain tumors⁸⁵ failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm.⁸⁶ Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation.⁸⁷ A placebo effect was also noted in patients with multiple myeloma⁸⁸ and patients with primary brain tumors.⁸⁹ In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue.⁹⁰ In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7).⁹¹ This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional randomized controlled trials are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF.³⁷

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines.⁹² In a randomized controlled trial evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo.⁹³ A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo.⁹⁴ Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis.³⁷

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups.⁹⁵

Antidepressants have failed to demonstrate benefit in CRF without depression.⁸ However, if a patient has both fatigue and depression, antidepressants may help.⁹⁶ A selective serotonin receptor inhibitor is recommended as a first-line antidepressant.⁹⁷ Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.