Dexamphetamine

To evaluate the effectiveness of pharmacologic interventions used for fatigue in patients with cancer

Databases searched were PaPaS, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, Dissertation Abstracts International (DAI), metaRegister of Controlled Trials (mRCT) (January 2007–October 2009). Journals searched were British Journal of Cancer, Journal of Clinical Oncology, Journal of Pain and Symptom Management, and Journal of Palliative Medicine. The reference lists of all articles were checked for additional studies. Conference abstracts also were searched.

Search keywords were neoplasms, bone marrow transplantation, cancer, carcinoma, tumour, adenocarcinoma, leukemia, lymphoma, malignant, radiotherapy, fatigue, tired, weary, weariness, exhausted, lack or loss or lost energy or vigor, apathy or lassitude or lethargy, or feeling drained, sleepy, or sluggish.

Studies were included in the review if they

• Assessed drug therapy for the management of cancer-related fatigue (CRF) compared to placebo, usual care, or a nonpharmacologic intervention.
• Were randomized, controlled trials (single-blind and open-label were allowed).
• Included adult patients with a clinical diagnosis of cancer.

This review was an update of a previous review. The updated search retrieved 647 additional references. Of those, six additional studies met the inclusion criteria. The final sample of studies included was 31.

The review included 7,104 participants who received a drug intervention for CRF.

Psychostimulants

• Four trials examined methylphenidate, and one used dexamphetamine. These included 426 patients total.
• Evidence existed of a significant effect on fatigue with methylphenidate over placebo, and evidence supported the use of psychostimulants in the treatment of CRF.
• The standardized mean difference was positive, with a small effect and narrow confidence interval (CI) (total mean difference = –0.28; 95% CI [-0.48, -0.09]; Z = 2.83; p = 0.005).
• Fatigue was measured with the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) in all studies.

Erythropoietin and Darbepoetin

• Eleven studies were combined in total and demonstrated a positive effect. The weighted mean difference of studies using the FACT-F outcome measure in erythropoietin gave a score of 4.33, which was a clinically significant difference. The conclusion was limited to patients with anemia who were undergoing chemotherapy. Greater improvement was more likely in those with lower hemoglobin levels.
• In placebo-controlled trials of darbepoetin, the mean difference using the FACT-F score was -1.96, which was less than the minimally clinical significant difference.
• Combined analysis for both agents gave a mean difference score of 3.75, which was clinically significant. 
• Erythropoietin and darbepoetin cannot be recommended because of adverse events associated with these drugs.

Antidepressants/Paroxetine

• Two studies using paroxetine and a trial using sertraline were analyzed. Analysis showed no benefit for the treatment of CRF.

Progestational Steroids

• In studies that could be combined, no evidence existed to support continued use for the treatment of fatigue.
• The clinical significance of results of ibandronate were unclear.
• One study of etanercept during chemotherapy had statistically significant results, but the study had a small sample size and poor design. It was suggested that additional trials be conducted.
• One study of donepezil showed no benefit over placebo.

Four trials of methylphenidate provided evidence for use that was supportive but associated with a small effect size in a dose of 10–20 mg per day. Serious adverse events were minimal; however, clinicians need to review contraindications before prescribing. Additional large-scale trials were suggested using methylphenidate to further evaluate use in CRF. Erythropoietin and darbepoetin can no longer be recommended for CRF because of increased adverse events associated with these drugs. No current evidence exists to support the use of steroids.

• Reviewers found major limitations in the reporting of trials and multiple methods of measuring outcomes.
• Some outcomes in trials were not reported due to extensive missing data.
• These findings point to the need for improved research reporting to meet Consolidated Standards of Reporting Trials (CONSORT) guidelines and the benefit that could be derived from use of consistent methods of measuring outcomes.

To determine the efficacy of pharmacological treatment on nonspecific fatigue in palliative care, including patients with advanced cancer and other chronic conditions associated with fatigue.

Databases searched were EMBASE, PsychLit, CENTRAL, and MEDLINE. Reference lists of identified articles were reviewed for inclusion, and textbooks were handsearched. Conference proceedings of the American Society of Clinical Oncology (ASCO) from 2000 to 2008 and the 2005 meeting of the European Cancer Conference were included in the search.

An extensive listing of keywords and specific search methods per database are provided in the article.

Studies were included in the review if

• They were randomized, controlled trials
• The primary outcome was fatigue or related terms, such as asthenia
• Participants were 18 years or older
• The study included evaluation of the effect of pharmacologic treatment of fatigue with psychostimulants, amantadine, corticosteroids, donazepine, and antidepressants if used for the treatment of fatigue. 

Studies were excluded if they studied megestrol or focused on physiologic deficiencies, such as lack of hemoglobin and use of erythropoietin.

Initial searching provided 2,000 titles. Of those, 22 met the inclusion criteria. They included data from 11 drugs:  amantadine (6), pemoline (3), methylphenidate (3), dexamphetamine (2), paroxetine (2), acetyl-L-carnitine (2), testosterone (2), fluoxetine (1), donepezil (1), modafinil (1), and acetylsalicylic acid (1). If two or more studies of the same medication could be analyzed in the same subpopulation of patients, meta-analysis was performed. Meta-analysis was performed for amantadine, pemoline, methylphenidate, and modafinil.

• The final sample of 22 studies included 1,632 patients.
• Studies were performed in patients with multiple sclerosis (MS) (10), HIV (4), cancer (6), postpolio (1), and endstage chronic obstructive pulmonary disease (COPD) (1).

Most studies showed some beneficial effect; however, a substantial similar placebo effect was often observed.

Amantadine

• Meta-analysis was conducted for three (n = 154) studies comparing amantadine to placebo in patients with MS.
• Standard mean difference (SMD) favored amantadine (SMD = 1.68; 95% confidence interval [CI] [1.24,1.92]; Z = 12.76; p < 0.00001).
• No statistically significant heterogeneity existed.
• Study samples were generally small, and several methodologic weaknesses were seen.

Pemoline

• Pemoline was used in three studies on MS.
• Meta-analysis demonstrated no benefit (SMD = –0.11; 95% CI [–0.42, 0.2]; Z = 0.71; p = 0.48).
• There was significant heterogeneity among the studies.

Methylphenidate

• Two studies in patients with cancer were included.
• There was a slightly superior effect compared to placebo (SMD = 0.49; 95% CI [0.15, 0.83]; Z = 2.86; p = 0.004).
• There was significant heterogeneity.

Dextroamphetamine

• Two studies compared the drug to placebo in patients with cancer. No significant benefits were seen.

Paroxetine

• There were no significant effects demonstrated in one study in patients with COPD and one in patients with cancer.

Testosterone

• No significant effects were demonstrated in studies on HIV.

Acetyl-L-carnitine

• No significant effects were shown in one study on cancer and one on MS.

Modafinil

• Meta-analysis in two studies on MS showed no significant effect.

Donepezil

• One study in 142 patients with cancer showed no benefit compared to placebo.

Other

• Fluoxetine was inferior to testosterone in one study on HIV.
• Acetylsalicylic acid was associated with relief of fatigue compared to placebo in one study on MS.

Methylphenidate and amantadine showed promise for reducing fatigue in patients with advanced disease. Amantadine has not been studied in patients with cancer-related fatigue, but it has been shown to be effective in patients with MS. The meta-analysis included only a few studies and the evidence was weak, pointing to the need for additional research in this area. It is not clear whether amantadine would be useful for patients with cancer, as this has not been studied.

The analysis was performed only in palliative care populations and did not include studies of methylphenidate in patients with cancer during active treatment, which also have shown some efficacy. However, side effects included insomnia, anorexia, behavior change, and vertigo in studies reviewed with methylphenidate. In addition, although statistically significant, effect sizes were small. These findings suggest that use in patients with cancer, who also may experience anorexia and sleep disorders from other causes, has potential benefits that would need to be balanced with potential adverse effects. Carnitine, acetylsalicylic acid, and modafinil have been used in a few studies with positive results. These drugs warrant additional investigation to confirm efficacy in different patient populations with fatigue.

To test the hypothesis that use of dexamphetamine in fatigued patients with advanced cancer would produce a clinically significant improvement with minimal side effects.

Patients with a prognosis of more than two months and fatigue rated at least 4 out of 10 were randomized to receive either dexamphetamine or lactose placebo. Patients were given a daily dose of 20 mg in two doses daily at 8 am and noon. Patients were contacted daily by telephone if at home to record acceptability and improve compliance. If the dose was not tolerated, it was reduced by 50%. The trial was conducted for eight days, and measurement was repeated every two days.

• In total, 50 patients (36 men, 14 women) were enrolled, and 39 completed the study.
• Patients had advanced cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 3.
• Mean age was 67.8 years for the control group and 73.3 years for the experimental group. 
• Diagnoses varied, but all patients were in palliative care.
• Patients were excluded if they were currently receiving chemotherapy, had anxiety requiring medication, had untreated depression, had recently used monoamine oxidase inhibitors (MAOIs), had an untreated medical condition, or had a hemoglobin less than 100 mg/dL with transfusion planned.

Single multisite study in a palliatve care service in Australia

The study was a randomized, double-blind, placebo-controlled trial.

• Brief Fatigue Inventory (BFI)
• McGill Quality of Life Questionnaire
• ECOG Performance Status
• Self-reported and clinician-reported side effects.
• It was identified from previous work that a two-point decrease in fatigue levels on a 10-point scale was clinically relevant, and this was used for power analysis in sample size planning. A 20% drop-out rate was incorporated in planning for 90% power.
• Other measurements and tools used included albumin levels, hemoglobin levels, oxygen saturation on room air, and other medications.

A transient improvement was observed in fatigue in the dexamphetamine arm (p = 0.039) only on day 2 of the trial. No other significant differences existed between groups. Age and sex were significant predictors of severity of fatigue; those who were younger (p = 0.03) and male (p = 0.047) had more severe fatigue. Both groups had nonsignificant improvement in quality of life measures on some subscales, indicating a potential overall placebo effect. Medication was associated with an increased pulse rate, suggesting that the dosage given had a physiologic effect.

Although well tolerated, 20 mg of dexamphetamine does not improve fatigue or quality of life in patients with advanced cancer. This study agreed with null effects reported by others. Short-term results seen may indicate a response to initiation of a psychostimulant, and changing the dosage over time may have more effect.

• A significant number of drop-outs resulted in a small final sample size.
• Although the authors stated planned approaches to monitor patient compliance with the medication regime, no relevant findings were identified, so actual medication adherence is unknown.
• No longer-term follow-up was conducted. 
• Patients studied were very ill, with low performance status. Findings may not be applicable for individuals with less severe disease.

Optimum dosage across studies has not been defined.