Progestins

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.

All patients received basic treatment with polyphenols (300 mg/day) from alimentary sources (e.g., onions, apples, oranges, red wine, and green tea) or supplementary tablets. Patients also received antioxidant agents (a-lipoic acid and carbocisteine), as well as vitamins A, C, and E, orally. All patients then were randomized to one of the following five treatment arm interventions:

1. Progestational agent medroxyprogesterone acetate (MPA) 500 mg/day or megestrol acetate (MA) 320 mg/day
2. Oral supplementation of eicosapentaenoic acid (EPA)-enriched nutritional supplements, with docosahexaenoic acid, high-calorie, and high-protein content
3. L-carnitine 4 g/day, orally
4. Thalidomide 200 mg/day, orally
5. MPA or MA plus pharmacologic nutritional support, L-carnitine, and thalidomide.

The planned treatment duration was four months. Patient outcomes were evaluated at 4, 8, 16, and 24 weeks.

• The sample was comprised of 125 adult patients with cancer and cancer cachexia (mean age = 69.1 years [range 35–80]).
• The male/female ratio was 74/51.
• A majority (83%) of patients experienced more than 5% weight loss before study entry and were stage IV (94.4%).
• Patients had varied diagnoses, the most common being lung (14.4%) and breast (14.4%) cancer.
• Patients were excluded if they were women of child-bearing age, had significant comorbidities, had a mechanical obstruction to feeding, underwent medical treatments that induced significant changes to body metabolism or weight, or had contradiction to MPA or MA.

Policlinico Universitario and Ospedale Oncologico Regionale, Cagliari, Italy

The study was a randomized, phase II, two-center clinical trial with five treatment arms.

Multidimensional Fatigue Symptom Inventory–Short Form (MFSI-SF)

When comparing baseline and posttreatment measures, statistically significant improvements in fatigue outcomes were observed in the L-carnitine treatment arm (p = 0.039) and the MPA/MA plus pharmacologic nutritional support, L-carnitine, and thalidomide arm (p = 0.015). Fatigue worsened significantly in patients receiving EPA-enriched oral supplementation treatment (p = 0.051).

• No placebo arm was included because an approved drug for cancer cachexia treatment was available at the time of study (MPA or MA).
• The results were from an interim report.