Sertraline

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.

The sertraline intervention required patients to take 50 mg/day of the study drug or a matched placebo for the study period. Patients who developed symptoms of major depression were referred to a psychiatrist coinvestigator at the institution. If there was a definite indication for antidepressants or if patients decided to stop the study due to adverse events, the drug was discontinued gradually by reducing the dose to 25 mg/day for one week before stopping. Patient outcomes were assessed at baseline and 4, 8, 12, 16, 26, 39, and 52 weeks.

• The study was comprised of 189 patients with advanced cancer for whom the responsible oncologist doubted benefits of treatment with antidepressants.
• In the sertraline group (n = 95), the male-to-female ratio was 55:40. There were multiple primary cancer sites, and the majority had received prior chemotherapy (n = 78).
• In the placebo group (n = 94), the male-to-female ratio was 56:38. There were multiple primary cancer sites, and the majority had received prior chemotherapy (n = 78).
• Patients were excluded if they had major depression, delirium, coexisting disorders, were taking medications that contraindicated sertraline treatment, or had a history of psychiatric illness.

This was a multicenter trial conducted in the oncology clinics of several Australian hospitals.

Patients were undergoing the active treatment phase of care.

The study was a double-blind, placebo-controlled, centrally randomized trial that was stratified for institution, sex, anticipated future cytotoxic treatment, and Performance Score:

1. Sertraline (n = 95)
2. Placebo control (n = 94).

• Functional Assessment of Cancer Therapy–Fatigue (FACT-F)
• Utility-Based Questionnaire-Cancer (UBQ-C)
• Somatic and Psychological Health Report (SPHERE)

Sertraline had no significant effect in improving fatigue compared to placebo. Outcomes were compared on the basis of scores at baseline and four and eight weeks.

• The study population was poorly defined, and the exclusion criteria of major depression were arbitrary and left to the responsible oncologist.
• The study was closed at the first interim analysis because sertraline showed no benefit to patients.

Sertraline was started at a dosage of 25 mg/day in a single daily dose, with a possible dosage increase based on individual response and tolerability until 100 mg/day. A minimum dosage of 50 mg/day had to be reached. Patient outcomes were assessed at baseline (T0), week 4 (T1), and week 12 (T2).

• The study was comprised of 35 adult patients with cancer undergoing chemotherapy treatment with mood depression (scoring greater than five on the SCID-PO scale-depression subscale).
• The majority of patients were female (85.7%) and were diagnosed with colorectal cancer (20%), breast cancer (54.3%), lung cancer (8.6%), and onco-hematologic pathology (17.1%).

Psychooncology Unit, St. Giovanni Battista Hospital, University of Turin, Italy

Patients were undergoing the active treatment phase of care.

The study used a pilot, open-label, noncomparative, prospective design.

Montgomery-Åsberg Depression Rating Scale (MADRS)

For lassitude (fatigue), a subitem on the MADRS, there was a significant difference between baseline and week 12. Between baseline and week 4, an improvement was evident but not significant. Fatigue was not a major outcome.

• The study had a small sample size.
• The study had an open-label design without a control group.
• There was heterogeneity in terms of cancer stage and diagnosis.