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      Effect of Methylphenidate in Patients with Cancer-Related Fatigue: A Systematic Review and Meta-Analysis

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          Abstract

          Background

          Cancer-related fatigue (CRF) is a common symptom affecting patients with cancer. There are an increasing number of trials examining potential treatments for CRF. Methylphenidate represents one of the most researched drugs and an up-to-date assessment of the evidence for its use is needed. Trials of methylphenidate for CRF provided inconsistent results. This meta-analysis was aimed at assessing the effect and safety of methylphenidate on CRF.

          Methods

          We comprehensively searched the Pubmed, EMBASE, PSYCHInfo and the Cochrane databases in order to identify published studies on the effect of methylphenidate on CRF. Primary outcomes included fatigue. Secondary outcomes included depression, cognition and adverse effects.

          Findings

          A meta-analysis was conducted on five randomized controlled trials and 498 patients were enrolled. Despite a large placebo effect observed in the studies included, pooled data suggested therapeutic effect of methylphenidate on CRF. Subgroup Analyses showed that the efficacy of methylphenidate on CRF is getting better with prolonging treatment duration, with a MD of −3.70 (95% CI −7.03– −0.37, p = 0.03) for long-time group and a MD of −2.49 (95% CI −6.01–1.03, p = 0.17) for short-time group. In general, there was no impact of methylphenidate on depression and cognition associated with CRF. Adverse events were similar between methylphenidate and placebo groups except that more patients reported vertigo, anxiety, anorexia and nausea in methylphenidate group compared to placebo group.

          Conclusion

          Existing trials of methylphenidate on CRF provided limited evidence for the use of methylphenidate to treat CRF. The absolute numbers still remain small, and further confirmation is needed before firm recommendations on their usage and safety can be made in the treatment of CRF.

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          Most cited references28

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          The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory.

          Fatigue is a major disease and treatment burden for cancer patients. Several scales have been created to measure fatigue, but many are long and difficult for very ill patients to complete, or they are not easy to translate for non-English speaking patients. The Brief Fatigue Inventory was developed for the rapid assessment of fatigue severity for use in both clinical screening and clinical trials. The study enrolled 305 consecutive, consenting adult inpatients and outpatients with cancer who could understand and complete the self-report measures used in the study. The same instruments also were administered to 290 community-dwelling adults to obtain a comparison sample. Research staff completed a form that indicated the primary site and stage of the cancer, rated the Eastern Cooperative Oncology Group performance status of the patient, described the characteristics of the pain, and described the current pain treatment being provided to the patients. The BFI was shown to be an internally stable (reliable) measure that tapped a single dimension, best interpreted as severity of fatigue. It correlated highly with similar fatigue measures. Greater than 98% of patients were able to complete it. A range of scores defining severe fatigue was identified. The BFI is a reliable instrument that allows for the rapid assessment of fatigue level in cancer patients and identifies those patients with severe fatigue.
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            Evidence report on the occurrence, assessment, and treatment of fatigue in cancer patients.

            To determine the occurrence of cancer-related fatigue, the methods used to assess it, and the efficacy of the available treatments, we performed literature searches that identified English-language publications on these topics. Twenty-seven studies were identified in which the quantitative estimation of the occurrence of cancer-related fatigue was an end point. Fifty-six were judged to be relevant to the assessment of fatigue, and 10 randomized controlled clinical trials of treatments of cancer-related fatigue were retrieved. The occurrence of cancer-related fatigue was found to range from 4% to 91%, depending on the population studied and the methods of assessment. Few population-based studies and no longitudinal studies of cancer-related fatigue have been performed. The methods of fatigue assessment were highly variable. Exercise programs show promise to prevent or treat fatigue in some subsets of cancer patients, and the use of epoetin alfa for correction of anemia has been shown to ameliorate fatigue. The number of subjects in the treatment trials was small and their methodologic quality was inconsistent.
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              NCCN Practice Guidelines for Cancer-Related Fatigue.

              These guidelines propose a treatment algorithm in which patients are evaluated regularly for fatigue, using a brief screening instrument, and are treated as indicated by their fatigue level. The algorithm's goal is to identify and treat all patients with fatigue that causes distress or interferes with daily activities or functioning. Management of fatigue begins with primary oncology team members who perform the initial screening and either provide basic education and counseling or expand the initial screening to a more focused evaluation for moderate or higher levels of fatigue. At this point the patient is assessed for the five primary factors known to be associated with fatigue: pain, emotional distress, sleep disturbance, anemia, and hypothyroidism. If any of these conditions are present, it should be treated according to practice guidelines, and the patient's fatigue should be reevaluated regularly. If none of the primary factors is present or the fatigue is unresolved, a more comprehensive assessment is indicated--with referral to other care providers as appropriate. The comprehensive assessment should include a thorough review of systems, review of medications, assessment of comorbidities, nutritional/metabolic evaluation, and assessment of activity level. Management of fatigue is cause-specific when conditions known to cause fatigue can be identified and treated. When specific causes, such as infection, fluid and electrolyte imbalances, or cardiac dysfunction, cannot be identified and corrected, nonpharmacologic and pharmacologic treatment of the fatigue should be considered. Nonpharmacologic interventions may include a moderate exercise program to improve functional capacity and activity tolerance, restorative therapies to decrease cognitive alterations and improve mood state, and nutritional and sleep interventions for patients with disturbances in eating or sleeping. Pharmacologic therapy may include drugs such as antidepressants for depression or erythropoietin for anemia. A few clinical reports of the use of corticosteroids and psychostimulants suggest the need for further research on these agents as a potential treatment modalities in managing fatigue. Basic to these interventions, the effective management of cancer-related fatigue involves an informed and supportive oncology care team that assesses patients' fatigue levels regularly and systematically and incorporates education and counseling regarding strategies for coping with fatigue (Johnson, 1999), as well as using institutional fatigue management experts for referral of patients with unresolved fatigue.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                8 January 2014
                : 9
                : 1
                : e84391
                Affiliations
                [1 ]Department of Neurosurgery, Shanghai Institute of Neurosurgery, PLA Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
                [2 ]Neuroscience Center, Changzheng Hospital, Second Military Medical University, Shanghai, China
                University of Louisville, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: LJH YD SG. Performed the experiments: SG PS HJ. Analyzed the data: SG PS HJ. Contributed reagents/materials/analysis tools: HH EBQ WC. Wrote the paper: SG YD LJH.

                Article
                PONE-D-13-41152
                10.1371/journal.pone.0084391
                3885551
                24416225
                109b8d05-a24b-4a22-8ddd-54fca8e752f1
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 9 October 2013
                : 19 November 2013
                Page count
                Pages: 8
                Funding
                Dr. Yan Dong is supported by Natural Science Foundation from Science and Technology Commission of Shanghai Municipality (11ZR1448700) and Research Foundation for Returned Scholars from Ministry of Education of China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Clinical Research Design
                Clinical Trials
                Meta-Analyses
                Drugs and Devices
                Drug Research and Development
                Mental Health
                Non-Clinical Medicine
                Evidence-Based Medicine
                Oncology
                Cancer Treatment
                Chemotherapy and Drug Treatment
                Clinical Trials (Cancer Treatment)
                Palliative Care

                Uncategorized
                Uncategorized

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