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DEPARTMENTS: Cochrane Nursing Summary

Interventions for the Management of Fatigue in Adults With a Primary Brain Tumor: A Cochrane Systematic Review Summary

Lee, Yee Mei PhD

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doi: 10.1097/NCC.0000000000000486
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Cancer-related fatigue is a severe, persistent sense of physical, emotional, and/or cognitive tiredness and lack of energy that is not relieved by rest or sleep.1 It occurs as a consequence of the disease itself and cancer treatment or symptom control such as chemotherapy and antiepileptics.2–4 Between 80% and 90% of patients experience cancer-related fatigue that persists in one-third of patients with cancer for months and years after therapy.5 The authors of this Cochrane review identified fatigue as the most common and severely debilitating symptom affecting quality of life for adults with a primary brain tumor (PBT).1

The effect of fatigue on patient's quality of life has been described as both profound and pervasive; hence, it is timely for oncology nurses to recognize the significance of this symptom and be updated on the management of fatigue in patients with PBT to assist in both understanding the effect and implementing evidence-based practice for this group of patients. The systematic review addressed the knowledge and practice gap on the pharmacological and nonpharmacological interventions for high levels of fatigue reported by adult patients with PBT.1

Debilitating fatigue is associated with excessive drowsiness, feeling clumsy, and inability to concentrate, and they fall under the somnolence syndrome. These symptoms were reported to have a cyclical pattern with increased severity during day 1 to 21 and then day 30 to 35 after treatment, and these symptoms last as long as 3 months posttreatment or longer in some cases.1 The cluster of symptoms arising from persistent fatigue is also associated with sleep disturbance, cognitive complaints, depression, and anxiety, further adversely affecting recovery and quality of life.1 Having identified the clinical importance of providing evidence to inform care, the authors undertook this systematic review of evidence of the effectiveness for the management of fatigue in patients with a PBT.


The objective of review was to assess the effectiveness and safety of pharmacological and nonpharmacological interventions for adults with a PBT and high levels of fatigue.


A comprehensive search strategy was conducted for this review with searches of Medline, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Excerpta Medica Database, PsycINFO, unpublished and gray literatures, and hand-searched reference lists of included studies, previous systematic reviews, and conference materials.

The inclusion criteria were randomized controlled trials that evaluated the effect of pharmacological and nonpharmacological interventions (psychological or behavioral interventions) in managing fatigue. Importantly, given the low number of studies on this topic, the authors also included a narrative description of other studies to provide valuable information for deeper context on the topic. Fatigue was defined by a pre-established cutoff-using questionnaire, validated measure, or presence/absence report among adults with PBT. Eight studies were excluded from meta-analysis because of the heterogeneity of participants (with and without fatigue) included and low level of fatigue reported in some of the studies.

The primary outcome of interest was self-reported improvement of fatigue using any validated scales. Short-term and long-term effects of the interventions were also included due to potential differences in effectiveness intervention endpoints. The secondary outcomes included improvement physically and cognitively and emotional and overall survival. Methodological qualities of the trial were assessed independently using the Cochrane “risk of bias” tool and was reported as at low risk of bias.


A single study that investigated the effectiveness of modafinil versus placebo using a cross-over design was included. It recruited 37 participants across 3 centers in the Netherlands, and 25 participants completed both treatment and had all outcomes measured.6 The washout period was considered adequate because the half-life of modafinil is 10 to 12 hours.

The review findings showed no significant difference in fatigue measures between modafinil and placebo scores for fatigue-causing concentration issues, reduced motivation, and reduced activity or fatigue severity. It was not clear if this was evidence that the drug was ineffective or whether the study lacked sufficient participants to reliably identify an effect. Five participants dropped out of the trial due to adverse events associated with modafinil use including tingling sensations, depressive feelings or behaviors, nervousness, dizziness, vertigo, headaches, loss of appetite, and seizures. Two participants on placebo also reported adverse events and dropped out of the trial. However, there was no difference in adverse events reported between groups.

Targeted future research is important because the fatigue that occurs during radiation therapy may continue even after the treatment. Further compounding this is that fatigue does not occur in isolation. As reported by Faithfull and Brada,7 fatigue is one of the symptoms of excessive drowsiness, feeling clumsy, and inability to concentrate, and they fall under the somnolence syndrome. Thirdly, these symptoms were reported to have a cyclical pattern with increased severity during day 1 to 21 and then day 30 to 35 after treatment, and these symptoms last as long as 3 months posttreatment or longer in some cases. If research is to investigate interventions for fatigue management, a holistic approach would be recommended, and interventions can be tiered to the severity of symptoms regardless of the type of cancer. This is to increase the generalizability of the interventions and to ensure that the studies are adequately powered, given that the worldwide incidence of PBT is low, resulting in low accrual rate, and fatigue is interrelated with other symptoms (confounders), making it difficult to distinguish absolute risks and benefits of any interventions studied.


Fatigue in patients with PBT is highly prevalent and distressing both during treatment and years after completion of treatment.1 The finding of this Cochrane review on the effectiveness of any treatment for high fatigue with patients with PBT was unclear. The 1 included trial found no evidence of a difference between modafinil and placebo in treating fatigue. It is possible that this could be due to the trial not reaching its planned number of participants and hence being underpowered to detect a true effect. Several other studies investigated the management of fatigue, but in these studies, high fatigue was not essential for participation. The authors concluded that we do not currently know whether any treatments are effective in the management of people with PBT and high fatigue.1

The authors of this review excluded 8 studies from analysis on the basis of clinical heterogeneity, including the lack of high self-reported fatigue; fatigue was not a necessary inclusion criterion, and 5 studies were of people not on active cancer treatment. The lack of evidence on effective interventions for fatigue management in the setting of PBT highlights that further research is warranted to develop effective, patient-centric management strategies.

A major aspect of cancer care in patient management for fatigue is understudied especially in the population with PBT. Future research should seek to build on and be informed by the gaps highlighted in this systematic review to develop fatigue management interventions. Such strategies would have the potential to ameliorate patient's distress and improve overall outcomes, and it is important for the cancer research community to consider the gap in clinical knowledge identified in this systematic review.

Nurses are becoming more aware that the number of cancer patients experiencing fatigue is on the rise especially because the life expectancy of people who receive a diagnosis of cancer increases the burden associated with this symptom continues to grow. Nurses are also instrumental in identifying, evaluating, and managing patients with fatigue on a daily basis. A systematic review investigating interventions for fatigue management in cancer patients supports evidence-based nursing practice in addressing this issue. With the lack of evidence in this aspect and poorly understood causes of fatigue, it is proposed that a systematic review is conducted to investigate current evidence on the overall management strategies for a more comprehensive approach to cancer-related fatigue in patients with PBT.

Yee Mei Lee, PhD
Advanced Practice Nurse
Assistant Director of Nursing (Clinical)
Head of Oncology Nursing
National University Cancer Institute, Singapore


1. Day J, Yust-Katz S, Cachia D, et al. Interventions for the management of fatigue in adults with a primary brain tumour. Cochrane Database Syst Rev. 2016;4:CD011376.
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6. Boele FW, Douw L, de Groot M, et al. The effect of modafinil on fatigue, cognitive functioning, and mood in primary brain tumor patients: a multicenter randomized controlled trial. Neuro Oncology. 2013;15(10):1420–1428.
7. Faithfull S, Brada M. Somnolence syndrome in adults following cranial irradiation for primary brain tumours. Clini Oncol (R Coll Radiol). 1998;10(4):250–254.
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