Three Part Question
In [children with a brain tumour]is [methylphenidate] useful [for treating fatigue]?
A 9-year-old boy with a brain tumour attends my outpatient clinic for review. His current most disabling symptom is fatigue. His parents have done a Google search and found that methylphenidate can be used to treat fatigue in adults. They ask my opinion as to whether this would be an option for their son. What should I advise?
MEDLINE was searched from 1950 to February 2011 and EMBASE from 1980 to 31 March 2011 via the OVID interface. The advanced search mode was used. A keyword search was performed using ‘methylphenidate’ ‘cancer’ and ‘fatigue*’ as individual groups. The searches were then combined using the AND function. The results were subsequently restricted using the limits: ‘all children 0–18 yrs’ in MEDLINE and ‘child ’ in EMBASE.
The Cochrane library was searched using the terms ‘methylphenidate’, ‘fatigue’, ‘cancer’ AND ‘child’. The search of EMBASE yielded no papers.
The search of MEDLINE revealed one paper which was read in full and shown to be for patients aged 18–70 years. The search of the Cochrane Library revealed no papers. Therefore, no relevant paediatric papers were found.
There were no papers found exploring the use of methylphenidate to treat fatigue in children with cancer. It was therefore decided to expand the search to include adult papers.
A second search was executed in the advance search mode of MEDLINE: The following keywords were used: ‘methylphenidate (exploded)’, ‘fatigue (exploded)’ and ‘neoplasms (exploded)’. These searches were then combined using the AND function. The results were then restricted using the limits: ‘Date limits: Publication year 2000—Current’, and ‘Article, Journal and Publication Type limits: Randomised Control Trial’. This search was then repeated in EMBASE. The Cochrane library was also searched using the terms ‘fatigue’, ‘methylphenidate’ and ‘cancer’.
The MEDLINE search yielded seven results. One paper was duplicated, therefore, only six studies were included. The EMBASE search yielded 13 results, three of which were duplicates from the MEDLINE search. The remaining 10 were screened and excluded as they were not relevant and/or were not randomised control trials. Six studies were relevant.
The search of the Cochrane library revealed three review articles, one of which was relevant and included a meta-analysis involving four of the original RCTs from the MEDLINE search. The other two were excluded as one was not specific to cancer-related fatigue, while the other was an earlier version of the included review. Relevant studies therefore include one Cochrane review and two individual RCTs
|Author, date and country
||Study type (level of evidence)
|Cochrane Review: Minton et al|
|Random Effects Model (Forest Plot) of 5 RCTs looking at psychostimulants vs placebo to treat cancer-related fatigue.
2 RCTs—breast cancer; 1 RCT
breast and ovarian cancer having chemotherapy;
1 RCT—brain tumours having radiotherapy;
1 RCT—active treatment of any tumour
413 in trial||Cochrane Systematic Review||Fatigue assessment tool||Evidence of a significant effect on treating fatigue with MPH over placebo. Z score=2.83 (p=0.005), SMD—0.28, 95% CI −0.48 to −0.09. Follow up 8 weeks–6 months|
|Roth et al|
|32 men with Men with advanced prostate cancer||RCT, double-blind, placebo controlled||Brief Fatigue Inventory Scores||Significant reduction in fatigue in both MPH and control groups. Greater decrease in fatigue scores in MPH group (p=0.03). follow up =6 weeks 6/16 patients withdrew from MPH group due to raised BP and tachycardia|
|Moraska et al|
|148 Adults with cancer||RCT, double-blind, placebo controlled||Brief Fatigue Inventory Scores||No significant benefit with MPH (p=0.35). Subset analysis: those with more severe fatigue and/or more advanced disease showed evidence of greater improvement with MPH (mean improvement 19.7 vs 2.1, p=0.02). follow up = 4 weeks|
Non-specific fatigue is a common and often disabling symptom in cancer patients. Estimates of prevalence vary from 60% to 100% depending on the methods used to assess fatigue (Wagner, De Waele). The subjectivity of fatigue and the likely multifactorial aetiology makes identification and successful management extremely challenging. Ullrich et al undertook a retrospective cross-sectional study of symptoms and suffering, at the end of life, in children with cancer. This demonstrated that up to 96% of children were fatigued, with nearly 50% of them suffering significantly with this symptom. Of these children, treatment of fatigue was attempted in only 13% with success in 25% of those for which it was attempted.
Studies by Hockenberry et al and Vallance et al have explored the aetiology of paediatric cancer-related fatigue. Hockenberry et al assessed the relationship between abnormalities of ATP synthesis caused by depletion of plasma carnitine and fatigue, and provided support for an association between reduced carnitine levels and increased fatigue after one to two courses of chemotherapy. Vallance et al analysed the effect of dexamethasone on sleep disturbance and fatigue. In multiple regression models, risk was significantly related to pharmacokinetic parameters. Polymorphisms in three genes (AHSG, IL6, POLDIP3) were significantly associated with sleep measures but not with fatigue. No direct relationship between dexamethasone and fatigue was established.
Current practice in the management of childhood cancer-related fatigue is based upon adult guidelines. Screening for fatigue is the first step, with emphasis on clinical staff asking specifically about fatigue in consultations, and subsequently risk-stratifying using tools such as 0–10 severity rating scale and/or the FACIT-F (Functional Assessment of Cancer Illness Therapy—Fatigue Subscale). Mandrell et al have recently provided evidence for the use of a 13-item reduced version of the fatigue scale—adolescent instrument with 66.6% sensitivity and 82.6% specificity.
National Comprehensive Cancer Network Guidelines recommend a two-stage approach to management of fatigue. These include treating the treatable (eg, depression, renal failure, anaemia) and psychosocial interventions (eg, education, stress management, coping strategies, behavioural interventions and energy conservation techniques).
Our search found no papers exploring the use of methylphenidate to treat fatigue in children with cancer, but a Cochrane review undertaken by Minton in 2009 and published in 2010, found five studies looking at the use of psychostimulants in adults with cancer. These were combined in a random-effects model n=413.(Lower, Mar Fan, Butler, Bruera, Auret). The studies are statistically homogeneous with I2=0%. Four of these studied the effects of methylphenidate,(Lower, Mar Fan, Butler, Bruera) and a fifth study (Auret) looked at dexamphetamine. The standardised mean difference on analysis was positive with a small effect seen and a narrow CI. This can be interpreted clinically as evidence of a mild to moderate improvement in fatigue in those treated with a psychostimulant compared with those receiving placebo. The five studies did differ in population variation (one breast and ovarian tumours, two breast tumours, one brain tumour and one mixed tumour type), design and follow-up, but used the same outcome measure (FACT-F), and so it is possible to obtain a weighted mean difference of –2.21. The Cochrane review concluded that the use of psychostimulants leads to an observable improvement in cancer-related fatigue.
There were two studies published in 2010 following the Cochrane review. Roth, in a study of men with prostate cancer, reported that the methylphenidate group, as compared with placebo, reported greater decrease on Brief Fatigue Inventory severity scores (p=0.03) and a trend toward greater decrease on Brief Fatigue Inventory total scores (p=0.07). A significantly greater number of subjects in the methylphenidate group demonstrated clinically significant improvement in fatigue on total Brief Fatigue Inventory scores (7 of 10 vs 3 of 13) and Brief Fatigue Inventory severity scores (8 of 10 vs 3 of 13). Moraska found no evidence that methylphenidate, compared with placebo, improved cancer-related fatigue in patients with a heterogenous group of cancers (p=0.35). However, a subset analysis suggested that patients with more severe fatigue, or more advanced disease, did have some fatigue improvement with methylphenidate (p=0.02).
Overall, the studies are heterogeneous with small numbers, short follow-up duration, and variation in dosage of methylphenidate. The study populations had participants of varying ages, undergoing different types of treatment, for example, chemotherapy and/or radiation therapy and at different stages in treatment. The pathogenesis of tumours (eg, brain, breast, ovarian, prostate) in the study groups may be strikingly different, which may explain some of the variation in the results.
Although there are no studies in children to date, anecdotally, we are aware of methylphenidate being used by local palliative care teams to treat fatigue in children. Methylphenidate is frequently used in children to treat other conditions, in particular, attention deficit hyperactivity disorder (ADHD). It has a recognised side-effect profile, including appetite suppression, hypertension and insomnia, and the risk of these must be weighed against potential benefits. Clinicians are currently extrapolating the evidence of benefit found in adult studies to the paediatric population using methylphenidate when fatigue is refractory and no other options are available. However, it is important that trials are undertaken in children in the future to establish indications to initiate methylphenidate treatment, evaluation of dosage, duration of treatment and assessment of benefit.
BP, blood pressure; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue Subscale; MPH, methylphenidate; RCTs, randomised control trials; SMD, standardised mean difference.
Clinical Bottom Line
There is currently no evidence for the use of methylphenidate to treat cancer-related fatigue in children.
There is some evidence for the use of methylphenidate for this indication in adults (Grade A).
- Minton O, Richardson A, Sharpe M, et al. Drug therapy for the management of cancer related fatigue. Cochrane Database Syst Rev 2010;(7). Art. No. CD006704.
- Roth A, Nelson C, Rosenfield B, et al. Methylphenidate for fatigue in ambulatory men with prostate cancer. Cancer 2010;116:5102–10.
- Moraska AR, Sood A, Dakhil SR, et al. Phase III, randomized, double-blind, placebo-controlled study of long-acting methylphenidate for cancer-related fatigue: North Central Cancer Treatment Group NCCT -N05C7 trial J Clin Oncol 2010;28:3673–9.
- Wagner LI, Cella D. Fatigue and cancer: causes, prevalence and treatment approaches. Br J Cancer 2004;91:822–8.
- De Waele S, Van Belle S. Cancer-related fatigue. Acta Clin Belg 2010;65:378–85.
- Ullrich CK, Dussel V, Hilden JM, et al. Fatigue in children with cancer at the end of life. J Pain Symptom Manage 2010;40:483–94.
- Hockenberry M, Hooke MC, Wand C, et al. Carnitine plasma levels and fatigue in children/adolescents receiving cisplatin, ifosfamide, or doxorubicin. J Pediatr Haemtol Oncol 2009;31:664–9.
- Vallance K, Liu W, Mandrell BN, et al. Mechanisms of dexamethasone-induced disturbed sleep and fatigue in paediatric patients receiving treatment for ALL. Eur J Cancer 2010;46:1848–55.
- Mandrell BN, Yang J, Hooke MC, et al. Psychometric and clinical assessment of the 13-item reduced version of the fatigue scale-adolescent instrument. J Pediatr Oncol Nurs 2011;28:287–94.
- Lower EE, Fleishman S, Cooper A, et al. Efficacy of dexmethylphenidate for the treatment of fatigue after cancer chemotherapy: a randomized clinical trial. J Pain Symptom Manage 2009;38:650–62.
- Mar Fan HG, Clemons M, Xu W, et al. A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer. Support Care Cancer 2008;16:577–83.
- Butler JM Jr, Case LD, Atkins J, et al. A phase III, double-blind, placebo-controlled prospective randomized clinical trial of d-threo-methylphenidate HCl in brain tumour patients receiving radiation therapy. Int J Radiat Oncol Biol Phys 2007;69:1496–501.
- ruera E, Valero V, Driver L, et al. Patient-controlled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol 2006;24:2073–8.
- Auret KA, Schug SA, Bremner AP et al. A randomized, double-blind, placebo-controlled trial assessing the impact of dexamphetamine on fatigue in patients with advanced cancer. J Pain Symptom Manage 2009;37:613–21