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Psychostimulants for the Management of Cancer-Related Fatigue: A Systematic Review and Meta-Analysis
Vol. 41 No. 4 April 2011
Journal of Pain and Symptom Management
761
Review Article
Psychostimulants for the Management of Cancer-Related Fatigue: A Systematic Review and Meta-Analysis Ollie Minton, MSc, Alison Richardson, PhD, Michael Sharpe, PhD, Matthew Hotopf, PhD, and Patrick C. Stone, MD Division of Mental Health (O.M.) and Division of Community Health Sciences (P.C.S.), St. George’s, University of London, London; School of Health Sciences (A.R.), University of Southampton, Southampton; Centre for Clinical Brain Sciences (M.S.), University of Edinburgh, Edinburgh; and Institute of Psychiatry (M.H.), King’s College, London, United Kingdom
Abstract Context. Cancer-related fatigue (CRF) is a common and distressing symptom affecting patients with cancer. There is an increasing number of drug trials examining potential treatments for CRF. Methylphenidate represents one of the most researched drugs in this area, and an up-to-date assessment of the evidence for its use is needed. Objectives. To assess and summarize the increasing evidence for the use of psychostimulants, particularly methylphenidate, in the treatment of CRF. Methods. A systematic review of electronic databases was conducted from inception to the start of October 2009, together with cross-referencing of cited abstracts and hand searching of relevant cancer journals. Results. A meta-analysis was conducted on five psychostimulant trials (n ¼ 426 participants). The overall standardized mean difference was 0.28 (95% confidence interval [CI] 0.48, 0.09; P ¼ 0.005), although several trials failed to find any benefit over placebo. There were no differences in the frequency of adverse events between methylphenidate and placebo: combined odds ratio 1.24 (95% CI 0.42, 3.62). Conclusion. There is preliminary evidence for the use of psychostimulants 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. J Pain Symptom Manage 2011;41:761e767. Ó 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Psychostimulants, cancer fatigue, systematic review
Address correspondence to: Ollie Minton, MSc, Division of Mental Health, St. George’s, University of London, 6th Floor, Hunter Wing, Cranmer Terrace, London SW17 ORE, United Kingdom. E-mail: ominton@ sgul.ac.uk Accepted for publication: July 8, 2010. Ó 2011 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
Introduction Cancer-related fatigue (CRF) is a significant clinical problem affecting patients at all stages of treatment and increasing with advanced disease.1 At present, there is no clearly 0885-3924/$ - see front matter doi:10.1016/j.jpainsymman.2010.06.020
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superior treatment for CRF, and the choice of intervention depends on the individual clinician. Management options include the use of exercise2 and/or psychosocial interventions.3 For some patients, pharmacological intervention may be appropriate. Our group has previously undertaken a Cochrane systematic review of drug treatments for CRF.4 We identified preliminary evidence to support the use of psychostimulants and erythropoietins and isolated evidence in support of other treatments. Several studies have been published since the original review was undertaken, and our systematic review has recently been updated. The purpose of this study is to specifically focus on increasing evidence for the use of psychostimulants and, in particular, the role of methylphenidate in the treatment of CRF. Methylphenidate is a psychostimulant, with its main role being in the treatment of attention deficit disorder (ADD).5 It is similar in structure and mechanism of action to the amphetamines. These drugs act to increase the levels of dopamine in the brain. Their mechanism of action works to increase the levels of this neurotransmitter in the central nervous system (CNS).6 This is achieved by blocking dopamine breakdown in the synaptic cleft and inhibiting its uptake back into the cell, as well as stimulating neurotransmitter production. The end result of all these effects is an increased level of dopamine available to bind to active receptors. The complete biology of these mechanisms is beyond the scope of this study, and the interested reader is referred to a recent review of the area.7 These nonspecific mechanisms of action have limited the use of psychostimulants to date. In recent practice, this has meant that, outside their indication for ADD, these drugs have no other licensed indications for use.8 They have, however, been used beyond license for various indications in patients with advanced disease; evidence is available for the use of these drugs in opioid-induced sedation,9,10 in the treatment of depression,11 and the management of fatigue (in patients with human immunodeficiency virus).12 There is now an increasing number of published trials that have examined the role of methylphenidate in the treatment of CRF, and this review will summarize the available data.
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Methods A systematic search was undertaken of the following electronic databases from inception to the first week of October 2009: Medline, EMBASE, CINAHL, and the Cochrane register of controlled trials. An exhaustive list of search terms was used, and a systematic review methodology was applied. These methods are detailed elsewhere.13 In brief, one author (O. M.) screened relevant titles and abstracts; full-text articles were retrieved where necessary. The final list of included studies was agreed on by all the authors. A study was included only if it was a randomized controlled trial designed to test the use of a psychostimulant against placebo or usual care in the treatment of CRF. Where necessary, the authors were contacted for raw data suitable for inclusion in a metaanalysis. Data were extracted and independently reviewed using predesigned data extraction forms. Data were entered into Cochrane review manager software (RevMan 5).14 Metaanalysis was performed using a random effects model.
Results Five published trials examining the use of psychostimulants in the treatment of CRF were identified. Four studies examined methylphenidate (Bruera et al.,15 Butler et al.,16 Lower et al.,17 and Mar Fan et al.18), and one examined dexamphetamine (Auret et al.19). The characteristics of the studies varied widely in terms of the treatment duration and the population studied. These details are summarized in Table 1. The trials are discussed in order of number of participants. All the studies reviewed were stated to be doubleblind and placebo-controlled trials in the original articles. The study by Lower et al.17 is the largest to have been conducted. The authors examined the role of methylphenidate after the completion of chemotherapy in patients not on current anticancer treatment. The exact distribution of disease stages was unclear from the original article. The stated aim was to examine the effect of methylphenidate on CRF after chemotherapy. Participants met the criteria proposed by Cella et al.20 for CRF syndrome at baseline. These
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Table 1 Details of Included Psychostimulant Trials Trial Lead Author and Year
Number of Participants
Auret, 2009
n ¼ 50 (36 males, 14 females) Mean age: 71
Bruera, 200615
n ¼ 107 (39 males, 68 females) Mean age: 65
Butler, 200716
n ¼ 68 (34 males, 34 females) Mean age: 56
Lower, 200917
n ¼ 152 (15 males, 137 females) Mean age: 53
Mar Fan, 200818
n ¼ 57 (all females) Mean age: 50
19
Type and Duration of Interventions
Outcome Measure Used
Mixed tumor types off treatment >4 on a 0e10 VAS fatigue for entry to trial Dexamphetamine 10 mg twice a day or matching placebo for eight days Mixed tumor types off treatment >4 on a 0e10 VAS fatigue for entry to trial Methylphenidate 5 mg as required up to 20 mg per day or matching placebo for one week Primary brain tumor patients or those with brain secondaries undergoing radiotherapy No baseline level of CRF required for entry Methylphenidate 5 mg twice a day increasing to 20 mg per day for up to eight weeks or matching placebo Analysis on n ¼ 52 because of dropout Any tumor type recently treated with chemotherapy Met CRF syndrome criteria for entry into trial Methylphenidate 5 mg as required up to 20 mg per day for eight weeks or matching placebo Breast cancer patients undergoing chemotherapy No baseline level of CRF required for entry Methylphenidate 5 mg twice a day increasing to 10 mg twice a day for 12 weeks or matching placebo
BFI
criteria indicate the presence of clinically significant CRF. The entry criteria also included a performance status of at least one (defined as restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature) and a life expectancy of greater than six months. The tumor groups studied were mainly breast and ovarian. Patients were randomized to methylphenidate given initially at 5 mg twice daily, increasing to a maximum of 50 mg per day over an eight-week period or to identically matched placebo tablet. The average dose achieved was between 20 and 30 mg per day. This is the largest study published to date and is the only one with a statistically significant difference between groups. The primary outcome measure was change in fatigue scores between groups at eight weeks compared with baseline, measured using the Functional Assessment of Cancer Therapy-Fatigue subscale (FACT-F).21 There was an overall difference of
FACT-F
FACT-F
FACT-F
FACT-F
3.7 points on the FACT-F between groups at eight weeks, the predefined time. This is a clinically significant change on this scale. An exploratory analysis by the authors also demonstrated significant differences in the FACT-F scores at a number of other time points. The study by Bruera et al.15 examined patients with advanced disease no longer receiving active treatment. The entry criteria required a fatigue score greater than four on a 0e10 visual analogue scale (VAS; where zero was no fatigue and 10 was worst possible fatigue). The National Comprehensive Cancer Network (NCCN) guidelines for CRF22 rate this score as moderate fatigue. The stated aim of the study was to examine the use of patient-controlled methylphenidate for patients with fatigue in advanced cancer. All tumor types were included, and the largest single group was breast cancer. Methylphenidate 5 mg or matching placebo was given on an ‘‘as needed’’ basis initiated by
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the patients themselves over a one-week period. The dose could be increased up to 20 mg per day by the patient, depending on response. Subjects were closely monitored by a research nurse on a daily basis over this time. In both groups, there was an improvement in fatigue scores as measured by the FACT-F, with a reduction in scores of between seven and nine points. This is a clinically significant reduction on this scale. However, no statistically significant difference was found between groups on Day 8dthe primary outcome measure. The study by Auret et al.19 examined patients with advanced cancer no longer receiving active treatment. The entry criteria required a fatigue score greater than four on a 0e10 VAS (where zero was no fatigue and 10 was worst possible fatigue). As previously mentioned, the NCCN guidelines for CRF22 rate this score as moderate fatigue. The stated aim of the study was to examine the use of dexamphetamine to improve clinically significant CRF in advanced cancer. Patients were randomized to receive dexamphetamine 10 mg increasing to 20 mg or matching placebo for eight days. Although 50 patients were entered, only 39 completed the study. The results were analyzed on an intention-totreat basis. No significant differences were found between noncompleters in each group. There was no change in Brief Fatigue Inventory23 (BFI) scores in either group over the eight-day period. There were no statistically or clinically significant differences between the treatment groups in BFI scores at the time of assessment on Day 8, which was the predefined primary outcome measure. The study by Butler et al.16 examined patients undergoing cranial radiotherapy with either a primary brain tumor or brain secondaries. The stated aim of the study was to examine the efficacy and toxicity of methylphenidate in reducing the CNS side effects of cranial radiotherapy. This is the only trial where the drug is used prophylactically. There was no minimum level of fatigue required for entry. Patients were randomized to methylphenidate or matching placebo. The initial dose was 5 mg twice daily or matching placebo, increasing to a maximum of 15 mg twice daily. The proposed role of methylphenidate was to prophylactically reduce fatigue both during and after radiotherapy. The study closed prematurely because of slow accrual and was underpowered as a result. The
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primary outcome was the change in fatigue score at eight weeks after the completion of radiotherapy. There was, however, significant dropout over this time, and the final analysis was conducted on a smaller sample than the original number recruited (Table 1). A number of time points were examined, and the fluctuation in fatigue scores was observed. However, at no time points were fatigue scores in treatment groups significantly different. The stated aim of the study by Mar Fan et al.18 was to examine the effects of methylphenidate on fatigue and cognitive function in women undergoing adjuvant chemotherapy. There was no baseline level of fatigue required for entry. Patients were randomized to receive either methylphenidate or matching placebo, initially at 5 mg twice daily and increasing to 10 mg twice daily depending on response. However, this trial failed to accrue the necessary numbers and was subsequently underpowered. A comment was made by the authors that the participants were reluctant to take additional medication in general and methylphenidate in particular. There was no clinically significant change in FACT-F scores between baseline and end of treatment in the methylphenidate or the placebo group. An analysis conducted when the trial closed failed to identify a statistically significant difference between treatment groups. Although individually these studies were difficult to interpret, it was possible to combine them in a meta-analysis (Fig. 1). This found a significant effect of psychostimulants over placebo (standardized mean difference 0.28; 95% CI 0.48, 0.09; P ¼ 0.005). All but one of the studies used the FACT-F,24 and it was, therefore, possible to obtain a weighted mean difference of the four studies included. The two-point change identified on this scale by the metaanalysis is the minimally clinically significant difference reported for this scale.25 The rate of adverse effects also was analyzed (Fig. 2), and the combined odds ratio between drug and placebo was 1.24 (95% CI 0.42, 3.62), indicating no difference.
Discussion Since our original systematic review was undertaken,4 more evidence has emerged
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Fig. 1. Psychostimulant studies.
about the use of methylphenidate to treat CRF. The absolute numbers of participants studied are still relatively small (n ¼ 426 total), and most of the trials have failed to demonstrate any statistically significant benefit over placebo. Several studies are likely to be underpowered to detect statistically significant differences as a result of very small sample sizes, as indicated by the wide CIs seen on metaanalysis. Nonetheless, there was a trend in many of these studies toward methylphenidate being of benefit. There also is little or no statistical heterogeneity in the meta-analysis as denoted by the I2 value of zero. There is however significant clinical heterogeneity among these trials, which makes interpretation more difficult, with wide variation in the types of patients included and the range of tumor types and the disease stages being studied. In addition, there is variation in duration of treatment with methylphenidate (from one to more than eight weeks). The larger trials are more heavily weighted within the analysis, and the largest single trial is the only one to demonstrate a significant treatment effect over placebo. However, although the absolute treatment effect
is relatively small, it is still larger than the overall treatment effect size for exercise in CRF.2 Although it has been possible to combine the studies for methylphenidate, it has so far not been possible to synthesize psychosocial interventions for CRF in this way.3 This was because the trials have varied so widely in design, making it impractical to combine the data. The main limitation of any meta-analysis is the data on which it is based. There initially needs to be an exhaustive search for studies to ensure that missing data are minimized, or the conclusions will be biased as a result. It also is not always possible to combine single studies into a meta-analysis; for instance, when the data are not extractable from the published material and the author(s) are unable to provide it. These requirements were addressed by using a Cochrane systematic review methodology to ensure a comprehensive search and contacting authors to obtain unpublished data suitable for the analysis where indicated. This was necessary for two of the five studiesdAuret et al.19 and Butler et al.16 Data from this analysis also may not be immediately applicable to all tumor types
Fig. 2. Adverse events.
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and stages. This is especially likely in patients with advanced disease where the data demonstrate no benefit in this subgroup. The clinical application of these findings will need to be addressed by the individual clinician, although recommendations are made based on these data. The analysis of serious adverse effects failed to demonstrate any significant differences between groups. The data suggest that, despite commonly voiced concerns, these drugs do not cause major problems in this group of patients. Some minor side effects were noted, but these were no greater with drug than placebo. This finding is supported by the results of a recent review of safety concerns regarding the long-term use of methylphenidate.26 The author of this review identified 26 trials and concluded that adverse effects were minimal in short-term use (up to six to eight weeks of treatment). There are no data available on the longterm use of these drugs in any condition other than ADD. However, there are concerns over their long-term use in children with this diagnosis.27 These relate, among other problems, to potential cardiovascular effects and growth restriction. It is unclear how these findings might relate to adult patients with cancer. The exception to this observation is the potential for abuse when methylphenidate is given to specific groups.26 The danger for abuse is highest when taken for nonclinical reasons, such as use as a performance enhancer.28 It is unlikely that this would be a significant factor in patients with advanced disease but could limit use in other patient groups. Although methylphenidate has been used in pediatric cancer survivors for cognitive deficits,29 these drugs cannot be recommended for long-term use in adult cancer survivors as it is likely that the potential benefits are more than outweighed by the concerns over long-term adverse effects. In this group of patients, it is, therefore, much more likely that exercise or psychosocial interventions will be the treatment modality of choice. Current evidence suggests that the main role for these drugs is short-term use in patients receiving anticancer treatment or for patients with advanced disease. There are additional studies ongoing, and the evidence about the use of methylphenidate in particular groups is likely to continue to evolve.
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Conclusions The evidence suggests that methylphenidate may be effective in the management of CRF. However, in the absence of convincing results from a single, large, well-conducted randomized controlled trial, this advice must be considered to be tentative and provisional. If methylphenidate were to be used in patients with CRF, it would be prudent to restrict its use to patients with advanced disease or for shortterm use in patients on active treatment. The clear advantage of methylphenidate in cancer is its rapid onset of action within 24e48 hours, and so the drug can be discontinued if ineffective. There is no evidence to support safe prescribing beyond eight weeks of treatment. These drugs should only be prescribed under expert supervision and with active monitoring. Nonetheless, psychostimulants are one of the few interventions available to treat CRF that are supported by trial data. Further research is needed before their use can be recommended more widely.
Disclosures and Acknowledgments This study is based on a Cochrane Review published in The Cochrane Library 2010 (see www.thecochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent version of the review. This review was not funded by a specific grant, but two authors have personal support. Dr. Minton is funded by a Cancer Research UK psycho-oncology fellowship (grant number C31193/A10090), and Dr. Hotopf is supported by the National Institute of Health Research Specialist Biomedical Research Centre in Mental Health at South London, the Maudsley NHS Foundation Trust, and the King’s College London. The authors declare no conflicts of interest. The authors thank Dr. K. Auret and Dr. D. Case for the additional raw data they provided for inclusion in the meta-analysis.
References 1. Stone PC, Minton O. Cancer-related fatigue. Eur J Cancer 2008;44:1097e1104.
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Psychostimulants for Cancer-Related Fatigue
2. Cramp F, Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev 2008;(2):CD006145. 3. Goedendorp M, Gielissen M, Verhagen C, Bleijenberg G. Psychosocial interventions for reducing fatigue during cancer treatment in adults. Cochrane Database Syst Rev 2009;(1):CD006953. 4. Minton O, Stone P, Richardson A, Sharpe M, Hotopf M. Drug therapy for the management of cancer related fatigue. Cochrane Database Syst Rev 2008;(1):CD006704. 5. Jensen PS. Review: methylphenidate and psychosocial treatments either alone or in combination reduce ADHD symptoms. Evid Based Ment Health 2009;12:18. 6. Volkow ND, Wang G-J, Fowler JS, Ding YS. Imaging the effects of methylphenidate on brain dopamine: new model on its therapeutic actions for attention-deficit/hyperactivity disorder. Biol Psychiatry 2005;57:1410e1415. 7. Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR. New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol 2007;47:681e698. 8. Martin J, ed. British national formulary, 56th ed. London, UK: British Medical Association and the Royal Pharmaceutical Society of Great Britain, 2008. 9. Wilwerding M, Charles LL, James AM, et al. A randomized, crossover evaluation of methylphenidate in cancer patients receiving strong narcotics. Support Care Cancer 1995;3:135e138.
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therapy. Int J Radiat Oncol Biol Phys 2007;69: 1496e1501. 17. 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;38:650e662. 18. 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;16:577e583. 19. Auret KA, Schug SA, Bremner AP, Bulsara M. A randomized, double-blind, placebo-controlled trial assessing the impact of dexamphetamine on fatigue in patients with advanced cancer. J Pain Symptom Manage 2009;37:613e621. 20. Cella D, Peterman A, Passik S, Jacobsen P, Breitbart W. Progress toward guidelines for the management of fatigue. Oncology (Williston Park) 1998;12:369e377. 21. Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other anemiarelated symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 1997;13:63e74. 22. National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Cancer-related fatigue. 2010. Available from http://www.nccn.org/ professionals/physician_gls/f_guidelines.asp. Accessed November 21, 2010.
10. Bruera E. Methylphenidate in the prevention of the neuropsychological effects of increased doses of opioids. Psychooncology 1996;5:15.
23. Mendoza TR, Wang XS, Cleeland CS, et al. The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer 1999;85:1186e1196.
11. Candy B, Jones L, Williams R, et al. Psychostimulants for depression. Cochrane database of systematic reviews: Reviews 2008, issue 2. Chichester, UK: John Wiley & Sons, Ltd., 2008.
24. Cella D. Factors influencing quality of life in cancer patients: anemia and fatigue. Semin Oncol 1998;25:43e46.
12. Cella D, Davis K, Breitbart W, Curt G, Fatigue Coalition. Cancer-related fatigue: prevalence of proposed diagnostic criteria in a United States sample of cancer survivors. J Clin Oncol 2001;19:3385e3391. 13. Minton O, Richardson A, Sharpe M, Hotopf M, Stone P. A systematic review and meta-analysis of the pharmacological treatment of cancer-related fatigue. J Natl Cancer Inst 2008;100:1155e1166.
25. Cella D, Eton DT, Lai JS, Peterman AH, Merkel DE. Combining anchor and distributionbased methods to derive minimal clinically important differences on the Functional Assessment of Cancer Therapy (FACT) anemia and fatigue scales. J Pain Symptom Manage 2002;24:547e561. 26. Godfrey J. Safety of therapeutic methylphenidate in adults: a systematic review of the evidence. J Psychopharmacol 2009;23:194e205.
14. Anonymous. Review Manager (RevMan) version 5.0. Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.
27. Lerner M, Wigal T. Long-term safety of stimulant medications: used to treat children with ADHD. J Psychosoc Nurs Ment Health Serv 2008;46:38e48.
15. Bruera E, Valero V, Driver L, et al. Patientcontrolled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol 2006;24:2073e2078.
28. Dupont RL, Coleman JJ, Bucher RH, Wilford BB. Characteristics and motives of college students who engage in nonmedical use of methylphenidate. Am J Addict 2008;17:167e171.
16. 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 tumor patients receiving radiation
29. Conklin HM, Lawford J, Jasper BW, et al. Side effects of methylphenidate in childhood cancer survivors: a randomized placebo-controlled trial. Pediatrics 2009;124:226e233.
Journal of Pain and Symptom Management
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Review Article
Psychostimulants for the Management of Cancer-Related Fatigue: A Systematic Review and Meta-Analysis Ollie Minton, MSc, Alison Richardson, PhD, Michael Sharpe, PhD, Matthew Hotopf, PhD, and Patrick C. Stone, MD Division of Mental Health (O.M.) and Division of Community Health Sciences (P.C.S.), St. George’s, University of London, London; School of Health Sciences (A.R.), University of Southampton, Southampton; Centre for Clinical Brain Sciences (M.S.), University of Edinburgh, Edinburgh; and Institute of Psychiatry (M.H.), King’s College, London, United Kingdom
Abstract Context. Cancer-related fatigue (CRF) is a common and distressing symptom affecting patients with cancer. There is an increasing number of drug trials examining potential treatments for CRF. Methylphenidate represents one of the most researched drugs in this area, and an up-to-date assessment of the evidence for its use is needed. Objectives. To assess and summarize the increasing evidence for the use of psychostimulants, particularly methylphenidate, in the treatment of CRF. Methods. A systematic review of electronic databases was conducted from inception to the start of October 2009, together with cross-referencing of cited abstracts and hand searching of relevant cancer journals. Results. A meta-analysis was conducted on five psychostimulant trials (n ¼ 426 participants). The overall standardized mean difference was 0.28 (95% confidence interval [CI] 0.48, 0.09; P ¼ 0.005), although several trials failed to find any benefit over placebo. There were no differences in the frequency of adverse events between methylphenidate and placebo: combined odds ratio 1.24 (95% CI 0.42, 3.62). Conclusion. There is preliminary evidence for the use of psychostimulants 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. J Pain Symptom Manage 2011;41:761e767. Ó 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Psychostimulants, cancer fatigue, systematic review
Address correspondence to: Ollie Minton, MSc, Division of Mental Health, St. George’s, University of London, 6th Floor, Hunter Wing, Cranmer Terrace, London SW17 ORE, United Kingdom. E-mail: ominton@ sgul.ac.uk Accepted for publication: July 8, 2010. Ó 2011 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
Introduction Cancer-related fatigue (CRF) is a significant clinical problem affecting patients at all stages of treatment and increasing with advanced disease.1 At present, there is no clearly 0885-3924/$ - see front matter doi:10.1016/j.jpainsymman.2010.06.020
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superior treatment for CRF, and the choice of intervention depends on the individual clinician. Management options include the use of exercise2 and/or psychosocial interventions.3 For some patients, pharmacological intervention may be appropriate. Our group has previously undertaken a Cochrane systematic review of drug treatments for CRF.4 We identified preliminary evidence to support the use of psychostimulants and erythropoietins and isolated evidence in support of other treatments. Several studies have been published since the original review was undertaken, and our systematic review has recently been updated. The purpose of this study is to specifically focus on increasing evidence for the use of psychostimulants and, in particular, the role of methylphenidate in the treatment of CRF. Methylphenidate is a psychostimulant, with its main role being in the treatment of attention deficit disorder (ADD).5 It is similar in structure and mechanism of action to the amphetamines. These drugs act to increase the levels of dopamine in the brain. Their mechanism of action works to increase the levels of this neurotransmitter in the central nervous system (CNS).6 This is achieved by blocking dopamine breakdown in the synaptic cleft and inhibiting its uptake back into the cell, as well as stimulating neurotransmitter production. The end result of all these effects is an increased level of dopamine available to bind to active receptors. The complete biology of these mechanisms is beyond the scope of this study, and the interested reader is referred to a recent review of the area.7 These nonspecific mechanisms of action have limited the use of psychostimulants to date. In recent practice, this has meant that, outside their indication for ADD, these drugs have no other licensed indications for use.8 They have, however, been used beyond license for various indications in patients with advanced disease; evidence is available for the use of these drugs in opioid-induced sedation,9,10 in the treatment of depression,11 and the management of fatigue (in patients with human immunodeficiency virus).12 There is now an increasing number of published trials that have examined the role of methylphenidate in the treatment of CRF, and this review will summarize the available data.
Vol. 41 No. 4 April 2011
Methods A systematic search was undertaken of the following electronic databases from inception to the first week of October 2009: Medline, EMBASE, CINAHL, and the Cochrane register of controlled trials. An exhaustive list of search terms was used, and a systematic review methodology was applied. These methods are detailed elsewhere.13 In brief, one author (O. M.) screened relevant titles and abstracts; full-text articles were retrieved where necessary. The final list of included studies was agreed on by all the authors. A study was included only if it was a randomized controlled trial designed to test the use of a psychostimulant against placebo or usual care in the treatment of CRF. Where necessary, the authors were contacted for raw data suitable for inclusion in a metaanalysis. Data were extracted and independently reviewed using predesigned data extraction forms. Data were entered into Cochrane review manager software (RevMan 5).14 Metaanalysis was performed using a random effects model.
Results Five published trials examining the use of psychostimulants in the treatment of CRF were identified. Four studies examined methylphenidate (Bruera et al.,15 Butler et al.,16 Lower et al.,17 and Mar Fan et al.18), and one examined dexamphetamine (Auret et al.19). The characteristics of the studies varied widely in terms of the treatment duration and the population studied. These details are summarized in Table 1. The trials are discussed in order of number of participants. All the studies reviewed were stated to be doubleblind and placebo-controlled trials in the original articles. The study by Lower et al.17 is the largest to have been conducted. The authors examined the role of methylphenidate after the completion of chemotherapy in patients not on current anticancer treatment. The exact distribution of disease stages was unclear from the original article. The stated aim was to examine the effect of methylphenidate on CRF after chemotherapy. Participants met the criteria proposed by Cella et al.20 for CRF syndrome at baseline. These
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Table 1 Details of Included Psychostimulant Trials Trial Lead Author and Year
Number of Participants
Auret, 2009
n ¼ 50 (36 males, 14 females) Mean age: 71
Bruera, 200615
n ¼ 107 (39 males, 68 females) Mean age: 65
Butler, 200716
n ¼ 68 (34 males, 34 females) Mean age: 56
Lower, 200917
n ¼ 152 (15 males, 137 females) Mean age: 53
Mar Fan, 200818
n ¼ 57 (all females) Mean age: 50
19
Type and Duration of Interventions
Outcome Measure Used
Mixed tumor types off treatment >4 on a 0e10 VAS fatigue for entry to trial Dexamphetamine 10 mg twice a day or matching placebo for eight days Mixed tumor types off treatment >4 on a 0e10 VAS fatigue for entry to trial Methylphenidate 5 mg as required up to 20 mg per day or matching placebo for one week Primary brain tumor patients or those with brain secondaries undergoing radiotherapy No baseline level of CRF required for entry Methylphenidate 5 mg twice a day increasing to 20 mg per day for up to eight weeks or matching placebo Analysis on n ¼ 52 because of dropout Any tumor type recently treated with chemotherapy Met CRF syndrome criteria for entry into trial Methylphenidate 5 mg as required up to 20 mg per day for eight weeks or matching placebo Breast cancer patients undergoing chemotherapy No baseline level of CRF required for entry Methylphenidate 5 mg twice a day increasing to 10 mg twice a day for 12 weeks or matching placebo
BFI
criteria indicate the presence of clinically significant CRF. The entry criteria also included a performance status of at least one (defined as restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature) and a life expectancy of greater than six months. The tumor groups studied were mainly breast and ovarian. Patients were randomized to methylphenidate given initially at 5 mg twice daily, increasing to a maximum of 50 mg per day over an eight-week period or to identically matched placebo tablet. The average dose achieved was between 20 and 30 mg per day. This is the largest study published to date and is the only one with a statistically significant difference between groups. The primary outcome measure was change in fatigue scores between groups at eight weeks compared with baseline, measured using the Functional Assessment of Cancer Therapy-Fatigue subscale (FACT-F).21 There was an overall difference of
FACT-F
FACT-F
FACT-F
FACT-F
3.7 points on the FACT-F between groups at eight weeks, the predefined time. This is a clinically significant change on this scale. An exploratory analysis by the authors also demonstrated significant differences in the FACT-F scores at a number of other time points. The study by Bruera et al.15 examined patients with advanced disease no longer receiving active treatment. The entry criteria required a fatigue score greater than four on a 0e10 visual analogue scale (VAS; where zero was no fatigue and 10 was worst possible fatigue). The National Comprehensive Cancer Network (NCCN) guidelines for CRF22 rate this score as moderate fatigue. The stated aim of the study was to examine the use of patient-controlled methylphenidate for patients with fatigue in advanced cancer. All tumor types were included, and the largest single group was breast cancer. Methylphenidate 5 mg or matching placebo was given on an ‘‘as needed’’ basis initiated by
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the patients themselves over a one-week period. The dose could be increased up to 20 mg per day by the patient, depending on response. Subjects were closely monitored by a research nurse on a daily basis over this time. In both groups, there was an improvement in fatigue scores as measured by the FACT-F, with a reduction in scores of between seven and nine points. This is a clinically significant reduction on this scale. However, no statistically significant difference was found between groups on Day 8dthe primary outcome measure. The study by Auret et al.19 examined patients with advanced cancer no longer receiving active treatment. The entry criteria required a fatigue score greater than four on a 0e10 VAS (where zero was no fatigue and 10 was worst possible fatigue). As previously mentioned, the NCCN guidelines for CRF22 rate this score as moderate fatigue. The stated aim of the study was to examine the use of dexamphetamine to improve clinically significant CRF in advanced cancer. Patients were randomized to receive dexamphetamine 10 mg increasing to 20 mg or matching placebo for eight days. Although 50 patients were entered, only 39 completed the study. The results were analyzed on an intention-totreat basis. No significant differences were found between noncompleters in each group. There was no change in Brief Fatigue Inventory23 (BFI) scores in either group over the eight-day period. There were no statistically or clinically significant differences between the treatment groups in BFI scores at the time of assessment on Day 8, which was the predefined primary outcome measure. The study by Butler et al.16 examined patients undergoing cranial radiotherapy with either a primary brain tumor or brain secondaries. The stated aim of the study was to examine the efficacy and toxicity of methylphenidate in reducing the CNS side effects of cranial radiotherapy. This is the only trial where the drug is used prophylactically. There was no minimum level of fatigue required for entry. Patients were randomized to methylphenidate or matching placebo. The initial dose was 5 mg twice daily or matching placebo, increasing to a maximum of 15 mg twice daily. The proposed role of methylphenidate was to prophylactically reduce fatigue both during and after radiotherapy. The study closed prematurely because of slow accrual and was underpowered as a result. The
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primary outcome was the change in fatigue score at eight weeks after the completion of radiotherapy. There was, however, significant dropout over this time, and the final analysis was conducted on a smaller sample than the original number recruited (Table 1). A number of time points were examined, and the fluctuation in fatigue scores was observed. However, at no time points were fatigue scores in treatment groups significantly different. The stated aim of the study by Mar Fan et al.18 was to examine the effects of methylphenidate on fatigue and cognitive function in women undergoing adjuvant chemotherapy. There was no baseline level of fatigue required for entry. Patients were randomized to receive either methylphenidate or matching placebo, initially at 5 mg twice daily and increasing to 10 mg twice daily depending on response. However, this trial failed to accrue the necessary numbers and was subsequently underpowered. A comment was made by the authors that the participants were reluctant to take additional medication in general and methylphenidate in particular. There was no clinically significant change in FACT-F scores between baseline and end of treatment in the methylphenidate or the placebo group. An analysis conducted when the trial closed failed to identify a statistically significant difference between treatment groups. Although individually these studies were difficult to interpret, it was possible to combine them in a meta-analysis (Fig. 1). This found a significant effect of psychostimulants over placebo (standardized mean difference 0.28; 95% CI 0.48, 0.09; P ¼ 0.005). All but one of the studies used the FACT-F,24 and it was, therefore, possible to obtain a weighted mean difference of the four studies included. The two-point change identified on this scale by the metaanalysis is the minimally clinically significant difference reported for this scale.25 The rate of adverse effects also was analyzed (Fig. 2), and the combined odds ratio between drug and placebo was 1.24 (95% CI 0.42, 3.62), indicating no difference.
Discussion Since our original systematic review was undertaken,4 more evidence has emerged
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Fig. 1. Psychostimulant studies.
about the use of methylphenidate to treat CRF. The absolute numbers of participants studied are still relatively small (n ¼ 426 total), and most of the trials have failed to demonstrate any statistically significant benefit over placebo. Several studies are likely to be underpowered to detect statistically significant differences as a result of very small sample sizes, as indicated by the wide CIs seen on metaanalysis. Nonetheless, there was a trend in many of these studies toward methylphenidate being of benefit. There also is little or no statistical heterogeneity in the meta-analysis as denoted by the I2 value of zero. There is however significant clinical heterogeneity among these trials, which makes interpretation more difficult, with wide variation in the types of patients included and the range of tumor types and the disease stages being studied. In addition, there is variation in duration of treatment with methylphenidate (from one to more than eight weeks). The larger trials are more heavily weighted within the analysis, and the largest single trial is the only one to demonstrate a significant treatment effect over placebo. However, although the absolute treatment effect
is relatively small, it is still larger than the overall treatment effect size for exercise in CRF.2 Although it has been possible to combine the studies for methylphenidate, it has so far not been possible to synthesize psychosocial interventions for CRF in this way.3 This was because the trials have varied so widely in design, making it impractical to combine the data. The main limitation of any meta-analysis is the data on which it is based. There initially needs to be an exhaustive search for studies to ensure that missing data are minimized, or the conclusions will be biased as a result. It also is not always possible to combine single studies into a meta-analysis; for instance, when the data are not extractable from the published material and the author(s) are unable to provide it. These requirements were addressed by using a Cochrane systematic review methodology to ensure a comprehensive search and contacting authors to obtain unpublished data suitable for the analysis where indicated. This was necessary for two of the five studiesdAuret et al.19 and Butler et al.16 Data from this analysis also may not be immediately applicable to all tumor types
Fig. 2. Adverse events.
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and stages. This is especially likely in patients with advanced disease where the data demonstrate no benefit in this subgroup. The clinical application of these findings will need to be addressed by the individual clinician, although recommendations are made based on these data. The analysis of serious adverse effects failed to demonstrate any significant differences between groups. The data suggest that, despite commonly voiced concerns, these drugs do not cause major problems in this group of patients. Some minor side effects were noted, but these were no greater with drug than placebo. This finding is supported by the results of a recent review of safety concerns regarding the long-term use of methylphenidate.26 The author of this review identified 26 trials and concluded that adverse effects were minimal in short-term use (up to six to eight weeks of treatment). There are no data available on the longterm use of these drugs in any condition other than ADD. However, there are concerns over their long-term use in children with this diagnosis.27 These relate, among other problems, to potential cardiovascular effects and growth restriction. It is unclear how these findings might relate to adult patients with cancer. The exception to this observation is the potential for abuse when methylphenidate is given to specific groups.26 The danger for abuse is highest when taken for nonclinical reasons, such as use as a performance enhancer.28 It is unlikely that this would be a significant factor in patients with advanced disease but could limit use in other patient groups. Although methylphenidate has been used in pediatric cancer survivors for cognitive deficits,29 these drugs cannot be recommended for long-term use in adult cancer survivors as it is likely that the potential benefits are more than outweighed by the concerns over long-term adverse effects. In this group of patients, it is, therefore, much more likely that exercise or psychosocial interventions will be the treatment modality of choice. Current evidence suggests that the main role for these drugs is short-term use in patients receiving anticancer treatment or for patients with advanced disease. There are additional studies ongoing, and the evidence about the use of methylphenidate in particular groups is likely to continue to evolve.
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Conclusions The evidence suggests that methylphenidate may be effective in the management of CRF. However, in the absence of convincing results from a single, large, well-conducted randomized controlled trial, this advice must be considered to be tentative and provisional. If methylphenidate were to be used in patients with CRF, it would be prudent to restrict its use to patients with advanced disease or for shortterm use in patients on active treatment. The clear advantage of methylphenidate in cancer is its rapid onset of action within 24e48 hours, and so the drug can be discontinued if ineffective. There is no evidence to support safe prescribing beyond eight weeks of treatment. These drugs should only be prescribed under expert supervision and with active monitoring. Nonetheless, psychostimulants are one of the few interventions available to treat CRF that are supported by trial data. Further research is needed before their use can be recommended more widely.
Disclosures and Acknowledgments This study is based on a Cochrane Review published in The Cochrane Library 2010 (see www.thecochranelibrary.com for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and The Cochrane Library should be consulted for the most recent version of the review. This review was not funded by a specific grant, but two authors have personal support. Dr. Minton is funded by a Cancer Research UK psycho-oncology fellowship (grant number C31193/A10090), and Dr. Hotopf is supported by the National Institute of Health Research Specialist Biomedical Research Centre in Mental Health at South London, the Maudsley NHS Foundation Trust, and the King’s College London. The authors declare no conflicts of interest. The authors thank Dr. K. Auret and Dr. D. Case for the additional raw data they provided for inclusion in the meta-analysis.
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2. Cramp F, Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev 2008;(2):CD006145. 3. Goedendorp M, Gielissen M, Verhagen C, Bleijenberg G. Psychosocial interventions for reducing fatigue during cancer treatment in adults. Cochrane Database Syst Rev 2009;(1):CD006953. 4. Minton O, Stone P, Richardson A, Sharpe M, Hotopf M. Drug therapy for the management of cancer related fatigue. Cochrane Database Syst Rev 2008;(1):CD006704. 5. Jensen PS. Review: methylphenidate and psychosocial treatments either alone or in combination reduce ADHD symptoms. Evid Based Ment Health 2009;12:18. 6. Volkow ND, Wang G-J, Fowler JS, Ding YS. Imaging the effects of methylphenidate on brain dopamine: new model on its therapeutic actions for attention-deficit/hyperactivity disorder. Biol Psychiatry 2005;57:1410e1415. 7. Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR. New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol 2007;47:681e698. 8. Martin J, ed. British national formulary, 56th ed. London, UK: British Medical Association and the Royal Pharmaceutical Society of Great Britain, 2008. 9. Wilwerding M, Charles LL, James AM, et al. A randomized, crossover evaluation of methylphenidate in cancer patients receiving strong narcotics. Support Care Cancer 1995;3:135e138.
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