Pharmacologic interventions for fatigue in cancer and transplantation: a meta-analysis

Abstract

Background

Our objective was to determine whether, compared with control interventions, pharmacologic interventions reduce the severity of fatigue in patients with cancer or recipients of hematopoietic stem-cell transplantation (hsct).

Methods

For a systematic review, we searched medline, embase, the Cochrane Central Register of Controlled Trials, cinahl, and Psychinfo for randomized trials of systemic pharmacologic interventions for the management of fatigue in patients with cancer or recipients of hsct. Two authors independently identified studies and abstracted data. Methodologic quality was assessed using the Cochrane Risk of Bias tool. The primary outcome was fatigue severity measured using various fatigue scales. Data were synthesized using random-effects models.

Results

In the 117 included trials (19,819 patients), the pharmacologic agents used were erythropoietins (n = 31), stimulants (n = 19), l-carnitine (n = 6), corticosteroids (n = 5), antidepressants (n = 5), appetite stimulants (n = 3), and other agents (n = 48). Fatigue was significantly reduced with erythropoietin [standardized mean difference (smd): −0.52; 95% confidence interval (ci): −0.89 to −0.14] and with methylphenidate (smd: −0.36; 95% ci: −0.56 to −0.15); modafinil (or armodafinil) and corticosteroids were not effective.

Conclusions

Erythropoietin and methylphenidate significantly reduced fatigue severity in patients with cancer and in recipients of hsct. Concerns about the safety of those agents might limit their usefulness. Future research should identify effective interventions for fatigue that have minimal adverse effects.

INTRODUCTION

Cancer-related fatigue is increasingly being recognized as one of the most important symptoms in patients with cancer ^1,2. It has been described as an unexpected tiredness that is more intense and severe than the fatigue experienced in healthy people ³. Cancer-related fatigue can affect up to 80%–90% of cancer patients, and it can occur before diagnosis, during cancer treatment, and after completion of cancer therapies^1,4–9. The origin of cancer-related fatigue is multifactorial: it can be a result of the cancer itself, of cancer treatments, and of comorbid medical and psychological conditions ^10,11. Recipients of hematopoietic stem-cell transplantation (hsct) also experience fatigue, likely related to similar underlying mechanisms ^12,13.

Interventions including physical activity and psychological and pharmacologic approaches have been investigated for the management of fatigue in cancer patients, and several systematic reviews have been published ^14–22. The evaluation of pharmacologic interventions is particularly important, because medications can be associated with adverse effects and high costs. Thus, a good understanding of the benefits and risks are necessary to guide decision-making. However, the systematic reviews of pharmacologic interventions published to date had restrictive inclusion and exclusion criteria, limiting the number of studies included ^18,22. The reviews therefore lacked precision in their estimates of treatment effects and had limited power to identify effective interventions.

Our primary objective was to determine whether, compared with control interventions, pharmacologic interventions reduce the severity of fatigue in patients with cancer or in recipients of hsct.

METHODS

We followed the prisma (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement for the systematic review ²³. A search for eligible randomized trials indexed from 1980 to 11 May 2017 was conducted in the medline, medline in-process, embase, Cochrane Central Register of Controlled Trials, cinahl, and Psychinfo electronic databases. The search strategy included mesh terms and text words that identified patients with cancer or recipients of hsct who received an intervention to reduce fatigue. Table i shows the full search strategy.

TABLE I.

Search strategies

Database	Set	History
MEDLINE, 1946 to Week 1, May 2017
	1	fatigue/ or (fatigue or fatigued).ti,ab,kf.
	2	exp neoplasms/ or stem cell transplantation/ or cord blood stem cell transplantation/ or hematopoietic stem cell transplantation/ or mesenchymal stem cell transplantation/ or peripheral blood stem cell transplantation/ or bone marrow transplantation/ or transplantation, autologous/ or exp antineoplastic agents/ or chemotherap*.mp. or exp antineoplastic protocols/ or (cancer* or neoplas* or oncolog* or tumor* or tumour* or transplant* or chemotherap*).mp.
	3	randomized controlled trial.pt.
	4	controlled clinical trial.pt.
	5	randomized.ab.
	6	randomised.ab.
	7	randomly.ab.
	8	(trial or trials).ti,ab.
	9	or/3–8
	10	1 and 2 and 9
	11	limit 10 to yr=“1980 -Current”
	12	limit 11 to humans
MEDLINE in-process and other non-indexed citations, 10 May 2017
	1	(fatigue or fatigued).ti,ab,kw.
	2	(neoplasm* or neoplas* or cancer* or oncolog* or tumor* or tumour* or transplant*).mp.
	3	(hsct or bmt or chemotherap* or (antineoplas* adj2 protocol*) or (antineoplas* adj2 (agent* or drug or treatment*))).mp.
	4	or/2–3
	5	(RCT or RCTS).ti,ab.
	6	randomized.ab.
	7	randomised.ab.
	8	randomly.ab.
	9	(trial or trials).ti,ab.
	10	or/5–9
	11	1 and 4 and 10
EMBASE, 1980 to Week 19, 2017
	1	*fatigue/ or (fatigue or fatigued).ti,ab,kw.
	2	exp neoplasm/ or exp antineoplastic agent/ or (antineoplas* adj2 protocol*).mp.
	3	(neoplas* or cancer* or oncolog* or tumor* or tumour* or transplant* or chemotherap*).mp.
	4	or/2–3
	5	1 and 4
	6	cancer fatigue/ or (cancer* adj2 fatigue*).ti,ab,kw.
	7	5 or 6
	8	limit 7 to (randomized controlled trial or controlled clinical trial)
	9	(randomized or randomised or randomly).ab.
	10	(trial or trials).ti,ab.
	11	or/9–10
	12	8 or (7 and 11)
	13	limit 12 to conference abstract
	14	12 Not 13
	15	limit 14 to human
PsycINFO, 1806 to Week 1, May 2017
	1	fatigue/ or (fatigue or fatigued).ti,ab,id.
	2	exp neoplasms/ or chemotherapy/ or exp antineoplastic drugs/
	3	((“stem cell*” or “stem-cell*” or “cord blood” or “bone marrowor autologous”) adj3 transplant*).mp.
	4	(cancer* or neoplas* or oncolog* or tumor* or tumour* or transplant* or chemotherap*).mp.
	5	or/2–4
	6	1 and 5
	7	limit 6 to “0300 clinical trial”
	8	randomized.ab.
	9	randomised.ab.
	10	randomly.ab.
	11	(trial or trials).ti,ab.
	12	(RCT or CCT).ti,ab.
	13	clinical trials/
	14	or/8–13
	15	7 or (6 and 14)
	16	limit 15 to yr=“1980 -Current”
Cochrane Central Register of Controlled Trials, Issue 5, 12 May 2017
	1	MeSH descriptor: [Fatigue] this term only
	2	(fatigue or fatigued):ti,ab
	3	(or #1-#2)
	4	MeSH descriptor: [Neoplasms] explode all trees
	5	MeSH descriptor: [Antineoplastic Agents] explode all trees
	6	MeSH descriptor: [Antineoplastic Protocols] explode all trees
	7	(neoplas* or cancer* or oncolog* or tumor* or tumour* or transplant* or chemotherap*):ti,ab
	8	(or #4-#7)
	9	#3 and #8 Publication Year from 1980 to 2017
CINAHL, 1983 to 11 May 2017
	1	(MH “Cancer Fatigue”) OR (MH “Fatigue”)
	2	TI (fatigue OR fatigued) OR AB (fatigue OR fatigued)
	3	1 OR 2
	4	(MH “Neoplasms+”) OR (MH “Antineoplastic Agents+”) OR (MH “Antineoplastics, ImmuNosuppressives”)
	5	TX (antineoplastic N2 protocol*)
	6	(MH “ImmuNocompromised Host”)
	7	4 OR 5 OR 6
	8	3 AND 7
	9	(MH “Double-Blind Studies”) OR (MH “Randomized Controlled Trials”) OR (MH “Triple-Blind Studies”) OR (MH “Single-Blind Studies”)
	10	AB randomized or randomised or randomly or trial or trials
	11	9 OR 10
	12	8 AND 11

Study Selection and Data Abstraction

Inclusion and exclusion criteria were defined a priori. Studies were included if participants were adults or children with cancer or recipients of hsct and if the study was a fully published primary randomized or quasi-randomized trial with a parallel-group design that evaluated a pharmacologic intervention for the management of fatigue.

Studies were excluded if fewer than 75% of the participants had cancer or were undergoing hsct, if fatigue was not an endpoint or was reported as an adverse effect, if the intervention was direct cancer treatment, and if fewer than 5 participants were randomized to any study arm. Inclusion was not restricted by language. For the purpose of the analysis, studies were limited to those using a systemically administered pharmacologic agent. Studies using non-systemically administered pharmacologic agents were excluded, as were studies in which only education or advice was provided.

Two reviewers (PDR and SO or LS) independently evaluated the titles and abstracts of publications identified by the search. Any publication considered potentially relevant by at least one reviewer was retrieved in full and assessed for eligibility. Inclusion of studies in this meta-analysis was determined by agreement of two reviewers (PDR and SO or LS). Discrepancies between the two reviewers were resolved by consensus and adjudication by a third reviewer if required (LLD or LS). The kappa statistic was used to evaluate agreement for study inclusion between the two reviewers. Strength of agreement was defined as slight (0.00–0.20), fair (0.21–0.40), moderate (0.41–0.60), substantial (0.61–0.80), or almost perfect (0.81–1.00) ²⁴.

Data were abstracted in duplicate by two reviewers (DT and PDR) and any discrepancies were resolved by consensus. We contacted authors of manuscripts when publications were missing data for the primary fatigue outcome.

Outcomes

The primary outcome was severity of self-reported fatigue using various fatigue scales. Change scores and end-of-intervention scores were both evaluated. For studies that used more than one fatigue scale, we a priori defined a hierarchy, based on prevalence, for the inclusion of scales in the analysis. Table ii shows the prevalence of the scales reported in our systematic review.

TABLE II.

Self-report fatigue assessment scales used in the included trials^a

Fatigue scale	Studies (n)	Score range	Interpretation of higher score
Functional Assessment of Cancer Therapyb (13-item fatigue subscale)	55	0–52	Less fatigue
EORTC QLQ-C30 (fatigue subscale)	23	0–100	More fatigue
Brief Fatigue Inventoryc	23	0–10	More fatigue
Profile of Mood Statesd (fatigue subscale)	11	0–28	More fatigue
Visual Analog Scale	8	0–10	More fatigue
Number Rating Scale	7	0–10	More fatigue
Edmonton Symptom Assessment System (fatigue subscale)	4	0–10	More fatigue
Multidimensional Fatigue Symptom Inventory–Short Form	4	NA	More fatigue
Multidimensional Assessment of Fatigue (revised Piper Fatigue Scale)	3	1–50	More fatigue
Multidimensional Fatigue Inventory-20	2	4–20	More fatigue
Others (used in 1 study each)	16	—	—

^aSome studies used more than one fatigue scale.

^bFACIT.org, Elmhurst, IL, U.S.A.

^cMD Anderson Cancer Center, Houston, TX, U.S.A.

^dMHS Assessments, Toronto, ON.

EORTC = European Organisation for Research and Treatment of Cancer; QLQ-C30 = 30-question core Quality of Life Questionnaire; NA = not available.

The secondary outcome was the severity of self-reported fatigue using the most common fatigue scale (determined after all scales had been categorized).

Intervention and Control Groups

The intervention was any systemically administered pharmaceutical agent. In studies with more than two arms, the least “active” agent (for example, placebo, usual care, or lowest dose) was used as the control group. Where multiple pharmacologic agents were evaluated, the “intervention group” was the highest dose or the most commonly evaluated intervention (determined after all interventions had been abstracted and categorized).

We categorized the control group type as placebo, usual care, or other pharmacologic intervention.

Study Covariates

Study-level variables included age of the participants (adult or child), cancer diagnosis (breast, lung, other single cancer type, or more than one cancer type), inclusion of hsct patients, timing of the intervention (during cancer treatment, after completion of treatment, or both during and after treatment), exclusive enrolment of palliative care patients (as defined by each study), presence of fatigue as an eligibility criterion for enrolment (as defined by each study), and duration of intervention [<8 weeks, ≥8 weeks, or variable (based on median duration reported by each study)]. We also evaluated the methodologic aspects of the studies.

Risk-of-Bias Assessment

We used the Cochrane Collaboration tool for assessing the risk of bias in randomized trials ²⁵. We evaluated sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, and attrition bias. Because of their potential effect on bias, adequate sequence generation and adequate allocation concealment were prioritized a priori for the stratified analyses ²⁶.

Data Analysis

For this meta-analysis, we combined data at the study level and not at the individual patient level. All synthesized outcomes were continuous. For fatigue scores with missing summary measures, we made these assumptions to facilitate data synthesis: the mean can be approximated by the median; the range contains 6 standard deviations; the 95% confidence interval (ci) contains 4 standard errors; and the interquartile range contains 1.35 standard deviations. Where required, instruments were rescaled such that higher scores reflected more fatigue. We synthesized outcomes when data from at least three studies within a stratum were available.

For the primary outcome of severity of fatigue for all fatigue scales, data were synthesized using the standardized mean difference (smd). For the secondary outcome of the most commonly used fatigue scale, data were synthesized using the weighted mean difference (wmd). A smd or wmd less than 0 indicates that the mean fatigue scores were lower (better) in the intervention group than in the control group. Effect sizes were weighted using the inverse variance method. Given an anticipation of heterogeneity between the studies, a random-effects model was used for all analyses. Statistical heterogeneity between the trials was assessed using the I² value, which describes the percentage total variation for all studies attributable to heterogeneity rather than to chance.

For the primary analysis, individual pharmacologic intervention groups were compared with all control groups using all fatigue severity scales. Change scores and end-of-intervention scores were both evaluated. Where possible, interventions were also evaluated against placebo. A secondary analysis evaluating the most commonly used fatigue severity scale was similarly conducted.

Potential publication bias was explored by a visual inspection of funnel plots when at least 10 studies were available for synthesis ²⁵. In the event of potential publication bias, the “trim and fill” technique was used to determine the effect of such bias ²⁷. In that technique, outlying studies are deleted, and hypothetical negative studies with equal weight are created.

Meta-analyses were conducted using Review Manager (version 5.2: Cochrane Collaboration, Nordic Cochrane Centre, Copenhagen, Denmark). All tests of significance were two-sided, and statistical significance was defined as p < 0.05.

RESULTS

Figure 1 presents the flow diagram of study identification and selection. The search strategy identified 11,793 citations, of which 617 were retrieved for full-text evaluation. Within those 617 citations, 117 studies met the eligibility criteria and were included in the systematic review. Figure 1 indicates the reasons for exclusions. Agreement for study inclusion was almost perfect between the two reviewers (kappa: 0.97; 95% ci: 0.95 to 0.99).

FIGURE 1.

Study identification and selection, and reasons for study exclusion. RCT = randomized controlled trial; AE = adverse event; SRs = systematic reviews.

Tables iii and iv present the characteristics and details of the 117 included studies, which were conducted in more than 30 countries. Most of the studies (69.2%) were published during or after 2007. All were conducted exclusively in adults; no pediatric patients were included in any study. Breast cancer (15.4%) was the most common cancer diagnosis studied. Twenty studies (17.1%) were conducted exclusively in the palliative care setting.

TABLE III.

Characteristics of 117 studies included in the systematic review

Characteristic	Value [n (%)]
Study population
Adults	117 (100)
Children	0
Cancer diagnosis
Breast	18 (15.4)
Lung	11 (9.4)
Other single cancer type	25 (21.4)
More than one cancer type	63 (53.8)
Included HSCT recipients	2 (1.7)
Timing of intervention
During cancer treatment	80 (68.4)
After treatment completion	15 (12.8)
Both during and after treatment	18 (15.4)
Not reported	4 (3.4)
Palliative care setting only	20 (17.1)
Required fatigue for eligibility	28 (23.9)
Pharmaceutical company sponsor	42 (35.9)
Duration of intervention
<8 Weeks	43 (36.8)
≥8 Weeks	57 (48.7)
Variable	17 (14.5)
Intervention type
Erythropoietins	31 (26.5)
Stimulants	19 (16.2)
L-Carnitine	6 (5.1)
Corticosteroids	5 (4.3)
Antidepressants	5 (4.3)
Appetite stimulants	3 (2.6)
Other agents	48 (41.0)
Route of administration
Oral	67 (57.3)
Subcutaneous	36 (30.8)
Intravenous	13 (11.1)
Intramuscular	1 (0.9)
Control group type
Placebo	75 (64.1)
Usual care	26 (22.2)
Other pharmacologic	16 (13.7)
Low risk of bias
Adequate sequence generation	68 (58.1)
Adequate allocation concealment	41 (35.0)
Participants and personnel blinded	44 (37.6)
Outcome assessors blinded	55 (47.0)
Lack of attrition bias	95 (81.2)
Free of selective reporting	106 (90.6)

HSCT = hematopoietic stem-cell transplantation.

TABLE IV.

Details of the 117 included studies

Agent category and reference	Age (years)	Cancer diagnosis	Timing	HSCT	Fatigue eligibility	Intervention	Control
Erythropoietins
Johansson et al., 2001 28	NR	Prostate cancer	Both	No	No	Epoetin beta	Epoetin beta
Littlewood et al., 2001 29	18.7–88.6	>1 Type	On therapy	No	No	Epoetin alfa	Placebo
Osterberg et al., 2002 30	28–86	>1 Type	On therapy	No	No	Epoetin beta	Placebo
Vansteenkiste et al., 2002 31	36–80	Lung cancer	On therapy	No	No	Darbepoetin alfa	Placebo
Boogaerts et al., 2003 32	24–85	>1 Type	On therapy	No	No	Epoetin beta	Usual care
Glaspy et al., 2003 33	NR	>1 Type	On therapy	No	No	Darbepoetin alfa	rHuEPO
Glossmann et al., 2003 34	19–65	Lymphoma	On therapy	No	No	Epoetin beta	Placebo
Iconomou et al., 2003 35	33–85	>1 Type	On therapy	No	No	rHuEPO	Usual care
Kotasek et al., 2003 36	NR	>1 Type	On therapy	No	No	Darbepoetin alfa	Placebo
Smith et al., 2003 37	NR	>1 Type	Off therapy	No	No	Darbepoetin alfa	Placebo
Chang et al., 2004 38	27–85	Breast cancer	On therapy	No	No	Epoetin alfa	Usual care
Leyland Jones et al., 2005 39	24–84	Breast cancer	On therapy	No	No	Epoetin alfa	Placebo
O’Shaughnessy et al., 2005 40	42–64	Breast cancer	On therapy	No	No	Epoetin alfa	Placebo
Witzig et al., 2005 41	20–88	>1 Type	On therapy	No	No	Epoetin alfa	Placebo
Littlewood et al., 2006 42	NR	Lymphoma	On therapy	No	No	Darbepoetin alfa	Placebo
Morishima et al., 2006 43	22–79	>1 Type	On therapy	No	No	Epoetin beta	Epoetin beta
Norager et al., 2006 44	59–68	Colon cancer	On therapy	No	No	Darbepoetin alfa	Placebo
Savonije et al., 2006 45	46–68	>1 Type	On therapy	No	No	Epoetin alfa	Usual care
Straus et al., 2006 46	20–88	>1 Type	On therapy	No	No	Epoetin alfa	Usual care
Wilkinson et al., 2006 47	30–87	Ovarian cancer	On therapy	No	No	Epoetin alfa	Usual care
Charu et al., 2007 48	NR	>1 Type	On therapy	No	No	Darbepoetin alfa	Placebo
Charu et al., 2007 49	NR	>1 Type	On therapy	No	No	Darbepoetin alfa	Usual care
Zemelka et al., 2007 50	46–72	Lung cancer	On therapy	No	No	Erythropoietin	Usual care
Heras et al., 2008 51	35–70	>1 Type	On therapy	No	No	Epoetin beta	Epoetin beta
Hoskin et al., 2009 52	35–99	Head-and-neck	On therapy	No	No	Epoetin alfa	Usual care
Tsuboi et al., 2009 53	NR	>1 Type	On therapy	No	No	Epoetin beta	Placebo
Auerbach et al., 2010 54	27–97	>1 Type	On therapy	No	No	Darbepoetin alfa	Darbepoetin alfa
Engert et al., 2010 55	18–60	Lymphoma	On therapy	No	No	Epoetin alfa	Placebo
Ichinose et al., 2010 56	NR	>1 Type	On therapy	No	No	Darbepoetin alfa	Darbepoetin alfa
Pronzato et al., 2010 57	27–77	Breast cancer	On therapy	No	No	Epoetin alfa	Usual care
Milroy et al., 2011 58	34–83	Lung cancer	On therapy	No	No	Epoetin alfa	Usual care
Stimulants
Bruera et al., 2006 59	22–85	>1 Type	On therapy	No	Yes	Methylphenidate	Placebo
Butler et al., 2007 60	28–83	Brain tumours	On therapy	No	No	D-Methylphenidate	Placebo
Mar Fan et al., 2008 61	36–74	Breast cancer	On therapy	No	No	D-Methylphenidate	Placebo
Auret et al., 2009 62	NR	>1 Type	NR	No	Yes	Dexamphetamine	Placebo
Lower et al., 2009 63	NR	>1 Type	On therapy	No	Yes	D-Methylphenidate	Placebo
Moraska et al., 2010 64	NR	>1 Type	On therapy	No	Yes	Methylphenidate	Placebo
Roth et al., 2010 65	NR	Prostate cancer	On therapy	No	Yes	Methylphenidate	Placebo
Gehring et al., 2012 66	NR	Brain tumours	On therapy	No	No	Modafinil	Methylphenidate
Kerr et al., 2012 67	51–90	>1 Type	Off therapy	No	Yes	Methylphenidate	Placebo
Bruera et al., 2013 68	32–83	>1 Type	Off therapy	No	Yes	Methylphenidate	Placebo
Suh et al., 2013 69	NR	>1 Type	Off therapy	No	No	Caffeine	Placebo
Hovey et al., 2014 70	NR	>1 Type	On therapy	No	Yes	Modafinil	Placebo
Spathis et al., 2014 71	NR	Lung cancer	On therapy	No	Yes	Modafinil	Placebo
Berenson et al., 2015 72	43–85	Multiple myeloma	On therapy	No	Yes	Armodafinil	Placebo
Page et al., 2015 73	20–79	Brain tumours	On therapy	No	No	Armodafinil	Placebo
Richard et al., 2015 74	NR	Prostate cancer	On therapy	No	Yes	Methylphenidate	Placebo
Heckler et al., 2016 75	NR	>1 Type	Off therapy	No	No	Armodafinil	Placebo
Jean-Pierre et al., 2016 76	18–90	>1 Type	Both	No	Yes	Modafinil	Placebo
Lee et al., 2016 77	19–79	Brain tumours	On therapy	No	No	Armodafinil	Placebo
Corticosteroids
Inoue et al., 2003 78	28–78	>1 Type	On therapy	No	No	Dexamethasone	Placebo
Zarger-Shoshtari et al. 2009, 79	34–92	Colorectal cancer	On therapy	No	No	Dexamethasone	Placebo
Yennurajalingam et al., 2013 80	29–89	>1 Type	Both	No	Yes	Dexamethasone	Placebo
Paulsen et al., 2014 81	NR	>1 Type	Both	No	Yes	Methylprednisolone	Placebo
Eguchi et al., 2015 82	46–84	>1 Type	Off therapy	No	No	Methylprednisolone	Placebo
L-Carnitine
Cruciani et al., 2009 83	53.7–84.6	>1 Type	Both	No	Yes	L-Carnitine	Placebo
Mantovani et al., 2010 84	NR	>1 Type	Both	No	No	L-Carnitine	Nutritional supplement
Cruciani et al., 2012 85	NR	>1 Type	Both	No	Yes	L-Carnitine	Placebo
Kraft et al., 2012 86	NR	Pancreatic cancer	Both	No	No	L-Carnitine	Placebo
Hershman et al., 2013 87	26–80	Breast cancer	On therapy	No	No	Acetyl-L-carnitine	Placebo
Iwase et al., 2016 88	22–70	Breast cancer	Both	No	Yes	L-Carnitine	Usual care
Antidepressants
Capuron et al., 2002 89	25–74	Malignant melanoma	On therapy	No	No	Paroxetine	Placebo
Morrow et al., 2003 90	23–87	>1 Type	On therapy	No	Yes	Paroxetine	Placebo
Roscoe et al., 2005 91	31–79	Breast cancer	On therapy	No	Yes	Paroxetine	Placebo
Stockler et al., 2007 92	NR	>1 Type	On therapy	No	No	Sertraline	Placebo
Heras et al., 2013 93	32–89	>1 Type	On therapy	No	Yes	Paroxetine	Placebo
Appetite stimulant
Simons et al., 1996 94	NR	>1 Type	Off therapy	No	No	Medroxyprogesterone acetate	Placebo
De Conno et al., 1998 95	NR	>1 Type	Off therapy	No	No	Megestrol	Placebo
Westman et al., 1999 96	37–89	>1 Type	On therapy	No	No	Megestrol acetate	Placebo
American ginseng
Barton et al., 2010 97	NR	>1 Type	On therapy	No	Yes	American ginseng	Placebo
Barton et al., 2013 98	NR	>1 Type	Both	No	Yes	American ginseng	Placebo
Adenosine 5′-triphosphate (ATP)
Agteresch et al., 2000 99	NR	Lung cancer	Off therapy	No	No	ATP	Usual care
Beijer et al., 2010 100	NR	>1 Type	Both	No	No	ATP	Usual care
Celecoxib
Cerchietti et al., 2007 101	44–90	Lung cancer	Off therapy	No	No	Celecoxib	Placebo and fish oil
Maccio et al., 2012 102	NR	>1 Type	Both	No	No	Celecoxib, megestrol acetate, L-carnitine, and antioxidants	Megestrol acetate
Donepezil
Bruera et al., 2007 103	NR	>1 Type	NR	No	Yes	Donepezil	Placebo
Lawrence et al., 2016 104	39–79	Breast cancer	Both	No	No	Donepezil	Placebo
Traditional Chinese Medicinea
Sun et al., 2010 105	18–80	>1 Type	On therapy	No	No	Traditional Chinese medicines	Usual care
Kuo et al., 2012 106	NR	Breast cancer	Off therapy	No	No	Tien-Hsien liquid practical	Placebo
Zhao et al., 2012 107	NR	Breast cancer	On therapy	No	Yes	Spore powder of Ganoderma lucidum	Placebo
Xue et al., 2015 108	NR	Lung cancer	On therapy	No	No	Decoctions and patent medicines	Usual care
Others (agents used in only 1 study)
Young et al., 1993 109	20–49	>1 Type	On therapy	HSCT	No	TPN plus glutamine	TPN
Borghardt et al., 2000 110	20–70	Head-and-neck cancer	On therapy	No	Yes	Splenic peptides	Placebo
Martin et al., 2002 111	NR	>1 Type	On therapy	No	No	Proteolytic enzymes	Placebo
Bruera et al., 2003 112	NR	>1 Type	Off therapy	No	No	Fish oil	Placebo
Diel et al., 2004 113	27–97	Breast cancer	On therapy	No	No	Ibandronate	Placebo
Monk et al., 2006 114	25–83	>1 Type	On therapy	No	No	Etanercept	Usual care
Semiglazov et al., 2006 115	25–55	Breast cancer	On therapy	No	No	Mistletoe preparation	Placebo
Berk et al., 2008 116	23–91	>1 Type	On therapy	No	No	β-Hydroxyl β-methyl butyrate (HMB), glutamine, and arginine	Isonitrogenous,isocaloric
Troger et al., 2009 117	NR	Breast cancer	On therapy	No	No	Iscador M specialb	Usual care
Jeong et al., 2010 118	NR	>1 Type	On therapy	No	Yes Bojungikki-tang (TJ-41)		Usual care
Tian et al., 2010 119	NR	Lung cancer	Off therapy	No	No	Feiji recipe	Usual care
Anthony et al., 2011 120	NR	>1 Type	On therapy	No	No	Iron sucrose plus ESA	ESA
Barton et al., 2011 121	NR	>1 Type	On therapy	No	No	Valerian	Placebo
Dimsdale et al., 2011 122	NR	>1 Type	On therapy	Both	No	Eszopiclone	Placebo
Ikeguchi et al. 2011, 123	NR	Colorectal cancer	On therapy	No	No	Fucoidan	Usual care
Chen et al., 2012 124	NR	>1 Type	Both	No	Yes	Astragalus membranaceus	Placebo
Zhang et al. 2012, 125	NR	Lung cancer	On therapy	No	No	Buckangling	Placebo
Del Fabbro et al., 2013 126	NR	>1 Type	On therapy	No	No	Testosterone	Placebo
del Giglio et al., 2013 127	NR	>1 Type	On therapy	No	Yes	Paullinia cupana	Placebo
Lesser et al., 2013 128	28–85	Breast cancer	On therapy	No	No	Coenzyme Q10	Placebo
Wen et al., 2013 129	NR	>1 Type	On therapy	No	No	Thalidomide and megestrol acetate	Megestrol
Hansen et al., 2014 130	46–68	Breast cancer	On therapy	No	No	Melatonin	Placebo
Hui et al., 2014 131	27–75	>1 Type	On therapy	No	No	Fentanyl	Placebo
Law et al., 2014 132	30–73	Breast cancer	On therapy	No	No	Virgin coconut oil	Usual care
Lee et al., 2014 133	NR	Colorectal cancer	Off therapy	No	No	Probiotic preparation	Placebo
Sanchez-Lara et al., 2014 134	NR	Lung cancer	On therapy	No	No	Eicosapentaenoic	Usual care
Terkawi et al., 2014 135	NR	Breast cancer	On therapy	No	No	Lidocaine	Placebo
Wang et al., 2014 136	NR	Lung cancer	On therapy	No	No	rHuBNP	Usual care
Liu et al., 2015 137	40–74	>1 Type	On therapy	No	No	Olanzapine	Usual care
Birgegard et al., 2016 138	21–87	>1 Type	On therapy	No	No	Iron isomaltoside	Iron sulphate
Jeon et al., 2016 139	NR	Colon cancer	On therapy	No	No	Vitamin C	Placebo
Mofid et al. 2016, 140	NR	>1 Type	On therapy	No	Yes	Royal jelly and honey	Honey
Faramarzi et al., 2017 141	NR	Rectal cancer	On therapy	No	No	Conjugated linoleic acid	Placebo
Martins et al., 2017 142	NR	Head-and-neck cancer	On therapy	No	No	Guarana	Placebo
Ribeiro et al., 2017 143	NR	Colorectal cancer	Both	No	No	Zinc supplement	Placebo
Sun et al., 2017 144	18–90	Gastric cancer	Off therapy	No	No	Jinlongshe granule	Placebo

^aStudies included differing agents within Traditional Chinese Medicines.

^bIscador Ltd., Lörrach, Germany.

HSCT = hematopoietic stem-cell transplantation; NR = not reported; SC = subcutaneous; rHuEPO = recombinant human erythropoietin; PO = oral; IV = intravenous; CTx = chemotherapy; TPN = total parenteral nutrition; ESA = erythropoiesis stimulating agents; IM = intramuscular; CFU = colony-forming units; rHuBNP = recombinant human B-type natriuretic peptide.

The pharmacologic interventions studied were erythropoietins (n = 31, 26.5%), stimulants (n = 19, 16.2%), l-carnitine (n = 6, 5.1%), corticosteroids (n = 5, 4.3%), anti-depressants (n = 5, 4.3%), appetite stimulants (n = 3, 2.6%), and others (n = 48, 41.0%). The comparison groups were placebo (n = 75, 64.1%), usual care (n = 26, 22.2%), and other pharmacologic interventions (n = 16, 13.7%).

Table ii lists all the fatigue assessment scales used in the various studies. The scale most commonly used was the Functional Assessment of Cancer Therapy (fact) 13-item fatigue scale (FACIT.org, Elmhurst, IL, U.S.A.). Of all the studies included in our systematic review, only 35 (29.9%) could be included in any synthesis because of the requirements that an estimate of central tendency (mean or median) and a measure of variability be presented and that at least three studies with such data be included within a stratum. The pharmacologic agents for which synthesizable data were available were erythropoietins, stimulants, and corticosteroids.

Table v shows the effects of the evaluable pharmacologic agents by either change scores or end-of-intervention score. In evaluating erythropoietin, only change scores could be evaluated because too few studies reported end-of-intervention scores for any analysis. Compared with all controls and placebo, erythropoietin significantly improved fatigue. Compared with all controls, its smd was −0.52 (95% ci: −0.89 to −0.14). When the comparison was restricted to studies that reported fatigue using the fact, fatigue was significantly improved in patients receiving erythropoietin compared with all control patients (wmd: −2.98; 95% ci: −4.41 to −1.55).

TABLE V.

Effect of erythropoietins, stimulants, and corticosteroids on fatigue using all fatigue scales and the FACT scale^a

Agent and comparators	Outcome
	Fatigue change score						End-of-intervention fatigue score
	Studies (n)	Pts (n)	Effect	95% CL (%)	I2	p Value	Studies (n)	Pts (n)	Effect	95% CL (%)	I2	p Value
Erythropoietins
All scales
All interventions vs. all controls	14	3,037	−0.52 SMD	−0.89, −0.14	96	0.007	2			NSP
All interventions vs. placebo	6	1,057	−0.19 SMD	−0.32, −0.07	0	0.003	1			NSP
FACT scale
All interventions vs. all controls	12	2,587	−2.98 WMD	−4.41, −1.55	79	<0.001	0			NSP
All interventions vs. placebo	4	683	−2.49 WMD	−4.06, −0.92	0	0.002	0			NSP
Stimulants
All scales
All interventions vs. all controls	9	1,240	−0.16 SMD	−0.34, 0.02	42	0.08	13	1,287	−0.09 SMD	−0.28, 0.11	50	0.51
All interventions vs. placebob	9	1,240	−0.16 SMD	−0.34, 0.02	42	0.08	12	1,263	−0.08 SMD	−0.28, 0.12	53	0.44
Stratified by agent for all scales
Methylphenidate vs. all controls	5	369	−0.36 SMD	−0.56, −0.15	0	<0.001	6	305	−0.32 SMD	−0.80, 0.17	73	0.20
Modafinil/armodafinil vs. all controls	4	871	0.01 SMD	−0.21, 0.22	36	0.94	5	905	−0.04 SMD	−0.17, 0.09	0	0.51
FACT scale
All interventions vs. all controls	7	596	−1.35 WMD	−3.47, 0.78	50	0.21	7	424	0.80 WMD	−1.57, 3.18	0	0.51
All interventions vs. placebob	7	596	−1.35 WMD	−3.47, 0.78	50	0.21	7	424	0.80 WMD	−1.57, 3.18	0	0.51
Methylphenidate vs. all controls	4	346	−2.87 WMD	−4.68, −1.07	0	0.002	3	150	0.71 WMD	−3.18, 4.59	0	0.72
Modafinil/armodafinil vs. all controls	3	250	1.24 WMD	−2.19, 4.68	49	0.48	4	274	0.89 WMD	−2.17, 3.94	3	0.57
Corticosteroids
All interventions vs. all controls	3	165	−0.43 SMD	−1.00, 0.14	67	0.14	2			NSP
All interventions vs. placebob	3	165	−0.43 SMD	−1.00, 0.14	67	0.14	2			NSP

^aOutcomes using the FACT (FACIT.org, Elmhurst, IL, U.S.A.) were rescaled (multiplied by −1) such that higher scores reflect more fatigue. One study contributed twice: results were reported separately for the lymphoma and multiple myeloma groups (Littlewood et al., 2001²⁹ and Littlewood et al., 2006⁴²).

^bAll synthesized studies were placebo-controlled.

FACT = Functional Assessment of Cancer Therapy; Pts = patients; CL = confidence limits; SMD = standardized mean difference; NSP = no synthesis possible (too few studies); WMD = weighted mean difference.

Table v also shows the effect of stimulants compared with all control treatments and with placebo. As a group, stimulants were not effective for improving change or end-of-intervention fatigue scores. However, when stratified by specific agent, methylphenidate was associated with a significant improvement in fatigue (smd: −0.36; 95% ci: −0.56 to −0.15; and wmd: −2.87; 95% ci: −4.68 to −1.07); modafinil (or armodafinil) was not effective in any comparison. Corticosteroids were not associated with improvement in fatigue (Table v).

Given the small number of studies having data available for synthesis, stratified analyses could not be conducted for l-carnitine, antidepressants, and appetite stimulants. All other agents were examined in only one or two studies, and thus data synthesis was not possible (see Table iv). Figure 2 presents the funnel plot for erythropoietin compared with all controls; no evidence of publication bias was observed.

FIGURE 2.

Funnel plot comparing erythropoietins with all control medications. SE = standard error; SMD = standardized mean difference.

DISCUSSION

In the present systematic review and meta-analysis, erythropoietin and methylphenidate were found to be associated with significant improvements in fatigue for patients with cancer and for recipients of hsct; modafinil (or armodafinil) and corticosteroids were not found to be effective. Also, despite a very large number of randomized trials, data synthesis was limited. Most interventions were studied only once or twice; and even for agents that were studied more often, the data could not be synthesized because of limited data reporting from many of the studies.

Erythropoietin was found to be effective in reducing fatigue, but the size of the effect—a wmd of 2.49 compared with placebo according to the fact 13-item fatigue subscale—was small. The minimal clinically important difference for the fact 13-item fatigue subscale has been reported to be 3–3.5 ¹⁴⁵, which suggests that, although statistically significant, the observed effect is not meaningful to patients. Combined with concerns about the tumour protection, venothrombotic events, and worse survival potentially associated with erythropoietin ^146,147, that minimal change in outcome suggests that this agent should not routinely be used in clinical practice for fatigue reduction.

The other pharmacologic agent that was found to be effective for fatigue was methylphenidate. However, the wmd of methylphenidate also did not meet the threshold for clinical importance. Further, a Cochrane review of methylphenidate for attention deficit hyperactivity disorder suggested that this agent is associated with an increased risk of non-serious adverse events—sleep problems and decreased appetite being most common ¹⁴⁸. Those issues suggest that methylphenidate should not routinely be used to manage fatigue in patients with cancer and in recipients of hsct, but could selectively be used in specific patients for whom the potential benefits outweigh the disadvantages.

None of the studies found during the systematic review of literature included children. That omission is important, because patients with childhood cancer experience severe fatigue ^149,150 and are vulnerable to long-term side effects of treatments ¹⁵¹. Pharmacologic interventions might not have been applied in children because dosing considerations and safety concerns add complexity. However, future studies should consider the pediatric population when formulating eligibility criteria.

An interesting observation was that, despite the large number of randomized trials, relatively few studies had data available for meta-analysis. Although the fact 13-item fatigue subscale was used in many of the trials, publications were inconsistent in whether they reported fact change scores or end-of-intervention scores. Additionally, many of the studies did not report a measure of central tendency and a measure of variability for either of the two fatigue outcomes (change or end-of-intervention score). The lack of well-reported fatigue data raises potential concerns about a form of publication bias in which negative endpoints are not reported or the data are not shown. Future randomized studies focused on fatigue reduction should be encouraged to explicitly report data that could be combined for analysis in systematic reviews.

The present systematic review complements two previously published meta-analyses evaluating the effects of pharmacologic agents on fatigue in cancer patients ^18,152. Our review adds important insights, given that the review by Mustian et al. ¹⁸ reported many types of interventions, citing 14 studies of pharmacologic interventions that were analyzed as a single group. To inform practice, studies must evaluate pharmacologic agents separately. The review by Minton and Stone ¹⁵², which analyzed specific pharmacologic interventions, is now outdated, being based on a literature search conducted in 2009.

The strengths of the present review are its broad eligibility criteria, its inclusion of publications in all languages, and its focus on systemically administered pharmacologic agents. However, our meta-analysis was limited because of the data reporting in the primary studies. Furthermore, wide variations in dose and schedule were noted for the individual pharmacologic agents studied, and the limited number of studies available for synthesis meant that stratified analyses were not possible.

CONCLUSIONS

Erythropoietin and methylphenidate significantly reduce fatigue severity in patients with cancer and recipients of hsct; however, the magnitude of the benefit is of questionable clinical significance. Use of those agents is potentially further limited by concerns about safety. Pharmacologic interventions should not routinely be used to reduce fatigue severity. Future meta-analyses should obtain individual data from trials to better understand how pharmacologic interventions affect fatigue. Research is required to identify interventions for fatigue that are effective and have minimal adverse effects.

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.