Table 3.

Summary of randomized controlled trials on pharmacological treatments of fatigue in patients with advanced cancer.

Study	Population	Study Design	Intervention	Comparative Intervention	Primary Outcome (Assessment Tool)	Comments
Methylphenidate (MPH)
Centeno 2020 [33] Spain Advanced cancer	ITT = 100, PP = 77 Intervention: Mean age = 66 Men = 52% Placebo: Mean age = 68 Men = 53%	Randomized, double blind, placebo controlled	Methylphenidate 10–25 mg/day for 6 days	Placebo	Effect on fatigue after 6 days. (ESAS, FACT-F).	No significant difference between treatment arms (ESAS p = 0.52, FACT-F p = 0.3). Mean improvement in MPH group: ESAS −2.3 (SD 2.6), FACT-F −3.4 (SD 2.5) Placebo group: ESAS −1.9 (SD 2.5), FACT-F −2.4 (SD 2.9)
Pedersen 2020 [34] Denmark Cancer, palliative care.	ITT = 38, PP = 28 Intervention: Mean age: 69 Men: 29% Placebo: -	Randomized, double blind, placebo controlled	10 tablets of Methylphenidate 10 mg and 10 tablets placebo, randomly packed	Placebo, own control.	Effect on fatigue after 2 and 5 h. (VAS tiredness).	Significant effect with MPH but not placebo after 2 h (mean difference in decrease -12, SD 20, p = 0.004) and after 5 h (mean difference in decrease -12, SD 19, p = 0.001)
Richard 2015 [35] Canada Advanced Prostate cancer	ITT = 24, PP = 23 Intervention: Median age = 63 Men = 100% Placebo: Median age = 74 Men = 100%	Randomized, double blind, placebo controlled	Methylphenidate 5–10 mg/day for 12 weeks	Placebo	Effect on fatigue after 10 weeks (FACT-F).	After 10 weeks mean difference in change from baseline was 5.6 points in favor of intervention (95% CI 1.0–10.3), p = 0.022.
Mitchell 2015 [36] Australia Advanced cancer	ITT = 43, PP = 24 Intervention: Median age = 71 Men = 52% Placebo: -	Randomized, N-of-1, double blind, placebo controlled crossover, multicycle design.	Methylphenidate 5 mg × 2 for 3 days, placebo for 3 days, methylphenidate 5 mg × 2 for 3 days. 3 cycles.	Placebo for 3 days, Methylphenidate for 3 days, placebo for 3 days. 3 cycles.	Effect on fatigue as individual comparison + population estimate (FACIT-F).	No difference was detected between groups characterized as responders and non-responders after 84 completed cycles, mean difference 3.2 (95% credible interval −2.0, 9.0). 7 patients had clinically significant positive effect of MPH.
Escalante 2014 [37] USA Breast cancer (local/ metastatic)	ITT = 42, PP = 33 Intervention: Mean age = 57 Men = 0% Placebo: -	Randomized, placebo controlled, crossover	Methylphenidate 18 mg/day for 14 days + placebo for 14 days.	Placebo for 14 days + methylphenidate 18 mg/day for 14 days.	Effect on fatigue assessed as improvement of worst level of fatigue after 14 days. (BFI)	No significant difference between treatment groups (p = 0.54) regarding worst level of fatigue after 14 days of treatment.
Bruera 2013 [38] USA Advanced cancer	ITT = 190, PP = 140 Intervention: Mean age = 58 Men = 33% Placebo: -	Randomized, 4-arm, placebo controlled	Methylphenidate 5–20 mg/day + nurse telephone intervention OR control telephone intervention for 15 days	Placebo + nurse telephone intervention OR control telephone intervention for 15 days	Effect on fatigue after 15 days (FACIT-F)	All groups showed significant effect in improved fatigue on day 15. MPH was not superior to placebo from baseline to end of trial (5.5 vs. 6.0, p = 0.69).
Roth 2010 [39] USA Advanced prostate cancer	ITT = 32, PP = 23 Intervention: Mean age = 68 Men = 100% Placebo: Mean age = 71 Men = 100%	Randomized, double blind, placebo controlled	Methylphenidate 5–30 mg for 6 weeks. Individual titration of dose after day 3.	Placebo	Effect on fatigue after 6 weeks. (BFI).	Significant effect of both MPH and placebo (improvement in BFI total score 3.63, p = 0.01 and 2.58, p = 0.02), comparison between groups not shown. Methylphenidate reduced BFI severity score more than placebo (p = 0.03). RR for fatigue improvement in MPH group was 3.04 (CI 1.04–8.86) compared to placebo (p = 0.02)
Modafinil
Lee 2016 [40] USA Glioma	ITT = 81, PP = 62 Intervention: Median age = 56 Men = 57% Placebo: Median age = 54 Men = 53%	Randomized, placebo controlled, multicenter pilot study	Armodafinil 150 mg 8 weeks during radiotherapy. Intervention start within 10 days of RT start.	Placebo	Effect on fatigue after 42 days (FACIT-F).	No significant difference in median change in FACIT-F was detected between armodafinil, −1 (range −22 to 48) and placebo, −3 (range −38 to 22), p = 0.30.
Spathis 2014 [41] UK Advanced lung cancer	ITT = 208, PP =160 Intervention: Median age = 68 Men = 49% Placebo: Median age = 69 men = 50%	Randomized, double blind, placebo controlled	Modafinil 100 mg day 1–14, 200 mg day 15–28	Placebo	Effect on fatigue on day 28 (FACIT-F).	No significant effect between treatment arms. Mean score difference between treatment arms 0.20 (95% CI; −3.56–3.97) based on mean score change in modafinil group 5.29 (95% CI 2.57 to 8.02) and placebo group 5.09 (95% CI 2.54 to 7.65).
Hovey 2014 [42] Australia Metastatic breast or prostate cancer	ITT = 83, PP = 66 Intervention: Mean age = 66 Men = 78% Placebo: Mean age = 68 Men = 78%	Randomized 2:1, double blind, placebo controlled, multicenter study	Day 0 + 21: Chemotherapy Day 3–17: Modafinil 200 mg. Min 2, max 4 cycles	Placebo	Effect on chemotherapy-induced fatigue (cumlative MDASI AUC during first 7 days of TP 1 and 2)	No significant effect between treatment arms (MDASI AUC3–10 35.9 vs 39.6, 95% CI −8.9 to 1.4, p = 0.15).
Dexamphetamine
Auret 2009 [43] Australia Advanced cancer	ITT = 50, PP = 39 Intervention: Mean age = 73 Men = 64% Placebo: Mean age = 67 Men = 80%	Randomized, double blind, placebo controlled	Dexamphetamine 10 mg × 2 for 8 days.	Placebo	Effect on fatigue after 8 days (BFI).	No significant difference in effect between groups (p = 0.414) at day 8. Mean decrease in BFI 1.08 in intervention group vs. 0.98 in placebo group.
Melatonin (MLT)
Lund Rasmussen [44] 2015 Denmark Advanced cancer	ITT = 72, PP = 44 Intervention: Mean age = 65 Men = 29% Placebo: Mean age = 62 Men = 34%	Randomized, placebo controlled, double blind, crossover	Melatonin 20 mg for 1 week, wash out 2 days, placebo for 1 week.	Placebo for 1 week, wash out 2 days, Melatonin 20 mg for 1 week.	Effect on fatigue during first intervention with MLT for one week (MFI-20)	No significant effect of MLT was detected. Mean difference in change between week with intervention and placebo 2.8 units (SD 25.6, p = 0.47).
Testosterone
Del Fabbro 2013 [45] USA Advanced cancer, hypogonadal men	ITT = 43, PP = 29 Intervention: Mean age = 57 Men = 100% Placebo: Mean age = 63 Men = 100%	Randomized, double blind, placebo controlled	Testosterone 150–200 mg, injection day 1, 15, 29, 43, 57.	Placebo	Effect on fatigue at day 29. (FACIT-F).	No significant difference in fatigue scores between intervention (4, SD 8) and placebo (−2, SD 12), p = 0.12.
Corticosteroids
Paulsen 2014 [46] Denmark Advanced cancer	ITT = 49, PP = 47 Intervention: Mean age = 62 Men = 50% Placebo: Mean age = 66 Men = 52%	Randomized, double blind, placebo controlled	Methyl- prednisolone 16 mg × 2 for 7 days.	Placebo	Effect on pain intensity after 7 days. Fatigue secondary outcome (EORTC-C30).	Significant improved (p = 0.003) fatigue in the intervention arm (−17, CI 95%, −27 to −6) compared to worsened fatigue in the placebo arm (3, CI 95%, −5 to 11).
Tanioka 2018 [14] Japan Metastatic colorectal cancer	ITT = 74, PP = 72 Intervention: Median age = 65 Men = 61% Placebo: Median age n = 68 Men = 63%	Randomized, double blind, placebo controlled.	Dexamethasone 2 mg for 4 weeks, 1 week after end of targeted therapy.	Placebo	Effect on fatigue assessed as incidence of fatigue (CTCAE v.4). Assessment by patients and investigators	Significantly less fatigue grade ≥ 2 according to patients (p = 0.03), but not investigators (p = 0.69).
Eguchi 2015 [47] Japan Cancer, palliative care	ITT = 35, PP = 34 Intervention: Median age = 71 Men = 61% Placebo: Median age = 68 Men = 62%	Pilot randomized, multicenter, double blind, placebo controlled	Methyl- prednisolone 32 mg for 7 days.	Placebo	Effect on fatigue after 7 days (VAS).	No significant difference between groups (p = 0.484). Mean change in intervention arm (−1.56, SD 32.5) compared to placebo (−9.06, SD 27.2).
Yennurajalingam 2013 [48] USA Advanced cancer	ITT = 132, PP = 84 Intervention: Median age = 60 Men = 47% Placebo: -	Randomized, double blind, placebo controlled	Dexamethasone 4 mg × 2 for 14 days	Placebo	Effect on fatigue after 15 days (FACIT-F).	Significant improved in intervention group compared to placebo, p = 0.008. Mean change from baseline with dexamethasone was 9, (SD 10.3) and with placebo 3.1 (SD 9.59).

Abbreviations: AUC: Area under Curve, BFI: Brief Fatigue Inventory; CI: Confidence Interval; CTCAE v4: National Cancer Institute’s Common Terminology Criteria for Adverse Events; EORTC-C30: European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire 30; ESAS: Edmonton Symptom Assessment Scale; FACIT-F: Functional Assessment of Chronic Illness Therapy-Fatigue; FACT-F: Functional Assessment of Cancer Therapy-Fatigue; I: Intervention; ITT: Intention To Treat; MDASI: MD Anderson Symptom Inventory; MFI-20: Multidimensional Fatigue Inventory-20; mg: milligram; MLT: Melatonin; MPH: Methylphenidate; PP: Per Protocol; RR: Response Rate; RT: Radio Therapy; SD: Standard Deviation; TP. Treatment Period; VAS: Visual Analogue Scale; vs: versus.