Exhausted? Let’s Stimulate the Discussion on Cancer-Related Fatigue!

Pharmacotherapy Rounds

Sumon K. Sen, PharmD PGY2 Internal Medicine Pharmacy Resident

South Texas Veterans Health Care System, San Antonio, Texas Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center The University of Texas Health Science Center at San Antonio

September 19, 2014

Learning Objectives

1. Explore the incidence and complications of cancer-related fatigue 2. Identify risk factors for cancer-related fatigue 3. Evaluate literature for evidence in psychostimulants and cancer-related fatigue 4. Summarize recommendations regarding psychostimulant use in cancer-related fatigue

Cancer-Related Fatigue (CRF) I. Epidemiology1-3

a. Nearly 13 million people have a history of cancer in the United States i. 1.6 million people will be diagnosed this year

ii. Approximately 66.1% will survive at least 5 years after diagnosis iii. Fatigue is the most common symptom patients experience with cancer with prevalence

rates above 60% to 90% b. CRF affects quality of life, physical and psychosocial functioning, and decreases adherence to

chemotherapy c. Reported as the most distressing symptom associated with cancer and its treatment, more than

pain, nausea, or vomiting II. Definition2,4,5

a. “Unusual, persistent, subjective sense of tiredness related to cancer and cancer treatment that interferes with usual functioning” per the National Comprehensive Cancer Network (NCCN)

III. Diagnosis6 a. Fatigue must be persistent with increasing need for rest, limb heaviness, diminished

concentration, inertia, emotional lability, and post-exertional malaise with cancer or treatment for cancer serving as underlying cause

Table 1. International Classification of Diseases (10th edition) Criteria7

Symptoms have been present every day or nearly every day during the same 2-week period in the past month • Significant fatigue, diminished energy or increased need of rest, disproportionate to any recent change in

activity level • Plus five (or more) of the following

o Complaints of generalized weakness or limb heaviness o Diminished concentrations or attention o Decreased motivation or interest in engaging in usual activities o Insomnia or hypersomnia o Experience of sleep as unrefreshing or nonrestorative o Perceived need to struggle to overcome inactivity o Marked emotional reactivity (sadness, frustration, or irritability) to feeling fatigued o Difficulty in completing daily tasks attributed to feeling fatigued o Perceived problems with short-term memory o Post-exertional malaise lasting several hours

• The symptoms cause clinically significant distress or impairment in social, occupational or other important areas of functioning

• There is evidence from history, physical examination, or laboratory findings that symptoms are a consequence of cancer or cancer-related therapy

• The symptoms are not primarily the consequence of comorbid psychiatric disorders, such as major depression, somatization disorder, somatoform disorder or delirium

IV. Mechanism of CRF2,3 a. Not well understood

Sen Page 2

Figure 1. Mechanisms in CRF3

HPA: Hypothalamic-pituitary—adrenal axis; ATP: adenosine triphosphate; CRF: cancer-related fatigue

V. Etiology of CRF2,7,8

Figure 2. Causes of Fatigue8

VI. Contributory comorbid conditions2,3,9 Table 2. Comorbidities Type Comments Anemia • Hemoglobin level of <12 g/dl

• Incidence of anemia differs by type, stage, and duration of cancer/ treatment Cachexia/ Nutritional disorders

• Leads to anorexia, weight loss, fatigue, and impaired function • Affects 50%-85% cancer patients • Cancer and chemotherapy may interfere with diet and fluid intake

Sleep Disorders • Secondary to dysfunction of HPA axis Depression • Correlations between depression and fatigue in patients with cancer

• Neither condition was found to be predictive of the other • Uncertain whether fatigue and depression share common pathway

Mechansims of CRF

Serotonin Dysregulation

HPA-Axis Dysfunction

Circadian Rhythm

Disruption

Muscle Metabolism/ATP

Dysregulation

Vagal Afferent Nerve Activation

Cytokine Dysregulation

Cancer effects Cancer

treatment adverse effects

Psychosocial factors

Comorbid conditions

Comorbid symptoms

Sen Page 3

Management

I. Non pharmacological10 a. Energy conservation and activity management (ECAM)10,11

i. Allows patients to find ways to decrease effort required to perform, to eliminate, and to alternate rest and activity with tasks

ii. ECAM has been found to have a modest benefit in patients with cancer undergoing cancer treatment

b. Cognitive-behavioral therapy (CBT)12 i. Increase cognitive control through cognitive restructuring, relaxation, imagery,

visualization, attention diversion ii. May be beneficial in improving cancer-related symptoms of pain, sleep disturbance, as

well as fatigue c. Acupuncture10,13

i. In a randomized controlled trial 302 patients were evaluated with 6 weeks of acupuncture vs usual care, and found improvements in fatigue

ii. Further study needed to conclude benefits with this intervention d. Psychosocial interventions10

i. Management of anxiety, stress, depression through support groups, education, and counseling, guided imagery

ii. Three meta-analyses showed that psychosocial interventions had a small to moderate effect on CRF

e. Exercise10 i. Meta-analyses have found exercise effectively reduces fatigue12

1. Moderate effect on fatigue, however, fatigue was not used as a criteria for study entry in trials

2. Type of exercise range from aerobic to home programs that reduce CRF ii. Mixed effects are reported for resistance exercise

iii. Guidelines from the American College of Sports Medicine (ACSM) recommend patients with cancer engage in at least 150 minutes of moderate aerobic activity each week

iv. Fatigue may serve as barrier to participate in exercise interventions in which other strategies may be appropriate

II. Pharmacological treatments a. Minton et al (2010) conducted meta-analysis of total of 50 studies (only 31 studies suitable for

analysis) evaluating CRF14 i. Psychostimulants: lead to an observable improvement in fatigue

ii. Erythropoietin: provides significant reduction in fatigue iii. Darbepoietin: fatigue reduced but not clinically significance iv. Paroxetine: trials demonstrate an improvement in mood without associated

improvement in fatigue v. Progestational steroids: no superiority over placebo for this class of drugs

vi. Conclusion: further randomized control trials needed, but psychostimulants may be helpful in CRF

Sen Page 4

b. Erythropoietin-stimulating agents (ESA)15 i. Corrects anemia with hemoglobin <10 g/dL to decrease fatigue

ii. Adverse drug reaction: Increased risk of thrombotic events, hypertension, tumor growth, decreased survival

iii. ESAs are not indicated for use of CRF treatment and should only be used for anemia treatment

c. Antidepressants i. Paroxetine6

1. Mechanism of action: selective serotonin reuptake inhibitor 2. Studies evaluating effectiveness of paroxetine in treating fatigue during and

post-cancer treatment resulted in no beneficial effect on fatigue ii. Sertraline16

1. Mechanism of action: selective serotonin reuptake inhibitor 2. No improvement in symptoms, well-being, or survival in patients with

advanced cancer without major depression iii. Bupropion17,18

1. MOA: primarily dopaminergic and noradrenergic 2. Some potential as an effective pharmaceutical agent for treating CRF

d. Donepezil19 i. Mechanism of action: long-acting selective acetylcholinesterase inhibitor

ii. In a prospective, double-blind, placebo, randomized, controlled trial to evaluate the effectiveness of donepezil vs placebo on fatigue with patients with advanced cancer, no benefit found

e. Thyreoliberin20 i. Mechanism of action: thyrotropin-releasing hormone [TRH] regulating thyroid axis and

may produce mood elevating effects ii. Proof-of-concept study suggest benefits with TRH in the treatment of CRF

f. Levocarnitine1 i. Mechanism of action: micronutrient important for the processing of long-chain fatty

acids and energy production in mammalian cells ii. Conclusions from studies treating CRF limited by small sample size and study design, but

results encourage further study g. Ginseng20,21

i. Mechanism of action: reduce cytokines related to inflammation and to help regulate cortisol levels

ii. American ginseng product safe and potentially effective at 2000 mg daily for 8 weeks iii. More research is needed to confirm findings that this agent is beneficial iv. One major disadvantage of ginseng is lack of regulation, potentially allowing dosing

inconsistencies and contamination h. Guarana (Paullinia cupana)23

i. Mechanism of action: stimulates sympathetic neurons ii. Improved CRF in women undergoing chemotherapy for breast cancer

Sen Page 5

i. Corticosteroids i. Yennurajalingam et al24

1. 84 patients with advanced cancer treated with dexamethasone 4 mg or placebo twice daily for 14 days

2. Found improvement in FACIT-F score (Appendix A) without differences in adverse effects

j. Psychostimulants

Clinical Question: What is the role of psychostimulants in cancer-related fatigue? I. Literature evaluation

a. Methylphenidate (MPH) i. Systematic review: Gong et al 2014

ii. Lower et al 2009 iii. Bruera et al 2013

b. Modafinil i. Jean-Pierre et al 2010

ii. Spathis et al 2014

•Indications/Uses: •Approved for the treatment of attention deficit hyperactivity disorder and narcolepsy

•Mechanism of action •Inhibits dopamine and norepinephrine reuptake into cell •Stimulates neurotransmitter production resulting in increased dopamine levels to bind active receptors

•Adverse events (AE): Irritability, anorexia, insomnia, mood lability, nausea, tachycardia, potential cardiovascular effects, growth restriction

Methylphenidate14,20

•Indications/Uses: •Wake promoting agent, obstructive sleep apnea, narcolepsy, Parkinson’s disease, multiple sclerosis

•Mechanism of action •Affects histamine, epinephrine, γ-aminobutyric acid (GABA), and glutamate •Enhances catecholamine signaling and decreases GABA release by binding directly to dopamine/norepinephrine receptors

•AE: Headache, infection, nausea, nervousness, anxiety, and insomnia

Modafinil25,26

Sen Page 6

Table 3. Gong S, Sheng P, Jin J, et al. Effect of methylphenidate in patients with cancer-related fatigue: a systematic review and meta-analysis. PLoS ONE;2014:9(1):e84391.27

Purpose To evaluate use, efficacy, and safety of MPH in the treatment of CRF Included Trials • Bruera et al 2006

• Butler et al 2007 • Lower et al 2009 • Moraska et al 2010 • Roth et al 2010

Outcomes • Primary outcome: fatigue scores with FACT-F and BFI Results

• Subgroup analyses showed efficacy of MPH improved with longer treatment duration

o −3.70 (95% CI (−7.03 to −0.37); p = 0.03) for long-time group (>4 weeks) o −2.49 (95% CI −6.01 to 1.03); p = 0.17) for short-time group (<4 weeks)

• More reported vertigo, anxiety, anorexia, and nausea in MPH vs PB but no statistically significant risk ratio for study discontinuation (p=0.17)

Critique Strengths • Varity of cancers (breast, prostate, lung,

genitourinary, gastrointestinal, hematologic, brain tumor)investigated

• Randomized trials chosen • Separated FACT-F and BFI scales

Limitations • Few studies available • Numbers of patients were very small • Heterogeneity with BFI scale • Did not define psychiatric conditions

Conclusion • Limited evidence for the use of MPH to treat CRF but may be effective for management Take Home Points

• Long term treatment (>4 weeks) may be beneficial over short term treatment (<4 weeks)

BFI: Brief Fatigue Inventory; CRF: cancer-related fatigue; FACT-F: Functional Assessment of Cancer Therapy for Fatigue; MPH: methylphenidate; PB: placebo

Sen Page 7

Table 4. 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(5):650-62. 28

Purpose To determine if dexmethylphenidate (D-MPH) will reduce fatigue vs placebo after chemotherapy in cancer patients

Design • Multicenter, randomized, placebo-controlled, parallel-group study Population • Inclusion: men or women aged 18–70 years with cancer, previously treated with ≥4 cycles

chemotherapy completed ≥2 months, life expectancy of >6 months, ECOG ≤2, MMSE ≥20,BDI-II <18 (no greater than moderate depression), CGI-S score ≥3 (mildly impaired)

• Exclusion: concurrent treatment with anticancer therapies (biological and/or radiation therapy), history of major psychiatric illness, prior treatment with MPH/D-MPH, use of monoamine oxidase inhibitors within 30 days, seizure disorder or drug/alcohol abuse

Methods • 5 mg D-MPH twice a day (10 mg/day) vs PB twice a day up to 50 mg daily • Subjects seen weekly for efficacy and safety assessments

Outcomes • Primary: change from baseline in the FACIT-F total score at Week 8 • Secondary: cognitive function

Statistical Analysis

• Required 60 subjects per group to detect a 15% relative difference with 80% power • ANCOVA for primary analysis • T test for continuous variables, Fisher’s exact test for categorical measures, Cochran-Mantel-

Haenszel test for categorical variables Results • Baseline characteristics: well matched except D-MPH-treated subjects had lower screening ECOG

performance status scores • N=154 (breast and ovarian cancers, post chemotherapy)

Efficacy outcomes D-MPH PB P Value FACIT-F score at Week 8 [mean(SEM)] -10.5 (1.2) -6.8 (1.2) 0.02 CGI-S score of 1, 2, or 3 at Week 8 [n(%)] 54 (72) 45 (58.4) 0.02 CGI-I score of 1, 2, or 3 at Week 8 [n(%)] 58 (77) 52 (68) 0.06 HSCS overall score [mean(SEM)] 12.2 (1.8) 9.0 (1.7) 0.18 Modified SNAP score [mean(SEM)] 8.7 (0.9) 8.4 (0.9) 0.81

• Most commonly reported AEs were headache, nausea, and dry mouth; higher rate of AEs in the D-MPH treatment group

Select Adverse Events % D-MPH (n=76) % PB (n=78) Headache 40.8 33.3 Nausea 27.6 7.7 Dry mouth 26.3 12.8

• 11% vs 1.3% (D-MPH vs PB) had AEs that led to study discontinuation (p=0.02) Critique Strengths

• Randomized, double-blinded • Excluded psychiatric disorders • Defined CRF from proposed ICD 10

criteria • Longer follow up

Limitations • Almost all female with breast cancer/ovarian

cancer • Stage of disease not reported • Considerably younger (mean age 53)

Conclusion • D-MPH produced significant improvement in fatigue but no reduction in cognitive impairment Take Home Points

• More AE seen with D-MPH vs placebo • May provide improvement in women with breast/ovarian cancer during chemotherapy

ADD: attention deficit disorder; BDI-II: Beck Depression Inventory-II; CGI-I: Clinical Global Impression- Improvement; CGI-S: Clinical Global Impression-Severity; D-MPH: dexmethylphenidate; ECOG: Eastern Cooperative Oncology Group; FACIT-F: Functional Assessment of Chronic Illness Therapy-Fatigue Subscale; HSCS: High Sensitivity Cognitive Screen; MMSE: mini-mental status examination; PB: placebo; SEM: standard error of mean; SNAP: Swanson, Nelson Pelham Attention Deficit/Hyperactivity Scale

Sen Page 8

Table 5. Bruera E, Yennurajalingam S, Palmer JL, et al. Methylphenidate and/or a nursing telephone intervention for fatigue in patients with advanced cancer: a randomized, placebo-controlled, phase II trial. J Clin Oncol. 2013;31(19):2421-27.29

Purpose To compare the effects of methylphenidate vs placebo on CRF Design • Randomized, placebo-controlled, phase II trial

• 5mg MPH every 2 hours PRN up to 20 mg daily vs PB for 14 days + NTI calls 4-6 times over 2 weeks • 5 mg every 2 hours PRN up to 20 mg daily vs PB for 14 days + CTI calls 4-6 times over 2 weeks

Population • Inclusion: advanced cancer, > 4 on ESAS scale, >24 on MMSE, Hgb >8 g/dL, no history of tachycardia, arrhythmia, uncontrolled hypertension, glaucoma, severe anxiety disorders, majors depression, substance abuse; not currently taking monoamine oxidase inhibitors, tricyclic antidepressants, clonidine, warfarin, or erythropoietin

• Exclusion: pregnant, lactating Outcomes • Primary: median difference in FACIT-F fatigue at day 15

• Secondary: anxiety, depression, sleep Statistical Analysis

• Wilcoxon two-sample test • Kruskal-Wallis test • Signed ranked test • Chi-square test for adverse events • Two-sided tests with p<0.05 considered statistically significant

Results • Baseline characteristics: No statistically significant differences, well matched • N=141

FACIT-F Score ESAS Fatigue Score Treatment Median Day 15 P value Median Day 15 P value MPH 5.5

0.69 -2

0.86 PB 6 -2 Intervention NTI 6

0.27 -2.5

0.14 CTI 5.5 -2 All groups MPH + NTI 4

0.16

-3

0.45 MPH + CTI 7 -1 PB + NTI 8.5 -2 PB + CTI 5 -2

• Grade ≥ 3 adverse events between groups was not statistically significant (p= 0.06) Critique Strengths

• Randomized, placebo-controlled trial • Inclusion/exclusion

Limitations • Underpowered • Stage of cancer/tumor type/chemotherapy not

reported • Low dose of MPH • Short duration of treatment

Conclusion • MPH, NTI, or combination were not superior to PB in CRF improvement Take Home Points

• Several cancer-related symptoms were significantly improved in the nursing telephone intervention group compared with those receiving the control telephone intervention

• Absence of methylphenidate effect might have been due to benefit from the nursing intervention showing more benefit than methylphenidate

CRF: cancer-related fatigue; CTI: control telephone intervention; ESAS: Edmonton Symptom Assessment Scale; FACIT-F: Functional Assessment of Chronic Illness Therapy-Fatigue Subscale; MMSE: mini-mental status examination; MPH: methylphenidate; NTI: nursing telephone intervention

Sen Page 9

Table 6. Jean-Pierre P, Morrow GR, Roscoe JA, et al. A Phase 3 randomized, placebo-controlled, double-blind, clinical trial of the effect of modafinil on cancer-related fatigue among 631 patients receiving chemotherapy. Cancer. 2010;15:3513-20. 30

Purpose To evaluate modafinil in cancer patients undergoing chemotherapy Design • Multicenter, randomized, double-blind, placebo-controlled Phase III clinical trial Population • Inclusion: at least 18 years old, life expectancy >6 months, initial cancer treatment of at least four

planned cycles of chemotherapy at least two weeks apart • Exclusion: previous modafinil or psychostimulant use within 30 days, pregnant, nursing,

uncontrolled anemia, cardiac disease, uncontrolled hypertension, alcohol or drug abuse, severe headaches, seizure disorder, narcolepsy, Tourette’s syndrome, other psychiatric disorders

Methods • 200 mg daily of modafinil vs PB • Treatment began on Day 5 of Cycle 2 and ended after Day 7 of Cycle 4 • Medication was discontinued if chemotherapy was discontinue/ delayed > three weeks

Outcomes • Primary: CRF was assessed using Item 3 of the BFI • Secondary: daytime sleepiness, depression

Statistics • Analyses were performed on an intent-to-treat basis • Analysis of covariance (ANCOVA) was used to address the primary objective • 586 participants would provide 90% power to detect a difference of 0.75 points between groups,

based on an alpha-level of 0.05 Results

• Baseline characteristics: 67% females; baseline cancer: breast 35%; alimentary 25%; lung 16% • N=867; 631 with evaluable data

Outcome Change in outcome for modafinil vs placebo at median baseline

P value

BFI-3 (Fatigue) -0.33 0.08 ESS (Sleepiness) -1.03 0.002 CESD (Depression) 0.34 0.6 POMS-DD (Depression) -0.04 0.87

Fatigue severity at baseline

Difference between modafinil vs placebo

P value

Mild 0.74 0.09 Moderate 0.2 0.411 Severe -0.44 0.033 Maximum Fatigue -0.76 0.01

• AE similar; modafinil vs PB (p = 0.46) Author’s Conclusion

• Study supports the use of modafinil as an effective treatment for severe CRF in patients undergoing chemotherapy

Critique Strengths • Blinded • Study design • Intent to treat • Characterized the severity level of CRF • Heterogeneous sample

Limitations • Single item fatigue measure potential susceptible

to bias • Mostly female patients

Take Home Points

• Modafinil shown to reduce excessive daytime sleepiness • Although the difference between the group adjusted means was statistically significant this small

change is unlikely to be of clinical significance • May be helpful in severely fatigued patients • No difference in alleviating depression

AE: adverse events; BFI: Brief Fatigue Inventory; CES-D: Center for Epidemiologic Studies Depression; CRF: cancer-related fatigue; ESS: Epworth Sleepiness Scale; PB: placebo; POMS: Profile of Mood States Depression Dejection

Sen Page 10

Table 7. Spathis A, Fife K, Blackhall F, et al. Modafinil for the treatment of fatigue in lung cancer: results of a placebo-controlled, double-blind, randomized trial. J Clin Oncol. 2014;32(18):1882-8.31

Purpose To establish its efficacy and tolerability in fatigued patients with advanced non-small cell lung cancer Design • Placebo-controlled, double-blind, randomized-controlled trial Population • Inclusion: adult outpatients with stage 3a/3b/4 NSCLC, WHO performance status of 0 to 2, numeric

rating scale score of > 5 • Exclusion: received radiotherapy or chemotherapy within the last 4 weeks; blood transfusion,

steroids, or antidepressants in the last 2 weeks; major psychiatric illness; uncontrolled hypertension; history of arrhythmia; left ventricular hypertrophy

Methods • Modafinil 100 mg days 1-14 and 200 mg days 15-28 vs PB • Assessments in clinic/telephone on days 0, 14, and 28

Outcomes • Primary: fatigue measured by FACIT • Secondary: daytime sleepiness, depression, and quality of life

Statistics • Required sample size of 206 to have 80% power • Modified intention-to-treat (ITT) analysis • Changes in FACIT-Fatigue score at day 28 from baseline compared using ANCOVA • Secondary outcomes analyzed by ANCOVA or Mann-Whitney U test

Results

• N= 208 Difference Between Treatments Scale ∆ in Modafinil arm ∆ in PB arm P value FACIT-F 28 days 5.29 5.09 0.92 FACIT-F 14 days 5.78 4.33 0.33 ESS -1.84 -1.78 0.94 HADS-Depression -1 0 0.39 QOL-LAS 0 0 0.60

Adverse Effects Adverse event Modafinil PB Headache 22.1% 24.3% Nausea/Vomiting 15.4% 19.4% Anxiety 8.7% 9.7% Other 43.3% 34% Any 55.8% 54.4%

• Subgroup analysis o Exploratory analyses showed no difference across subgroups defined by stage of disease,

performance status, age, sex, and severity of baseline fatigue • More withdrew from the modafinil than PB group (modafinil, n=30; PB, n=16; p <0.02)

Author’s Conclusion

• There is insufficient evidence to prescribe modafinil for patients with CRF outside of a clinical trial

Critique Strengths • Double-blind trial • Largest trial with modafinil • Sample size met power • Intent-to-treat analysis • Frequent follow up assessments

Limitations • Speaking on phone may serve as benefit • Attrition rate of 22% • No baseline depression score

Take Home Points

• Clinically significant placebo effect found in this trial is an important finding • Patients with severe fatigue did not show benefit • Modafinil had a greater dropout rate vs placebo • Safety of modafinil has not been established

ANCOVA: analysis of covariance; CRF: cancer-related fatigue; FACIT-F: Functional Assessment of Chronic Illness Therapy-Fatigue; ESS: Epworth Sleepiness Scale; HADS: Hospital Anxiety and Depression Scale; ITT: intent to treat; NSCLC: non-small cell lung cancer; PB: placebo; QOL-LAS: Quality of life linear analog scale; WHO: World Health Organization

Sen Page 11

Summary

Concerns with Trials in CRF and Psychostimulants

I. Overall concern with trials a. Potential heterogeneity of study populations b. No consensus defining CRF c. Small number of patients d. Patients suffer from concomitant conditions attributable to fatigue e. Short term treatment f. Safety data for long term use is unavailable in CRF g. CRF includes patients with very different potential causes of fatigue h. Open-label designs without placebo i. Baseline fatigue assessment difficult

Safety Concerns32

I. Methylphenidate A. In 2006, safety concerns reported with MPH as treatments for ADHD regarding cardiovascular

safety33 B. MPH may increase blood pressure, heart rate, headache, insomnia, decrease appetite, mucosal

dryness, and some neurological symptoms C. Schelleman et al (2012) found initiation of MPH associated with a 1.8 fold risk in sudden death or

ventricular arrhythmia but may be due to chance34 D. Lasheen et al (2013) found MPH in advanced cancer (n=62), is well tolerated with some agitation,

insomnia, and dry mouth in a retrospective analysis35 II. Modafinil36

A. Insomnia, irritability, muscle tension, headache, appetite suppression seen in < 20% of patients

Methylphenidate •Benefit may be seen in longer therapy vs short therapy •Adverse effects seen with therapy •Mixed effectiveness

Modafinil •Benefit may be seen in severe fatigue •Placebo groups has been found to be beneficial •Clinical significance in benefit is questionable

Sen Page 12

Conclusion and Recommendations

I. Current National Comprehensive Cancer Network (NCCN) guidelines (2014) and American Society of Clinical Oncology (ASCO) guidelines (2014) recommend physical activity, psychosocial interventions, management of co-morbidities, and possible use of psychostimulant5,37

II. Should we be using psychostimulants in our CRF patients? a. Modafinil should not be considered at this time due to mixed effectiveness and lack of robust

studies b. Methylphenidate has mixed data regarding effectiveness, but due to adverse effects seen in

trials, should not be considered at this time

Sen Page 13

Reference:

1. Carroll JK, Kohl S, Mustian KM, Roscoe JA, Morrow GR. Pharmacologic treatment of cancer-related fatigue. The Oncologist. 2007;12(1):43-51. 2. National Cancer Institute. Surveillance, epidemiology, and end results. SEER stat fact sheets: all cancer sites. Retrieved September 17, 2014. from

http://seer.cancer.gov/statfacts/html/all.html. 3. Ryan JL, Carroll JK, Ryan EP, et al. Mechanisms of cancer-related fatigue. The Oncologist. 2007;12(Supplement 1):22-34. 4. Hofman M, Ryan JL, Figueroa-Moseley CM, Jean-Pierre P, Morrow GR. Cancer-related fatigue: the scale of the problem. The Oncologist. 2007:12(1):4-10. 5. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Cancer Related Fatigue version 1.2014. [Accessed August 7, 2014].

Available at: http://www.nccn.org. 6. Mitchell SA. Cancer-related fatigue: state of the science. PMR. 2010;2(5):364-83. 7. Lop A, Manfredi AM, Bonura S. Fatigue in cancer patients receiving chemotherapy: an analysis of published studies. Ann Oncol. 2004;15 (5): 712-20. 8. Wagner LI, Cella D. Fatigue and cancer: causes, prevalence and treatment approaches. Br J Cancer. 2004;91:822-8. 9. Richard PO, Fleshner NE, Bhatt JR, Hersey KM, Chahin R, Alibhai SM. A phase II, randomized, double-blind, placebo-controlled trial of methylphenidate for

reduction of fatigue in prostate cancer patients receiving LHRH-agonist therapy. BJU Int. 2014. 10. BowerJE. Cancer-related fatigue – mechanisms, risk factors, and treatments. Nat Rev Clin Oncol. 2014. 11. Barsevick AM, Dudley W, Beck S, Sweeney C, Whitmer K, Nail L. A randomized clinical trial of energy conservation for patients with cancer-related fatigue.

Cancer. 2004 Mar 15;100(6):1302-10. 12. Cramp F, Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev. 2012;11. 13. Molassiotis A, Bardy J, Finnegan-John J, et al. Acupuncture for cancer-related fatigue in patients with breast cancer: a pragmatic randomized controlled trial. J

Clin Oncol. 2012;30(36):4470-6. 14. Minton O, Richardson A, Sharpe M, Hotoopf M, Stone PC. Psychostimulants for the management of cancer-related fatigue: A systematic review and meta-

analysis. J Pain Symptom Manage. 2001;41(4):761-7. 15. Kelada O, Marignol L. Erythropoietin-stimulating agents and clinical outcomes in metastatic breast cancer patients with chemotherapy-induced anemia: a

closed debate? Tumour Biol. 2014;35(6):5095-100. 16. Stockler MR, O'Connell R, Nowak AK, et al. Effect of sertraline on symptoms and survival in patients with advanced cancer, but without major depression: a

placebo-controlled, double-blind randomised trial. Lancet Oncol. 2007;8(7):603-12. 17. Moss EL, Simpson JS, Pelletier G, Forsyth P. An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer

patients and their partners. Psychooncology. 2006;15(3):259-67. 18. Cullum JL, Wojciechowski AE, Pelletier G, Simpson JS. Bupropion sustained release treatment reduces fatigue in cancer patients. Can J Psychiatry.

2004;49(2):139-44. 19. Bruera E, El Osta B, Valero V, et al. Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial. Clin Oncol. 2007;25(23):3475-81. 20. Kamath J, Feinn R, Winokur A. Thyrotropin-releasing hormone as a treatment for cancer-related fatigue: a randomized controlled study. Support Care

Cancer. 2012;20(8):1745-53. 21. Ruddy KJ. Laying to rest psychostimulants for cancer-related fatigue. J Clin Oncol. 2014;32(18):1865-7. 22. Barton DL, Liu H, Dakhil SR, et al: Wisconsin ginseng (Panax quinquefolius) to improve cancer-related fatigue. J Natl Cancer Inst. 2013;105(16):1230-8. 23. de Oliveira Campos MP, Riechelmann R, Martins LC, Hassan BJ, Casa FB, Del Giglio A. Guarana (Paullinia cupana) improves fatigue in breast cancer patients

undergoing systemic chemotherapy. J Altern Complement Med. 2011;17(6):505-12. 24. Yennurajalingam S, Frisbee-Hume S, Palmer JL, et al. Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-

controlled trial in patients with advanced cancer. J Clin Oncol. 2013;31(25):3076-82. 25. Boele FW, Douw L, de Groot M, et al. The effect of modafinil on fatigue, cognitive functioning, and mood in primary brain tumor patients: a multicenter

randomized controlled trial. Neuro Oncol. 2013;15(10):1420-8. 26. Spathis A, Dhillan R, Booden D, Forbes K, Vrotsou K, Fife K. Modafinil for the treatment of fatigue in lung cancer: a pilot study. Palliat Med. 2009;3(4):325-31. 27. Gong S, Sheng P, Jin J, et al. Effect of methylphenidate in patients with cancer-related fatigue: a systematic review and meta-analysis. PLoS

ONE;2014:9(1):e84391. 28. 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(5):650-62. 29. Bruera E, Yennurajalingam S, Palmer JL, et al. Methylphenidate and/or a nursing telephone intervention for fatigue in patients with advanced cancer: a

randomized, placebo-controlled, phase II trial. J Clin Oncol. 2013;31(19):2421-27. 30. Jean-Pierre P, Morrow GR, Roscoe JA, et al. A Phase 3 randomized, placebo-controlled, double-blind, clinical trial of the effect of modafinil on cancer-related

fatigue among 631 patients receiving chemotherapy. Cancer. 2010;15:3513-20. 31. Spathis A, Fife K, Blackhall F, et al. Modafinil for the treatment of fatigue in lung cancer: results of a placebo-controlled, double-blind, randomized trial. J Clin

Oncol. 2014;32(18):1882-8. 32. Fredriksen M, Halmøy A, Faraone SV, Haavik J. Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: a review of

controlled and naturalistic studies. Eur Neuropsychopharmacol. 2013;23(6):508-27. 33. Nissen SE. ADHD drugs and cardiovascular risk. N Engl J Med. 2006;354(14):1445-8. 34. Schelleman H, Bilker WB, Kimmel SE, et al. Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry. 2012;169(2):178-85. 35. Lasheen W, Walsh D, Mahmoud F, et al. Methylphenidate side effects in advanced cancer: a retrospective analysis. Am J Hosp Palliat Care. 2010;27(1):16-23. 36. Lindsay SE, Gudelsky GA, Heaton PC. Use of modafinil for the treatment of attention deficit/hyperactivity disorder. Ann Pharmacother. 2006;40(10):1829-33. 37. Bower JE, Bak K, Berger A, et al: Screening, assessment, and management of fatigue in adult survivors of cancer: An American Society of Clinical Oncology

Clinical Practice Guideline Adaptation. J Clin Oncol. April 14, 2014 38. Wigal S, Swanson JM, Feifel D, et al. A double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride and d,l-threo-methylphenidate

hydrochloride in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2004;43(11):1406-14. 39. Richardson LA, Jones GW. A review of the reliability and validity of the Edmonton Symptom Assessment System. Curr Oncol. 2009;16(1):55. 40. Cella D, Eton DT, Lai JS, Peterman AH, Merkel DE. Combining anchor and distribution based methods to derive minimal clinically important differences on the

Functional Assessment of Cancer Therapy (FACT) anemia and fatigue scales. J Pain Symptom Manage. 2002;24:547-61. 41. Stein, KD, Martin SC, Hann DM, Jacobsen PB. A multidimensional measure of fatigue for use with cancer patients. Cancer Practice. 1998;6:143-52. 42. Hann DM, Denniston MM, Baker F. Measurement of fatigue in cancer patients: further validation of the Fatigue Symptom Inventory. Qual Life

Res. 2000;9(7):847-54. 43. Sailors MH, Bodurka DC, Gning I, et al. Validating the M. D. Anderson Symptom Inventory (MDASI) for use in patients with ovarian cancer. Gynecol

Oncol. 2013;130(2):323-8. 44. Stein KD, Jacobsen PB, Blanchard CM, et al. Further validation of the multidimensional fatigue symptom inventory-short form. J Pain Symptom Manage.

2004;27(1):14-23. 45. Michopoulos I, Douzenis A, Kalkavoura C, et al. Hospital anxiety and depression scale (HADS): validation in a greek general hospital sample. Ann Gen

Psychiatry. 2008;7:4.

Sen Page 14

46. Smarr KL, Keefer AL. Measures of depression and depressive symptoms: Beck Depression Inventory-II (BDI-II), Center for Epidemiologic Studies Depression Scale (CES-D), Geriatric Depression Scale (GDS), Hospital Anxiety and Depression Scale (HADS), and Patient Health Questionnaire-9 (PHQ-9). Arthritis Care Res. 2011;63(S11):S454-66.

47. Radloff LS. The CES-D scale: A self report depression scale for research in the general population. Applied Psychological Measurements. 1977;1:385-401. 48. Busner J, Tarugm SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37. 49. Verger E, Salamero M, Conill C. Can Karnofsky performance status be transformed to the Eastern Cooperative Oncology Group scoring scale and vice versa?

Eur J Cancer. 1992;28(8-9):1328-30. 50. Ridha B, Rossor M. The mini mental state examination. Practical Neurology. 2005;5(5):298-303. 51. Huschka MM, Mandrekar SJ, Schaefer PL, Jett JR, Sloan JA. A pooled analysis of quality of life measures and adverse events data in north

central cancer treatment group lung cancer clinical trials. Cancer. 2007;109(4):787-95. 52. Norcross JC, Guadagnoli E, Prochaska JO. Factor structure of the profile of mood states (POMS): two partial replications. J Clin Psychol. 1984;40(5):1270-7. 53. Methylphenidate. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at:

http://www.micromedexsolutions.com. Accessed September 17, 2014. 54. Modafinil. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at:

http://www.micromedexsolutions.com. Accessed September 17, 2014. 55. Morrow GR, Gillies LJ, Hickok JT, et al. The positive effect of the psychostimulant modafinil on fatigue from cancer that persists after treatment is completed

(abstrac 8012). J Clin Oncol. 2005;23(suppl):732s. 56. Morrow GR, Ryan J, Kohli S, et al., Modafinil (Provigil) for persistent post-treatment fatigue: an open label study of 82 women with breast cancer (abstract 11-

070). Support Care Cancer. 2006;14:619. 57. Blackhall L, Petroni G, Shu J, Baum L, Farace E. A pilot study evaluating the safety and efficacy of modafinal for cancer-related fatigue. J Palliat

Med. 2009;12(5):433-9. 58. Spathis A, Dhillan R, Booden D, Forbes K, Vrotsou K, Fife K. Modafinil for the treatment of fatigue in lung cancer: a pilot study. Palliat Med. 2009;23(4):325-31. 59. Hovey E, de Souza P, Marx G, et al. Phase III, randomized, double-blind, placebo-controlled study of modafinil for fatigue in patients treated withdocetaxel-

based chemotherapy. Support Care Cancer. 2014;22(5):1233-42. 60. Sarhill N, Walsh D, Nelson KA, et al. Methylphenidate for fatigue in advanced cancer: A prospective open-label pilot study. Am J Hosp Palliat Care.

2001;18(3):187-92. 61. Sugawara Y, Akechi T, Shima Y, et al: Efficacy of methylphenidate for fatigue in advanced cancer patients: A preliminary study. Palliat Med. 2002;16:261-3. 62. Bruera E, Valero V, Driver L, Shen L, Willey J, Zhang T, Palmer JL. Patient-controlled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-

controlled trial. J Clin Oncol. 2006;24(13):2073-8. 63. Bruera E, Driver L, Barnes EA, et al. Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report.

J Clin Oncol. 2003;21(23):4439-43. 64. Hanna A, Sledge G, Mayer ML, et al. Phase II study of methylphenidate for the treatment of fatigue. Support Care Cancer. 2006;14(3):210-5. 65. Butler Jr. JM, Case LD, Atkins J, Frizzell B. A phase III, double-blind, placebo-controlled prospective randomized clinical trial of d-threo-methylphenidate HCl in

brain tumor patients receiving radiation therapy. Int J Radiat Oncol Biol Phys. 2007;69(5):1496-501. 66. Mar Fan HG, Clemons M, Xu W, Chemerynsky I, Breunis H, Braganza S, Tannock IF. A randomized, 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(6):577-83.

67. Johnson RL, Block I, Gold MA, Markwell S, Zupancic M. Effect of methylphenidate on fatigue in women with recurrent gynecologic cancer. Psychooncology. 2010;19(9):955-8.

68. Moraska AR, Sood A, Dakhil SR, et al. Phase III, randomized, double-blind, placebo-controlled study of long-acting methylphenidate for cancer-related fatigue: North Central Cancer Treatment Group NCCTG-N05C7 trial. J Clin Oncol. 2010;28(23):3673-9.

69. Roth AJ, Nelson C, Rosenfeld B, et al. Methylphenidate for fatigue in ambulatory men with prostate cancer. Cancer. 2010;116(21):5102-10. 70. Cueva JF, Calvo M, Anido U,et al. Methylphenidate in the management of asthenia in breast cancer patients treated with docetaxel: results of a pilot study.

Invest New Drugs. 2012;30(2):688-94. 71. Escalante CP, Meyers C, Reuben JM, et al. A randomized, double-blind, 2-period, placebo-controlled crossover trial of a sustained-release methylphenidate in

the treatment of fatigue in cancer patients. Cancer J. 2014 Jan-Feb;20(1):8-14. 72. Siu WKS, Law M, Liu RY, et al. Use of methylphenidate for the management of fatigue in Chinese patients with cancer. Am J Hosp Palliat Care. 2014;31(3):281-

6.

Sen Page 15

Appendices

Appendix A. Select Fatigue Measures Brief Fatigue Inventory (BFI)3,38

• Uni-dimensional • Evaluates fatigue over 24 hours • > 7 correlates with severe fatigue • 9 items:

• 3 items: current, usual, and worst fatigue in the past 24 hours • 6 items: extent fatigue interferes with different aspects of life (work or social) during the

preceding 24 hours Edmonton Symptom Assessment Scale (ESAS)39

• Multi-dimensional • Assesses 9 symptoms on a visual analogue scale

o Pain, fatigue, nausea, depression, anxiety, drowsiness, dyspnea, anorexia, well-being • Valid/reliable for assessing intensity of symptoms in patients with cancer

Functional Assessment of Cancer Therapy for Fatigue (FACT-F)40,41

• Multi-dimensional • General quality of life with 28 questions and an additional 13 questions on fatigue (the ‘fatigue’

subscale) • Two to three point change is the clinically significant difference reported for this scale

Functional Assessment of Chronic Illness Therapy (FACIT)40,41

• Multi-dimensional • Same as FACT but expands to other chronic illnesses (HIV, Parkinson’s, multiple sclerosis) • 27 questions in four domains (physical, social, emotional, functional) and 13-item fatigue subscale • Evaluates response in last 7 days

Fatigue Symptom Inventory (FSI)42

• Multi-dimensional • 13-item self-reported instrument that was designed to measure the intensity and duration of

fatigue and its interference with the individual's ability to participate fully in life in last 7 days • Validated measure of both overall fatigue and of how fatigue might interfere with activities of

daily living MD Anderson Symptom Inventory (MDASI)43

• Uni-dimensional • 13-item symptom common across all cancer types (pain, fatigue, nausea, disturbed sleep, being

distressed, shortness of breath, difficulty remembering, lack of appetite, feeling drowsy, dry mouth, feeling sad, vomiting, and numbness or tingling)

Multidimensional Fatigue Symptom Inventory (MFSI)41

• Multidimensional • Evaluates global, somatic, affective, cognitive and behavioral symptoms of fatigue • 83-item questionnaire • Items are rated on a 5-point scale

Multidimensional Fatigue Symptom Inventory Short Form (MFSI-SF)44

• Multidimensional • 30-item measure evaluating general fatigue, physical fatigue, emotional fatigue, mental fatigue,

and vigor • Reliable and valid scale in cancer patients

Appendix B. Other Measures Beck Depression Inventory (BDI)45,46

• Measures depression • Examine both somatic and cognitive aspects of depression • The BDI is a 21-item self-reporting scale

Beck Depression Inventory II46

• Indicates severity of depression • 21-item scale • Revision of BDI (above)

Sen Page 16

Center for Epidemiology - Depression (CES-D)47

• Measures depression in past week • 20-item measure • >16 cutoff = at risk for depression

Clinical Global Impression Scale48

• Easy to use and applicable to all psychiatric disorders • Clinical Global Impression Severity Scale (CGI-S): symptoms, behavior, and function in the past

seven days • Clinical Global Impression Improvement Scale (CGI-I): measure at baseline and then compare the

patient's overall clinical condition to the one week period just prior to the initiation of medication • No universally accepted scoring guidelines for the seven anchor points; designed to be based

solely on clinical judgment Eastern Cooperative Oncology Group (ECOG)49

• Assesses functional status in cancer correlating with patient survival • Score 0: fully active, carry all pre-disease performance without restriction • Score 5: dead

Epworth Sleepiness Scale (ESS)31

• Measures daytime sleepiness • Differentiates between average sleep issues that require intervention

High Sensitivity Cognitive Screen (HSCS)9

• Tests six cognitive domains (memory, language, visual-motor, spatial, attention/concentration, self-regulation/planning)

• Sensitive in detecting subtle cognitive impairment Hospital Anxiety and Depression Scale (HADS)45

• Detects depression and anxiety in outpatient clinic • Identifies patients requiring further psychiatric evaluation and assistance, not for diagnosis

Mini-Mental State Exam (MMSE)50

• Assesses cognitive function (screen, severity of impairment) • Scores 0-30 (30 means normal, 0 means impaired)

Quality of Life Linear Analog Scale (QOL-LAS)51

• Measures quality of life • Single-item measure comparable to multi-item global measures • Recommended in lung cancer trials

Profile of Mood States (POMS)52

• Assesses transient, fluctuating affective mood state • 65 item scale • Measures six identifiable mood/affective states: Tension-Anxiety (T), Depression-Dejection (D),

Anger-Hostility (A), Vigor-Activity (V), Fatigue-Inertia (F), and Confusion-Bewilderment (C)

Swanson, Nelson Pelham Attention Deficit/Hyperactivity Scale (SNAP)28

• Assesses inattention and hyperactivity/impulsivity in children • Modified scale may be used to assess behavioral symptoms in adults

Appendix C. Medication Review53,54

Drug Dose Excretion Half Life Adverse Effect Methylphenidate (Ritalin, Concerta)

2.5 mg/day up to 54 mg/day; administer 30-45 minutes prior to meals

Urine d-MPH: 6 hours; l-MPH: 1-3 hours

Cardiovascular events, peripheral vasculopathy, priapism, visual disturbance, hypertension, psychiatric disorder, seizures disorder, abuse potential

Dexmethylphenidate (Focalin)

2.5 mg/day up to 27 mg/day Urine 2-4.5 hours

Modafinil (Provigil) 50 mg up to 200 mg daily Urine 15 hours CNS effects, dermatologic effects, hypersensitivity disorders, headache, decreased appetite

Sen Page 17

Appendix D. Modafinil Trials and CRF Study Design Intervention/Scale Used Conclusion Morrow 200555

N=51; completed breast cancer treatment

OL study Modafinil 200 mg daily for 4 weeks

Patients with fatigue persisting two years post cancer treatment showed benefit with modafinil

Morrow 200656

N=82 women with breast cancer

OL study Modafinil 200 mg daily for 4 weeks BFI

Modafinil reduced CRF in breast cancer patients for whom fatigue persisted up to two years post chemotherapy

Blackhall 200957

N=27 OL, pilot study Modafinil 100 mg weeks 1-2, 200 mg weeks 3-4

BFI

Study showed modafinil improved BFI score by end of 4 weeks

Spathis 200958

N=20; NSCLC OL, pilot study Modafinil 100 mg for one week up to 200 mg in

second week FACIT-F

Modafinil showed decreased fatigue scores during 14 day study period

Boele 201325

N=37; glioma or meningioma Multicenter, DB, PB, crossover study

Modafinil 200 mg daily up to 400 mg daily vs placebo for 6 weeks CIS

Study did not find beneficial effects of modafinil on fatigue, depression, overall HRQOL, or cognitive functioning vs placebo

Hovey 201459

N=83; metastatic prostate/ breast cancer undergoing docetaxel chemotherapy (every 21 days; minimum dose 50 mg/m2)

Phase III, multicenter, R, DB, PB study

Modafinil 200 mg daily vs PB for 15 days MDASI

Study found trend towards improvement of docetaxel-related fatigue with modafinil. Complications included nausea and vomiting

BFI: Brief Fatigue Inventory; CIS: Checklist Individual Strength; DB: double-blind; FACT-F: Functional Assessment of Cancer Therapy for Fatigue; FACIT-F: Functional Assessment of Chronic Illness Therapy-Fatigue; LHRH: luteinizing hormone releasing hormone; NSCLC: non-small cell lung cancer; OL: open-label; PB: placebo; R: randomized

Sen Page 18

Appendix E. Methylphenidate trials and CRF Study Design Intervention/Outcome measure used Conclusion Sarhill 200160

N=9 with advanced cancer treated with methylphenidate

Prospective, OL, pilot trial

Methylphenidate 10 mg BID Methylphenidate relieves fatigue in advanced cancer with few side effects

Sugawara 200261

N=14; advanced cancer Pilot study Methylphenidate 5-10 mg daily

VAS

Improved fatigue after 7 days but without a validated fatigue instrument

Bruera 200362

N=31 Prospective, OL study

Methylphenidate 5 mg up to 20 mg daily for 7 days

Methylphenidate administration improved fatigue, appetite, anxiety, and insomnia

Bruera 200663

N=112

R, DB, PB trial

Methylphenidate 5 mg up to 20 mg daily vs placebo for 7 days FACIT-F

Both methylphenidate and placebo resulted in symptom improvement, but methylphenidate was not superior to PB; methylphenidate was not significantly superior to placebo after 1 week of treatment

Hanna 200664

N=37, with breast cancer (moderate to severe fatigue)

Phase II trial

Methylphenidate 5 mg BID for 6 weeks BFI

Women with breast cancer suffering from moderate to severe fatigue may benefit from methylphenidate

Butler 200765

N=68, primary brain tumor patients undergoing radiotherapy

Phase III, prospective, R, trial

D-methylphenidate 5 mg BID up to 15 mg daily vs placebo for 8 weeks FACT-F

High dropout rate over time and final analysis conducted on smaller sample size than original one; study did not show improvement in fatigue

Mar Fan 200866

N=57 women R, PB, DB trial

D-Methylphenidate 5 mg BID up to 10 mg BID vs PB for 12 weeks FACT-F

No benefit on fatigue or cognitive dysfunction. However, study lacked power to determine difference

Johnson 201067

N=32 women, gynecologic cancer OL trial Methylphenidate 5 mg to 10 mg BID over a 8-

week period FSI

This study supports use of methylphenidate in active treatment for recurrent gynecologic cancer

Sen Page 19

Moraska 201068

N=148 Phase III, R, DB, PB study

Methylphenidate (target dose, 54 mg/d) or placebo for 4 weeks BFI

Trial was unable to support long-acting methylphenidate in decreasing CRF. Subset showed patients with more severe fatigue and more advanced disease did have some fatigue improvement

Roth 201069

N=32 advanced prostate cancer R, DB PB study Methylphenidate 5 mg up to 30 mg vs placebo for

6 weeks BFI and FSS

Methylphenidate is effective in treating fatigue in men with prostate cancer; however, 37.5% participants had to discontinue methylphenidate because of clinically significant increase in blood pressure or tachycardia

Cueva 201270

N=10, breast cancer patients treated with docetaxel

Pilot study

Methylphenidate 10 mg BID with one cycle of docetaxel FACT-F

Pilot study concludes methylphenidate may improve fatigue and quality of life

Escalante 201471

N=42, lymphoma, myeloma, or breast, gastrointestinal, or lung cancer (no men)

R, DB, PB crossover trial

Methylphenidate 18 mg daily followed by placebo for 4 weeks OR placebo followed by methylphenidate for 4 weeks BFI

This trial included several cancer types, and a majority had advanced disease but did not show improvement in CRF

Richard 20149

N=24, prostate cancer treated with LHRH agonist (minimum of six months)

Single center, R, DB, PB trial

Methylphenidate up to 10 mg daily for 10 weeks FACT-F

Methylphenidate arm demonstrated a statistically significant improvement of fatigue

Siu 201472

N=25, palliative patients Prospective study Methylphenidate 5 mg daily for 8 days up to 10

days in 29 days as tolerated BFI

One-third of the patients complained of intolerable side effects and stopped treatment before day 8; no significant improvement seen with methylphenidate

BFI: Brief Fatigue Inventory; DB: double-blind; FACT-F: Functional Assessment of Cancer Therapy for Fatigue; FACIT-F: Functional Assessment of Chronic Illness Therapy-Fatigue; LHRH: luteinizing hormone releasing hormone; NSCLC: non-small cell lung cancer; OL: open-label; PB: placebo; R: randomized; VAS: visual analog scale

Sen Page 20