Modafinil/Armodafinil

To review the efficacy and safety of modafinil for the treatment of cancer-related fatigue (CRF).

Databases searched were MEDLINE, International Pharmaceutical Abstracts, and Google Scholar (1950–November 2008).

Search keywords were modafinil, cancer, and fatigue.

Studies were included in the review if they were written in English.

No exclusion criteria were specified.

Articles were identified using the keywords, and publications were analyzed for significance. References from the identified articles were also reviewed for pertinence.

• Four studies were reviewed in detail, comprising a total of 805 patients.
• Two studies reported patients with breast cancer, one reported patients with cerebral tumors, and one reported that the diagnoses were unknown.

• One open-label trial demonstrated the effectiveness of 200 mg of modafinil daily, given for one month, in reducing fatigue and improving patient-reported global effectiveness.  Fifty-one percent of participants reported improvement in sleep and less daytime drowsiness.
• One open-label trial in women with breast cancer reported that 90% of participants reported improvement in fatigue with 200 mg of modafinil daily for one month.
• One randomized, dose-controlled trial was conducted in patients with cerebral tumors who had neurobehavioral dysfunction and/or fatigue posttreatment. Improvements in fatigue scores were seen eight weeks after baseline. Adverse effects included headache, insomnia, dizziness, dry mouth, depressed consciousness, and nausea.  The authors concluded that modafinil was effective in improving fatigue, with a low incidence of adverse reactions.
• One phase III, randomized, placebo-controlled, double-blind trial was conducted in 642 patients with cancer who reported fatigue while receiving chemotherapy. Those receiving modafinil had a significant decrease in fatigue levels compared with patients receiving placebo.

This review discussed the strengths and weaknesses of four relevant studies. The authors concluded that the preliminary findings demonstrated the benefits of modafinil use with minimal toxicity and that modafinil can be considered a treatment option for patients with CRF. Additional long-term placebo-controlled trials are needed in this area.

• Some of the evidence reviewed in this study was taken only from abstracts.
• The literature evaluated and selected were not clearly outlined.
•  No inclusion and exclusion criteria were specified other than language.

• FINAL NUMBER STUDIES INCLUDED = 10
• TOTAL PATIENTS INCLUDED IN REVIEW = 1,582
• SAMPLE RANGE ACROSS STUDIES: 23–631 patients

Four studies examined modafinil, and six evaluated used methylphenidate. The meta-analysis showed that methylphenidate reduced fatigue significantly (SMD = –0.28, p = 0.0005) and had no impact on sleep quality. Modafinil did not demonstrate a significant reduction in fatigue. Adverse effects were reported in 6.5% of patients getting methylphenidate, and no differences in study dropouts related to side effects existed between those on methylphenidate and those receiving placebo. The analysis showed no significant difference in risk of adverse events between those receiving either drug and those on placebo.

The findings showed that methylphenidate was associated with improvement in cancer-related fatigue, with no significantly increased risk of side effects. Modafinil was not associated with any improvement.

• Relatively small number of studies

The findings suggest that methylphenidate is helpful to reduce cancer-related fatigue, with minimal adverse effects. Modafinil was not shown to be beneficial. Nurses need to be aware of the benefits and potential adverse effects when using psychotropic drugs to combat fatigue in patients with cancer.

To study effects of armodafinil on cancer-related fatigue in patients with multiple myeloma

Patients were randomly assigned to study groups in this crossover design study. One group was a treatment-only arm that got armodafinil, and the other was a placebo-first arm that received a placebo followed by armodafinil. Patients received armodafinil 150 mg once daily for 56 days in the treatment-only group. In the other group, patients received a placebo for 28 days and armodafinil on days 29–56. Assessments were done at baseline and at days 15, 28, 43, and 56. Five variations of study assessments were used to address potential memorization effects, and the order in which versions were used was varied.

• SITE: Multi-site    
• SETTING TYPE: Not specified    
• LOCATION: California

• PHASE OF CARE: Active antitumor treatment

Double-blind, randomized, crossover-controlled trial

• Brief Fatigue Inventory (BFI)
• Hospital Anxiety and Depression Scale (HADS)
• Epworth sleepiness scale
• Trail Making Test (TMT) version B
• Symbol Digits Modalities Test (SDMT)
• Digit span test
• Functional Assessment of Chronic Illness Scale–Fatigue (FACIT-F)
• Functional Assessment of Cancer Therapy–General (FACIT-G)

Adverse effects observed during armodafinil treatment were similar between groups. Fatigue as measured by the BFI scale decreased significantly for both groups over time with no difference between groups. Outcomes measured by FACIT scores increased significantly in the placebo-first group by day 28, and FACIT fatigue scores improved significantly in both groups. Anxiety decreased significantly from baseline in both groups. Depression scores only declined significantly in the placebo-first group by day 28. Degree of sleepiness decreased significantly in the placebo group. There were no significant changes in study measures between day 28 and day 56 in which all patients received armodafinil.

Armodafinil was not shown to significantly improve symptoms of fatigue, anxiety, or depression in patients with multiple myeloma.

• Small sample (< 100)
• Other limitations/explanation: 20% drop-out rate prior to day 56; more patients in the treatment-only group dropped out.

Armodafinil, a medication similar to modafinil, was not shown to be effective for the reduction of fatigue, anxiety, or depression.

The primary aim was to evaluate the safety and efficacy of modafinil in improving cancer-related fatigue (CRF) in patients with cancer.

The secondary aim was to assess the effect of modafinil on depression, quality of life (QOL), functional status, and cognitive function.

After initial assessment for all outcome measures, patients were treated with self-administered modafinil at an initial dose of 100 mg per day during weeks one to two. During weeks three to four, the dose was increased to 200 mg per day. All study parameters were reassessed at week two and at week four (completion of the trial).

• Twenty-seven patients were enrolled, and 19 completed the study.
• Average age was 60 years.
• Of the participants, 37% were male and 63% were female.
• Eastern Cooperative Oncology Group (ECOG) Performance: ECOG 1 was 37%; ECOG 2 was 44%; and ECOG 3 was 19%.

This was an open-label pilot study.

• Primary Aim: Brief Fatigue Inventory (BFI)–Fatigue
• Secondary Aim
  • Cognitive Measures
    • Hopkins Verbal Learning Test (HVLT)—assessed verbal learning and memory
    • Grooved Pegboard Test—fine motor ability and hand-eye coordination
    • Controlled Oral Word Association Test (COWAT)—verbal fluency
    • Trail Making Test (TMT) Parts A & B—visual attention, motor speed, and cognitive flexibility
  • Other Measures
    • Hospital Anxiety and Depression Scale (HADS)—depression
    • Functional Assessment of Cancer Therapy-Brain (FACT-BR)—QOL
    • Barthel Index—functional status
    • ECOG—performance status
    • National Cancer Institute (NCI) Common Toxicity Criteria (CTC), version 2.0––scored severity of detected side effects

BFI was improved at two weeks for 46% of participants, and at four weeks, 75% had a significantly improved score (p = 0.025). FACT-BR showed an improvement in all subsets of well-being except social/family at two and four weeks (p < 0.05). HADS score declined significantly at two and four weeks (p < 0.001). Cognitive function was not significantly changed, except TMT-B showed a trend for an overall improvement. Functional status (Barthel Index) did not change, but overall performance status (ECOG) improved, with 40% of patients improving at least one level. Most side effects were mild. Side effects seen were dizziness, nausea, diarrhea, and heartburn.

Modafinil use was associated with improvement in fatigue, depression, and QOL measures and was well tolerated.

• The study had a small sample size, with an almost 30% drop-out rate.
• The study was an open-label design pilot study.
• No control comparison was included.

To investigate the effects of modafinil on fatigue, depression, cognitive impairment, and health-related quality of life in patients with primary brain tumors

The intervention consisted of subjects receiving modafinil versus a placebo over six weeks. The week 1 dosage was 100 mg twice daily and the weeks 2–6 dosages were 200 mg twice daily. The cross-over occurred after the completion of week 6; thus, subjects who initially received the placebo followed the same dosing schedule over the next six weeks while those who had taken modafinil previously were given a placebo. Neuropsychological assessments and self-report measures were completed at baseline, six weeks, and 12 weeks.

• N = 37  
• AVERAGE AGE = 48.16 years (SD = 12.02 years)
• MALES: 37.8%, FEMALES: 62.8%
• KEY DISEASE CHARACTERISTICS: Gliomas and meningiomas with stable tumor status for six months
• OTHER KEY SAMPLE CHARACTERISTICS: Subjects had to score > 27 on the Checklist Individual Strength Test indicating the presence of fatigue. Exclusions include psychiatric disease or depressive disorders and medication interactions with modafinil.  

• SITE: Multi-site    
• SETTING TYPE: Outpatient    
• LOCATION: VU University Medical Center (Amsterdam), Academic Medical Center (Amsterdam), and Medical Center Haaglanden (Hague)

PHASE OF CARE: Multiple phases of care

Randomized, controlled, double-blinded clinical trial using a cross-over design. Measurements were performed at baseline, six weeks, and 12 weeks.

• Rey Auditory Verbal Learning Test (RAVLT)
• Memory Comparison Test
• Stroop Color and Word Test (Stroop)
• Letter Digit Substitution Test
• Concept Shifting Test (CST)
• Categorical Word Fluency Test
• Checklist Individual Strength (CIS)
• Center for Epidemiologic Studies Depression Scale (CES-D)
• Medical Outcomes Study Short-Form Health Survey (MOS SF-36)
• Medical Outcomes Study Subjective Cognitive Functioning Scale (MOS)

The CIS severity and reduced motivation scores for fatigue were lower after treatment with both modafinil (p = 0.01, p = 0.021) and placebo arms (p < 0.001, p = 0.027), but there was no difference in scores between trial arms. Significant improvements in working memory (p = 0.04, p = 0.043), information-processing (p = 0.036, p = 0.04), and attention (p = 0.015, p = 0.013) were found after treatment with modafinil and the placebo, respectively. There were no differences in scores between trial arms. Health-related quality of life measured by the physical component summary of the SF-36 was significantly improved for both modafinil (p = 0.001) and placebo arms (p = 0.008). There were no differences in depressive symptoms following modafinil or placebo.

The results indicate that there were no significant differences observed in fatigue, cognitive functioning, health-related quality of life, and mood between modafinil and a placebo. These findings may be related to the study design, duration of treatment, low study accrual, subject withdrawals, and lack of longitudinal follow-up.

• Small sample (< 100)
• Subject withdrawals ≥ 10%

Findings do not support the use of modafinil to improve fatigue, cognitive functioning, mood, and health-related quality of life in patients with brain tumors.

To compare the effectiveness of immediate-release and sustained-release methylphenidate versus modafinil in improving cognitive function in patients with primary brain tumors.

Patients were randomized to receive one of the following three interventions for a total of four weeks:  immediate-release methylphenidate, 10 mg twice daily; sustained-release methylphenidate, 18 mg daily; or modafinil, 200 mg daily. Neurocognitive tests were performed prior to the intervention and were repeated approximately 30 days later, after completion of the intervention.

• Twenty-four patients with primary brain tumors were included.
• Mean age was 44.98 years.
• The sample was 54% male and 46% female.
• Most (62.5%) of patients’ tumors were in the left hemisphere.
• Prior treatment history included radiation therapy (83%) and chemotherapy (87.5%). Of all the participants, 62.5% received chemotherapy during the study.

• Single site
• Outpatient
• MD Anderson Cancer Center, Houston, Texas

Patients were undergoing multiple phases of care.

The study was a randomized, clinical trial.

Objective Cognitive Function Instruments

• Wechsler Adult Intelligence Scale, third edition (WAIS-III) Digit Span and Digit Symbol subtests
• Trail Making Test (TMT) Parts A and B
• Hopkins Verbal Learning Test (HVLT) Immediate Recall, Delayed Recall, and Delayed Recognition Trials
• Multilingual Aphasia Examination Controlled Oral Word Association (MAE COWA) category
• Lafayette Instrument Grooved Pegboard Test

Subjective Anxiety Instruments

• State-Trait Anxiety Inventory (STAI) to measure state and trait anxiety  
• Profile of Mood States (POMS) to measure tension and anxiety

Subjective Depression Instruments

• Beck Depression Inventory (BDI)
• Profile of Mood States (POMS) Questionnaire, Depression-Dejection Scale

Subjective Fatigue Instruments

• Brief Fatigue Inventory (BFI)
• POMS questionnaire, Fatigue-Inertia Scale

Subjective Sleep-Wake Disturbance Instrument

• Brief Sleep Disturbance Scale (BSDS)

• Over time, no differences were found in cognitive function in regard to attention or motor function.
• Over time, mixed results were found in regard to the speed of processing:
  • The WAIS-III Digit Symbol subtest showed significant improvement (p = 0.02), but TMT Part A did not.
  • The HVLT Delayed Recognition Trial showed a signficiant decline (p = 0.03) in memory, but the other memory-related trials did not.
• In regard to the use of either stimulant and executive function over time, the TMT Part B score improved significantly (p = 0.02); however, the MAE COWA score declined significantly (p = 0.02).
• In regard to differences between the methylphenidate and modafinil treatment groups over time, researchers found the following:
  • A significant difference (p = 0.05) in attention. Attention-related scores of patients taking methylphenidate were stable on the WAIS-III Digit Span subtest; the scores of patients taking modafinil worsened over time.
  • A difference in the speed of processing as measured by TMT Part A. Patients using modafinil improved in comparison to patients taking methylphenidate, whose scores either remained stable or declined slightly (p = 0.05).
• In regard to subjective measures of other symptoms, researchers noted, with use of either stimulant over time:
  • Significant improvement (p < 0.01) of depression, as measured by the BDI and POMS Depression-Dejection Scale.
  • Significant improvement (p = 0.04) of fatigue, as measured by the BFI.
  • Significant improvement of fatigue (p < 0.01), as measured by the POMS Fatigue-Inertia Scale.
  • Significant improvement (p = 0.03) of anxiety, as measured by the state subtest of the STAI.
• No differences were found over time in regard to sleep-wake disturbances.
• No differences were found between treatment groups in subjective symptom measures over time.

Although this study revealed some improvements in specific cognitive domains over time (e.g., executive function, speed of processing), it is unclear whether these improvements were due to the use of a stimulant; a specific medication (modafinil versus methylphenidate); or other variables, such as practice effects related to the absence of alternative neuropsychological tests. Making definitive interpretations based on this small study is difficult because the findings were confounded by the use of two stimulants (one with two different dosage schedules) and the lack of a control group (patients who were not receiving stimulants).

• The study had a small sample size, with less than 30 participants.
• The study had risks of bias due to no control group and no blinding.
• Participant withdrawals were 10% or greater.
• The investigators were unable to achieve the sample size recommended by the power analysis due to poor accrual and a high drop-out rate (29%). Treatment groups differed significantly in regard to age (p = 0.02) and gender (p = 0.03). Age and gender influence neuropsychological test results.

No evidence was provided to support the use of stimulants to improve cognitive function. The study supports the conduct of future research of this topic in studies with larger sample sizes and in randomized, clinical trials with a nonintervention arm.

To assess the combined and comparative effect of cognitive behavioral therapy (CBT) and armodafinil to improve sleep and daytime functioning in survivors of cancer.

Participants were randomized to (a) CBT-I and placebo, (b) CBT-I and armodafinil 50 mg b.i.d., (c) placebo BID, or (d) armodafinil 50 mg BID. All received written sleep hygiene guidelines. Participants had CBT-I in 30–60-minute individual, in-person sessions during weeks 1, 2, and 4; and had 15–30-minute phone sessions during weeks 3, 5, and 7. Study medicine was taken for 47 days from 7 am to 9 am and 12 pm to 2 pm.

• N = 88  
• MEAN AGE = 56 years 
• MALES: 12%, FEMALES: 88%
• KEY DISEASE CHARACTERISTICS: Patients with any cancer who completed chemotherapy and/or radiation not less than one month prior and had no measurable disease
• OTHER KEY SAMPLE CHARACTERISTICS: Patients discontinued any prescribed or OTC sleep medications one week prior to the study and for the duration of the study

• SITE: Not stated/unknown    
• SETTING TYPE: Not specified  
• LOCATION: United States and Canada

• PHASE OF CARE: Transition phase after active treatment

• Four am factorial
• Randomized and blinded trials for medications but not for CBT-I

• Quantitative data of fatigue assessment using brief fatigue inventory (BFT)
• Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale

Improvement in fatigue was noted with CBT for insomnia (p = 0.002 on BFI;  p < 0.001 on FACIT-F). No improvement in fatigue was noted with placebo, on armodafinil alone, or on armodafinil with CBT-I.

CBT for insomnia appears to improve fatigue in patients with insomnia, and armodafinil was not shown to improve fatigue in patients with insomnia and fatigue.

• Small sample (less than 100)
• Study was a secondary aim of a previous trial.

This study shows that CBT for insomnia may be beneficial to patients with fatigue and that armodafinil does not improve fatigue.

To determine whether modafinil could reduce fatigue related to docetaxel chemotherapy

Patients with metastatic breast or prostate cancer receiving docetaxel chemotherapy and experiencing significant fatigue were randomized to receive modafinil or placebo for 15 days beginning with their third cycle of treatment and repeated for 2–4 subsequent chemotherapy cycles.

• N = 83  
• MEAN AGE = 66.4 years in the modafinil group and 68 years in the placebo group
• MALES: 78%, FEMALES: 22%
• KEY DISEASE CHARACTERISTICS: Primarily Caucasian; metastatic breast/prostate cancer; received at least two cycles of docetaxel; MDASI fatigue score (≥ 4/10); Hgb ≥ 10

• SITE: Multi-site  
• SETTING TYPE: Not specified  
• LOCATION: Australia

• PHASE OF CARE: Active anti-tumor treatment

• Phase II randomized, double-blind, placebo-controlled.
• Eligible patients were randomized 2:1 to modafinil or placebo and stratified according to tumor type.

• MD Anderson Symptom Inventory (MDASI)
• Secondary outcomes measures included depression, sleep disturbance, exercise, cognition, and mood states.

The goal was a 10% or greater relative difference between the two treatment groups.

The primary endpoint of reduced fatigue during docetaxel chemotherapy was not statistically different between the two treatment arms.

• Small sample (< 100)
• Key sample group differences that could influence results
• Measurement validity/reliability questionable
• Questionable protocol fidelity
• Other limitations/explanation: Study had to be repowered due to limited recruitment. Unclear how secondary measures were evaluated. Use of dexamethasone premedication.

Features a trend in docetaxel-related fatigue. Effectiveness was not established for the broader cancer-related fatigue treatment.

To examine the effect of modafinil on patient-reported fatigue in patients with cancer who were undergoing chemotherapy.

Assessments were conducted at baseline after randomization and shortly after cycle two of therapy. Modafinil or placebo was started at 100 mg on day 10 or day five of study cycle two, then increased to a full dose of 200 mg after three days. This regimen then was continued until day seven of treatment cycle four, at which time all patients discontinued medication.

• A total of 877 participants were enrolled, and 631 were analyzed.
• Mean ages for the study groups were 60 and 61 years (range 18–90), and 66% to 68% were female.
• The most common sites were gastrointestinal, breast, and lung. The sample also included genitourinary, gynecologic, hematologic, and other cancers.
• Participants were required to be beginning a cancer treatment course of at least four planned cycles of chemotherapy with at least two weeks apart, with no concurrent radiation or interferon treatment.
• Patients were excluded if they had taken modafinil or any psychostimulant within the past 30 days.
• Participants had at least a score of 2 on the Brief Fatigue Inventory (BFI) question 3 (worst level of fatigue).
• Of the patients, 57% had received prior chemotherapy, and 22% to 24% had received prior radiation therapy.
• Most (67%–70%) participants were married, and about half had some college education.

This multisite study was set in 23 geographical areas across the United States among University of Rochester Cancer Center Community Clinical Oncology Program (URCC CCOP) affiliates.

This was a randomized, placebo-controlled, double-blind trial.

• BFI, question 3
• Epworth Sleepiness Scale (ESS) to measure excessive daytime sleepiness
• Profile of Mood States depression subscale (POMS-DD)
• Missing scores at cycle four were replaced with scores from cycle three for those who completed the study and only had evaluable data through cycle three (n = 58 for modafinil; n = 29 for placebo).

ANCOVA for BFI fatigue score showed an interaction between treatment effects and baseline BFI score (p = 0.017). A significant difference existed between the study groups for those who had severe fatigue at baseline (BFI of 7 or greater), with average score in the modafinil group. No differences in fatigue were observed between the study groups for those who had mild or moderate baseline fatigue. Daytime sleepiness on ESS showed significant improvement in the modafinil group (p = 0.002). No significant differences existed in depression outcomes between the groups. In the modafinil group, 11% of patients experienced adverse events, and in the placebo group, 9% had adverse events. Only three adverse events were judged to be definitely associated with treatment with modafinil: allergic reaction, dyspnea, and headaches.

The findings supported the use of 200 mg of modafinil as an effective treatment for severe cancer-related fatigue in patients undergoing chemotherapy. Modfinil was not effective for patients with less severe fatigue.

• It is not clear what the statistical effect was of the replacement of missing cycle four data with data from cycle three. The authors analyzed multiple data replacements to test this and found no differences. This suggests that the time frames of the study measures were irrelevant.
• The study demonstrated effectiveness for the short term during active treatment with only chemotherapy; the findings may not be the same for other groups of patients or other time frames of observation.
• Diversity of the sample in terms of racial and some other demographic findings was limited.
• Although no significant differences existed between study groups that would have affected the study results, the findings may not be applicable to other patients with different demographic characteristics.

To evaluate if armodafinil versus placebo reduced fatigue and improved quality of life when measured via the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale at baseline and 42 days.

Prior to starting treatment, participants completed several questionnaires rating fatigue and quality of life. The participants were randomly assigned 1:1 to the armodafinil group or placebo group, and questionnaires were completed again at day 22, day 43, and day 56, with the primary end point being day 43, as this was the end of radiation therapy for most patients enrolled. Participants in the armodafinil group received 150 mg daily for eight weeks.

• N = 62   
• AGE RANGE =19–79 years; armodafinil group (median = 56 years), placebo group (median = 54 years)
• MALES: 55.6%, FEMALES: 44.4%
• CURRENT TREATMENT: Chemotherapy, radiation
• KEY DISEASE CHARACTERISTICS: Grade 2–4 glioma, grade 4 most common, receiving 50–60 Gy radiation therapy total
• OTHER KEY SAMPLE CHARACTERISTICS: Karnofsky score greater than 60, ability to read and write in English, no history of major mental illness. The majority of patients were receiving concomitant temozolomide.

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Dana–Farber Cancer Institute, Boston, MA

PHASE OF CARE: Active antitumor treatment

Randomized, placebo-controlled, pilot trial

• Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
• FACT-General (FACT-G)
• Brief Fatigue Inventory (BFI)
• Cancer Fatigue Scale (CFS)
• Beck Depression Inventory (BDI)

No statistically significant findings using any questionnaire were reported between the treatment arm and the placebo arm at any point measured (day 21, 42, or 26).

Based on this study, one can conclude that armodafinil is not effective in reducing fatigue or improving quality of life in this patient population. It would be helpful to know if the FACIT-F questionnaire has been used in this patient population previously with no concurrent interventions.

• Small sample (< 100)
• Risk of bias (no blinding)
• Findings not generalizable

The findings of this study indicate that more education regarding the multiple factors that can cause fatigue in this patient population is needed, as well as tools to measure this fatigue more effectively to better gauge interventions. The study stated that fatigue is reported during radiation therapy in this patient population, but the questionnaires used did not capture that.

Patients were randomized to receive a placebo or 150 mg per day dose of armodafinil. Armodafinil was taken daily during seven weeks of radiation therapy and then an additional four weeks. There were no dose modifications or drug holidays. If patients could not tolerate the study agent, it was discontinued. Fatigue, cognitive function, and quality of life were assessed at baseline, at the end of RT, and four weeks after RT. Toxicities were evaluated weekly.

• N = 54
• MEDIAN AGE = 59 years (range = 20–79 years)
• MALES: 46%, FEMALES: 54%
• KEY DISEASE CHARACTERISTICS: All patients had brain tumors and were receiving brain irradiation.

• SITE: Multi-site
• SETTING TYPE: Not specified
• LOCATION: North Carolina

PHASE OF CARE: Active antitumor treatment

Double blinded, placebo-controlled, randomized, controlled trial (n = 26 [armodafinil], n = 28 [control])

• Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) subscale
• Brief Fatigue Inventory (BFI)
• Epworth Sleepiness Scale (ESS)
• Functional Assessment of Cancer Therapy–Brain (FACT-B) scale
• Verbal fluency category test
• Hopkins Verbal Learning Test–Revised (HVLT-R)
• Trail Making Test (TMT) parts A and B
• Backwards Digit Span Test

Nine patients dropped out of the study by the end of RT. The most common adverse effects were headache, insomnia, nausea, anxiety, arthralgia, dizziness, dry mouth, sinusitis, and throat and respiratory infections. There were no significant differences in adverse events between the study groups. There were no significant differences between groups in fatigue. In both groups, fatigue increased during treatment and improved following the completion of RT. Neurocognitive measures improved slightly over time in both groups with no significant difference between the groups. Among patients with the most fatigue at baseline, those taking armodafinil showed improvements in fatigue at the end of RT. Armodafinil also did not improve neurocognitive outcomes at the end of RT or at four weeks post RT in the subsets of participants with high or low levels of fatigue at baseline.

Armodafinil was not shown to improve fatigue or cognitive function measures in patients receiving brain irradiation. Armodafinil appeared to show some benefit in improving fatigue among those with high levels of fatigue at baseline.

• Small sample (< 100)
• Findings not generalizable
• Subject withdrawals ≥ 10%  
• Other limitations/explanation: The size of the final sample was underpowered. No intent to treat analysis was described. The sample was limited to patients receiving brain irradiation.

The findings did not provide overall support for effectiveness of armodafinil to reduce fatigue in this study although patients with the highest level of fatigue at baseline appeared to have some benefit. Additional research is warranted to determine if there is any benefit of psychostimulants for fatigue and cognitive impairment in patients with brain tumors undergoing radiation therapy.

To determine the feasibility of conducting a randomized, controlled trial to assess the efficacy and safety of modafinil for the treatment of fatigue in patients with lung cancer.

Patients with non-small cell lung cancer (NSCLC) took modafinil in a fixed dose-titration schedule (100 mg daily on day 1 and increasing in the second week to 200 mg daily) for 14 days.

• Twenty patients (6 females, 14 males) were included.
• Median age was 74 years. 
• All patients had NSCLC.

• Multisite
• Inpatient
• United Kingdom

This was an intervention feasibility study.

• Chalder Fatigue Questionnaire (CFQ)
• Epworth Sleepiness Scale (ESS)
• Hospital Anxiety and Depression Scale (HADS)
• Functional Assessment of Cancer Therapy-Fatigue (FACT-F)

• There was a change in fatigue between days 0 and 14.
• Mean fatigue decreased from 6.9 to 3.7.
• There were statistically and clinically significant improvements in fatigue scores from days 0 to 7.
• There was no statistically significant change from days 7 to 14.

It is feasible to conduct randomized, controlled trials.

The study had a small sample size, with less than 30 patients.

• This was an inexpensive pharmacologic intervention for cancer-related fatigue.
• Randomized, controlled trials are needed to confirm the benefit.
• The intervention was well tolerated in patients with advanced cancer.
• Poststudy, 10 patients chose to continue taking modafinil.

To establish the safety and efficacy of modafinil for the treatment of fatigue in patients with non-small cell lung cancer

Patients were randomized to take either oral modafinil 100 mg or a matched placebo capsule. Patients took the medication on a fixed-dose titration schedule of one capsule daily for 14 days and then two capsules daily for the next 14 days. Assessments were done at baseline and on days 14 and 28.

• N = 160
• MEAN AGE = 68.9 years
• MALES: 50%, FEMALES: 50%
• KEY DISEASE CHARACTERISTICS: All patients had non-small cell lung cancer.

• SITE: Multi-site  
• SETTING TYPE: Outpatient  
• LOCATION: United Kingdom

Double-blinded, placebo-controlled, randomized, controlled trial

• Functional Assessment of Chronic Illness Treatment–Fatigue (FACIT-F) scale for fatigue
• Epworth Sleepiness Scale (ESS)
• Hospital Anxiety and Depression Scale (HADS)

Fatigue declined in all patients with no significant differences between groups. Modafinil appeared to be well-tolerated with no difference between groups in adverse events; however, more patients in the modafinil group withdrew from the study (p = .02). 42% of those receiving modafinil and 23% of those on the placebo reported that the treatment was not helpful.

Modafinil was not shown to be effective in reducing fatigue in this study.

• Subject withdrawals ≥ 10% 
• Other limitations/explanation: It is not clear what phase of care patients were in and whether receiving active treatment.  

The findings of this study do not show the efficacy of modafinil in the treatment of cancer-related fatigue. Nurses should be aware that there is insufficient evidence to support effectiveness of modafinil for fatigue and should advocate for the use of interventions that have demonstrated effectiveness.