Modafinil/Armodafinil

• FINAL NUMBER STUDIES INCLUDED = 6
• TOTAL PATIENTS INCLUDED IN REVIEW = 550 (prevention intervention); 169 (amelioration intervention)
• KEY SAMPLE CHARACTERISTICS: In both intervention groups, adults aged ≥ 18 years, received radiotherapy for the treatment of brain metastasis, primary or secondary brain tumors, or prophylaxis for other cancer. For amelioration, intervention group documented cognitive impairment in at least one cognitive domain at baseline. At least 80% of the sample had to receive radiotherapy, and radiotherapy may have been provided during childhood, but the cognitive intervention performed in adulthood.

PHASE OF CARE: Multiple phases of care

Three cognitive interventions aimed at preventing cognitive decline during radiation therapy were reported. Two were pharmacologic. One tested memantine versus a placebo and found significant improvement in overall cognitive function, and one tested methylphenidate versus a placebo but failed to detect any significant differences between groups. The third study was nonpharmacologic and investigated the use of a rehabilitation program to prevent cognitive decline but did not statistically compare differences between groups. Three cognitive interventions aimed at ameliorating cognitive decline were reported. All three were pharmacologic studies. Two studies compared methylphenidate versus modafinil and one study examined donepezil versus a placebo. Both methylphenidate and modafinil interventions resulted in improved cognitive function. Combination therapy resulted in greater adverse events. Donepezil was found to improve the domain of memory after radiotherapy.

The authors reported that there was evidence for the use of memantine for preventing cognitive decline in patients receiving radiotherapy for brain metastasis. Likewise, there was supporting evidence for the use of donepezil in improving memory after radiotherapy for primary or metastatic brain tumors. There was limited evidence for cognitive behavioral or training interventions in preventing cognitive decline.

• Small sample sizes of less than 30 subjects
• High risk of bias, particularly for nonpharmacologic interventions
• Large number of patient withdrawals

Patients who receive cranial radiation therapy for primary brain tumors or metastatic lesions are at risk for declining cognitive function. The use of memantine during radiation therapy may aid in preventing cognitive decline. Those who develop cognitive decline after the completion of radiation therapy, even years afterwards, may benefit from donepezil administration. Additional exploration of interventions that may prevent or ameliorate cognitive decline related to cranial radiation therapy is warranted.

The study's primary aim was to evaluate the safety and efficacy of modafinil in improving cancer-related fatigue. Its secondary aim was to determine the effect of modafinil on depression, quality of life, functional status, and cognitive function.

Participants were given 100 mg of modafinil daily for weeks 1 and 2, and then 200 mg daily for weeks 3 and 4. Participants older than 80 were dose-reduced and received 50 mg of modafinil daily for weeks 1 and 2, then 100 mg daily for weeks 3 and 4. There was no control group.

Testing was completed at baseline, week 2, and at the completion of the trial. 

• The total number of participants was 27, with 19 completing the study.
• The average participant age was 60 years.
• 63% of participants were female and 37% were male.
• 37% of participants had an Eastern Cooperative Oncology Group (ECOG) score of 1, 44% had a score of 2, and 19% had a score of 3. 

This was a prospective, open-label pilot study.

• The Hopkins Verbal Learning Test (HVLT) assessed verbal learning and memory.
• The Grooved Pegboard Test assessed fine motor ability and hand-eye coordination.
• The Controlled Oral Word Association Test (COWAT) assessed verbal fluency.
• The Trailmaking Test, Parts A and B (TMT-A & B) assessed visual attention, motor speed, and cognitive flexibility.
• The Brief Fatigue Inventory (BFI) assessed fatigue.
• The Hospital Anxiety and Depression Scale (HADS) assessed depression.
• The Functional Assessment of Cancer Therapy-Brain (FACT-BR) assessed cancer-related quality of life for patients with brain tumors
• The Barthel Index assessed functional status.
• The Eastern Cooperative Oncology Group (ECOG) performance status measured general well-being; scores range from 0 (indicating perfect health with no restriction of activities) to 5 (indicating death). 
• The National Cancer Institute Common Toxicity Criteria (CTC), Version 2.0 scored the severity of detected side effects.

Fatigue (as measured by the BFI) was improved at week 2 for 46% of participants; at week 4, 75% had a significantly improved score (p = 0.025). Functioning (as measured by the FACT-BR) showed an improvement in all subsets of well-being at weeks 2 and 4 (p < 0.05) except social/family. Depression (as measured by the HADS) declined significantly at weeks 2 and 4 (p < 0.001). 

Functional status (as measured by the Barthel Index) did not change, but overall ECOG performance status improved, with 40% of patients improving at least one level. Cognitive function was not significantly changed, although the TMT-B did show a trend of overall improvement. 

Modafinil did not significantly improve learning and memory, fine motor ability, verbal fluency, or executive function, but results are limited due to the small sample size.

• This was a pilot study addressing fatigue, with cognitive function measured as a secondary outcome.
• The study had a small number of participants, with a drop-out ratio of 30%.
• The study had an open-label design.
• There was no control group. 
• Results for improvement on the TMT-B may be due to Type I error, given the multiple tests (multiple comparisons) examined in this trial.
• The study had limited cognitive assessment.
• The issue of practice effects was not addressed in a repeated measures study.

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.

The study's primary aim was to examine the effect of modafinil on persistent fatigue after treatment. Its secondary aim was to examine the effect of modafinil on cognitive function of patients with breast cancer.

In phase 1, participants were given 200 mg of modafinil daily for four weeks. Participants with a positive response in phase 1 were randomized to phase 2. In phase 2, participants continued to receive 200 mg of modafinil orally once per day or a placebo for four weeks. Repeated measures were completed at baseline (week 0), week 4, and week 8. Participants were stratified by treatment type: chemotherapy, radiation, or both chemotherapy and radiation. 

• The total number of participants was 82, with 76 completing phase 1 and 68 completing phases 1 and 2.
• The median participant age was 54, with a range of 33–83.
• All participants were female.
• All participants had breast cancer and were being treated with surgery and chemotherapy; 87% also received radiation.
• 75% of participants had at least some college education.

The study took place at the University of Rochester Medical Oncology Clinic in New York. 

The study was a prospective, open-label clinical trial.

• The Cognitive Drug Research (CDR) assesses domains of attention and memory, including speed of memory, continuity of attention, quality of episodic and working memory, and power of attention.
• The Brief Fatigue Inventory (BFI) assess fatigue.

Approximately 70% of the participants in the active treatment group had an improvement in continuity of attention from baseline to after treatment (week 8), compared with 52% in the placebo group; however, this difference was not statistically significant (p = 0.19).

In phase 1, modafinil had a significant effect on speed of memory (p = 0.0073) and quality of episodic memory (p = 0.0001). No significant effect in continuity of attention, quality of working memory, or power of attention was observed during this phase.

In phase 2, those who continued modafinil demonstrated significantly greater improvement in cumulative speed of memory (p = 0.029), quality of episodic memory (p = 0.0151), and continuity of attention (p = 0.0101).

Modafinil significantly improved some cognitive functioning, including speed of memory and episodic memory, but failed to demonstrate improvement in working memory.

• Findings were a secondary analysis; cognitive functioning was not the study's primary outcome.
• The study was an open-label trial, and thus participants were not blinded to their assignment.
• The study had a relatively small sample size.
• The majority of participants were an educated group of Caucasian women, limiting generalizability.
• The study did not report if differences existed between the original enrolled sample (n = 82) and those who completed the entire study (n = 68).
• Although not statistically significant, the participants assigned to the modafinil group had a mean age which was five years younger than the placebo group.
• Although the Cognitive Drug Research has been used reliably in other populations, it does not indicate if it has been used in cancer populations.

The study's primary aim was to assess the effectiveness of single-dose modafinil on cognitive function in patients with advanced cancer treated in palliative care settings. Its secondary aim was to assess the effectiveness of modafinil on other symptoms.

On day 1, patients were randomly assigned to receive either 200 mg of modafinil or an oral placebo. On day 4, each patient group was given the alternative treatment that was not dispensed on day 1.

• The number of participants was 28.
• The median participant age was 62, with a range of 40–79.
• 57% of the participants were male and 43% were female.
• All participants had advanced cancer, with a variety of hematologic and solid tumors.
• All participants had a tiredness score fo 50 mm on the Edmonton System Assessment Scale and a score range of 40–70 on the Karnofsky Performance Status Scale. 

The study took place in the palliative care department of Herning Hospital in Denmark.

The study was a double-blind, randomized, cross-over, single-dose trial.

• The Finger Tapping Test (FTT) is well-validated test of psychomotor speed that is used for detecting lateral cerebral lesions and unspecific psychomotor impairment.
• The Trail Making Test, Part B (TMT-B) is a test of visual information processing used to assess visual search skills, scanning, speed of processing, mental flexibility, attention, and psychomotor speed. 
• The Edmonton System Assessment Scale assesses nine symptoms common in patients with cancer: pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath.
• The Karnofsky Performance Status Scale measures general well-being. Scores range from 0 (death) to 100 (perfect health with no complaints or signs of disease).

Patients on the modafinil treatment group saw statistically significant improvements in psychomotor speed with the dominant hand (as measured by the FTT) and speed of processing (as measured by the TMT-B), as compared with the placebo group (p = 0.006). The modafinil treatment group also showed statistically significant improvements in depression and drowsiness as compared with the placebo group (p = 0.042).

The frequency and intensity of side effects were similar on both treatments, and no statistically significant differences were reported. However, four patients experienced disrupted sleep and vivid dreams after modafinil treatment.

Modafinil improved attention and psychomotor speed and diminished depression and drowsiness.

• The number of participants was small, but was in congruence with priori power analyses.
• The study design had limited administration of the medication (only one single dose) and follow-up; therefore, no conclusions can be made about long-term usage of modafinil.
• The authors reported that patients were allowed to use supplemental doses of short-acting opioids for breakthrough pain throughout the study, except before testing on study days. The holding of as-needed opioids is an ethical concern for patient comfort. Although opioid use was controlled, patients may have been in pain, which would confound cognitive results.
• No information regarding pain prior to cognitive testing was noted.
• The authors did not address practice effects with repeated administration of the TMT-B.

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.

A uniform NCCN consensus determined that recommendations were appropriate (NCCN Category of Evidence and Consensus = 2A).

Some interventions that may be useful to improve or maintain cognitive function might not be included in these guidelines because this manuscript did not detail search strategies, inclusions and exclusions, or the number of articles included in the recommendations.

The NCCN cognitive function algorithm aids healthcare professionals considering the assessment and treatment of cancer-related cognitive function. Nonpharmacologic interventions should be recommended to oncology survivors experiencing cognitive issues. Pharmacologic interventions may be considered when medical conditions permit and potential contributing factors are ruled out or managed.