Methylphenidate

• 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.

To assess the safety and efficacy of methylphenidate for cancer-related fatigue. Secondary outcomes included depression, cognition, and adverse effects.

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: PubMed. EMBASE, PsycINFO, Cochrane Collaboration

KEYWORDS: Methylphenidate, dimethylphenidate, Ritalin, cancer, fatigue, asthenia, tiredness, and randomized controlled trial

INCLUSION CRITERIA:  Randomized controlled trials, adults older than 18 years, the trial examined efficacy of methylphenidate on fatigue, and results were sufficient to calculate effect sizes

EXCLUSION CRITERIA: None specified

TOTAL REFERENCES RETRIEVED: N = 374

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: The Jadad scale was used for quality assessment.

• N (studies) = 5
• SAMPLE RANGE ACROSS STUDIES: 10–62
• TOTAL PATIENTS INCLUDED IN REVIEW: 198
• KEY SAMPLE CHARACTERISTICS: Three studies included mixed tumor types, one was in prostate, and one was in patients with primary brain tumor.

PHASE OF CARE: Multiple phases of care

Meta-analysis was done with studies grouped according to the measure of fatigue that was used. In studies using the FACT-F (three studies), results showed a favorable effect of methylphenidate with a mean difference of -3.13 and a signficant overall effect (p -0.01). In studies using the BFI, results showed a favorable effect with mean difference of -0.69, but the Z test of overall effect was not significant. Methylphenidate had no effect on depression (two studies) or cognitive impairment (two studies). Studies varied widely in terms of the duration of treatment. Treatment for greater than four weeks was superior compared to placebo. However, treatment for less than four weeks did not show a significant effect compared to placebo. Rates of adverse effects between those getting methylphenidate and those getting a placebo were not significantly different. Those receiving methylphenidate had significantly more vertigo, anxiety, and nausea.

Results suggest that treatment with methylphenidate for at least four weeks is effective in reducing cancer-related fatigue and is not associated with a high rate of adverse effects. Treatment with methylphenidate did not improve depression or cognitive impairment. Use of different methods of measurement of fatigue showed different results.

Few studies were included, and some of these had very small sample sizes. Included studies did not provide sufficient information on relevant concomitant conditions of patients, such as sleep disorders and anxiety. Dosages and dosage increase approaches with methylphenidate varied.

Findings suggest that treatment with methylphenidate for at least four weeks can be helpful in managing cancer-related fatigue. However, the most appropriate dosages are not clear. Patients can experience side effects, and if methylphenidate is used, nurses need to monitor patients for side effects. Further large studies are needed to strengthen evidence related to effects and side effects of methylphenidate.

• FINAL NUMBER STUDIES INCLUDED = 12
• TOTAL PATIENTS INCLUDED IN REVIEW = 442
• SAMPLE RANGE ACROSS STUDIES = 12–107 patients
• KEY SAMPLE CHARACTERISTICS: Although education status may influence neuropsychological test results, only half of the studies provided this information. Likewise, menopausal status may affect cognition, and this was only reported by two thirds of the studies.

PHASE OF CARE: Late effects and survivorship

Studies of pharmacologic interventions were not found to be effective in improving cognitive function. Medications reviewed included d-methylphenidate (n = 1), epoetin alfa (n = 2), and ginkgo biloba (n = 1). Evidence for nonpharmacologic interventions was mixed. No improvements in cognitive function were found with Tibetan sound meditation (n = 1). Natural restorative therapy (n = 1) improved attention only when comparing the baseline with the final 90-day evaluation (p = 0.01). Exercise (n = 1) improved attention (p = 0.019) and verbal memory (p = 0.048) but not working memory. Cognitive rehabilitation (n = 1) improved four out of six measures of information processing speed (p < 0.05) but not attention, verbal memory, or executive function. Cognitive behavioral training (n = 2) improved verbal memory (p < 0.05) in both studies and was effective in improving in information processing speed when compared to baseline scores in one study (p ≤ 0.01) but not the other. Computerized cognitive training was effective in one study in improving processing speed (p = 0.009), executive function (p = 0.008), and a measure of executive function and language (p = 0.003) but not verbal memory. However, in another study, there was no difference in verbal memory or information processing speed between the intervention and control groups.

Nonpharmacologic interventions, especially cognitive training, may have a role for improving attention, information processing speed, and verbal memory. Exercise and computerized cognitive training may be effective for improving executive function. However, additional research validating these findings with larger sample sizes and evaluating other cognitive domains is needed. In addition, studies determining the dose or duration of interventions is required for a durable response.

• A small number of studies (n = 12) were included in the review for multiple types of interventions.
• Only one study had a sample size greater than 100 (range = 12–107).
• Studies of low quality were included. 

These findings suggest that nonpharmacologic, not pharmacologic, interventions may be helpful in managing chemotherapy-induced cognitive impairment in patients with breast cancer. However, these findings were based on a small number of studies per intervention. Additional research validating which interventions might be useful in improving cognitive impairments in women receiving chemotherapy for breast cancer is needed. 

To provide a systematic review examining the management of opioid-induced central side effects including sedation, cognitive failure, sleep disturbance and myoclonus

• The literature reviewed included research, case reports, and retrospective chart reviews in an effort to establish evidence levels for practice guidelines and make recommendations for future research and practice. 
• This review is part of a larger review to produce guidelines on the use of opioids in adult patients with cancer pain.

Databases: Medline, EMBASE, Cochrane Library

Keywords: Narcotic, opioid analgesics, opioid, neoplasms, myoclonus, sleep initiation and maintenance disorders, hallucination, sleep disorder, fatigue, delirium, hyperalgesia, sedation, confusion, opioid-induced hyperalgesia, analgesics

Inclusion criteria: Studies were included that were conducted with human, adult patients with chronic cancer pain, contained data on the efficacy of a treatment for an opioid central nervous system adverse effect (e.g., sedation, cognitive impairment, myoclonus, hyperalgaesia, insomnia), and were published in the English language.

Exclusion criteria: Studies were excluded if they were comparing the efficacy or side effects of different opioids, the efficacy or side effects of adjuvant analgaesics, different doses of opioids, or different routes of administration of opioids.
 

A total of 318 manuscripts were screened. Inclusion and exclusion criteria were screened from titles and abstracts; duplication studies were eliminated. No scoring criteria for evidence recommendations were presented, but levels of evidence were presented for each central side effect.

Cognitive failure was evaluated by sedation and psychomotor speed; those studies consisted of two randomized controlled trials, one retrospective chart review, and four case reports. Four studies were focused on the central side effect of delirium, and two randomized controlled trials were focused on psychomotor aspects of cognitive function. Five side effects of opioid therapy were identified: sedation, cognitive impairment, myoclonus, sleep disturbance, and hyperalgesia.

Forty studies were potentially eligible, with a final 26 meeting all inclusion criteria. The final sample of studies included 86 subjects, ranging from case reports of one subject (n = 2), a case report of six subjects (n = 1), a retrospective chart review of 40 subjects (n = 1), and randomized controlled trials of 12–20 subjects (n = 2).

The adult subjects in the studies had varying cancers and were receiving opioid administration for chronic pain in palliative care inpatient and outpatient settings. Ages, education, occupational attainment, and socioeconomic data were not provided across the studies.

This systematic review is applicable in palliative care.

In two similar randomized controlled trials using the same psychomotor test battery, methylphenidate improved verbal and visual memory, arithmetic, and tapping speed as compared to placebo for subjects receiving morphine, whereas IV infusion only improved tapping speed. Delirium was improved by donepezil in 7 of 9 patients as measured by the Clinical Global Impression of Improvement Scale on retrospective chart review, whereas improvements were observed in only 2 of 6 patients with delirium receiving donepezil in a case report series. Atypical antipsycholtics and neuroleptics have also been used to improve delirium that is resistant to donepezil, according to three additional case reports: physostigmine (N = 1), olanzapine (N = 1), and quetiapine (N = 6).                                                                     

Seven studies were identified as related to cognitive impairment: two were randomized controlled, and five were case reports or case series.Three of the case reports combined totaled 12 patients. Two more studies were related to delirium.

The authors weakly recommended the use of methylphenidate for the symptom management of opioid-induced cognitive failure. Other agents lack evidence to make a recommendation.

Further study is warranted with incorporation of cognitive test batteries for multiple cognitive domains.

Limitations include small sample size, use of varying medications as the intervention, outcome focus on delirium as cognitive impairment, and use of case reports and retrospective chart reviews.

This study was conducted to assess the effects of methylphenidate (MPH) on neuropsychological functions for patients with cancer on continuous subcutaneous (SQ) infusion of narcotics for pain.

Participants were assessed immediately before and two hours after dose for two days.

• The total number of participants was 20. Nineteen were used in data analyses.
• The average participant age was 55 ± 12 years
• 60% of participants were male and 40% were female. 
• Participants had varied solid tumors, including lung, gastrointestinal, breast, prostate, and ovarian cancer.
• Participants were required to have received narcotics for at least five days before admittance to the study.
• No rescue doses were given to participants during the time frame of 7–10 am.

The study took place at Edmonton General Hospital in Alberta, Canada.

The study was a randomized, double-blind, placebo-controlled, crossover trial.

• Finger Tapping Test for motor function
• 20-item arithmetic test (5 questions each on addition, subtraction, multiplication, and division)
• Reverse Memory of Digits—attention Visual memory (VM) for attention and visual memory
• Subjective interview in which patients described which treatment helped more with confusion and sleepiness
• Edmonton Staging System for Cancer Pain (Stage I, II, III) Visual Analogue Scale for pain, nausea, drowsiness, confusion, depression, and activity

Significant improvement was noted in drowsiness, confusion, tapping speed, arithmetic skills, reverse digits, and visual memory (p < 0.001). Patients and investigators blindly chose MPH as more effective over the placebo in 13 of 14 cases.

In patients with cancer who had significant pain, immediate improvements in alertness, attention, and memory were noted. 

• The study had a small sample size.
• There was no control group as a comparison.
• No temporal level was provided of how long the MPH treatment would be beneficial.
• The study displayed limited cognitive assessment and lack of follow-up.
• The study was limited to patients on stable narcotic infusion.

This study was conducted to assess the effect of prophylactic d-methylphenidate HCl (d-MPH), a central nervous system stimulant, on quality of life and cognitive function in patients with brain tumors undergoing radiation therapy.

The treatment group received a starting dose of 5 mg twice daily of d-MPH; this was escalated to a maximum of 15 mg twice daily. Patients were stratified by tumor type (primary versus metastatic), treatment (radiation therapy alone versus radiation therapy plus chemotherapy), and Karnofsky Performance Status (< 90 versus 90), and were randomized within strata to one of the two treatment arms.

• The total number of participants was 68. 
• There were 34 participants in the treatment group and 34 in the placebo group.  
• The median age of the treatment group was 52, with a range of 31–79.
• The median age of the placebo group was 60, with a range of 28–83. 
• 54.4% of participants were male and 45.6% were female, distributed across each group.
• 48.5% of participants had primary brain cancer and 51.5% had metastatic brain cancer.

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

• Mini-Mental State Examination (MMSE) for global cognitive functioning
• Functional Assessment of Cancer Therapy (FACT)-Brain for cancer-related quality of life specific to patients with brain tumors
• Functional Assessment of Cancer Therapy-F for cancer-related quality of life pertaining to symptom of fatigue
• Center for Epidemiologic Studies-Depression Scale (CES-D) for depressive symptoms

There was no difference in cognitive functioning at baseline, end of radiation therapy, or at 4, 8, and 12 weeks after brain radiation therapy. No difference in fatigue or quality of life was observed. 

Prophylactic use of d-MPH in patients with brain tumors undergoing radiation therapy did not result in an improvement in cognitive functioning, quality of life, or fatigue.

• The study's primary outcome was fatigue.
• The study had limited measurement of cognitive function; the MMSE is a global indicator.
• There was a small sample size and a high dropout rate. Only 47% of participants completed the eight-week assessment.
• The study was stopped prematurely because of slow accrual and stoppage of funding by the sponsoring drug company.
• Four patients (6%) experienced side effects; two experienced nausea and vomiting, one experienced tachycardia on the placebo arm, and one went off the study due to an increase in liver enzymes.

To assess effectiveness of methylphenidate versus placebo to reduce cancer-related fatigue and to analyze cytokine levels and symptoms of cognitive function

Patients were randomized to receive either methylphenidate 18 mg per day for two weeks followed by placebo for two weeks, or to receive placebo for the first two weeks followed by methylphenidate for three weeks. All completed a battery of tests at baseline and were asked to record fatigue level and interference with activities in a daily diary. Additional fatigue measurement occurred at week 1 and week 3. Bloodwork for cytokine levels was obtained at baseline, crossover, and the end of the study.

• N = 33
• MEAN AGE = 57 years (range 32–79 years)
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: All had breast cancer; 74% had metastatic disease; 84% were currently on chemotherapy.
• OTHER KEY SAMPLE CHARACTERISTICS: 74% were white; 68% had more than high school education; 52% were working full-time or part-time.

• SITE: Single site
• SETTING TYPE: Outpatient    
• LOCATION: MD Anderson Cancer Center, Texas

PHASE OF CARE: Multiple phases of care

Double-blind, placebo-controlled crossover RCT

• Wechsler Adult Intelligence Scale (WAIS)
• Digit Span and Digit Symbol Tests
• Hopkins Verbal Learning Test
• Controlled Oral Word Association
• Trial Making Test Parts A and B
• Grooved Pegboard Test
• Brief Fatigue Inventory (BFI)
• Beck Depression Inventory II
• Brief Sleep Disturbance Scale
• Profile of Mood States (POMS)
• MD Anderson Symptom Inventory
• Work Productivity and Impairment Questionnaire (WPAI)
• Multiple inflammatory cytokine levels

There were no significant differences between treatment arms for fatigue by BFI scores or diaries. There was no carryover effect of methylphenidate, so data were pooled for analysis. There were no differences in symptom inventory results. The WAIS-III digit span test demonstrated improved cognitive processing speed in the treatment versus placebo condition (p = .01), and the subscale of confusion on POMS was lower with methylphenidate (p = .05). There was a significant correlation between BFI interference and activity level and the Hopkins Verbal Learning Test showing declining memory with higher levels of fatigue (p < .05).  Patients receiving methylphenidate missed fewer hours of work due to health (p = .03). There were no significant differences in or correlations with cytokine levels. There were no serious adverse events with methylphenidate.

This study did not show improvement in fatigue with methylphenidate. Findings suggest that some aspects of cognitive function are related to fatigue level.

• Small sample (< 100)
• Other limitations/explanation: The study was underpowered.

Findings do not show that methylphenidate improved fatigue symptoms, but it may have had some effect on missing work and some aspects of cognitive function. Further exploration of associations between fatigue and cognitive impairment associated with chemotherapy is warranted.

The study was conducted to investigate the clinical improvement observed in patients with advanced cancer and hypoactive delirium after the administration of methylphenidate hydrochloride (MPH).

First, a 10 mg test dose of MPH was given orally to all participants. If there were no distressing side effects, participants were given 10 mg of MPH twice daily at 8 am and 12 pm. Follow-up was daily for hospital inpatients and every three to four days for patients in the community. Doses of MPH were increased in 5 mg increments to reach the maximum tolerable dose for the patient’s satisfaction and the resolution of delirium.

Measurements were taken before delirium and delusions (T0), at baseline prior to the MPH treatment (T1), one hour after after the MPH dose (T2), and when a stable dose was achieved (T3). 

The Mini-Mental State Examination was used as an assessment tool on a daily basis for inpatients and every three to four days for outpatients.

• All participants had a diagnosis of advanced metastatic cancer. Participants had lung, colon, breast, prostate, cervical, or testicular cancer. 
• The total number of participants was 14.
• Participants were between the ages of 41–80 years.
• 64% of participants were male and 36% were female.

The study utilized a case series design for patients with advanced cancer and hypoactive delirium.

• The Mini-Mental State Examination (MMSE) measured global cognitive function.
• No specific information was provided on the instruments used to assess psychomotor retardation, sleep and drowsiness, absence of delusions, or absence of delirium.

All participants had a positive response to MPH that included increased alertness, partial-to-complete resolution of psychomotor retardation, normalization of slurred speech, and a marked increase in energy levels.

All 14 participants showed improvement in their cognitive function as documented by the MMSE. In 13 patients, the median MMSE score improved to 28 (mean = 27.8, standard deviation = 2.4, p = 0.02) compared with the median score one hour after the first dose of MPH. One patient died before reaching a stable dose of MPH.

The pretreatment MMSE median score was 21 (mean = 20.9, standard deviation = 4.9), which improved to a median of 27 (mean = 24.9, standard deviation = 4.7) after the first dose of MPH (p < 0.001).

MPH improved alertness and general cognitive function in a small sample of patients with advanced cancer. However, due to confounding issues with disease and treatment responses, more research is warranted to determine its effectiveness.

• The study had a small sample size.
• The study was limited to patients with advanced cancer.
• All participants received MPH, so there was no control group.
• The study had a limited measurement of cognitive function, as the MMSE is a global indicator with known practice effects.
• The study did not explain its assessment of psychomotor functioning or its determination of sleep and drowsiness.
• There were confounding issues with brain metastases in 29% of participants.
• There were confounding issues with pain medications in 57% of patients.
• There was no discussion regarding the clinical significance of the changes in MMSE scores.

To compare the effectiveness of immediate-release or 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 a day
• Sustained-release methylphenidate 18 mg daily
• Modafinil 200 mg daily

Neurocognitive tests were done prior to the initiation of the intervention and repeated approximately 30 days later after completion of the intervention.

• A total of 24 patients participated in the study.
• Participants' average age was 44.98 years.
• The sample was 54% male and 46% female.
• 62.5% of patients’ tumors were in the left hemisphere.
• Prior treatment history included radiation therapy (83%) and chemotherapy (87.5%). A total of 62.5% were receiving chemotherapy during the study.
   

• Single site 
• Outpatient 
• University of Texas M.D. Anderson Cancer Center in Houston

Patients were in mutliple phases of care.

The study was conducted as a randomized clinical trial.

Objective Cognitive Function Instruments

• Wechsler Adult Intelligence Scale III (WAISIII)—digit span and digit symbol
• Trail Making Test—parts A and B
• Hopkins Verbal Learning Test (HVLT)—immediate recall, delayed recall, and delayed recognition
• Multilingual Aphasia Examination (MAE)—controlled oral word association (COWA)
• Lafayette Grooved Pegboard

Subjective Anxiety Instruments

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

Subjective Depression Instruments

• Beck Depression Inventory (BDI)
• Profile of Mood States (POMS)—depression-dejection

Subjective Fatigue Instruments

• Brief Fatigue Inventory (BFI)
• Profile of Mood States (POMS)—fatigue

Subjective Sleep-Wake Disturbance Instrument

• Brief Sleep Disturbance Scale (BSDS)

In regards to cognitive function, no differences were found over time with either stimulant in attention or motor function. Mixed results were found over time with stimulant use in speed of processing: significant improvement was found with the WAISIII digit symbol test (p = 0.02), but not with TMT-A. Similarly, a significant decline was found in memory as measured by the delayed recognition subtest of the HVLT (p = 0.03), but not with other subtests of that measure. When evaluating any stimulant use over time in regard to executive function, a significant improvement was found as measured by the TMT-B (p = 0.02) but a significant decline was found as measured by the COWA (p = 0.02). When evaluating differences between the methylphenidate and modafinil treatment groups over time, a significant difference was found in attention (p = 0.05): patients on methylphenidate had stable scores as measured by the digit span test and those on modafinil had worse scores over time. Likewise, a difference was seen in speed of processing (only as measured by the TMT-A) that found patients on modafinil improved in comparison to patients on methylphenidate, who either remained stable or had slight declines (p = 0.05)

In subjective measures of other symptoms, significant improvement was found over time with any stimulant use in depression as measured by the BDI (p < 0.01) and the POMS-Depr (p < 0.01), fatigue as measured by the BFI (p = 0.04) and POMS-fatigue (p < 0.01), and anxiety as measured by the STAI-state (p = 0.03). In contrast, no differences were seen over time for sleep-wake disturbances. No differences were found between treatment groups in subjective symptom measures over time.

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

• The sample size was small with less than 30 participants.
• The lack of a control group introduced a risk of bias.
• The key sample group had differences that could influence the results.
  • The study was unable to meet the sample size recommended by power analysis because of poor accrual and a substantial dropout rate (29%). 
  • The treatment groups varied significantly in age (p = 0.02) and gender (p = 0.03), both of these characteristics are known to influence neuropsychological test results.
• More than 10% of subjects withdrew from the study.

The study does not provide any support at this time to recommend the use of stimulants to improve cognitive function. Future research studies with larger sample sizes and randomized clinical trials with a nonintervention arm are warranted.

The study's primary aim was to evaluate the potential therapeutic effect and safety of dexmethylphenidate (d-MPH) in the treatment of patients with chemotherapy-related fatigue. Its secondary aim was to examine the impact of d-MPH on cognitive functioning.

Participants were randomized to a placebo group or an intervention group receiving 5 mg of d-MPH twice daily (10 mg/day total).

• The total number of participants was 154.
• There were 76 participants in the intervention group and 78 in the placebo group.
• The average participant age was 52.8 ± 9.3 years.
• 94.7% of the participants were female and 5.3% were male.
• The majority of participants had breast or ovarian cancer. 

The study took place across 24 academic and community-based cancer centers.

This was a randomized, double-blind, placebo-controlled, parallel-group study.

Cognitive measures were taken with the

• Mini-Mental State Examination (MMSE) for global cognitive functioning
• High Sensitivity Cognitive Screen (HSCS) for memory, language, attention, concentration, visual motor, spatial awareness, and self-regulation
• Modified Swanson, Nelson and Pelham Attention Deficit/Hyperactivity Scale (SNAP).

Other measures were taken with the

• ICD-10 Criteria for fatigue
• Beck Depression Inventory (BDI) for depression
• Clinical Global Impression Scale (CGI-S) for severity of illness
• Functional Assessment of Chronic Illness Therapy - Fatigue Subscale (FACIT-F) for chronic illness and quality of life specific to fatigue symptoms
• ECOG performance status for general well-being. Scores range from 0 (indicating perfect health with no restriction of activities) to 5 (indicating death).

The primary outcome of focus was fatigue. Participants treated with d-MPH had significant improvement in fatigue symptoms at week 8 on the FACIT-F (p = 0.02) and on the CGI-S (p = 0.02). The d-MPH treatment group had higher drug-related events (63% vs. 28%) and greater discontinuation of medication (11% vs. 1.3%) than the placebo group. Cognitive function was not significantly improved.

d-MPH can be of benefit in the treatment of fatigue. However, results do not support d-MPH-mediated reduction in cognitive impairment in adult patients with cancer after chemotherapy.

• The study was underpowered to determine an effect on cognitive functioning.
• HSCS has been reported to be susceptible to practice effects and therefore may have underestimated the level of cognitive impairment in participants.
• The small number of men and the fact that most participants had diagnoses of breast or ovarian cancer limit generalizability.

To investigate the effects of dexmethylphenidate (d-MPH) on fatigue and cognitive function in women undergoing adjuvant chemotherapy for early breast cancer

Participants were randomized to a placebo group or a treatment group receiving d-MPH. The treatment group was started on 5 mg twice a day of d-MPH. If this was well-tolerated, the dose was increased one week later to 10 mg twice a day. The treatment group then continued taking d-MPH at a maximum of 10 mg twice a day until the end of the final cycle of chemotherapy. If participants did not tolerate 10 mg twice a day, the dose was reduced to 5 mg twice a day for the remainder of their treatment.

• The total number of participants was 57.
• The treatment group had 29 participants, and the placebo group had 28 participants.
• The median age of the treatment group was 50, with a range of 36–72.
• The median age of the placebo group was 51, with a range of 37–74.
• All participants were female.
• All participants had breast cancer.
• All participants were scheduled to receive four or more cycles of adjuvant chemotherapy and were enrolled after at least one cycle of chemotherapy.

Three hospital-based outpatient clinics in Toronto, Canada

Prospective, randomized, double-blind, placebo-controlled trial

• Mini-Mental State Examination ((MMSE) for global cognitive functioning
• High Sensitivity Cognitive Screen (HSCS) for memory, language, attention, concentration, visual-motor, spatial, and self-regulation
• Hopkins Verbal Learning Test-Revised (HVLT-R) for immediate and delayed recall (alternate forms used)
• Functional Assessment of Cancer Therapy-General (FACT-G) for cancer-related quality of life
• Functional Assessment of Cancer Therapy (FACT-F) for cancer-related quality of life pertaining to fatigue symptoms
• Hospital Anxiety and Depression Scale (HADS)

No difference was seen between groups on any of the cognitive assessments completed at baseline, end of chemotherapy, and at six-month follow-up.

The study failed to demonstrate a beneficial effect of d-MPH on either fatigue or cognitive dysfunction during adjuvant chemotherapy for breast cancer.

• No baseline assessment of cognitive function was conducted prior to chemotherapy treatment; the baseline assessment was completed after the participant already had received at least one cycle of chemotherapy. 
• No descriptive information was provided regarding the sample (e.g., educational level, disease stage).
• The study was closed early because of failure to achieve the accrual goal. This primarily was due to patient reluctance to take additional medication in general and d-MPH in particular. 
• HSCS is subject to substantial practice effect and is not recommended for serial measures.
• The sample size was insufficient to achieve the necessary statistical power.

This study was conducted to test whether methylphenidate (MPH) treatment would improve neurobehavioral functioning in patients with malignant glioma.

Participants were administered 5 mg of MPH daily, increasing dosage by 5 mg twice daily until a response or dose-limiting toxicity was noted.

• The number of participants was 30.
• The average participant age was 40.3 with a range of 15–70.
• 66.7% of participants were male and 33.3% were female. 
• 76.7% of participants had anaplastic glioma, 20% had glioblastoma multiforme, and 3.3% had medulloblastoma.

The study had a pre- and post-test design.

• Digit Span for attention
• Digit Symbol Substitution Task for graphomotor skills 
• Hopkins Verbal Learning Test for memory
• Controlled Oral Word Association Test (COWAT) for verbal fluency
• Trail Making Test (TMT) Parts A and B for visual attention, motor speed, cognitive flexibility
• Grooved Pegboard Test for motor speed and dexterity
• Beck Depression Inventory (BDI) for depression
• State-Trait Anxiety Inventory (STAI) for anxiety
• Functional Independence Measure (FIM) for functional ability to perform activities of daily living

Objective improvements were observed in psychomotor speed, memory, visual-motor function, executive function, and motor speed and dexterity (all p < 0.05). Subjective improvements in improved energy, improved ability to ambulate, better concentration, and brighter mood were reported.

There was a significant improvement noted in cognition that cannot be explained by improved mood or use of glucocorticoids. The authors suggest that stimulants such MPH improve motivation and drive.

• The study had a small sample size.
• The study was limited to patients with malignant glioma.
• The study did not specify how long each participant was treated with MPH before the post-test.
• There was a lack of long-term follow-up.
• Participants were given variable dosing, so the study cannot recommend one specific dose.
• There was a large variation in patient age. 

This study was conducted to examine the effect of exercise and methylphenidate (MPH) on fatigue, functional ability, and cognitive function in patients with melanoma. It also aimed to determine the percentage of patients who adhered to interferon-alfa, MPH, and exercise treatment.

The intervention group was given 20 mg of long-acting MPH every morning for four months and took part in at least 15–20 minutes of aerobic exercise four days per week. The duration and intensity of exercise gradually increased over the study's four months.

Assessments were completed prior to the first dose of interferon-alfa. Subsequent assessments of functional ability and cognition function (using Trail Making Test forms) and quality of life were repeated at one and four months after baseline. Subsequent assessments of fatigue scale, body weight, daily activity, and medication logs were submitted monthly.

• The total number of individuals involved in the study was 28.
• There were 12 participants and 16 historic controls. 
• The average age of the treatment group was 44, with a range of 20–64. Age information for the historic group was not provided.
• Gender information was not provided.
• 92% of the participants were Caucasian.
• The treatment group tended to have completed more years of formal education.
• Participants had newly diagnosed melanoma with surgical intervention, no prior treatment, and were actively undergoing treatment with interferon-alfa.

The study took place at a university-based cancer center.

This was a longitudinal pilot study with descriptive/exploratory design. It made use of a historic control group for comparison.

• The Trail Making Test (TMT) Parts A and B measured visual attention, motor speed, and cognitive flexibility.
• The Schwartz Cancer Fatigue Scale measured fatigue with 6 items. Scores range from 6–36, with higher scores indicating greater fatigue.
• The Medical Outcomes Study Short Form (SF-36) measured quality-of-life and global function with physical and mental health subscales. Scores range from 0–100, with higher scores indicating higher functioning.
• Adherence was measured with daily activity and medication logs.
• Body weight was measured to the nearest 0.1 kg and obtained monthly.

Functional ability increased an average of 6% for all participants and 9% for the treatment group. A percent change in a 12-minute walk was negatively related to TMT-A (p = 0.04) and TMT-B (p = 0.05), suggesting a relationship between higher exercise and improved cognitive functioning (indicated by lower scores on TMT). Taking MPH was correlated with improved TMT-B performance at 4 months (r = -0.85, p < 0.001). 

All participants' cognitive function scores were within normal ranges at baseline. Sixty-six percent of participants adhered to MPH at four months; all subjects continued to exercise at four months.

The combination of exercise and MPH has positive effects on cognitive function, functional ability, and fatigue over time. The authors suggest that MPH may have contributed to better exercise adherence.

• The study had a small sample size.
• One-third of the participants stopped taking MPH within the first week; for one participant, this was due to significant side effects related to anxiety.
• Two participants regularly exercised prior to enrollment, but the study did not address which group they were assigned to, potentially influencing outcomes.

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.