Assessment and Management of Cancer- and Cancer Treatment-Related Cognitive Impairment

Introduction

Cognitive impairment (CI) resulting from a diagnosis of cancer and subsequent treatment is one of the most common and troubling sequelae experienced by cancer survivors. Obvious manifestations are due to cancers that originate in, or metastasize to, the central nervous system (CNS). Less obvious, until recent years, are occurrences of CI that can result from the diagnosis and treatment of non-CNS cancers. Non-CNS cancers include solid tumors originating in the breast, colon, and prostate, as well as hematologic cancers such as leukemia or lymphoma. Regardless of the type of cancer, the resulting CI can have a meaningful negative impact on cancer survivors’ quality of life.¹ Appropriate assessment and management are critical to providing optimal care to cancer survivors. The purpose of this article is to briefly describe the state-of-the-evidence on incidence, possible mechanisms, and presentation of cancer- and treatment-related CI, as well as provide guidance for assessment and management.

Incidence

The incidence of cancer- and treatment-related CI is not known, but estimates range as high as 75% for non-CNS cancers^2–6 and 90% for CNS cancers⁷ during and following treatment. Some CI is present prior to treatment in about 25–30% of cancer survivors,⁸ which may be related to the individual’s immunologic response to cancer.⁹

A subset of survivors (about 25%) may continue to experience CI up to 20 years following the completion of cancer treatment.^10,11 Survivors’ report that CI affects their social and professional lives, and in some instances, results in difficulty returning to work and the need to change jobs.^12,13

Possible mechanisms

A number of mechanisms have been proposed for cancer- and treatment-related CI. Evidence suggests that more chemotherapeutic agents cross the blood-brain barrier than was originally thought.¹⁴ These agents may cause direct injury to neuroprogenitor cells and oligodendrocytes.¹⁵ Associated decreases in brain volume for regions such as the hippocampus are evident on magnetic resonance imaging (MRI).¹⁶ Indirect injury may be caused by systemic release of proinflammatory cytokines due to immune responses to tissue invasion from the cancer and toxicity of chemotherapeutic agents. This systemic release is also associated with the proinflammatory cytokine production within the CNS by microglial cells, which potentially causes neuronal damage due to oxidative stress.¹⁷ To complicate our understanding of mechanisms, a number of confounding factors related to cancer and cancer treatment—such as age-related cognitive decline, hormone reduction, decreased oxygenation associated with treatment-induced anemia, fatigue, anxiety, and depression—are associated with CI.¹¹

Many questions remain about causal mechanisms and specific risk factors related to the increased severity and duration of CI seen in a subset of cancer survivors. While the presence of a primary brain tumor or CNS metastasis has been associated with CI, any cancer especially when advanced, can cause cognitive changes from systemic effects of hypercalcemia, metabolic disturbances, infections, or multisystem failure. Research is ongoing to investigate the potential for genetic predisposition to cancer- and treatment-related CI. For example, those carrying the apolipoprotein E4 allele, which is associated with Alzheimer’s disease and potential susceptibility to neuronal damage, could be associated with greater risk for CI during cancer treatment.¹⁸ Additionally, work is being done to investigate genetic variation related to neurotransmitter metabolism (e.g., catechol-O-methyltransferase val158met polymorphism).¹⁹

Cognitive reserve (high level of literacy, education, and/or intelligence quotient) is under study as a potential protective factor.²⁰ For example, individuals with high baseline cognitive performance may have more cushion against cognitive detriments than individuals with a lower baseline cognitive performance. Highly educated individuals may continue to perform well above normal limits on cognitive tasks yet report experiencing significant changes in their abilities.

Presentation

The lay public frequently refers to cancer- and treatment-related CI as “chemo-brain,” as the symptoms are commonly experienced during and shortly following treatment with chemotherapy.²¹ Non-CNS CI typically is often subtle in nature. The most common complaints include slower thinking; difficulty focusing; trouble with short-term memory, word finding, task planning and completion, and juggling multiple tasks.²² These problems are consistent with impairment in cognitive domains for short-term (working) memory, attention and concentration, processing speed, visuospatial ability, and executive function.²³ While these problems may not be readily observed by others, survivors are aware, and often frustrated, that they are not functioning at the same level as before their cancer diagnosis.²²

The symptoms of CI associated with CNS cancers are due to tumor location and direct injury to specific areas of the brain. Surgical resection of CNS tumors includes a margin of surrounding tissue and is responsible for impairment in the associated cognitive domains controlled by those areas. For example, surgical resection of a left hemispheric tumor may result in impaired memory, executive functioning, and concentration.²⁴ Likewise, radiotherapy delivered to a specific CNS area can cause cognitive deficits directly related to the treatment area. More global CI can result from whole brain radiotherapy or intrathecal chemotherapy. Thus, the severity of CNS-related CI is directly related to the volume and location of tissue involved by the tumor and/or treatment.

Assessment

Assessment of changes in cognitive function throughout cancer treatment and survivorship is important as survivors report cognitive problems during their cancer trajectory.^25,26 Despite increasing acknowledgment that cancer- and cancer treatment-related CI exists and can impact social functioning, occupational performance, and general wellbeing, concrete assessment guidelines have yet to be established.

The National Comprehensive Cancer Network (NCCN) Survivorship Guidelines acknowledge the value of patient reports of CI and recommend assessment of cognitive function in the presence of focal neurologic deficits and/or cognitive complaints. However, these guidelines do not recommend any specific objective or subjective instrument.²⁷ Regardless, patients who report cognitive problems should be evaluated, and tools may include patient selfreport, clinical assessment, and objective neuropsychological assessment.

Patients’ and/or family members’ concerns are often the impetus for bringing attention to the need for evaluation. A comprehensive clinical assessment should be conducted to carefully appraise patient reports of cognitive problems. Clarifying questions may determine more details regarding the presenting complaint, including specific cognitive issues (e.g., difficulty with memory, wording finding, or multitasking), the trajectory over time, and impact on daily functioning.²⁸ Family members can be a valuable source of information as to the onset, clinical course, and magnitude of deficits, as well as provide insight into a patient’s living situation, level of social functioning, and lifestyle factors (e.g., alcohol/drug use, physical activity) that may influence cognition functioning.²⁹

Several subjective instruments have been used in studies of cancer patients to evaluate participant’s perception of their cognitive functioning, Table 1.^30–33 Although these self-report measures may be reflective of patients’ psychological status and may be influenced by cooccurring symptoms (e.g., fatigue), they provide valuable insights into the impact of CI on activities of daily living.

Table 1.

Selected Instruments to Measure Self-Reported Cognitive Function in Cancer Patients

Test	Description	Cognitive Domains
Attentional Function Index30	• Brief 13-item 100mm visual analogue scale: 0=“not at all” to 100=“a great deal”. • Higher scores indicate better cognitive functioning. • Easy to administer.	Attention, executive function, working memory.
Functional Assessment of Cancer Therapy- Cognitive Function (version-3)31	• Longer 37-item 5-point Likert scale: 0=“never/not at all” to 4=“several times a day/very much”. • Higher scores indicate better cognitive functioning. • Easy to administer.	Mental acuity, attention and concentration, verbal and nonverbal memory, verbal fluency.
NIH-PROMIS Measures Perceived Cognitive Concerns (Impairment) Perceived Cognitive Ability32	• Brief 8-item 5-point Likert scale: 0=“not at all” to 4=“very much”. • Cognitive concern items negatively worded; cognitive ability items positively rated. Higher scores indicate better cognitive functioning. • Easy to administer.	Global measure of perceived cognitive concerns, ability, functional status.
Patient’s Assessment of Own Functioning33	• Longer 33-item 6-point Likert scale: 0=“almost never” to 6=“almost always”. • Higher scores indicate poorer cognitive functioning. • Easy to administer.	Memory, executive functioning, language, communication, sensory- perceptual and motor skills.

A thorough evaluation of an individual’s cancer history, comorbidities, current medications, and pertinent laboratory values can provide essential information regarding risk factors, as well as identifying potentially reversible factors contributing to cognitive problems (e.g., mood disorders, insomnia). Key components of the cancer history include tumor type, staging, treatment history, and overall disease trajectory (e.g., metastatic disease). Systemic effects from cancers contributing to CI should be explored, such as hypercalcemia, metabolic disturbances, infections, or multisystem failure. Since most patients receive multimodal therapy, it may be difficult to discern if specific treatments are responsible for CI. However, dose intensity and/or cumulative dosing effects specific to cranial irradiation and chemotherapy have been found.³⁴

Psychological factors such as stress, anxiety, and depression can contribute to CI.^27,35 Emotional distress, such as anxiety and depression, often correlate with subjective measures of cognitive functioning and may influence performance on objective neuropsychological tests.^36,37 Fatigue, sleep disruption, pain, infection, nutritional deficits, and hormonal changes are other indirect factors that should be included in the differential when evaluating a patient.

Patients with greater comorbidity levels, especially illnesses such as diabetes and cardiovascular disease, may have CI prior to initiating cancer treatments.³⁸ Other comorbidities that are known to affect cognition include neurologic illnesses (e.g., stroke, Alzheimer’s disease, developmental disorders), metabolic diseases, hypertension, and/or head injury. Medications that have been shown to influence cognition include, but not limited to, antidepressants, antiemetics, antiepileptics, anxiolytics, antipsychotics, anesthesia, immunosuppressants, opioids, sedatives, and steroids. Therefore, all prescriptions, over the counter medications, and supplements should be reviewed for potential toxicities and interactions.

Laboratory testing should include complete blood count, electrolytes (e.g., calcium, sodium), renal and liver function, and thyroid level tests, Table 2. A physical examination should note any potential sensory deficits (e.g., hearing, vision) and/or focal neurological deficits. Although neuroimaging (e.g., MRI, positron emission tomography, electroencephalogram) has been used to study neural and electrophysiologic markers associated with CI, it is generally not considered feasible for clinical evaluation.³⁹ NCCN Survivorship Guidelines recommend imaging outside of clinical trials only to rule-out structural abnormalities in high-risk patients with focal neurologic deficits.²⁷

Table 2.

Diagnostic tests to consider in the workup of cognitive problems

Test	Differential Diagnosis
Complete blood count, differential	Anemia; Infection
Electrolytes	Metabolic imbalances
Renal function tests	Renal dysfunction
Liver function tests	Liver dysfunction
B12, folate	Nutritional deficiencies
Thyroid stimulating hormone, T4 levels	Thyroid dysfunction
Magnetic resonance imaging (brain)	Metastatic disease to the CNS
Neuropsychological evaluation	Objective cognitive deficits in specific domains

In patients who demonstrate CI not due to reversible causes, objective neuropsychological testing may be warranted. Most neuropsychological tests were designed to assess patients with dementia or head injury.³⁶ Information regarding tests that are sensitive and specific to subtle cancer and treatment-related cognitive changes is limited.⁴⁰

Specific neuropsychological tests recommended by the International Cognition and Cancer Task Force for clinical trials include tests (i.e., Hopkins Verbal Learning Test-Revised, Trail Making Tests, Controlled Oral Word Association Test) that evaluate cognitive domains (i.e., learning and memory, processing speed, executive function) most vulnerable in patients with cancer.^8,41,42 These objective measures are generally used in studies and require referral to a neuropsychologist with special training. Unless gross CI is suspected, clinical interpretation of neuropsychological tests in the context of cancer- and treatment-related CI may not be informative.

In conclusion, assessing patients for CI is difficult because of the lack of clinically useful instruments. Clinicians are encouraged to consider a combination of assessments: patient reports of cognitive concerns, clinical assessment of difficulty with routine functioning (e.g., forgetting appointment times, difficulty remembering medication schedules), and referral when warranted to neuropsychologists for further evaluation.

Management

Interventions to prevent CI or maintain cognitive function in cancer survivors can be categorized into non-pharmacologic and pharmacologic interventions. This section will describe interventions with sufficient evidence to suggest clinical application.

Non-pharmacologic Interventions

Exercise/Physical Activity

Exercise has been tested to improve cognitive function in several oncology populations, Table 3, and address cancer-related symptoms, including fatigue, sleep disturbance, and depressive symptoms. Recently, the NCCN Survivorship Guidelines²⁷ have identified exercise as an option to address cancer and cancer treatment-related CI. Exercise has been shown to be effective in reducing stress and inflammation, which may ultimately improve CI.

Table 3.

Cognitive interventions involving exercise/physical activity

Study/Study Design	Sample	Intervention	Findings
Mustian, 2015/RCT43	n=479 Receiving chemotherapy Non- metastatic cancer; primarily breast cancer	Home based walking, resistance training for 6 weeks	Improved perceived cognitive function; reduced inflammatory markers
Derry, 2015/RCT44	n=200 ~11 months post-treatment (except hormonal therapy) Stage 0-IIIA breast cancer	90 minutes twice weekly: Hatha Yoga	Improved perceived cognitive function; reduced inflammatory markers
Janelsins, 2012/RCT45	n=358 2–24 months post-adjuvant therapy (except hormonal therapy) Primarily breast cancer	75 minutes twice weekly for 4 weeks: breathing exercise, yoga, meditation	Improved perceived cognitive function, specifically memory
Miki, 2014/RCT46	n=78 ~5 years post-diagnosis Breast/prostate cancer aged > 65 years	5 minutes once weekly for 4 weeks: speed-feedback therapy on bicycle ergometer	Improved frontal battery assessment
Knobf, 2014/UT47	n=26 < 36 months post-diagnosis Stage I-II breast cancer	10–45 minutes 3 times/week for 6 months: progressive aerobic endurance training	Improved perceived cognitive function
Reid-Arndt, 2012/UT48	n=23 ~6.5 years post-diagnosis, completed chemotherapy >1 year Any cancer; primarily breast cancer; no brain metastases	60 minutes twice weekly for 10 weeks: Tai Chi	Improved perceived cognitive function, immediate and delayed memory, verbal fluency, attention, executive function
Baumann, 2011/UT49	n=47 Duing allogeneic hematopoietic stem cell transplant	60 minutes twice weekly: resistance training	Improved attention and working memory
Oh, 2011/RCT50	n=81 During or after adjuvant therapy Any cancer; primarily breast cancer	90 minutes/week for 10 weeks: Medical Qigong	Improved perceived cognitive function
Rodgers, 2009/RCT51	n=41 During hormonal therapy ~34 months since surgery Stage I-IIIA breast cancer	Physical activity program for 12 weeks	No change in perceived cognitive function
Korstjens, 2006/UT52	n=658 ~25 months post treatment (except hormonal therapy) Any cancer; primarily breast cancer	60 minutes twice weekly for 12 weeks: aqua aerobics, group sports, or individual endurance, strength training, plus psychoeducation	Improved perceived cognitive function
Schwartz, 2002/UT53	n=12 During interferon therapy Stage II-III melanoma	15–20 minutes aerobic exercise 4 times/week, plus methylphenidate	Improved perceived cognitive function

RCT=randomized control trial; UT=Uncontrolled trial

Relatively few clinical trials of exercise/physical activity have been completed: 6 randomized controlled trials (RCT) and 5 uncontrolled trials (UT).^43–53 Most studies found improvement in perceived cognitive function; two studies demonstrated positive effects on inflammatory markers during exercise.^43,44 Breast cancer survivors performing yoga significantly improve perceived cognitive function, as compared to usual care^44,45 and a reduction in inflammatory markers in the exercise group was observed in one study.⁴⁴ Similarly, Mustian and colleagues⁴³ noted improvement in perceived cognitive function, reduction in inflammatory markers (Interferon-γ, Interleukin-8, Interleukin-1B), and an increase in anti-inflammatory cytokines (Interleukin-6, Interleukin-10, TNF-α receptor antagonist) in survivors receiving a home-based exercise program consisting of aerobic walking and band resistance training compared to usual care. Oh and colleagues⁵⁰ tested the impact of Qigong, a set of coordinated gentle exercises, meditation, and breathing exercises; they demonstrated improved perceived CI and reduced inflammation using serum C-reactive protein levels in cancer survivors after chemotherapy.

Other physical activity studies used one-group designs,⁵³ were not randomized,^{47–49,52,53} or were combined with additional interventions (psycho-education, methylphenidate).^52,53 Korstjens and colleagues⁵² evaluated the effects of a twelve-week rehabilitation program that combined exercises with a psycho-educational component focused on coping with cancer. Schwartz and colleagues⁵³ combined 15–30 minutes of aerobic exercises with methylphenidate 20 mg daily. Both studies noted improvements in cognitive function; however combining interventions confounds identifying the effect of exercise.

While these results appear promising, more research is needed to explore the effectiveness of exercise/physical activity on cognitive function in cancer survivors. Research is needed to identify the type of exercise (anaerobic and aerobic), timing and frequency (dose), and duration to achieve optimal results for improving cancer- and cancer treatment-related CI for cancer survivors.

Cognitive Training

Cognitive training includes “any intervention aimed at improving, maintaining, or restoring mental function through the repeated and structured practice of tasks which pose an inherent problem or mental challenge.”⁵⁴,p.⁷⁵ Cognitive training is designed to increase sensory stimulation and performance of cognitively challenging activities, thereby promoting neuroplasticity⁵⁵ and improving cognitive outcomes.⁵⁶

Six RCTs and 1 UT have been conducted in cancer survivors, Table 4.^57–65 These studies have consistently demonstrated that cognitive training in cancer survivors is an acceptable and feasible intervention with promising results. Cognitive training has been successfully studied in both primary brain tumor^{57,59,64–56} and breast cancer survivors.^58,60–63 Although cognitive training may be an effective intervention, more research is needed to understand the sustainability of effects. Additionally, more research with larger samples and various cancer diagnoses are needed to address limitations and provide sufficient evidence to guide clinical practice.

Table 4.

Cognitive training interventions.

Study/Study Design	Sample	Intervention	Findings
Gehring, 2009/RCT57	n=140 ~3 years post-treatment Low-grade or anaplastic glioma	60 minutes twice weekly for 6 weeks: computerized attention training with compensatory retraining	Improved perceived cognitive function immediate and 6-months post-intervention; improved attention and memory 6-months post-intervention
Poppelreuter, 2009/RCT58	n=96 ~2 months post-adjuvant chemotherapy Stage I-II breast cancer	4 one-hour sessions: attention and memory training either in- person or computerized	No intervention effects
Hassler, 2010/UT59	n=11 ~15 months post-diagnosis High-grade glioma	90 minutes/week for 10 weeks: CT perception, concentration, attention, memory, retention	Improved verbal memory, learning
Von Ah, 2012/RCT60	n=88 ~5.5 years post-treatment (except hormonal therapy) f Early-stage breast cancer	10 one-hour sessions for 6–8 weeks: CT memory or processing speed	Improved perceived cognitive function; CT-memory: improved immediate and delayed memory; CT-speed: improved immediate and delayed memory, processing speed
Damholdt, 2016/RCT61	n=157 ~4.5 years post-diagnosis Breast cancer, any stage	Web-based CT with telephone support over 6 weeks	Improved verbal learning, working memory at 5 months post- intervention
Kesler, 2013/RCT62	n=41 ~6 years post-adjuvant chemotherapy Stage I-IIIA breast cancer	48 20–30 minute sessions 4 times/week for 12 weeks: CT executive function involving 13 different exercises	Improved cognitive flexibility, verbal fluency, processing speed; marginally improved verbal memory
Bray, 2017/RCT63	n=242 ~27 months post-adjuvant chemotherapy Solid non-central nervous system, non-metastatic cancer; primarily breast cancer	Home-based computerized CT for 15 weeks	Improved perceived cognitive function
Zuchella, 2013/RCT64	n=53 2 weeks post-operative rehabilitation Primary brain tumor	16 1-hr sessions over 4 weeks: CT executive function, memory recognition, time and spatial orientation, visual attention, logical reasoning	Improved executive function, memory, time and spatial orientation, attention, logical reasoning
Miotti, 2013/UCT65	n=21 6 months post- chemotherapy/radiotherapy Primary brain tumor	30 minute semantic organizational strategy training	Improved word categorization (memory)

RCT=randomized control trial; UT=Uncontrolled trial; CT=cognitive training

Pharmacologic Interventions

Pharmacologic agents have shown some effectiveness managing cognitive problems associated with various dementias or attention deficit disorders; thus, researching their effectiveness in cancer survivors is warranted, Table 5.^53,66–87 Most pharmacologic clinical trials to date have been limited by small samples due to recruitment difficulties and attrition. However, NCCN Survivorship Guidelines has included consideration for some pharmacologic agents in CI management, with close patient monitoring.²⁷

Table 5.

Pharmacologic interventions

Study/Study Design	Sample	Intervention	Findings
Methylphenidate and Dexmethylphenidate
Bruera, 1992/RCT66	n=20 Receiving opioids Advanced cancer without brain metastases; primarily lung cancer	MPH undisclosed dose	Improved alertness, attention, memory
Butler, 2007/RCT67	n=68 Receiving whole/partial radiotherapy with/without chemotherapy Primary/metastatic brain tumor	d-MPH 5 mg twice daily, escalated to 15 mg twice daily	No difference between groups
Escalante, 2014/RCT68	n=38 During or post-adjuvant chemotherapy or hormonal therapy Breast cancer, any stage	Sustained-release MPH 18 mg daily	Improved processing speed
Gagnon, 2005/UT69	n=14 During hypoactive delirium state Advanced cancer; primarily lung cancer	MPH 10 mg twice daily, escalated in 5 mg doses to MTD	Improved alertness; psychomotor retardation resolution; slurred speech normalized; increased energy and global cognitive function
Gehring, 2012/RCT70	n=24 During or post- chemotherapy/radiotherapy Primary brain tumor	IR-MPH 10 mg twice daily OR SR-MPH 18 mg daily OR modafinil 200 mg daily	Mixed results between stimulants; some improved processing speed, executive function
Lower, 2009/RCT171	n=154 ~29 months post-chemotherapy All cancers except brain; primarily breast cancer	d-MPH 5 mg twice daily	No difference between groups
Mar Fan, 2008/RCT72	n=57 During adjuvant chemotherapy Early-stage breast cancer	d-MPH 5 mg twice daily for one week escalated to 10 mg twice daily, if tolerated	No difference between groups
Myers, 1998/UT73	n=30 ~46 months post-diagnosis Primary brain tumor	MPH 5 mg daily, escalated to 5 mg twice daily until MTD/response	Improved psychomotor speed, memory, visual-motor, executive function, dexterity; improved perceived energy, ambulation, concentration, mood
Schwartz, 2002/UT53	n=12 During interferon therapy Stage II-III melanoma	Long-acting MPH 20 mg daily for 4 months plus 15–20 minutes aerobic exercise four times/week	Improved perceived cognitive function
Modafinil and armodafinil
Blackhall, 2009/UT78	n=27 All cancers during trajectory	Modafinil 100 mg daily for two weeks, then 200 mg daily	Trends of improved executive function
Boele, 2013/RCT79	n=37 ~50 months post-diagnosis Primary brain tumor	Modafinil 100 mg twice daily for one week, then 200 mg twice daily	Improved working memory, information-processing, attention
Gehring, 2012/RCT70	n=24 During or post- chemotherapy/radiotherapy Primary brain tumor	See MPH section	See MPH section
Kohli, 2009/RCT80	n=82 ~22 months post-chemotherapy Breast cancer	Modafinil 200 mg daily	Improved attention, speed of memory, quality of episodic memory
Lundorff, 2009/RCT81	n=28 Advanced cancer without brain metastases; primarily lung cancer	Modafinil 200 mg daily	Improved psychomotor speed, processing speed, attention
Page, 2015/RCT82	n=54 During partial/whole-brain radiotherapy Primary brain tumor	Armodafinil 150 mg daily	No difference between groups
Donepezil
Jatoi, 2005/RCT83	n=9 During prophylactic cranial radiation Small cell lung cancer	Donepezil 5 mg daily for 4 weeks, then 10 mg daily plus Vitamin E 1000 IU daily	No difference between groups
Lawrence, 2016/RCT84	n=62 1–5 years post-adjuvant chemotherapy Breast cancer	Donepezil 5 mg daily for 6 weeks, then 10 mg daily	Improved memory
Rapp, 2015/RCT85	n=198 ~38 months post-diagnosis and >6 months post-partial/whole- brain radiotherapy Primary/metastatic brain tumor	Donepezil 5 mg daily for 6 weeks, then 10 mg daily	Improved memory, motor speed, dexterity
Shaw, 2006/UT86	n=35 >6 months post-partial/whole- brain radiotherapy Primary brain tumor	Donepezil 5 mg daily for 6 weeks, then 10 mg daily	Improved attention, concentration, verbal memory, figural memory, verbal fluency
Memantine
Brown, 2013/RCT87	n=508 Receiving whole-brain radiotherapy Metastatic brain tumor; primarily lung cancer	Memantine 5 mg daily for 1 week, incrementally increasing to 10 mg twice daily	Reduced rate of cognitive decline for memory, executive function, processing speed

RCT=randomized control trial; UT=uncontrolled trial; MPH=methylphenidate; d-MPH=dextromethylphenidate; IR=immediate-release; SR=sustained-release; MTD=maximum tolerated dose

Methylphenidate and dexmethylphenidate are Schedule II psychostimulants used to treat attention deficit disorders and narcolepsy. Nine research studies^53,66–73 and four systematic reviews/meta-analyses^74–77 have examined pharmacologic benefits with mixed results reported. One RCT⁶⁶ and two UTs^69,73 using subjective measures for cognitive function reported positive benefits in survivors with advanced cancer, while the remaining six studies reported equivocal findings.^{53,67,68,70–72} These studies were limited by small samples and one study combined stimulant use with an exercise intervention, confounding stimulant effectiveness.⁵³

Modafinil and armodafinil are psychostimulants used primarily to treat sleep disorders, including narcolepsy. They act centrally to increase alertness, wakefulness, attention, and memory. Five RCTs,^70,79–82 one UT,⁷⁸ and one systematic review⁷⁴ reported their effectiveness in survivors of breast,⁸⁰ brain,^70,79,82 and advanced cancers.^78,81 Modafinil doses began at 100 mg daily and were increased to 200 mg daily, as tolerated,^70,78–81 while armodafinil was 150 mg/day;⁸² one study reduced modafinil to 50–100 mg in patients older than 80 years.⁷⁸ Four studies using modafinil reported improvements in cognitive function: speed of memory and quality of episodic memory,⁸⁰ attention and psychomotor speed,⁸¹ cognitive flexibility,⁷⁸ and executive function;⁷⁰ while no difference in cognitive function was observed in two studies using either modafinil or armodafinil.^83,82 All six studies had small samples, contributing to equivocal/mixed results.^70,78–82

Donepezil is an acetylcholinesterase inhibitor used to treat Alzheimer’s dementia and may improve memory in cancer survivors. Three RCTs,^83–85 one phase II open-label study⁸⁶ and one systematic review⁷⁴ reported the effects of donepezil on memory in survivors of small cell lung,⁸³ breast, and brain cancers.^74,85,86 Additionally, one study combined donepezil with vitamin E for the intervention.⁸³ Donepezil doses began at 5 mg daily with goals of 10 mg daily.^83–86 Most studies had small samples,^83,84,86 yet improvements in memory were observed, particularly for those with severe impairment.

Memantine blocks N-methyl-d-aspartate receptors to treat moderate-to-severe dementia. One large multisite RCT,⁸⁷ reported in a systematic review,⁷⁴ explored memantine’s effect on cognitive function in cancer patients receiving whole brain radiotherapy for brain metastases. Memantine 5 mg/day was escalated during radiotherapy to 10 mg twice daily and sustained for a total of 24 weeks. Brown and colleagues reported that memantine resulted in better cognitive function with delayed timing to cognitive failures, specifically for memory, executive function, and processing speed.

While results for pharmacologic agents may suggest some cognitive function effectiveness, these studies reflect the complexities of underlying mechanisms contributing to the development of cognitive impairment in cancer survivors. Additional research with larger samples and more diversity in cancer diagnoses is warranted.

Conclusion

Advances in research and practice have identified that CI is a significant sequela of cancer. Future research is needed to characterize CI throughout the cancer trajectory and identify effective management strategies that are feasible, satisfactory, and translatable.

Implementation of cognitive interventions begins with a thorough assessment of subjective cognitive function, including examination of co-occurring symptoms and comorbidities, and engaging survivors in conversations reviewing potential management strategies and their preferences. As CI is an emerging cancer survivorship issue, nurse practitioners can play a significant role to identify cognitive concerns, assess impact on activities of daily living, discuss evidence involving cognitive interventions, initiate interventions or make referrals to available intervention studies, and monitor cognitive function over time. Furthermore, with cancer survivorship care transitioning to primary care, nurse practitioners are well-positioned to address issues of cognitive function within their clinical practice.

Highlights.

• Cognitive impairment may result from cancer or cancer-related treatment.

• Cognitive impairment is a troubling sequelae experienced by cancer survivors.

• Cognitive impairment includes issues with memory, attention, and processing speed.

• Cognitive interventions include exercise, cognitive training, and medications.