Erythropoiesis Stimulating Factors (ESA)

• 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. 

The study's primary aim was to evaluate the effect of epoetin alfa on changes in quality of life and utility scale scores at week 12. Its secondary aim was to evaluate transfusion reduction and hemoglobulin level increase.

Participants were screened at the initiation of chemotherapy with hemoglobin (Hgb) levels ≤ 15.0 grams per deciliter (g/dL). Randomization occurred when the Hgb level was decreased to 12.0 g/dL. They received 40,000 IU of erythropoietin subcutaneously each week for 16 weeks or for 4 weeks after the completion of chemotherapy, whichever was longer (the maximum amount of time participants could receive erythropoietin was 28 weeks).

• All participants were female and had breast cancer. 
• The number of participants was 354.
• There were 176 participants in the treatment gruop and 178 in the control group.
• The average participant age in the treatment group was 50.4 years, with a range of 27–85.
• The average participants age in the control group was 50.1 years, with a range of 27–85.

This multi-site study was conducted in Canada. 

The study was a phrase III, randomized, open-label, multi-center trial. 

• The Health Utilities Index Mark (HUI) measured eight components of quality of life, including cognition.
• The Functional Assessment of Cancer Therapy (FACT) - Anemia and Fatigue measured cancer-related quality of life specific to symptoms of anemia and fatigue.
• The Cancer Linear Analog Scale (CLAS) measured quality of life.
• The EuroQol 5-Dimension (EQ-5D) is a linear analog scale of 0–100, with 100 representing the best imaginable health. It is described as the use of a thermometer, known as a feeling thermometer.

Based on the subscale HUI survey, significant improvement in cognition (p = 0.02) was found in participants who received erythropoietin.

• Improvement in cognition was based on a subjective, not objective, measurement.
• Cognitive improvement may be independent of hematologic change, as it was not correlated with changes in Hgb level.

No objective measure for cognitive function was used.

The study's primary aim was to assess whether erythropoietin (epoetin alfa) would improve cognitive performance in a group of patients with cancer who were anemic and receiving chemotherapy. Its secondary aim was to confirm the positive impact of erythropoietin on hematologic parameters and quality of life.

Participants were treated with 40,000 units of erythropoietin weekly for 12 weeks. After the first four weeks of therapy, if the increase in hemoglobulin (Hgb) was less than 1 g/dL over the baseline value, the dose of erythropoietin was increased to 60,000 units weekly. In patients whose Hgb level exceeded 13.0 g/dL, erythropoietin was withheld until Hgb decreased to less than 12.0 g/dL, and resumed at that point to 75% of the previous dose. All participants also received 200 mg of oral elemental iron daily throughout the study. Questionnaires were administered prior to epoetin alfa therapy and at the study's completion.

• The number of participants was 55, with 50 completing the study.
• The average participant age was 58.9 ± 9.9 years.
• 63.6% of the participants were female and 36.4% were male.
• 30.8% of the participants had breast cancer, 21.8% had colorectal cancer, 18.2% had lung cancer, 18.2% had genitourinary cancer, and 11.0% had another form of cancer.
• The average participant years of education attained was 8.7 ± 4.2. 
• The average participant Hgb level was 10.35 ± 0.50 g/dL.

This was a single-site study in Greece.

The study utilized a prospective, longitudinal, single-arm design. 

• The Mini-Mental State Examination (MMSE) measured global cognitive function.
• The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-30 (EORTC QLQ-C30) measured global and functional quality of life using six subscales (global, physical, role, cognitive, emotional, social functioning) and three symptom scales (for fatigue, pain and nausea/vomiting). Scores range from 0–100, with higher scores indicating higher quality of life for the global and functional scales. The Greek version was employed. 

There were no significant differences in cognitive function between erythropoietin responders and non-responders. Sixteen percent of patients had cognitive impairment at baseline measurement (MMSE score < 24). MMSE mean scores increased from 27.24 at baseline to 27.90 at week 12 (p < 0.016). Change in Hgb levels were associated with the magnitude of improvement in quality-of-life parameters such as fatigue (p < 0.01), social function (p < 0.01), and role function (p < 0.01). MMSE changes were not associated with changes in Hgb levels. 

The study failed to demonstrate a clinical benefit of erythropoietin on cognitive function during treatment.

• The study had a small sample size.
• There was no control or comparison group.
• The MMSE is not sensitive enough to detect subtle cognitive changes and has ceiling effects; overall, patients had high baseline scores.
• There was a lack of alternate forms for repeated administration.

To investigate whether any association exists between hemoglobin (Hgb) levels and functional capacity, cognitive impairment, and comorbidities in older adult patients with lung cancer who were treated with chemotherapy

Patients were evaluated prior to the initiation of chemotherapy (baseline) and before each subsequent cycle (after 21 days) for quality of life, mental capacity, functional status, depression, and comorbidities.

• The study reported on a sample of 42 patients with a median age of 76.6 years (± 4.8 years).
• Participants were 73.8% male and 26.2% female.
• The patients were included if they were more than 70 years old and had a confirmed diagnosis of lung cancer for which they were undergoing chemotherapy. 
• Patients were excluded if they had symptomatic brain metastases, preexisting major neurologic or psychiatric problems, or a history of substance abuse.

• Single site
• Rome, Italy

A descriptive prospective study design was used.

• MMSE—global cognitive function
• Comprehensive Geriatric Assessment (CGA)—a multidimensional, interdisciplinary diagnostic process to determine the medical, psychological, and functional capabilities of a frail older person. Includes
  • Activities of Daily Living (ADL)—scores ranging between 0–8 were used to assess functional status for self-care activities.
  • Instrumental Activities of Daily Living (IADL)—scores ranging between 0–8 were used to assess functional status for higher level activities.
  • Geriatric Depression Scale (GDS)—15-item questionnaire
  • Mini Nutritional Assessment (MNA)
• Cumulative Illness Rating Scale-Geriatric (CIRS-G)—assesses the number and severity of comorbid conditions
• Quality of life (QOL)/fatigue outcomes were measured by a visual analogue scale (VAS)

Hgb level was significantly correlated with cognitive function at baseline prior to chemotherapy (r = 0.61, p < 0.002), as well as after one (r = 0.48, p < 0.002) and two cycles (r = 0.60, p < 0.002) of chemotherapy. A significant association was discovered between the change in Hgb levels and cognitive capacity as defined by the MMSE after the first (r = 0.48, p < 0.002) and second cycle (r = 0.60, p < 0.002) of chemotherapy. Significant associations were found between Hgb levels and VAS, CIRS-G, ADL, IADL assessments, and GDS at baseline and GDS at baseline and after one and two cycles of chemotherapy (p < 0.05). The strength of these correlations varied. Change in Hgb level was associated with the change in all above parameters with the exception of IADL, which was not significant.

Although the study was not designed to demonstrate a clinical benefit of erythropoietin on cognitive function during treatment, the authors noted that 14 patients who received erythropoietin during the first two cycles of chemotherapy experienced increases in the Hgb level and CGA indexes whereas patients who did not receive erythropoietin had a lowering of the Hgb levels and worsening of their CGA scores.

• The study had a small sample size for multiple chemotherapy regimens and variability in stage of disease.
• The study included patients with brain metastases as long as they were not “symptomatic.” 
• The study was not designed to specifically evaluate the effect of erythropoietin on cognitive function in patients with cancer.
• MMSE is not sensitive enough to detect subtle cognitive changes.
• There was a lack of alternate forms for repeated administration of MMSE.
• Other factors such as performance status, chemotherapy regimen, and response to chemotherapy may have interacted with Hgb level and other examined variables.

The study was conducted to investigate post-hoc the potential impact of erythropoietin on cognitive function following chemotherapy for breast cancer.

Patients were randomized when their hemoglobin (Hgb) level decreased to ≤ 12 g/dL. Depending on the remaining duration of chemotherapy, erythropoietin was administered for a period of time between 16 or 28 weeks. Patients were randomized to receive either 40,000 units of erythropoietin weekly or the standard of care.

• All participants were female and had breast cancer.
• Participants were selected from a primary study group receiving adjuvant chemotherapy.
• The number of participants was 87.
• The number of participants in the treatment group (erythropoietin arm) was 45.
• The number of participants in the control group (standard care) was 42.
• Participants spent an average of 23 months in the intervention group and 24 months in the standard-of-care group. 

This multi-site study took place in Canada.

The study was a randomized, controlled trial.

• Primary Cognitive Endpoint: Proportion with moderate-severe cognitive impairment at 12–30 months following completion of chemotherapy as measured by High Sensitivity Cognitive Screen (HSCS) for memory, language, attention, concentration, visual motor, spatial, and self-regulation
• Secondary Cognitive Endpoint: Proportion that scored in lowest quartile of any of four variables in the Hopkins Verbal Learning test–Revised (HVLT-R) for total recall, delayed recall percent retained, and discrimination index
• Functional Assessment of Cancer Therapy (FACT)-F for cancer-related quality of life specific to symptoms of fatigue
• Hospital Anxiety and Depression Scale (HADS) for anxiety and depression.

Participants showed no improvement in cognitive function or fatigue, as measured by the HSCS or HVLT-R. There was reported improvement in quality of life.

The study failed to demonstrate a protective effect of erythropoietin on cognitive dysfunction after chemotherapy in survivors of breast cancer.

• The study had a small sample size, given the variability in chemotherapy regimens and use of hormonal therapy.
• No baseline testing of cognitive function was conducted.
• The study lacked a control group.
• There were significant differences between groups in overall quality-of-life, anxiety, and depression scores.
• The selection of the delayed 12–30 month time frame may not have been the ideal time for assessment of the impact of erythropoietin on cognitive function.
• HSCS has not been shown to be a very sensitive test for detecting subtle cognitive impairments in the sample population. 

The study's primary aim was to examine the relationship of changes in Hgb levels following erythropoietin treatment to changes in cognitive functioning, as studied in older adult patients with cancer undergoing chemotherapy treatment. Its secondary aim was to assess the relationship of changes in Hgb levels following erythropoietin treatment to changes in functions studied in the Comprehensive Geriatric Assessment.

The study's treatment cycle was 12 weeks. For the first 2 weeks, all patients were treated with 10,000 units of erythropoietin twice daily for 6 days a week. For the following 10 weeks, participants were administered 10,000 units of erythropoietin 3 times a week. Participants were also treated with 125 mg of intravenous sodium ferric gluconate complex weekly, or more than once a week if serum iron values were below the inferior limit of normal range. All assessments, including cognition (as based on the MMSE) were completed at baseline prior to treatment with erythropoietin, and at weeks 4, 8, and 12 of treatment.

• The number of participants was 10.
• The average participant age was 71.4, with a range of 68–75.
• 50% of participants were female and 50% were male.
• 40% of participants had non–small-cell lung cancer, 10% had oral cancer, 10% had ovarian cancer, 10% had breast cancer, 10% had endometrial cancer, 10% had colon cancer, and 10% had stomach cancer.
• All participants had an ECOG performance status of 0–2 and an initial MMSE score of 19 or greater. 

The study took place at a single-site location in Italy. 

The study was a prospective single-arm trial.

The Mini-Mental State Examination (MMSE) measured global cognitive function.

The Comprehensive Geriatric Assessment (CGA) is a multidimensional, interdisciplinary diagnostic process that determines the medical, psychological, and functional capabilities of a frail elderly person. It includes

• Activities of Daily Living Scale (ADL). Scores ranging between 0–8 were used to assess functional status for self-care activities.
• Instrumental Activities of Daily Living Scale (IADL). Scores ranging between 0–8 were used to assess functional status for higher-level activities.
• Geriatric Depression Scale (GDS), a 15-item questionnaire.
• The Mini Nutritional Assessment (MNA).

Nine participants (90%) showed significant improvement in cognitive function compared to baseline (p < 0.005), with eight of these patients also responders to erythropoietin in showing correction of anemia. All of these patients maintained improved MMSE scores after weeks 8 and 12 (p = 0.009 and 0.006). There was significant correlation between changes in Hgb levels and cognitive functioning (p = 0.049). There were no significant changes in ADL, IADL, GDS, or MNA scores as compared to baseline scores.

At baseline, the mean Hgb level was 10.3 g/dL, and 40% of patients displayed cognitive impairment (MMSE score < 24). After four weeks of treatment, Hgb levels increased significantly (p < 0.001). 

The study found that treating anemic patients undergoing chemotherapy significantly improved anemia, and that this improvement was correlated with an improvement in cognitive function. However, definitive conclusions cannot be drawn from this study because of multiple limitations.

• The study had a very small sample size for the participants' multiple types of cancer, regimens, and variability in stage of disease.
• The study lacked a control group as a comparison.
• All patients were anemic at baseline.
• The MMSE is not sensitive enough to detect subtle cognitive changes.
• There was a lack of alternate forms for repeated administration of MMSE, so practice effects may have influenced study outcomes.
• The study followed an atypical erythropoietin dosing schedule.

The study was conducted to assess the feasibility of quantifying the effect of epoetin alfa in patients with breast cancer who were receiving adjuvant chemotherapy on asthenia, executive cognitive functioning, and quality of life. 

Participants were randomized to receive 40,000 units weekly of erythropoietin or a placebo. Erythropoietin or placebo administration began on day 1 of chemotherapy. Both the erythropoietin and placebo were then dose-escalated, with the goal of keeping Hgb levels between 12 g/dL and 14 g/dL. All assessments were administered prior to the start of chemotherapy, one week prior to cycle 4, and 6 months following the completion of chemotherapy.

• All participants were female and had breast cancer.
• The number of participants was 100.
• There were 51 participants in the treatment group and 49 in the control group.
• The median age of the treatment group was 53 years.
• All patients were treated with four cycles of doxorubicin and cyclophosphamide.
• All participants had a Karnofsky performance status of ≥ 70%.
• Individuals who had packed red blood cell transfusions within 14 days of study entry, clinically significant anemia (not defined), or uncontrolled or severe cardiovascular disease were excluded from the study.

The study's setting is unknown. 

The study utilized a longitudinal, double-blind, randomized, controlled design. 

• The Executive Interview (EXIT-25) measured executive function.
• The Clock Drawing Task (CLOX) measured executive function.
• The Functional Assessment of Cancer Therapy (FACT)-Anemia measured cancer-related quality of life specific to the symptom of anemia.
• The Karnofsky Performance Status scale (KPS) measured general well-being. Scores range from 0 (death) to 100 (perfect health with no complaints or signs of disease).
• Quality of life was measured by a validated linear analogue scale (LASA).
• The Profile of Mood States (POMS) was also utilized.

A significantly higher mean Hgb level in patients on erythropoietin treatment was reported (p < 0.001). However, there were no significant differences in cognitive function.

The study failed to demonstrate a difference in cognitive functioning between patients in the erythropoietin and placebo groups.

• The number of erythropoietin doses administered to the treatment group was unclear, which could influence study results.
• The CLOX test was determined to be an insensitive measure for detecting cognitive changes.
• There was a lack of alternate forms for cognitive tests, so practice effects may have influenced study outcomes.

The study's primary aim was to evaluate the effects of erythropoietin (epoetin alfa) on cognitive function and mood in patients with breast cancer. Its secondary aim was to evaluate the effects of erythropoietin on fatigue and quality of life of patients with breast cancer.

At the beginning of 4 weeks of chemotherapy, patients were randomly assigned to receive 40,000 units of epoetin alfa subcutaneously once weekly or a placebo, as administered over 12 weeks.

• All participants were female and had breast cancer.
• The number of participants was 94.
• There were 47 participants in the erythropoietin group and 47 in the placebo group.
• The average participant age was 53.3 ± 9.7 years in the erythropoietin group and 54.3 ± 12.0 in the placebo group.
• All participants were scheduled to receive four cycles of anthracycline-based adjuvant or neoadjuvant chemotherapy with or without a taxane.
• All participants had a Karnofsky performance score of ≥ 70% and an estimated life expectancy of ≥ 1 year.

The study took place at 13 sites in the United States.

The study utilized a longitudinal, exploratory, double-blind, randomized, placebo-controlled design.

• The Executive Interview (EXIT-25) measured executive function.
• The Clock Drawing Task (CLOX) measured executive function.
• The Functional Assessment of Cancer Therapy (FACT)-Anemia measured cancer-related quality of life specific to the symptom of anemia.
• The Karnofsky Performance Status scale (KPS) measured general well-being. Scores range from 0 (death) to 100 (perfect health with no complaints or signs of disease).
• Quality of life was measured by a linear analogue scale assessment.
• The Profile of Mood States (POMS) was also utilized. 

Although patients in the treatment arm had a greater improvement in executive function between baseline and after completion of the treatment phase, this difference was not significant. The mean change over time in executive function was similar between the two groups at the six month follow-up assessment.

The study was unable to demonstrate an effect of erythropoietin on executive cognitive functioning.

• The number of doses of erythropoietin given in the treatment group was unclear.
• The authors stated that the CLOX test was found to be an insensitive measure for detecting cognitive changes.
• There was a lack of alternate forms for repeated administration with the EXIT-25 and CLOX tests.
• The results were confounded by chemotherapy treatment variations and the eventual administration of epoetin to the placebo group after the initial treatment phase.