Ginkgo Biloba

• FINAL NUMBER STUDIES INCLUDED = 13
• TOTAL PATIENTS INCLUDED IN REVIEW = 1,138
• SAMPLE RANGE ACROSS STUDIES = 20–210 patients
• KEY SAMPLE CHARACTERISTICS: Most studies included only women with breast cancer. All participants received chemotherapy with or without radiation therapy or hormonal therapy. Most participants were aged about 55 years. The majority of studies were conducted in the United States. Most outcomes were evaluated in the short-term (i.e., less than three months).

PHASE OF CARE: Late effects and survivorship

Risk of bias was high in 11 studies but unclear in  two studies that evaluated psychostimulants.

Pharmacologic interventions: No improvements in cognitive function were found using psychostimulants (four studies) or ginkgo biloba. Patients reported better cognitive function using epoetin alfa with doses titrated for hemoglobin levels (p < 0.05). However, a death caused by a cerebrovascular accident was noted.

Nonpharmacologic interventions: Small-group memory training improved self-reported cognitive function, and both memory and speed of processing after small-group training improved immediate and delayed recall (p < 0.05). Home-based online executive function training improved verbal function and attention (p < 0.05). Speed-feedback therapy during biking improved executive and motor function (p < 0.05). Cognitive behavioral therapy-based interventions (two studies), Tibetan sound meditation, and hatha yoga did not improve cognitive function.

The pharmacologic studies reviewed did not support the use of psychostimulants or ginkgo biloba to improve cognitive function after chemotherapy for breast cancer. Epoetin alfa was not recommended for practice because of safety concerns. The nonpharmacologic studies reviewed provided some evidence that cognitive training and speed-feedback therapy might improve cognitive function for breast cancer survivors.

The risk of bias was high for most studies. Therefore, although positive results were found, well-designed, prospective RCTs need to be completed to confirm these findings. It is unclear how sustainable the positive results of the cognitive training and exercise interventions might be because follow-up was limited to less than three months.

This systematic review provided limited support for cognitive training and structured exercise to improve cognitive function after chemotherapy for breast cancer. Cognitive training is currently categorized as likely to be effective for cognitive impairment.

• 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 test the hypothesis that ginkgo biloba may be helpful for radiation-induced cognitive impairment

120 mg ginkgo biloba was given for 24 weeks and then discontinued for 6 weeks as a washout period. Tests were administered at baseline, 12 weeks, 24 weeks, and 30 weeks after the initial evaluation.

• The study reported on a sample of 34 patients with a median age of 47 years (range 22–82).
• Participants were 32% male and 68% female.
• Cognitive impairment and depressed mood were present in the sample at baseline.
• All participants had brain irradiation six or more months prior to study entry and no evidence of disease progression.

• Single site
• Outpatient    
• North Carolina

Phases of Care: Late effects and survivorship

An open label phase II study design was used.

• Mini mental state exam
• Trail Making Test parts A and B
• Digit Span Test
• Revised Rey-Osterrieth Complex Figure Test
• Verbal fluency (FAS) test
• California Verbal Learning Test II
• FACT-Brain
• Profile of Mood States (POMS)

Trail Making Test (TMT) results improved significantly from baseline to 24 weeks; however, TMT-Part B continued to improve significantly from week 24 to week 30 after ginkgo was stopped. It is unclear if changes seen demonstrate improvement with treatment or learning effect. Scores for immediate and delayed recall on the Rey-Osterreith Figure were better (p < 0.0002), but these were not measured and reported at 30 weeks. There were no other changes in mental function scores. POMS scores improved for overall mood for the first 24 weeks and then began to decline. By 24 and 30 weeks, only 19 patients remained in the study. Most common toxicities reported were cognitive issues and memory problems. Five patients (16%) discontinued treatment because of gastrointestinal symptoms. One patient discontinued treatment because of intracranial bleed in one patient. Another five patients (16%) discontinued treatment because of no perceived benefit.

Findings from the study do not provide clear support for the effectiveness of gingko biloba on cognitive impairment caused by brain irradiation.

• The study had a small sample size with less than 30 participants.
• A risk of bias was possible because there was no control group, no blinding, and no random assignment.
• Findings were not generalizable.
• Subject withdrawals were greater than or equal to 10% of participants.
• There was a potential testing effect in the study.

Findings do not support effectiveness of gingko biloba to improve cognitive function in patients who have impairment associated with brain radiation.

Evaluate ginkgo biloba for the prevention of cognitive decline associated with adjuvant treatment for breast cancer

Patients were randomized to receive 60 mg of ginkgo biloba or a matching placebo twice a day starting before the second cycle of thermotherapy and continuing throughout treatment and 1 month beyond chemotherapy completion. Participants were stratified by type of chemotherapy, age, menopausal status, and lymph node involvement. Data were collected at baseline before the first or second chemotherapy cycle, during chemotherapy, at the first visit after chemotherapy (1 month), and at 6, 12, 18, and 24 months post-chemotherapy.

• A total of 210 participants were enrolled in the study.
• The median age was 50 years.
• The sample was 100% female.
• All participants had newly diagnosed breast cancer and were chemotherapy naïve. 
• All were receiving adjuvant chemotherapy. About 80% were receiving doxorubicin/cyclophosphamide with or without taxanes.
• 42% of the women were post-menopausal. 
• 94% of the women were Caucasian.

• Multi-site  
• Outpatient 
• 23 institutions in the United States

Participants were receiving active antitumor treatment.

Double-blind, randomized, placebo-controlled study

• High-Sensitivity Cognitive Screen (HSCS)
• Profile of Mood States (POMS)
• Cognitive subscale of the Perceived Health Scale (PHS)
• Common Terminology Criteria for Adverse Events (CTCAE) grading of adverse events
• Trail Making Test (TMT) A and B

No significant differences were seen between groups over 24 months in any study measures. All cognitive test scores improved from baseline to the first chemotherapy follow-up and then stabilized.

The study does not support the use of ginkgo biloba for prevention of cognitive impairment resulting from chemotherapy treatment in women with breast cancer.

• A risk of bias existed because of the very homogenous sample.
• The measurement validity and reliability was questionable because use of the same cognitive measures repeatedly could have resulted in improvement from practice effects.

Findings do not support the use of ginkgo biloba to prevent cognitive changes resulting from chemotherapy in patients with breast cancer.