Supplement Shows Promise for Improving Cancer-Related Cognitive Impairment

Cancer-related cognitive impairment (CRCI) in breast cancer survivors improved significantly after treatment with the glutamate regulator oxaloacetate, a preliminary single-arm clinical study showed.

All 16 evaluable patients in the trial had statistically significant and clinically meaningful improvement in a standardized assessment of cognitive function after 8 weeks. The mean score on the scale almost doubled. Fatigue and physical functioning also improved significantly, and a trend toward improvement in insomnia was evident.

Aside from gastrointestinal symptoms, the treatment was generally well tolerated, reported Patricia Ganz, MD, of UCLA Health in Los Angeles, and colleagues in JCO Oncology Advances.

“These early findings give us a strong reason to continue studying oxaloacetate as a potential approach for managing cognitive problems after breast cancer treatment,” Ganz said in a press release.

A randomized, placebo-controlled study is expected to begin before the end of the year.

Despite the small number of patients and lack of control group, the results are impressive, said Halle Moore, MD, of the Cleveland Clinic, who was not involved in the study.

“They had impressive improvement in patient-perceived cognitive function measures and improvement in fatigue and physical functioning,” Moore told MedPage Today. “It would be great to have a relatively easy option for patients to use for this troublesome symptom. I think the main point is that it supports proceeding to a longer randomized trial where we would compare to a control group.”

The intervention stands out from most previous studies that have focused on cognitive-behavioral interventions, such as exercise and managing anxiety, depression, and associated symptoms or issues, she added.

“I will be interested to see where this research goes, and I would love to have more options for our patients,” said Moore.

A substantial fraction of patients with cancer exhibit post-treatment cognitive impairment — commonly called chemo brain or brain fog. The condition is especially prevalent in breast cancer survivors and has been studied most extensively in patients with breast cancer but is not limited to those patients.

“It’s an issue for all types of cancer,” said Moore. “Breast cancer is just such a common cancer and there are so many breast cancer survivors, but we are seeing [cognitive impairment] more often in other cancers.”

Although the precise cause of and mechanisms underlying CRCI remain unclear, the condition became more prevalent in breast cancer following widespread adoption of adjuvant chemotherapy for early disease. Some of the agents used in adjuvant regimens cross the blood-brain barrier and have recognized neurotoxic effects. Early reports suggested a direct relationship between the intensity of chemotherapy treatment and cognitive dysfunction.

Oxaloacetate is a natural human metabolite involved in intracellular energy production. Additionally, oxaloacetate has a key role in regulation of the neurotransmitter glutamate, which has been studied extensively for its contributions to cognitive function. Several clinical studies evaluated oxaloacetate’s ability to improve cognition and reduce fatigue. A small randomized study of patients with symptoms of long COVID showed significant improvement in cognitive performance with oxaloacetate and correlations between symptom response and cognitive gains.

Evidence linking oxaloacetate to cognitive function, as well as the paucity of pharmacologic interventions for CRCI, provided the rationale for a prospective clinical study in breast cancer survivors with diagnosed CRCI. Eligible patients were 1 to 5 years removed from cancer treatment and had a score of <12 on the PROMIS questionnaire, indicating moderately severe impairment.

Given the lack of a control group, the investigators approached the study with some skepticism, and sought to minimize the trial’s limitations with an initial two-step design, which defined a positive outcome as a 4-point improvement in the FACT-Cog PCI in the first nine patients. The preliminary data analysis showed a 27-point improvement.

“The impressive and universal improvements in perceived cognitive impairment in the first nine study participants encouraged us to redesign the study to be able to complete it with a smaller total sample size and to hasten the development of a randomized, placebo-controlled trial,” the authors wrote.

The investigators enrolled a total of 18 patients, who received oxaloacetate 500 mg twice daily for 8 weeks. All but two patients completed the study. The primary endpoint was perceived change in cognitive impairment at 8 weeks.

Every patient who completed the study had significant improvement from baseline, and the mean score on the FACT-Cog PCI increased from 29.1 at baseline to 55.5 at 8 weeks, moving the cohort from impaired to within the normal range. Improvement was observed after 4 weeks and generally increased during the remaining 4 weeks of the study. Neuropsychological testing showed improvement in executive function and processing speed.

The most commonly reported adverse effects (AEs) were indigestion, bloating, constipation, diarrhea, and nausea. Two study participants discontinued because of gastrointestinal symptoms. No serious AEs occurred during the study.