CIPN Tied to Compromised Executive and Neuromuscular Function

PHOENIX — Chemotherapy-induced peripheral neuropathy (CIPN) is linked to a decline in executive and neuromuscular function, a new finding that may increase the risk for compromised mobility and fall risk.

“Among older cancer survivors treated with chemotherapy, the presence of CIPN was independently associated with reduced executive function,” study investigator Brendan L. McNeish, MD, of the Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pennsylvania, told Medscape Medical News.

“Importantly, given the emerging relationship of executive function with mobility in this population, stakeholders and clinicians are called to acknowledge that chemotherapy-related mobility declines in CIPN survivors are likely due to both neuromuscular and executive dysfunction,” he said.

The findings (abstract #12) were presented on November 3 at the 2023 American Association of Neuromuscular Electrodiagnostic Medicine (AANEM) Annual Meeting.

Research Gap

Characterized by numbness, tingling, pain, and motor impairment, CIPN affects up to 50% of all patients with cancer that is treated with taxane-, platinum-, or vinca alkaloid–based chemotherapy. The condition is among the leading dose-limiting toxicities, potentially increasing mortality risk.

Though the effects of chemotherapy on cognitive function are well-established, less is known about a potential relationship between this side-effect and CIPN, McNeish said.

“Chemotherapy can be neurotoxic, but few studies have linked neurotoxicity to the central nervous system and peripheral nervous system,” McNeish said.

To compare cognitive outcomes in patients treated with chemotherapy who did and did not develop CIPN, the investigators conducted a cross-sectional study that included 50 chemotherapy-treated cancer survivors at a single time point post-chemotherapy. The mean age of participants was 65.6 years, and 90% were women.

Twenty-two (44%) patients had CIPN on the basis of patient-reported distal paresthesias or numbness that started when chemotherapy was initiated and was present at the time of study enrollment.

Patients with CIPN had a greater decline in executive function compared with those without the condition, as measured by the Trail Making Test Part B (TMT-B; CIPN-positive, 84.9 sec vs 59.1 sec, respectively; P = .01), and the Stroop Color and Word Test (SCWT; CIPN-positive, 178.1 sec vs CIPN-negative, 152.7 sec; P = .04), and lower rapid reaction accuracy (CIPN-positive, 60.3% vs CIPN-negative, 70.6%; P = .01).

The association between CIPN and decreased executive function remained after multivariate adjusting for age, gender, depression, and benzodiazepine use for TMT-B (beta, 18.7; P = .046) and rapid reaction accuracy (beta, -.088; P = .018), but not SCWT (beta, 9.52; P = .233).

Clinical Guidance

A recent study by the same investigators showed a link between executive function and balance in cancer survivors (mean age, 65.6 years; 88% women) treated with chemotherapy.

Another study of 116 patients treated with chemotherapy, including 32 who developed CIPN, showed that those with CIPN were nearly three times more likely to report a fall or near fall than were those without CIPN symptoms. In addition, those with CIPN symptoms were also more likely to have received medical care for falls.

Based on the current findings, the research suggests that “current clinical approaches to caring for this growing population [of cancer patients] should not assume that the well-known increased fall risk is solely related to CIPN.”

McNeish speculated that two potential hypotheses could explain the association between CIPN and reduced executive function in older cancer survivors.

“First, CIPN is associated with other conditions such as depression and anxiety which are associated with reduced executive function,” he said.

“The second is that cancer-related cognitive dysfunction and CIPN share pathogenic mechanisms of neuronal injury, inflammation, and advanced aging, and thus some patients are vulnerable to both central (cancer-related cognitive function) and peripheral (CIPN) neurotoxicity.”

Either way, McNeish noted that “all interventions should measure both CIPN and executive function, as one could confound the other.”

Need for Increased Awareness

Commenting on the study for Medscape Medical News, Ting Bao, MD, co-director of the Leonard P. Zakim Center for Integrative Therapies & Healthy Living at the Dana-Farber Cancer Institute, in Boston, Massachusetts, said that the findings underscore that “there is a need for increased awareness of the diverse manifestations of chemotherapy-induced neuropathy.”

These include the fact that “neurotoxic chemotherapy impacts both the peripheral and central nervous systems, affecting balance through distinct mechanisms.”

Although treatments routinely recommended for CIPN include duloxetine, tricyclic antidepressants, or gabapentin as well as topical agents such as lidocaine, evidence also shows benefits of nonpharmacologic approaches including exercise, acupuncture, and yoga. Bao’s own research has suggested those benefits can extend improved balance and reduced fall risk.

Bao and colleagues recently conducted a randomized study that included 41 patients with CIPN to receive either yoga or usual care.

“The findings revealed that after eight biweekly sessions of yoga, there was a notable improvement in the far-reach test, which is a predictor of fall risk,” she said.

To validate these findings, the researchers are currently conducting a larger randomized controlled trial, she said.

In the meantime, “further research into the mechanisms and effective treatments for chemotherapy-induced neurotoxicity is essential,” added Bao.

McNeish and Bao report no relevant disclosures to report.