WHETHER EXPERIENCING NUMBNESS AND PAIN in their hands or feet, or a mental fog that shadows their ability to do once-routine tasks, people who have cancer can continue to experience troubling side effects even after their last day of treatment.  

Highlighting treatment-related neurotoxicity, researchers at the American Association for Cancer Research (AACR) Annual Meeting 2023 explored the prevalence and biologic mechanisms of these troubling side effects in cancer survivors at a session titled “The Dark Side of Our Treatments: Therapy-induced Comorbidities,” in Orlando on April 14. (The AACR publishes Cancer Today.)

Nerve Function

Nathan Staff, a neurologist and researcher at Mayo Clinic in Rochester, Minnesota, noted that up to 50% of patients who receive a neurotoxic chemotherapy will experience chemotherapy-induced peripheral neuropathy (CIPN)—a common side effect of chemotherapy drugs that is often experienced as pain or numbness in the hands and legs. The side effect can jeopardize outcomes for patients, who may need dose-adjustments or treatment changes, and leads to high health care-related costs, particularly as more people age and, due to advances in treatments, live longer after cancer.

In one study of 509 patients who received neurotoxic chemotherapy between 2006 and 2008, more than half experienced CIPN, Staff said. In addition, patients who had CIPN during treatment were significantly more likely to be taking a neuropathic pain agent, such as an opioid or a serotonin-norepinephrine reuptake inhibitor, five years later. These long-term effects can be especially troublesome for children treated for cancer—with one study finding that more than half of childhood cancer survivors have signs of CIPN long term.

During his presentation, Staff provided an overview of the four neurotoxic compounds known to cause CIPN. First are platinum compounds, such as cisplatin, carboplatin and oxaliplatin. Patients taking these chemotherapy drugs can experience numbness and weakness that can lead to gait issues. Of these platinum agents, he mentioned oxaliplatin may cause cold sensations in the hands and when drinking liquids, and cisplatin is also associated with hearing loss. He added that these compounds, which are prescribed for colon cancer, lung cancer and other cancers, can damage neurons even after patients stop taking the medication, with symptoms worsening over time.

“The thing that is unusual about the platinum disorders is that once you stop the platinum therapy, the patient can actually get worse over time … so you know if a patient develops neuropathy on the platinum compound, they are likely to continue to get worse once you stop it,” Staff said.

Taxanes, which include paclitaxel and docetaxel, are the second category of neurotoxic compounds. These chemotherapy agents are used to treat a number of cancers, including breast cancer. Neurotoxicity from these chemotherapies can manifest as painful sensations, including feelings of burning or tightening around the body, but weakness is uncommon. Staff noted that these symptoms can improve after treatment is stopped. Another category of chemotherapy agents is the vinca alkaloids, such as vincristine and vinblastine. These agents, often prescribed for acute lymphocytic leukemia and lymphoma, tend to cause loss of sensation in hands and feet with or without pain, along with weakness, causing walking difficulties especially in children, Staff noted. The final category of drugs, called proteasome inhibitors, such as bortezomib and carfilzomib, can cause painful burning sensations without weakness.

The National Cancer Institute (NCI) has sponsored several clinical trials to test different agents for the prevention and treatment of CIPN, but only one approach showed efficacy: The drug duloxetine improved pain in cancer patients taking taxanes and platinum therapy.

“Unfortunately, there hasn’t been much success in the prevention world,” Staff said. “With treatment trials, a number of things we typically use for neuropathy did not show benefit in CIPN except for duloxetine.”

Sharing research about how peripheral neuropathy typically presents in cancer patients, Stefanie Geisler, a neurologist and researcher at Washington University School of Medicine in St. Louis, shared findings from a study that included 131 patients with CIPN who participated in the Peripheral Neuropathy Research Registry, a multi-institution study. She noted that many health care providers associate CIPN with pain, but patients are also commonly bothered by numbness and weakness. Patients who have pain typically always have numbness as well, but numbness is the first sign that the axons, the cablelike strands that deliver electrical impulses to neurons and cells throughout the body, are dying, she said.

Geisler described her research in mice that focused on the SARM1 protein that drives axon degeneration pathways found almost exclusively in neurons. She noted that when researchers engineered mice so they would not express SARM1 and exposed them to the chemotherapy drug vincristine, their neural axons were still intact. Geisler and her team developed an agent that binds with SARM1 to effectively block this pathway and preserve axon and nerve function in mice after exposure to chemotherapy agents.

Brain Fog

Another common side effect, cancer-related cognitive impairment (CRCI) refers to a broad range of symptoms that include difficulty with multitasking, concentration and attention. But like with CRPN, scientists are still trying to determine mechanisms at play and prevention and treatment strategies. “Treatments are limited at this point. We treat it as a brain injury with cognitive training and rehabilitation as the mainstays,” Staff said, adding that studies are looking into exercise, mind-body therapies and pharmacotherapy as potential interventions.

“I think part of the problem that comes up with this is it is difficult to pin down which mechanism is taking precedent in a given patient,” Staff said, adding that that chemotherapy, radiation, immunotherapy, targeted chemotherapeutic agents, endocrine therapies and stem cell transplants have all been associated with CRCI symptoms. In addition, the cancer itself can impact cognitive function, through resulting systemic inflammatory response, nutritional deficiencies and anemia. “It’s a very diverse and complex interplay of these things for the population as a whole,” Staff said.

Erin Gibson, a neuroendocrinologist and researcher at Stanford University School of Medicine in California, presented findings that showed how microglia, which are immune cells in the central nervous system that insulate and nourish nerve axons, become dysregulated after chemotherapy administration. However, by using a microglia-depleting drug in mice, her lab’s research showed they were able to prevent damage to the myelin and protect axons. In researching mechanisms that can lead to impaired cognitive function, she found that mice treated with a microglial inhibitor had thicker myelin and performed better in cognitive tests even after receiving methotrexate, suggesting an important target for future research.

During her research, Gibson, who studies the role of circadian rhythms in treatment response and patient outcomes, also noticed that mice that were injected with chemotherapy in the morning were more likely to die from the injection. Upon further research, her lab observed differences in the concentration of the drug that made it to the brain based on the time of day the drug was administered. In fact, mice that received the chemotherapy drug methotrexate in the morning had double the concentration of the drug reach their brains, compared with those that received methotrexate at night. Her findings and the work of others suggest that neural cells follow circadian rhythms, which may be important for timing treatments.

“Finding ways to sort of harness time-of-day effects might be a way that we can ameliorate some of these negative side effects with CRCI while increasing some of the efficacy of these drugs,” Gibson said.

Making progress in preventing and treating these side effects will require more efforts from researchers to understand the complex mechanisms that spur chemotherapy-related neurotoxicity, the presenters said. Staff noted chemotherapy-induced neurotoxicity was highlighted as one of the 2023 Cancer Grand Challenges, a program from the NCI and Cancer Research UK that provides funding for innovative interdisciplinary research advancing the science around some of the greatest challenges in cancer. “Hopefully, we’ll be having some large multidisciplinary teams to be tackling this problem,” he said.

Marci A. Landsmann is the managing editor of Cancer Today.