Characterized by pain and loss of sensation in the hands and feet, chemotherapy-induced peripheral neuropathy (CIPN) can interfere with cancer patients’ treatment and significantly diminish their quality of life. Researchers at The University of Texas MD Anderson Cancer Center are testing new treatments for CIPN, a serious adverse effect of chemotherapy and unfortunately one of the most common.
“Neuropathy is a pretty pervasive problem; it can happen to patients with any type of cancer and be caused by many types of chemotherapy,” said Sarah Prinsloo, Ph.D., an assistant professor in the Department of Palliative, Rehabilitation, and Integrative Medicine. “And there aren’t a lot of effective treatments on the market for it.”
Dr. Prinsloo and others are working to change this. In preclinical studies and clinical trials, she and her colleagues are testing pharmacological and noninvasive neuromodulation treatments to control—and perhaps even reverse—CIPN.
A complex complication
Chemotherapy induces neuropathy by damaging the nerves that control sensation and sometimes those that control mobility. But why CIPN affects who it does, when it does, is unclear.
“Many factors might contribute to CIPN, including patients’ inherent susceptibility, their genetic makeup, and the amount and duration of their chemotherapy,” said Salahadin Abdi, M.D., Ph.D., a professor in and chair of the Department of Pain Medicine.
Both the onset and duration of CIPN vary among individuals. Some patients experience neuropathy with the first dose of chemotherapy; others may not experience it until late into treatment. Some patients continue to have neuropathy well after treatment has ceased; in others, the neuropathy ends as soon as treatment stops.
What patients with CIPN experience also varies. “It’s classified as a pain syndrome, but patients with neuropathy can have a variety of symptoms. Some patients do have pain, but some just have weird sensations. Sometimes they get super cold; sometimes they are hot. And sometimes it feels like something heavy is sitting on their legs,” Dr. Prinsloo said. “Most of our patients describe numbness, tingling, and complete loss of sensation.”
In some cases, Dr. Prinsloo said, neuropathy in the feet becomes so pronounced that patients can no longer drive because they cannot feel the pressure they are putting on the pedals. Others lose their sense of balance and require the use of a walker.
CIPN is typically treated with antidepressants, anticonvulsants, and/or analgesics. Topical numbing agents such as lidocaine are sometimes used, and opioids may be employed in cases involving extreme pain. However, none of these options are especially effective, and all have adverse effects.
“Overall, the current medications for treating CIPN are not satisfactory,” Dr. Abdi said. “Other options need to be developed.”
Neuromodulation offers an alternative
Given the limitations of currently available pharmaceutical interventions, more physicians and their patients are turning to nonpharmaceutical means of addressing neuropathy. One area that has shown particular promise is neuromodulation.
“Anything the brain can learn to do—including processing pain—it can learn to do differently,” Dr. Prinsloo said. “Neuromodulation is training the brain to do something different than what it is currently doing using feedback, stimulation, or other nonpharmaceutical means.”
Neuromodulation-based interventions under investigation at MD Anderson include scrambler therapy, repetitive transcranial magnetic stimulation (rTMS), and neurofeedback.
Scrambler therapy prevents damaged nerves from sending their information to the brain to interpret, allowing only normal information through. The result is a reduced perception of pain and improved perception of sensation.
“Patients with CIPN seem to respond well to scrambler therapy, but we do not know why that’s the case.” Dr. Abdi said. “What we do know is that these patients feel better, their pain gets better, they can reduce their medication, and they are able to feel their hands and feet again.”
Scrambler therapy, which has no known adverse effects and can be repeated, is delivered over 10 days in 45-minute sessions. Electrodes are placed around the areas of worst neuropathy to stimulate the C nerve fibers that carry sensory information to the brain. The therapy typically begins to reduce pain within 5–10 minutes and can have long-lasting results.
“The benefit lasts for several months,” Dr. Abdi said. “And when the pain comes back, it’s never as bad as it was prior to treatment.”
Dr. Abdi has used scrambler therapy to treat more than 20 patients with CIPN or neuropathy of other etiologies, including shingles and phantom limb pain. Most of the patients have responded well, but results in patients with CIPN have been particularly promising.
“The results we’re seeing are phenomenal,” Dr. Abdi said. “We looked at 10 patients with CIPN, and they had an average 62.5% reduction in their pain. Nine of those patients reduced their medication. And eight patients had significant improvement in their sensation.”
Dr. Abdi said that he and his colleagues are planning a randomized controlled trial of scrambler therapy, noting that patients will be followed up for at least 6 months to determine the long-term effects of the treatment. In the long run, he said, scrambler therapy may be widely used to treat not only CIPN but also other neuropathic pain syndromes, such as diabetic neuropathy.
“Scrambler therapy is effective for CIPN, and most probably for other types of neuropathy,” Dr. Abdi said. “Given the option to treat my patients with a therapy that does not have adverse effects, it’s an easy decision for me to look into scrambler therapy.”
Neurofeedback is a form of operant conditioning, which modifies behavior by reinforcing the positive consequences of the preferred behavior.
“The brain likes to learn,” Dr. Prinsloo said. “Once it figures out that it will get a reward if it changes its function in a particular site, it will keep trying to earn that reward by doing the new function over and over and over again. Eventually, that becomes the normal function of that part of the brain.”
A course of neurofeedback treatment takes 20 sessions, each lasting less than an hour. Electroencephalography (EEG) sensors are placed on the patient’s scalp at the appropriate locations to track the brain waves in the regions that are active during neuropathy pain episodes. Researchers show the patient a video representation of his or her brain waves while they monitor the patient’s EEG. Every time the patient adjusts his or her brain wave pattern in the way desired, he or she receives positive visual and auditory feedback.
Although patients usually feel relief from symptoms within the first 10 sessions, Dr. Prinsloo said, “If we stop giving them feedback too early, they won’t memorize it. So the goal of those second 10 sessions is memorization. Once we get their neuropathy symptoms to drop, we just repeat the reinforcement until they memorize it.”
In a pilot study of neurofeedback, Dr. Prinsloo and her colleagues randomly assigned 30 CIPN patients with any type of cancer at any stage to a neurofeedback group and another 32 CIPN patients to a wait-list control group (these patients were offered neurofeedback following the study). At the completion of the study, patients in the neurofeedback group had clinically and statistically significant reductions in their CIPN.
Importantly, the neurofeedback group had a 100% completion rate, which Dr. Prinsloo attributes to the patients’ strong desire to obtain relief. She and her colleagues are now investigating neurofeedback for CIPN in a clinical trial for breast cancer patients (No. 2015-0399).
Repetitive transcranial magnetic stimulation
rTMS, which has been around since the 1980s, was first approved by the U.S. Food and Drug Administration to treat depression and more recently approved for language and motor mapping prior to neurosurgery. rTMS has been experimentally shown to be effective for chronic pain syndromes and epilepsy; now, Dr. Prinsloo is investigating the therapy in a clinical trial for colorectal cancer patients with oxaliplatin-induced neuropathy (No. 2016-1134).
“A lot of literature suggests that rTMS works for chronic pain, and some literature suggests that it works for CIPN,” Dr. Prinsloo said. “But no study has looked at it in this population.”
Patients in the trial, which has just begun enrollment, complete rTMS in 10 sessions, each lasting less than an hour. During each session, patients sit in a comfortable chair, and an electromagnetic coil is placed against the side of the head. Targeted magnetic pulses induce electrical currents in the motor strip of the brain to encourage it to change its activity. The treatment has only a few mild adverse effects, such as scalp irritation.
Preclinical work shows promise
Annemieke Kavelaars, Ph.D., a professor in and chair ad interim of the Department of Symptom Research, is using rodent models to investigate several potential pharmaceutical approaches to preventing CIPN, most of which involve protecting the mitochondria in peripheral neurons—cells with a length of up to a meter. For a peripheral neuron to function correctly, it must be able to transport proteins made in the cell body, located in the dorsal root ganglia adjacent to the spinal cord, all the way to the end of the axon in the body’s extremities. This process requires good energy metabolism, which depends on the cell’s mitochondria.
“Chemotherapy damages those energy-producing mitochondria, mainly in the periphery, and that’s why CIPN often starts in the toes, extends to the feet, and then begins to involve hands and, if it gets worse, expands upward to the trunk,” Dr. Kavelaars said. “Because of the damage to those energy factories, the peripheral nerve endings begin to retract from the skin in the hands and feet, and that’s probably contributing to the numbness that people with neuropathy feel.”
Among the agents she and her team have investigated are metformin, the widely used antidiabetic drug, and pifithrin-μ (PFT-μ), a small compound that inhibits the binding of p53 to mitochondria.
“We have seen that if we protect the mitochondria with either metformin or PFT-μ, we can prevent both the pain and the loss of sensation that comes with neuropathy,” Dr. Kavelaars said.
Dr. Kavelaars and her team are also investigating agents that might reverse CIPN. “Many investigators have shown that there are compounds that can help prevent neuropathy—at least in rodent models—but to repair the damage that’s already been done is much more challenging,” she said. “Our recent studies are among the first to show that neuropathy can indeed be reversed with a pharmaceutical.”
One such drug is the novel selective HDAC6 (histone deacetylase 6) inhibitor ACY-1083. “With this drug, we’re seeing more of the healthy mitochondria being transported to the periphery and then regrowth of the damaged nerve endings. The pain and numbness go away,” Dr. Kavelaars said. “It repairs the problem, getting to the cause of the issue.”
In addition to repairing nerve damage, metformin, PFT-μ, and ACY-1083 have been shown to enhance the anticancer effects of other cancer therapies in vitro and even in vivo. In fact, another HDAC6 inhibitor, ricolinostat, which is less selective than ACY-1083, is already being tested for its anticancer-enhancing effects in a clinical trial at MD Anderson (No. 2011-0167, which has completed enrollment).
On the horizon
Even as neuromodulation-based therapies move forward in clinical trials and as new—and existing—agents accumulate promising preclinical data, questions about neuropathy remain.
“We need to understand much more about how neuropathy normally resolves. A significant portion of patients with neuropathy continue to have the problem after they complete chemotherapy, but there’s also a large group whose pain goes away when treatment stops,” Dr. Kavelaars said. “And we don’t know why some people continue to have the problem and others don’t.”
The answers to these questions, Dr. Kavelaars hopes, will help researchers develop even more effective therapies for CIPN.
“After years of frustration, we’re finally moving toward finding interventions that can truly resolve CIPN,” Dr. Kavelaars said. “There’s real relief for these patients on the horizon.”
For more information, Dr. Salahadin Abdi at 713-792-0883 or firstname.lastname@example.org, Dr. Annemieke Kavelaars at 713-794-4453 or email@example.com, or Dr. Sarah Prinsloo at 713-563-9627 or firstname.lastname@example.org. For more information about clinical trials for patients with neuropathy, visit www.clinicaltrials.org and search for study No. 2015-0399 or 2016-1134.
Krukowski K, Ma J, Golonzhka O, et al. HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy. Pain. 2017;158:1126–1137.
Maj MA, Ma J, Krukowski K, et al. Inhibition of mitochondrial p53 accumulation by PFT-μ prevents cisplatin-induced peripheral neuropathy. Front Mol Neurosci. 2017;10:108.
Majithia N, Smith TJ, Coyne PJ, et al. Scrambler therapy for the management of chronic pain. Support Care Cancer. 2016;24:2807–2814.
Mao-Ying QL, Kavelaars A, Krukowski K, et al. The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model. PLoS One. 2014;9: e100701.
Prinsloo S, Novy D, Driver L, et al. Randomized controlled trial of neurofeedback on chemotherapy-induced peripheral neuropathy: a pilot study. Cancer. 2017;123:1989–1997.
OncoLog, November-December 2017, Volume 62, Issue 11-12