CURE

SUMMER / 2014

Lessons Learned: Peripheral Neuropathy with Cancer

When trying to cope with peripheral neuropathy, sufferers could benefit from others’ success.

Since 2005, Linda McIntosh, a retired nurse in Groton, Conn., has been living with Waldenström macroglobulinemia, a rare form of non-Hodgkin lymphoma. She received the diagnosis at age 58, and chemotherapy has kept the cancer at bay for nearly a decade, but she says the most challenging aspect of her experience has been coping with nerve damage called neuropathy, the numbness and pain in her hands and feet that one study indicated is a symptom in around 45 percent of those who receive a diagnosis of Waldenström. For McIntosh, neuropathy has become her constant companion.

“The person who diagnosed it as neuropathy said, ‘You’ve got neuropathy, live with it.’ ”

Statistics indicate that up to 90 percent of patients who receive nerve-damaging chemotherapy agents may experience neuropathy, though the exact figure is unknown because there can be numerous inciting factors.

Many hear a response similar to the one McIntosh received from her healthcare team, due to the lack of information and treatment. For example, nerve damage can be a symptom of the cancer itself, as in McIntosh’s case, or a side effect of cancer treatment, including chemotherapy and radiation—with drug-induced causes now representing a growing percentage of cases.

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Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of certain classes of chemotherapy drugs, including platinumbased drugs, taxanes, vinca and plant alkaloids, certain immunomodulating agents and others. How these drugs affect the nerves differs, depending on the amount of the drug used, the treatment schedule, the patient’s age and pre-existing issues that can put the patient at risk.

CIPN symptoms usually begin during chemotherapy when patients experience tingling, numbness and pain in their hands and feet, customarily beginning in the tips of the fingers and toes. Some patients also develop weakness or may have trouble walking or even performing everyday tasks, such as dressing themselves.

Often, CIPN resolves when treatment ends. But for an estimated 40 percent of patients, it continues or even worsens as time progresses—again depending on the drug.

My job is to figure out the cause. There is often a reason why one patient gets severe symptoms from chemotherapy and another doesn’t.”

—Michael Stubblefield

CIPN affects the peripheral nerves, which include the sensory, motor and autonomic nerves. Symptoms of sensory nerve damage include numbness, tingling, temperature sensitivity, tightness and pain in the feet and hands. Motor nerve damage may result in foot drop and muscle weakness, affecting patients’ balance and ability to carry items. Autonomic nerves regulate involuntary body functions such as heartbeat, blood flow, breathing and digestion, and when they are involved, the result can be diarrhea, constipation, urine retention, impotence or unstable blood pressure upon standing, which can lead to dizziness and falling.

One challenge is insufficient information to help identify which patients are at risk for developing neuropathy with specific drugs and why. This spring, the American Society of Clinical Oncology released clinical practice guidelines for CIPN, which referred to the lack of high-quality evidence for any treatment to prevent CIPN while confirming the variations in severity, depending on regimens, duration of exposure and assessment methods.

A task force created by the National Comprehensive Cancer Network (NCCN) reviewed the incidence of CIPN across studies and found differences in incidence among breast cancer patients based on the drugs they were given in combination with taxanes. According to the study, 57 to 83 percent of patients with breast cancer treated with paclitaxel experienced neuropathy with 2 to 33 percent being severe, whereas incidence of neuropathy with docetaxel was 11 to 64 percent overall, with 3 to 14 percent severe. The incidence among those treated with cisplatin ranged from 28 to 100 percent. While it’s still unknown why some patients get neuropathy and others don’t, a number of theories are under investigation, including a possible correlation between inherited genes and a patient’s predisposition to neuropathy.

Peripheral neuropathy can also result from radiation. Although rare, it usually appears as a late effect years after treatment has ended. Radiation-induced peripheral neuropathy is not yet fully understood, but possible reasons for it include nerve compression by radiation-induced scar tissue or direct damage to nerves. Like CIPN, radiation-induced peripheral neuropathy has no clear treatment and is a chronic condition.

Getting to the Cause

Michael Stubblefield, associate professor and attending physician in physical medicine and rehabilitation at Memorial Sloan Kettering Cancer Center in New York, warns his medical residents not to assume a patient’s neuropathy is caused by chemotherapy until they have ruled out any pre-existing conditions that may have left the patient predisposed to developing CIPN.

“I tell my residents that we need to start at the brain and work our way down, ruling things in or out,” he says. “Did the patient have a stroke? Could they have a spinal cord injury? Could they have a preexisting peripheral nerve issue that was undiagnosed? Older patients could have degenerative disease, or they could have nerve root injury. Spinal stenosis, a narrowing of the spinal canal, can be caused by anything from arthritis to degenerative disease and can cause neuropathic symptoms.”

Stubblefield has had patients who were alcoholics but would not admit it, a condition that can also cause neuropathy, as can a vitamin B12 deficiency or diabetes. “My job is to figure out the cause,” he says. “There is often a reason why one patient gets severe symptoms from chemotherapy and another doesn’t.”

Everything works a little bit for someone.

—Edward Agura

He also says that knowing the root cause helps him narrow the treatment choices. “If it’s a B12 deficiency, it’s easily treatable by replacing vitamin B12,” he says.

“If existing spinal stenosis is a major contributing factor to why a patient developed leg pain and foot drop, then treating the spinal stenosis is often key to restoring their function and quality of life.”

For patients who have no identifiable cause for their condition, the neuropathy is referred to as idiopathic. Stubblefield attributes the variations in severity to genetics that create some unknown predisposition that puts patients on one side of the bell-shaped curve or the other.

Treatment Options

The bell curve is little comfort to Edward Agura, director of the Blood and Marrow Transplant Services at Texas Oncology in Dallas. He says newer drugs have opened a “Pandora’s box of neuropathy” for his patients with myeloma and points to Thalomid (thalidomide) and its derivatives—Pomalyst (promalidomide) and Revlimid (lenalidomide)—as drugs that work for myeloma, but with a common thread: neuropathy.

“Everyone can have a different level of severity, so I am always asking about neuropathy, and I have to lower the dosage in around one in 10 patients.”

In treating his patients for neuropathy, Agura goes down a laundry list of options, including anticonvulsant drugs such as gabapentin and pregabalin, antidepressants such as duloxetine, or opioids such as oxycodone, which have their own side effects.

If these don’t work, he offers options other patients have found successful, such as vitamin B12, acupuncture or a topical compound that is applied to the skin and contains the anesthetic ketamine.

“Everything works a little bit for someone,” he says.

Then there are patients like the young law enforcement officer who Agura treated for myeloma and whose neuropathy was particularly bad. “He couldn’t hold a gun anymore,” Agura says. “But when his neuropathy began climbing up his legs and reached his male anatomy he was in real agony. He had to retire and today takes a combination of drugs just to function.”

Agura is frustrated that there are so few options for his patients, some of whom have to choose between treatment and living with neuropathy.

Researcher Ellen M. Lavoie Smith, assistant professor in the School of Nursing at the University of Michigan in Ann Arbor, also recalls the patient who she says motivated her to research options for the small percentage of patients who experience severe pain. Smith says the woman was being seen at a neuropathy clinic she ran before moving to the University of Michigan.

“She was a young breast cancer patient who had minimal neurotoxic treatment but had significant pain from her fingers to her elbows and from her feet to her knees,” Smith recounts. “When she told her oncologist, he didn’t believe her and thought she was drug-seeking or crazy.” When Smith moved to Michigan, she focused her research on severe neuropathy and on the central nervous system as a means to control pain via the brain.

Smith led a phase 3 trial that revealed that duloxetine, an antidepressant that works by increasing pain-inhibiting neurotransmitters in the brain, decreased pain severity in 59 percent of patients experiencing CIPN, making it the first effective drug in treating this condition.

Other Treatment Options

Agura offers patients experiencing neuropathy any successful options his other patients have found, including acupuncture and CET (combination electro-chemical therapy), which has shown success in treating diabetic neuropathy. “I think if you are conscientious, you keep your eyes and ears open because there are many things that would help people, and we aren’t trained to offer them.”

CET combines two procedures: an ankle block performed with local medication and EST (electronic signal treatment), delivered by an electro-medical wave generator specifically developed for peripheral neuropathy and severe neuromuscular pain. The combination can provide relief for neuropathic pain while increasing blood flow to the affected areas, potentially regenerating nerves over the long term.

One of Agura’s patients, Wilkes Elgiar, a retired bank vice president, found success with CET after his neuropathy worsened with treatment.

“Revlimid caused numbness but no pain. Then with Velcade and Cytoxan, it was burning pain up my legs and very uncomfortable,” Elgiar says. “It got to the point where the only way I could sleep was to wear shoes.”

Elgiar tried several drugs, none of which worked, and began CET after seeing an ad for a neuropathy clinic. He says the pain is gone, prompting Agura to refer other patients to see if the treatment helps.

Other treatments being studied include new drugs, complementary therapies and options such as TENS (transcutaneous electrical nerve stimulation), a small electrical device that uses electrodes attached to the skin with wires where pain exists to transmit electric current. One theory is that as a result of the pain from the current, nerves are stimulated to release endorphins, the body’s natural painkillers.

Also under investigation is “scrambler therapy,” another treatment based on electrical stimulation through electrodes applied to the skin near the source of pain. According to the creators of the treatment, the perception of pain is substituted when the electrical stimulation uses the same pain pathway, replacing the earlier pain messages. A single-arm clinical study reported in the Journal of Pain and Palliative Care Pharmacotherapy showed a 30 percent reduction in the level of pain for participants one month after using the therapy.

Cancer survivor Meg Hentges says she feels strongly about taking part in clinical trials, because it was through a trial that she found a solution to her neuropathy. Hentges was treated for breast cancer in 2010 at age 49 and developed neuropathy during treatment. When it didn’t resolve, the Santa Rosa, Calif., resident was offered gabapentin by her oncologist. “A side effect was possible edema [swelling] in the hands and feet,” she says, “and he said it didn’t have a good success rate, so I turned it down.”

At that point, she says, the neuropathy, which she compares to walking on rocks, was adversely affecting her quality of life. She tried acupuncture and vitamins, neither of which helped. She even wore cotton socks that she dampened and then froze. She says with a laugh that they didn’t help. Then in November 2013, her oncologist told her about a clinical trial for a new drug called tetrodotoxin, often abbreviated TTX, which uses a toxin found in certain fish species, such as puffer fish. The drug works by blocking pain signals from the nerves to the brain.

Hentges says that after receiving the injections twice a day for four days, her pain was gone. She was granted compassionate use of the drug and is spreading the word of her success so others will sign up when the clinical trials open for enrollment. The drug has gained expanded access from the FDA while continued clinical trials are in the works.

“I was a professional guitar player,” Hentges says. “But I haven’t played in the past three years because of pain. Now I am playing again.”

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