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Vitamin E May Lesson Neurotoxity Associated with Cisplatin Chemotherapy

ARTICLE IN BRIEF

In a randomized, placebo controlled trial, vitamin E seemed to prevent neurotoxicity in patients undergoing cisplatin-based chemotherapy.

Vitamin E may help protect against nerve damage caused by cisplatin-based chemotherapy without diminishing the drug's effectiveness, according to a new study published in the March 2 issue of Neurology.

“The results of our study indicate that vitamin E supplementation significantly protects against cisplatin peripheral neurotoxicity and reduces the incidence and intensity of neuropathic signs and symptoms,” Andrea Pace, MD, a neurologist at Regina Elena National Cancer Institute in Rome and the study's lead author told Neurology Today. “Another important point is that vitamin E supplementation does not interfere with cisplatin anti-tumor activity.”

Finding a way to protect against the neurotoxicity caused by platinum-based chemotherapy agents would be a major advance because patients can develop side-effects that are so debilitating that they have to cut back on their treatment or sometimes even quit it, she said. Patients can develop tingling and loss of feeling in their fingertips and toes and have problems with balance and walking. Loss of hearing can also be an issue.

“The clinical use of cisplatin chemotherapy is limited by severe neurotoxicity reported in up to 90 percent of patients receiving a cumulative dose higher than 300 mg/m2,” according to background information in the published report.

Some previous research has suggested that vitamin E, an antioxidant, could be helpful, but the approach is still unproven. “Recent studies support that cisplatin-induced neuropathy is related to degeneration of large dorsal root ganglion cell bodies with loss of large myelinated fibers,” the researchers wrote. “Evidence suggests that the side effects induced by cisplatin treatment are, at least in part, the result of the formation of free radicals.”

“Many authors, given the high concentration of vitamin E in dorsal root ganglia, have hypothesized that vitamin E may have a stronger neuroprotective activity than other antioxidants,” the authors pointed out. “However, the small size of the published studies does not make it possible to draw definitive conclusions.”

STUDY PROTOCOLS, RESULTS

For this latest study — conducted at the institute in Rome and the National Neurologic Institute C Besta in Milan — 108 patients with solid tumors who were slated for treatment with cisplatin were randomly assigned to either receive vitamin E supplements or a placebo. Treatment with vitamin E (400 mg/day) or the placebo was started orally after randomization and on average about three days before the initiation of chemotherapy. It continued until three months after discontinuation of cisplatin.

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DR. ANTHONY WINDEBANK said the paper on vitamin E “is an interesting study and it is rational — it makes sense that vitamin E might be protective. But the problem with this study is that there is such a small number of patients and they had a large number of drop outs, which makes it difficult to interpret.”

Prior to starting treatment, study participants underwent a neurological evaluation that served as a baseline for comparison later. It included a standardized history for detection of neuropathic symptoms and an assessment of pin-prick and vibratory sensations, strength, and deep tendon reflexes.

Clinical neurotoxicity status was graded with the Total Neuropathy Score (TNS), a validated score that includes clinical signs and symptoms and neurophysiological examination, and vibratory sensation was examined using the Reidel-Seiffer tuning fork. Patients also underwent an electrophysiological exam using surface electrodes to assess nerve conduction velocity and the amplitude of potentials of sensory median and sural nerves. Patients were then re-evaluated with the same examinations after three cycles of cisplatin and one month after the end of treatment. Neurotoxicity incidence was considered the primary endpoint.

The study suffered from a high drop-out rate, though researchers said they had expected that to happen and had planned for it by enrolling more people than statistically needed up front. Of the 108 people who began the study, 40 dropped out, mostly because of disease progression. Then 27 of the remaining 68 were not included in the final analysis because they received a cumulative dose of cisplatin that was lower than 300 mg/m2, the cisplatin cumulative dose considered neurotoxic.

The researchers said a comparison of the remaining two groups of participants showed no differences in disease status. Twenty six of the 41 patients had lung cancer, nine had glioblastoma, and there was one case each of endometrial cancer, bladder cancer, surrenal gland cancer, and carcinosarcoma. Cisplatin was given as part of a combination regimen that varied depending on the type of tumor, though none of the other drugs used had a neurotoxic effect.

The investigators reported that the incidence of neurotoxicity, as measured using TNS, was lower in the vitamin E group than in the controls (5.9 percent versus 41.7 percent) and the severity of neurotoxicity was also lower. (On average, a TNS score of 1.4 versus 4.1.)

Clinical neurological exams done at the end of treatment on patients receiving vitamin E supplementation showed deep tendon reflex alteration in 11.8 percent (compared to 37.5 of controls), distal reduction of pin sensibility in 23.5 percent (compared to 41.6 percent of controls), reduction of vibration sensibility in 5.8 percent (compared to 25 percent of controls), and paresthesia in 17.6 percent (compared to 37.5 percent of controls). Follow-up electrophysiological exams (sural sensory action potentials) also showed fewer signs of damage in the group that took Vitamin E. Not only did the vitamin regimen provide a protective effect, it did not seem to interfere with the anti-tumor activity of cisplatin, the researchers reported.

“Peripheral neurotoxicity is the main dose-limiting toxicity of cisplatin chemotherapy,” Dr. Pace told Neurology Today. “Vitamin E neuroprotection may improve quality of life of patients treated with cisplatin, but may also improve the therapeutic index allowing higher dosage and even re-treatment at cancer recurrence.”

EXPERTS COMMENT

Anthony Windebank, MD, professor of neurology at the Mayo Clinic College of Medicine in Rochester, MN, said finding a way to protect against the neurotoxicity of platinum-based drugs is crucial because 20 to 30 percent of cancer patients go off the drugs because they develop severe neuropathy that can persist long after treatment is stopped or even permanently.

“The neuropathy is very troubling for patients. Now that we have many people surviving cancer after chemotherapy treatment, we have to pay more attention to the side effects,” Dr. Windebank, who was not involved with the study, told Neurology Today.

He said this current paper on vitamin E “is an interesting study and it is rational — it makes sense that vitamin E might be protective. But the problem with this study is that there is such a small number of patients and they had a large number of drop outs, which makes it difficult to interpret.”

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DR. JAMES W. RUSSELL said more large clinical trials are needed to establish efficacy of vitamin E for cisplatin-induced neuropathy.

James W. Russell, MD, associate professor of neurology, anatomy and neurobiology at the University of Maryland School of Medicine, told Neurology Today that although there is promising preclinical and clinical evidence of the benefit of vitamin E in cisplatin-induced neuropathy, phase 3 studies with large numbers of people are needed to establish efficacy.

Other antioxidants are being evaluated for treating cisplatin-induced neuropathy, he noted. For example, gluthathione and alpha-lipoic acid might provide a protective effect by preventing mitochondrial damage caused by cisplatin. As with vitamin E, these other potential antioxidant therapies will need to be evaluated in appropriately randomized, blinded clinical studies, he said.

Dr. Pace agreed that additional research is needed on vitamin E — for instance, animal studies suggest that the vitamin may protect against ototoxicity, though that has not be proven in humans. He also stressed that patients should not take vitamin E on their own.

“At present we do not have adequate randomized controlled trial evidence on the interaction of common antioxidants with radiations and chemotherapy,” he said. “Cancer patients should not self-medicate with high doses of antioxidants.”

References

Pace A, Ginnarelli D, Cognetti F, et al. Vitamin E neuroprotection for cisplatin neuropathy: A randomized, placebo-controlled trial. Neurology 2010;74:762–766