Acetyl-l-Carnitine Yields Mixed Results for Chemo-Induced Neuropathy

The impact of acetyl-l-carnitine on chemotherapy-induced peripheral neuropathy may depend largely on the clinical context and patient population, a pair of phase III trials suggests.

Acetyl-l-carnitine (ALC), a natural substance marketed over the counter as a dietary supplement, is popular among cancer patients as a result of preclinical and early-phase data in chemotherapy-related neuropathy and also a study in patients with diabetes-related peripheral neuropathy.

But in a trial among 409 U.S. women receiving adjuvant chemotherapy for breast cancer, those who took ALC not only had no decrease in the development of peripheral neuropathy symptoms relative to peers who were given a placebo, but actually had an increase. And they had a higher rate of serious neuropathy, too.

In contrast, in a trial among more than 200 Chinese patients with various cancers who had peripheral neuropathy from previous chemotherapy, those who took ALC were more likely than those who took a placebo to have an improvement of at least one grade in their neuropathy. They also were more likely to have improvements in fatigue and strength.

Taken together, the two trials, which were reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology, provide yet another cautionary lesson on the complexity of combining conventional and complementary therapies.

“The use of ALC for prevention is not recommended, and I would say, based on [these results], should be cautioned against. It will be interesting to see the carnitine data and to understand, as much as possible, why the trial was negative,” commented Debra L. Barton, Ph.D., of the Mayo Clinic in Rochester, Minn., who was invited to discuss the research. “Further studies are needed to really understand if ALC should be used to treat peripheral neuropathy.”

ALC for Prevention of Peripheral Neuropathy

Dr. Dawn L. Hershman

In the first trial, Southwest Oncology Group (SWOG) protocol S0715, investigators led by Dr. Dawn L. Hershman randomized women receiving adjuvant taxane chemotherapy for early breast cancer evenly to either oral ALC 1,000 mg three times daily or matching placebo, for 24 weeks.

Compared with their counterparts in the placebo group, women in the ALC group were more likely to have a greater than 5-point adjusted decrease on the neurotoxicity subscale of the Functional Assessment of Cancer Therapy–Taxane (FACT-NTX) instrument at 12 weeks (odds ratio, 1.48; P = .08) and also at 24 weeks (38% vs. 28%; OR, 1.57; P = .05).

This magnitude of worsening is clinically meaningful, maintained Dr. Hershman of Columbia University in New York, “so this is not like a lot of studies where you find a statistically significant difference that’s not clinically meaningful.”

In addition, the incidence of grade 3/4 neurotoxicity was 3.8% with ALC, much higher than the 0.5% seen with placebo.

Patients in the ALC group also had scores on the FACT trial outcome index subscale (FACT-TOI), an overall measure of function, that were on average 3.5 points lower (worse) than those among their placebo counterparts (P = .03). There were no significant differences between groups in terms of fatigue and other toxicities.

The investigators have collected biosamples and will be assessing potential biological correlates with peripheral neuropathy outcomes, according to Dr. Hershman.

“We are looking at DNA, oxidative stress, and carnitine levels to better understand the mechanisms of chemotherapy-induced peripheral neuropathy to begin with, because there is not a whole lot known in terms of mechanism,” she said. “If we can figure out what makes people worse, then we will maybe be able to figure out how to make people better from a more mechanistic standpoint, because there are very few drugs to treat chemotherapy-induced peripheral neuropathy.”

An obvious concern from the trial’s findings is that ALC may somehow potentiate the neurotoxic effects of taxanes. “Based on these data, physicians should be telling patients not to take ALC during adjuvant chemotherapy,” Dr. Hershman concluded. “You need to talk to patients. We know from the literature that overwhelmingly large number of patients take supplements during chemotherapy and afterward, many of which have not been tested. It’s important to get that history from patients.”

Dr. Barton, the discussant, praised the trial’s rigorous methodology and proposed that there may have been several reasons for the lack of ALC benefit in preventing neuropathy, despite compelling earlier data.

Previous prevention research was done in animals and thus may not translate to humans, she said. And a positive trial for treatment in humans used intravenous administration, which may result in different bioavailability. Finally, “ALC capsules needed to be taken three times a day, and they are rather large, and these patients were, after all, on chemotherapy. They were likely nauseated [and] dyspeptic, and taking what some might call a horse pill three times a day could not have been an easy task. The study did use pill diaries, but we know those aren’t a perfect tool for adherence.”

“The great thing is that the study collected blood and they are able to look at carnitine levels,” Dr. Barton said. “So if carnitine is up in the group that got acetyl-carnitine and not in the group that got placebo, well, I think that pretty much confirms that this just didn’t work.”

ALC for Treatment of Peripheral Neuropathy

In the second trial, protocol ZHAOKE-2007L03540, investigators led by Dr. Yuanjue Sun of the Sixth Affiliated Hospital of Shanghai (China) Jiao Tong University, enrolled 239 patients who had cancer of various types and stages, had completed chemotherapy, and had had at least grade 2 peripheral neuropathy for up to 6 months.

They were randomly assigned to receive either oral ALC at a dose of 3 g/day or matching placebo, for 8 weeks, with outcomes assessed at clinic visits or by telephone.

Analyses showed that compared with their counterparts in the placebo group, patients in the ALC group were more likely to have had an improvement of at least one grade in their neuropathy, both at 8 weeks (51% vs. 24%; P less than .001) and at 12 weeks (58% vs. 40%; P less than .001).

In terms of secondary outcomes, the ALC group was also more likely to have had an improvement in cancer-related fatigue (31% vs. 20%; P = .048), physical strength (29% vs. 13%; P = .02), and electrophysiology in peripheral nerves (75% vs. 58%; P = .02).

The two groups had statistically indistinguishable rates of adverse events (20% vs. 15%) and adverse reactions (6% vs. 5%). The most common events were gastrointestinal ones and skin allergies.

“This is the first time to confirm that ALC has a positive effect to cure chemotherapy-induced peripheral neuropathy in the Chinese population,” Dr. Sun commented through a translator.

“I think the very important thing for this trial is, it is a different kind of patient population. Before this, most clinical trials were performed in [whites] or maybe Americans. This is an only-Asian [population],” he noted, and it is possible that there are genetic differences in how ALC is metabolized.

Dr. Barton, the discussant, took a cautionary view, saying that “there are some things to consider before going out and telling patients to consider acetyl-carnitine for their peripheral neuropathy.”

It was unclear from the results reported whether the two treatment groups were well balanced and what criteria were used to define improvement for the secondary outcomes, she noted. Additionally, “outcome measures were all provider graded, [and there were] no self-report measures, so it is difficult to understand the impact of treatment on symptoms, particularly from the patient perspective,” she noted.

Dr. Hershman, Dr. Sun, and Dr. Barton disclosed no relevant conflicts of interest; the ZHAOKE-2007L03540 trial was sponsored by Lee’s Pharmaceutical Limited.

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