Zosia Chustecka

June 08, 2012

June 6, 2012 (Chicago, Illinois) — The antidepressant duloxetine (Cymbalta) could offer a new option to cancer patients for alleviating pain from chemotherapy-induced peripheral neuropathy (CINP). Positive results from a phase 3 trial, the first in this indication, were hailed as practice-changing here at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO).

However, patients should be discouraged from using the acetyl-L-carnitine (ALC) supplement to prevent or treat CINP; a separate study presented produced unexpected negative results.

Ellen Lavoie Smith, PhD, assistant professor of nursing at the University of Michigan in Ann Arbor, and lead author of the duloxetine trial, noted that duloxetine "is the first drug shown to be effective for this terrible pain in a randomized clinical trial." Duloxetine didn't work for every patient, she noted, but it was effective for a majority.

"We now have a treatment that could improve quality of life for many of our patients," she added.

Being able to offer something for CINP pain is important because the pain can be so debilitating that it can lead to a reduction in the chemotherapy dose, which decreases the likelihood of the successful treatment of the cancer.

Many patients experience CINP as a numbness and tingling, a bit like electric shocks, particularly in their hands and feet, but about 30% find it very painful, Dr. Smith said. It can also be chronic, lasting for months or years after the chemotherapy, which can be distressing and disabling, she added.

A variety of interventions are already used for CINP, including gabapentin, pregabapentin, and tricyclic antidepressants, but the use of these is not supported by randomized clinical trial data, she said. In fact, a clinical trial showed that tricyclic antidepressants are not effective, she noted.

A clinician not involved with the study said that he plans to use duloxetine. "We use a lot of platinum drugs, which have known neurotoxicity, and we use gabapentin and pregabapentin in these patients, but after hearing this presentation, I will use [duloxetine]," said Nicholas Vogelzang, MD, who moderated a press briefing in which highlights of this study were presented. Dr. Vogelzang is chair of the ASCO Cancer Communications Committee and medical director at the US Oncology Comprehensive Cancer Centers of Nevada.

"We also use gabapentin," said Hope Rugo, MD, who treats breast cancer patients at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, and who was at the press briefing.

"We find it useful, despite the lack of data from randomized clinical trials, but it causes somnolence, so duloxetine is a good alternative," she said. ' Dr. Rugo explained that nonsteroidal anti-inflammatory drugs are not effective for this type of pain.

Starting With Lower Dose

Duloxetine is already marketed for use in depression and in painful diabetic peripheral neuropathy.

For the potential indication of CINP, duloxetine was started at a dose of 30 mg daily for 1 week, followed by 60 mg daily for 4 additional weeks. "The gradual dosing was important to reduce side effects, which can include dry mouth, sleepiness, and nausea," Dr. Smith said.

The most commonly reported adverse effect in this trial was moderate to severe fatigue, reported by 11% of patients in the duloxetine group and 3% in the placebo group.

The majority of the 231 patients participating in the trial had either gastrointestinal or breast cancer, and had been treated with taxane or platinum chemotherapy. More than half (58%) had taken oxaliplatin. To enter the study, patients had to score at least 4 on a 10-point CINP pain score.

Patients responses on the Brief Pain Inventory-Short Form (BSI-SF) showed that 59% of patients in the duloxetine group experienced pain reduction, as did 39% in the placebo group.

About one third of patients in both treatment groups reported no change in pain, whereas 11% in the duloxetine group and 28% in the placebo group reported an increase in pain.

Dr. Smith explained that duloxetine is thought to work in this indication by inhibiting the pain-processing pathways in the brain, presumably involving noradrenaline and serotonin; the drug is an inhibitor of these neurotransmitters. She speculated that patients who respond to duloxetine have an abnormality in the pain-processing pathway, and said the next step is to try to find a way to identify these people.

Negative Study of ALC

The findings on the use of the ALC supplement were highlighted in a review session by Debra Barton, PhD, AOCN, RN, associate professor of oncology at the Mayo Clinic in Rochester, Minnesota.

"Patients should be warned against the use of this supplement," she said. In the study, patients were taking the supplement to prevent CINP, but the results showed an increase in its incidence; "most concerning, there was an increase in grade 3 neuropathy," she said.

The ALC study was presented by Dawn Hershman, MD, MS, assistant professor of medicine at the Columbia University Medical Center in New York City. The phase 3 placebo-controlled study, which involved 409 women with breast cancer who were undergoing treatment with taxanes, looked at the effects of ALC 1000 mg taken 3 times daily.

The study set out to confirm previous preclinical and phase 2 data that suggested that ALC, a natural compound involved in tubulin acetylation and neuronal protection, is effective in the prevention and treatment of CINP, the researchers explain.

However, at 12 weeks, there was no evidence that ALC has a positive affect on CINP; at 24 weeks, there was an increase in self-reported CINP. In particular, grade 3/4 neurotoxicity was more frequent in the ALC group than in the placebo group (P = .04), the researchers note.

"Patients should be discouraged from using ALC and other supplements without proven efficacy," Dr. Hershman and colleagues conclude.

Dr. Smith has disclosed no relevant financial relationships.

2012 Annual Meeting of the American Society of Clinical Oncology: Abstract CRA9013, presented June 5, 2012; Abstract 9018, presented June 4, 2012.

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