Mixed Success in Search for Solution to Chemo-Induced Sensory Neuropathy

[Hopeful]

Elsevier Global Medical News. 2009 Jun 19, D McNamara

ORLANDO (EGMN) - Significant, moderate, and no improvement at all—these are results of three studies that assessed strategies to prevent or minimize sensory neuropathy associated with chemotherapy.
Venlafaxine significantly reduced neuropathic pain compared to placebo in patients treated with oxaliplatin in one study. A topical gel of baclofen, amitriptyline, and ketamine brought moderate relief to patients in another experiment. But vitamin E failed to reduce incidence of neuropathy in a different trial.
With no proven pharmacologic treatments, chemotherapy-induced peripheral neuropathy (CIPN) is often a dose-limiting toxicity. "Chemotherapy-induced neuropathy ... is a very, very complex side effect where we have little understanding of the underlying pathophysiology," said study discussant Charles S. Cleeland, Ph.D., chair of the Department of Symptom Research at M.D. Anderson Cancer Center, Houston. He had no relevant disclosures.
Investigators looking for solutions to this problem presented the studies at the annual meeting of the American Society of Clinical Oncology:
Venlafaxine Succeeds in Small Trial
Dr. Jean-Philippe Durand presented prospective, double-blind, randomized phase III study results that showed venlafaxine (Effexor) significantly reduced neuropathic pain associated with oxaliplatin (Eloxatin) compared to placebo. More than 70% of patients had colorectal cancer.
In this EFFOX study, Dr. Durand and his associates found that 31% of 22 patients treated with venlafaxine (used off-label) were free of acute neuropathy symptoms for at least five days - compared with a 5% of 23 patients given placebo. "So we achieved the primary endpoint," Dr. Durand, a medical oncologist at Cochin Hospital in Paris, said in an interview. He and his coauthors had no disclosures.
A secondary endpoint was a response of 50% or greater. This was achieved by 69% of the venlafaxine group and 26% of the placebo group. Neurotoxicity was assessed using a rating scale of symptom relief and the Neuropathic Pain Symptom Inventory.
Patients had a mean age of 68 years and were randomized October 2005 to May 2008 to placebo or 50 mg of venlafaxine one hour prior to oxaliplatin infusion, followed by 37.5 mg twice a day of venlafaxine extended-release from day 2 to day 11. Side effects associated with venlafaxine included emesis in 4 patients and somnolence in 3 patients. FOLFOX (folinic acid [leucovorin], fluorouracil, and oxaliplatin and GEMOX (gemcitabine and oxaliplatin) were the most common chemotherapy regimens.
"Dosing was interesting in that they started it prior to therapy and kept it up for ten days," Dr. Cleeland said.
"The interesting and intriguing point of this [study] was in terms of the duration of the effect," Dr. Cleeland said. They reported 33% in the placebo group versus essentially nobody in the treated group reporting neuropathy at three months. So the signal is there ... and I would say it's worth pursuing."
"Venlafaxine could prevent, maybe, the chronic neuropathy," Dr. Durand said. "Neurotoxicity is the dose-limiting toxicity with oxaliplatin, so maybe [with this approach] we can give more."
Topical Gel Reduces Symptoms
Debra L. Barton, R.N., Ph.D., and colleagues from the North Central Cancer Treatment Group (NCCTG) demonstrated that a topical combination of baclofen, amitriptyline, and ketamine (BAK) moderately improved symptoms of chemotherapy-induced sensory neuropathy in a double-blind, randomized, placebo-controlled study of 208 patients.
Prior to the trial, there were only limited data, including case reports, to support use of BAK to treat peripheral sensory neuropathy, Dr. Barton said, recalling, "I'm pretty skeptical. Someone called me and said I should study this for chemotherapy-related perioperative neuropathy."
So she did. The investigators randomized 104 patients to 10 mg of baclofen, 40 mg of amitriptyline HCl, and 20 mg of ketamine compounded in a pluronic lecithin organogel and another 104 patients to placebo in a gel. All participants had CIPN rated greater than 4 on a scale of 1 to 10, lasting at least one month.
Primary outcome was change in the sensory subscale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - CIPN20 at 4 weeks compared to baseline. This and other measures favored treatment (See Table). The study, Trial NO6CA, was sponsored by the National Cancer Institute.
The topical gel was well tolerated with no significant difference in adverse effects compared with placebo. There was no evidence of systemic toxicity, said Dr. Barton, associate professor of oncology at the Mayo Clinic College of Medicine in Rochester, Minn. She had no disclosures.
Owing to the investigational new drug status, the Food and Drug Administration regulated the BAK concentrations in the study. "Even though we had positive results, we did not have as great an effect ... as a compounding pharmacist who uses higher concentrations and uses it more frequently," Dr. Barton said in an interview. "We want to go back to the FDA to get increased doses."
Dr. Cleeland described this study as very interesting. "The idea of a topical is exciting because perhaps any problems with drug interactions might be helped by handling it in that way," he said, adding, "We have a signal again I would say, and perhaps worth pursuing."
No Less Neuropathy With Vitamin E
Nurse practitioner Lisa Kottschade found that twice-daily vitamin E did not significantly reduce incidence of chemotherapy-induced sensory neuropathy in a phase III, double-blind, and placebo controlled study of 189 patients.
Ms. Kottschade was disappointed with the findings. "Basically, it was negative, it didn't work," she said in an interview. "There was no significant difference between the two arms in terms of neuropathy." The results contrast with promising data from small, pilot studies in the literature.
Dr. Cleeland said the study was "beautifully presented" and described it as "an honest, frank, negative trial [that] can't be more negative."
He added, "At least at this dose, if you think about using vitamin E, I think perhaps you ought to think again."
Patients undergoing treatment with neurotoxic chemotherapy between December 2006 and December 2007 took either 400 mg of vitamin E twice daily or placebo. The primary endpoint, incidence of grade 2+ sensory neuropathy toxicity was 34% in the vitamin E group and 29% in the placebo arm (P = .42).
The investigators also found no significant differences between groups on secondary outcomes: time to onset of neuropathy, chemotherapy dose reductions attributed to neuropathy, or neuropathy symptoms reported via patient questionnaire.
The treatment was well tolerated overall. "The vitamin E was not toxic but did not prevent sensory neuropathy," said Ms. Kottschade, assistant professor of oncology at Mayo Clinic College of Medicine, also in Rochester, Minn.


Hopeful