Preventing Chemotherapy-Induced Peripheral Neuropathy Remains Elusive

Alice Goodman

Identifying agents that can prevent chemotherapy-induced peripheral neuropathy (CIPN) is a work in progress. Studies of some interventions suggest modestly encouraging findings, but research on prevention has been hampered by a poor understanding of the different mechanisms of this toxic­ity with the various chemotherapy agents that induce CIPN.1

“We still have much work to do. We are getting better at trial design, finding the best outcome measures, and including homogeneous populations in clinical trials. We need better preclinical models and better biomarkers,” stated Dawn Hershman, MD, of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center in New York City.

“One problem in studying CIPN is that numerous anticancer drugs cause these symptoms, and the mechanism for each drug may be different. Our approach to treating one symptom can be problematic. We may miss signals that one drug works for one type of CIPN but not another,” she explained.

Hershman reviewed completed clinical trials for the prevention of CIPN at the 2012 Multinational Association of Supportive Care in Cancer Intern­a­tion­al Symposium.1 She emphasized that a drug that works for prevention may not be effective for treatment of CIPN, and vice versa.

Vitamin E has been studied in neuropathic pain, based on positive pilot and phase 2 studies suggesting a neuroprotective effect when given with platinum or taxanes. However, a phase 3 placebo-controlled study found no effect of vitamin E 300 mg twice daily on any CIPN parameters in patients treated with adjuvant platinum or taxane therapy.2

“Think twice about recommending vitamin E to your patients for prevention of CIPN,” Hershman said.
Calcium/magnesium has been studied in patients with colon cancer undergoing adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) therapy.3 The study of 104 patients had a primary end point of development of grade 2 or higher CIPN. The intervention appeared to be beneficial, but the study was closed prematurely because of concern that calcium/magnesium could decrease treatment efficacy; further analysis showed that this concern was false.

“Even with a smaller sample size, there is a likely benefit of calcium/ magnesium in this setting, with a suggestion of significant im­provement in objective and patient-reported outcomes,” she stated.

Acetyl-L-carnitine is a supplement that improves neuropathy in patients with diabetes and HIV infection and is also reported to improve fatigue and cognition, with toxicity limited to mild nausea.1 Based on positive results of a small phase 2 trial showing improvement in sensory and motor neuropa­thy, the Southwest Oncology Group mounted a phase 3 trial in approximately 400 patients with breast cancer treated with taxanes.4 No effect of acetyl-L-carnitine was observed at 12 weeks, but at 24 weeks worsening neuropathy was observed in the group treated with the supplement.

“This is a big surprise. After controlling for age and regimen, the odds ratio for worsening neuropathy was 1.57. This study shows that we have to be careful when we give agents to patients. Not everything we give is benign, and this is a good reason to study these agents,” Hershman said.

Glutamine has also been studied in CIPN in a small trial of 86 patients with colon cancer and oxaliplatin-induced peripheral neuropathy.5 The study found a reduction in grades 1 and 2 neuropathy as well as a significantly lower incidence of grades 3 and 4 neuropathy in the glutamine-treated group, according to patient-reported outcomes, but no difference in electrophysiological abnormalities with glutamine. Hershman commented that electrophysiologic ex­am may not be the right end point to study.

With these equivocal results in a small trial, glutamine is not a strong recommendation.

Although 4 clinical trials of amifostine conducted in patients treated with cisplatin found that pretreatment with amifostine reduced, prevented, or provided some protection against cumulative neurotoxicity, in the American Society of Clinical Oncology 2008 clinical practice guideline update, amifostine is not recommended for prevention of cisplatin- or paclitaxel-induced neuropathy due to insufficient data.6

Ongoing clinical trials of prevention of CIPN include phase 3, placebo-controlled trials of alpha lipoic acid and of erythropoietin.

A separate 12-week, single-blind study at Hershman’s institution is looking at electroacupuncture given weekly with paclitaxel chemotherapy in 50 patients with stage I to III breast cancer.7

Results of these studies are awaited, she said, but prevention of CIPN remains the ideal rather than the reality.

References

  1. Hershman D. Cancer induced peripheral neuropathy: prevention. Presented at: 2012 Multinational Assoc­i­ation of Supportive Care in Cancer International Symposium; June 28-30, 2012; New York, NY.
  2. Kottschade LA, Sloan JA, Mazurczak MA, et al. The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: results of a randomized phase III clinical trial. Support Cancer Care. 2011;19:1769-1777.
  3. Grothey A, Nikcevich DA, Sloan JA, et al. Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J Clin Oncol. 2011;29:421-427.
  4. Hershman DL, Unger JM, Crew KD, et al. SWOG S0715: randomized placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy during adjuvant breast cancer therapy. Presented at: 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago, IL. Abstract 9018.
  5. Wang WS, Lin JK, Lin TC, et al. Oral glutamine is effective for preventing oxaliplatin-induced neurop-athy in colorectal cancer patients. Oncologist. 2007;
    12:312-319.
  6. Hensley ML, Hagerty KL, Kewalramani T, et al. Amer­ican Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy or radiation therapy protectants. J Clin Oncol. 2009;27:
    127-145.
  7. Hershman DL. Acupuncture study for the prevention of taxane induced myalgias and neuropathy. Clin­i­cal
    Trials.gov Web site. http://clinicaltrials.gov/ct2/ show/NCT01163682?term=electroacupuncture&
    rank=31. Updated October 27, 2011. Accessed Sep­t­ember 5, 2012.
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Last modified: May 21, 2015