By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports no financial relationships relevant to this field of study.
Chemotherapy-induced peripheral neuropathy is common in children treated for a variety of cancers, but the long-term prognosis for recovery is excellent.
Purser MJ, et al. Chemotherapy-induced peripheral neuropathy among pediatric oncology patients. Can J Neurol Sci 2014;41:442-447.
With improvement in cancer survival, long-term neurotoxicity is becoming an ever-increasing concern. Varying with the chemotherapeutic agent, drug dose, duration of exposure, and diagnostic criteria, the incidence of chemotherapy-induced peripheral neuropathy (CIPN) varies from 30-75% in adults. What is its incidence in children?
Between 2001-2011, 274 pediatric patients treated at Children’s Hospital of Eastern Ontario for acute lymphoblastic leukemia (ALL), lymphoma, brain tumor, or Wilms’ tumor were considered for this retrospective cohort study. Inclusion criteria were age < 18 years, pathologic or imaging confirmation of diagnosis, and treatment with chemotherapy, with exclusion criteria encompassing lack of treatment with chemotherapy, alternative cause other than neuropathy found for symptoms, or incomplete medical records. Charts were reviewed to determine the presence of sensory complaints, ataxia, or weakness, and electrodiagnostic studies and imaging studies were examined. CIPN was diagnosed if sensory or motor difficulties developed during chemotherapy that the treating neurologist or oncologist believed to be due to peripheral neuropathy. If a central cause could explain the symptoms, they were not diagnosed as CIPN. Statistical analysis was performed using the unpaired, two-tailed student t-test, with P ≤ 0.05 considered significant.
Among the 274 patients, 22 did not meet inclusion criteria and were excluded from further study. Among the remaining 252 eligible patients, the average age of cancer diagnosis was 6.7 years for ALL, 10.8 years for lymphoma, 6.4 years for brain tumor, and 3.5 years for Wilms’ tumor. None had a personal or family history of hereditary neuropathy. CIPN was diagnosed in 18.3% (46/252) of the entire cohort, 18.8% of ALL, 9.4% of lymphoma, 23.7% of brain tumors, and 17.9% of Wilms’ tumor. Using the U.S. Department of Health and Human Services Common Terminology Criteria for Adverse Events (CTCAE), 78% (36/46) of CIPN patients experienced grade 2 toxicity, implying moderate symptoms affecting activities of daily living. CIPN most often presented with either purely motor (46%) or sensorimotor (39%) symptoms, with 15% experiencing sensory symptoms alone. Motor symptoms included foot drop, clumsy ataxic gait, and impaired fine motor movements, while sensory symptoms included limb paresthesiae and pain. Among the eight patients who underwent confirmatory electrodiagnostic studies, all but one had an axonal neuropathy, with small fiber neuropathy suspected in the outlier. Although 62 children underwent radiotherapy, none had asymmetrical symptoms or fasciculations suggestive of radiation nerve injury. Recovery from CIPN was excellent among surviving patients, with 93% (41/46) showing no clinical deficits on last follow-up, an average of 56 months following CIPN diagnosis.
Commentary
No effective agents convincingly prevent CIPN, including alpha-lipoic acid, calcium/magnesium, glutathione, recombinant human leucocyte inhibitory factor, or vitamin E. Administering bortezomib (Velcade, used to treat multiple myeloma and mantle cell lymphoma) weekly rather than twice weekly, and subcutaneously rather than intravenously, will decrease, but not prevent, the incidence of CIPN and lessen its severity. Once established, pain associated with CIPN may be treated with duloxetine, the only agent shown in a double-blind, crossover trial to be effective, though the magnitude of benefit was modest. Agents used for neuropathic pain, including antiepileptic and tricyclic antidepressant medication, may be offered, but none have proven superior to placebo in CIPN clinical trials. Topical menthol, applied twice daily, has reportedly provided relief, but only in individual case reports. Amitriptyline, baclofen, and ketamine, compounded in a gel, were compared to placebo in a randomized North Central Cancer Treatment Group trial, and demonstrated significant motor subscale improvement, with statistically non-significant improvement in sensory neuropathy. Hence, it requires more study before it can be recommended.
