Cumulative neurotoxicity along with axonal disorders are common in PIPN . The cellular microtubules of malignant cells and axons of peripheral nerves are the targets of paclitaxel and it inhibits tubulin depolymerization . It was estimated that 60%-70% of patients who received this chemotherapeutic agent developed dose-dependent neurotoxicity [4, 14].
The aim of the current double-blind placebo-controlled trial was to trace the efficacy of omega-3 fatty acids (mainly DHA), in prophylaxis against paclitaxel induced neurotoxicity. To do this, eligible patients with node positive breast cancer undergoing chemotherapy with paclitaxel were randomly assigned to take oral supplements of omega-3 fatty acids or a placebo during the course of their therapy cycles and one month after the end of chemotherapy.
There was a significant difference in PIPN incidence between the two study groups so that 70% of patients taking omega-3 fatty acid supplements did not develop PN while incidence was 40.7% in the placebo group. It seems that omega-3 fatty acids, in particular DHA, had neuroprotective effects and that they decreased the paclitaxel-associated neurotoxicity considerably. Our results are in accordance with previous studies that have investigated the efficacy of these fatty acids in diabetic neuropathy. They showed that omega-3 fatty acids could attenuate the severity of neuropathy in patients with type 2 diabetes mellitus [13, 15]. They also prevented the lowering of nerve conduction velocity in the sciatic nerve of diabetic rats by improving the activity of Na+/K + ATPase . There was a considerable trend that did not reach significance for the differences of PIPN severity between group I and II, while the frequencies of PN were higher in the placebo group almost in all scoring categories (Table 1) and severe neuropathy was not seen in the omega-3 supplemented group.
Neurophysiologic studies improve the accuracy and precision of peripheral neuropathy evaluation and help to identify patients at risk of peripheral neuropathy even before the onset of clinical symptoms [4, 17]. rTNS is a composite scale used to assess the incidence and severity of PIPN that can be easily used in the research and clinical centers . Generally, rTNS is well correlated with the oncologic toxicity scales including National Cancer Institute- Common Toxicity Criteria (NCI-CTS), Eastern Cooperative Oncology Group (ECOG), Ajani, and the extended TNS version with these additional parameters: motor symptoms, autonomic symptoms and quantitative sensory testing (QST) .
PIPN is associated with a decrease of a-SAP without significant changes of nerve conduction velocity as it was seen in this study and these changes are indicators of axonal dysfunction rather than myelin disorders . In the current study, a considerable difference was observed in sural nerve a-SAP between the two groups with a sharp decrease in the placebo group. Argyriou et al. , evaluated the role of clinical and NCS measurements to predict the outcomes of CIPN. They found that only the decrease of the sural a-SAP was associated with the worse neurological outcomes. Our results showed that omega-3 fatty acids prevented the significant decrease of sural nerve a-SAP in group I that it may be related to their ability of PIPN reduction in this group.
Previous studies have shown that there are no known pharmacologic agents to prevent or to cure PN in cancer patients. In recent years, the efficacy of some vitamins and minerals, amino acids, cytokines, carnitines, antidepressants and anticonvulsants have been tested . Vitamin E, acetyl-L carnitine, and glutamine are among the oral supplements which have been studied to prevent or attenuate PIPN, but they were not evaluated in large randomized placebo-controlled trials or they had little success in this regard . An ideal neuroprotective agent for prophylaxis against PIPC should be safe for the patients without reducing the efficacy of the therapy, DHA may be the answer.
Growing evidences have demonstrated the positive influences of omega-3 fatty acids in the prevention of a wide range of psychiatric, arrhythmic, and neurological disorders such as Alzheimer’s and Parkinson’s diseases, major depression. schizophrenia and dementia. Omega-3 fatty acids are a branch of long chain polyunsaturated fatty acids, originated from marine and plant sources. By incorporating into the neuronal cell membrane phospholipids, they influence critical membrane-associated functions like signal transduction, ion channel dependent transportations (via voltage-dependent sodium channels and L-type calcium channels), receptors physiological properties, and neurotransmission [6, 20]. In addition to their direct effect on neuropathic pain, omega-3 fatty acids inhibit the production of proinflammatory cytokines associated with neuropathic pain (i.e., IL-1β, IL-6, and TNF-α) , and the role of DHA in myelogenesis has been documented in the previous studies [6, 7, 20]. Lauretania F et.al, have shown that DHA was an effective agent that improved axonal degeneration in the patients . In another study accomplished by Ward R et.al, DHA had a significant neuroprotective role in the axonal damage due to spinal cord injury . With respect to DHA, it was conjugated with paclitaxel to form DHA-paclitaxel, a taxane-fatty acid conjugate with intratumoral activation. DHA-paclitaxel was more efficient treating cancer and caused significantly less toxicity over existing paclitaxel . In addition, neurotoxicity may be prevented by cox-2 inhibition  and omega-3 fatty acids inhibit the generation of cox-2 mRNA .
US Food and Drug Administration (FDA) has recommended that a total maximum dose of 3 grams per day of DHA and EPA omega-3 fatty acids can be safely consumed . In this study, the total dose of omega-3 fatty acids administered was 1244.1 mg per day (640 mg: 54% DHA, 10% EPA, three times a day) which was far below the maximum daily allowance of omega-3 fatty acids consumption for more caution. Although in a number of placebo-controlled prospective trials no considerable adverse effects were reported of omega-3 fatty acids, to prevent patients from experiencing nausea and gastrointestinal disturbances, they were advised to take fish oil pearls with meals and to keep them in a freezer . There was a dramatic increase of serum concentrations of EPA & DHA in the group taking omega-3 fatty acid supplements and a significant difference was observed between two the study groups in terms of this issue, which could be an indicator of participant compliance.