Background
Paclitaxel is one of the taxane-derived chemotherapeutic agents used for treatment of solid tumors including those of the breast, ovary, lung, and Kaposi’s sarcoma. It was originated from the Pacific yew
Taxus brevifolia. Paclitaxel is an antimicrotubular agent that polymerizes tubulin, resulting in formation of stabilized disordered microtubules without dynamic instability that holds up cell division [
1,
2].
Paclitaxel-induced peripheral neuropathy (PIPN) is the major dose-limiting side effect of paclitaxel [
2]. The precise pathology of PIPN is not fully understood. Paclitaxel induces an axonal sensory peripheral neuropathy (PN) as a result of aggregation of microtubules in axons and Schwann cells. It may also cause fiber demyelination in some severs cases [
1].
Signs of paclitaxel neurotoxicity usually take three weeks to appear, mainly affecting the sensory, rather than motor or autonomic nervous systems. The most common symptoms of PIPN include numbness, tingling, paresthesias, and a burning pain in a stocking-glove distribution. The onset of symptoms is often in hands and feet simultaneously, and some patients complain of facial discomfort [
3,
4].
Omega-3 fatty acids eicosapentaenoic acid ( EPA) and docosahexaenoic acid (DHA) are polyunsaturated fatty acids(PUFAs) incorporated into the phospholipid membrane of cells including those of the central and peripheral nervous systems [
5]. They have many beneficial effects in some psychiatric and neurodegenerative diseases. They determine the biophysical properties of neuronal membranes and regulate signal transduction by their effect on ion channels and receptor functions [
6]. Moreover, the production of proinflammatory cytokines which induce neuropathy is attenuated by EPA and DHA, in particular DHA [
5,
6]. DHA-induced myelinogenesis has been reported in the previous studies [
7].
Most adverse effects associated with chemotherapy are ameliorated after cessation of the therapy, but PN maybe partly reversible or even irreversible in some patients and as such can significantly decrease the patients’ quality of life. Taken together, we designed a randomized placebo-controlled trial to evaluate the possible effect of omega-3 fatty acid supplementation on PIPN in patients with breast cancer. To our knowledge, there have been no previous studies done to demonstrate the possible effects of omega-3 fatty acid supplementation on PIPN.
Discussion
Cumulative neurotoxicity along with axonal disorders are common in PIPN [
3]. The cellular microtubules of malignant cells and axons of peripheral nerves are the targets of paclitaxel and it inhibits tubulin depolymerization [
4]. 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 [
16]. 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 [
8]. 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) [
8].
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 [
4]. 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. [
18], 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 [
19]. 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 [
19]. 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) [
5], 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 [
20]. In another study accomplished by Ward R et.al, DHA had a significant neuroprotective role in the axonal damage due to spinal cord injury [
21]. 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 [
22]. In addition, neurotoxicity may be prevented by cox-2 inhibition [
23] and omega-3 fatty acids inhibit the generation of cox-2 mRNA [
24].
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 [
25]. 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 [
25]. 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.
Conclusions
Although the survival rate of breast cancer patients improved by significant advances in treatment strategies, disabling and dose-limiting peripheral neuropathy due to chemotherapy with paclitaxel decreases the patients’ quality of life and sometimes forces the oncologist to change or even end the treatment [
18]. No standard therapeutic agent exists for the prevention or treatment of chemotherapy-induced neuropathy [
19]. Thus, finding a novel neuroprotective agent seems to be critical. Omega-3 fatty acids were efficient for prophylaxis against PIPN in this study. According to our knowledge, this is the first time that the efficacy of omega-3 fatty acids has been assessed for their ability to reduce incidence and severity of PIPN.
There were some limitations in the design of this double-blind placebo-controlled randomized trial. The lack of long term follow up of outcomes measured was a potential limitation of the study. In addition, Sun flower soft gelatin capsules used as placebo had no fishy taste, and the psychological status of the patients was not evaluated in this study although it may has been affected by omega-3 fatty acids. Relatively small sample size was another possible limitation of the current trial.
Polymorphisms of corresponding cytochrome P-450 enzymes could influence the paclitaxel clearance and drug-related side effects [
17]. Therefore, genotyping could help to identify those cancer patients who are at risk of developing neurotoxicity so that they may be advised to take neuroprotectant supplements before the onset of painful and disabling PIPN. The effectiveness of omega-3 fatty acids supplementation for neuroprotection of patients with breast cancer treated with paclitaxel is supported by results from the present study. Another double-blind placebo-controlled randomized clinical trial with larger sample size is needed to confirm these findings.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
Zohreh Ghoreishi participated in the study design and coordinations and helped to prepare the draft of the manuscript and interpreting of the results, Ali Esfahani was the oncologist contributor of the study and helped to recruitment of the eligible patients and implementation the chemotherapy and intervention for the study subjects, Abolghasem Djazayeri participated in the study design, Mahmoud Djalali participated in the laboratory testing, Banafsheh Golestan participated in the study design from the statistical view of point, Hormoz Ayromlou performed the clinical and electrophysiological examinations, Shahriar Hashemzade and Vahid Montazeri participated in the recruitment of the eligible patients, Mahammad Asghari Jafarabadi, helped to analyze data and preparing tables and figures. Seyed ali Keshavarz participated in the study design, interpreting the results and he also helped to draft the manuscript. Masoud Darabi helped to set up the measuring the serum concentrations of omega-3 fatty acids.