Vitamin E is a fat-soluble vitamin found in seeds, nuts, leafy vegetables, and vegetable oils. It is a type of antioxidant and helps prevent cell damage caused by free radicals (highly reactive chemicals). It is being studied in the prevention and treatment of some types of cancer. Vitamin E has been used as an oral or parenteral supplement and as a solution for topical application. Vitamin E has been examined in management of diarrhea, mucositis, peripheral neuropathy, skin effects, cognitive impairment, and hot flashes.
Albers, J.W., Chaudhry, V., Cavaletti, G., & Donehower, R.C. (2011). Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database of Systematic Reviews (Online), Feb. 16 (2), CD005228.
Examine the efficacy of purported chemoprotective agents to prevent or limit neurotoxicity of cisplatin and related agents
TYPE OF STUDY: Combined systematic review and meta-analysis
DATABASES USED: Cochrane Neuromuscular Disease Group Specialized Register, Cochrane Central Register of Controlled Clinical Trials, MEDLINE, EMBASE, LILACS, and CINAHL
KEYWORDS: Extensive list provided in article appendix
INCLUSION CRITERIA: Quasi-randomized or randomized clinical trials whose participants received cisplatin (or related compounds) chemotherapy with or without a potential chemoprotectant and were evaluated zero to six months after completing chemotherapy using quantitative sensory testing (primary) or other measures, including nerve conduction studies or neurologic impairment rating using validated scales (secondary)
TOTAL REFERENCES RETRIEVED: Sixteen randomized trials were evaluated in the initial 2006 review. In the 2010 update, 11 additional randomized trials not among the 2006 review were identified.
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Cochrane method of evaluation for risk of bias done by two authors and finalized by consensus
Cisplatin is considered to have neurotoxic effects, with patients developing sensory neuropathy. Symptoms of pain, numbness, and tingling are observed mostly in the extremities from a distal to proximal distribution. The neuropathy experienced by patients may recover partially or may become permanent. Neuroprotective agents such as acetylcysteine, acetyl-L carnitine, amifostine, calcium and magnesium, growth factors, glutathione, ORG 2766, oxcarbazepine, and vitamin E have been tested. The five newly added randomized controlled trials included three chemoprotective agents not previously described in the 2006 review.
From the data examined in this updated review, inconclusive evidence exists for recommending any neuroprotective agent tested to prevent or limit the neurotoxicity of platinum chemotherapy.
While 1,537 participants were included in the 2010 update, few trials were amenable to meta-analysis. Clinical trials of neuroprotective agents are plagued by issues of study design, including small sample size, unclear randomization and blinding procedures, and lack of quantitative measures, especially conventional QST or electrophysiologic evaluation.
Fu, X., Wu, H., Li, J., Wang, C., Li, M., Ma, Q., & Yang, W. (2017). Efficacy of drug interventions for chemotherapy-induced chronic peripheral neurotoxicity: A network meta-analysis. Frontiers in Neurology, 8, 223.
STUDY PURPOSE: To evaluate status of research on pharmacologic interventions for CIPN
TYPE OF STUDY: Meta-analysis and systematic review
DATABASES USED: Medline, Embase, and China National Knowledge Internet
YEARS INCLUDED: (Overall for all databases) Information for dates of search not provided, articles included were from 1995 to 2014
INCLUSION CRITERIA: The study (a) assessed CIPN in patients with cancer, (b) compared two or more drugs or placebo, (c) provided sufficient data to assess differences, and (c) assessed incidence or severity of CIPN
EXCLUSION CRITERIA: None listed
TOTAL REFERENCES RETRIEVED: 1,839
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: No description of quality evaluation
FINAL NUMBER STUDIES INCLUDED: 23
TOTAL PATIENTS INCLUDED IN REVIEW: 2,298
SAMPLE RANGE ACROSS STUDIES: 20-732
KEY SAMPLE CHARACTERISTICS: All but one of the studies focused on patients getting platinum-based chemotherapy and 12 of 23 only included people with colorectal cancer.
PHASE OF CARE: Active antitumor treatment
Contrary to the title, this article does not include any commonly prescribed prescription drugs, including gabapentin, pregabalin, or duloxetine. This review included studies of amifostine, Vitamin E, calcium and magnesium infusions, and glutathione. Eighteen studies had a placebo control group and had no control group. Neither blinding nor control were needed for inclusion. Findings indicate that Vitamin E and amifostine reduce incidence of CIPN, while glutathione and amifostine reduced severity of CIPN. There was one study (n = 20) included that had patients getting amifostine who all had cervical cancer and were receiving cisplatin with radiation therapy. The authors of this original study (Gallardo et al., 1999) found no statistically significant difference in neurotoxicity between those getting amifostine and those who did not. It is therefore unclear how the authors of the meta-analysis found otherwise. There was also only a single study of glutathione versus placebo versus calcium/magnesium (n = 93, 33 of whom received glutathione) included. The original study (Dong et al., 2010) showed no significant differences in CIPN incidence or severity between the three groups. Four studies of Vitamin E, two which were placebo controlled and two with no control group.
The limitations, including lack of quality control, small sample sizes, focus on platinum use, and GI malignancies, limit the generalizability of the findings from this meta-analysis.
Findings from this study suggest that amifostine, glutathione, and Vitamin E may be helpful for CIPN but no recommendations for practice can be made at this time due to limitations of this meta-analysis.
Hershman, D.L., Lacchetti, C., Dworkin, R.H., Lavoie Smith, E.M., Bleeker, J., Cavaletti, G., . . . American Society of Clinical Oncology. (2014). Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. Journal of Clinical Oncology, 32, 1941–1967.
STUDY PURPOSE: To provide evidence-based guidance on optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy in adult cancer survivors
TYPE OF STUDY: Systematic review
DATABASES USED: Ovid Medline (1946–April, week 2, 2013); EMBASE (1980–2013, week 16); AMED Allied and Complementary Medicine (1985–April 2013)
KEYWORDS: chemotherapy-induced peripheral neuropathy; adult cancer survivors; randomized clinical trials
INCLUSION CRITERIA: Adult cancer survivors with chemotherapy-induced peripheral neuropathy; randomized trials
EXCLUSION CRITERIA: Phase 1 trials; published in a language other than English; less than 10 patients; focused on radiation or stem cell transplant neuropathy; animal studies
TOTAL REFERENCES RETRIEVED = 1,252
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: An expert panel representing neurology, nursing, medical oncology, community oncology, pain research, and genetics met through teleconference and emails to review and develop the American Society of Clinical Oncology guidelines.
PHASE OF CARE: Active antitumor treatment
Forty-two randomized clinical trials involved 19 various interventions for prevention of chemotherapy-induced peripheral neuropathy. These agents included anticonvulsants, antidepressants, vitamins, minerals, and other chemoprotectant drugs. Only six randomized clinical trials discovered six different drugs, such as antidepressants, anticonvulsants, and a topical gel, for the prevention of chemotherapy-induced peripheral neuropathy. The following are not recommended for use: acetyl-l-carnitine, amifostine, amitriptyline, calcium and magnesium, glutathione, nimodipine, ORG 2766, trans retinoic acid, rhuLIF, and vitamin E. Venlafaxine is not recommended for routine use in clinical practice. Although data support potential utility, evidence is not strong enough to suggest use. For treatment of chemotherapy-induced peripheral neuropathy, clinicians can offer duloxetine. No recommendation is made regarding ALC. Tricyclic antidepressants or gabapentin through trial use may be reasonable. The panel felt that trying topical gel containing baclofen, amitriptyline, and ketamine would be reasonable.
No agents were recommended for the prevention of chemotherapy-induced peripheral neuropathy, but duloxetine is moderately recommended for the treatment of chemotherapy-induce peripheral neuropathy. Even though conclusive evidence is lacking to recommend tricyclic antidepressants such as nortriptyline, gabapentin, and a topical gel containing baclofen,amitriptyline, and ketamine for treatment of chemotherapy-induced peripheral neuropathy, the expert panel agreed that offering these agents based on treatment for neuropathic pain is reasonable. The panel also recommended that patients be counseled regarding the lack of evidence in treating chemotherapy-induced peripheral neuropathy with these agents.
Nurses are at the frontline in assessing patients who are receiving agents with the potential for chemotherapy-induced peripheral neuropathy. Nurses should be aware of the standard of care in treating this population. Many drugs prescribed have no evidence in preventing or treating these patients. However, with these American Society of Clinical Oncology guidelines, a role for duloxetine is clear and a role for tricyclic antidepressants is possible. Nurses need to be knowledgeable about this information to better inform patients.
Afonseca, S.O., Cruz, F.M., Cubero Dde, I., Lera, A.T., Schindler, F., Okawara, M., . . . Giglio, A. (2013). Vitamin E for prevention of oxaliplatin-induced peripheral neuropathy: A pilot randomized clinical trial. Sao Paulo Medical Journal, 131, 35–38.
To evaluate if oral daily vitamin E is an effective agent in preventing oxaliplatin-induced peripheral neuropathy
Patients were randomized to receive either an oral placebo daily or 400 mg of oral vitamin E daily starting five days before their oxaliplatin-based regimen and continued until completion of the oxaliplatin-based regimen. Both groups received calcium 1 gram IV and magnesium 1 gram IV supplementation 30 minutes before and the same dose after the completion of 12 cycles of oxaliplatin infusions.
In evaluating the effectiveness of oral vitamin E 400 mg daily for prevention of oxaliplatin-induced peripheral neuropathy, this study sought to detect a 50% reduction in associated peripheral neuropathy. The results showed no significant decrease in the incidence of acute oxaliplatin-induced peripheral neuropathy comparing vitamin E and placebo groups (p = 0.43) and no significant difference in the grade (p = 0.45) or time to onset of peripheral neuropathy (p = 0.66) between groups. Incidence of vomiting, nausea, mucositis, fatigue, headache, vertigo, and bleeding observed between groups showed no statistical difference. Incidence of diarrhea was increased in the vitamin E group (p = 0.06).
There is no difference in the incidence, grade, or time to onset of peripheral neuropathy when comparing vitamin E given at 400 mg orally daily or placebo in patients receiving 12 cycles of an oxaliplatin-based regimen (i.e., FOLFOX, FLOX, EOX).
This small pilot study showed no benefit of vitamin E in preventing or reducing the onset or grade of peripheral neuropathy with oxaliplatin-based regimens over 12 weeks. Patients receiving vitamin E had increased signs and symptoms of diarrhea. Further nursing research is needed to evaluate the therapeutic value of vitamin E in this setting.
Argyriou, A.A., Chroni, E., Koutras, A., Ellul, J., Papapetropoulos, S., Katsoulas, G., . . . Kalofonos, H.P. (2005). Vitamin E for prophylaxis against chemotherapy-induced neuropathy: A randomized controlled trial. Neurology, 64, 26–31.
Patients were enrolled to test vitamin E as prophylaxis against chemotherapy-induced peripheral neuropathy.
Patients were randomly divided into groups assigned to receive chemotherapy treatment with (group I) or without vitamin E supplementation (group II). Group II served as control. Patients assigned to group I received alpha-tocopherol (i.e., vitamin E) orally at a dose of 300 mg per day twice daily during chemotherapy and as long as three months after chemotherapy was completed.
The study had a pilot, randomized, controlled, open label with blind assessment design.
The clinical evaluation of neuropathy was based on a modified Neurologic Symptom Score (NSS) and Neurologic Disability Score (NDS). NSS selected symptoms such as weakness, numbness, or pain, scoring as present (1) or absent (0). Clinical signs (i.e., cranial nerves function; joint position, pin prick, and vibration sensation; muscle strength and deep tendon reflexes) were assessed using a modified version of NDS ranging from 0 (no deficit) to 4 (absence of function/severest deficit). Electrophysiologic examination included motor conduction of ulnar and peroneal nerves. Measures were taken at baseline and repeated after the third and sixth cycles as well as three months after cessation by the same neurologist.
Vitamin E supplementation significantly decreased the incidence of neurotoxicity, with 25% of patients receiving Vitamin E experiencing chemotherapy-induced peripheral neuropathy compared to 73.3% in the control group.
This pilot study with a small sample size and many variables assessed make achieving a statistically significant result by chance alone more likely.
Small sample size
Kottschade, L.A., Sloan, J.A., Mazurczak, M.A., Johnson, D.B., Murphy, B.P., Rowland, K.M., . . . Loprinzi, C.L. (2011). The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: Results of a randomized phase III clinical trial. Supportive Care in Cancer, 19, 1769–1777.
The aim of the study was to evaluate the efficacy of Vitamin E for the prevention of chemotherapy-induced peripheral neuropathy.
Patients who were to receive taxane or platinum-based chemotherapy were randomized to receive placebo or vitamin E 300 mg by mouth twice daily. Treatment was begun within four days of the first chemotherapy treatment and continued throughout treatment and for one month beyond completion of chemotherapy. Patient assessments were conducted at baseline, prior to each chemotherapy treatment, and at one and six months after chemotherapy.
The study was conducted at multiple outpatient locations that were part of the North Central Cancer Treatment Group.
Phase of care
The study had a double blind, randomized, placebo-controlled trial design.
No significant differences were noted between groups regarding study outcomes.
The findings do not demonstrate an effect of Vitamin E oral supplements on peripheral neuropathy from chemotherapy.
Findings do not support the use of Vitamin E to prevent chemotherapy-induced peripheral neuropathy. Nurses can guide patients regarding the evidence in this area.
Pace, A., Giannarelli, D., Galie, E., Savarese, A., Carpano, S., Della Giulia, M., . . . Cognetti, F. (2010). Vitamin E neuroprotection for cisplatin neuropathy: a randomized, placebo-controlled trial. Neurology, 74, 762–766.
The aim of the study was to evaluate the neuroprotective effect of vitamin E in patients treated with cisplatin.
Patients were randomized to either vitamin E 400 mg per day (α-tocopherol) or placebo. The vitamin E (or placebo) was started orally before chemotherapy and continued for three months after completion of cisplatin.
The study was conducted at multiple outpatient sites: the National Cancer Institute in Rome and the National Neurologic Institute in Milan, Italy.
The study had a phase III randomized, placebo-controlled trial design.
Neurotoxicity score was significantly lower in patients receiving vitamin E than in the placebo group (mean score of 1.4 versus 4.1; unpaired t test, p < 0.01). Neurotoxicity incidence differed significantly between groups (group 1, 1 of 17 participants; group 2, 10 of 24 participants; p < 0.01). Also, the relative risk of developing signs or symptoms of neurotoxicity was significantly lower in group 1 than group 2 (relative risk of 0.14, 95% confidence interval [0.02, 1], p < 0.05). At follow-up, compared with baseline, mean sural and sensory median nerve amplitude values were significantly decreased in the control group (p = 0.02 and p = 0.008, respectively), while median nerve amplitude was unchanged and sural nerve amplitude was decreased, but not significantly, in patients receiving Vitamin E.
Vitamin E may be helpful in reducing neurotoxic effects of cisplatin, but larger randomized trials are needed.
Cisplatin-induced peripheral neuropathy can be painful and also interfere with a patient’s quality of life; however, future research is needed with larger trials before Vitamin E is recommended. Also, drug interactions need to be considered.
Pace, A., Savarese, A., Picardo, M., Maresca, V., Pacetti, U., Del Monte, G., . . . Bove, L. (2003). Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. Journal of Clinical Oncology, 21, 927–931.
This study evaluated the neuroprotective effect of vitamin E in patients with solid tumor malignancy treated with cisplatin chemotherapy.
Patients were randomly assigned to either group 1, which received vitamin E supplementation during cisplatin chemotherapy, or to group 2, which received cisplatin chemotherapy alone. Vitamin E 300 mg per day was administered orally before cisplatin chemotherapy and continued for three months after the suspension of treatment.
Twenty patients dropped out of the study. Plasma levels of vitamin E were in the normal range and not significantly different between the two groups (8.06 and 7.17 mg/ml, respectively). Twelve of the 14 patients in the control group developed CIPN as compared to 4 of 13 patients who received vitamin E supplementation.
Vitamin E supplementation significantly protects against cisplatin-induced peripheral neuropathy and reduces incidence and intensity of neurologic signs and symptoms.
Stubblefield, M.D., Burstein, H.J., Burton, A.W., Custodio, C.M., Deng, G.E., Ho, M., . . . Von Roenn, J.H. (2009). NCCN task force report: Management of neuropathy in cancer. Journal of the National Comprehensive Cancer Network, 7(Suppl., 5), S1–S26.
This study outlines the common antineoplastic agents known to cause neuropathy and provides information on incidence, onset dosages, the signs and symptoms, and general course and patterns of resolution. Agents identified include platinum compounds, vinca alkaloids, taxanes, bortezomib, ixabepilone, thalidomide, and lenalidomide. In addition to outlining the mechanisms of neuropathy development in cancer, the study discusses neurophysiologic and objective testing, noting that findings on electromyographic (EMG) and nerve conduction studies (NCS) can lag behind clinical symptoms. The study also identifies commonly used physician-based grading systems, including the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) and Eastern Cooperative Oncology Group (ECOG) systems, and notes that these two grading systems lack inter-rater reliability. Patient-based instruments for assessment include the Functional Assessment of Cancer Treatment (FACT) and the Patient Neurotoxicity Questionnaire (PNQ). The authors note that the routine assessment of pain secondary to neuropathy, using instruments such as the Brief Pain Inventory (BPI), is useful.
Routine assessment should be conducted and continued throughout therapy. Key points in assessment that should be included are:
Proposed agents for prevention of CIPN identified include:
Agents used for pain management:
Current literature is inconclusive on the benefits of neurostimulation in treating CIPN. The authors note that evidence is scarce on efficacy of complimentary and alternative medicine (CAM) therapies and the need for appropriately powered and controlled studies in this area. However, acupuncture was identified as a promising adjunct option. The article also provides safety tips and issues for management of functional deficits in PIN, including situations in which to avoid or discontinue physical training, footwear selection, orthosis, and safety aspects of the household environment. Finally, the article addresses how autonomic neuropathy from chemotherapy occurs, but has not been well documented or studied.
The article provides a comprehensive review of current knowledge about CIPN and common approaches toward assessment, prevention, and management. The authors do not make specific recommendations for treatment, research to validate evaluation tools, and exploration of combinations and scheduling of pain medications. In addition, testing of the safety and effectiveness of therapeutic interventions and dietary supplements are needed.