Vitamin E for prophylaxis against chemotherapy-induced neuropathy
A randomized controlled trial
Citation Manager Formats
Make Comment
See Comments

Abstract
Background: The authors conducted a pilot, randomized, open label with blind assessment, controlled trial to determine whether vitamin E supplementation has a neuroprotective effect in chemotherapy-induced peripheral nerve damage.
Methods: Thirty-one patients with cancer treated with six courses of cumulative cisplatin, paclitaxel, or their combination regimens were randomly assigned in two groups and followed by neurologic examination and electrophysiologic study. Patients assigned in Group I (n = 16) received oral vitamin E at a daily dose of 600 mg/day during chemotherapy and 3 months after its cessation were compared to patients of Group II (n = 15), who received no supplementation and served as controls. The severity of neurotoxicity was summarized by means of a modified peripheral neuropathy score.
Results: The incidence of neurotoxicity differed between the two groups, occurring in 4/16 (25%) patients assigned in the vitamin E supplementation group and in 11/15 (73.3%) patients assigned in the control group (p = 0.019). Mean peripheral neuropathy scores were 3.4 ± 6.3 for patients of Group I and 11.5 ± 10.6 for patients of Group II (p = 0.026). The relative risk (RR) of developing neurotoxicity was significantly higher in case of control patients, RR = 0.34, 95% CI = 0.14 to 0.84.
Conclusion: Vitamin E supplementation in cancer patients may have an important neuroprotective effect.
Peripheral neuropathy is a common dose-limiting adverse effect of a number of effective chemotherapeutic agents, including platinum compounds, taxanes, and vinca alkaloids.1 The symptoms usually begin during chemotherapy and may worsen after cessation of treatment.
Paclitaxel is a taxoid used for the treatment of various primarily solid tumors. This drug induces a dose-dependent predominately sensory axonopathy.2 Cisplatin is an effective chemotherapeutic agent mainly used for the treatment of ovarian and lung malignancies. Dorsal root ganglion is involved in cisplatin toxicity, resulting in a sensory neuronopathy.3 There have been efforts to prevent paclitaxel and cisplatin-induced neurotoxicity, but they have not been successful.4 An ideal approach should clearly demonstrate neuroprotection and be safe for patients, without reducing the efficacy of chemotherapeutic agents on the tumors.
Recent pilot studies5,6⇓ have shown that the plasma level of vitamin E in cancer patients is significantly decreased after two to four courses of cisplatin chemotherapy. Furthermore, vitamin E deficiency results in sensory neuronopathy that is mainly characterized by symptoms similar to those of the chemotherapy-induced neuropathy.
Based on the above, we conducted a pilot, randomized, open label with blind assessment, controlled trial aiming to examine whether vitamin E supplementation has a neuroprotective effect in chemotherapy-induced peripheral nerve damage.
Patients and methods.
Forty patients with cancer treated with six courses of cumulative cisplatin, paclitaxel, or their combination regimens for a nonmyeloid malignancy were enrolled. Patients were recruited during March 2003 to March 2004 from the Oncology Division of the University Hospital of Patras, Greece, and the clinical and electrophysiologic evaluations were performed in the Neurology Department of the same institution.
We tested the hypothesis that vitamin E supplementation would reduce the occurrence and severity of neurotoxicity associated with chemotherapy. We sought to estimate the efficacy of vitamin E supplementation in preventing cisplatin or paclitaxel-induced peripheral neuropathy. The demonstration of significantly lower incidence of neurotoxicity in patients receiving vitamin E supplementation vs controls was required. We also estimated the safety of vitamin E long-term administration at a dose of 600 mg/day.
Patients who were at least 18 years of age were enrolled if they had satisfactory liver and renal function, life expectancy of at least 9 months, WHO performance score of 0 to 1, ability to understand medical advice, and could provide written informed consent. Patients with a history of peripheral neuropathy (i.e., hereditary, associated with nutritional agents and paraneoplastic causes) as well as patients with systemic diseases (i.e., diabetes mellitus, systemic lupus erythematosus, HIV, alcohol abuse) and those who had received chemotherapy in the past were excluded. Additionally, patients in whom the electrophysiologic study at baseline confirmed some type of peripheral neuropathy were drawn out of the study, before being randomized. The stage of disease was not within inclusion/exclusion criteria, as the study cohort was intended to represent the wide range of patients treated with cisplatin, paclitaxel, or their combination regimens in community-based medical oncology practices.
Patients meeting the inclusion criteria 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 the first group received orally Alpha-tocopherol (Eviol, GA Pharmaceuticals, Athens, Greece; i.e., vitamin E) at a dose of 300 mg/day twice daily during chemotherapy and up to 3 months after its cessation.
The randomization plan was based on a simple randomization made by an oncology coauthor. Specifically, determination of whether a patient would be supplemented with vitamin E (Case I) or not (Case II) was based on random sampling numbers (I or II) contained in a set of opaque, sealed envelopes. In case of patients’ satisfying all entry criteria, a numbered envelope was opened assigning them to either Group I or II. The details of the series regarding randomization into groups were known only to the oncology randomization coordinator.
All patients enrolled were evaluated at baseline by the same neurologist, who carried out first the clinical examination and then the electrophysiologic evaluation. The findings of all electrophysiologic evaluations both pre- and post-treatment were confirmed by an independent neurologist. Both neurologists were blinded to patients’ randomization. The details regarding randomization were revealed to them at the completion of the study.
The clinical evaluation of neuropathy was based on a modified Neurologic Symptom Score (NSS) and Neurologic Disability Score (NDS) proposed by Dyck et al.7 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, pinprick, 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).
Neurophysiologic examination was carried out unilaterally (right side), employing standard methods by means of surface stimulation and recording.8 Electrophysiologic study included motor conduction of ulnar and peroneal nerves with measurements of peak to baseline amplitude of compound muscle action potential (a-CMAP), distal motor latency (DML), motor conduction velocity (MCV), and F-wave minimum latency estimated from measurements of 20 F-waves. Sensory conduction of ulnar (orthodromic technique), sural, and superficial peroneal nerves (antidromic technique and proximal segment) with measurements of peak-to-peak amplitude of sensory action potentials (a-SAP) and sensory conduction velocities (SCV) were also recorded. For longitudinal comparison of neurophysiologic variables we adopted the widely accepted criteria of identification of abnormalities, based on serial measurements on healthy human subjects.8,9⇓
The battery of the clinical and electrophysiologic tests described above was repeated by the same neurologist after the third course, the sixth course of chemotherapy, and up to 3 months after its cessation. The results of the clinical and electrophysiologic study were summarized by means of a previously described, modified Peripheral Neuropathy (PNP) score.10 PNP scores graded neurotoxicity as mild (1 to 11), moderate (12 to 23), and severe (>24) corresponding to the WHO grading scales 1 to 3 for chemotherapy-induced peripheral neuropathy.11
Safety was evaluated by monitoring overall adverse effects, which were reported by patients throughout the study period either spontaneously or in response to questioning by the senior oncology investigator who was also blinded to patients’ randomization. Adverse effects reported were then graded for potential relations to vitamin E supplementation. The judgment as to whether an adverse event was related to vitamin E was taken by the same investigator. The study protocol was approved by the institutional review board of Patras Medical School and a written informed consent was obtained from all patients.
Statistical analysis.
Two study populations were designed for purposes of statistical analysis: intent-to-treat (ITT) population (all randomized patients) and efficacy (EFF) population (all randomized patients who completed the study). The primary efficacy variable (i.e., incidence of neurotoxicity) was analyzed for both ITT and EFF populations. For the ITT analysis, patients who failed to complete the study were counted as having presented neurotoxicity. Secondary efficacy variables (i.e., clinical and electrophysiologic subsequent scores) were analyzed only for the EFF population.
For between group comparisons, the changes in mean clinical and electrophysiologic scores were calculated by subtracting each patient’s baseline value from last value, and were examined using independent sample t-tests. All tests were two tailed and significance was set at the p < 0.05 level. Statistical analysis was performed using the SPSS software for Windows release 10.0.
Results.
Thirty-one (77.5%) of the 40 patients enrolled completed the study successfully. Nine patients, four from Group I and five from Group II, discontinued the study and thus they were not included in the efficacy analysis. Three of them died during the study period, five patients withdrew early due to disease progression, and one patient changed residency and continued chemotherapy elsewhere. A diagram showing the flow of participants through each stage of this trial is presented in the figure.
Figure. Flow diagram of participants through each stage of the trial.
Eighteen (58%) male and 13 (42%) female cancer patients with mean age 59.2 ± 9.5 years, assigned to either Group I (n = 16) or Group II (n = 15), have completed the study and were included in the efficacy evaluation. EFF population (n = 31) presented similar demographic and baseline characteristics to those of the ITT patients (n = 40). At baseline, patients and controls shared similar demographic and clinical characteristics (age, sex, specific tumor type) (table 1). Likewise, the intensity of drug administration (cisplatin, paclitaxel, or their combination on a body surface area basis) was equivalent for both groups (bottom line of table 1).
Table 1 Patient characteristics (ITT population, n = 40) according to group
Cisplatin, paclitaxel, or both were administered to ITT patients (n = 40) in combination regimens according to the specific tumor type as follows: 10 breast cancer, 8 lung (NSCLC) cancer, and 3 ovarian cancer patients were treated with paclitaxel 175 mg/m2 on day 1 and carboplatin AUC 6 on day 1 every 3 weeks. Six lung (SCLC) cancer patients were treated with cisplatin 60 mg/m2 on days 1 to 3 and topotecan hydrochloride 0.9 mg/m2 on days 1 to 3 every 3 weeks. Another five lung (SCLC) cancer patients were treated with cisplatin 20 mg/m2 on days 1 to 3, etoposide 75 mg/m2 on days 1 to 3, and irinotecan 120 mg/m2 on day 2 every 3 weeks. Four patients with cervical cancer were treated with paclitaxel 175 mg/m2 on day 1, cisplatin 70 mg/m2 on day 1, and ifosfamide 1.5 g/m2 on days 1 to 3 every 3 weeks. Two patients with testicular cancer were treated with cisplatin 40 mg/m2 on days 1 to 3, etoposide 120 mg/m2 on days 1 to 3, and bleomycin 15 mg/m2 on days 1 to 3. Finally, two patients with head and neck cancer were treated with cisplatin 100 mg/m2 on day 1 and 5-FU 1,000 mg/m2 on days 1 to 5.
Interpretation of data in each group of patients.
Group I.
Neurotoxicity occurred in 4 out of the 16 patients (25%) (table 2). According to the PNP score, the severity of neurotoxicity was graded as mild in one of them and moderate in the other three. They predominantly complained about numbness/paresthesia limited to fingers/toes (n = 2) or in a stocking-and-glove (n = 2) distribution, while 3 of them had suppressed ankle reflexes. On electrophysiologic evaluation performed at the last follow-up as compared to baseline values, two patients showed a similar reduction in the ulnar (60%), sup. peroneal (30%), and sural a-SAP (40%), while the ulnar (80%) and peroneal (85%) a-CMAP were as well decreased. One patient showed decreased sup. peroneal (50%) and sural a-SAP (45%), whereas in the other one a decrease in the sural a-SAP (40%) was observed. Absence of neurotoxicity was observed in the remaining 12 patients of this group. The overall group’s mean PNP scores were 3.4 ± 6.3 (range 0 to 17).
Table 2 Occurrence and severity of neurotoxicity between the two groups of patients
Group II.
Neurotoxicity occurred in 11 out of the 15 patients (73.3%) (see table 2). According to the PNP score, the severity of neurotoxicity was graded as mild in 3, moderate in 5, and severe in 3 patients. Predominately distal numbness/paresthesia limited to fingers/toes (n = 3) and in a stocking-and-glove (n = 5) distribution were observed. Patients with severe neuropathy (n = 3) complained about distal numbness/paresthesia extending up to the knees/elbows. All three patients who developed severe neurotoxicity had decreased pin and vibration sensation up to the knees/elbows and ankle reflexes absent and reduced reflexes elsewhere. They also had moderate toe extensor and finger abduction weakness. Sensory conduction study revealed complete absence of a-SAP in all nerves examined after the third course of chemotherapy. Sural a-SAP reappeared with low amplitude (2.1 mV) in one of them at the last follow-up; so did the sup. peroneal a-SAP (1.8 mV) in another. Absence of neurotoxicity was observed in the remaining 4 patients of this group. The overall group’s mean PNP scores were 11.5 ± 10.6 (range 0 to 30).
Comparison of data between the two groups of patients.
In the EFF population, the incidence of neurotoxicity was higher (Yates corrected, p = 0.019) in the controls’ Group II (11/15 patients, 73.3%) when compared to patients of the vitamin E supplementation Group I (4/16 patients, 25%). On an intention-to-treat basis (ITT population) the results concerning the primary efficacy variable (i.e., incidence of neurotoxicity) were reanalyzed. A similar pattern to that observed in the EFF population (Yates corrected, p = 0.023 vs p = 0.019) was revealed (16/20, 80% in Group II vs 8/20, 40% in Group I). Mean PNP scores were higher in Group II (11.5 ± 10.6) than in Group I (3.4 ± 6.3) (Wilcoxon signed ranks test, p = 0.026). The relative risk (RR) of developing neurotoxicity was significantly higher in the control group than in the treatment group, RR = 0.34, 95% CI = 0.14 to 0.84.
Intergroup comparison of the mean changes at baseline and at each of the follow-up evaluations revealed differences in the ulnar (independent samples t-test, p = 0.04) and sup. peroneal sensory (p = 0.03) conduction study and a tendency to significance (p = 0.069) in the sural a-SAP. No statistical difference of any motor conduction variables was found between groups. Overall changes in mean electrophysiologic scores from baseline to subsequent scores within and between study groups are described in table 3.
Table 3 Changes in mean electrophysiologic scores from baseline to subsequent scores between study groups
Adverse effects were not uncommon, being reported in similar rates from patients of both groups. Gastrointestinal toxicity, primarily in the form of nausea and vomiting, was the most common observed adverse effect. Alopecia and myelosuppression manifested as leukopenia, neutropenia, or thrombocytopenia were also common among patients. Other adverse effects such as fever and tinnitus were rare. None of the adverse events reported were related to the vitamin E administration, since they represent the most common cisplatin and paclitaxel-induced side effects.
Discussion.
We investigated a potential neuroprotective effect of vitamin E supplementation in cancer patients treated with cisplatin, paclitaxel, or their combination regimens. The evaluation of nerve function was based on symptoms, clinical signs, and electrophysiologic findings, summarized by means of a modified PNP score, previously applied in studies referred to toxic neuropathies.12–14⇓⇓
Neurotoxicity occurred in 73.3% of controls, a percentage that matched those previously reported.2,3⇓ Overall, the signs and symptoms point toward a symmetric, distal mainly sensory neuropathy. Electrophysiologic studies supported the diagnosis showing significant reduction of sensory potential amplitude implying loss of function of some sensory fibers.
Our main finding was that vitamin E supplementation significantly decreases the incidence of neurotoxicity, being present in 25% of patients receiving vitamin E supplementation as opposed to 73.3% of the controls. Furthermore, as estimated by PNP scores, the severity of neurotoxicity was higher in the controls (p = 0.026). In a recent study,12 similar incidence rates of neurotoxicity (30.7% in vitamin E group and 85.7% in the control group) were reported.
Cisplatin and paclitaxel constitute two of the most widely known and active chemotherapeutic agents, which by generating free radicals cause extensive tissue damage through reactions with all biologic macromolecules.15 Vitamin E is widely known as an important antioxidant in humans acting as a scavenger of free radicals.16 There are several clues suggesting vitamin E as a potential candidate for neuroprotection against drug toxicity. 1) Reduced plasma level of vitamin E was demonstrated in a small series of cancer patients during chemotherapy.5 2) There are many similarities between cisplatin and paclitaxel-induced neuropathy and vitamin E deficiency–induced neuropathy.17 Nerve conduction study in vitamin E-deficient patients revealed absence or marked decrease of sensory action potentials, findings consistent with sensory axonal loss.18 3) Vitamin E supplementation in experimental animals did not influence chemotherapeutic agents’ antitumor activity.12 Further, a meta-analysis suggested that vitamin E poses some anticancer properties.19 4) Studies on patients with cardiovascular diseases showed that vitamin E supplementation is safe even when administered for several months at a dose as high as 900 mg/day.20 In agreement with the above cited study, no adverse effects related to the vitamin E administration were recorded in our series.
The cisplatin-induced neurotoxicity could be attributed to its accumulation in the peripheral nervous system and particularly in dorsal root ganglia, which, unlike other neural structures, are not protected by the blood–brain barrier.21 As a result, the clinical syndrome caused by cisplatin is best described as sensory neuronopathy rather than neuropathy.22 One can hypothesize that high concentrations of this drug induce a significant exhaustion of vitamin E, leaving the neural tissue more vulnerable to the damaging properties of free radicals. Similarly, dorsal root ganglia could also be affected in vitamin E deficiency neuropathy.23
Paclitaxel-induced neuropathy has a less clearly defined pathophysiology. Although aggregation of neurotubules and therefore disruption of axonal transport has repeatedly been reported, the primary target of paclitaxel toxicity is a matter of debate.4 Occasionally predominance of large-fiber loss and simultaneous involvement of upper and lower limbs advocate in favor of neuronopathy of dorsal root ganglia cells rather than neuropathy.24 This view was not supported by the findings of a pathologic study on rats systematically treated with paclitaxel, which disclosed severe changes of the peripheral nerves and to a lesser extent of the spinal rootlets as well as the posterior columns of spinal cord but not the dorsal ganglion cells.25 Interestingly, central extensions of sensory ganglion cells in the posterior white matter are also structures particularly sensitive to vitamin E deficiency.16 Irrespective of primary damage site, the clinical picture of paclitaxel neurotoxicity is compatible with dysfunction of mainly the large, myelinated sensory fibers.26
There are limitations in the design of the current study. Being a pilot study, it relies on a small sample size. This may influence the ability of this work to assess the safety of vitamin E and its ability to blunt the effects of chemotherapy. Another possible limitation is the lack of a placebo group that would ensure the highest quality of study design. We did not use placebo in order to facilitate a double-blind study due to financial and logistic restrictions. However, our findings were based not solely on subjective measurements but clinical and electrophysiologic examination performed by neurologists blinded to patients’ randomization, ensuring the best possible interpretation of the results.
Thus far, the issue of prevention or treatment of neuropathy induced by anticancer agents has not been satisfactorily addressed. The effectiveness of vitamin E supplementation for neuroprotection of cancer patients treated with cisplatin, paclitaxel, or their combination chemotherapy regimens is supported by the results of the present trial. A large multicenter double-blind, placebo-controlled, randomized trial is necessary to address this issue.
Footnotes
-
See Commentary, page 1
- Received May 5, 2004.
- Accepted August 20, 2004.
References
- ↵
- ↵
Lipton RB, Apfel SC, Dutcher JP, et al. Taxol produces a predominantly sensory neuropathy. Neurology. 1989; 39: 368–373.
- ↵
- ↵
- ↵
Weijl NI, Hopman GD, Wipkink-Bakker A, et al. Cisplatin combination chemotherapy induces a fall in plasma antioxidants of cancer patients. Ann Oncol. 1998; 9: 1331–1337.
- ↵
- ↵
Dyck PJ, Thomas PK, eds. Peripheral neuropathy (ed 3). Vol 2. Philadelphia, PA: WB Saunders, 1993; 1310–1317.
- ↵
Kimura J. Electrodiagnosis in diseases of nerve and muscle, principles and practice (ed 3). Oxford University Press, 2001; 91–166.
- ↵
- ↵
- ↵
- ↵
Pace A, Savarese A, Picardo M, et al. Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. J Clin Oncol. 2003; 21: 927–931.
- ↵
Berger T, Malayeri R, Doppelbauer G, et al. Neurological monitoring of neurotoxicity induced by paclitaxel/cisplatin chemotherapy. Eur J Cancer. 1997; 33: 1393–1399.
- ↵
Chaundhry V, Cornblath DR, Corse A, et al. Thalidomide-induced neuropathy. Neurology. 2002; 59: 1872–1875.
- ↵
- ↵
Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. Oxford: Oxford University Press, 1993; 188–276.
- ↵
Satya-Murti S, Howard L, Krohel G, Wolf B. The spectrum of neurological disorder from vitamin E deficiency. Neurology. 1986; 36: 917–921.
- ↵
- ↵
Brigelius-Flohe R, Kelly FJ, Salonen JT, Neuzil J, Zingg JM, Azzi A. The European perspective on vitamin E: current knowledge and future research. Am J Clin Nutr. 2002; 76: 703–716.
- ↵
Leger C-L. Vitamin E. Current state of knowledge, role in the prevention of cardiovascular disease, bioavailability. Oléagineux Corps gras Lipides. 2000; 7: 258–265.
- ↵
Gregg RW, Matshela MJ, Monpetit VJA, et al. Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurological tissue and morphological evidence of toxicity. J Clin Oncol. 1992; 10: 795–803.
- ↵
- ↵
- ↵
- ↵
- ↵
Disputes & Debates: Rapid online correspondence
- Vitamin E for prophylaxis against chemotherapy-induced neuropathy: A randomized controlled trial
- Andrea Pace, Regina Elena National Cancer Institute, Via Chianesi 53, 00144, Rome, Italypace@ifo.it
- Loredana Bove, Bruno Jandolo
Submitted March 16, 2005 - Reply to Pace et al
- Andreas A. Argyriou, University of Patras Medical School, P.O. Box 1045, Rion-Patras, Greeceandargyriou@yahoo.gr
- E. Chroni, A. Koutras,J . Ellul, S. Papapetropoulos, G. Katsoulas, G. Iconomou and H.P. Kalofonos
Submitted March 16, 2005
REQUIREMENTS
If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.