Vitamin E for prophylaxis against chemotherapy-induced neuropathy

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.

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.

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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).

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.

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.