In the November WMSHP Newsletter, Sakar Wahby, a pharmacy practice resident at Spectrum Health, writes about recent studies of vitamin E's potential neuroprotective effect in patients receiving chemotherapy drugs.

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Neuroprotection in Patients Receiving Chemotherapy

Sakar Wahby, Pharm.D.
Pharmacy Practice Resident
Spectrum Health, Grand Rapids, MI
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Cancer has been the leading cause of death in the United States for the population younger than 85 years of age since 1999.¹ Chemotherapeutic agents have played a big role in curative therapy for various types of cancers since their discovery in the nineteen fifties and sixties. However, these agents have the potential for causing adverse events such as nausea, vomiting, alopecia, and myelosuppression. Other side effects could be specific to some agents and cause damage to certain organs of the body such as toxicity to the gastrointestinal tract, the immune system, the kidneys, heart, and nerve tissues.²

Neurotoxicity is one of the widely known side effects for a various number of chemotherapeutic agents. Among the classes of chemotherapy known to cause neurotoxicity are the platinum compounds (cisplatin, oxaliplatin, and carboplatin), the taxanes (paclitaxel and docetaxel), vinca-alkaloids (vincristine, vinblastine, and vinorelbine), methotrexate, thalidomide, and ifosfamide. Neurotoxicity caused by vincristine, cisplatin, paclitaxel, and oxaliplatin can limit the dose of these agents that potentially can be used for treatment, thus leading to discontinuation of therapy and thereby hindering the possible full use of very effective cancer treatments.²

Currently no standard of therapy is approved for neuroprotection for cancer patients who are treated with chemotherapy. Two pilot, randomized, controlled trials (Pace et al. and Argyriou et al.) were conducted in Europe investigating the effectiveness of vitamin E as a neuroprotective agent in patients receiving cisplatin or paclitaxel.^3,4

Cisplatin is a widely used agent in the treatment of various solid tumors such as testicular, ovarian, cervical, head & neck, bladder, and lung cancer. The incidence of neuropathy is up to 100% with this agent, and the severity varies depending on cumulative doses, duration of treatment, and possible underlying diseases that can also cause neuropathy, in addition to having received previous treatments with other neurotoxic medications.^2,5 With cisplatin treatment, neurotoxicity is cumulative and signs and symptoms of neuropathy usually appear with cumulative doses of 300-500 mg/m². Patients treated with cisplatin present with sensory signs and symptoms of paresthesia and numbness. The former manifests itself as tingling, "pins-and-needles" sensation, pulling, pressure, and tightness in the limbs, most often seen in the toes and feet.^2,5

Paclitaxel is a taxane compound used in the treatment of ovarian, breast, and lung cancer.⁵ Besides myelosuppression, paclitaxel can cause neurotoxicity with severity depending on single-dose and cumulative doses administered. At doses of 135 mg/m² mild neuropathies have been observed in 50% of patients, but neurotoxicity can be dose-limiting when 175 mg/m² doses are administered. A dose greater than 200 mg/m² can cause significant neurotoxicity. The pattern of neurotoxicity from paclitaxel is manifested as paresthesia and numbness in a glove and stocking distribution in the limbs, Lhermitte’s sign (sensation similar to electrical shock) and loss of deep tendon reflexes. ^2,5

Both pilot studies have shown vitamin E to be effective in reducing the incidence and severity of neurotoxicity in patients receiving chemotherapy and vitamin E.

Pace et al. randomized 47 patients into two groups. Group one received a cisplatin regimen with vitamin E and group two received a cisplatin-only regimen serving as control. After six cycles of cisplatin administration, the incidence of neuropathy was significantly lower in the vitamin E + cisplatin group as compared to the control group (cisplatin alone). Four out of 13 patients in the vitamin E group (30.7%) and 12 out of 14 patients in the control group (85.7%) reported some sign or symptom of neuropathy (p<0.01). The relative risk of developing neurotoxicity was lower in the vitamin E group compared to the control group (RR= 0.36; 95% CI = 0.15-0.83, P<0.001).³

Argyriou et al. evaluated the neuroprotective effect of vitamin E in patients receiving cisplatin, paclitaxel, or combination of both agents. A statistically significant higher incidence of neurotoxicity were reported in the chemotherapy regimen group (16/20, 80%), versus (8/20, 40%) in the vitamin E + chemotherapy group (Yates p value= 0.023). The relative risk of developing neurotoxicity was lower in the vitamin E group compared to control (RR=0.34, 95% CI =0.14-0.84).⁴

The results of both studies have shown great potential for vitamin E in reducing the incidence of neuropathy, acting as a free radical scavenger and protecting non-tumor cells from free radical damage. However, this hypothesis raises a concern regarding the potential of vitamin E to protect cancer cells as well from free radical damage, therefore reducing the efficacy of chemotherapy.⁶

Neither study was powered enough to evaluate overall response rate and overall survival rate of those patients given vitamin E compared to placebo. Therefore, using vitamin E as a standard therapy with chemotherapeutic agents causing neurotoxicity can not be recommended at this time. Larger randomized, placebo controlled studies are warranted to further establish efficacy and safety of vitamin E in combination with chemotherapy.

 

References:

1. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ. Cancer Statistics, 2005. CA Cancer J Clin. 2005 Jan;55(1):10-30.
2. DeVita VT Jr., Hellman S, Rosenberg SA. CANCER: Principles & Practice of Oncology. 6th ed. Vol. 2. Philadelphia: Lippincott Williams & Wilkins; 2001.
3. Pace A, Savarese A, Picardo M, Maresca V, Pacetti U, Del Monte G et al. Neuroprotective Effect of Vitamin E Supplementation in Patients Treated With Cisplatin Chemotherapy. J Clin Oncol. 2003 Mar;21(5):927-31.
4. Argyriou AA, Chroni E, Koutras A, Ellul J, Papapetropoulos S, Katsoulas G et al. Vitamin E for Prophylaxis Against Chemotherapy-Induced Neuropathy. Neurol. 2005;64:26-31.
5. National Comprehensive cancer network [homepage on the internet]. NCCN Clinical Practice Guidelines in Oncology [updated 2005; cited 2006 Feb 26]. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp?button=I+Agre
6. Labriola D, Livingston R. Possible Interactions Between Dietary Antioxidants and Chemotherapy. Oncology. 1999 Jul;13(7):1003-8.