- Vitamin E is a generic term encompassing different chemical compounds, each having a different metabolism and biological activity.
- Vitamin E compounds are fat-soluble antioxidants and some of them might have additional presumed anticancer properties.
- As an adjunct to conventional anticancer therapy, vitamin E might reduce side effects (i.e. oral mucositis, hand-foot-syndrome and peripheral neurotoxicity).
- No clinical trials describing the use of vitamin E monotherapy as an anticancer treatment have been published.
- Vitamin E is considered to have a very low toxicity, and is generally well-tolerated in low doses.
Vitamin E is a generic term encompassing natural (alpha-, beta-, gamma-, and delta-tocopherol, and alpha-, beta-, gamma-, and delta-tocotrienol) and synthetic (all-rac-alpha-tocopherol) forms, and the esters thereof. The role of some forms of vitamin E in cancer prevention and therapy has been proposed.
This summary focuses on vitamin E during cancer, i.e. when used as an anticancer agent or to alleviate the adverse events of cancer treatments. Vitamin E in the prevention of cancer is not covered by this summary.
No clinical trials describing the use of vitamin E monotherapy as an anticancer treatment have been published. The available peer-reviewed clinical literature describes the use of alpha-tocopherol, all-rac-alpha-tocopherol, and tocotrienol as components of multivitamin regimens or mixtures of micronutrients, in combination with non-cancer drugs, or as adjuncts to conventional chemotherapy or radiation. In 5 randomized, placebo-controlled studies in adults and children, it was found that topical vitamin E might prevent oral mucositis induced by chemotherapy or radiotherapy. In five randomized, controlled or placebo-controlled clinical studies a decrease of the incidence and severity of peripheral neurotoxicity induced by taxanes or platinum-based chemotherapy by alpha-tocopherol was found, but this finding was not confirmed in two other randomized, placebo-controlled studies.Vitamin E is considered to have a very low toxicity, and is generally well-tolerated. However, special consideration should be given when high doses of alpha-tocopherol are administered to cardiovascular disease patients or individuals taking anticoagulant therapy (e.g., warfarin), and to those with vitamin-K-related clotting disorders. Non-healthy patients should not take daily doses of 400 IU or higher. Little information is available on the adverse events of other forms of vitamin E.
Luc Geeraert, CAM Cancer Consortium. Vitamin E during cancer treatment [online document], September 30, 2015.
Summary updated in September 2015 by Luc Geeraert
Summary fully revised and updated in July 2013 by Luc Geeraert
Summary first published in August 2011, authored by Luc Geeraert
Natural Vitamin E includes eight chemical forms (alpha-, beta-, gamma-, and delta-tocopherol, and alpha-, beta-, gamma-, and delta-tocotrienol), which have different metabolism and biopotency in vivo1,2. Alpha-tocopherol (d-alpha-tocopherol or RRR-alpha-tocopherol) is considered the biologically most important form of vitamin E. The synthetic form of vitamin E is known as all-rac-alpha-tocopherol (dl-alpha-tocopherol). Often commercial supplements of synthetic (all-rac-alpha-tocopherol) or natural (alpha-tocopherol) vitamin E contain the vitamin as an acetate or succinate ester.
Vitamin E is fat-soluble and can be found in a wealth of food sources, e.g., green leafy vegetables, whole grains, nuts and seeds, wheat germ, eggs, and in plant oils (especially oils derived from safflower, sunflower, cottonseed, and palm)3,4. The ratios of the different chemical forms of vitamin E depend on the food source.
Commercial supplements contain vitamin E derived from natural sources or synthetic vitamin E. Supplements derived from natural sources contain only one chemical form of vitamin E, most often alpha-tocopherol, or a mixture of tocopherols and even tocotrienols. Synthetic preparations contain exclusively all-rac-alpha-tocopherol. Often the vitamin E in supplements has been esterified (acetate or succinate ester) to prevent its oxidation by air oxygen.
Application and dosage
The recommended daily allowance for adults is 15 mg per day for alpha-tocopherol, an amount which is easily met by dietary sources, and 30 mg per day for synthetic all-rac-alpha-tocopherol5. The upper limit for intake is 1,000 mg per day. Very often, the dosage of vitamin E is given in international units (IU) referring to the activity in the rat resorption-gestation test: 1 mg is equivalent to 1.49 IU of natural alpha-tocopherol or 2.22 IU of all-rac-alpha-tocopherol. It is important to note that the different chemical forms of vitamin E might have different biological functions and that activity measurements based on the rat resorption-gestation test are indicative for activity in only one biological role.
Vitamin E supplements are taken as capsules, with a typical dose being 400 IU per day, which is above the recommended daily allowance. Vitamin E is also an ingredient in many multivitamin-mineral supplements.
Plasma alpha-tocopherol levels are saturable; a dose of approximately 800 IU is sufficient to achieve the upper limit2. In healthy subjects, the alpha-tocopherol concentration cannot be increased beyond two to three times the normal one, irrespective of the amount supplied or the duration of supplementation6.
Vitamin E was discovered in 1922 as a micronutrient necessary for reproduction in female rats7. Since, it has been proposed to have numerous biological functions in humans, though its essential functions are still not understood6. Vitamin E deficiency due to dietary limitations has not been established.
Most research has focused on the antioxidant properties of vitamin E. Being an antioxidant, it was assumed that the vitamin might be beneficial against chronic diseases with oxidative stress components, including cancer2.
Claims of efficacy / Mechanism(s) of action / Alleged indication(s)
Vitamin E, in all its chemical forms, is primarily considered a fat-soluble antioxidant2,8. It was found to prevent lipid peroxidation and other radical-driven oxidative events in lipophilic compartments (e.g., cell membranes).
Moreover, vitamin E has activities beyond its antioxidant properties that might be more important to understand its biological roles1,2. Although various mechanisms of action have been proposed, the mechanisms leading to the putative anticancer effects of (some chemical forms of) vitamin E have not been conclusively described.
In vitro and animal studies showed limited or no evidence for an anticancer effect of alpha-tocopherol, while gamma-tocopherol, the succinate ester of alpha-tocopherol, and tocotrienols were found to be more promising vitamin E forms in cancer1,3,9-11.
In general, vitamin E has also a modulating effect on the immune system12.
The metabolic fate of the individual tocopherols and tocotrienols in the body is very different, which may influence their respective activities in the body. In general, plasma and tissues are enriched in alpha-tocopherol due to the activity of the hepatic alpha-tocopherol transfer protein2,8,13. Hence, there is a concern that alpha-tocopherol supplementation might deplete the body of other vitamin E forms like gamma-tocopherol and tocotrienols3,14.
Prevalence of use
The use of vitamin E supplements is widespread among cancer patients and longer-term survivors, with 20-50% of the patients using supplements of the vitamin15.
In many countries, vitamin E is available as over-the-counter supplement.
Cost(s) and expenditures
Vitamin E supplements are very inexpensive, costing around 10 euro cent or dollar cent for 400 IU.
No clinical trials using vitamin E monotherapy as an anticancer treatment have been published.
The available peer-reviewed literature describes the use of vitamin E as a component of multivitamin regimens or mixtures of micronutrients, in combination with non-cancer drugs, or as an adjunct to conventional chemotherapy or radiation. Only the peer-reviewed literature describing studies measuring the isolated contribution of vitamin E in such combination therapies have been considered. Please see table 1 for a description of studies.
In a phase I clinical trial in 12 patients with incurable malignancies, supplementation of chemotherapy (5-fluorouracil + leucovorin) with oral alpha-tocopherol did not increase its anticancer effect when compared with historical data16. Addition of maximal therapeutic doses of alpha-tocopherol to chemotherapy did not increase the side effects of the chemotherapy itself, again when compared with historical data.
In a non-randomized, double-blind, placebo-controlled pilot clinical trial, in 240 women with early breast cancer, adjuvant palm oil tocotrienol-rich fraction did not decrease breast-cancer-specific mortality or breast cancer recurrence as compared to tamoxifen alone17. (See also table 1.)
Reduction of adverse effects
A number of studies describe the addition of vitamin E supplements to conventional anticancer therapies in an effort to reduce its adverse effects. The studies are described in table 1.
Oral all-rac-alpha-tocopherol supplementation did not protect against radiation-related adverse events nor did the compound have an effect on quality of life in a randomized, double-blind, placebo-controlled study of 248 head and neck cancer patients treated with radiotherapy18-20. In a randomized, controlled study of 60 patients with oral cancer it was found that oral alpha-tocopherol may protect cell membranes from radiation damage21. In 62 endometrial and cervical cancer patients, topical alpha-tocopherol acetate was found to reduce the acute adverse effects of radiotherapy on the vagina22.
Several studies, including paediatric studies, found indications that topical vitamin E supplementation might prevent oral mucositis induced by chemotherapy or radiotherapy. In a randomized, double-blind, placebo-controlled study in 18 patients treated with chemotherapy for various types of malignancy, topical vitamin E oil was more effective in resolving oral lesions than was placebo23. In a randomized, placebo-controlled study in 19 acute myeloid leukaemia patients, topical all-rac-alpha-tocopherol, in addition to chemotherapy, prevented mucositis especially during induction therapy24. A randomized, double-blind, placebo-controlled in 54 head and neck cancer patients treated with radiotherapy, found prevention of oral mucositis by topical all-rac-alpha-tocopherol acetate25. In children, similar findings were reported. In a randomized study in 80 children treated with chemotherapy, topical vitamin E was found to be an effective treatment of chemotherapy-induced oral mucositis, while oral vitamin E was not effective26. A randomized, single-blind, placebo-controlled study in 72 chemotherapy-treated children with haematological malignancies found topical tocopherol acetate to be an effective treatment of oral mucositis27. However, series of N-of-1, double-blind, randomized, placebo-controlled trials in 16 children treated with doxorubicin-containing regimens did not find reduction of chemotherapy-induced oral mucositis by topical all-rac-alpha-tocopherol28.
Two studies were performed to assess the effect of vitamin E on radiation-induced cutaneous damage: a randomized, double-blind, placebo-controlled study in 24 patients testing oral alpha-tocopherol29, and a controlled study in 100 breast cancer patients testing topical vitamin E30. In combination with pentoxifylline, a drug improving blood flow through peripheral blood vessels, oral vitamin E supplementation was found to reduce radiation-induced fibrosis, but vitamin E alone had no effect.
In a randomized, controlled study in 89 oral cavity cancer patients31, and in a randomized, double-blind, placebo-controlled in 36 patients with thyroid cancer32, oral alpha-tocopherol and oral vitamin E, respectively, were found to protect salivary glands against radiation-induced dysfunctions.
In four randomized, controlled or placebo-controlled clinical studies including 47, 31, 30, and 32 cancer patients respectively treated with cisplatin and/or paclitaxel, alpha-tocopherol acetate supplementation reduced the incidence and severity of chemotherapy-induced neurotoxicity33-36. This finding was confirmed in a bigger randomized, double-blind, placebo-controlled study in 108 cancer patients treated with cisplatin37. However, in a randomized, double-blind, placebo-controlled study in 207 cancer patients treated with taxanes or platinum compounds38, and in a randomized, double-blind, placebo-controlled study in 34 patients with colorectal and gastric cancer treated with oxaliplatin-based regimens39, oral all-rac-alpha-tocopherol and oral vitamin E, respectively, were not found to reduce incidence and severity of chemotherapy-induced neurotoxicity.
Supplementation with oral vitamin E or oral alpha-tocopherol, respectively, did not protect against cardiotoxicity caused by doxorubicin in a randomized controlled study in 63 patients with acute myeloid leukaemia40, and in an uncontrolled trial in 21 patients with metastatic breast cancer41.
In three uncontrolled trials, in 5 and 32 breast cancer patients, and in 14 patients with hepatocellular carcinoma, respectively, oral vitamin E supplementation was beneficial to the resolution of hand-foot skin syndrome related to sorafenib or capecitabine therapy42-44. These results are preliminary at best.
Preliminary findings from two uncontrolled studies in 16 and 20 patients with different types of solid tumours45,47, and from one controlled study in 37 breast cancer patients46, of oral all-rac-alpha-tocopherol acetate in the prevention of doxorubicin-induced alopecia, suggest that it is not effective for this condition.
Vitamin E is considered to have a very low toxicity, and is generally well-tolerated5. The vitamin is not mutagenic, teratogenic nor carcinogenic48. Humans show few side effects following supplemental doses below 2,100 mg of alpha-tocopherol per day for a few weeks to a few months. The effects of life-long exposure to high doses of alpha-tocopherol supplements are unknown5.
In vitro, alpha-tocopherol was found to inhibit platelet aggregation49. In the ATBC cancer prevention study, a higher mortality due to haemorrhagic stroke was found in the all-rac-alpha-tocopherol treatment group50. In adults, high-dose alpha-tocopherol supplementation (1,000 IU per day) antagonized vitamin K, which is a crucial vitamin in clotting51. A population study showed that vitamin E supplementation (of 400 IU per day or more) was associated with a significantly increased risk of mortality in people with a history of severe cardiovascular disease52. In conclusion, vitamin E can affect bleeding and carries the risk of haemorrhagic stroke, and special consideration should therefore be given to cardiovascular disease patients or individuals taking nitrates or the anticoagulant warfarin, and to those with vitamin-K-related clotting disorders5.
In a meta-analysis of 19 clinical trials (9 tested vitamin E alone) with a total of 135,967 participants, it was found that daily supplementation of more than 400 IU may increase all-cause mortality, an effect which was dose-dependent53. Hence, non-healthy patients should not take daily doses of 400 IU or higher.
Vitamin E might have the potential to increase the risk of second primary cancers, and to increase the all-cause mortality in patients with head and neck cancer18-20.
Little information is available on the adverse events of other forms of vitamin E5.
Special consideration should be given when high doses of vitamin E are administered to individuals with cardiovascular disease, taking anticoagulant therapy (e.g., warfarin) or vitamin-K-related clotting disorders, as high doses of alpha-tocopherol may increase the bleeding tendency5.
Non-healthy individuals should not take daily doses of 400IU or higher53.
As vitamin E has antioxidant properties, a negative effect on the anticancer activity of therapies generating increased reactive oxygen species, e.g. radiation and some chemotherapeutics, is conceivable54.
Little research has investigated the influence of vitamin E on the activity of chemotherapeutic drugs or radiation. In most of the few studies performed in vitro and in tumor-bearing mice, no negative effect and even an enhancement of the anticancer effect of chemotherapeutic drugs or radiation was observed9,55-57. However, one in vitro study showed that alpha-tocopherol inhibited the antiproliferative and proapoptotic effects of different chemotherapeutic agents belonging to the class of protein kinase inhibitors58. In cancer patients, no evidence was found for a negative effect of vitamin E on chemotherapeutic treatment outcome59,60.
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