This blog is a collation of clinical studies and results to show association of vitamin intake and cancer risk and some basic information on natural food sources of the different vitamins. The key conclusion from various studies is that taking vitamins from natural food sources are beneficial for us and can be included as part of our daily diet/nutrition, while use of excessive multivitamin supplementation are not helpful and do not add much value in providing anti-cancer health benefits. They can be associated with increased cancer risk and can cause potential harm. Hence these supplements must only be used upon recommendation of medical professionals in the right context and condition.
Vitamins are essential nutrients from foods and other natural sources that our body needs. A lack of specific vitamins can cause severe deficiencies that manifest as different disorders. A balanced, healthy diet with adequate intake of nutrients and vitamins is associated with a reduction in risk of death from cardiovascular diseases and cancer. The nutrient source ideally should be from foods we eat, but in the current fast paced times that we live in, a daily dose of multivitamin is the substitute for a healthy nutritious diet.
A multivitamin supplement a day has become a norm for many individuals globally as a natural way of boosting their health and well being. Use of Multivitamins is on the rise in the aging baby boomer generation for health benefits and supporting general well being. Most people believe that high dose vitamin intake is an anti-aging, immunity-boosting and disease prevention elixir, that even if not effective, can do no harm. There is the belief that since vitamins are from natural sources and promote good health, more amounts of these taken as supplements should only benefit us further. With the widespread and excessive use of vitamins across global populations, there have been multiple observational retrospective clinical studies that have looked at associations of different vitamins with their cancer preventative role.
Food Sources vs. Dietary Supplements
A recent study by the Friedman School and Tufts University School of Medicine examined the potential benefits and harms of vitamin supplement use. The researchers examined data from 27,000 healthy adults who were 20 years or older. The study evaluated the vitamin nutrient intake either as natural foods or supplements and the association with all-cause mortality, death by cardiovascular disease or cancer. (Chen F et al, Annals of Int. Med, 2019)
The study found overall greater benefits of vitamin nutrient intake from natural food sources instead of supplements. Adequate intake of Vitamin K and Magnesium from foods were associated with lower risk of death. Excessive Calcium intake from supplements, of greater than 1000 mg/day, was associated with a higher risk of death from cancer. Use of Vitamin D supplements in individuals who did not have signs of Vitamin D deficiency was associated with increased risk of death from cancer.
There are multiple other clinical studies that have evaluated the association of use of specific vitamin supplements and risk of cancer. We will summarize this information for specific vitamins including their natural food sources, and scientific and clinical evidence for their benefits and risks with cancer.
Vitamin A – Sources, Benefits and Risk in Cancer
Sources : Vitamin A, a fat-soluble vitamin, is an essential nutrient which supports normal vision, healthy skin, growth and development of cells, improved immune function, reproduction and fetal development. Being an essential nutrient, Vitamin A is not produced by the human body and is obtained from our healthy diet. It is commonly found in animal sources such as milk, eggs, liver and fish-liver oil in the form of retinol, the active form of Vitamin A. It is also found in plant sources such as carrot, sweet potato, spinach, papaya, mango and pumpkin in the form of carotenoids, which are provitamin A that are converted to retinol by the human body during digestion. Though Vitamin A intake benefits our health in many ways, multiple clinical studies have examined the association between vitamin A and various types of cancers.
Association of Vitamin A with Increased Risk of Cancer
Some recent observational retrospective clinical studies have highlighted that supplements like beta-carotene can further increase the risk of lung cancer especially in current smokers and people who have a significant smoking history.
In one study, researchers from the Thoracic Oncology program at Moffitt Cancer Center in Florida, studied the connection through examining data on 109,394 subjects and concluded that ‘among current smokers, beta-carotene supplementation was found to be significantly associated with an increased risk of lung cancer’ (Tanvetyanon T et al, Cancer, 2008).
Besides this study, earlier studies also done in male smokers, such as CARET (Carotene and Retinol Efficacy Trial) (Omenn GS et al, New Engl J Med, 1996), and the ATBC (Alpha-Tocopherol Beta-Carotene) Cancer Prevention Study (ATBC Cancer Prevention Study Group, New Engl J Med, 1994), also showed that taking high doses of Vitamin A not only did not prevent lung cancer, but showed a significant increase in lung cancer risk among the study participants.
In another pooled analysis of 15 different clinical studies published in the American journal of Clinical Nutrition in 2015, over 11,000 cases were analyzed, to determine the association of levels of Vitamins and cancer risk. In this very large sample size, levels of retinol were positively associated with prostate cancer risk. (Key TJ et al, Am J Clin. Nutr., 2015)
An observational analysis of over 29,000 participant samples collected between 1985-1993 from the ATBC cancer prevention study, reported that at the 3 year follow-up, men with higher serum retinol concentration had an elevated risk of prostate cancer (Mondul AM et al, Am J Epidemiol, 2011). A more recent analysis of the same NCI driven ATBC cancer prevention study with a follow-up to 2012, confirmed the earlier findings of the association of higher serum retinol concentration with increased risk of prostate cancer (Hada M et al, Am J Epidemiol, 2019).
Hence, despite the fact that natural beta-carotene is essential for a balanced diet, an excessive intake of this through multivitamin supplements can become potentially harmful. As the studies indicate, high intake of retinol and carotenoid supplements have the potential to increase the risk of cancers such as lung cancer in smokers and prostate cancer in men.
Association of Vitamin A with Decreased Risk of Skin Cancer
A clinical study examined the data related to Vitamin A intake and the risk of cutaneous squamous cell carcinoma (SCC), a type of skin cancer, from participants in two large, long-term observational studies. The studies were the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). Cutaneous squamous cell carcinoma (SCC) is the second most common type of skin cancer with an estimated incidence rate of 7% to 11% in the United States. The study included data from 75,170 US women who participated in the NHS study, with a mean age of 50.4 years, and 48,400 US men who participated in the HPFS study, with a mean age of 54.3 years.(Kim J et al, JAMA Dermatol., 2019).
Key findings of the study were that Vitamin A intake was associated with lower risk of skin cancer (SCC). The group that had the highest average daily Vitamin A consumption had a 17% reduced risk of cutaneous SCC when compared to the group that consumed the least Vitamin A. It was mostly obtained from food sources and not from dietary supplements. Higher intake of total vitamin A, retinol, and carotenoids, which are generally obtained from various fruits and vegetables, was associated with lower risk of SCC.
Sources, Benefits and Risk of Vitamin B6 and B12 in Cancer
Sources : Vitamin B6 and B12 are water soluble vitamins commonly found in many foods. Vitamin B6 are pyridoxine, pyridoxal and pyridoxamine compounds. It is an essential nutrient and is a coenzyme for many metabolic reactions in our body, plays a role in cognitive development, hemoglobin formation and immune function. Vitamin B6 rich foods include fish, chicken, tofu, beef, sweet potatoes, bananas, potatoes, avocados and pistachios.
Vitamin B12, also known as cobalamin, helps in keeping the nerve and blood cells healthy and is necessary for making DNA. Its deficiency of vitamin B12 is known to cause anemia, weakness and fatigue and hence it is imperative that our daily diets include foods containing Vitamin B12. Alternatively, people use vitamin B supplements or B-complex or multivitamin supplements that include these vitamins. Sources of vitamin B12 are fish and animal products like milk, meat and eggs and plants and plant products like tofu and fermented soy products and seaweeds.
Association of Vitamin B6 with Cancer Risk
A small number of clinical trials completed to date have not shown that vitamin B6 supplementation can reduce mortality or help prevent cancer. An analysis of data from two large clinical studies in Norway found no association between vitamin B6 supplementation and cancer incidence and mortality. (Ebbing M, et al, JAMA, 2009) Thus, the evidence for the use of vitamin B6 to prevent or treat cancer or reduce toxicity associated with chemotherapy is not clear or conclusive. Although, 400 mg of vitamin B6 may be effective in reducing the incidence of hand-foot syndrome, a chemotherapy side-effect. (Chen M, et al, PLoS One, 2013) The supplementation of vitamin B6, however, has not shown to increase the risk of cancers.
Association of Vitamin B12 with Cancer Risk
There are rising concerns on long term use of high dose Vitamin B12 and its association with the risk of cancer. Different studies and analysis were carried out to investigate the impact of Vitamin B12 intake on cancer risk.
A clinical trial study, named the B-PROOF (B Vitamins for the Prevention of Osteoporotic Fractures) trial, was done in Netherlands to assess the effect of daily supplementation with vitamin B12 (500 μg) and folic acid (400 μg), for 2 to 3 years, on fracture incidence. Data from this study was used by researchers to further investigate the impact of long term supplementation of Vitamin B12 on cancer risk. The analysis included data from 2524 participants of the B-PROOF trial and was found that long term folic acid and vitamin B12 supplementation was associated with a high risk of overall cancer and a significantly higher risk of colorectal cancer. However, researchers suggest confirming this finding in larger studies, so as to decide whether Vitamin B12 supplementation should be restricted to only those with a known B12 deficiency (Oliai Araghi S et al, Cancer Epidemiol Biomarkers Prev., 2019).
In another international study published recently, the researchers analyzed the results from 20 population based studies and data from 5,183 lung cancer cases and their matched 5,183 controls, to evaluate the impact of high vitamin B12 concentration on cancer risk via direct measurements of circulating vitamin B12 in pre-diagnostic blood samples. Based on their analysis, they concluded that higher vitamin B12 concentrations are associated with increased risk of lung cancer and for every doubling levels of Vitamin B12, the risk increased by ~15% (Fanidi A et al, Int J Cancer., 2019).
Key findings from all these studies suggest long term use of high dose Vitamin B12 is associated with the increased risk of cancers like colorectal cancer and lung cancer. While this does not mean we completely remove Vitamin B12 from our diets, since we do need adequate amounts of Vitamin B12 as part of a normal diet or if having a B12 deficiency. What we need to avoid is the excessive vitamin B12 supplementation (beyond the adequate level).
Sources, Benefits and Risk of Vitamin C in Cancer
Sources : Vitamin C, also known as ascorbic acid, is a water-soluble, essential nutrient found in many food sources. It has antioxidant properties that helps protect our cells from damage caused by free radicals. Free radicals are reactive compounds that are produced when our body metabolizes food and also produced due to environmental exposures such as cigarette smoking, air pollution or ultraviolet rays in sunlight. Vitamin C is also needed by the body to make collagen that helps in wound healing; and also helps in keeping the immune system robust and strong. Food sources rich in Vitamin C include the citrus fruits such as orange, grapefruit and lemon, red and green peppers, kiwi fruit, cantaloupe, strawberries, cruciferous vegetables, mango, papaya, pineapple and and many other fruits and vegetables.
Beneficial Association of Vitamin C with Cancer Risk
There have been many clinical studies investigating the beneficial effects of using high dose Vitamin C in different cancers. Well-designed clinical trials of Vitamin C use in the form of an oral supplement found no benefits for people with cancer. However, more recently, Vitamin C given intravenously has been found to show beneficial impact unlike the dose in the oral form. Their intravenous infusions have been found to be safe and to improve efficacy and lower toxicity when used along with radiation and chemotherapy treatments.
A clinical study was done on newly diagnosed glioblastoma (GBM) patients, to assess the safety and impact of pharmacological ascorbate infusion, given along with the standard of care treatment of radiation and temozolomide (RT/TMZ) for GBM. (Allen BG et al, Clin Cancer Res., 2019) The results of this study suggests that infusing high dose Vitamin C or ascorbate in GBM patients doubled their overall survival from 12 months to 23 months, especially in subjects that had a known marker of poor prognosis. 3 of the 11 subjects were still alive at the time of writing this study in 2019. The only negative effects experienced by the subjects were dry mouth and chills associated with the ascorbate infusion, while the other more severe side-effects of fatigue, nausea and even hematological adverse events associated with TMZ and RT were decreased.
Vitamin C supplementation has also shown a synergistic effect with a hypomethylating agent (HMA) drug Decitabine, for acute myeloid leukemia. The response rate for HMA drugs is generally low, at only about 35-45% (Welch JS et al, New Engl. J Med., 2016). A recent study done in China tested the impact of combining Vitamin C with Decitabine on elderly AML patients. Their results showed that patients who took Decitabine in combination with Vitamin C had a higher complete remission rate of 79.92% versus the 44.11% in those who only took Decitabine (Zhao H et al, Leuk Res., 2018) The scientific rationale behind how Vitamin C improved the Decitabine response was determined and it was not just a random chance effect.
These studies indicate that high dose Vitamin C infusions can not only improve therapeutic tolerability of chemotherapy drugs, but have the potential for increasing a patients’ quality of life and decreasing toxicity of radiation and chemotherapy treatment regimen. High dose vitamin C given orally is not absorbed optimally to achieve the high concentrations with the intravenous vitamin C infusion, hence did not show benefits. High dose vitamin C (ascorbate) infusion has also shown promise in reducing toxicity of chemotherapies such as gemcitabine, carboplatin and paclitaxel in pancreatic and ovarian cancers. (Welsh JL et al, Cancer Chemother Pharmacol., 2013; Ma Y et al, Sci. Transl. Med., 2014)
Sources, Benefits and Risk of Vitamin D in Cancer
Sources : Vitamin D is a nutrient that is needed by our bodies to maintain strong bones by helping in absorbing calcium from foods and supplements. Also needed for many other body functions including muscle movement, nerve signaling and functioning of our immune system to fight infections. Food sources rich in Vitamin D are fatty fishes such as salmon, tuna, mackerel, meat, eggs, dairy products, mushrooms. Our bodies also make Vitamin D when the skin is directly exposed to sunlight.
Association of Vitamin D with Cancer Risk
A prospective clinical study was done to address the question on whether Vitamin D supplementation helps in cancer prevention. The clinical trial VITAL (VITamin D and omegA-3 trial) (NCT01169259) was a nationwide, prospective, randomized trial, with the results recently published in the New England Journal of Medicine (Manson JE et al, New Engl J Med., 2019).
There were 25,871 participants in this study that included men 50 years and older and women 55 years and older. The participants were randomly divided into a group taking Vitamin D3 (cholecalciferol) supplement of 2000 IU per day, that is 2-3 times the recommended dietary allowance. The placebo control group did not take any Vitamin D supplement. None of the enrolled participants had a prior history of cancer.
The results of the VITAL study showed no statistically significant difference in cancer diagnosis between the Vitamin D and placebo groups. Hence, high dose Vitamin D supplementation was not associated with lower risk of cancer or lower incidence of invasive cancer. Thus, this large-scale, randomized study clearly shows that high dose Vitamin D supplementation may help with bone related conditions but excessive supplementation does not add value from a cancer prevention perspective.
Sources, Benefits and Risk of Vitamin E in Cancer
Sources : Vitamin E is a group of fat soluble antioxidant nutrients found in many foods. It is made of two groups of chemicals: tocopherols and tocotrienols, with the former being the major source of vitamin E in our diets. The antioxidant properties of vitamin E help in protecting our cells from damage caused by reactive free radicals and oxidative stress. It is needed for numerous health benefits ranging from skin-care to improved heart and brain health. Foods rich in Vitamin E include corn oil, vegetable oils, palm oil, almonds, hazelnuts, pinenuts, sunflower seeds besides many other fruits and vegetables. Foods higher in tocotrienols are rice bran, oats, rye, barley and palm oil.
Association of Vitamin E with Cancer Risk
Multiple clinical studies have shown an increased cancer risk with higher doses of Vitamin E.
A study based in different neuro oncology and neurosurgery departments across US hospitals analyzed structured interview data from 470 patients that was conducted following diagnosis of brain cancer glioblastoma multiforme (GBM). The results indicated that Vitamin E users had a higher mortality when compared to those that did not use Vitamin E. (Mulphur BH et al, Neurooncol Pract., 2015)
In another study from Sweden and Cancer Registry of Norway, the researchers took a different approach on determining risk factors for brain cancer, glioblastoma. They took serum samples up to 22 years prior to glioblastoma diagnosis and compared the metabolite concentrations of serum samples of those that developed the cancer from those that did not. They found significantly higher serum concentration of Vitamin E isoform alpha-tocopherol and gamma-tocopherol in cases that developed glioblastoma. (Bjorkblom B et al, Oncotarget, 2016)
A very large Selenium and Vitamin E Cancer Prevention Trial (SELECT) was done on over 35,000 men to assess the risk-benefit of Vitamin E supplementation. This trial was done on men who were 50 years or older and who had low prostate specific antigen (PSA) levels of 4.0 ng/ml or less. Compared to those who did not take Vitamin E supplements (Placebo or reference group), the study found an absolute increase in risk of prostate cancer in those taking vitamin E supplements. Hence, the dietary supplementation with Vitamin E is associated with an increased risk of prostate cancer among healthy men. (Klein EA et al, JAMA, 2011)
In the alpha-tocopherol, beta-carotene ATBC cancer prevention study done on male smokers over 50 years old, they found no reduction in the incidence of lung cancer after five to eight years of dietary supplementation with alpha-tocopherol. (New Engl J Med, 1994)
Benefits of Vitamin E in Ovarian cancer
In the context of ovarian cancer, Vitamin E compound tocotrienol has shown benefits when used in combination with the standard of care drug bevacizumab (Avastin) in patients who were resistant to chemotherapy treatment. Researchers in Denmark, studied the effect of the tocotrienol subgroup of Vitamin E in combination with bevacizumab in ovarian cancer patients that did not respond to chemotherapy treatments. The study included 23 patients. Combination of tocotrienol with bevacizumab showed very low toxicity in the patients and had a 70% disease stabilization rate. (Thomsen CB et al, Pharmacol Res., 2019)
Sources, Benefits and Risk of Vitamin K in Cancer
Sources : Vitamin K is a key nutrient that is needed for blood clotting and healthy bones, besides many other functions in the body. Its deficiency can cause bruising and bleeding problems. It is found naturally in many foods including green leafy vegetables such as spinach, kale, broccoli, lettuce; in vegetable oils, fruits such as blueberries and figs and even in meat, cheese, eggs and soybeans. Currently there is no clinical evidence of association of Vitamin K with increased or decreased risk of Cancer.
All the multiple different clinical studies indicate that vitamin and nutrient intake in the form of natural foods, fruits, vegetables, meat, eggs, dairy products, grains, oils as part of a healthy, balanced diet is what is most beneficial for us. Excessive use of multivitamins or even individual vitamin supplements has not shown to add much value in preventing the risk of cancer, and could have potential for causing harm. In most cases, the studies have found an association of higher doses of vitamins with increased risk of cancer. Only in some specific contexts as in the case of Vitamin C infusion in GBM or Leukemia patients or use of tocotrienol in ovarian cancer patients has shown beneficial impact on improving outcomes and reducing side-effects.
Therefore, the scientific evidence is indicating that a routine and random use of excessive vitamin supplements is not helpful for reducing cancer risk. These supplements should be used upon recommendations from medical professionals in the right context and condition. Hence organizations including the Academy of Nutrition and Dietetics, the American Cancer Society, the American Institute of Cancer Research and the American Heart Association do not promote the use of dietary supplements to prevent cancer or heart disease.
Cancer patients often have to deal with different chemotherapy side effects which affect their quality of life and look out for alternative therapies for cancer.Taking the right nutrition and supplements based on scientific considerations (avoiding guesswork and random selection) is the best natural remedy for cancer and treatment related side-effects.