Beta-Carotene Supplementation and Lung Cancer Risk

Introduction

Lung cancer is one of the most common frequently diagnosed cancers.1 Lung cancer occurs when cells in the lungs become abnormal and grown uncontrollably. As these cells develop, they can form tumors which can spread to other parts of the body.2 According to the American Cancer Society, approximately 228,150 people are diagnosed with lung cancer each year in the United States. Among those diagnosed with lung cancer, there about 142,670 deaths each year. Of those with lung cancer, 80-85% have none-small lung cell cancer (NSCLC) while 10-15% have small cell lung cancer (NSLC).2 Smoking is the main risk factor for developing NSCLC. Other risks factors include second-hand smoke, radon exposure, asbestos exposure, high arsenic consumption, and vitamin supplements. Many studies have tested vitamin supplementation to help prevent lung cancer. However, these studies have not been promising. Some studies have shown that beta-carotene supplementation can lead to an increased risk of lung cancer in those who smoke.3

The Cancer Society states that beta-carotene is the orange pigment found in yellow, orange, and dark green fruits and vegetables. This compound is an antioxidant which protects the body from free radicals. Beta-carotene is converted to vitamin A in the body. When beta-carotene is consumed in whole food sources, adverse risks are minimized and may help reduce risk for other types of cancer. However, when consumed in supplement form, it can lead to adverse risk such as lung cancer as previously mentioned. Other risk factors for beta-carotene supplementation include birth defects and liver damage.4 While studies have been conducted on the relationship between beta-carotene supplementation and lung cancer risk, the results have varied. Therefore, it is essential to determine the risks and benefits of beta-carotene supplementation regarding lung cancer.

Literature Review

The Alpha-Tocopherol Beta Carotene (ATBC) Cancer Prevention Study Group conducted a randomized, double-blind, placebo-controlled primary-prevention trial to determine if dietary supplementation with alpha-tocopherol and/or beta-carotene would reduce the risk of lung cancer and other cancers.5 29,133 men aged 50-69 years old who smoked were placed in one of four groups. They either received 50 mg of alpha-tocopherol per day, 20 mg of beta-carotene per day, a combination of alpha-tocopherol and beta-carotene, or a placebo. The follow-up continued for five to eight years. The number of lung cancer cases and other cancer cases were identified by the Finnish Cancer Registry. There was an inverse association between intake of alpha-tocopherol and beta-carotene at baseline and lung cancer risk during the study. There were 876 new diagnoses of lung cancer and 564 deaths from lung cancer during the study. Alpha-tocopherol use had a small reduction in lung cancer but was not significant. Beta-carotene intake led to a higher incidence of lung cancer compared to those who did not take beta-carotene. Beta-carotene use also had a higher incidence of death in those with lung cancer. There were no apparent significant benefits of supplementation with alpha-tocopherol or beta-carotene.5

The nested-case control study by Woodson et al was conducted to determine the effect of alpha tocopherol and beta-carotene in reducing lung, prostate, and other cancers.6 This study occurred within the ATCB study. Whole blood was collected from the study participants. DNA was then isolated from the blood sample. Glutathione S-transferase mu-1(GSTM1) genotyping was conducted to differentiate homozygous null from heterozygous and homozygous wild-type. A statistical analysis was then performed to determine the association of risk factors and lung cancer. Smoking was linked to an increase in lung cancer. The participants that received alpha tocopherol did not have an increased risk of lung cancer in those who smoked compared to the group that did not receive supplementation who smoked. There was no significant risks or benefits with beta-carotene supplementation when compared to those who received a placebo.6

The Carotene and Retinol Efficacy Trial (CARET) was multicenter, randomized, double-blind, placebo-controlled primary prevention trial that was conducted to determine the effects beta-carotene and retinol supplementation had on lung cancer.7 18,314 smokers, former smokers, and workers expose to asbestos. They wither received 30 mg of beta-carotene plus 25,000 IU of retinol in the form of retinyl palmitate or a placebo. The participants were encouraged not to consume more than 5,500 IU of supplemental vitamin A per and encouraged not to consume supplemental beta-carotene. The participants visited a study center once a year while active during the study were called twice in four-month intervals. 388 new cases of lung cancer were diagnosed during the five-year follow-up. 254 of those resulted in death. The treatment group had a relative risk of lung cancer. There was not a significant effect on lung cancer survival in those who received the treatment of beta-carotene and retinol. The study ended early since there was a 28% higher incidence rate in lung cancer for the treatment group compared to the placebo group. Since beta-carotene and retinol were combined in the treatment group, it was difficult to determine which caused the increase in lung cancer.7

Redlich et al conducted a randomized control study to determine intervention effects of the CARET.8 As mentioned previously, the CARET was ended early due to the high incidence of lung cancer in the treatment group.7 The study by Redlich et al included 21 participants that met criteria for the CARET (exposed to asbestos, current or former smoker, 45 and 70 years old, and not on vitamin A supplementation) but did not participate in the study were recruited.8 They received the same intervention treatment as the CARET participants (30 mg of beta-carotene plus 25,000 IU of retinol in the form of retinyl palmitate or a placebo) for six months. The participants had nutrient levels measured and had a bronchoscopy. They underwent bronchoscopy after six months when they were no longer taking the intervention supplements. Beta-carotene and retinol levels were increased in the treatment group. Bronchoalveolar lavage (BAL) cells were increased in the treatment group which could mean that beta-carotene supplementation can increase beta-carotene levels in lung tissue.8 While this study did not focus on beta-carotene in relation to lung cancer, it is important to note that beta-carotene can affect BAL cells in lung.

A randomized, double-blind, placebo-controlled trial by Hennekens et al was conducted to see if beta-carotene supplementation could reduce risk of cancer and cardiovascular disease.9 22,071 male physicians participated in the study. 11% smoked and 39% were former smokers. Initially there were four groups. One group received 325 mg of aspirin on alternate days plus a beta-carotene placebo. One group received 50 mg of beta-carotene alternate days a plus aspirin placebo One group received both active treatments and one group received both placebos. After six years of the study, the aspirin regimen was cancelled and the participants either received beta-carotene or a beta-carotene placebo. The study was conducted for twelve years. Plasma beta-carotene was measured in the blood to determine compliance. There was not a significant benefit or harm with use beta-carotene supplementation on lung cancer development or other cancer development. Since most of these individuals were healthy, the beta-carotene supplementation may not have been as effective versus individuals with poor health.9

The randomized double-blind trial by Kamangar et al was conducted to determine the effect different supplements had on lung cancer prevention.10 29,584 healthy people participated in this study. They were randomized into eight different groups. The supplement combinations were factor A: retinol and zinc; factor B: riboflavin and niacin; factor C: ascorbic acid and molybdenum; or factor D: beta-carotene, alpha tocopherol, and selenium. The doses were one to two times the United States Recommended Dietary Allowance (RDA) The participant took the supplements an average of five years. There were 147 deaths from lung cancer from the beginning of the trial to ten years after the trial. During the trial, the combination of beta-carotene, alpha tocopherol, and selenium had a nonsignificant risk reduction in lung cancer development. However, after the trail ended there were no significant effects on lung cancer mortality in any of the treatment groups.10

The study by Kim et al studied the effects of antioxidant supplementation in ferrets to determine lung cancer risk.11 Ferrets were used since they have a similar absorption and metabolism of carotenoids to humans. They are also affected by smoke carcinogenesis in a similar way to humans. The ferrets received one of the following interventions: the control received no vitamin supplementation or exposure to cigarette smoke, the SM+NNK group received smoke‐exposure and a nicotine-derived nitrosamine ketone (NNK) injection, the AOX group received supplementation with beta-carotene (0.85 mg/kg body weight per day), alpha tocopherol (22 mg/kg body weight per day) and ascorbic acid (3 mg/kg body weight per day), and the SM+NNK+AOX group received smoke‐exposure plus a NNK injection with antioxidant supplementation. DNA damage was higher in the SM+NNK group compared to the control group. The AOX group had greater DNA protection which led to less lung cancer risk.11 While antioxidant supplementation showed promise in reducing DNA damage and lung cancer risk, it is difficult to determine if a specific antioxidant or the combination of antioxidants help with risk reduction.

Conclusion

Each of these studies provided insight on beta-carotene supplementation in relation to lung cancer risk. Unfortunately, the date was inconsistent for each study. Therefore, it is difficult to determine if beta-carotene supplements are more beneficial or more harmful in relation to lung cancer. As a dietitian, I would recommend my clients to consume fruits and vegetables versus taking supplements to increase antioxidant intake. According to the Cancer Society, consuming fruits and vegetables in their whole form has less risks than consuming supplements.

References

1. Cancer.org. (2019). Key Statistics for Small Cell Lung Cancer. [online] Available at: https://www.cancer.org/cancer/small-cell-lung-cancer/about/key-statistics.html
2. Cancer.org. (2019). What Is Non-Small Cell Lung Cancer?. [online] Available at: https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html
3. Cancer.org. (2019). Non-Small Cell Lung Cancer Risk Factors. [online] Available at: https://www.cancer.org/cancer/non-small-cell-lung-cancer/causes-risks-prevention/risk-factors.html
4. Cancernz.org.nz. (2019). [online] Available at: https://cancernz.org.nz/assets/Nutrition-and-physical-activity/Information-sheets/IS-BETA-CAROTENE-12May2010.pdf
5. The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. (1994). The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers. New England Journal of Medicine, 330(15), pp.1029-1035.
6. Woodson, K., Stewart, C., Barrett, M., Bhat, N., Virtamo, J., Taylor, P. and Albanes, D. (1999). Effect of Vitamin Intervention on the Relationship between GSTM1, Smoking, and Lung Cancer Risk Among Male Smokers. [online] Cancer Epidemiology, Biomarkers & Prevention.
7. Omenn, G., Goodman, G., Thornquist, M., Balmes, J., Cullen, M., Glass, A., Keogh, J., Meyskens, F., Valanis, B., Williams, J., Barnhart, S. and Hammar, S. (1996). Effects of a Combination of Beta Carotene and Vitamin A on Lung Cancer and Cardiovascular Disease. New England Journal of Medicine, 334(18), pp.1150-1155.
8. Redlich, C., Blaner, W., Van Bennekum, A., Chung, J., Clever, S., Holm, C. and Cullen, M. (1998). Effect of supplementation with beta-carotene and vitamin A on lung nutrient levels. Cancer Epidemiology, Biomarkers & Prevention, 7(3), pp.211-214.
9. Hennekens, C., Buring, J., Manson, J., Stampfer, M., Rosner, B., Cook, N., Belanger, C., LaMotte, F., Gaziano, J., Ridker, P., Willett, W. and Peto, R. (1996). Lack of Effect of Long-Term Supplementation with Beta Carotene on the Incidence of Malignant Neoplasms and Cardiovascular Disease. New England Journal of Medicine, 334(18), pp.1145-1149.
10. Kamangar, F., Qiao, Y., Yu, B., Sun, X., Abent, C., Fan, J., Mark, S., Zhao, P., Dawsey, S. and Taylor, P. (2006). Lung Cancer Chemoprevention: A Randomized, Double-Blind Trial in Linxian, China. Cancer Epidemiology Biomarkers & Prevention, 15(8), pp.1562-1564.
11. Kim, Y., Lian, F., Yeum, K., Chongviriyaphan, N., Choi, S., Russell, R. and Wang, X. (2007). The effects of combined antioxidant (β-carotene, α-tocopherol and ascorbic acid) supplementation on antioxidant capacity, DNA single-strand breaks and levels of insulin-like growth factor-1/IGF-binding protein 3 in the ferret model of lung cancer. International Journal of Cancer, 120(9), pp.1847-1854.