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    Posted: 10/31/2008    Updated: 12/09/2008
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    Volume 7, Issue 4

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Report to Nation Finds Declines in Cancer Incidence, Death Rates

High Dose Chemotherapy Prolongs Survival for Leukemia

Prostate Cancer Study Shows No Benefit for Selenium, Vitamin E

The Nation's Investment in Cancer Research FY 2009

caBIG: Connecting the Cancer Community

Past Highlights
Selenium and Vitamin E Cancer Prevention Trial (SELECT)

Key Points
  • SELECT stands for the Selenium and Vitamin E Cancer Prevention Trial, a prevention clinical trial to see if one or both of these dietary supplements prevent prostate cancer.
  • SELECT is continuing to evaluate the effects of the supplements but participants are no longer taking study supplements. The independent Data and Safety Monitoring Committee for the trial found that selenium and vitamin E, taken alone or together for an average of five and one-half years, did not prevent prostate cancer.
  • The SELECT data showed two concerning, but not statistically significant, trends: there were slightly more cases of prostate cancer in men taking only vitamin E and slightly more cases of diabetes in men taking only selenium. Neither of these findings proves an increased risk from the supplements and may be due to chance.

1. What is SELECT?

SELECT stands for the Selenium and Vitamin E Cancer Prevention Trial, a clinical trial to see if one or both of these substances can help prevent prostate cancer when taken as dietary supplements. The trial is funded primarily by the National Cancer Institute (NCI) and is being coordinated by the Southwest Oncology Group (SWOG), an international network of research institutions that receives NCI funding. Enrollment for the trial began in 2001 and ended in 2004. More than 400 sites in the United States, Puerto Rico, and Canada are taking part in the study. Over 35,000 men are participating in SELECT.

2. What is the status of SELECT? Did these supplements prevent prostate cancer?

SELECT participants were told in October 2008 to stop taking their study supplements but will continue to have their health monitored by study staff for about three more years (see . The study initially was planned for a follow-up of a minimum of seven years and a maximum of 12 years. However, the independent Data and Safety Monitoring Committee (DSMC) for the trial met on September 15, 2008, to review SELECT study data and found that selenium and vitamin E, taken alone or together did not prevent prostate cancer. They also determined that it was unlikely selenium and vitamin E supplementation would ever produce a 25 percent reduction in prostate cancer, as the study was designed to show.

Although there were no statistically significant differences (in other words, these differences could have occurred by chance alone) in the rates of prostate cancer between the four groups in the trial, the DSMC was concerned about the larger numbers of cases in men taking only vitamin E. The difference does not prove that vitamin E causes prostate cancer and may be due to chance. The numbers and percentages of prostate cancer by study group are:

  • Placeboes only group: 4.36 percent five-year incidence of prostate cancer (416 prostate cancer cases)
  • Vitamin E supplement and selenium placebo: 4.93 percent five-year incidence (473 prostate cancer cases).
  • Selenium supplement and vitamin E placebo: 4.56 percent five-year incidence (432 prostate cancer cases), and
  • Selenium supplement and vitamin E supplement: 4.56 percent five-year incidence (437 prostate cancer cases)
Initial results of SELECT were published online in JAMA-Express on December 9, 2008 and will appear in the first print edition of JAMA in January 2009.

3. Did the SELECT supplements affect any other cancer or disease?

There was no difference in the incidence of lung or colorectal cancers, all cancers combined, all deaths combined, or the overall incidence of cardiovascular events between the study groups. Based on data reported from the beginning of the trial, there were more new cases of diabetes in men taking only selenium (10 percent of these men) as compared to the men taking placebo (9.3 percent). This finding was not statistically significant, does not prove an increased risk from selenium and may be due to chance. The percentage of men who were reported to have diabetes after the start of the trial was 9.7 percent in the vitamin E only group and 9.1 percent in the selenium and vitamin E group.

4. What is happening to the men on SELECT?

Men on the study were informed about the initial findings and told to stop taking their study supplements. Participants will continue to have their health monitored by study staff, continue to respond to the study questionnaires, and will provide a blood sample at their five-year anniversary of joining the trial (if they have not already done so). The information from the questionnaires and the blood samples will allow a complete analysis of the study, including important molecular-level research on the role of antioxidants in cancer prevention and the natural history of prostate cancer, other cancers, and diseases of male aging.

5. What if a participant has moved or otherwise lost contact with their SELECT study team?

Any participant in SELECT who has lost contact with their study team can contact the NCI's Cancer Information Service (CIS) for more information and for a referral to SELECT study staff. Participants in the United States and Puerto Rico can call the CIS toll-free at 1-800-4-CANCER (1-800-422-6237), Monday-Friday, 9 a.m. - 4:30 p.m. local time or use our LiveHelp® online chat service at, Monday-Friday, 9 a.m. - 11 p.m. Eastern time. E-mails can also be sent to

6. Who got which supplement?

Men who participated in this study took two capsules a day. Participants were randomly assigned (that is, assigned by chance) to receive:

  • selenium and vitamin E
  • selenium and a placebo
  • vitamin E and a placebo
  • two placebos

Two placebos were used in the trial: one looked like a selenium capsule; the other looked like a vitamin E capsule. Each placebo contained only inactive ingredients. Neither the participants nor the researchers know who received the selenium and vitamin E, or the placebos, a process known as "blinding."

7. Have the men been "unblinded"?

Study investigators have carefully considered how to follow (monitor) participants and feel it would be most proper and useful to continue to follow SELECT participants in a blinded fashion for up to three more years. Men in SELECT are regularly reminded to get prostate cancer screening tests and get asked questions about diabetes and other health issues. Because the men are followed so closely, knowledge obtained from unblinding would not necessarily result in any additional health benefits. Data from men who delay unblinding until after follow-up will provide the most reliable information on how to assess prostate cancer, adult onset diabetes, or other diseases of male aging as well as contribute useful information to substudies that rely on SELECT enrollees for their analyses (see Question 23).

If a participant asks to know which supplements he was receiving, he can make that request to the study staff. Local sites do not have this information on hand but will obtain it from the central SELECT office and will inform the men as soon as possible. Men who request to be unblinded will continue to be followed by study staff in the manner originally outlined in the study.

8. What are a man's chances of developing prostate cancer?

Except for skin cancer, prostate cancer is the most common type of cancer in men in the United States. In the U.S. in 2008, there will be an estimated 186,320 new cases of prostate cancer and 28,660 deaths from this disease (1). All men are at risk for prostate cancer, but those at highest risk fall into one or more of the following categories: age 55 years or older; African American; have a father or brother with prostate cancer.

9. What is selenium? Why study it for prostate cancer prevention?

Our bodies need selenium, a nonmetallic trace element that we get from food - especially plant foods such as rice and wheat, seafood, meat, and Brazil nuts. Selenium is an antioxidant that may help control cell damage that can lead to cancer.

The Nutritional Prevention of Cancer (NPC) study, first reported in 1996, included 1,312 men and women who had a history of non-melanoma skin cancer. Results of the trial showed that men who took selenium to prevent new non-melanoma skin cancers received no benefit from selenium in preventing that disease. However, approximately 60 percent fewer new cases of prostate cancer were observed among men who had taken selenium for six and one-half years than among men who took the placebo (2). In a 2002 follow-up report, the data showed that men who took selenium for more than seven and one-half years had about 52 percent fewer new cases of prostate cancer than men who took the placebo (3). This trial is one of the reasons for studying selenium in SELECT.

10. What is vitamin E? Why study it for prostate cancer prevention?

We get vitamin E in a wide range of foods, especially vegetables, vegetable oils, nuts, and egg yolks. Vitamin E, like selenium, is an antioxidant, which may help control cell damage that can lead to cancer.

In a 1998 study of 29,133 male smokers in Finland (known as the Alpha-Tocopherol, Beta-Carotene Trial, or ATBC), 32 percent fewer new cases of prostate cancer and 40 percent fewer deaths from prostate cancer were observed among men who took vitamin E in the form of alpha-tocopherol to prevent lung cancer than among men who took a placebo. Some men also took beta-carotene, but neither substance helped prevent lung cancer and beta-carotene did not affect prostate cancer (4).

11. What do researchers hope to learn from SELECT?

A large trial of selenium and vitamin E was needed to substantiate earlier, separate findings from studies in which prostate cancer was not the primary study outcome. The primary goal of SELECT was to assess the effect of these substances on the number of new cases of prostate cancer diagnosed during routine clinical practice.

Other objectives of SELECT include assessments of the impact of selenium and vitamin E on the incidence of lung cancer and colon cancer, as well as on total cancer incidence and survival. SELECT will provide the basis for studying the molecular genetics of cancer risk and associations between diet and cancer. A biorepository of blood samples obtained from SELECT participants at their entry into the trial and again after five years was created for use in molecular and mechanistic studies of prostate and other cancers, and other diseases of male aging. Additionally, SELECT has been examining the impact of selenium and vitamin E supplementation on participant quality of life, and findings from this aspect of the study will be presented in a future publication.

12. Who was eligible to participate in SELECT? Were there restrictions on eligibility?

Many diseases, including prostate cancer, occur more frequently in older persons. The risk of developing prostate cancer increases with age. More than 90 percent of prostate cancer cases occur in men age 55 or older (5).

African American men had to be age 50 or older to participate, and men of other races and ethnicities had to be 55 or older. The age for eligibility was lower for African American men because, on average, they get the disease at an earlier age.

13. Could men with benign prostatic hyperplasia (BPH) join SELECT?

Men with benign prostatic hyperplasia (BPH), a benign enlargement of the prostate gland, could join SELECT because BPH is not a cancerous or a precancerous condition. In BPH, the prostate grows larger and presses against the urethra and bladder, interfering with the normal flow of urine. More than half of the men in the United States between the ages of 60 and 70, and as many as 90 percent of men between the ages of 70 and 90, have symptoms of BPH.

BPH can be treated with four different U.S. Food and Drug Administration (FDA)-approved drugs: finasteride (Proscar®), terazosin (Hytrin®), doxazosin (Cardura®), and tamsulosin (Flomax®). Men were not excluded from SELECT on the basis of taking these drugs. Instead, use of these medications was recorded by SELECT investigators.

14. Could men on SELECT take finasteride? How many men on SELECT used this drug?

Finasteride is a synthetic drug which acts by inhibiting the conversion of testosterone to a more readily available form. It is used as a treatment in benign prostatic hyperplasia (BPH) in low doses, prostate cancer in higher doses and hair loss in its lowest doses. In 2003, the SWOG-coordinated Prostate Cancer Prevention Trial, in which more than 18,000 men took either 5 mg finasteride or a placebo to see if the drug reduced the risk of developing prostate cancer, showed a 25 percent reduction in prostate cancer in men taking finasteride (6). Finasteride is not currently approved by the U.S. FDA for reducing the risk of developing prostate cancer. Men in SELECT were made aware of these findings and were allowed to take the drug. Overall, about 2.6 percent of men on SELECT had been on the finasteride arm of PCPT, but had stopped taking their study drug, and 4.8 percent of men on SELECT reported use of finasteride for BPH (at the 5 mg/day dose) or for hair growth (at a 1 mg/day dose) during the course of the study.

15. What tests were used to determine eligibility for SELECT? What tests are being done during the study?

The tests included a digital rectal examination (DRE) and a prostate-specific antigen (PSA) test. During a DRE, a doctor inserts a gloved finger into the rectum and feels the prostate gland through the rectal wall to check for bumps or abnormal areas. The PSA test measures the level of PSA, a protein produced by cells of the prostate gland, in the blood. A person's PSA level can rise as a result of cancer or benign (not cancerous) conditions. Doctors often use the PSA test and DRE as prostate cancer screening tests in men who have no symptoms of the disease.

To be eligible for the SELECT trial, participants had to have a DRE that found no signs of prostate cancer and a total PSA level less than or equal to 4.0 nanograms per milliliter (ng/ml). During the trial, DREs and PSA tests are suggested, but not required, on an annual basis throughout the course of the study. Even though supplement use is being stopped in SELECT, the participants will continue to have their health monitored by study staff, including PSA testing or DREs.

16. Who pays for these tests?

Physician, medical examination, and general clinic costs, including DREs, are charged to the participant in the same way as if he were not part of the trial. These costs may be covered by a participant's health insurance. Financial assistance may be available for some men. SELECT, however, pays for follow-up PSA tests. Men with questions about insurance coverage or reimbursement should check with their local SELECT site.

17. How much selenium was being used in SELECT? What risks were involved with taking selenium?

The amount of selenium (provided as l-selenomethionine) was 200 micrograms (µg) daily. Although the initial results of the NPC trial showed an overall decrease in cancer incidence from selenium, a 2003 update reported 17 percent more new non-melanoma skin cancers in the selenium group compared with the placebo group (7). It is not clear how these results would apply to men who did not already have skin cancer when they enrolled in SELECT, or to men who are not at increased risk for skin cancer.

Since the start of SELECT, four studies have been published looking at the effect of selenium on blood glucose and risk of diabetes: two studies suggested that higher levels of selenium taken from supplements or received naturally were associated with an increased risk of diabetes. One study showed no association between the two, and one showed that people with higher levels of selenium in their blood had a reduced risk of diabetes (8-11). Starting in early 2007, the SELECT DSMC was specifically asked to review the study data for cases of diabetes because of these findings.

18. Why didn't the selenium supplement in SELECT prevent prostate cancer?

There are several possibly explanations for why selenium supplements did not prevent prostate cancer in men on SELECT. For example, the findings from the NPC study may not have been correct, and selenium may not affect prostate cancer risk; the participants on the NPC study were deficient in selenium compared with SELECT participants, and supplements given to the men in SELECT may have exceeded an optimum preventive range; or the formulation of selenium used in the NPC trial (high-selenium yeast) may have been more active than the l-selenomethionine used in SELECT, Early tests showed that for the selenium yeast, the amount of selenium per dose was highly variable in the NPC trial and that was cause for concern and a reason why it was not used in SELECT. Also, the inorganic compounds present in the yeast can be toxic or lead to lower body stores of active selenium.

19. How much vitamin E was being used in SELECT? What risks were involved?

The amount of vitamin E (provided as dl-alpha-tocopheryl acetate) was 400 milligrams (mg), which is equivalent to 400 International Units (IU) per day. This dose of vitamin E can thin the blood somewhat. Men with uncontrolled high blood pressure were not eligible to take part in SELECT because taking this much vitamin E might have increased their risk of stroke.

Vitamin E has been shown to increase the risk of some cardiovascular conditions. In a 2005 study, men and women with vascular disease or diabetes who took 400 IU of vitamin E daily for seven years had a 13 percent increased risk of heart failure compared with participants taking a placebo (12). Heart failure is a condition in which the heart's ability to pump blood is weakened. A 2005 analysis of several studies in which people with various medical problems took vitamin E suggested a link between high doses of vitamin E (400 IU or more) and increased mortality (13).

In SELECT, there was no difference in the number of cardiovascular events, cardiovascular deaths, or overall deaths between the study groups.

20. Why didn't vitamin E supplements prevent prostate cancer in SELECT?

There are several possible explanations for why vitamin E supplements did not prevent prostate cancer in men on SELECT. For example, the dose of vitamin E used (400 IU/day) may have been less effective than was the lower dose (50 IU/day) used in the ATBC study (the formulations were identical), vitamin E may be more protective against prostate cancer in smokers (of whom there were relatively few [7.5 percent] in SELECT compared to ATBC where smokers and former smokers were the participants), and the initial findings of the ATBC may have been due to chance.

21. What other requirements were there for SELECT participants?

Upon enrollment, men were asked to have toenail clippings collected to assess selenium levels in the body because selenium concentrates in fingernails and toenails. Toenails were chosen over fingernails because they take longer to grow and thus contain more history of someone's selenium intake. Blood samples were collected upon enrollment to assess levels of vitamin E, and again at five years after a man joined the study. These blood samples are placed in the SELECT biorepository for future studies.

Also upon enrolling, men filled out a questionnaire about their diet and past supplement use. There is also an annual questionnaire that asks for updates of supplement use. Men did not have to change their diets during this study. Each man is offered a supply of a special daily multivitamin, manufactured by The Perrigo Company, Allegan, Michigan, that contains no selenium or vitamin E. Vitamin E, selenium, placebo capsules, and multivitamins were provided free of charge to enrollees. SELECT men will still be able to receive and take the multivitamin now that supplement use has been stopped.

22. What happens if a participant develops prostate cancer while involved in SELECT?

Participants diagnosed with prostate cancer during the study are referred for treatment and continue to be followed by the SELECT study staff, although less frequently.

Costs for diagnosis and treatment of prostate problems, prostate cancer, or other medical conditions during the study are charged to the participant in the same way as if he were not part of the trial. A participant's insurance will pay for diagnosis and treatment according to the plan's policies. If the participant has no insurance, social services may be available at the local level to cover costs for diagnosis and treatment.

23. How much did SELECT cost? Who else funded the study, and why?

NCI is the primary funding agency for SELECT, awarding about $114 million to SWOG from 1999 through 2008, with an additional $4.5 million contributed by the National Center for Complementary and Alternative Medicine (NCCAM), also an agency of the National Institutes of Health (NIH). NCI has been funding a substudy to see if the supplements affect colon polyp growth. In addition, ancillary studies are funded by three other NIH institutes:

  • The National Institute on Aging (NIA) has provided almost $7 million for the Prevention of Alzheimer's Disease with Vitamin E and Selenium (PREADVISE) trial. This trial is NIA's add-on to SELECT. It is evaluating whether these supplements can help prevent memory loss and dementia, such as that found in Alzheimer's disease. Studies show that increased oxidative stress may damage brain cells and is linked with Alzheimer's disease. Animal and tissue culture studies of vitamin E and selenium suggest that they can protect brain cells from oxidative damage.
  • The National Eye Institute (NEI) has provided almost $2 million for the SELECT Eye Endpoints Study (SEE). Age-related macular degeneration (AMD) and cataract are two leading causes of visual impairment in older Americans. AMD is a disease that affects the central vision, and is the leading cause of visual problems and blindness, with about 25 percent of people over 65 showing some AMD. Cataract is a clouding of the eye's lens that causes loss of vision. More than 50 percent of adults in the U.S. age 75 and older suffer from visually significant cataracts. Some evidence suggests that the dietary supplements (selenium and vitamin E) being studied in SELECT might prevent these eye problems. The SELECT Eye Endpoints (SEE) study is looking at this question in a large group of SELECT participants.
  • National Heart, Lung and Blood Institute (NHLBI) has given more than $3 million for the Respiratory Ancillary Study (RAS). The overall objective of RAS is to understand whether supplements being studied in SELECT impact the loss of lung function experienced with aging, which is higher in persons smoking cigarettes. This study closed to accrual in 2007. Sites that were invited to participate had a higher percentage of current and former smokers than the overall SELECT study.

24. What other research is being done for prostate cancer prevention?

In 2003, the Prostate Cancer Prevention Trial, in which more than 18,000 men took either finasteride or a placebo to see if the drug reduced the risk of developing prostate cancer, showed a 25 percent reduction in prostate cancer in men taking finasteride. Finasteride is not currently approved by the FDA for reducing the risk of developing prostate cancer. (See for more information).

Currently, NCI has several different agents in early prevention clinical trials of men at risk for prostate cancer or who have been diagnosed with prostate cancer and have not yet received treatments. These agents include Polyphenon E, a green tea extract; di-indolylmethane (DIM), a compound found in brassica vegetables such as broccoli, kale and cauliflower; lycopene, a carotenoid found in tomatoes and other red plants; and soy.

25. Where is more information about SELECT available?

In the United States and Puerto Rico, call the NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237) for information in English or Spanish. People with TTY equipment can call 1-800-332-8615 for information in English.

The following Web sites provide additional information:


Selected References

  1. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers. JAMA 2009; 301(1) published online December 9, 2008. Print edition January 2009.

  2. National Cancer Institute (2008). SEER Cancer Statistics Review 1975-2005. Bethesda, MD: Retrieved October 24, 2008, from

  3. Clark LC, Combs GF Jr., Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. Journal of the American Medical Association 1996; 276(24):1957-1963.

  4. Duffield-Lillico AJ, Reid ME, Turnbull BW, et al. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: A summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiology, Biomarkers & Prevention 2002; 11(7):630-639.

  5. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: Incidence and mortality in a controlled trial. Journal of the National Cancer Institute 1998; 90(6):440-446.

  6. National Cancer Institute (2008). SEER Cancer Statistics Review 1975-2005. Bethesda, MD: Retrieved October 24, 2008 from

  7. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. New England Journal of Medicine 2003; 349:215-224.

  8. Duffield-Lillico AJ, Slate EH, Reid ME, et al. Selenium supplementation and secondary prevention of nonmelanoma skin cancer in a randomized trial. Journal of the National Cancer Institute 2003; 95(19):1477-1481.

  9. Stranges et al. Effects of Long-Term Use of Selenium Supplements on the Incidence of Type 2 Diabetes. Annals of Internal Medicine; 147:217-233, 2007.

  10. Bleys J et al. Serum Selenium and Diabetes in U.S. Adults. Diabetes Care; 30:829-834, 2007.

  11. Rajpathak et al. Toenail Selenium and Cardiovascular Disease in Men with Diabetes. Journal of the American College of Nutrition; 24: 250-256, 2005.

  12. Czernichowet et al. Antioxidant supplementation does not affect fasting plasma glucose in the Supplementation with Antioxidant Vitamins and Minerals (SU.VI.MAX) study in France: association with dietary intake and plasma concentrations. American Journal of Clinical Nutrition; 84:395-9, 2006.

  13. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: A randomized controlled trial. Journal of the American Medical Association 2005; 293(11):1338-1347.

  14. Miller ER III, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Annals of Internal Medicine 2005; 142(1):37-46.

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