《外科护理学》课程阅读资料（英文）前列腺癌 prostate cancer.pdf

ORIGINAL CONTRIBUTION Vitamin E and the Risk of Prostate Cancer The Selenium and Vitamin E Cancer Prevention Trial (SELECT) Eric A. Klein, MD Ian M. Thompson Jr, MD Catherine M. Tangen, DrPH John J. Crowley, PhD M. Scott Lucia, MD Phyllis J. Goodman, MS Lori M. Minasian, MD Leslie G. Ford, MD Howard L. Parnes, MD J. Michael Gaziano, MD, MPH Daniel D. Karp, MD Michael M. Lieber, MD Philip J. Walther, MD, PhD Laurence Klotz, MD J. Kellogg Parsons, MD, MHS Joseph L. Chin, MD Amy K. Darke, MS Scott M. Lippman, MD Gary E. Goodman, MD Frank L. Meyskens Jr, MD Laurence H. Baker, DO L IFETIME RISK OF PROSTATE CANcer in the United States is currently estimated to be 16%.1 Although most cases are found at an early, curable stage, treatment is costly and urinary, sexual, and bowelrelated adverse effects are common.2 Even men who choose active surveillance as an initial management strategy face anxiety, uncertain prognosis, and a measurable risk of sepsis with follow-up biopsies,3 and more than onethird of those who initially defer therapy are ultimately treated.4,5 With such a high prevalence, risk of morbidity from treatment, and treatment-related costs, primary prevention of prostate cancer is an attractive option. With considerable preclinical and epidemiological evidence that selenium and vitamin E may reduce prostate cancer risk, we conducted and reported the results of a prospective randomized trial examining the effect of these 2 agents for prostate cancer prevention.6Coordinated by SWOG, a federally funded cancer research cooperative group, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) Author Affiliations are listed at the end of this article. Corresponding Author: Eric A. Klein, MD, Glickman Urological and Kidney Institute, Cleveland Clinic, Desk Q10-1, 9500 Euclid Ave, Cleveland, OH 44195 (kleine @ccf.org). Context The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically nonsignificant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer. Objective To determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men. Design, Setting, and Participants A total of 35 533 men from 427 study sites in the United States, Canada, and Puerto Rico were randomized between August 22, 2001, and June 24, 2004. Eligibility criteria included a prostate-specific antigen (PSA) of 4.0 ng/mL or less, a digital rectal examination not suspicious for prostate cancer, and age 50 years or older for black men and 55 years or older for all others. The primary analysis included 34 887 men who were randomly assigned to 1 of 4 treatment groups: 8752 to receive selenium; 8737, vitamin E; 8702, both agents, and 8696, placebo. Analysis reflect the final data collected by the study sites on their participants through July 5, 2011. Interventions Oral selenium (200 µg/d from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac--tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years. Main Outcome Measures Prostate cancer incidence. Results This report includes 54 464 additional person-years of follow-up and 521 additional cases of prostate cancer since the primary report. Compared with the placebo (referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio [HR], 1.17; 99% CI, 1.004- 1.36, P=.008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93-1.27; P=.18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89-1.22, P=.46). Compared with placebo, the absolute increase in risk of prostate cancer per 1000 personyears was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination. Conclusion Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men. Trial Registration Clinicaltrials.gov Identifier: NCT00006392 JAMA. 2011;306(14):1549-1556 www.jama.com Author Video Interview available at www.jama.com. ©2011 American Medical Association. All rights reserved. JAMA, October 12, 2011—Vol 306, No. 14 1549 Corrected on October 11, 2011 Downloaded from jama.ama-assn.org by guest on October 18, 2011

VITAMIN E AND PROSTATE CANCER began accrualon August 22.2001.and study end points and a blood sample sclenium with matching placebo men or at agc 55 vcars for all other atAnnd d Men were and miz ed into 1 of 4 safety monitoring committee met yearly group: ned interimanaly selenium(2 sis,the independent data and safety vitamin Eplacebo,vitaminE(00IU/ cer diagnoses.On of a rac-o-tocopherol ace eptemb lated to the lack ofefficacy of the agents nts because of lack of Participants wi out prost on prevention of prostate cancer.Since reduction and cer were m nfcontin od pressure tion Statistical Analysis rticle s with weight and smoking stats:partic a median follow-up of 5.5 years,the during the study were monitored an cancer incidence resulting from rou- numbers o of prostate ane community ers not cen C6951358 vitamin E:432 (HR esting and p tate h included in the ana is five nres standard of care in the fied comparisons of the 4study 25f0 m acco the re con 1(HR 1)for placcho.Ah multivitamin contain tamin nium plus 1E,an ing comm and sa ten informed cons nt and the local in nce level of 0o wa the increa of prostate cancer ob specified to test for the preventive effec whi asked abor int nificance (P=06)and a statisticall new medical events in the previous ported,we have reported-sided Pva I he prim ry en point of th placebo group P16). determined by routine clinical man cancer is a 2-sided question. Since that time.participant fol- by central pa nis On May 20 en pla 2011,the data and safety monitoring co and achof cancers Men wi ch6-month study visit.Medical rec min his recor on rds were o rand clin sis was periorm data using study sites and coincided with the pre report and planned final analysis at e were ed to ELEC last participant was ran entra d ed h METHODS nent of gl ason score.Median bas ch study group time interaction f th and fo up pla he cumu ative incidence curves to SELECT have been previously pub- nal report no for the competing risk of death s a lished.o The study enrolled health ip continued in an un en at average :1 2008 mntil July 2011.The fina study site visits included follow-up for stitute Inc,Cary,North Carolina). 2011A All rights reserved. Downloaded from iama ama-assn org by quest on October 18.2011

began accrual on August 22, 2001, and randomized 35 533 men into 4 groups: selenium with matching placebo, vitamin E with matching placebo, both agents, or placebo. Based on a preplanned interim analysis, the independent data and safety monitoring committee met on September 15, 2008, and recommended the early discontinuation of study supplements because of lack of efficacy for risk reduction and because futility analysis demonstrated no possibility of benefit to the planned degree with additional follow-up.6 As reported in the initial article,6 with a median follow-up of 5.5 years, the numbers of prostate cancers detected were 473 (hazard ratio [HR], 1.13; 99% CI, 0.95-1.35) for vitamin E; 432 (HR, 1.04; 99% CI, 0.87-1.24) for selenium; 437 (HR, 1.05; 99% CI, 0.88- 1.25) for selenium plus vitamin E; and 416 (HR, 1.0) for placebo. Although these results were not statistically significant, the data and safety monitoring committee expressed concern about the increased risk of prostate cancer observed in the vitamin E plus placebo group, which approached statistical significance (P=.06) and a statistically nonsignificant increased risk of type 2 diabetes mellitus in the selenium plus placebo group (P=.16). Since that time, participant follow-up has continued, allowing observation of additional events. On May 20, 2011, the data and safety monitoring committee reviewed trial data and recommended reporting thefinding regarding increased risk of prostate cancer with vitamin E. This recommendation was based on final data collection from the study sites and coincided with the preplanned final analysis at 7 years after the last participant was randomized. METHODS Detailed descriptions of the rationale, design, conduct, and initial results of SELECT have been previously published.6,7 The study enrolled healthy men at average risk of prostate cancer based on a baseline prostate-specific antigen (PSA) of 4 ng/mL and normal digital rectal examination (DRE) commencing at age 50 years for black men or at age 55 years for all others. Men were randomized into 1 of 4 groups: selenium (200 µg/d from L-selenomethionine) with matching vitamin E placebo, vitamin E (400 IU/d of all rac--tocopherol acetate) with matching selenium placebo, both agents, or matching placebo (FIGURE 1). Participants without prostate cancer were monitored every 6 months with an annual limited physical examination including blood pressure, weight, and smoking status; participants who developed prostate cancer during the study were monitored annually thereafter. Participants were recommended to undergo PSA and DRE testing and prostate biopsy based on the standard of care in their community and in accordance with the participant’s preference. To facilitate adherence, a multivitamin containing no selenium or vitamin E was offered. All participants were required to provide written informed consent and the local institutional review board of each study site approved the study. At study visits, men were asked about new medical events in the previous 6 months. The primary end point of the study was prostate cancer incidence as determined by routine clinical management and confirmed by central pathology review. Blinded follow-up continued until October 23, 2008, at which time participants discontinued use of study supplements. Prostate cancer status was determined by self-report at each 6-month study visit. Medical records were obtained thereafter and clinical stage and diagnostic method were abstracted. The pathology report and tissue were forwarded to the SELECT central pathology laboratory for confirmation of diagnosis and for assignment of Gleason score. Median baseline and follow-up plasma vitamin E and selenium levels are included in the original report.6 Follow-up continued in an unblinded fashion at study sites from October 2008 until July 2011. The final study site visits included follow-up for study end points and a blood sample from participants diagnosed with prostate cancer. An independent data and safety monitoring committee met yearly commencing with study inception, reviewing data on safety, adherence, and prostate and other cancer diagnoses. On September 15, 2008, the committee recommended reporting initial results related to the lack of efficacy of the agents on prevention of prostate cancer. Since that time the committee has continued to meet yearly via teleconference. Statistical Analysis The primary end point was prostate cancer incidence resulting from routine community care. Cancers not centrally confirmed (17% of the total) are included in the analysis. Five prespecified comparisons of the 4 study groups were conducted: selenium vs placebo, vitamin E vs placebo, selenium plus vitamin E vs placebo, selenium vs selenium plus vitamin E, and vitamin E vs selenium plus vitamin E. Although a 1-sided significance level of .005 was specified to test for the preventive effect for each supplement comparison and thus 99% confidence intervals are reported, we have reported 2-sided P values throughout because the comparison of prevention vs increased risk of cancer is a 2-sided question.6 A proportional hazards model was used to compare prostate cancer and other cancer incidence between placebo and each of the 3 study groups with active agents. Men without the end point of interest were censored at their last contact date. An additional analysis was performed on all the data using a variable for selenium supplementation, a variable for vitamin E supplementation, and an interaction term. In all cases, the proportional hazards assumption was evaluated by assessing each study group time interaction. The cumulative incidence curves for prostate cancer were generated accounting for the competing risk of death.8 A 2 test was used to test the difference in the relative risk of diabetes. Data were analyzed using SAS version 9.2 (SAS Institute Inc, Cary, North Carolina). VITAMIN E AND PROSTATE CANCER 1550 JAMA, October 12, 2011—Vol 306, No. 14 ©2011 American Medical Association. All rights reserved. Corrected on October 11, 2011 Downloaded from jama.ama-assn.org by guest on October 18, 2011

RESULTS The current report includes data as of July 5, 2011. There are 54 464 additional person-years offollow-up since the primary report, an increase of 23%. A summary of baseline characteristics is displayedinTABLE 1and an updatedflow diagram in Figure 1. The frequency of use of DRE and PSA is displayed in TABLE 2; there were no differences between groups in the intensity of PSA testing, absolute PSA levels, PSA change from study entry to year 1, nor rates of testing following study unblinding. A total of 521 additional prostate cancers have been diagnosed since the initial report: 113 in the placebo group, 147 in the vitamin E group, 143 in the selenium group, and 118 in the combination group (TABLE 3). The rate of prostate cancer detection was greater in all treatment groups when compared with placebo but was statistically significant only in the vitamin E alone group (HR, 1.17; 99% CI, 1.004- 1.36; P=.008; Table 3). After adjustment for the marginal effects of vitaTable 1. Baseline Participant Characteristics No. (%) of Participants Placebo (n = 8696) Vitamin E Alone (n = 8737) Selenium Alone (n = 8752) Vitamin E Selenium (n = 8702) Age, y Median (IQR) 63 (58-67) 62 (58-67) 63 (58-68) 62 (58-67) 50-54 355 (4) 403 (5) 337 (4) 385 (4) 55-64 5078 (58) 5142 (59) 5075 (58) 5051 (58) 65-74 2702 (31) 2642 (30) 2734 (31) 2731 (31) 75 561 (6) 550 (6) 606 (7) 535 (6) Race/ethnicity White 6862 (79) 6893 (79) 6944 (79) 6872 (79) Black 1083 (12) 1106 (13) 1054 (12) 1075 (12) Hispanic, nonblack 496 (6) 476 (5) 484 (6) 484 (6) Hispanic, black 76 (1) 103 (1) 86 (1) 96 (1) Aboriginal 27 (1) 22 (1) 41 (1) 29 (1) Asian/Pacific Islander 128 (1) 110 (1) 111 (1) 123 (1) Unknown 24 (1) 27 (1) 32 (1) 23 (1) PSA, ng/mL Median (IQR) 1.1 (0.6-1.9) 1.1 (0.6-1.9) 1.1 (0.6-1.9) 1.1 (0.6-1.8) 0.1-1.0 4133 (48) 4234 (48) 4247 (49) 4235 (49) 1.1-2.0 2735 (31) 2648 (30) 2652 (30) 2657 (31) 2.1-3.0 1153 (13) 1222 (14) 1199 (14) 1147 (14) 3.1-4.0 668 (8) 627 (7) 649 (7) 656 (7) 4.0 5 (1) 3 (1) 2 (1) 1 (1) Missing 2 (1) 3 (1) 3 (1) 6 (1) Abbreviations: IQR, interquartile range; PSA, prostate-specific antigen. Figure 1. Patient Flow Diagram 35 533 Men Randomized at 427 participating centers 802 Died or were lost to follow-up 7894 Were alive and being followed up 743 Died or were lost to follow-up 7994 Were alive and being followed up 812 Died or were lost to follow-up 7940 Were alive and being followed up 737 Died or were lost to follow-up 7965 Were alive and being followed up Updated Analysis as of July 5, 2011 7594/7894 Had follow-up data (13 573 additional person-years of follow-up) Updated Analysis as of July 5, 2011 7650/7994 Had follow-up data (13 685 person-years of follow-up) Updated Analysis as of July 5, 2011 7626/7940 Had follow-up data (13 613 person-years of follow-up) Updated Analysis as of July 5, 2011 7620/7965 Had follow-up data (13 593 person-years of follow-up) 8896 Included in the primary analysis (58 753 person-years of follow-up) 8737 Included in the primary analysis (59 087 person-years of follow-up) 8752 Included in the primary analysis (58 907 person-years of follow-up) 8702 Included in the primary analysis (58942 person-years of follow-up)a 8856 Randomized to receive placebo 8696 Received placebo as randomized 160 Excluded 155 Removed from 2 participating sites (poor data and participant management and regulatory issues) 5 Ineligible 1 Had prior prostate cancer 4 Randomized in error (never received proper informed consent) 8904 Randomized to receive vitamin E 8737 Received vitamin E as randomized 167 Excluded 156 Removed from 2 participating sites (poor data and participant management and regulatory issues) 11 Ineligible 5 Had prior prostate cancer 6 Randomized in error (never received proper informed consent) 8910 Randomized to receive selenium 8752 Received selenium as randomized 158 Excluded 155 Removed from 2 participating sites (poor data and participant management and regulatory issues) 3 Ineligible 1 Had prior prostate cancer 2 Randomized in error (never received proper informed consent) 8863 Randomized to receive selenium + vitamin E 8702 Received selenium + vitamin E as randomizeda 161 Excluded 155 Removed from 2 participating sites (poor data and participant management and regulatory issues) 6 Ineligible 3 Had prior prostate cancer 3 Randomized in error (never received proper informed consent) a Since the primary publication, there was additional review and 1 additional participant was found to have had prior prostate cancer. VITAMIN E AND PROSTATE CANCER ©2011 American Medical Association. All rights reserved. JAMA, October 12, 2011—Vol 306, No. 14 1551 Corrected on October 11, 2011 Downloaded from jama.ama-assn.org by guest on October 18, 2011

min E and selenium, the interaction between vitamin E and selenium was statistically significant (P=.02), indicating no increased risk of prostate cancer when vitamin E and selenium were taken together. The risk of Gleason 7 or greater disease was higher for all 3 interventions (vitamin E: HR, 1.16 [99% CI, 0.86-1.58]; selenium: HR, 1.21 [99% CI, 0.90-1.63]; combination: HR, 1.23 [99% CI, 0.91-1.66]) but did not reach statistical significance for any group (Table 3). The elevated risk estimate for vitamin E was consistent across both low- and high-grade disease. The cumulative incidence curves of prostate cancer by supplement group compared with placebo are presented in FIGURE 2. The difference in rates of prostate cancer between vitamin E and placebo became apparent during the participants’ third year in the trial, at which point the HR was 1.10, and increased slightly each year thereafter. The proportional hazards assumption was reasonable for each study group (all P.17). The unadjusted absolute increase in risk of cases of prostate cancer per 1000 person-years compared with placebo was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination. Virtually all men with prostate cancer were without metastases at diagnosis (TABLE 4). Gleason 6 was the most common grade over all. For those with more aggressive disease, Gleason 7 was the most common score. Stage and grade distributions were similar among groups. In the initial SELECT report a statistically nonsignificant increased risk of type 2 diabetes mellitus (as defined by self-report or new use of glitazone medications) was observed in the selenium supplementation group (HR, 1.07). In the updated results the HR is 1.04 and is not statistically significant (P=.34; TABLE 5). Table 5 also displays updated data on the prespecified secondary end points of lung, colorectal, and total other cancers, deaths, and grade 4 cardiovascular events. There are no statistically significant differences in Table 2. Diagnostic Testing Placebo (n = 8696) Vitamin E Alone (n = 8737) Selenium Alone (n = 8752) Vitamin E Selenium (n = 8702) Prostate biopsy, men ever having biopsy, No. Before unblindinga 1041 1046 1003 1014 After unblinding 256 268 267 254 DREs per participant, No. Before unblinding 3.20 3.20 3.20 3.21 After unblinding 0.64 0.63 0.64 0.64 No. of PSA tests/participant Before unblinding 3.87 3.88 3.87 3.90 After unblinding 0.84 0.85 0.86 0.86 Geometric mean PSA (95% CI), ng/mL Year 0 1.13 (0.24 to 4.41) 1.12 (0.23 to 4.37) 1.12 (0.23 to 4.41) 1.13 (0.23 to 4.42) Year 1 1.16 (0.22 to 4.82) 1.14 (0.21 to 4.75) 1.14 (0.21 to 4.89) 1.15 (0.21 to 4.91) Year 2 1.18 (0.21 to 5.08) 1.15 (0.21 to 4.95) 1.17 (0.21 to 5.12) 1.16 (0.21 to 5.08) Year 3 1.19 (0.21 to 5.25) 1.17 (0.20 to 5.26) 1.20 (0.21 to 5.31) 1.19 (0.20 to 5.39) Year 4 1.23 (0.21 to 5.62) 1.19 (0.20 to 5.40) 1.23 (0.21 to 5.61) 1.23 (0.21 to 5.66) Year 5 1.25 (0.21 to 5.81) 1.23 (0.21 to 5.62) 1.26 (0.21 to 5.89) 1.23 (0.21 to 5.66) Year 6 1.28 (0.21 to 6.03) 1.23 (0.20 to 5.83) 1.26 (0.20 to 5.98) 1.25 (0.20 to 6.00) Year 7 1.30 (0.21 to 6.27) 1.26 (0.21 to 5.91) 1.30 (0.21 to 6.22) 1.28 (0.20 to 6.22) Year 8 1.31 (0.20 to 6.52) 1.29 (0.20 to 6.30) 1.39 (0.23 to 6.59) 1.35 (0.22 to 6.58) PSA velocity, year 0-year 1 median (Q1-Q3) 0 (−0.20 to 0.30) 0 (−0.20 to 0.22) 0 (−0.20 to 0.28) 0 (−0.20 to 0.30) Abbreviations: DRE, digital rectal examination; PSA, prostate-specific antigen. aTrial was unblinded on October 23, 2008. Data in the primary article are as of this date. Table 3. Number and Risk of Prostate Cancers Placebo (n = 8696) Vitamin E Alone (n = 8737) Selenium Alone (n = 8752) Vitamin E Selenium (n = 8702) No. of prostate cancers October 2008 416 473 432 437 July 2011 529 620 575 555 Hazard ratio, (99% CI) October 2008 1.13 (0.95-1.35) 1.04 (0.87-1.24) 1.05 (0.88-1.25) P value .06 .62 .52 July 2011 1.17 (1.004-1.36) 1.09 (0.93-1.27) 1.05 (0.89-1.22) P value .008 .18 .46 Absolute riska 9.3 10.9 10.1 9.7 Gleason 7, No. 133 155 161 164 Hazard ratio (99% CI) 1.16 (0.86-1.58) 1.21 (0.90-1.63) 1.23 (0.91-1.66) P value .20 .11 .08 aProstate cancers per 1000 person-years. VITAMIN E AND PROSTATE CANCER 1552 JAMA, October 12, 2011—Vol 306, No. 14 ©2011 American Medical Association. All rights reserved. Corrected on October 11, 2011 Downloaded from jama.ama-assn.org by guest on October 18, 2011

the HRs between groups, suggesting neither benefit nor harm from dietary supplementation with selenium or vitamin E for these end points. COMMENT Prevention of prostate cancer remains an important public health goal because of the relatively high incidence and the high likelihood of curativeintent treatment of this cancer even when indolent disease is present,9 and treatment related costs and morbidity. Although 2 large randomized trials have demonstrated that 5-reductase inhibitors reduce prostate cancer risk by 20% to 25%,10,11 the use of these agents is controversial because of concerns related to an observed increased risk of high-grade disease.12 SELECT was designed to assess the effect of selenium and vitamin E alone and in combination as supplements to a normal diet on their ability to prevent prostate cancer in men at average risk. Other randomized studies have shown no benefit to dietary supplementation with selenium, lycopene, or soy in reducing the risk of invasive cancer in men with high-grade prostatic intraepithelial neoplasia on biopsy.13,14 In this article, we report an observation of important public health concern that has emerged with continued follow-up of SELECT participants. With primary end point ascertainment based on contemporary community practice across the United States, Canada, and Puerto Rico using PSA and DRE as indications for biopsy, the risk of prostate cancer at 7 years of median follow-up was increased by 17% in men randomized to supplementation with vitamin E alone, a difference that started to appear about 3 years after randomization. Although there is debate about how to best handle accumulating results after the publication of primary findings and the appropriate threshold for statistical significance, the increased rate of prostate cancer in the vitamin E group was seen as early as 2006 and continued until the present analysis (HRs ranged from 1.12 to 1.17) suggesting that the current results are not an outlier observation due to multiple looks at the data. Extended follow-up with additional events has resulted in narrowed confidence intervals. A biological explanation for the observed increased risk of prostate cancer in the vitamin E arm is not apparent from these data. The risk does not appear to be due to an increased biFigure 2. Cumulative Incidence of Prostate Cancer No. at risk Placebo Cumulative cases Cumulative cases Vitamin E 8620 29 32 8565 8344 127 8397 135 8081 201 8150 223 7831 268 7839 314 7471 367 7442 415 6399 446 6394 512 4044 503 4010 586 1833 524 1821 614 70 529 50 620 Selenium vs placebo Selenium Placebo 0.15 0.09 0.10 0.11 0.12 0.13 0.14 0.08 0.04 0.05 0.07 0.06 0.03 0.02 0.01 0 No. at risk Placebo Selenium Cumulative cases 1 31 8600 8565 2 8344 8360 123 3 8081 8131 202 4 7831 7826 293 5 7471 7456 384 6 6399 6425 474 7 4044 4075 532 8 1833 1829 563 9 70 66 575 10 Years After Randomization Probability No. at risk Placebo Vitamin E + selenium Cumulative cases 25 8592 8565 8344 8389 105 8081 8136 193 7831 7862 295 7471 7486 378 6399 6378 458 4044 4035 509 1833 1835 545 70 76 555 0.15 0.09 0.10 0.11 0.12 0.13 0.14 0.08 0.04 0.05 0.07 0.06 0.03 0.02 0.01 0 1 2 3 4 5 6 7 8 9 10 Years After Randomization Vitamin E + selenium vs placebo Probability Vitamin E + selenium Placebo Vitamin E vs placebo Vitamin E Placebo 0.15 0.09 0.10 0.11 0.12 0.13 0.14 0.08 0.04 0.05 0.07 0.06 0.03 0.02 0.01 0 1 2 3 4 5 6 7 8 9 10 Years After Randomization Probability VITAMIN E AND PROSTATE CANCER ©2011 American Medical Association. All rights reserved. JAMA, October 12, 2011—Vol 306, No. 14 1553 Corrected on October 11, 2011 Downloaded from jama.ama-assn.org by guest on October 18, 2011