《外科护理学》课程阅读资料（英文）前列腺癌 prostate cancer

ORIGINAL CONTRIBUTION Vitamin E and the Risk of Prostate Cancer The Selenium and Vitamin E Cancer Prevention Trial (SELECT) Erie A.Klein,MD enium and Vitamin E Cancer Prevention Trial Catherine M.Tangen.DrPH atscanosgantneaenpOs risk wit John J.Crowley.PhD into the retionship of vitamin nd prostate cancer. M.Scott Lucia.MD Phyllis I Goodman.MS 时ntdmon o叶 Lori M.Minasian.MD Leslie C.Ford,MD 200 gtgbgnenancodedapostaite J.Michael Caziano,MD.MPH or black men and 55 fo lot Daniel D.Karp.MD 636p0 Michael M.Lieber.MD d by the study site on their part Philip J.Walther.MD.PhD nterver ions Oral/d fromL-selenon nine)with atched vi MD MHS ium placeb both or both matched ollo-upo Joseph LChin minimum of 7 and maximum of 12 years Amy K.Darke,MS Main Outcome Measures Prostate cancer incidence Scott M.Lippman.MD Gary E.Goodman,MD h 529 men c state cance er.620 men in Erank L Mevskens Ir MD 136,P= p(HR.1.09:99% Laurence H.Baker,DO C,0.93-127P=18 edwD stat cance n with vitamin E significantly increased the risk though most cases are found at an e stage Trial Registration Clinicaltrials.go AMA2013011549.1556 www.jama.com related adverse effects are common. Even men whe choos e active surveil egy face anxiety.uncertain prog treatment,and treatment-related costs vention.Co primary prevention of prostate cancer erally funde ancer research oopera d a measurable risk of sepsis with fol with preclinical and are ultimately treated "5 with such a available at www.jama.com. ported the and Kdr 22011 American medical association.all rishts reserved. mm.m8品20H30141549 Downloaded from jama.ama-assn.org by guest on October 18.2011

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 CAN￾cer in the United States is cur￾rently estimated to be 16%.1 Al￾though most cases are found at an early, curable stage, treatment is costly and urinary, sexual, and bowel￾related adverse effects are common.2 Even men who choose active surveil￾lance as an initial management strat￾egy face anxiety, uncertain prognosis, and a measurable risk of sepsis with fol￾low-up biopsies,3 and more than one￾third 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 sele￾nium and vitamin E may reduce pros￾tate cancer risk, we conducted and re￾ported the results of a prospective randomized trial examining the effect of these 2 agents for prostate cancer pre￾vention.6Coordinated by SWOG, a fed￾erally funded cancer research coopera￾tive group, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) Author Affiliations are listed at the end of this ar￾ticle. 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 pri￾mary 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, pla￾cebo. 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 vi￾tamin 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 pla￾cebo (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 person￾years 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, vita￾min E with matching placebo, both agents, or placebo. Based on a preplanned interim analy￾sis, the independent data and safety monitoring committee met on Septem￾ber 15, 2008, and recommended the early discontinuation of study supple￾ments because of lack of efficacy for risk reduction and because futility analy￾sis demonstrated no possibility of ben￾efit to the planned degree with addi￾tional 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 sele￾nium; 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 sig￾nificant, the data and safety monitor￾ing committee expressed concern about the increased risk of prostate cancer ob￾served in the vitamin E plus placebo group, which approached statistical sig￾nificance (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 fol￾low-up has continued, allowing obser￾vation of additional events. On May 20, 2011, the data and safety monitoring committee reviewed trial data and rec￾ommended reporting thefinding regard￾ing increased risk of prostate cancer with vitamin E. This recommendation was based on final data collection from the study sites and coincided with the pre￾planned 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 pub￾lished.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 nor￾mal 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 can￾cer were monitored every 6 months with an annual limited physical exami￾nation including blood pressure, weight, and smoking status; partici￾pants who developed prostate cancer during the study were monitored an￾nually thereafter. Participants were rec￾ommended 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 partici￾pants were required to provide writ￾ten informed consent and the local in￾stitutional 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 man￾agement and confirmed by central pa￾thology review. Blinded follow-up con￾tinued until October 23, 2008, at which time participants discontinued use of study supplements. Prostate cancer sta￾tus was determined by self-report at each 6-month study visit. Medical rec￾ords were obtained thereafter and clini￾cal stage and diagnostic method were abstracted. The pathology report and tissue were forwarded to the SELECT central pathology laboratory for con￾firmation of diagnosis and for assign￾ment of Gleason score. Median base￾line and follow-up plasma vitamin E and selenium levels are included in the original report.6 Follow-up continued in an un￾blinded fashion at study sites from Oc￾tober 2008 until July 2011. The final study site visits included follow-up for study end points and a blood sample from participants diagnosed with pros￾tate cancer. An independent data and safety monitoring committee met yearly commencing with study inception, re￾viewing data on safety, adherence, and prostate and other cancer diagnoses. On September 15, 2008, the committee rec￾ommended reporting initial results re￾lated to the lack of efficacy of the agents on prevention of prostate cancer. Since that time the committee has contin￾ued to meet yearly via teleconference. Statistical Analysis The primary end point was prostate cancer incidence resulting from rou￾tine community care. Cancers not cen￾trally confirmed (17% of the total) are included in the analysis. Five prespeci￾fied comparisons of the 4 study groups were conducted: selenium vs placebo, vitamin E vs placebo, selenium plus vi￾tamin E vs placebo, selenium vs sele￾nium 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 re￾ported, we have reported 2-sided P val￾ues throughout because the compari￾son 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 pla￾cebo 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 analy￾sis was performed on all the data using a variable for selenium supplementa￾tion, a variable for vitamin E supple￾mentation, and an interaction term. In all cases, the proportional hazards as￾sumption was evaluated by assessing each study group  time interaction. The cumulative incidence curves for prostate cancer were generated account￾ing 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 In￾stitute 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

VItAmIn EAND PROSTATE CANCER Figure 1.Patient Flow Diagran 737 9478e 72075ea3 Since the primary publication.there was addit指onal 1 additional ipant was found to have had prior prostate cancer RESULTS wo.%lo时Particinants di primary report.an of (n85 n-8702 ge: n (0R) of 2586 of DRE PSAdi-playcd 514259 50755 5051(58 ct 561 550同 55间 in absolute PSA levels.PSA change 6862(79) 6872.g A total Hspn，nonblack 27 41们 9(c1) 43 sian/Pacific Islander 2( PSA in all treatment 0.1-1.0 334 24749 pared wit was statisti 1-30 115313 1224 1114 1147141 y signif (HR.117:99% 6 Missing ment for the marginal effects of vita CR,imerguartle range 2011 American Medical Association.All rights reserved. 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 addi￾tional 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 be￾tween groups in the intensity of PSA test￾ing, absolute PSA levels, PSA change from study entry to year 1, nor rates of testing following study unblinding. A total of 521 additional prostate can￾cers have been diagnosed since the ini￾tial report: 113 in the placebo group, 147 in the vitamin E group, 143 in the selenium group, and 118 in the com￾bination group (TABLE 3). The rate of prostate cancer detection was greater in all treatment groups when com￾pared with placebo but was statisti￾cally significant only in the vitamin E alone group (HR, 1.17; 99% CI, 1.004- 1.36; P=.008; Table 3). After adjust￾ment for the marginal effects of vita￾Table 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

VITAMIN E AND PROSTATE CANCER Table 2.Diagnostic Testing placebo 1041 104 3.20 320 3.20 391 After unblinding 0.64 0.63 0.64 0.64 8 PSA(5C).ng/'mL. 1.1302404.410 1.120.230437 1.12023t0441 1.13023o4.40 Year 1 11610204.8 1.14021to4.75 1.14021to489 1.150.21049 11902152 1170200528 1200218 1230211o5.6g 1.19020o540 23021o5.6 1021o56 301021106.2☑ 12602105.9 300210622 1.280201o622 1.35 1Q1-Q3 2 Table3.Number and Risk of Prostate Cancers thereafer.The proporion ar min n=8702 justed absolute increase in risk of 47 47 ases of prostate cancer per as 16 for vitamin E.0.8 for sele 1.13095135 104087-1241.05088-1.2 71004-13010909g-120105089-12 sis (TABLE 4).Gleason 6 was the m 93 common grade over all.For those witl 18015g21901 310.911.6间 andgade ne 1000 person-yeer -t min E and selenium.the interaction (Table 3).The elevated risk estimate for between vitamin E and ent across both f-report or new use of glitazone was o Dro state cancer by supplement group taken together.The of Glea (Pand is n of pr tate cancer between vitamin e plays updated data on the prespecificd .0.86 selenium:HR,1 placebo be m e apparent du n ore 199%CL091-166D butdid notreach trial.at whicho oint the HiR was 1.10 tal, statistical significance for any group and increased slightly each year 2011A Downloaded from iama ama-assn org by quest on October 18.2011

min E and selenium, the interaction between vitamin E and selenium was statistically significant (P=.02), indi￾cating no increased risk of prostate can￾cer 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 unad￾justed 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 sele￾nium, and 0.4 for the combination. Virtually all men with prostate can￾cer were without metastases at diagno￾sis (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 sta￾tistically nonsignificant increased risk of type 2 diabetes mellitus (as defined by self-report or new use of glitazone medications) was observed in the se￾lenium 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 dis￾plays updated data on the prespecified secondary end points of lung, colorec￾tal, 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

VITAMIN E AND PROSTATE CANCER at the data.Extended follow-up with cer in the vitamin E arm is not appar COMMENT Prevention ol pro igure 2.Cumulative Incidence of Prostate Cancer Vitamin Eve placebo and the high likelih cancer even tors reduce he use of these agents is to an high-grade disease SELECT was de. signed to as th eiectofsele tion as supplements to a no nal diet on their abili y toprevent prostate ance ized studies have shown Selenium vs placebe or soy in high-grad prostaticintraepithelialnco 2 based on contem porary community practice across ate sing 蓝腮 and DRE as indications for hions the Vitamin E+selenium vs placeb 179%n ed t to appe le accumulating r Its after th the a significance,the increased rate o E group 2g ued until the 2011 American Medical Association.All rights reserved. m8m8品20洲306a141ss 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 vi￾tamin E for these end points. COMMENT Prevention of prostate cancer remains an important public health goal be￾cause of the relatively high incidence and the high likelihood of curative￾intent 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 inhibi￾tors reduce prostate cancer risk by 20% to 25%,10,11 the use of these agents is controversial because of concerns re￾lated to an observed increased risk of high-grade disease.12 SELECT was de￾signed to assess the effect of selenium and vitamin E alone and in combina￾tion as supplements to a normal diet on their ability to prevent prostate cancer in men at average risk. Other random￾ized studies have shown no benefit to dietary supplementation with sele￾nium, lycopene, or soy in reducing the risk of invasive cancer in men with high-grade prostatic intraepithelial neo￾plasia on biopsy.13,14 In this article, we report an observa￾tion of important public health con￾cern 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 supple￾mentation with vitamin E alone, a dif￾ference 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 contin￾ued until the present analysis (HRs ranged from 1.12 to 1.17) suggesting that the current results are not an out￾lier observation due to multiple looks at the data. Extended follow-up with additional events has resulted in nar￾rowed confidence intervals. A biological explanation for the ob￾served increased risk of prostate can￾cer in the vitamin E arm is not appar￾ent from these data. The risk does not appear to be due to an increased bi￾Figure 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

VITAMIN E AND PROSTATE CANCER Table 4.Clinical and Path ogical Characteristics of Ind SELECT,interventio with 400 IU of vi In-8752 6=8702 had no yoamedn Total prostate cancers diagnosed,No 33间 22 lthough like 87(16 114(1) 12121) 10118) cer incidence (HR.1.049%Cl.0.95 444但4 50682 47482 47586 9(1 71 81) both ATBC and PHS I were designed and analyzed as facte 2a-b 1432万 13802 12723 144268 ials.so the reported effect ofv 3a-b 11) 3(<1) 31) 2≤1) ary factor (beta carotene or vitamin C N spectively).In cont 37872 4417的 39770 39372 SELECT was 14528 1672 16629 15428 the pouental interac <1) Not sta ed 2R470m 4357 299711 39172 deed obse ager 1930 17028 15928) 15328 hat more t 150%of ndi Not staoed 12 10 nts containing vitamin Eand 2869 31067 28164 28163) of them are taking at least400 28 only 22.4IU for 170 men,s the implicati s of our obse al.Con stent w ow-up did not demonstrate a benef opsy rate prompted b cha nges in DRE in the general population of healthy nts The current findi modest benefits for vita min E ave the effects of vitamin Esupplementa ized clinical the inc 15 ion on pro and (as I part o a combina forced by the Pyalue (of the in rted a 3%risk reduction for p related macular degener at ehits were demor er Pall r a events d for the tant di infe be addressed by analysis of the effects with tions in elderly individuals.pre line plasma AIBC were all long-term 43 ampsia in women with type and toenail selenium levels from who had never smokeda and 89 curren sion of ca cis or macular degenera- smokers in SE on Moreover,the increased inc and C)men in ATBC were notscre show that vitamin Esupplementation so that prostate cancer was diagnosed at creased incidence of lung cancer with 1554 8品261 2011Am n Medical All rights reserved. Downloaded from iama ama-assn org by quest on October 18.2011

opsy rate prompted by changes in DRE, PSA, or unblinding. There was not a sta￾tistically significant increased risk of prostate cancer in the vitamin E and se￾lenium combination group (HR, 1.05; P=.46), suggesting that selenium may have a protective effect by dampening the increased risk associated with vi￾tamin E alone, a hypothesis rein￾forced by the P value (.02) of the in￾teraction term in the marginal analysis. Tests of this hypothesis and other po￾tential explanations for the results will be addressed by analysis of the effects of baseline plasma vitamin E levels and their interaction with baseline plasma and toenail selenium levels from samples collected from participants at study entry. Despite the lack of a mechanistic explanation, the findings show that vitamin E supplementation in the general population of healthy men significantly increases the risk of being diagnosed with prostate cancer. The currentfindings of SELECT differ from findings from other large random￾ized intervention trials that examined the effects of vitamin E supplementa￾tion on prostate cancer risk. The Alpha￾Tocopherol, Beta Carotene (ATBC) trial reported a 35% risk reduction for pros￾tate cancer in men taking 50 mg/d of vi￾tamin E for a median of 6.1 years,15 al￾though there are important differences with SELECT: (1) the participants of ATBC were all long-term smokers (36 years on average) compared with 43% who had never smoked and 8% current smokers in SELECT; (2) prostate can￾cer was a secondary end point in ATBC; and (3) men in ATBC were not screened so that prostate cancer was diagnosed at more advanced stages than in SELECT. In the Physicians Health Study II (PHS II) conducted contemporaneously with SELECT, intervention with 400 IU of vi￾tamin E every other day for a median of 8 years had no effect on the incidence of prostate cancer (HR,0.97; 95% CI, 0.85-1.09; P =.58), although like SELECT there was no effect on total can￾cer incidence (HR, 1.04; 95% CI, 0.95- 1.13; P=.41) or overall mortality (HR, 1.08; 95% CI, 0.98-1.19).16 Furthermore, both ATBC and PHS II were designed and analyzed as facto￾rial trials, so the reported effect of vi￾tamin E is estimated across the second￾ary factor (beta carotene or vitamin C, respectively). In contrast, SELECT was designed as a 4-group trial because of concerns about the potential interac￾tion of vitamin E and selenium, for which a statistically significant inter￾action between these agents was in￾deed observed. Given that more than 50% of indi￾viduals 60 years or older are taking supplements containing vitamin E and that 23% of them are taking at least 400 IU/d17 despite a recommended daily di￾etary allowance of only 22.4 IU for adult men,18 the implications of our obser￾vations are substantial. Consistent with the original SELECT report, longer fol￾low-up did not demonstrate a benefit for selenium or vitamin E supplemen￾tation on risk of colorectal or lung can￾cer or cardiovascular events. Although modest benefits for vita￾min E supplementation have been ob￾served in a limited number of random￾ized clinical trials for Alzheimer disease19 and (as 1 part of a combina￾tion of oral antioxidants) for age￾related macular degeneration,20 no ben￾efits were demonstrated for prevention of cardiac events or mortality,21-23 co￾lorectal adenomas,24 respiratory infec￾tions in elderly individuals,25 pre￾eclampsia in women with type 1 diabetes,26 or prevention or progres￾sion of cataracts or macular degenera￾tion.27,28 Moreover, the increased inci￾dence of prostate cancer seen in SELECT, the previously reported in￾creased incidence of lung cancer with Table 4. Clinical and Pathological Characteristics of Incident Prostate Cancers No. (%) of Cancers Placebo (n = 8696) Vitamin E Alone (n = 8737) Selenium Alone (n = 8752) Vitamin E  Selenium (n = 8702) Total prostate cancers diagnosed, No. 529 620 575 555 After unblinding for primary article 416 (79) 473 (76) 432 (75) 437 (79) Diagnosed prior to unblinding but data received afterwards 26 (5) 33 (5) 22 (4) 17 (3) Diagnosed after unblinding 87 (16) 114 (18) 121 (21) 101 (18) Confirmation status Confirmed by central pathologya 444 (84) 506 (82) 474 (82) 475 (86) T stage TX 5 (1) 9 (1) 7 (1) 8 (1) T1a-c 375 (72) 460 (75) 425 (76) 391 (72) T2a-b 143 (27) 138 (23) 127 (23) 144 (26) T3a-b 1 (1) 3 (1) 3 (1) 2 (1) Not staged 5 10 13 10 N stage NX 378 (72) 441 (73) 397 (70) 393 (72) N0 145 (28) 167 (27) 166 (29) 154 (28) N1 0 0 2 (1) 1 (1) Not staged 6 12 10 7 M stage MX 364 (70) 435 (72) 399 (71) 391 (72) M0 159 (30) 170 (28) 159 (28) 153 (28) M1a-c 0 3 (1) 7 (1) 3 (1) Not staged 6 12 10 8 Gleason score 4-6 286 (69) 310 (67) 281 (64) 281 (63) 7 102 (24) 118 (25) 135 (31) 124 (28) 8-10 31 (7) 37 (8) 26 (6) 40 (9) Not graded 110 155 133 110 aThere were no disagreements. The cases not confirmed by central pathology review were either because no materials or inadequate materials were sent for review. VITAMIN E AND PROSTATE CANCER 1554 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

VITAMIN E AND PROSTATE CANCER Table 5.Secondary End Points Efficacy Trial(CARET)and the in- risk of colon polyps seenn suggest that caution should be used zamo99%C 1.090.72-1.6409310.63-1.461210.81-181 when recommending or studying high valu thetic zard ratio%C 1110761.61)1.021070-150111076-162 I physiology 579 57 00a 0970.83-110.9610.83-1.13)102088-1.1g CARET emphasize the impe 110g 7961Hg12119122,1 large-scale,populatio efits and a 564 010861.1098084-1190960821.12 as dietary supplements Because a sta ato99%C】 ant i 669 10 60 nium we belieye that caut ion should .91-1.18 0.94-1.22 7 Jy5,201 factorial designs 869 are 918 913 8 e risk(99%Cn 0.93-1.1刀1 4093-1.17刀 908-1.1 cause of their statistic in 969 909 943 treatme t component 093083-1.0的097086-1.090.97086-109 tha tamin of participants in as only parent after sgratsugeh.chem d that fects from these agents may continue average risk of prostate cancer sub- over-the-counter products in the even after int stopp low-up even in trials closed before the who took a common dos and formu A Dep nof vitamin E (400 IU/d)have a and Re have the o P The obs d179 er. prosta cancer in re ann ates to gene the pote Coodn and Da ment of stances such as vitamins to cause Ca The lac of be t from dietar other agents with】 at t dress these issues. ng common health conditions and f Th d and V. CONCLUSION nd Extended follow 22011 American medical asseciation.all rishts reserved. m.8m8品20306，a14155 Downloaded from jama.ama-assn.org by guest on October 18.2011

high-dose beta carotene in both ATBC15 and the Beta-Carotene and Retinol Efficacy Trial (CARET),29 and the in￾creased risk of colon polyps seen in a trial administering high-dose folate,30 suggest that caution should be used when recommending or studying high doses of micronutrients. As opposed to synthetic pharmaceuticals, these natu￾rally occurring dietary constituents are part of normal physiology, and a U-shaped-dose response curve may ex￾ist where either deficiency or supra￾physiological doses are harmful. The findings of SELECT, ATBC, and CARET emphasize the importance of large-scale, population-based, random￾ized trials in accurately assessing the benefits and harms of micronutrients as dietary supplements. Because a sta￾tistically significant interaction was ob￾served between vitamin E and sele￾nium, we believe that caution should be used when designing factorial pre￾vention trials in the future. Although factorial designs are appealing be￾cause of their statistical efficiency, in￾teractions can make it difficult to evalu￾ate the underlying effects of each treatment component.31 Furthermore, the fact that the in￾creased risk of prostate cancer in the vi￾tamin E group of participants in SELECT was only apparent after ex￾tended follow-up (allowing for addi￾tional events) suggests that health ef￾fects from these agents may continue even after the intervention is stopped, emphasizing the need for long-term fol￾low-up even in trials closed before the planned intervention period is com￾pleted. Consenting SELECT partici￾pants have the opportunity to transi￾tion to a centralized follow-up study where annual updates to general health and cancer status are obtained either via a mailed questionnaire or data en￾tered by the participant on the SELECT participant Web site, which will allow additional follow-up to further ad￾dress these issues. CONCLUSION Extended follow-up of SELECT par￾ticipants shows that healthy men with average risk of prostate cancer sub￾jected to contemporary community standards of screening and biopsy who took a common dose and formu￾lation of vitamin E (400 IU/d) have a significantly increased risk of prostate cancer. The observed 17% increase in prostate cancer incidence demon￾strates the potential for seemingly innocuous yet biologically active sub￾stances such as vitamins to cause harm. The lack of benefit from dietary supplementation with vitamin E or other agents with respect to prevent￾ing common health conditions and cancers or improving overall survival, and their potential harm, underscore the need for consumers to be skepti￾cal of health claims for unregulated over-the-counter products in the absence of strong evidence of benefit demonstrated in clinical trials. Author Affiliations: Department of Urology, Glick￾man Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio (Dr Klein); Cancer Therapy and Re￾search Center, University of Texas Health Science Cen￾ter, San Antonio (Dr Thompson); SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Se￾attle, Washington (Drs Tangen and Crowley and Mss Goodman and Darke); Department of Pathology, Uni￾versity of Colorado Health Science Center, Aurora (Dr Lucia); Division of Cancer Prevention, National Can￾cer Institute, Bethesda, Maryland (Drs Minasian, Ford, and Parnes); Veterans Epidemiology Research and In￾formation Center, VA Boston Healthcare System, and the Brigham and Women’s Hospital, Division of Ag￾ing, Boston, Massachusetts (Dr Gaziano); Depart￾ment of Thoracic/Head and Neck Medical Oncol￾ogy, Division of Cancer Medicine, MD Anderson Cancer Center/University of Texas, Houston (Drs Karp and Lippman); Department of Urology, Mayo Clinic, Rochester, Minnesota (Dr Lieber); Department of Urol￾ogy, Duke University Medical Center, Durham, North Carolina (Dr Walther); Department of Urology, Sun￾Table 5. Secondary End Points Placebo (n = 8696) Vitamin E Alone (n = 8737) Selenium Alone (n = 8752) Vitamin E  Selenium (n = 8702) Colorectal cancer, No. 75 85 74 93 Hazard ratio (99% CI) 1.09 (0.72-1.64) 0.96 (0.63-1.46) 1.21 (0.81-1.81) P value .60 .79 .22 Lung cancer, No. 92 104 94 104 Hazard ratio (99% CI) 1.11 (0.76-1.61) 1.02 (0.70-1.50) 1.11 (0.76-1.62) P value .49 .89 .48 All other primary cancers, excludes prostate, includes colorectal and lung, No. 579 570 557 594 Hazard ratio (99% CI) 0.97 (0.83-1.14) 0.96 (0.83-1.13) 1.02 (0.88-1.19) P value .65 .54 .74 All cancers, including prostate 1108 1190 1132 1149 Hazard ratio (99% CI) 1.07 (0.96-1.19) 1.02 (0.92-1.14) 1.02 (0.92-1.14) P value .13 .59 .60 Deaths, all cause 564 571 551 542 Hazard ratio (99% CI) 1.01 (0.86-1.17) 0.98 (0.84-1.14) 0.96 (0.82-1.12) P value .91 .67 .47 October 23, 2008a Diabetesb 669 700 724 660 Relative risk (99% CI) 1.04 (0.91-1.18) 1.07 (0.94-1.22) 0.97 (0.85-1.11) P value .47 .16 .61 July 5, 2011 Diabetesb 869 918 913 875 Relative risk (99% CI) 1.05 (0.93-1.17) 1.04 (0.93-1.17) 0.99 (0.89-1.12) P value .29 .34 .91 Cardiovascular events, grade 4c 969 909 939 943 Hazard ratio (99% CI) 0.93 (0.83-1.05) 0.97 (0.86-1.09) 0.97 (0.86-1.09) P value .11 .45 .51 aDate of data freeze for initial publication bPrevalent cases at baseline and men who never submitted a form with a diabetes assessment are excluded from the analysis. cTime to first reported cardiovascular event, cardiovascular procedure (eg, coronary artery bypass graft surgery), or hem￾orrhagic stroke, all men. Cardiovascular end points were not centrally adjudicated. VITAMIN E AND PROSTATE CANCER ©2011 American Medical Association. All rights reserved. JAMA, October 12, 2011—Vol 306, No. 14 1555 Corrected on October 11, 2011 Downloaded from jama.ama-assn.org by guest on October 18, 2011

VITAMIN E AND PROSTATE CANCER D ance tical analysis:Tangen.Crowley,P.Goodman ompe ton nt of Heal Mas ad ful a f th Dr C Dr bo pili nd and the a Me Dr Chin n ng payn agon: RENCES 2010.CA entsNEng Med. 量y0 Buring JE,Christen WG,et al.Vita vivors N Enel Med 2008358012) rom D Vargo R.Berg R coli 2011 9751035.101 e to treat TeeherotatsaEad 31 ancers in male s E and C in ES,Ajan UA. 0 AH. 9737 ooley TA,Lesenring W.Cre yJ,Storer BE.Es nd caty gtatonsofo6oa 28e HR.T AR,Br ano M. ance 117.11 17):121 120 007297212351-2359 12.Theoret MR.JusticeR.Kecgan ation 1568品29洲06 O2011A Medic All rights reserved Downloaded from iama ama-assn org by quest on October 18.2011

nybrook Medical Center, North York, Ontario, Canada (Dr Klotz); Department of Surgery, Moores Cancer Center, University of California San Diego, La Jolla (Dr Parsons); London Health Sciences Center, London, Sur￾gical Oncology, Ontario, Canada (Dr Chin); Swedish Medical Center Cancer Institute, Medical Oncology, Seattle, Washington (Dr Goodman); University of Cali￾fornia at Irvine, Department of Medicine, Orange (Dr Meyskens); and University of Michigan, Division of Hematology/Oncology, Ann Arbor (Dr Baker). Dr Karp’s previous affiliation was Beth Israel Deaconess Medical Center, Medical Oncology, Boston, Massa￾chusetts. Author Contributions: Dr Tangen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Klein, Thompson, Tangen, Crowley, P. Goodman, Minasian, Ford, Parnes, Lieber, Walther, Klotz, Lippman, G. Goodman, Baker. Acquisition of data: Klein, Thompson, Tangen, Crowley, Lucia, P. Goodman, Parsons, Chin. Analysis and interpretation of data: Klein, Thompson, Tangen, Crowley, P. Goodman, Minasian, Ford, Karp, Klotz, Darke, Lippman, G. Goodman, Meyskens. Drafting of the manuscript: Klein, Thompson, Tangen, P. Goodman, Lieber, Klotz, G. Goodman, Baker. Critical revision of the manuscript for important in￾tellectual content: Klein, Thompson, Tangen, Crowley, Lucia, P. Goodman, Minasian, Ford, Parnes, Karp, Walther, Parsons, Chin, Darke, Lippman, Meyskens, Baker. Statistical analysis: Tangen, Crowley, P. Goodman, Darke. Obtained funding: Klein, Thompson, Lippman, Baker. Administrative, technical, or material support: Klein, Thompson, Lucia, Minasian, Parnes, Lieber, Walther, Parsons, Chin, Lippman. Study supervision: Thompson, Crowley, P. Goodman, Minasian, Ford, Klotz, Lippman, G. Goodman, Baker. Conflict of Interest Disclosures: All authors have com￾pleted and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Thompson re￾ported receiving research support from the National Cancer Institute for a randomized controlled trial test￾ing finasteride against placebo, both of which are sup￾plied by Merck. Dr Gaziano reported receiving grant support (to his institution) from Wyeth (now Pfizer) in the form of vitamin and placebo pills and packag￾ing. Dr Karp reported receiving grants to his institu￾tion from Pfizer. Dr Klotz reported receiving travel sup￾port for meetings from sanofi-aventis, Merck, and AstraZeneca and research support for investigator￾initiated trials from Abbott and GlaxoSmithKline, and institutional grants pending. Dr Chin reported receiv￾ing consultancy fees from Janssen, Amgen, Novartis, and Firmagon; receiving payment for lectures from Fir￾magon; and payment for development of educa￾tional presentations from AstraZeneca, Novartis, and Firmagon. Dr Meyskens reported being a co-founder of Cancer Prevention Pharmaceuticals. Dr Baker re￾ported board membership for Merck for which he re￾ceives no compensation. Otherwise there were no other conflicts of interest disclosed. Funding/Support: This work was supported in part by Public Health Service Cooperative Agreement grant CA37429 awarded by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and in part by the National Cen￾ter for Complementary and Alternative Medicine (Na￾tional Institutes of Health). Study agents and pack￾aging were provided by Perrigo Co, Allegan, Michigan; Sabinsa Corp, Piscataway, New Jersey; Tishcon Corp, Westbury, New York; and DSM Nutritional Products Inc, Parsipanny, New Jersey. Disclaimer: Dr Gaziano, a contributing editor forJAMA, was not involved in the editorial review of or the de￾cision to publish this article. Role of the Sponsor: This work was supported by the National Institutes of Health, primarily the National Cancer Institute (NCI) and the National Center for Complementary and Alternative Medicine. Represen￾tatives from the National Institutes of Health (NCI) par￾ticipated in design, oversight, and reporting of this study. Online-Only Material: The Author Video Interview is available at http://www.jama.com. REFERENCES 1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277-300. 2. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate￾cancer survivors. 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