Progression From High-Grade Prostatic Intraepithelial Neoplasia to ...

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JOURNAL OF CLINICAL ONCOLOGY

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Progression From High-Grade Prostatic Intraepithelial Neoplasia to Cancer: A Randomized Trial of Combination Vitamin-E, Soy, and Selenium Neil E. Fleshner, Linda Kapusta, Bryan Donnelly, Simon Tanguay, Joseph Chin, Karen Hersey, Anne Farley, Ken Jansz, D. Robert Siemens, Kiril Trpkov, Louis Lacombe, Martin Gleave, Dongsheng Tu, and Wendy R. Parulekar From the University Health Network, Toronto; Credit Valley Hospital, Mississauga; London Health Sciences Centre, London; National Cancer Institute of Canada Clinical Trials Group, Queen’s University, Kingston; Burlington Urology, Burlington, Ontario; Prostate Cancer Centre; University of Calgary, Calgary, Alberta; McGill University Health Centre, Montreal; Hotel Dieu de Quebec, Quebec City, Quebec; and the University of British Colombia, Vancouver, British Colombia, Canada. Submitted August 12, 2010; accepted January 27, 2011; published online ahead of print at www.jco.org on May 2, 2011. Supported by Grant No. 15469 from the Canadian Cancer Society Research Institute. Presented in part in abstract form at the 104th Annual Meeting of the American Urology Association, April 25-29, 2009, Chicago, IL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: Neil E. Fleshner, MD, MPH, FRCSC, Princess Margaret Hospital, 3-130, 610 University Ave, Toronto, Ontario Canada M5G 2M9; e-mail: [email protected]. © 2011 by American Society of Clinical Oncology 0732-183X/11/2917-2386/$20.00 DOI: 10.1200/JCO.2010.32.0994

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Purpose High-grade prostatic intraepithelial neoplasia (HGPIN) is a putative precursor of invasive prostate cancer (PCa). Preclinical evidence suggests vitamin E, selenium, and soy protein may prevent progression of HGPIN to PCa. This hypothesis was tested in a randomized phase III double-blind study of daily soy (40 g), vitamin E (800 U), and selenium (200 ␮g) versus placebo. Patients and Methods Three hundred three men in 12 Canadian centers were analyzed. The main eligibility criterion was confirmed HGPIN in at least one of two biopsies within 18 months of random assignment. Treatment was administered daily for 3 years. Follow-up prostate biopsies occurred at 6, 12, 24, and 36 months postrandomization. The primary end point was time to development of invasive PCa. Kaplan-Meier plots and log-rank tests were used to compare two treatment groups for this end point. Results For all patients, the median age was 62.8 years. The median baseline prostate-specific antigen (PSA; n ⫽ 302) was 5.41 ug/L; total testosterone (n ⫽ 291) was 13.4 nmol/L. Invasive PCa developed among 26.4% of patients. The hazard ratio for the nutritional supplement to prevent PCa was 1.03 (95% CI, 0.67 to 1.60; P ⫽ .88). Gleason score distribution was similar in both groups with 83.5% of cancers graded Gleason sum of 6. Baseline age, weight, PSA, and testosterone did not predict for development of PCa. The supplement was well tolerated with flatulence reported more frequently (27% v 17%) among men receiving micronutrients. Conclusion This trial does not support the hypothesis that combination vitamin E, selenium, and soy prevents progression from HGPIN to PCa. J Clin Oncol 29:2386-2390. © 2011 by American Society of Clinical Oncology

INTRODUCTION

Prostate cancer (PCa) is the most common clinically diagnosed cancer among men in the Western world.1 There is considerable laboratory and epidemiologic data suggesting that certain micro or macronutrients may have the ability to prevent prostate cancer.2 High-grade prostatic intraepithelial neoplasia (HGPIN) is a putative precursor lesion of invasive PCa. Although there is some debate, many consider this lesion to fulfill the criteria of the preneoplastic state ofinvasivedisease.3-5 ConversionratesfromHGPINto invasive disease range from 15% to 65% depending on year of cohort analyzed as well as other factors including pathologist’s threshold and serum level of prostatespecific antigen (PSA).6

Vitamin E and selenium have been purported to be ideal candidate agents to prevent PCa. Vitamin E and selenium have demonstrable beneficial effects in vitro on cell proliferation and cell cycle turnover.7,8 Two nona priori end point randomized trials of these agents in skin and lung cancer prevention demonstrated benefit of these agents in terms of prostate cancer prevention, respectively.9,10 However, the recently reported Selenium and Vitamin E Cancer Prevention Trial (SELECT) study demonstrated no benefit of supplementation with vitamin E, selenium, or the combination of these agents in terms of primary prevention of PCa in a large randomized phase III setting.11 Soy has long been viewed as a candidate chemoprevention agent for PCa. It is widely consumed in Asia where PCa

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Vitamin-E, Soy, and Selenium in High-Grade Prostatic Intraepithelial Neoplasia

incidence and mortality are low.12 Furthermore, epidemiologic and basic laboratory studies suggest that soy and or its components, such as isoflavonoids, can have beneficial anticarcinogenic effects.13 In this article, we report the results from the phase III study (PRP.1) of combination vitamin E, selenium, and soy among men with HGPIN conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG). PATIENTS AND METHODS Study Design and Treatment PRP.1 was a multicenter, double blind, placebo controlled, phase III study of vitamin E, selenium, and soy in participants with HGPIN. Participants were stratified by center and randomly assigned using a minimization method by the central office of NCIC CTG to receive one package of nutritional supplement consisting of 20 g of soy protein, 400 U of vitamin E, and 100 ␮g of selenium or a whey-based placebo twice daily for 3 years. Treatment allocation was blinded to all participants and those involved in this study. Prohibited concomitant medications on study included any multivitamin containing selenium, and/or vitamin E higher than 100 U/d, any androgen therapies, or the 5␣ -reductase inhibitor, finasteride. The primary objective of this study was to compare the disease-free survival (DFS; time to diagnosis of PCa) between the two treatment groups. Secondary objectives included comparisons of toxicity and changes in serum PSA levels and other biomarkers including testosterone and oxidative biomarkers. Health Canada and the ethics boards of all participating institutions approved the protocol and all patients provided written informed consent before these investigations. Data were collected, managed, and analyzed at the NCIC CTG central office. An interim analysis was planned after observing half of the expected events for the primary end point. An independent data safety monitoring committee provided oversight of the study. Eligibility Eligible men for this study were those with a centrally confirmed diagnosis of HGPIN without invasive cancer over a two-biopsy set (including transition zone if possible) performed within 18 months of random assignment. At least one biopsy must have been performed within 6 months of random assignment. Medications prohibited before random assignment included vitamin E and selenium within 2 weeks, any androgen therapy or hormone therapy for benign prostatic hyperplasia within 3 months, and any prior pelvic radiotherapy or history of PCa. Assessments on Study Medical history, physical (including digital rectal examination), and serum PSA (free PSA if available) were measured every 6 months on study. Total testosterone was measured annually. Toxicity was assessed every 3 months until 12 months and then every 6 months as per the National Cancer Institute Common Toxicity Criteria version 2.0. Telephone contact was made between visits to verify compliance via packet counts and assess toxicities. Prostate biopsies were mandated at 6, 12, 24, and 36 months after random assignment. Study mandated pre- and postrandomization biopsies were reviewed by a designated central pathologist (L.K.) who determined pathologic end points. Statistical Analysis The primary end point, DFS, was defined as the time from random assignment to the development of PCa. Participants who remained disease free or died without PCa were censored at the time of the final assessment or time of death. The original calculation of sample size was based on data from observational studies among men with HGPIN that suggested that 65% to 70% of men with HGPIN would progress in 2 years without treatment and the assumption that nutritional supplementation would lead to a 15% increase in 2-year DFS from 30% for participants receiving placebo (corresponding to a hazard ratio of 0.66). Enrollment of 264 participants was required to detect this www.jco.org

difference with ␤ at .2, two-sided ␣ at .048, and 10% lost to follow-up. To gauge the prognosis of subjects entered on the study and its potential impact on the accuracy of the sample size calculation, a blinded review of the event rate was performed on 228 subjects accrued up to May 2003. This review, in addition to consideration of previously published data,14 led to an increase of the sample size to 306 participants based on an assumption of 2-year DFS of 60% among the placebo participants and detection of the same hazard ratio at the same ␣ and ␤ levels. Analysis of pretreatment characteristics, DFS, and all other efficacy analyses, such as the incidence of invasive PCa, were based on all randomly assigned participants (intention to treat). Safety and study medication exposure analyses were performed for all participants who had received at least one dose of study medication. Log-rank was used to compare DFS between two treatment groups and Cox proportional hazards models for the calculation of hazard ratio and associated 95% CI. The incidence of invasive PCa was estimated by dividing number of patients observed to the total participants-years of follow-up. Two-sided P values lower than .05 were deemed significant. No adjustments were made for the multiplicity of inferences for multiple clinical end points.

RESULTS

Accrual, Compliance, and Ineligibility The study commenced September 1999 and completed accrual in September 2004. A total of 310 patients were randomized. Seven patients withdrew consent for the study and thus 303 patients were included in the primary intention-to-treat efficacy analysis (Fig 1). A total of 51 patients (28 on arm 1 and 23 on arm 2) were found ineligible after review. The reasons for ineligibility were: PCa before random assignment or other prior malignancy (n ⫽ 17); selenium product used or other prior excluded treatment (n ⫽ 2), baseline blood or investigation not completed (n ⫽ 2); biopsy out of allowed time limits or no biopsy within 6 months before random assignment (n ⫽ 2); no HGPIN at random assignment (n ⫽ 28). With regards to compliance, 53.4% and 56.4% of men took the study medication twice per day at all times for the nutritional supplement and placebo groups, respectively. The median compliance rate based on products returned for those who did not take study medication twice per day was respectively 89% for nutritional supplement

Random assignment (N = 310)

No data after random assignment due to consent withdrawal after (n = 7) randomization

Allocated to supplement

(n = 156)

Allocated to placebo

(n = 147)

Received allocated intervention

(n = 153)

Received allocated intervention

(n = 146)

Did not receive allocated intervention

(n = 3) (n = 28)

Ineligible

Did not receive allocated intervention Ineligible

(n = 1) (n = 23)

Analyzed for efficacy end points

(n = 156)

Analyzed for efficacy end points

(n = 147)

Analyzed for safety end points

(n = 153)

Analyzed for safety end points

(n = 146)

Fig 1. CONSORT trial flow diagram.14a,14b



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Table 1. Baseline Demographics Demographic

Nutritional Supplement

Placebo Supplement

156 62.5 83.23

147 63.1 83.57

1.84 42.5

1.84 43.5

5.62 5.1

6.66 5.64

14.98 13.4

14.28 13.4

Sample size Median age, years Weight, kg Median time from biopsy to random assignment, months Any concomitant medication, % PSA, ng/mL Mean Median Total testosterone, nmol/L Mean Median Abbreviation: PSA, prostate-specific antigen.

group and 87% for placebo group. Dose reductions to one packet per day for gastrointestinal toxicity were noted in 127 subjects and were more common among men on placebo compared to those receiving the nutritional supplement (72 v 55 participants). A total of 34 patients refused follow-up prostate biopsies. Median follow-up for participants was 35.0 months (range, 0 to 44.2 months). Baseline Demographics and Laboratory Results The median age for the participants in the nutritional supplement treatment arm was 62.5 years compared to 63.1 years in the placebo arm; the median weight was 82.23 kg and 83.57 kg, respectively. Table 1 presents relevant demographic characteristics and laboratory results. As visible in this Table, no apparent difference was seen between the two treatment groups. The median PSA values for the nutritional supplement and placebo treatment groups were 5.1 and 5.64 ng/mL, respectively. The median total testosterone value was 13.4 nmol/L for both treatment arms. The planned interim analysis was not performed due to the small number of events.

involved cores and Gleason score distribution was the same between the two groups. Figure 2 shows the Kaplan-Meier curves for the cumulative incidence of all invasive PCas. The nutritional supplement had no impact on the development of invasive PCa: annual incidence of invasive PCa was 0.16 (95% CI, 0.11 to 0.20) and 0.15 (95% CI, 0.10 to 0.19) for participants in the nutritional supplement and placebo arms with a 2-year DFS of 68.9% and 73.4%, respectively (hazard ratio [HR], 1.03; 95% CI, 0.67 to 1.61). Baseline age, weight, PSA, and testosterone did not predict for the development of PCa (data not shown). Toxicity The nutritional supplement and placebo supplements had modest toxicity. Table 4 outlines major noted toxicities, the vast majority of which were grade 1 and 2. Frequently noted toxicities were gastrointestinal: flatulence and diarrhea. Breast symptoms are similar among both groups. One patient on the nutritional supplement was observed with grade 1 hyperglycemia and, on the placebo supplement group, there was one grade 1 and two grade 2 hyperglycemia events reported. During the conduct of this study, safety signals from other studies indicated that selenium and vitamin E might be associated with adverse outcomes. Increases in the risk of squamous cell and total nonmelanoma skin cancers have been associated with selenium supplementation.15 In addition, data from a large meta-analysis and a phase III study in patients with chronic diseases and/or cardiovascular disease noted an association between vitamin E supplementation ⱖ 400 U daily and total mortality and heart failure/hospitalizations for heart failure.16,17 This data was communicated to the data safety monitoring committee and participants on study. The protocol was amended to exclude patients with a previous history of nonmelanoma skin cancer. As presented in Table 4, one case of basal cell carcinoma was reported in the nutritional supplement arm. Three cases of ischemia/infarct and two cases of arrhythmia were reported in the nutritional supplement with no corresponding cases in the placebo group. DISCUSSION

Incidence of Invasive PCa and DFS Invasive PCa developed in a total of 80 participants. This corresponds to 26.4% of patients (Tables 2 and 3). The median number of

Table 2. Incidence of Invasive Prostate Cancer Participants by Randomized Arm

Parameter No. of invasive prostate cancer cases % Median No. of involved cores Range Gleason score Range Person-years of follow-up Annual incidence rate 95% CI

2388

Nutritional Supplement (n ⫽ 156)

Placebo (n ⫽ 147)

Total (N ⫽ 303)

41 26.3

39 26.5

80 26.4

1 1-3 6 5-7 264.47 0.16 0.11 to 0.20

1 () 1-4 6 3-8 264.32 0.15 0.10 to 0.19

1


6 528.78 0.15 0.12 to 0.18

PCa is not only a major cause of cancer-related mortality among men but also a significant cause of diminished quality of life among men who have had curative therapy.1,18 The descriptive epidemiology of PCa suggests that it is associated with lifestyle and perhaps amenable to a chemoprevention strategy.2 Although the 5-alpha reductase inhibitors have demonstrated activity in terms of PCa prevention,19 a nonpharmacologic approach has certain attractiveness in terms of population costs and perceived minimal toxicity. The chemopreventive association of PCa with vitamin E intake stemmed from the results of a non a priori end point from the Alpha Tocopherol Beta Carotene trial (ATBC).9 In ATBC, a lung cancer prevention study, men who were randomly assigned to vitamin E had a 33% lower risk of prostate cancer at 4 years and a 41% lower incidence of prostate cancer mortality at 6 years.20 Subsequent epidemiologic and in vitro and in vivo studies demonstrated a theoretical benefit to vitamin E.8 The association of selenium consumption and prostate cancer prevention was similarly first realized from the results of a non a priori end point in the context of a double blind, phase III trial among men with nonmelanoma skin cancer treated with 200 ␮g of selenium daily. A dramatic reduction in incidence of PCa (RR, 0.37; JOURNAL OF CLINICAL ONCOLOGY


Vitamin-E, Soy, and Selenium in High-Grade Prostatic Intraepithelial Neoplasia

Table 3. Log-Rank and Cox Regression Models for Disease-Free Survival by Assigned Treatment Univariate Analysis

Multivariate Analysis

Treatment

3-Year Disease-Free Survival

Hazard Ratio

95% CI

Log-Rank P

Hazard Ratio

95% CI

P From Cox Model

Nutritional supplement Placebo

0.69 0.73

1.034

0.667 to 1.605

.88

1.121

0.711 to 1.764

.625

Cumulative Incidence Rate

95% CI, 0.18 to 0.71; P ⫽ .002) was noted, as was a significant body of epidemiologic and laboratory studies.7,10 The theoretical beneficial effects of soy consumption in diminishing the burden of PCa are derived from numerous studies.13 Men in Asia have a lower incidence and death rate from PCa and soy is widely consumed in these populations. Subsequent laboratory studies have identified that soy-based isoflavones can inhibit cell progression, arrest cell cycle, induce gene promoter demethylation, and decrease angiogenesis in both hormone-sensitive and hormone-refractory cell lines and tumor model systems.12,13 In this trial, we decided to test these three agents in combination. The rationale for this was that there were no known negative interactions among them and some studies have suggested additive effects when given in combination.21 We also realized that a study with a 3 ⫻ 3 factorial design would be prohibitively costly. Patients with HGPIN were identified as a high-risk cohort to test a prevention strategy. HGPIN continues to have a controversial association with PCa development. In terms of its prevalence in high-risk populations, molecular alterations, and histologic appearance, it does appear to fulfill the criteria of a preneoplastic lesion.3-5 It must also be emphasized that when this study was conceived, it was estimated that up to 60% to 80% of men with HGPIN would progress to cancer. However, this was in an era of sextant prostate sampling and higher average PSA levels than today. These cohort effects have effectively lowered the progression rate of HGPIN to cancer to approximately 30% at 3 years, as seen today. There continues to be an ongoing debate as to whether a successful intervention in this group would result in inhibition of progression of the preneoplastic tissue or inhibited growth of previ-

0.8 0.7

Nutritional supplement Placebo

0.6 0.5 0.4 0.3 0.2 0.1 0

12

24

36

48

Time Since Random Assignment (months) Fig 2. Cumulative incidence rate for all randomly assigned participants. Presented here are Kaplan-Meier curves for the cumulative incidence of all invasive prostate cancers. The blue line displays incidence rates for the nutritional supplement arm, and the gold line displays incidence rates for the placebo arm. www.jco.org

ously unrecognized small foci of disease to sizes that are clinically detectable. Although not answerable, the point would be essentially academic as demonstrable benefits to patients would be realized regardless of the true mechanism. Our study results are consistent with the results of the SELECT trial.11 Inthatstudy,whichclosedearlyduetoafutilityanalysis,morethan 35,000 men were randomly allocated to receive vitamin E or selenium in a 2 ⫻ 2 factorial design (ie, selenium alone, vitamin E alone, selenium and vitaminE,orplacebo).Eligiblemenwereolderthan55years(50yearsifof African descent) and had a PSA level of lower then 4 ng/mL. No benefit was noted in any of the intervention arms. The PRP.1 study is the first randomized trial of a soy-based product in the setting of PCa prevention. It is also the first trial to follow men with HGPIN via serial biopsies over a 3-year period. Despite tantalizing epidemiologic and basic evidence, it does not appear to prevent the development of invasive PCa among men with HGPIN. As with any trial, there were limitations in study design that deserve comment. The study was arguably underpowered. As alluded to earlier, the study was designed at a time when progression rates were estimated to be higher. If the expected 2-year progression rate is between 25% to 30%, the power of the study to detect the same HR (0.66) would be between 65% to 72%. Nonetheless, the lack of any

Table 4. Toxicity Adverse Event Breast symptoms Tenderness, any Swelling/enlargement, any Other malignancies Total Acute myeloid leukemia Bladder Non-Hodgkin’s lymphoma Lung Skin Thyroid Cardiovascular Hypertension Ischemia/infarct Arrhythmia GI Constipation Diarrhea Flatulence Weight gain Pain Myalgia

Nutritional Supplement (n ⫽ 153)

Placebo (n ⫽ 146)

4 9

7 9

5 1 0 1 1 1 1

1 0 1 0 0 0 0

7 3 2

3 0 0

16 27 41 6

21 14 25 10

17

14



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trend whatsoever makes the chance of a large type II error quite small. Dose reduction was required in many men due to gastrointestinal adverse effects, even in the motivated trial population. Dose reduction was, however, more common among the subjects in the placebo treatment arm. In theory, larger doses of soy supplementation could have produced better clinical results but may not have been achievable from a compliance point of view. Central pathology review also posed a significant challenge to study conduct. Although prerandomization central pathology confirmation of HGPIN was mandated, some pathology departments of participating institutions would not release diagnostic blocks in a time sensitive manner to facilitate the pathology review. Original slides were therefore reviewed. A post hoc review of 96% of specimens was done and revealed a high rate of concordance between local and central pathologist diagnosis of HGPIN. Other agents have subsequently been studied among men with HGPIN. Betuzzi et al22 reported in a small randomized trial that green tea catechins prevented PCa among 60 participants. These results clearly deserve adequately powered confirmatory trials. The use of toremifene, an oral selective estrogen receptor modulator, has been studied in a phase IIb study setting.23 This study demonstrated a modest benefit for the 20-mg dose and no benefit for any of the other tested doses. The rationale for this observation is the ␣/␤ ratio of estrogen receptor subtypes. A definitive phase III trial has recently been presented, however, revealing no significant benefit (Annual Meeting of the American Urology Association, San Francisco, CA, May 29-June 3, 2010). REFERENCES 1. Jemal A, Siegel R, Ward E, et al: Cancer statistics 2009. CA Cancer J Clin 59:225-249, 2009 2. Stephenson AJ, Abouassaly R, Klein EA: Chemoprevention of prostate cancer. Urol Clin North Am 37:11-21, 2010 3. Zynger DL, Yang X: High-grade prostatic intraepithelial neoplasia of the prostate: The precursor lesion of prostate cancer. Int J Clin Exp Pathol 2:327-338, 2009 4. Epstein JI, Herawi M: Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: Implications for patient care. J Urol 175:820-834, 2006 5. Montironi R, Mazzucchelli R, Lopez-Beltran A, et al: Mechanisms of disease: High-grade prostatic intraepithelial neoplasia and other proposed preneoplastic lesions in the prostate. Nat Clin Pract Urol 4:321-332, 2007 6. Guzzo TJ, Kutikov A, Canter DJ, et al: The clinical and pathological history of prostate cancer progression in men with a prior history of high grade prostatic intraepithelial neoplasia. Can J Urol 15: 4174-4178, 2008 7. Venkateswaran V, Fleshner NE, Klotz LH: Synergistic effect of vitamin E and selenium in human prostate cancer cell lines. Prostate Cancer Prostatic Dis 7:54-56, 2004 8. Zhao H, Brooks JD: Selenomethionine induced transcriptional programs in human prostate cancer cells. J Urol 177:743-750, 2007 9. Albanes D, Heinonen OP, Huttunen JK, et al: Effects of alpha-tocopherol and beta-carotene sup-

Based on the accumulated data surrounding the preventative properties of vitamin E, selenium, and soy product, it can be concluded that these agents have no role in the primary prevention of invasive PCa in men with HGPIN at biopsy.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS Conception and design: Neil E. Fleshner, Karen Hersey, D. Robert Siemens, Martin Gleave, Dongsheng Tu, Wendy R. Parulekar Administrative support: Karen Hersey, Wendy R. Parulekar Provision of study materials or patients: Neil E. Fleshner, Bryan Donnelly, Simon Tanguay, Joseph Chin, Karen Hersey, Ken Jansz, D. Robert Siemens, Kiril Trpkov, Louis Lacombe, Martin Gleave, Wendy R. Parulekar Collection and assembly of data: Neil E. Fleshner, Linda Kapusta, Karen Hersey, Anne Farley, D. Robert Siemens, Martin Gleave, Dongsheng Tu, Wendy R. Parulekar Data analysis and interpretation: Neil E. Fleshner, Anne Farley, Martin Gleave, Dongsheng Tu, Wendy R. Parulekar Manuscript writing: All authors Final approval of manuscript: All authors

plements on cancer incidence in the AlphaTocopherol Beta-Carotene Cancer Prevention Study. Am J Clin Nutr 62:1427S-1430S, 1995 (suppl) 10. 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. JAMA 276:19571963, 1996 11. Lippman SM, Klein EA, Goodman PJ, et al: Effect of selenium and vitamin E on risk of prostate cancer and other cancers: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301:3951, 2009 12. Adlercreutz H, Markkanen H, Watanabe S: Plasma concentrations of phyto-oestrogens in Japanese men. Lancet 342:1209-1210, 1993 13. Kandaswami C, Lee LT, Lee PP, et al: The antitumor activities of flavonoids. In Vivo 19:895909, 2005 14. Davidson D, Bostwick DG, Qian J, et al: Prostatic intraepithelial neoplasia is a risk factor for adenocarcinoma: Predictive accuracy in needle biopsies. J Urol 154:1295-1299, 1995 14a. Schulz KF, Altman DG, Moher D, for the CONSORT Group: CONSORT 2010 statement: Updated guidelines for reporting parallel group randomised trials. Trials 11:32, 2010 14b. Moher D, Hopewell S, Schulz KF, et al, for the CONSORT Group: CONSORT 2010 explanation and elaboration: Updated guidelines for reporting parallel group randomised trial. BMJ 340: c869, 2010 15. Duffield-Lillico AJ, Shureiqi I, Lippman SM: Can selenium prevent colorectal cancer? A signpost

from epidemiology. J Natl Cancer Inst 96:16451647, 2004 16. Miller ER 3rd, Pastor-Barriuso R, Dalal D, et al: Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142:37-46, 2005 17. Lonn E, Bosch J, Yusuf S, et al: Effects of long-term vitamin E supplementation on cardiovascular events and cancer: A randomized controlled trial. JAMA 293:1338-1347, 2005 18. Katz G, Rodriguez R: Changes in continence and health-related quality of life after curative treatment and watchful waiting of prostate cancer. Urology 69:1157-1160, 2007 19. Thompson IM, Pauler DK, Goodman PJ, et al: Prevalence of prostate cancer among men with a prostate-specific antigen level ⬍ or ⫽4.0 ng per milliliter. N Engl J Med 350:2239-2246, 2004 20. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group: The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330:1029-1035, 1994 21. Kamat AM, Lamm DL: Chemoprevention of urological cancer. J Urol 161:1748-1760, 1999 22. Brausi M, Rizzi F, Bettuzzi S: Chemoprevention of human prostate cancer by green tea catechins: Two years later-a follow-up update. Eur Urol 54:472-473, 2008 23. Price D, Stein B, Sieber P, et al: Toremifene for the prevention of prostate cancer in men with high grade prostatic intraepithelial neoplasia: Results of a double-blind, placebo controlled, phase IIB clinical trial. J Urol 176:965-970, 2006

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