**1. Introduction**

428 Cancer Prevention – From Mechanisms to Translational Benefits

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Current controversy exists regarding the role of chemopreventative agents for prostate cancer. However, prostate cancer's role in our society remains prevalent. Prostate cancer continues to be the leading cause of newly diagnosed male cancers in the United States. In 2011, the American Cancer Society estimated 241,740 new cases and 28,170 deaths from prostate cancer.1 Only lung cancer has more male cancer deaths. Current treatment strategies such as surgery, radiation, chemotherapy and hormone therapies have been successful in decreasing prostate cancer related morbidity and mortality. However, the physician's armamentarium is focused on treating existing prostate cancer and not preventing it. Despite the prolongation of life for patients with prostate cancer, each therapy carries a side effect profile.

Due to improved early detection, prostate cancer is now often identified at an earlier stage and grade. Newly diagnosed tumors are often organ confined and slow growing. However, once a patient's PSA laboratory value is abnormal, he will most likely receive a prostate biopsy for diagnosis. Given the fact that less than 10% of Americans select active surveillance, screening starts a snowball effect that usually "buys" a treatment. It is well known that treatment including radical prostatectomy or radiation has been shown to overtreat prostate cancer in as many as 30-50% of patients.2 Morbidity, including incontinence and impotence can significantly affect a patient's quality of life. In addition, the knowledge of prostate cancer may cause emotional, financial and physical harm.3,4 Given that the US male population faces a 16.7% lifetime risk of prostate cancer, prostate cancer is an ideal candidate for prevention strategies.

Cancer chemoprevention focuses on the use of natural or synthetic agents to suppress, delay, or prevent the development of tumors. Natural substances have long been utilized with varying results for prostate cancer prevention. More recently in the 2000s, 5-alpha reductase inhibitors (5-ARI) have also been used. These substances have focused on both primary prevention and secondary prevention. Primary prevention focuses on deferring or preventing the presence of cancer prior to cancer formation. Secondary prevention focuses on preventing premalignant lesions from progressing to cancer. For prostate cancer, secondary prevention focuses on preventing the progression of high grade prostate epithelial neoplasia (HGPIN).

The Changing Landscape of Prostate

Selenium and Vitamin E Cancer Prevention Trial *(*SELECT).

have a significant effect on preventing prostate cancer. 17-19

**2.2 Micronutrients** 

blood pressure.

Hedgehog and Notch.20

PLCO trial examining 29,000 men.

physician.

Cancer Chemoprevention: Current Strategies and Future Directions 431

Micronutrients have long been sought after to provide a chemotherapeutic benefit for the development or prevention of prostate cancer. Antioxidants in vitro can inhibit cellular proliferation, induce apoptosis and modulate genes leading to the suppression of prostatic tumor. 15,16 The largest scale trial on micronutrients was for selenium and vitamin E in the

The interest in selenium began with the Nutritional Prevention of Cancer Trial, which used oral selenium for nonmelanoma skin cancer. Men were randomized to selenium versus placebo and were found to have a 65% reduction in prostate cancer incidence after a 4.5 year follow up. Vitamin E interest developed after a 32% reduction in prostate cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Trial (ATBC) trial, which was a double

These studies paved the way for the SELECT trial, published in 2009, which was a randomized, placebo controlled population based primary prevention trial focused on the effects of selenium and vitamin E on preventing prostate cancer. SELECT randomized 35,533 men to four treatment arms: selenium with placebo, selenium with vitamin E, Vitamin E with placebo, placebo with placebo. Study supplements included 200 micrograms l-selenomethionine, 400mg racemic alpha-tocopherol and an optional multivitamin containing no selenium or vitamin E. Eligible men were at least 50 years of age for African-Americans, at least 55 for Caucasians, negative DRE, PSA less than 4ng/mL, and normal

The primary endpoint was the presence of prostate cancer found on for cause biopsies. The indications for biopsy were not indicated in the protocol and were at the discretion of the

During the second interim analysis seven years after initiation of the trial, the independent Data and Safety Monitoring Committee recommended discontinuation of the SELECT because the data demonstrated no significant differences between groups. No statistically significant effects were reported on primary or secondary analyses of the data, suggesting no prostate cancer prevention benefits from selenium or vitamin E.17 Unfortunately, selenium and vitamin E, which initially demonstrated promise, was eventually found to not

Other chemopreventative micronutrients include lycopene, green tea, soy, DIM and curcumin. Molecular targets these agents affect include nuclear factor-KB, AKt, Wnt,

Lycopene is a biologically occurring carotenoid that is a potent antioxidant. It has been shown to be associated with lower prostate cancer risk in a number of epidemiologic studies.21 Using the preclinical TRAMP mouse model, prostate cancer was significantly decreased 60% vs. 95% (P=.01). However, no correlation was found with prostate cancer in a

Green tea contains several catechins believed to inhibit oncogenesis and provide antioxidants. Epidemiologic studies between Asian men with a high intake of green tea first suggested that green tea may provide a protective benefit against prostate cancer. Three

blind randomized placebo controlled trial for lung cancer incidence and mortality.

In December of 2010, the Federal Drug Administration's (FDA) Oncology Drugs Advisory Committee (ODAC) reviewed 5-ARI's indication for the prevention of prostate cancer in men at increased risk for prostate cancer. This committee ruled against the use of 5-ARI's for the use of prostate chemoprevention. Advocacy groups have since issues statements disagreeing with the FDA's ruling, highlighting the fact that controversy continues to exist. The goal of this paper is to examine the available agents and the current environment.
