Here's a very helpful article about the latest strategies for the prevention of prostate cancer. Notice the potent effect of vitamin E and selenium (but not vitamin A). The question about the helpfulness of Proscar is still confusing. For now, a good choice might be 1/2 Proscar taken every other day. Also notice the detrimental effect of estrogen levels (yes men have estrogen and women have testosterone). If you're interested in testing your own levels, click here.
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Chemoprevention of Prostate Cancer
Timothy C. Brand, MD
Edith D. Canby-Hagino, MD
A. Pratap Kumar, PhD
Rita Ghosh, PhD
Robin J. Leach, PhD
Ian M. Thompson, MD
∗
| * Corresponding author. |
| E-mail address: thompsoni@uthscsa.edu |
Prostate cancer is a major cause of morbidity, mortality, and expense in the United States, with an estimated 232,090 new cases and 30,350 deaths in 2005 [1]. Before the advent of prostate-specific antigen (PSA) screening in the mid-1980s, most prostate cancers were detected through digital rectal examination (DRE) and were often regionally advanced or metastatic at diagnosis. Then and now, patients who had metastatic disease had a life expectancy of 3 years or less [2]. With the recognition that PSA could be used for disease screening, the diagnosed prevalence of the disease in the population increased dramatically [3]. The lifetime risk for prostate cancer diagnosis now exceeds 17%, with 50% of men undergoing regular PSA screening [1], [4].
Unfortunately, although the focus on prostate cancer early detection is dramatically increasing the rate of diagnosis, mortality is only marginally affected. In the United States, mortality from the disease has reportedly decreased by 27% since 1994 [1], [5]. However, prostate cancer mortality actually increased shortly after screening began. Therefore, based on the rate before the outset of screening, the degree of mortality reduction has been slight (Fig. 1).
Fig. 1 Prostate
cancer deaths in the United States. (Data from US Mortality Public Use
Data Tapes, 1989–2002. Hyattsville, MD: National Center for Health Statistics,
Centers for Disease Control and Prevention; 2004; and Jemal A, Murray T, Ward E,
et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55(1):10–30.)
In addition to this modest reduction in mortality, major drawbacks of early diagnosis and treatment are side effects associated with therapy, including erectile dysfunction, urinary incontinence or retention, bowel toxicity, and emotional consequences, and the anxiety and stigma associated with diagnosis. Because the increased rate of detection approaches 18% while the lifetime risk of death from the disease remains at 3%, the risk for overdetection and overtreatment (referring to the treatment of a tumor that is destined to never cause morbidity or mortality) is real and may be substantial.
Against this backdrop, the opportunity to prevent prostate cancer is extremely attractive. Evidence clearly shows that this is a proven option for some patients.
When considering potential approaches to chemoprevention, researchers must consider who is at greatest risk for disease, which is frequently intertwined with the pathophysiology of the malignancy. In the risk/benefit or cost analysis of a chemopreventive agent, patients at greatest risk are the first to reach the threshold for initiating chemoprevention. Additionally, as risk factors and the pathophysiology of prostate cancer are more thoroughly understood, chemopreventive agents may be used selectively in individuals who have particular attributes that result in predisposition and increased risk (Fig. 2).
Fig. 2 A
paradigm for the effective screening and prevention for men at risk for prostate
cancer. (Data from Leach R, Pollock B, Basler J, et al. Chemoprevention
of prostate cancer. Focus on key opportunities and clinical trials. Urol Clin N
Am 2003;30(2):227–37.)
The list of established and proposed risk factors for prostate cancer is growing. Ethnicity is a well-accepted risk factor, with African-American men continuing to maintain the highest estimated incidence rate in 2005 [1]. Hispanic Caucasians men seem to have a lower risk for the disease compared with non-Hispanic Caucasians, whereas Asian men have the lowest risk [5]. A family history of prostate cancer, most notably in a first-degree relative (eg, father, brother, son), is a risk factor for prostate cancer. Two recent meta-analyses show a relative risk of 2.2 and 2.5 for individuals who have a first-degree relative who has prostate cancer [6], [7]. As the number of affected relatives increases, so does the risk for disease.
Significant evidence shows that genetic risk factors also contribute to an individual's risk for disease. Highly penetrant genes exhibiting a Mendelian pattern of inheritance likely account for only a small proportion of prostate cancer cases. However, increasing evidence shows that multiple heritable factors play a significant contributing role in the risk for development and progression of this malignancy. Evidence from a large-scale study of twins suggests that up to 42% of new cases of prostate cancer may be attributable to hereditary factors [8].
Several somatic alterations have been shown with variable degrees of certainty to be associated with increased risk for prostate cancer. Prostate carcinogenesis likely proceeds in a step-wise fashion, with phenotypic changes associated with genetic mutations and other somatic events. The first pathologic finding in the development of prostate cancer may be proliferative inflammatory atrophy (PIA). PIA may progress to prostatic intraepithelial neoplasia followed by localized prostate cancer [9], [10].
Epigenetic alterations also play an important role in the development and progression of prostate cancer. Two major pathways, including DNA methylation and histone acetylation, are mechanisms responsible for epigenetic regulation of gene expression. Methylation and demethylation of sequence elements in the promoter region genes involved in various cellular processes, including cell cycle, hormonal regulation invasion, and metastasis, play a critical role in the regulation of gene expression in various cancers such as prostate cancer. An excellent example for this kind of promoter methylation is GSTP1. Hypermethylation of the CpG island sequences in GSTP1 prevents the transcription of GSTP1[11], which can result in increased genomic instability during prostate carcinogenesis [10]. Growing clinical evidence shows correlation between this finding and clinical outcomes [12]. Similarly, histone acetylation involving histone acetyl transferases and histone deacetylase inhibitors play an important role in the epigenetic regulation of gene expression. Histone deacetylase inhibitors have been shown to exhibit antineoplastic activity in various models, including prostate cancer. Therefore, agents (eg, dietary) that modulate epigenetic events, such as promoter methylation/demethylation and histone acetylation/deacetylation, are promising for future clinical trials.
NKX3.1 may be a gatekeeper gene for normal prostate development. Gatekeeper genes are cancer susceptibility genes that maintain a constant cell number in renewing cell populations and ensure that cells respond appropriately to situations requiring net cell growth, such as after tissue damage [13]. Polymorphisms of NKX3.1 have been associated with higher-grade prostate cancer [14]. PTEN encodes a phosphatase that may be reduced in prostate cancer [15]. Its mechanism may relate to cell proliferation and apoptosis through inhibition of IGF-IR synthesis [16]. CDKN1B is another gene that may be related to prostate carcinogenesis [11].
Many constitutional variants are associated with risk for prostate cancer. Androgens clearly play a significant role in the clinical progression of prostate cancer [17]. Polymorphisms of SRD5A2, the gene that codes for the type 2 5ɑ-reductase, has been associated with an risk for prostate cancer [18], [19]. 5ɑ-reductase is an enzyme that converts testosterone to the stronger androgen, dihydrotestosterone. One report showed that men with 5ɑ-reductase deficiency had no identifiable prostatic epithelial tissue [20], and another showed that eunuchs had atrophic and frequently impalpable prostates [21].
Androgen receptor (AR) activity may promote the proliferation of androgen-independent prostate cancer cells even in the absence of androgens [22]. Several polymorphisms of the AR gene have been identified that are functionally consequential, including the first exon that encodes the transactivation domain and contains three polymorphisms [23]. One study showed that increased AR activity caused by short CAG repeats was associated with as much as a threefold increased risk for prostate cancer [24]. Nonetheless, several other studies have failed to confirm this association [18], [25], [26]. Vitamin D genotypes have also been shown to be related to prostate cancer risk [27], as may many other genetic polymorphisms [28], [29].
Age is clearly a risk factor for prostate cancer. The probability of developing prostate cancer from birth to age 39 is 1 in 9879, whereas the probability from birth to death is 1 in 6 [1]. With aging, in addition to genetic and epigenetic events, the prostate epithelial cell is exposed to significant oxidative stress that may lead to its neoplastic transformation [30], [31], [32]. Several pharmacologic means potentially alter the degree and effect of oxidative stress on the prostate cancer cell, which are discussed later [33], [34].
Evidence is accumulating to implicate inflammation and its associated molecules, such as nuclear factor κ B and cyclooxygenase (COX)-2, in causing certain cancers such as prostate. Expression of prostaglandins with an associated inflammatory response has been observed in the prostate. Arachidonic acid is metabolized to prostaglandins by COXs (Fig. 3) [16]. Products of arachidonic acid metabolism may result in progression to neoplasia by promoting cellular proliferation and angiogenesis [35]. Prostaglandin production causes increased production of vascular endothelial growth factor and decreased apoptosis. COX-2 may be overexpressed in prostate cancer, but this is debated [36], [37]. An association between prostatitis and prostate cancer has been suggested but, because of the potential for ascertainment bias (a patient who has a diagnosis of prostatitis is more likely to have undergone a PSA test from his interaction with a urologist), this association is unclear [38].
Fig. 3 Metabolism
of arachidonic acid.
Data conflict regarding the correlation between obesity and the risk for prostate cancer [39]. One study showed that an increased body mass index is associated with increased risk for prostate cancer [40]. Other studies have been less convincing, with one investigation finding an inverse correlation with the incidence of prostate cancer [41]. Several studies have shown that obesity correlates with worse oncologic outcome after prostatectomy [42], and may be associated with increased risk for death from prostate cancer [43].
PSA level seems to be a significant risk factor for prostate cancer. Fang and colleagues [44] found that baseline PSA levels correlated highly with risk for eventual prostate cancer diagnosis.
Finasteride is a selective inhibitor of type 2 5ɑ-reductase. To test whether finasteride would influence the development of prostate cancer, the Prostate Cancer Prevention Trial (PCPT) was designed. The results of this prospective, randomized, double-blinded, and placebo-controlled study were published in July 2003 [45]. In this study, 18,882 men who had no evidence of prostate cancer (ie, normal DRE and PSA <3 ng/mL) were randomized to undergo finasteride 5 mg/d or placebo for 7 years. Prostate biopsy was recommended if the annual PSA level, adjusted for the effect of finasteride, exceeded 4 ng/mL, or if DRE was abnormal. In addition, all consenting men were recommended to undergo an end of study biopsy (Fig. 4). The primary objective of the study was to determine whether finasteride therapy for 7 years reduced the period prevalence of prostate cancer.
Fig. 4 Schema
of the Prostate Cancer Prevention Trial. (Data from Thompson IM, Goodman
PJ, Tangen CM, et al. The influence of finasteride on the development of
prostate cancer. N Engl J Med 2003;349(3):215–24.)
Because overwhelming evidence showed that the trial was positive, an independent Data and Safety Monitoring Committee recommended study closure 15 months before the anticipated date of completion. In the finasteride group, 18.4% of men were diagnosed with prostate cancer compared with 24.4% from the placebo group, representing a 24.8% reduction in disease prevalence in men treated with finasteride. Balanced against the significant reduction in prostate cancers, a greater number and proportion of high-grade tumors were noted in the study's finasteride group. The prevalence of Gleason 7 to 10 cancers was 6.4% in the finasteride group compared with 5.1% in the placebo group.
Several possible reasons exist for the detection of higher-grade tumors in the finasteride group. The finasteride could have resulted in a hormonal pathologic effect caused by an alteration of the appearance of tumors that were detected with finasteride. Another possible operational bias may have related to disease ascertainment; because finasteride reduces the size of the prostate gland (22% size reduction in this study), the “sampling density” at prostate biopsy may have favored the detection of higher-grade disease. Two observations argue against the concept that finasteride induced high-grade disease: (1) the increased rate of high-grade disease was seen at year one of the study and did not change over the 7 years, and (2) the increased risk for high-grade disease was seen in the biopsies performed for elevated PSA or abnormal DRE, whereas those performed at the end of the study, after the greatest length of exposure to the medication, showed no increased detection.
Several authors have examined the impact of finasteride on life expectancy or death from prostate cancer [46], [47]. Unger and colleagues [48] modeled the results of finasteride use on the general United States population using the metric of person years of life saved. In this analysis, the investigators predicted more than 300,000 person years of life saved over 10 years in the United States with generalized finasteride use.
Patients contemplating finasteride for cancer prevention must consider other potential risks and benefits. The primary side effects noted were sexual symptoms such as erectile dysfunction, decreased libido, and decreased volume of ejaculate, but rates were generally only slightly greater in the finasteride group compared with the placebo group and other studies have shown that discontinuation of the drug resolves these symptoms. An additional benefit of finasteride is a reduced risk for complaints related to benign prostatic hyperplasia, which includes a lower rate of transurethral resection of prostate, and a lower risk for prostatitis [45].
Two additional important observations resulted from the PCPT. Although prostate cancer incidence rates in the aging male population were known to be high, the generally small tumors detected at autopsy were assumed to have not been found with mapping (6–12 biopsy core) prostate biopsies [49]. Furthermore, this trial marked the first time a group of men all underwent prostate biopsy regardless of PSA level. Analysis of the data found a 15% incidence of prostate cancer in men who had a PSA of 4 ng/mL or less [50]. A recent analysis of the performance characteristics of PSA across all men in the placebo group who underwent prostate biopsy found that a cut-point for PSA that detects 90% of all prostate cancers must be set at 1 ng/mL or less and is associated with approximately a 60% false-positive rate [51]. This study showed that PSA has improved sensitivity/specificity for detecting high-grade disease.
Dutasteride is a dual inhibitor of 5ɑ-reductase type 1 and 2 [52]. Dutasteride has been shown to result in greater reduction in serum dihydrotestosterone than finasteride [53]. The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial was designed to test the potential of dutasteride for prostate cancer prevention [54]. This 4-year, randomized, blinded, placebo-controlled study with a 0.5-mg daily dose of dutasteride will enroll 8000 men. Eligible men between ages 50 and 60 must have a PSA between 2.5 and 10 ng/mL, and those between ages 60 and 75 must have a PSA between 3 and 10 ng/mL. All must have a negative biopsy at entry into the study, and men with prostate size over 80 g are excluded. Biopsies will be obtained at the 2- and 4-year mark [54]. Initial results (the 2-year biopsy) should be available shortly.
There are eight stereoisomers of vitamin E. The most biologically active is alpha-tocopherol. Vitamin E may prevent cancer in several ways: it is an antioxidant, inhibits prostaglandins [55], inhibits protein kinase C activity [56], and blocks nitrosamine formation [57]. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) randomized almost 30,000 male smokers from Finland to receive either alpha-tocopherol or placebo. Beta-carotene was also tested, but did not influence the incidence of prostate cancer. The alpha-tocopherol group had a 32% decrease in the incidence of prostate cancer and a similar reduction in prostate cancer mortality [58].
Selenium is an essential trace element occurring in organic and inorganic forms. The organic form is found in grains, fish, meat, poultry, eggs, and dairy products [34]. The recommended daily allowance is 70 μg in men and 50 μg in women [59]. Selenium has been identified as an important constituent of several important antioxidant enzymes [34]. A previous randomized study evaluating prevention of nonmelanoma skin cancer in a population with known selenium deficiency found selenium to be associated with a 63% reduction in prostate cancer (a secondary end point) [60].
The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is a phase III randomized, placebo-controlled trial of selenium and vitamin E supplementation for a planned minimum of 7 years for prostate cancer prevention [61]. This trial is a two-by-two design with one group receiving both agents, one group receiving neither, one group receiving alpha-tocopherol, and one group receiving selenium. The study overaccrued its goal of 32,400 men within 3 years of initiation. Eligible men included those who were 55 years of age and older with a PSA of 4 ng/mL or less and a negative DRE. A lower age of enrollment was set for African-American men because they have an increased risk for disease and often develop the disease at an earlier age. The dose of alpha-tocopherol is 400 mg and 200 μg for selenomethionine. Biopsy is recommended for elevated PSA (≤ 4 ng/mL) or abnormal DRE [60]. Results are anticipated in several years.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors have been associated with polyp regression in familial adenomatous polyposis [62], [63]. Colonic tumors have a high concentration of prostaglandins that have been implicated in tumorigenesis [37], [64]. NSAIDs and COX-2 inhibitors have been shown to induce apoptosis of prostate cancer cell lines, perhaps related to high concentrations of prostaglandins in the prostate [65]. In epidemiologic studies, NSAIDs have been associated with up to a 39% risk reduction of prostate cancer [66]. Studies have shown that NSAIDs do not affect PSA, diminishing the possibility that the observed reduction is an artifact of detection [67]. A clinical trial using rofecoxib for prostate cancer prevention had accrued a significant number of patients when the drug was removed from the market and the study closed prematurely. With the current concerns regarding cardiovascular risks associated with NSAIDs, prevention trials for prostate cancer may not be possible [68].
Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have several potential mechanisms for cancer prevention. HMG-CoA reductase inhibits the synthesis of mevalonic acid, which synthesizes isoprenoids and cholesterol. Isoprenylation inhibitors are reported to induce apoptosis [19], [69], [70]. An observational study showed statins to be associated with a 63% reduction in prostate cancer risk [71], and a small cohort study showed that statins reduced PSA [72]. A major argument for investigating this class of agents for chemoprevention is the potential for several health benefits with one agent [73], [74].
Selective estrogen receptor modulators may prevent the pathogenesis of prostate cancer. Estrogens have been shown to promote prostatic growth [75]. Toremifene has been shown to prevent prostate cancer in a mouse model through nonandrogen pathways [75]. This agent is currently being tested in a large clinical trial for patients who have prostatic intraepithelial neoplasia. In addition, 2-methoxyestradiol (2-ME), an endogenous estrogenic metabolite found in human urine and serum, has been shown to inhibit the growth of prostate cancer cells in culture through induction of apoptosis involving G2/M checkpoint block. 2-ME has also shown promising activity in preventing the development of preneoplastic lesions in a transgenic adenocarcinoma of a mouse prostate model. Further efficacy of 2-ME was evaluated by administering it orally to patients who had hormone refractory prostate cancer who had undergone other failed treatments, including hormonal therapy. This study concluded that 2-ME was safe and well tolerated, and that PSA levels declined or stabilized in some patients. Because of its nontoxic nature and specificity toward actively proliferating cells such as tumor cells, 2-ME may be a promising agent for future clinical trials.
Numerous dietary interventions have been suggested for preventing prostate cancer, including red wine, flaxseed, fruits, vegetables, fish, soy, lycopenes, vitamin D, green tea, and others. These, for the most part, lack large-scale clinical trials, but may be the subject of further investigation [61]. Soy products, including tofu, may have a role in prostate cancer prevention [76]. Soy is a source of isoflavones, which have been shown to inhibit the growth of some prostate cancer cell lines in the laboratory [77].
Prostate cancer is a common malignancy with multiple potential opportunities for cancer prevention. As the genetic basis of this malignancy is further understood, prevention strategies will be developed for individual patients based on specific risk factors and pathways of carcinogenesis. The PCPT has conclusively proven that prostate cancer prevention is possible. The results of the SELECT should be available within several years. An enormous challenge for the medical community will be the development of an efficient strategy to evaluate the substantial number of dietary, behavioral, and pharmacologic prevention opportunities. Ultimately, the goal of prostate cancer prevention is to (1) identify men who are destined to develop clinically significant prostate cancer, and (2) provide individualized agents to prevent disease development.