Information about the prevention of cancer and the science of screening appropriate individuals at high-risk of developing cancer is gaining interest. Physicians and individuals alike recognize that the best “treatment” of cancer is preventing its occurrence in the first place or detecting it early when it may be most treatable.
The prostate is a male sex gland that is located between the bladder and the rectum. Prostate cancer occurs commonly in older men and is the second leading cause of cancer death in men in the United States. Prostate cancer is typically a disease of aging. It may persist undetected for many years without causing symptoms. In fact, most men die with prostate cancer not from prostate cancer. Approximately 20% of men will develop prostate cancer during their lifetime, yet only 3% will actually die of the disease.
The chance of an individual developing cancer depends on both genetic and non-genetic factors. A genetic factor is an inherited, unchangeable trait, while a non-genetic factor is a variable in a person’s environment, which can often be changed. Non-genetic factors may include diet, exercise, or exposure to other substances present in our surroundings. These non-genetic factors are often referred to as environmental factors. Some non-genetic factors play a role in facilitating the process of healthy cells turning cancerous (i.e. the correlation between smoking and lung cancer) while other cancers have no known environmental correlation but are known to have a genetic predisposition. A genetic predisposition means that a person may be at higher risk for a certain cancer if a family member has that type of cancer.
Heredity or Genetic Factors
Researchers have estimated that approximately 9% of prostate cancers may be the result of heritable susceptibility genes. Approximately 15% of men with prostate cancer have a first-degree male relative (father or brother) with prostate cancer, compared with 8% of the general population.
In a recent study conducted at the University of Utah, researchers identified a genetic alteration that increases the risk of developing prostate cancer. The researchers found four alterations or mutations of the Hereditary Prostate Cancer 2 (HPC2) gene that placed men at an increased risk of developing prostate cancer. Two of these alterations resulted in a high risk of prostate cancer, while the other two resulted in a moderate risk of prostate cancer. Men who carry one of the two high-risk alterations are 5 to 10 times more likely to develop prostate cancer, while men who carry one of the two moderate-risk alterations are 1.5 to 3 times more likely to develop prostate cancer than the general population.
Environmental or Non-Genetic Factors
Researchers are unsure why one man will develop prostate cancer and another will not. Interestingly, when people from areas with low prostate cancer rates move to areas with higher prostate cancer rates, they assume the rates of their new environment, although their genetic make-up clearly has not changed. This suggests that environmental factors may play a larger role than genetic factors in the development of prostate cancer. Although the causes of prostate cancer remain ambiguous, researchers have identified several risk factors that are associated with prostate cancer.
Age: The incidence of prostate cancer increases dramatically with increasing age. It is unusual for prostate cancer to occur in men under the age of 50. Prostate cancer is most common in men over the age of 55, with the average age at diagnosis being 70. The risk of prostate cancer increases exponentially after age 50. In fact, by the age of 60, as many 34% of men show early evidence of prostate cancer, whereas 70% of men in their 80s have the disease.
Diet: There is increasing evidence that diet plays a role in the development of prostate cancer. Some studies indicate that prostate cancer is more prevalent in populations that consume a diet high in animal fat and/or lacking certain nutrients. In fact, results from 15 out of 22 clinical studies indicate that a higher dietary fat intake is related to a higher risk for prostate cancer. One study showed that men with a high fat intake had a 40% higher risk of developing prostate cancer.
Several studies have suggested that diets high in nutrients such as lycopene, vitamin E and selenium could actually reduce the risk of prostate cancer, leading some researchers to theorize that diets low in these nutrients could increase the risk of prostate cancer. More research is needed to establish the link between diet and prostate cancer.
Hormones: Some research indicates that high testosterone levels may increase the risk of prostate cancer.
Race: Prostate cancer rates are highest among blacks, intermediate among whites and lowest among native Japanese and Native Americans. Black men are nearly twice as likely to develop prostate cancer as white men and are twice as likely to die from the disease.
Cancer is largely a preventable illness. Two-thirds of cancer deaths in the U.S. can be linked to tobacco use, poor diet, obesity, and lack of exercise. All of these factors can be modified. Nevertheless, an awareness of the opportunity to prevent cancer through changes in lifestyle is still under-appreciated.
Diet: Diet is a fertile area for immediate individual and societal intervention to decrease the risk of developing certain cancers. Numerous studies have provided a wealth of often-contradictory information about the detrimental and protective factors of different foods.
There is convincing evidence that excess body fat substantially increases the risk for many types of cancer. While much of the cancer-related nutrition information cautions against a high-fat diet, the real culprit may be an excess of calories. Studies indicate that there is little, if any, relationship between body fat and fat composition of the diet. These studies show that excessive caloric intake from both fats and carbohydrates lead to the same result of excess body fat. The ideal way to avoid excess body fat is to limit caloric intake and/or balance caloric intake with ample exercise.
It is still important, however, to limit fat intake, as evidence still supports a relationship between cancer and polyunsaturated, saturated and animal fats. Specifically, studies show that high consumption of red meat and dairy products can increase the risk of certain cancers. One strategy for positive dietary change is to replace red meat with chicken, fish, nuts and legumes.
High fruit and vegetable consumption has been associated with a reduced risk for developing at least 10 different cancers. This may be a result of potentially protective factors such as carotenoids, folic acid, vitamin C, flavonoids, phytoestrogens and isothiocyanates. These are often referred to as antioxidants.
There is strong evidence that moderate to high alcohol consumption also increases the risk of certain cancers. One reason for this relationship may be that alcohol interferes with the availability of folic acid. Alcohol in combination with tobacco creates an even greater risk of certain types of cancer.
While researchers have long evaluated the link between diet and all cancers, there also has been extensive research to investigate the link between diet and prostate cancer. Several recent studies have indicated that low-fat diets, lycopene, vitamin E and selenium may play a role in preventing, or at least slowing the development of prostate cancer.
Lycopene: Lycopene is a carotenoid found primarily in tomatoes and tomato products. In 57 out of 72 studies, lycopene was associated with a lower risk of prostate cancer. In one study, subjects received either lycopene supplements or no supplement prior to surgery. Only 33% of the lycopene-supplemented group experienced a spread of cancer, compared with 75% of the control group. In addition, the prostate-specific antigen (PSA) levels of the lycopene-supplemented group fell 20%, while the PSA levels of the control group remained unchanged.
Vitamin E: Vitamin E is available in two forms, alpha-tocopherol and gamma-tocopherol. Alpha-tocopherol is the major form of vitamin E in supplements, whereas gamma-tocopherol is the main form of vitamin E in the diet. Both of these micronutrients have been associated with a reduced risk of prostate cancer.
One study that actually focused on lung cancer suggested a benefit from vitamin E for the reduction of prostate cancer. The results showed that a 50mg/daily vitamin E supplementation over the course of 5 to 8 years correlated with a 32% reduction in the incidence of prostate cancer.
One multi-center study performed in Maryland explored the relationship between prostate cancer and three micronutrients: alpha-tocopherol, gamma-tocopherol and selenium. Researchers used plasma and toenail samples to measure the levels of the three micronutrients in 117 men with prostate cancer and 233 men with no evidence of cancer.
The results indicated that the three micronutrients were associated with a reduced risk of developing prostate cancer. The strongest association was observed for gamma-tocopherol. The risk of developing prostate cancer was five times lower for the men who had the highest fifth of gamma-tocopherol levels when compared with the men who had the lowest fifth. The risk of developing prostate cancer declined with increasing concentrations of gamma-tocopherol. Selenium and alpha-tocopherol were also associated with a reduced risk for prostate cancer, but only in the presence of higher concentrations of gamma-tocopherol. Since supplementation with alpha-tocopherol may actually lower gamma tocopherol levels, the researchers concluded that balancing these two micronutrients might be an important factor in reducing the risk of prostate cancer.
Selenium: Selenium is an essential trace element that is necessary for the formation and function of at least 13 proteins. Studies performed in animals have shown that increasing the dietary intake of selenium can lead to a reduction in the incidence of some cancers. Several studies have indicated an association between increased selenium intake and reduced risk of prostate cancer. Two recent studies comparing selenium-supplemented groups with control groups have demonstrated an approximately 60% reduction in prostate cancer risk. In response to these promising results, the National Cancer Institute (NCI) is currently recruiting 32,000 participants to evaluate the effects of selenium on prostate cancer, as well as colorectal cancer and cardiovascular disease.
Exercise: Higher levels of physical activity may reduce the incidence of some cancers. According to researchers at Harvard, if the entire population increased their level of physical activity by 30 minutes of brisk walking per day (or the equivalent energy expenditure in other activities), we would observe a 15% reduction in the incidence of colon cancer.
Hormonal Prevention: The association between lifetime testosterone levels and prostate cancer has led researchers to investigate whether finasteride, a hormone inhibitor, can reduce the incidence of prostate cancer. A large, randomized, placebo-controlled trial is currently underway to evaluate finasteride as a chemopreventive agent for prostate cancer. The results of this study are expected in 2004.
Screening and Early Detection
For many types of cancer, progress in the areas of cancer screening and treatment has offered promise for earlier detection and higher cure rates. The term screening refers to the regular use of certain examinations or tests in persons who do not have any symptoms of a cancer but are at high risk for that cancer. When individuals are at high risk for a type of cancer, this means that they have certain characteristics or exposures, called risk factors that make them more likely to develop that type of cancer than those who do not have these risk factors. The risk factors are different for different types of cancer. An awareness of these risk factors is important because 1) some risk factors can be changed (such as smoking or dietary intake), thus decreasing the risk for developing the associated cancer; and 2) persons who are at high risk for developing a cancer can often undergo regular screening measures that are recommended for that cancer type. Researchers continue to study which characteristics or exposures are associated with an increased risk for various cancers, allowing for the use of more effective prevention, early detection, and treatment strategies.
Prostate cancer is the second leading cause of cancer in the United States. While with most cancers, early detection increases the chance of a cure; it is unclear whether screening for prostate cancer reduces the number of deaths from this disease. Often, after a diagnosis of prostate cancer, physicians and patients will choose a course of “watchful waiting” rather than beginning treatment. Despite the controversy, it is still recommended that men undergo annual screening for this disease utilizing digital rectal examination (DRE), PSA blood test or transrectal ultrasonography. Currently, it is recommended that men begin annual screening with PSA and DRE at age 50 and that African-American men and men with a strong family history of prostate cancer begin annual screening at age 45.
Digital Rectal Exam (DRE): During a digital rectal exam (DRE), a physician inserts a gloved finger into the rectum to assess the texture and size of the prostate. The DRE is the most common prostate screening procedure and has been used for many years; however, whether the test is effective in decreasing the number of deaths from prostate cancer has yet to be determined.
PSA Blood Test: A simple blood test allows laboratory technicians to determine PSA levels. Prostate-specific antigen (PSA) is a protein that is normally secreted and disposed of by the prostate gland. High PSA levels may indicate the presence of prostate cancer cells or other noncancerous prostate conditions.
Transrectal Ultrasonography: During transrectal ultrasonography, a small probe is inserted into the rectum. The probe emits high frequency sound waves that bounce off of the prostate and produce echoes. A computer uses these echoes to create a picture called a sonogram that can show abnormal areas. Researchers have yet to determine whether transrectal ultrasonography is effective in reducing the number of deaths from prostate cancer.
While the current recommendations for screening are the standard, some research indicates that beginning screening earlier may be more effective. Researchers recently conducted a study using a computer program to estimate the number of lives that would be saved by giving the PSA test in each of seven different patterns. The researchers found that the most effective strategy was to begin PSA testing at 40, repeat the test at 45 and 50 and then test every two years thereafter.
Strategies to Improve Screening and Prevention
The potential for earlier detection and higher cure rates increases with the advent of more refined screening techniques. In an effort to provide more screening options and perhaps more effective prevention strategies, researchers continue to explore new techniques for the screening and early detection of cancer.
Improved PSA testing: Researchers continue to develop and refine laboratory tests to improve the specificity of PSA testing. PSA results that are more specific may help to eliminate the need for further invasive testing, relieve anxiety and reduce medical costs in patients with elevated PSA levels who have benign conditions.
Prostate specific antigens may be found in various forms in the blood, which can create difficulties with the specificity of PSA testing. Prostate specific antigens may be bound to different molecules in the blood or may exist as isolated “free” proteins. Alpha 1-protease inhibitor is one of the specific proteins that is commonly bound to PSA in the blood. Previous studies have shown that the ratio of free PSA to total PSA (all different forms of PSA) improves the accuracy of the detection of prostate cancer. In order to further derive specificity of PSA testing, scientists have recently developed a blood test, which can detect the presence of alpha 1-protease inhibitor bound to PSA.
In a recent clinical trial, 3 different forms of PSA were evaluated for accuracy in determining prostate cancer. The patients involved in this trial were divided into 2 groups: those who had confirmed prostate cancer and those who did not have prostate cancer. Blood samples from these individuals were tested for free PSA levels, PSA-alpha-1-protease inhibitor levels and total PSA levels.
The proportion of PSA-alpha-1-protease inhibitor levels compared to total PSA levels was shown to be lower in patients with cancer. This test alone improved the accuracy of determining prostate cancer. Moreover, when the results of PSA-alpha-1-protease inhibitor levels were combined with free PSA results, the accuracy of determining prostate cancer was improved to approximately 90%.
Insulin-like Growth Factor: Insulin-like growth factor (IGF-I) and intact IGF-binding protein-3 (IGF-BP3) might help distinguish benign prostatic hyperplasia (BPH) from prostate cancer. Increased levels of IGF-I and IGF-BP3 in men with low to moderate PSA levels are predictive of prostate cancer. In one study performed in Canada in 2000, researchers measured IGF-I and IGF-BP3 levels in two groups of men, those with BPH and those with prostate cancer whose PSA levels were moderate. The men with prostate cancer had significantly higher IGF-I and IGF-BP3 levels than the men with BPH. The researchers concluded that the ratio of IGF-I and IGF-BP3 to free PSA was superior to the currently used free/total PSA ratio in discriminating between BPH and prostate cancer.
Predictive Genetic Testing: Researchers have recently identified a genetic alteration that increases the risk of developing prostate cancer. There are four different alterations of the Hereditary Prostate Cancer 2 gene (HPC2) that place men at either a moderate or high risk of developing prostate cancer. While scientists do not yet understand how HPC2 alterations contribute to the subsequent development of prostate cancer, they continue to explore the characteristics of this gene. As the dynamics of this gene are uncovered, the information could contribute to the development of predictive genetic tests and possibly even new prostate cancer drugs that are designed to address this particular genetic alteration. Although the identification of the HPC2 is a promising development in prostate cancer research, more research is needed before HPC2 testing becomes available.
Researchers at the Johns Hopkins University Medical Center have studied the link between the GSTP1 gene and prostate cancer since 1994. In their most recent clinical study, Johns Hopkins researchers evaluated the accuracy of GSTP1 methylation levels in predicting the presence of prostate cancer. Researchers examined surgically removed prostate tissue from 69 patients with localized prostate cancer and 31 patients with BPH. Twenty-eight of the 69 patients with localized prostate cancer also had pre-cancerous tissue that was examined. The average ratios of methylated GSTP1 to a reference gene in the different tissue specimens were 0 for BPH tissue, 1.4 for precancerous tissue and 250.8 for clinically localized prostate cancer.
Researchers also looked at the efficacy of GSTP1 methylation measurement to diagnose prostate cancer in small biopsy samples. For this clinical study, the ratio of methalyated GSTP1 to the reference gene was measured in small biopsy samples taken from 21 patients with high levels of PSA. Of the 21 patients, 10 were correctly diagnosed as not having prostate cancer and 10 out of 11 were correctly diagnosed with prostate cancer using the GSTP1 ratio.
These results are encouraging and indicate that the measurement of GSTP1 methylation may be used to improve the accuracy for detecting early-stage prostate cancer.
Microbubble Ultrasound: A new development in ultrasound involves the use of color Doppler imaging with microbubble contrast so that physicians are better able to determine the presence and exact location of a mass within the prostate. Doppler imaging can sense differences in velocity (i.e. blood flow versus solid tissue) and transmits these differences through different color pixels to create a picture on a screen. Microbubbles are tiny bubbles of gas that can permeate through small blood vessels without creating any harm. The microbubbles further enhance imaging by increasing the intensity of backscatter signal. Since blood vessels and blood flow are more prevalent in cancerous tissues than regular tissues, microbubbles tend to concentrate in the cancer, which is revealed on the created picture. This allows physicians to more accurately locate where biopsies should be taken.
Researchers recently compared the use of the contrast-enhanced Doppler ultrasonography with a microbubble contrast agent to conventionally used grey-scale ultrasonography. Eighty-four men involved in this study first underwent the Doppler ultrasonography and 5 biopsies. Patients then underwent grey-scale ultrasonography and 10 biopsies. The accuracy of the biopsies could then be compared in the same patient.
The detection rate of prostate cancer was 27% with Doppler-guided biopsies compared with 20% with conventional ultrasonography. The overall core biopsy detection rate was 13% for Doppler-guided biopsies compared with only 4.9% for conventional ultrasonography. These results indicate that Doppler-guided biopsies with microbubble contrast may enable physicians to more accurately determine the optimal location for a biopsy. This will allow fewer biopsies than conventional ultrasonography with an improved rate of cancer detection. Biopsies are associated with pain, infection, blood in the urine, and/or blood in the sperm. In addition, cost could be reduced by approximately 50%.