Prostate Cancer Prevention and Treatment
Including Complementary Approaches

Article by Michael J. Altamura, M.D., F.A.C.S.

The Prevalence

Each year in the United States, approximately 220,000 new cases of prostate cancer will be diagnosed, and 30,000 men will die of prostate cancer.

The Risk

The lifetime risk of getting prostate cancer is 16% making prostate cancer the most common malignancy among men. The lifetime risk of death from prostate cancer is approximately 3.4% and represents the second cancer killer in men next to lung cancer.

The risk of prostate cancer is associated with a family history, age, race, ethnicity and geographic region.

• Family history: with one 1st degree relative the risk is doubled with 2 or more relatives, the risk is increased nearly fourfold

• Age: Prostate cancer is a disease of older men. Approximately 85% of all cases of prostate cancer are diagnosed in men older than 65. Another way to appreciate the difference that age makes is to look at the difference in the incidence of the disease at the different ages. For example, in men under 40, 1 in 13,000 men will be diagnosed with prostate cancer, whereas in men over 70, 1 in 6 men will be diagnosed of this disease.

• Race: The incidence of prostate cancer in African American men is 1.5 times higher then it is in Caucasian men.

• Ethnicity: Scandinavian men are also at very high risk for prostate cancer

• Geographic region: American men and men from Western Europe are at 10x greater risk for prostate cancer than Asian men.

Prevention of Prostate Cancer

The answer to this question is found in epidemiological studies of different geographic regions. These studies have helped to identify dietary differences between different regions of the world. This information has then led to recommendation regarding dietary changes and other measures that can be implemented to reduce the risk of prostate cancer. So I would like to touch on soy, antioxidants, and some vitamins that are showing great promise in reducing the risk of prostate cancer.

Soy—With regards to soy, we have not only seen that Asian men are 10x less likely to get prostate cancer than men from the US and Western Europe but there is also the fact that Asian men that emigrate to the US or Europe adopt the higher prostate cancer risk within one generation. Studies have identified a number of dietary factors that are partly responsible for these observations. One major difference is that the Asian diet is rich in soy, which is a major source of genistein and other isoflavonoids. The estrogenic effect of isoflavonoids is thought to be responsible for its beneficial effect.

Antioxidants—With regards to antioxidants, selenium has been studied most extensively.

Selenium is a mineral with antioxidant function. Studies have shown that the prevalence of prostate cancer is higher in those areas where the soil is lower in selenium content than where the content of selenium is higher. In another study, there was an amazing 63% lower incidence of prostate cancer and 50% reduction in mortality for men who received 200 mcg. of selenium supplementation versus placebo. In a study published in the J. Natl. Cancer Inst. the investigators found a significant inverse relationship between plasma selenium levels before diagnosis and the subsequent risk of advanced prostate cancer. In a fourth study that I would like to mention, toenail selenium level was measured in nearly 34,000 men enrolled in the Health Professionals Follow-Up Study and a significant inverse relationship was noted between toenail selenium level and risk of advanced prostate cancer compared with age-matched controls.

Lycopene—Data from the Health Professionals Follow-Up Study, a study including over 51,500 male health professionals, indicates that increased consumption of lycopene-rich tomato-based foods confers a 35% reduction in the risk of prostate cancer. However, this figure drops to 16% after 12 years. Moreover, increased consumption of tomato sauce was associated with a 44% reduction in the risk of prostate cancer at baseline and remained significant after 12 years of follow-up, with a 23% reduction noted in men who consumed at least two servings per week. In another study, the Physicians’ Health Study, a 40% reduction in the risk of prostate cancer was noted in men with the highest levels of plasma lycopene.

Vitamin E—Vitamin E is not only a well-known antioxidant but it also has the ability to induce cell cycle arrest and promotes apoptosis in prostate cancer cell lines. In a study called the ATBC Trial (alpha-tocopherol and beta carotene) a 34% reduction in the incidence of prostate cancer was noted in the men receiving vitamin E alone compared to placebo. Because the ATBC trial was originally designed to evaluate the role of supplementation on lung cancer development and on secondarily on other cancers, all men enrolled in the study smoked at least 5 cigarettes per day. It is therefore conceivable that the benefits of alpha-tocopherol might be greater in smokers than in nonsmokers.

Other Vitamins that may diminish the risk of prostate cancer include folic acid, vitamin D and vitamin A derivatives.

Folic Acid—A recent study from Italy offers evidence that increased consumption of folic acid, especially in combination with a low alcohol intake, may reduce the risk of prostate cancer. Multivitamins or other supplements are not commonly utilized in Italy, but the average multivitamin in the US contains 400 mcg of folic acid, which is similar to the amount that provided protection in these men. It's advisable, therefore, to consume more fruits, vegetables and fiber, to consume a low-cost multivitamin daily containing 400mcg of folic acid and to limit the intake of alcohol.

Vitamin D—While the major role of vitamin D in humans is the regulation of calcium uptake and bone metabolism, it is now also recognized that vitamin D is a potent regulator of cell growth and differentiation in many tissues including the prostate. Epidemiologic data show an inverse relationship between the level of solar radiation and prostate cancer incidence and mortality. Furthermore, African American men have a higher incidence of prostate cancer and lower serum levels of vitamin D compared with Caucasian men.

Vitamin A derivatives, called retinoids, have also been shown to inhibit proliferation and induce differentiation of prostatic epithelial cells. Retinoids have demonstrated the ability to suppress the development of prostatic and seminal vesicle carcinomas in rat models.

Dietary Fat—Three large studies, the National Health and Nutrition Examination Survey, The Netherlands cohort study and a Norwegian study all indicated no association between total fats and the incidence of prostate cancer. The Professionals Follow-Up Study offered evidence that alpha-linolenic acid, present in some vegetable oils, nuts, leafy vegetables and animal fats, is an independent risk factor for advanced prostate cancer.

On the other hand, increased consumption of marine fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were inversely correlated with the risk of prostate cancer and of advanced prostate cancer, such that each additional daily intake of 0.5G of marine fatty acid from food was associated with a 24% decrease in the risk of metastatic prostate cancer.

Chemoprevention Treatments at the Horizon

COX inhibitors—Arachidonic acid is found in large amounts in meats and animal fats. An enzyme called cyclooxygenase(COX) converts arachidonic acid to prostaglandin. There is now evidence to suggest that prostaglandins have a role in the development and progression of human cancer. Therefore, a cyclooxygenase inhibitor, such as Celebrex may prove useful as a preventive agent for prostate cancer.

Selective Estrogen Receptor Modulators—Evidence is accumulating that estrogens act synergistically with androgens to effect changes in the prostate. When estradiol is combined with androgen in rodents, it can potentiate carcinogenesis. This suggests that a selective estrogen receptor modulator, like Tamoxifen, might be effective at inhibiting androgen-promoted prostate cancer. I suspect that more studies will be forthcoming.

Screening for Prostate Cancer

Over the last couple of decades the two screening tests used for diagnosing prostate cancer have been the digital rectal exam and the PSA or Prostatic Specific Antigen. Widespread use of PSA has resulted in a dramatic increase in the detection of prostate cancer in the United States. This might be one of the factors associated with the decrease in prostate cancer mortality in the US.

However, there are problems with total PSA. It lacks sensitivity i.e. there are false negative results and more importantly, it lacks specificity, resulting in a high number of false-positive test results. This lack of specificity causes some men to undergo biopsy only to be found free of cancer. Because of this problem, studies have been done with PSA derivatives including PSA density, PSA velocity, free to total PSA ratio and age specific PSA cutoff points. But even these PSA derivatives have their limitations. More recently, the Bayer Corporation developed a specific assay to measure complexed PSA which has been found to have greater specificity than total PSA. We know that once PSA gains access to the systemic circulation, the majority is complexed to protease inhibitors. It has been established that this form constitutes a greater proportion of the total PSA in man with malignancy. Although this has been recognized for many years, reliable assays for complexed PSA were lacking until now. With increased specificity, we hope to more accurately identify men who should undergo prostate biopsy.

Should the PSA be done every year? Preliminary evidence indicates that a baseline PSA level less than 1 ng/ml would remain negative after 4 subsequent years of annual PSA testing in almost 99% of men. Furthermore, 99% of men with PSA levels of 1-2 ng/ml would have negative PSA test results the following year. So in men with PSA less than 2 the PSA does not have to be done every year unless there is a suspicious finding on the digital rectal examination.

In conclusion, the PSA and its derivatives are screening tools that must be interpreted in light of all the information that is available today in order to increase the sensitivity, the specificity and the yield of positive biopsies.

About Prostate Biopsy

Today prostate biopsies are done in an office setting under local anesthesia with minimal discomfort. The procedure is done through the rectum using a needle to obtain the prostate tissue samples under ultrasound guidance. After the procedure no pain medication should be necessary but one should relax for the rest of the day.

If the biopsy is positive, it will also indicate the extent of the disease and the grade i.e. how aggressive it is. The grade is determined by the Gleason score which reflects the degree of abnormality of the tumor cells. The Gleason score ranges from 2-10 with 10 representing the most aggressive cancer and, therefore, having the worst prognosis. The extent of the cancer in the prostate is important in the staging of the disease—the greater the cancer involvement, the higher the stage and the greater the chance that it has spread beyond the prostate.

Staging Work Up

Once the diagnosis of prostate cancer is confirmed on biopsy, are any other tests required before deciding upon treatment? Depending on the PSA, the Gleason score and the extent of the cancer found on the biopsy, the urologist may recommend a CT scan and possibly a bone scan. Once these imaging studies are done, the staging work up is completed and therapeutic options can be discussed.

Therapeutic Options

Therapeutic options include radical prostatectomy, radiation therapy and hormonal therapy.

Radical Prostatectomy
Yields the best results in patients with low grade, low stage tumors. It should be a serious consideration in men who are younger than 70 and otherwise in fairly good health.

Advantages:

Cure rate of 95% with low grade, low stage tumors

Psychological benefit of knowing sooner than later that one is permanently cured.

Disadvantages:

Major operation, possibly needing transfusion

Significant risk for impotence

Small risk of urinary incontinence

About 4 weeks recuperation time with 2 weeks of catheterization

Loss of wages

Brachytherapy (radioactive seed implantation)
Indicated in patients with PSA less than 10, Gleason score of 6 or less and involving only one side of the prostate.

Advantages:

Same day surgery

Surgery is minimally invasive and requires no incision

Usually no catheterization time

Return to work within 2 days with sedentary jobs

Cure rate approaching that of radical prostatectomy

Disadvantages:

Radiation cystitis

Radiation proctitis

Intensity Modulated Radiation Therapy (IMRT)
External radiation administered daily, 5 days/week for 7 weeks Can be used for any of the patients above plus those with PSA greater than 10, Gleason score greater than 6, or tumor involving more than one side who have clinically localized or locally advanced prostate cancer.

Advantages:

No surgery

The treatment is painless

Very high dose of radiation can be administered safely

Minimal loss of time from work

Disadvantages:

The side effects are basically the same as for Brachytherapy.

Combination Radiation Therapy (CRT)
IMRT administered for 4-5 weeks followed by Brachytherapy Indicated for patients who have a PSA greater than 10, Gleason score greater than 6 or tumor involving more than one side who have clinically localized or locally advanced prostate cancer.

Advantages and disadvantages are same as those noted under IMRT and Brachytherapy.

Hormonal Therapy
Can be used in conjunction with radiation to enhance the success of radiation therapy and for palliation in the case of incurable disease. In the later case it is used to put the cancer in remission as long as the cancer is hormone sensitive or treat the symptoms of metastatic disease such as urinary symptoms or bone pain.