Advances in Prostate Cancer Chemoprevention and TreatmentApril 2007
By Aaron E. Katz, MD
Lycopene, Vitamin E, and Selenium
An association has been found between high lycopene consumption and low risk of prostate cancer,11 and men who are diagnosed with this disease tend to have lower levels of lycopene in their bodies.12 Lycopene supplements are a helpful part of a chemoprevention program; they can slow the growth of tumors and lower PSA scores in men with prostate cancer. A potent carotenoid, lycopene has been investigated in preclinical and clinical studies, with interesting findings. We have recently explored the role of this antioxidant before radiation treatment and have found an increased cell death rate in animal tumors that were treated with lycopene prior to radiation.
Vitamin E is protective against prostate cancer; every man should take a minimum of 240 IU of vitamin E a day to protect against oxidative stress in the prostate.13,14 Selenium helps vitamin E to do its job of reducing oxidative stress. Population studies find that men with higher selenium intake have significantly lower prostate cancer risk—as well as lower risk for many other cancers. We recommend that men use this nutrient to prevent prostate cancer as well.15,16 One study linked selenium supplementation to a 63% reduction in prostate cancer recurrence in 974 men with a history of the disease.17
A trial of selenium and vitamin E chemoprevention is currently under way. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is a 12-year, Phase III, randomized, placebo-controlled trial involving 32,400 men at about 300 research centers in the United States and Canada. The subjects take 200 mcg of selenium (as L-selenomethionine) and/or 400 IU of vitamin E each day.18 This double-blind, population-based clinical trial will test the efficacy of selenium and vitamin E, alone and in combination, for the prevention of prostate cancer. The primary endpoint is the clinical incidence of prostate cancer, as determined by routine clinical diagnostic work-up, including yearly digital rectal exam and serum PSA level. Study enrollment began in 2001, and final results are anticipated in 2013. It is the largest trial ever mounted to evaluate the chemopreventive value of nutrients, singly or in combination. Our own research on patients with PIN supports the daily use of 400 IU of vitamin E, 200 mcg of selenium, and 20 mg of lycopene for chemoprevention.
Green Tea Polyphenols Show Promise
Although the term polyphenol refers to a class of food-derived chemicals containing a polyhydroxyphenol group, it has been adopted to broadly describe any botanical or herbal agent with antioxidant properties. Historical evidence and epidemiological studies were the first to suggest the potential anti-cancer benefit of drinking green tea for reducing breast, colon, and prostate cancer incidence.19-23 The most common green tea plant is Camellia sinensis, and the major active ingredients of green tea are thought to be the catechins.
The excellent preclinical and Phase I data on green tea polyphenolic compounds suggest interesting potential for using green tea as a chemopreventive agent. Ongoing clinical trials in various precancerous, preventive, and adjuvant settings will determine the usefulness of this widely studied agent.
Benefits of Soy Compounds
The active component within soy is believed to be genistein. We have been studying Genistein Combined Polysaccharide (GCP®), a nutritional supplement made by Amino Up Chemical Company, Ltd. It is prepared by fermenting soy extract with basidiomycetes mushrooms, a process that increases the bioavailability of the plant-derived estrogenic compounds, also known as isoflavones, found naturally in soy products. Genistein is the bioactive form of the isoflavone found at the highest concentration in soy. Isoflavones have been reported to have estrogenic and anti-estrogenic activity, as well as anti-tumor effects that are unrelated to estrogen activity. Evidence from epidemiological and preclinical studies suggests that isoflavones protect against hormone-related cancers, such as breast, colon, and prostate cancers.
Laboratory studies of isoflavones support their role in therapy for both prostate and bladder cancers. Researchers examined the effects of pure soy isoflavones (genistein, genistin, daidzein, and biochanin A) and soy phytochemical concentrate on the growth of mouse (murine) and human prostate cancer cell lines in vitro and in vivo. The soy isoflavones dose-dependently inhibited the growth of prostate cancer cell lines in vitro. Feeding mice inoculated with prostate carcinoma cells a diet enriched with genistein or soy products decreased tumor size, reduced angiogenesis, increased apoptosis, and slightly reduced cancer cell proliferation.24
Pomegranate Inhibits Cancer Cell Proliferation
Pomegranate (Punica granatum) is widely consumed as a fruit and juice, and both anecdotal and epidemiological evidence suggests that pomegranate juice may be a valuable cardioprotective agent and antioxidant.25,26 Constitutional analysis of pomegranate seeds and husks reveals that they contain sugars, sterols, proteins, pectins, and potent polyphenolic compounds, including punicalagins and ellagic acid, of which punicalagins seem to be the most widely active and abundant constituent.
While there are only a few studies of pomegranate extract as a chemopreventive agent in prostate cancer, the initial studies suggest that various pomegranate compounds may act synergistically to enhance pomegranate’s anti-proliferative activities in prostate cancer cell lines. These same studies noted that pomegranate fractions may also inhibit the action of aggressive PC-3 cells. In the most recent study of pomegranate juice supplementation in men with prostate cancer,27 a daily eight-ounce glass of pomegranate juice significantly increased PSA doubling time, thereby increasing the disease-free survival period. (Comment by Stephen B. Strum, MD: The study was fully accrued after efficacy criteria were met. There were no serious adverse events reported. None of the patients developed metastatic disease. Mean PSA doubling time significantly increased with treatment, from a mean of 15 to 54 months [P < 0.048]. In vitro assays using pre- and post-treatment patient serum on the growth of LNCaP showed a 12% decrease in cell proliferation and a 17% increase in apoptosis [P = 0.0048 and 0.0004, respectively].
Other Herbal Compounds
At the Center for Holistic Urology, we have been exploring a combination of herbs to determine whether they can affect rising PSA levels in men with a negative prostate biopsy. One of these herbs, Pao pereira bark extract, originates in the Amazon rain forest and has been used for centuries to fight disease and relieve fever. The other compound is Rauwolfia vomitoria extract, a tropical African shrub traditionally used as a laxative and hormonal regulator.
If You Are Diagnosed: Surgical Options
Let’s say your PSA score comes back high after a routine check-up. Your doctor feels a suspicious lump during the manual prostate exam, and a biopsy reveals that you have prostate cancer. Staging and Gleason grading indicate that the disease is localized, but should be treated. What next?
You have a lot of options. The surgical options for men with prostate cancer have never been as extensive as they are today. And no matter what the stage of prostate disease, you can benefit from the chemopreventive measures already described.
A couple of decades ago, radical prostatectomy—full-on removal of the entire prostate gland—was the gold standard of treatment. This surgery is still the preferred route for men under 65 years of age who have localized disease. It has high cure rates for disease that has not spread beyond the prostate. The problem is that a certain percentage of men who undergo radical prostatectomy may end up incontinent, impotent, or both.
A radical prostatectomy involves removal of the entire prostate gland and seminal vesicles, and, depending on the circumstances, sampling the lymph notes within the pelvis. (The lymph nodes are checked by a pathologist to see whether the disease has spread. Depending on what is found, additional treatments—including radiation, chemotherapy, or treatment with drugs that block testosterone production—may be recommended.) We perform several versions of radical prostatectomy, including:
Today, your chances of having a prostatectomy without suffering impotence or incontinence are better than ever, thanks to advances in surgical techniques seen over the past decade. A couple of the newer techniques are:
Cryosurgery, also called cryoablation, involves freezing cancer cells to death. We do this with pinpoint accuracy in fractions of a second. We use ultrasound to guide the placement of cryoneedles into the appropriate areas of the prostate. Argon gas is pumped through the needles to rapidly cool cancerous areas. After the tissue is frozen, helium gas is run through the same needles to thaw the tissue.
In seven- to eight-year studies, cryoablation has an 89-92% success rate as a primary treatment for localized or locally advanced disease (meaning disease that has spread just beyond the prostate). I have also used cryosurgery to treat patients who undergo radiation and later have a recurrence.
Our long-term results using cryosurgery in patients like these have been excellent. Ninety-seven percent of them survived for at least 10 years after the procedure. Only 12% of men who receive cryotherapy have a positive biopsy after treatment.
Cryoablation is now approved by the FDA and covered by Medicare. It is proving effective for men whose cancers have spread to areas just beyond the prostate, or those who have aggressive tumors (signified by a Gleason grade of 7 or higher). It is also a good alternative for men who cannot or prefer not to have surgery or radiation.
We perform cryosurgery in the hospital with either general or spinal (epidural) anesthesia. Some patients are advised to take hormone-blocking drugs to help shrink the prostate before undergoing surgery. Most procedures are done in an hour and a half at most. The cryoneedles are guided through the perineum, under the scrotum. In two or more freeze-thaw cycles, we freeze cancer cells to death, using thermocouples and a urethral warming device to protect healthy tissues from damage. If all goes well, the patient will be sent home that day or the next, and for a week or so will use a urethral catheter to drain urine from the bladder into a bag worn on one thigh.
In the past, impotence rates were very high after cryoablation. Currently, we are having much greater success in men with low-risk cancer, as the nerve bundles do not have to be frozen. We now have a way of accurately measuring the temperature outside the gland in the area of the nerve bundles. We can extend the ice to the capsule (the membrane covering the prostate) and eradicate the cancer in this region, while sparing sexual function. In the past three years, we have started a focal cryoablation program. For men with a small focus of cancer on one side of the gland, and a low Gleason score of 6 or less, the cancer can be ablated with a few needles. This appears to be a very effective mode of therapy for this subset of patients.
What About Drugs, Radiation, and Chemotherapy?
When we talk about drugs for prostate cancer treatment, we are referring to either chemotherapy agents or hormone-ablating drugs. Hormone ablation is often used as part of a cancer treatment plan that may also include surgery, chemotherapy, and radiation. Because drug treatments almost always have side effects, they are best avoided, and hopefully you can do so with the correct chemopreventive measures.
If you would like to learn more about drug, chemotherapy, and radiation therapy for prostate cancer—and about holistic ways to address the potentially significant side effects of these sometimes necessary therapies—please refer to my book, Dr. Katz’s Guide to Prostate Health: From Conventional to Holistic Therapies (Freedom Press, 2005). The book also contains information about holistic treatments for benign prostatic hypertrophy (BPH) and prostatitis, in addition to more in-depth information about prostate cancer chemoprevention and treatment.
Dr. Katz is associate professor of urology and director of the Center for Holistic Urology at Columbia University Medical Center in New York.
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