Advances in Holistic PC Chemoprevention and Treatment
Aaron Katz, M.D.
New York Presbyterian Hospital
Columbia University Holistic Urology Center
Edited from PCRI Insights November, 2008 v 11.4
Prostate cancer kills 31,000 men in the U.S. each year. Over 220,000 are diagnosed with the disease each year – the equivalent of a new diagnosis every 2.6 minutes. A man’s lifetime chance of developing this cancer is about one in six. At this writing, prostate cancer is present in more than nine million American men.
Ready for some good news? Prostate cancer is nearly 100% survivable if detected early.
At the New York Presbyterian Hospital/Columbia University Holistic Urology Center, we are well versed in the use and value of allopathic therapies for prostate cancer. I teach surgical, pharmacologic, and chemotherapeutic/radiation treatment methods to medical students here. Many patients with prostate cancer will benefit from some kind of surgery, and in late-stage cancer, we can use hormone-ablating drugs, chemotherapy, and radiation to extend life and relieve pain.
However, ours is unique among urological medical centers in that we also apply knowledge from alternative medicine to help heal our patients. We use scientifically validated herbal and nutritional medicines to support the patient’s body as it resists the cancer. Many of these medicines have demonstrated the ability to slow or reverse the growth of prostate cancer cells through various biological mechanisms.
Our team at the Holistic Urology Center is doing groundbreaking research on several of these natural medicines, publishing it in peer-reviewed journals, and presenting it at major scientific conferences. These are steps that must be taken by medical science in order to establish the safety and effectiveness of herbal and nutritional chemopreventive agents – substances that help to forestall the development or progression of cancer – and their value as part of a complementary medical approach to prostate cancer.
The natural or “holistic” approach may be particularly beneficial in patients who are diagnosed with very early prostate cancer that is less likely to spread. Due to widespread screening for prostate cancer using the PSA blood test, many men diagnosed in 2006 have low Gleason scores of 6 or less, or have a precancerous condition called prostatic intraepithelial neoplasia, or PIN.
MOVING BEYOND “WATCHFUL WAITING”
Men who are diagnosed with small, early-stage, less – aggressive prostate cancer – especially men who are older or have some other disease that makes surgery more dangerous – may be told by their urologist to “watch and wait.” The logic behind this is that the treatments usually applied could do more harm than good in such patients.
I think this watchful waiting approach is inappropriate.
This is not to say that we should intervene surgically and thereby risk potentially life-altering side effects to eradicate a cancer that will never be life threatening. An alternative to watchful waiting is applying holistic therapies that have growing scientific support in favor of benefit and have almost no potential for doing harm.
In patients who are good candidates for more aggressive medical treatments – including surgery or medications – I have found that applying holistic therapies as part of a comprehensive treatment plan improves outcomes.
Most urologists still rely exclusively on allopathic treatments for prostate cancer, and the advances in these treatments – along with early detection – seem to be paying off. According to the federal Centers for Disease Control and Prevention, the overall survival rate for prostate cancer has gone from 67% in the 1980s to nearly 97% today. (This figure obscures the fact that the prostate cancer death rate for African-Americans, Hispanics, and American Indian/Alaskan Natives is nearly twice that of Caucasians)1. Adding holistic therapies to our array of treatments can only improve the odds that you (or a man in your life) will never die of prostate cancer.
PROSTATE CANCER CHEMOPREVENTION
Chemoprevention is the use of agents that prevent the induction, growth, or progression of cancer. Prostate cancer has a long latency period, which means that it grows slowly and may exist for years before it is detected or causes symptoms. We can use this to our advantage when it comes to chemoprevention strategies. The major factors we address in prostate cancer chemoprevention are inhibiting oxidation and inflammation. We can use herbs, nutritional supplements, and dietary changes to address these factors that create and accelerate the disease. Prostate cancer chemoprevention will likely also help to prevent heart disease, osteoarthritis, benign prostatic hypertrophy (BPH), and prostatitis (inflammation of the prostate, usually caused by either bacterial infection or autoimmunity).
Oxidative stress is believed to be a strong link between diet and prostate cancer. Measurements of oxidation are significantly higher in the cancerous prostate than in the non-cancerous prostate2. Inflammation creates an additional free-radical burden, contributing to an escalating cycle in the prostate gland that sets the stage for the precancerous condition called prostatic intraepithelial neoplasia (PIN) and for cancer itself3.
THE PRECANCEROUS PROSTATE: PIN
Prostatic intraepithelial neoplasia is not cancer, but it is a portent of the disease4. We also refer to PIN as dysplasia, a generic term for abnormal cells that are likely to turn cancerous at some time in the future. Prostate cancer begins with very small changes in the size and shape of the prostate gland cells. These changed cells then proliferate throughout the prostate. PIN does not affect serum PSA concentration; it is detected only when we do a biopsy.
Men who have prostate cancer have areas of PIN in their prostates in more than 85% of cases5, and it can appear up to 10 years before a diagnosable cancer. In a series of 249 autopsy cases, approximately three quarters of the prostates with high-grade (severe) PIN harbored invasive adenocarcinoma, compared to only one quarter without high-grade PIN.
When we detect PIN, allopathy has no treatment for it. Usually, the recommendation is watchful waiting. This is prime time for the use of nutrients and herbs to decrease the inflammation that creates PIN and may transform it into full-blown cancer.
ANTI-INFLAMMATORY NUTRIENTS FOR PIN
Prostaglandins and leukotrienes are eicosanoids, or hormone-like chemicals created in the body from the fats we eat. They are manufactured through a cascade of biochemical reactions that involve the action of specific enzymes, including the COX (cyclooxygenase) enzymes, which mediate prostaglandin production, and the LOX (lipoxygenase) enzymes, which mediate leukotriene production.
The COX-2 enzyme is a well-known mediator of inflammation and plays a pivotal role in the creation of prostaglandins that accelerate inflammation. Anti-inflammatory COX-2
inhibitor drugs are designed to inhibit this single enzyme, in hopes of reducing the flames of inflammation at their source. However, these drugs do not affect other enzymes that also play a role in inflammation, including the LOX enzymes that create leukotrienes. Think of the COX and LOX enzymes as “matches” that light inflammatory flames. Now, imagine that we snuff out one match: as long as there is still fuel to burn, the other match is adequate to get the fire going.
COX and LOX enzymes are strongly affected by diet. When we over-consume foods rich in omega-6 fats: conventional meats, dairy products, and refined vegetable oils (including hydrogenated oils rich in trans fats), refined flour, and sugar, we predispose the body to over-react to any insult that causes inflammation, because we push the balance of eicosanoid production towards the side of inflammation. Some people are more prone than others to this kind of overreaction, probably due to genetic differences.
BPH, non-bacterial prostatitis, prostate cancer, and PIN have all been linked with a heightened state of chronic inflammation – as have Alzheimer’s disease and heart disease. Chronic inflammation puts us at increased risk of developing cancerous growths in the area of the body where that inflammation occurs. PIN is likely to be the first sign that inflammation is altering the cells of the prostate.
Studies of COX-2 inhibition with drugs like Vioxx® and Celebrex® – which many hoped would be useful in preventing colon cancer in people with precancerous polyps – demonstrated that COX-2 inhibition will reduce one fire, but will also increase other types of inflammation6. A study at the MD Anderson Cancer Center found that inhibiting the COX pathway caused an activation of the LOX pathway, increasing the “fires” started by LOX enzymes. Moreover, it appears that this LOX pathway is an important one in the development of PIN and prostate cancer.
Prostate cancer is driven by LOX metabolites. Inhibiting 5-LOX metabolites in test-tube studies causes a rapid, massive die-off of prostate cancer cells. The activity of the lipoxygenase enzymes creates 5-LOX, one of the hormone-like leukotrienes.
5-LOX is turning out to be important to our understanding of the interaction between inflammation and prostate cancer. Substantial research evidence tells us that we can slow or stop prostate cancer growth if we suppress 5-LOX – and, by so doing, reduce the formation of another biochemical known as 5-hydroxyeicosatetraenoic acid (5-HETE).
5-HETE is essential to the survival of prostate cancer cells, and by inhibiting its production, we can effectively starve a prostate tumor. We can send immortal cancer cells back into the series of biochemical reactions that lead to programmed cell death, and we can work against other processes that encourage tumor growth and spread. Moreover, we can achieve this with combinations of herbs that work to downplay the actions of the LOX and COX enzymes.
As we learned all this from our research and others’ studies, we reasoned that broad inhibition of pro-inflammatory enzymes made more sense than targeted, selective inhibition. Thus, we looked at herbs that could achieve this end.
Unlike highly selective, pharmaceutical COX-2 inhibitors, herbal anti-inflammatories inhibit the activity of the COX and LOX pathways. Aspirin does as well, but aspirin and other less selective nonsteroidal anti-inflammatory drugs (NSAIDs) are still more specific and targeted than herbs, and they create the risk of gastrointestinal bleeding – a side effect that hospitalizes tens of thousands of people each year.
At the Center for Holistic Urology, we have been conducting studies to determine whether herbs with anti-inflammatory and antioxidant actions can be used to slow or reverse the progression of PIN into prostate cancer. In 2002, my research team from Columbia presented the results of a study on a combination of 10 anti-inflammatory herbs at a meeting for the Society of Urologic Oncology at the National Institutes of Health. We found that this formula suppressed the growth of prostate cancer cells and caused many to undergo programmed cell death (apoptosis).
We are currently evaluating a group of 35 patients with biopsy-proven PIN who are using this herbal combination, which includes rosemary, turmeric, ginger, green tea, oregano, Chinese goldthread, and barberry. All of these herbs have some effect on the enzymes that mediate inflammation – specifically, the COX and LOX enzymes that we know play roles in prostate carcinogenesis. Our results at this point are preliminary, but they are certainly promising.
In this Phase I clinical trial, patients take this herbal combination daily for 18 months. Every six months, they have another biopsy, and those tissues are analyzed for molecular markers of inflammation that show us whether they are progressing toward cancer. We also measure PSA at each six-month follow-up visit. Of the 26 patients who have had at least two follow-up visits, 13 have had a decrease in PSA. Six of these men (46%) had a greater than 10% decrease, and 27% had over a 50% decrease. To date, 35 biopsies have been performed on 21 patients in the study; in 31 of the 35 biopsies, cancer had not developed, and 21 of them have been normal, showing no PIN or cancer. Four patients did develop cancer, but their tumors were very small, and there is good prognosis for a complete cure.
Other herbs known to help control prostate inflammation and carcinogenesis include pygeum, nettle root (Urtica dioica), saw palmetto, and frankincense (Boswellia serrata). Each has its own base of support in the scientific research of chemopreventive agents7-10.
LYCOPENE, VITAMIN E, AND SELENIUM
An association has been found between high lycopene consumption and low risk of prostate cancer11, and men who are diagnosed with this disease tend to have lower levels of lycopene in their bodies12. 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 prostate13,14. 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 well15,16. One study linked selenium supplementation to a 63% reduction in prostate cancer recurrence in 974 men with a history of the disease17.
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 day18. 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 workups, including yearly digital rectal exams and serum PSA level measurements. The 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 the incidence of breast, colon, and prostate cancer19-23. 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.
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.
There are a variety of scientifically validated herbal and nutritional medicines to support the patient’s body as it resists the cancer. Many of these medicines have demonstrated the ability to slow or reverse the growth of prostate cancer cells through various biological mechanisms. Research from the Center for Holistic Urology and elsewhere strongly suggests that if every man who was advised to pursue a program of watchful waiting entered into a focused chemoprevention program, we could slow or stop the progression of the disease – and we would probably see improvement in virtually every other aspect of his health.
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