Slowing the PSA

If you think about it, since we are all  (well – most of us men anyway) going to get prostate cancer if we live long enough, the goal is just to slow down the process sufficiently so that we die of something else. I often tell my patients, “If you die of a heart attack, in my field, we call that a cure!” Probably you can do this to some extent through dietary manipulations. I finally figured out how to provide you a link to my old blogsite (over on the left) which contains all sorts of discussions of pomegranate juice, curcumin, low fat diets, soy, etc. However, this week I will discuss the pharmaceutical approaches that may work.

The idea that you could use a drug to prevent cancer goes a long way back. For example, the NSABP P-1 trial showed that tamoxifen, an anti-estrogen could reduce the risk of developing breast cancer although there was some increase in blood clots and uterine cancer as a side effect. For prostate cancer, then, it would make sense that some of the drugs that lower testosterone or reduce its effects could have a benefit. In this case, however, the side effects of lowered testosterone – perhaps most disturbing to younger men – of decreased sexual desire and potency, make long term use more challenging. To understand the possible places you could block testosterone effects you can look at the figure on the left. The brain sends a small hormone message GnRH to the pituitary gland. This is the location of the mechanism for drugs like leuprolide (Lupron™) or goserelin (Zoladex™). They mimic GnRH and the pituitary gland “shuts down”, not releasing the LH, FSH shown in the arrow going to the gonads. The testicles then produce testosterone in response to LH. Testosterone enters the cell (pink) and is converted to dihydrotestosterone (DHT). This form of testosterone is about 10x more active in binding the androgen receptor (golden block marked AR). It turns out the best place to block testosterone without causing too many side effects is at these steps. Finasteride (Proscar™) and dutasteride (Avodart™) block the conversion of T to DHT. There aren’t too many side effects, and the prostate gland shrinks by about 30% over 3-6 months. If your prostate was enlarged, voila, you pee better! You could block DHT at the next step as shown by the blue “bullet” in the drawing, but this has more side effects. This is the site where bicalutamide (Casodex™) and the other antiandrogens (including the one that shows great promise in development, MDV 3100, work.

Three studies have shown promise that blocking the T -> DHT step (catalyzed by an enzyme known as 5-alpha reductase; blockers are called 5-ARIs) can slow (or prevent?) prostate cancer development. The first trial, PCPT, was sponsored by the National Cancer Institute and studied over 18,000 55+ year old men between 1993 and 2003. The participants took finasteride or placebo, and the main result was a reduction in prostate cancer of 25%. Among the many interesting things to come out of this trial was the discovery that if you biopsy men with no evidence of prostate cancer in this age range (negative DRE and PSA <3) you will find prostate cancer about 15% of the time. The leadership (notably Ian Thompson) also developed a risk calculator that you can use to find your own risk for developing prostate cancer. (I just ran my numbers and have an 18% chance that a biopsy would find disease).

A second study of 5-ARI prevention was called REDUCE and utilized dutasteride in a similar manner among >6000 men ages 55-75. This study also showed a reduction in the incidence of prostate cancers of about 23%. As with the PCPT trial, in later years there was some increase in higher grade cancers among dutasteride treated patients. This phenomenon has been analyzed extensively, especially by the PCPT trialists and is thought due to the increased chance of finding a high grade cancer when you shrink the prostate prior to doing biopsies. My personal recommendation based on these trials is that individuals with a positive family history for prostate cancer should definitely consider taking one of the 5-ARI drugs. Of course, the costs of doing that have raised considerable discussion. A recent article on this topic concluded, “Dutasteride is unlikely to be cost effective when considering the impact on survival differences among treated versus untreated groups. However, chemoprevention may be cost effective in high-risk populations when taking into consideration adjustments for the impact on quality of life.”

Finally, the third trial relevant to this discussion was reported at the recent GU Symposium and is called REDEEM. Quoting the Urology Times article, “In the study, 302 men with early-stage prostate cancer randomly received either dutasteride or placebo for 3 years. Prostate biopsies were taken at 18 and 36 months or if they were warranted because of indications of disease progression. Researchers found that those taking dutasteride had a longer time to cancer progression compared with those taking placebo. In the dutasteride group, 38% of the men experienced some progression of their cancer, compared with 49% of the placebo group.”

But what if you already have prostate cancer, you have been treated (radiation, surgery, or both) and your PSA is rising, and you want to avoid going on hormonal therapy? My personal experience is that the 5-ARI drugs won’t help much. The PSA will drop in about half, but the rate of rise in the handful of patients I have tried this approach is not effected unfortunately. That is not to say there aren’t “androgen deprivation light” types of treatment, but I’m not sure the 5-ARI drugs are strong enough. An option is to combine them with low doses of an anti-androgen, like flutamide. This approach has been tried with some success at our institution and others.