His and Her Health

The year 2003 appears to be the year of PSA (Prostate-Specific Antigen) as far as headlines and prostate cancer. There have been questions as to whether or not the PSA guidelines should be lower, and whether Proscar, the 5-Alpha-reductase agent normally used for benign prostatic hypertrophy, is an effective tool to prevent prostate cancer. In addition there has been controversy about the standard radical nerve-sparing prostatectomy and whether the laparoscopic approach is better or possibly the use of the robotically-assisted prostatectomy may in fact be the best. So lets try to make some sense of these areas of controversy.

A recent article in The New England Journal of Medicine, which was quoted in many of the major newspapers and on our site here.indicated that the present day guidelines for PSA may not be low enough and that many cases of prostate cancer are missed or diagnosed later because the guidelines are not tight enough or low enough. To urologists there has always been a focus on this concern. The average non-urologic physician uses the PSA guideline of 4 as being the maximal of normal. Urologists have never used this as their major guideline. They evaluate a PSA by many criteria including 1.) Age-correlated PSA, 2.) PSA in relationship to race, 3.) PSA density, 4.) PSA over time, 5.) Free PSA percentage and more recently complex PSA test.

In general the younger the patient the lower the PSA should be and therefore men older than 70 can have a normal PSA as high as 5.5, men 60 to 70 can have a normal PSA as high as 5.0, men 50 to 60 can have a normal PSA as high as 4.0, and men less than 50 can have a normal PSA as high as 3.5. In the case of African Americans I would suggest dropping this number as the max of normal by another 0.3 to 0.5. In addition small prostates should have relatively low values and large prostates higher values. By digital rectal exam one can estimate the size of the prostate and determine whether or not the PSA value is consistent with that size prostate.

When sonography of the prostate is actually done one can measure the volume of the prostate and come up with an actual PSA density which should be less than 0.1. Over time the PSA rises particularly since the prostate gland enlarges, but in general the increase per year is approximately 6 percent and in general the PSA should not rise more than 0.7 per year. PSA represents the total amount of PSA including the unbound free PSA, the protein bound PSA, and the weekly albumin-bound PSA. In determining free PSA percentage the weekly bound and the free PSA in relationship to the total PSA should be greater than 25% which would indicate benign prostate disease.

Less than 15 percent is suggestive of prostate cancer and a full evaluation by transrectal ultrasonography and saturation biopsy should be considered by your physician or urologists. Levels between 15 and 25 percent are in the gray zone and reevaluating the previous PSA criteria determines whether or not biopsy should be done. On the other hand. if there are abnormalities found on digital rectal exam or there is concern about prostate cancer in anyway a transrectal ultrasonography and biopsy are the only tools to make a definitive diagnosis of prostate cancer.

Recently a new tool known as the complex PSA which truly measures the free unbound PSA has been developed and researched. It may be a more accurate way of picking up prostate cancer at an earlier stage than other PSA standards.

A second area of major interest has been in the prevention of prostate cancer. Prostate cancer is a very slow-growing disease in most cases taking six to ten years from the time the first cell becomes malignant until the PSA rises and an additional six to ten years before the prostate feels abnormal.

Therefore the average 65-year-old male who is diagnosed with prostate cancer probably had the prostate cancer when he was 45 years of age.

Does diagnosing the cancer earlier improve the results of definitive therapy whether it be surgery or radiation for localized prostate cancer? No one is quite sure, however, it would seem logical that earlier diagnosis with riveted disease should lead to a better cure rate, longer duration to metastases, and a longer duration to PSA elevation. Proscar, a 5-Alpha-reductase agent that has been used for benign enlargement of the prostate, shrinking the prostate, and relieving obstructive symptoms, has been found to be effective in reducing the rate of prostate cancer in males treated over an eight year period of time on a daily basis.

A 5 mg dosage which is normally used to treat benign enlargement of the prostate has been found to reduce prostate cancer by 25 percent compared to those not treated with Proscar in an eight-year study of approximately 18,000 men. The incidence of the more undifferentiated faster-growing cancer appears to be 15 to 20 percent higher than the treated group probably because the undifferentiated cancers do not respond to hormonal manipulation and therefore would not respond to the effects of the 5-Alpha-reductase inhibition.

Let me explain. Testosterone does not cause prostate cancer, however, if you have prostate cancer cells it will be stimulated by testosterone, the male hormone produced by the testicle. The testosterone attaches to a testosterone-binding site on the cancer cell and is then carried into the cell by a transfer globulin and converted to dihydrotestosterone by the 5-Alpha-reductase enzyme system found within the cell.

It is the dihydrotestosterone that actively works on the nucleus making the prostate cancer grow and suppression of dihydrotestosterone can actually slow up the cancer or in many cases kill those cancer cells that are sensitive to this hormone response. Proscar inhibits 5-Alpha-reductase and therefore dihydrotestosterone is produced in smaller quantities inhibiting the growth of prostate cancer cells and in many cases actually killing the cells. A slight increase reported of undifferentiated cancer in the Proscar-treated patients is probably factitious.

When prostates are treated with 5-Alpha-reductase inhibitors like Proscar the prostate shrinks and smaller prostates give a higher incidence of prostate cancer on biopsy since the gland in smaller and equal numbers of cores have a greater chance of hitting the prostate cancer areas. Therefore in the eight year Proscar study where the Proscar-treated patients had a slight elevation in undifferentiated tumors the increase was probably related to the shrinkage of the gland and the higher biopsy rate than in the larger gland that had not had size reduction with Proscar.

Lastly once a prostate is treated with any hormones whether it be an LH/RH agonist like Lupron, Zoladex, or Eligard, and anti-androgen like Casodex, or a 5-Alpha-reductase inhibitor like Proscar determining whether or not the tumor is undifferentiated becomes impossible since the changes that occur by hormonal manipulation as described above frequently mimics undifferentiated cancer. More research will need to be done in this area, however, the fear of using a 5-Alpha-reductase inhibitor like Proscar should be eliminated in the mind of many patients.

Proscar is finasteride. A new drug called dutasteride recently developed by Glaxo-Smith-Kline-Beecham and now FDA approved for benign prostatic hypertrophy is also a 5-Alpha-reductase inhibitor. Studies are now going on to determine whether this drug is as or more effective in preventing prostate cancer.

A short study in which high-risk patients are being treated with placebo versus dutasteride (Avodart) is being done. Theoretically Avodart should prevent prostate cancer better than finasteride since it affects both the sub type 1 and 2 5-Alpha-reductase enzyme system; the sub type 2 not affected by Proscar is effective by Avodart and appears to be more closely associated with prostate cancer.

No one is quite sure who should consider using 5-Alpha-reductase inhibitors such as Proscar or Avodart to prevent prostate cancer, however, patients who have a familial history of prostate cancer, patients with higher-than-normal PSAs probably greater than 10, patients with a pre-malignant lesion known as PIN (prostatic intraepithelial neoplasia), and patients who have large symptomatic prostates in which BPH control and symptom relief is necessary should certainly consider 5-Alpha-reductase treatment.

Having discussed some of the problem areas of PSA and prostate cancer prevention during the last year lets also discuss some new treatment modalities for localized cancer of the prostate. Laparoscopic radical nerve-sparing prostatectomy is becoming a hot subject in the media, among patients, and of great interest by urologists.

The procedure has some theoretical positives including minimal incisions, shorter hospitalization, decreased morbidity, and decreased return to normal function. No one, however, is sure that doing a laparoscopic prostatectomy is as good a cancer operation as the standard nerve-sparing radical prostatectomy. No one is even sure whether continence is as good or bad and whether erectile dysfunction is as high or low. Until more of these are done over a longer period of time for all practical purposes this procedure has long-term unknowns. The learning curve for laparoscopic prostatectomy is extensive and it may take many dozens of patients before a physician is skilled in doing this procedure.

Most physicians feel comfortable doing an open radical prostatectomy which has become one of the most common urologic procedures done today in the operating room. The standard nerve-sparing prostatectomy can be done quickly and safely with minimal blood loss, excellent sexual results particularly in those patients under sixty, and excellent urinary control outcomes.

Over the last decade urologists have become very familiar with this procedure with hospitalizations as short as one to three days, potency rates as high as 70 percent in those under 60 years of age, and incontinence rates as low as five percent. Physicians who are non-skilled in laparoscopic urologic procedures should not be forced to do laparoscopic procedures particularly if they have reached a high skill level doing an open prostatectomy.

Robotic retropubic surgery appears to definitely decrease the incidence of blood loss and transfusion rates and decreases complications in general by four fold. The hospital stay appears to be shorter than both the standard radical prostatectomy and the laparoscopic approach.

Both of these procedures take a tremendous amount of training and for most surgeons the duration of the operation is quite extensive taking anywhere from four to six hours in inexperienced hands rather than the usual two to two and a half hours for the open procedure.

I am sure in time as the technology and instrumentation improves a laparoscopic as well as a robotic prostatectomy will become more and more common place as urologists become more skilled in these techniques and the instrumentation becomes more sophisticated. Medical, particularly immunological therapy, for prostate cancer may be the overall answer in treating prostate cancer. If medical techniques improve surgery itself in all forms may become passe. Immunological treatments using activated dendritic cells stimulated by prostate cancer membrane such as the Provenge therapy by Dendreon and immunological therapy being developed by Therion may be the treatment of the future. Prostate cancer vaccines may also be effective.

Research activity in prostate cancer has been growing in leaps and bounds as more and more money is being infused into the prostate cancer research arena. New techniques to diagnose prostate cancer at the earliest possible stage continues. A greater and greater interest in prostate cancer prevention either by drug therapy, environment, or dietary changes newer surgical techniques continue to be developed, but the major thrust is in medical therapy particularly immunotherapy.

Ten years from now the prostate cancer scene will be entirely different. The emphasis will be on prevention and medical therapy. Overall this should be more beneficial for men's health. (September, 2003)