"Prostate cancer is an insidious disease that arises silently, passes through a curable phase silently, and becomes incurable silently. If you wait for symptoms to signal its presence, it is too late to cure it."
William J. Catalona, M.D.

William J. Catalona, M.D. is a prostate cancer researcher and surgeon. He is a professor in the Department of Urology at the Northwestern University Feinberg School of Medicine and Director of the Clinical Prostate Cancer Program at Northwestern's Robert H. Lurie Comprehensive Cancer Center in Chicago. He was the first to perform the research that showed the PSA test could be used for first-line screening for prostate cancer. I spoke with Dr. Catalona about the on-going controversy over whether the PSA test should be used as widely as it is today.

DJ: In 1991, you wrote an article for the New England Journal of Medicine advocating the use of the PSA test to screen men for prostate cancer. What led you to that conclusion?

WC: I had performed preliminary studies of PSA levels in my patients with and without prostate cancer. Rough calculations suggested that PSA would be more accurate than the traditional digital rectal examination, which, at the time, was the only clinical test for prostate cancer. When I announced this at a national meeting, I was met with great skepticism. I then decided to perform a large prospective screening trial. I eventually enrolled 36,000 men in this trial and it lasted for 12 years. However, after enrolling the first 1600 patients, it became clear that PSA could be used as a first-line screening test, and I published these results in the New England Journal of Medicine in 1991.

DJ: How has PSA testing evolved over the last 15 years? Can you help us understand the terms: free PSA, PSA density, PSA velocity, and PSA doubling time?

WC: Initially, PSA was used as a dichotomous variable, i.e., if it was higher than 4.0, it was abnormal, and, if it was lower than 4.0, it was normal. Later we learned that a rising PSA was more suspicious for cancer than a stable PSA (PSA velocity and PSA doubling time) and that a high PSA level in a man with an enlarged prostate gland was less worrisome for cancer than in a man with a normal-sized or small gland (PSA density). We also learned that there were various isoforms of PSA in the blood and the more PSA that existed complexed to serum proteins; the less that was circulating as free PSA, the more likely the patient had cancer as the cause of an elevated PSA (free, complexed, and total PSA).

The informed use of these parameters improves the accuracy of PSA testing in detecting prostate cancer and in distinguishing the aggressive forms from the less aggressive forms of the disease. PSA doubling time and, better yet, PSA velocity, often gives a better idea of how aggressive a cancer is than the total PSA value does.

DJ: In the past few years, the controversy over PSA testing has heated up, to the point that some clinicians are recommending cutting back or eliminating the use of it. What are their objections and why do you disagree?

WC: They believe that, over the years, the cancers detected by repeated PSA screening and intensive biopsy schemes are getting smaller and smaller--the amount of PSA they produce is insignificant in relation to the amount produced by benign prostatic hyperplasia (BPH) tissue. Accordingly, they believe that PSA is no longer a marker for prostate cancer, but has become only a marker for prostate size.

They are wrong on several fronts: First, PSA does correlate with prostate cancer volume in 90% of patients with clinically localized disease. The only exceptions to this rule are patients with a large prostate gland and a small tumor. However, even in these patients, PSA density and percent of free PSA can help distinguish between benign prostate disease and prostate cancer. One important reason that they are wrong here is the use of the volume of the largest single tumor nodule in the prostate gland, called the index tumor, as the volume of cancer. A second reason they are wrong is that the volume of the tumor is not the most important endpoint in prostate cancer screening; the most important outcome is the 10-year cancer cure rate following treatment with surgery or radiation therapy. PSA does correlate strongly with 10-year progression-free survival.

So far, there are three major cancers for which screening has proven to be effective: cervical cancer, breast cancer, and colorectal cancer. The PSA test, with its ability to detect prostate cancer early, has proven its value over time.

DJ: In 1995 you advocated setting a new standard PSA cut-off of 2.5. Why do you recommend this significant change from the traditional 4.0?

WC: First, approximately 25% of men with a PSA between 2.5 and 4.0 are found to have prostate cancer on biopsy. Using the 4.0 cut-off for recommending a biopsy, approximately 30% of cancers have spread to the margins of the prostate or beyond at the time of diagnosis. However, the cancer is detected in an organ-confined stage and therefore more curable when using a cut-off of 2.5.

DJ: How do you define "cured"?

WC: My practical definition of "cured" means that there is no evidence of PSA progression 10 or 15 years after primary treatment, without the institution of further therapy.

DJ: What does all of this mean to the man who is walking in to his doctor's office? What information should he expect to be given if prostate cancer is found?

WC: Tumor stage, tumor grade, tumor volume, treatment options, and a firm recommendation for the preferred treatment for him.. In order for a patient to be appropriately treated or actively monitored, clinicians have to know the tumor characteristics.

DJ: What impact will advances in genetic technology have on the diagnosis and treatment of prostate cancer?

WC: All cancer is genetic in origin. Some of the genetic mutations are inherited from parents; others are acquired from exposure to the environment. However, fundamental insights into the genetic changes that give rise to prostate cancer will help identify molecular targets that will help identify susceptible individuals, improve diagnosis and staging, and reveal new opportunities for treatment and even prevention.

DJ: You first posited the use of the PSA to screen for prostate cancer at an NIH-sponsored meeting in 1988. The goal of that meeting was to find a way to reduce deaths from prostate cancer by the year 2000. Was that goal met and, if so, how?

WC: Since 1992, one year after my first PSA screening paper was published in the New England Journal of Medicine, there has been a 75% reduction in the proportion of prostate cancer patients who have advanced disease at the time of diagnosis and more than a 25% reduction in the age-specific prostate cancer mortality rate. Epidemiologic studies in the U.S. have shown that in regions where PSA screening is widely practiced, there is a lower percentage of patients with advanced disease at diagnosis and a lower prostate cancer mortality rate.

A population-based study from Seattle has shown a 75% reduction in the prostate cancer death rate in men under the age of 65 years who were screened compared with those who are not screened. Globally, there have been substantial reductions in the prostate cancer mortality rate in countries where PSA screening is widely practiced. Death rates continue to rise in countries where PSA screening is discouraged or not widely performed because of a lack of resources or infrastructure. There are prospective randomized clinical trials on prostate cancer screening underway now in the U.S. and Europe. The results of these trials will not be available for several years.

DJ: It was announced in the March issue of Business Week that you are working with Beckman Coulter, a diagnostics maker, to develop a more accurate PSA test. Can you tell us about it and other research projects you are working on now?

WC: The marker we are developing is called "pro" PSA. It is a type of free PSA that is a more specific marker for prostate cancer than total PSA or free PSA. It might improve the accuracy of PSA screening. We will soon launch clinical trials to try to understand the value of pro PSA compared with conventional PSA markers. My other area of research is prostate cancer genetics, including both the familial and the sporadic forms of the disease.

DJ: Thank you so much for taking the time to teach us more about PSA screening and its vital role in the control of this deadly disease.

Hear Dr. Catalona talk about this important new standard in the management of the disease. Download the conversation to your MP3 player or computer to discuss with your healthcare team.