NEJM study shows link between rapid rise in PSA levels, death from prostate cancer


Results show men should be tested early and annually

Men who experience a rapid rise in their PSA (prostate-specific antigen) levels during the year before a diagnosis of prostate cancer are at a significantly increased risk of death from prostate cancer even after undergoing a radical prostatectomy, researchers, including William J. Catalona, M.D., director of the Clinical Prostate Cancer Screening Program at Northwestern Memorial Hospital, have found.

In a study to be published in Thursday's New England Journal of Medicine, researchers found that the rate of rise in the PSA level, or the PSA velocity, prior to diagnosis was a more powerful indicator of eventual death from prostate cancer than the actual PSA level itself. Specifically, an annual PSA velocity of more than 2.0 ng (nanograms) per milliliters was associated with significantly increased risk of death from prostate cancer despite a radical prostatectomy.

"The study results indicate that men with a high PSA velocity should not be managed by 'watchful waiting' and many will require more than a radical prostatectomy to prevent prostate cancer death," Dr. Catalona said.

The results also imply that PSA velocity measurements during the year before the diagnosis of prostate cancer can help identify the potential aggressiveness of the cancers -- those with a sharp PSA increase are more likely to have a potentially lethal cancer, while those with milder increases are more likely to have a less aggressive cancer that is more amenable to treatment. Dr. Catalona recommends that since deaths from prostate cancer begin to occur in men in their 40s, men should begin tracking their PSA levels at age 40 to recognize a sharp rise.

"While I recommend a biopsy with a PSA level of 2.5 (ng per milliliters) or higher, this study shows us that no single value of PSA is as important as the trend," he said. "And the only way you can recognize a trend is if the testing is done early and every year."

Dr. Catalona, who is also a professor of urology at Northwestern University's Feinberg School of Medicine and director of the Familial Prostate Cancer Program at Northwestern's Robert H. Lurie Comprehensive Cancer Center, developed the PSA test as a screening test for prostate cancer, which is the second-leading cause of cancer death in men and kills nearly 30,000 men a year. PSA is a protein, in this case produced by the prostate gland, and plays a role in making semen a liquid when it leaves the body. For the most part, PSA stays in the prostate gland and is in the bloodstream in barely measurable amounts. But when something is going wrong in the prostate, PSA leaks into the bloodstream.

The generally accepted cutoff for recommending a biopsy was initially a PSA of 4.0 or higher. While there has been some debate in the urological community about that guideline and whether the PSA test is an appropriate predictor of prostate cancer, Dr. Catalona has urged an even lower PSA indicator. He and his colleagues found in a previous study that more than 20% of men with PSA scores between 2.5 and 4.0 have cancer. He recommends biopsies -- taking tissue samples to check for cancerous cells -- be conducted when the PSA level reaches 2.5.

"The normal PSA range for men in their 40s and 50s is 0.6-0.9, so when the PSA reaches 2.5 or higher, or when you witness a significant increase in a short period of time, a biopsy is needed," Dr. Catalona said. "This new study shows that a steep slope in those PSA levels is a major red flag."

The study of 1,095 men with localized prostate cancer, conducted with researchers from Brigham and Women's Hospital and the Dana-Farber Cancer Institute in Boston, Harvard Medical School, Washington University School of Medicine in St. Louis and the University of Connecticut, concludes that the PSA velocity is more important than any single value. Pre-treatment and follow-up information was compiled from Jan. 1, 1989 to June 1, 2002 on men who were treated with radical prostatectomy and who participated in a prospective prostate-cancer screening study directed by Dr. Catalona when he was at Barnes-Jewish Hospital in St. Louis.

The study found that men with an annual PSA velocity of more than 2.0 ng per milliliter during the year before diagnosis had substantially higher rates of recurrence as well as death from prostate cancer than men with an annual PSA velocity of 2.0 or less. Within seven years after radical prostatectomy, depending on PSA level at diagnosis, clinical tumor category and the initial Gleason score (a system used to grade the prostate cancer tissue), up to 28 percent of men with an annual PSA of 2.0 velocity or higher died of prostate cancer despite undergoing radical prostatectomy. While the relative risk of death from prostate cancer was nearly 10 times higher among men with a pre-operative PSA velocity of more than 2.0 compared to those with a velocity of 2.0 or less, the study found that these other variables were also important determinants of the risk of death from prostate cancer. Therefore, the exact degree of increase in the risk of death from prostate cancer for an individual patient with PSA velocity of more than 2.0 is impossible to discern without also considering other factors.

The study results, in conjunction with recent statistics showing declining death rates from prostate cancer, argue for a more thorough and aggressive approach to testing for prostate cancer, Dr. Catalona said. Deaths from prostate cancer have fallen about 20% among whites and about 16% among blacks since the mid-1990s after use of the PSA test became widespread. While other factors such as improved treatment methods have contributed to this decline, it is undeniable that early detection and treatment are vital.

While this new study looked at the possible implications of an annual PSA velocity of 2.0 or higher, Dr. Catalona recommends biopsies be conducted when PSA levels rise 0.75 ng/ml or more over a year. He believes the lower PSA velocity cutoff would detect not only the most aggressive cancers but also the more curable ones as well. Other indications for a biopsy are a PSA level higher than 2.5 ng/ml or findings suspicious for cancer on a digital rectal examination. The National Comprehensive Cancer Network recently issued new guidelines that suggest biopsies be conducted when the PSA level reaches 2.5 or the PSA velocity is 0.75 or higher.

"While some physicians counsel watchful waiting, the men I see in my office have the same attitude as women facing the possibility of breast cancer: they want it treated, they want it taken care of and they want it to be over," Dr. Catalona said. The lifetime risk of being diagnosed with prostate cancer -- 1 in 6 -- is higher than the 1-in-8 risk of breast cancer in women. "It's still a big problem and it kills a lot of men."

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Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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