Context required

The concept of normal becomes a bit less unwieldy when considered in context. In point of fact, to define “‘normal’ requires a context,” says Robert G. Uzzo, MD, FACS, chairman of the Department of Surgery and G. Willing Pepper Chair in Cancer Research at Fox Chase Cancer Center in Philadelphia and medical director of urology for Renal & Urology News. “Crying ‘fire’ in the movie theater is not normal unless there is a fire; then it is quite normal,” he observes.

In a medical context, normal does not always translate to healthy. “Normal can be something that the majority of people have, but it can also be what only a small fraction of people have,” contends Kamyar Kalantar-Zadeh, MD, PhD, MPH, of the University of California, Los Angeles (UCLA), where he is director of dialysis expansion and epidemiology at the Harbor-UCLA division of Nephrology & Hypertension.

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“Take the case of dental health. The majority of people have some kind of dental problem; almost nobody is without dental problems entirely. Therefore, by using the norm of the absolute majority, we would come up with defining ‘norm’ as something that is in fact not healthy. This is probably true for body composition as well.” Dr. Kalantar-Zadeh is medical directorof nephrology for Renal & Urology News.

“Normal” PSA elusive

PSA testing is a prominent example of how a “normal” clinical value is derived, accepted, and continuously revised. According to the National Cancer Institute, there is no specific normal or abnormal PSA level in patients ( After more than 20 years of research in the field, the researcher who pioneered diagnostic PSA testing, William J. Catalona, MD, agrees.

It was as an attendee at a 1988 NIH conference on prostate cancer that Dr. Catalona introduced the idea of using the PSA test for diagnostic purposes. Because he had been collecting PSA values on all of his patients—whether they had prostate cancer, benign prostatic hyperplasia, or no such problems—he even ventured that 4 ng/mL would probably be an appropriate cutoff point for “normal.”

Dr. Catalona was all but shouted down by his fellow attendees. Although the PSA test had been heartily approved two years earlier as a marker for men with established prostate cancer, “nobody believed it could be used as a screening test for prostate cancer because it wasn’t perfect,” Dr. Catalona says.

“There were some men with high PSA who didn’t have prostate cancer, and there were some men with low PSA who did. Everybody wants a pregnancy test: They want something that when it’s positive, the woman is always pregnant, and when it’s negative, the woman is never pregnant. They want a test which tells them this is definitely 100% abnormal and that is definitely 100% normal. The idea of using the PSA test diagnostically was rejected at first because it couldn’t do that.”

That left digital rectal examination as the only option for early diagnosis, but Dr. Catalona was sure that most asymptomatic men would not submit to such a test. He eventually convinced a skeptical PSA test manufacturer to supply him with 1,000 kits at cost for a study. His approved protocol dictated that a value greater than 4.0 was suspicious for cancer and biopsy would be recommended.

“This was very revolutionary because nobody could really accept that anyone would do a biopsy on the basis of a blood test,” recounts Dr. Catalona, professor of urology at Northwestern University’s Feinberg School of Medicine in Chicago and medical director of the private Urological Research Foundation in St. Louis, Mo.

Dr. Catalona published his results on 1,600 men in The New England Journal of Medicine in April 1991 (324: 1156-1161). The study ultimately involved 36,000 men over 12 years. Such a large and long-term trial captured the attention of the scientific world when the results revealed that men with a PSA greater than 2.5 incurred a nearly 50% risk of having it rise above 4.0 within four years. But because of the strict protocol, no patient could undergo biopsy until he hit the “normal” cutoff point of 4.0—even though he may well have developed cancer by then.

Dr. Catalona implored the institutional review board to allow him to change the protocol cutoff to 2.5. The board resisted at first but, by May 1995, had relented. “It isn’t that you were doing biopsies that you wouldn’t have otherwise done,” explains Dr. Catalona. “You were just moving them up and detecting cancer earlier.”

The likelihood of curing cancers contained within the prostate and had clear surgical margins improved from about 70% using the 4.0 cutoff to 81% using the 2.5 cutoff. The change to 2.5 was controversial, but further work conducted by Dr. Catalona’s team, in collaboration with researchers from the Harvard School of Public Health in Boston, showed that many cancers were being missed even at that threshold.

Because it has become apparent that there is no cutoff below which a patient can be considered without cancer, some experts are pushing to abandon the use of PSA thresholds. Instead, many are turning to PSA velocity—the year-to-year rise in test values.

Steady increases are certainly a cause for concern, as shown by H. Ballentine Carter, MD, director of the Division of Adult Urology, and Alan Partin, MD, PhD, Chairman of the James Buchanan Brady Urological Institute, both at Johns Hopkins University School of Medicine in Baltimore. Dr. Partin and Patrick Walsh, MD, developed the “Partin tables,” which correlate PSA level, Gleason score, and estimated clinical staging to determine the definitive pathologic stage of prostate cancer and the best course of treatment.

“Understanding how to use PSA tests has gotten a whole lot more complicated over the years,” observes Dr. Partin. “Probably the first inkling we had that there was really no such thing as a ‘normal’ test was right around the early 1990s when someone figured out that because older men had bigger prostates due to their age, you could really expect them to have a little bit higher value.”

As a result, Dr. Partin says, older men could avoid undergoing potentially painful and anxiety-producing biopsies. “But after about three or four years, we found out that we were missing a lot of potentially lifethreatening cancers by not doing biopsies on those men.” Urologists soon found that age was not the only factor skewing results. “We began to notice that we couldn’t use the test the same way for all races. For an African American man, it was better to use a cutoff value a bit lower than for a Caucasian,” Dr. Partin recalls.

“Nobody really understood if that was due to genetics or diet or culture. We investigated certain genes to see if perhaps the androgen receptor [in some men] was more sensitive to the blood test. Nothing really came out of it.”