Ms. Bruner and colleagues from Fox Chase Cancer Center are to be congratulated for their comprehensive, well-designed program to maximize our understanding of prostate cancer in young men who are at high risk for developing the disease. I
Prostate Cancer Screening: Optimal Use in African-American and Younger Men at Risk
Ms. Bruner and colleagues from Fox Chase Cancer Center are to be congratulated for their comprehensive, well-designed program to maximize our understanding of prostate cancer in young men who are at high risk for developing the disease. I would like to highlight and amplify their data in African-Americans-a sub-group that is well known to have higher prostate cancer incidence and mortality.
Specifically, Bruner et al found that 4 (7.7%) of 52 black men who were screened had prostate cancer. More striking was the fact that of the seven men who had either an abnormal digital rectal examination (DRE) or an elevated prostate-specific antigen (PSA) level (³ 2 ng/mL with a low free PSA [< 27%]), four (57%) had cancer. Furthermore, these men were young, with a mean age of only 46.75 years!
Population-based screening for prostate cancer has now been proven to decrease disease-specific mortality in a large Canadian trial. Furthermore, recent studies have fine-tuned the value of PSA testing. In particular, a PSA value of 4.0 ng/mL is too high for young men (< 50 years old) and for targeted screening of certain groups of individuals who may be at particular risk of developing prostate cancer, namely, black men and those with a family history of the disease. I believe that we should consider testing these high-risk men, starting at age 40 years, using a PSA cut-off point of 2.0 ng/mL. Average-risk men should be offered testing at age 50 years. In addition, recent data suggest that a PSA of 4.0 ng/mL may also be too high in average-risk men in their 50s and 60s and a lower cut-off should be considered.
Age-Specific PSA Ranges
The PSA test has been approved by the FDA as a method of screening for prostate cancer, but it is not perfect. Although PSA levels ³ 4.0 ng/mL have traditionally been considered to be abnormal, the use of this cut-off point will miss the approximately 21% of patients with prostate cancer who have PSA levels < 4.0 ng/mL.
Recently, the use of age-specific reference ranges (ASRRs) has generated particular interest. These ASRR’s, derived from control populations of men without prostate cancer, adjust for the increases in prostatic hyperplasia and PSA levels that occur with aging. Levels above the 95th percentile of these normal men by decade of age are considered to be abnormal.
The first ASRRs, developed by Oesterling and associates for use in Caucasian men (Table 1), resulted in a 22% improvement in PSA specificity (ie, the probability that the test could accurately identify men without prostate cancer and avoid unnecessary prostate biopsy in these men). Perhaps more important was the observation that, for young men (ages 40 to 49 years) the normal PSA value was lower than 4.0 ng/mL, namely, 0 to 2.5 ng/mL. Similarly, for men between 50 and 59 years of age, the normal value was between 0 and 3.5 ng/mL. Thus, the greatest contribution of ASRRs, in my opinion, is that they led to the recognition that a “normal” PSA of £ 4.0 ng/mL is not “set in stone” and, in fact, is too high for many patients.
Newer data have suggested that different racial groups may have different ASRRs. For instance, ASRRs are lower in Japanese men than in American men. Specifically, PSA levels should be between 0 and 2.0 ng/mL for Japanese men in their 40s and between 0 and 3.0 ng/mL for men in their 50s.
Working with US military health-care system patients, our group has shown that black men with newly diagnosed prostate cancer have higher serum PSA values than do whites, even after correction for stage, grade, and tumor volume. In view of these findings, we studied 3,475 men without clinical evidence of prostate cancer (1,802 Caucasians, 1,673 African-Americans) and 1,783 men with the disease (1,372 Caucasians, 411 African-Americans). Prostate-specific antigen concentration was analyzed as a function of age and race to determine operating characteristics of PSA for the diagnosis of prostate cancer.
Serum PSA concentration correlated directly with age for both black and white men (r = .40, P = .0001 for blacks and r = .34, P = .0001 for whites). African-American men had significantly higher PSA concentrations than did Caucasian men (P = .0001). When sensitivity was plotted against 1 – specificity, the area under the receiver operator characteristic (ROC) curve was 0.91 for black men and 0.94 for white men, indicating that the PSA test is an excellent early detection tool. (For comparison, the Pap smear for cervical cancer, which is an accepted clinical screening test, has an ROC value of 0.70.)
When we calculated ASRRs by the identical methodology used by Oesterling and colleagues in their 1993 study of primarily Caucasian patients from Olmstead County, Minnesota, we found very similar PSA values for white men but higher values for black men. Among African-Americans, PSA values ranged from 0 to 2.4 ng/mL in men 40 to 49 years old, 0 to 6.5 ng/mL in those 50 to 59 years old, 0 to 11.3 ng/mL in those 60 to 69 years old, and 0 to 12.5 ng/mL in those 70 to 79 years old. We then tested these new ranges in our group of black men with prostate cancer to determine how they would have performed. Unfortunately, these markedly higher ranges would have missed 41% of the cancers (sensitivity of only 59%).
The reason that these traditionally derived ranges performed so poorly is simple-they represent the 95th percentile of values in the black controls. Because there is more variability in PSA results in blacks without evidence of cancer, there is greater skewing of the results, which shifts the 95th percentile curve farther to the right (higher). This higher range, however, is not clinically useful.
We therefore developed ASRRs for black men with prostate cancer, selecting PSA upper limits of normal by decade to maximize cancer detection. In other words, we developed reference ranges by decade in the men with prostate cancer by using the 5th percentile of PSA values. Only the lowest 5% of prediagnosis PSA values in the black men with cancer are considered to be “normal,” and the remainder (95%) are above normal (95% sensitivity).
We refer to these ranges as the Walter Reed/Center for Prostate Disease Research ASRRs for maximal cancer detection (Table 1). They maximize sensitivity (cancer detection) without undue loss of specificity (false-positives/unnecessary transrectal ultrasound/biopsy).
Reference ranges for PSA have also been controversial for older men, because they raise the “normal” level above 4.0 ng/mL. Advocates of screening have been concerned that “important” cancers will be missed in these “older” men, who may be perfectly healthy and physiologically younger. The race-specific reference ranges that we have proposed have been criticized according to the same logic; many feel that it is inappropriate to raise the “normal” PSA level above 4.0 ng/mL in a high-risk group even in the older age groups. Specifically, Littrup argues that our Walter Reed/Center for Prostate Disease Research values are perhaps too complex and would favor only two PSA “normals”: > 2.0 ng/mL for “high-risk men” and > 4.0 ng/mL for the “general population” without age adjustment.
A PSA of 4.0 ng/mL is Too High for Young Men
The continuing controversy about the “exact” proper PSA by age and race notwithstanding, the most important concept, in my opinion, is the recognition that a PSA of 4.0 ng/mL is too high a screening cut-off point for younger men, such as African-Americans between the ages of 40 and 49. Bullock et al screened 214 black men in that age range and found a prevalence of prostate cancer of 0.9% (2 of 214) when a PSA of 4.0 ng/mL was used. Interestingly, the prevalence increased to 5.6% (2 of 36) when the black men also had a family history of prostate cancer.
Conversely, Catalona et al from the same institution found that the cancer detection rate was 38% in a small group of 16 black men between 40 and 49 years old who underwent a biopsy for PSA values between 2.6 and 4.0 ng/mL. In a follow-up series, these same investigators found an even higher prevalence rate of 42% among African-American men with a PSA between 2.6 and 4.0 ng/mL.
Until further data become available, we believe that African-American men with a PSA > 2.0 ng/mL and Caucasian men with a PSA > 2.5 ng/mL who are between 40 and 49 years of age should undergo further evaluation. In older men, particularly healthy men in their 50s and 60s, a clinician may use our age-adjusted sensitivity-based ranges (> 3.5 ng/mL) or may opt to e even more aggressive and use the 2.0-ng/mL cut-off point advocated by Littrup and Sparschu or the 2.5-ng/mL value recommended by Catalona and associates.[10,11]
Lower PSA-Referenced Ranges for Curable Cancer
The concept of developing PSA reference ranges not just for cancer, but rather, for curable cancer is quite new. To my knowledge, Reissigl et al from Austria were the first group to define PSA cut-off points by decade of age for curable prostate cancer. These PSA values ranged from 1.25 ng/ml for men in their 40s to 3.25 ng/mL for men in their 70s.
Curability definitions are somewhat arbitrary unless one waits the required 10 years or more to find out exactly which patients are, in fact, cured. Instead, pathologic tumor stage and grade in patients who have undergone a radical prostatectomy provide a reasonable surrogate for curability. To this end, in a large series from Johns Hopkins, Carter et al defined “curability” as an organ-confined tumor of any grade, or specimen-confined disease (ie, negative margins, seminal vesicles, and lymph nodes) with a Gleason sum £ 6.
Using this definition, I showed that only 45% of contemporary-era black men who underwent a radical prostatectomy at our hospital were “curable.” This compared to a 74% curable rate among the predominantly white patients reported by Carter et al. Furthermore, by lowering the pretreatment PSA value, the curability rates for both black and white men were strikingly better. Specifically, 94% of men from the Johns Hopkins series with a PSA value £ 4.0 ng/mL were curable, as were 83% of black men from Walter Reed.
With this in mind, I have reported PSA reference ranges for curable prostate cancer in African-American men who were considered cured and who had a pretreatment PSA value. I calculated age-adjusted 5th, 10th, and 25th percentiles of pretreatment PSA in order to define cut-off points for screening PSA values that would optimize curable prostate cancer in African-American men; these PSA values are shown in Table 2.
Based on this preliminary study, one would biopsy black men with a PSA value greater than approximately 1.0 ng/mL to have a 95% probability of diagnosing curable prostate cancer. Recognizing that lowering the PSA “normal” level always represents a trade-off of sensitivity vs specificity (unnecessary biopsies), the 90th or 75th percentile may be a better compromise. It should be emphasized that three of four of these PSA values for curable cancer are lower than the traditional normal level of 4.0 ng/mL. We are presently studying additional black and white patients to further define ASRRs for curable prostate cancer.
What is a “Normal” PSA in Young Men?
Our Department of Defense–funded Center for Prostate Disease Research (CPDR) has recently conducted two studies illustrating that a PSA of 4.0 ng/mL is significantly higher than normal among young men. In 750 black and 750 white military members between the ages of 15 and 45 years who had serum banked in the Army and Navy Serum Repository (ANSR), the mean PSA values were 0.52 and 0.47 ng/mL, respectively. The 95th percentile ranged from 1.16 to 1.38 ng/mL for blacks stratified by decade of age (1.38 ng/mL for the 40 to 49-year-old group); for whites the corresponding range was 0.71 to 1.13 ng/mL. Based on these new, as yet unpublished data, it appears that using even a PSA value of 2.0 ng/mL as a cut-off point for both black and white men is considerably higher than these 95th percentile values.
In collaboration with the Armed Forces Physical Fitness Institute, the CPDR also is conducting a prospective screening study of healthy officers enrolled in the US Army War College at Carlisle Barracks, Pennsylvania. In the first class of 234 individuals (mean age, 43.9 years), 204 had screening PSAs performed; the mean PSA value was 0.7 ng/mL. The study is still ongoing to determine how to optimize screening in this young population, but early findings clearly show that a PSA of 4.0 ng/mL is too high a cut-off point for men in their 40s.
Free PSA and Other New Screening Tools
Another recent development is the FDA approval of the “free” PSA test. Over the last few years, researchers discovered that the PSA protein may be free or bound to other proteins in the bloodstream. Most PSA is complexed to other proteins, most commonly, alpha-1 antichymotrypsin (ACT).
The percentage of free, complexed, and total PSA and their ratios are different between men who do and do not have prostate cancer, and these differences can be exploited to screen men for prostate cancer. The most useful ratio identified to date is the percentage of free to total PSA. Although studies are still being conducted, the lower the percentage of free PSA, the higher is one’s risk of prostate cancer. Specifically related to lowering total PSA, a total PSA cut-off of 2.5 ng/mL has been advocated to increase the odds of detecting curable prostate cancer in younger men, and use of a free PSA cut-off < 27% has been proposed to increase screeningaccuracy.
Recent work also has examined combination factor equations to predict prostate cancer. One recent example is the Prostasure index, which measures PSA, acid phosphatase (PAP), and creatinine kinase, and uses these factors plus the patient’s age in a neural network computer program to predict the likelihood of prostate cancer. Another example is the Cancer of the Prostate Risk Index (CAPRI) equation, which combines age, race, DRE findings, and PSA into a probability model for clinical decision-making. I believe that, in the future, our biopsy decisions will be based on these types of approaches. In particular, these approaches will enable us to fine-tune screening to a total PSA threshold of £ 2.0 ng/mL in many men.
With the life expectancy of the population steadily rising and people remaining healthier longer, prostate cancer will continue to increase in importance. Although controversial, screening for prostate cancer has now been shown to decrease disease-specific mortality in one large trial.
Despite the fact that PSA testing has now been used for more than a decade, it has only recently been observed that a PSA level of 4.0 ng/mL is not normal for everyone. Specifically, a PSA of 2.0 ng/mL should be used as the upper limit of normal for African-American men between 40 and 49 years old. Similarly, a PSA of 2.5 ng/mL should be the upper limit for Caucasian men in their 40s. Furthermore, to optimize the detection of curable cancer, a lower PSA threshold, ranging from 2.0 to 3.5 ng/mL, should be considered for older men of both races.
Finally, fine-tuning of PSA and use of other PSA-related screening tools will improve risk assessment for the early detection of prostate cancer in African-American and younger men at risk.
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