Dr. Powell is to be congratulated for an outstanding review article
on prostate cancer in African-American men. As he points out, the age-adjusted
incidence of prostate cancer in African-American (black) males is 50% higher
than that in Caucasian (white) men, and black men have the highest incidence
of prostate cancer in the world. Differences between blacks and whites
in the probability of being diagnosed with prostate cancer (9.6% vs 5.2%),
lifetime prostate cancer-specific mortality (3% vs 1.4%), and 5-year survival
(65% vs 78%) are all indicative of a major public health problem in the
black male population.
The etiology for these racial differences in the clinical behavior of
prostate cancer is unknown; hormonal, nutritional, genetic, behavioral,
and socioeconomic status factors have all been implicated. Now, in the
late 1990s, as more research funding is finally being devoted to prostate
cancer, it is critically important to find the cause or causes of this
racial disparity. Our research group, the Department of Defense (DoD) Center
for Prostate Disease Research (CPDR), is funded to study prostate cancer
and disease in the DoD health-care system. Because the CPDR has a mandate
to study an equal-access, geographically diverse system that provides health
care for a large number of African-American men, it is a good setting in
which to investigate this issue. I will review our ongoing investigations
in this area and compare/contrast our findings to Dr. Powell's exemplary
Use of PSA in Black Men
Despite the racial disparity noted above, encouraging recent data from
the Radiation Therapy Oncology Group (RTOG), US military, and Veterans
Administration suggest that if black men are afforded the same access
and medical care as white men, the outcome disparity may be minimized or
eliminated. Armed with this information, we may be able to affect prostate
cancer in this population with increased public awareness, early detection
programs, and proper detection tools.
For a number of years, the American Urological Association (AUA), American
Cancer Society (ACS), and American College of Radiology have recommended
that early detection programs using digital rectal examination (DRE) and
prostate-specific antigen (PSA) be started at age 40 in African-American
men. Despite this recommendation, until now, no data existed to document
the value of PSA testing for the early and accurate diagnosis of prostate
cancer in this population. The finding by our group and others that black
men with prostate cancer had higher PSA values at diagnosis, even after
adjustment for patient age and tumor stage, grade, and volume, created
an urgent need to examine the proper PSA "normal" ranges for
Age-Adjusted References Ranges for Black Men
Our article, "Age specific reference ranges for serum prostate
specific antigen in black men," published in the August 1, 1996, issue
of the New England Journal of Medicine documents the outstanding ability
of PSA to detect prostate cancer in both Caucasian and African-American
men and develops age-adjusted PSA reference ranges for maximal cancer detection
in this high-risk group of men. In this study, between January 1991
and May 1995 serum PSA concentration was determined for 3,475 men without
clinical evidence of prostate cancer (1,802 Caucasian, 1,673 African-American)
and 1,783 men with prostate cancer (1,372 Caucasian, 411 African-American).
All PSA examinations were performed in a central, single laboratory using
the Abbott IMx assay (normal, 0 to 4 ng/mL).
Prostate-specific antigen concentration was analyzed as a function of
age and race to determine the operating characteristics of PSA for the
diagnosis of prostate cancer. Serum PSA concentration correlated directly
with age for both African-American and Caucasian men (r = .40, P = .001
for African-Americans; r = .34, P = .0001 for Caucasians). African-American
men had significantly higher serum PSA concentrations than Caucasian men
(P = .0001)(Figure 1). When sensitivity
was plotted against specificity, the area under the receiver-operator-characteristic
(ROC) curve was .91 for African-American men and .94 for Caucasian 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 only .70.
When we calculated age-specific PSA reference ranges by the identical
methodology used by Oesterling and colleagues in their 1993 study of Olmstead
County, Minnesota, we found very similar values for white men but higher
values for black men. These ranges were 0 to 2.4 ng/mL for black men age
40 to 49, 0 to 6.5 ng/mL for men age 50 to 59, 0 to 11.3 ng/mL for men
age 60 to 69, and 1 to 12.5 ng/mL for men age 70 to 79. We then tested
these new ranges in our group of black men with prostate cancer to determine
how the ranges would have performed if they had been used to detect the
cancers. 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 of PSA results in blacks without evidence
of cancer, there is more skewness, which pushes the 95th percentile farther
to the right (higher). This higher range, however, is not clinically useful.
Accordingly, we developed age-adjusted reference ranges for black men with
prostate cancer, selecting upper limits of normal PSA by decade to maximize
cancer detection. In other words, we developed reference ranges by decade
in the men with prostate cancer by using the fifth percentile of PSA values.
Only the lowest 5% of prediagnosis PSA values in the black men with cancer
are "normal," and the remainder (95%) are above normal (95% sensitivity).
We call these ranges the Walter Reed/Center for Prostate Disease Research
(WR/CPDR) age-specific reference ranges for maximal cancer detection (Table
1). They maximize sensitivity (cancer detection) without undue loss
of specificity (false-positive results, unnecessary transrectal ultrasound/biopsy).
These values for maximal cancer detection for black and white men are compared
to the traditional normal ranges (0 to 4 ng/mL) and the previously developed
age-specific reference ranges in Table 2.
Now that we have shown that PSA is an outstanding tool for prostate cancer
detection in African-American men, as well as in Caucasian men, we need
to promote public awareness and encourage African-American men to be tested,
such as Dr. Powell and colleagues did in their landmark Detroit Education
and Early Detection (DEED) study.
Is African-American Race a Prognostic Factor for a Worse Outcome?
There is an ongoing debate as to whether African-American race, itself,
is a prognostic factor for worse outcome in men with localized (and advanced)
prostate cancer. As noted above, data from the RTOG, US military,
and Veterans Administration suggest that race alone is not a prognostic
factor. Conversely, a recent Surveillance, Epidemiology, and End Results
(SEER) database study in metropolitan Detroit found that, at all stages
of disease, blacks had a poorer survival than whites; this was especially
evident in younger men (less than 65 years of age). Powell et al also
found that survival was worse for African-American men under age 65 but
better for men over age 65, and used the phrase, "ethnic survival
crossover," to describe this phenomenon. More study needs to be done
to determine whether younger black men do have a worse survival, and, if
so, what causes this disparity.
In an attempt to answer these questions, our group has been comparing
outcome and tumor characteristics by race among men who have undergone
radical prostatectomy. In a consecutive group of 91 radical prostatectomy
patients, 28 (30.8%) of whom were African-American, blacks had higher tumor
volumes in all clinical stage categories (Table
3). Overall, the black men had a mean tumor volume of 5.42 cc, as
compared with a volume of 2.10 cc in the white patients. This greater tumor
volume was associated with more adverse pathologic features of the radical
prostatectomy specimens and worse outcome.
In a follow-up study, we compared 518 black and white men who had undergone
radical prostatectomy at Walter Reed Army Medical Center between 1975 and
1995. Table 4 compares the pathologic
variables of the radical prostatectomy specimens in these two groups. There
were nonsignificant trends for blacks to have higher pathologic stage and
Gleason grade. Most strikingly, the margin-positive rate was 50.5% in blacks,
as compared with 38.4% in whites (P = .038). These statistics are very
similar to those reported by Powell and associates.
Our survival analysis for black and white men was very interesting and
points to the need for careful multivariate analysis when trying to determine
whether race is a prognostic factor. Overall, the African-American men
had a lower recurrence-free survival. In other words, at a mean follow-up
of 23.3 months, black men were more likely to have had a recurrence (defined
as a rising PSA as the first evidence of failure). Even in one multivariate
analysis that adjusted for pathologic stage, grade, and pretreatment PSA
and acid phosphatase, black race remained an independent prognostic factor.
However, in another multivariate analysis that included margin positivity
in the model, race was no longer an independent prognostic factor (P =
Because clinical stage and pathologic stage categories may not accurately
reflect tumor volume and subtle pathologic features, such as margin positivity
and volume of high-grade cancer, it will be imperative to include these
factors in any multivariate analysis aimed at determining whether race
affects outcome. The Armed Forces Institute of Pathology and CPDR are currently
collaborating on a prospective radical prostatectomy study to compare three-dimensional
tumor volumes and careful quantitative histology with outcome in black
and white men.
Is Biology or Behavior and Access to Blame for the Poor Pathologic
Even if race itself is not found to be an independent prognostic marker
when these comprehensive pathologic assessments are included, we will still
be left with the question of what is responsible for the worse pathologic
findings in black men. Considering that the black men in our studies were
1 to 3 years younger than the white men and yet have bigger tumors with
more adverse pathologic features, is biology or behavior and access to
blame? My own bias is that behavior and access are largely at fault. African-American
men simply have not been educated about prostate cancer and the need for
early detection. If early detection programs were more universally available
to black men starting at age 40 and were accepted, I believe that we would
detect the majority of prostate cancers when they were smaller and with
fewer adverse pathologic features and would eliminate the current racial
This contention appears to be borne out by the early DEED study results
obtained by Powell and associates. Compared to a nonscreened population,
the screened African-American men undergoing radical prostatectomy had
a significantly higher rate of organ-confined disease and lower recurrence
rate at early follow-up. By instituting education about prostate cancer
and screening PSA in this high-risk population, the DEED project increased
the organ-confined rate in these men to 65%--a gratifying result. Furthermore,
at a mean follow-up of 18 to 20 months, of the 15 DEED men screened who
underwent a radical prostatectomy, only 1 (7%) suffered a recurrence, as
compared with 25% of the nonscreened clinic patients.
Also encouraging was the finding that the DEED screened men had lower
mean and median initial PSA values. Considering that pretreatment PSA correlates
directly with tumor volume in both black and white radical prostatectomy
patients, the DEED data suggest that screened African-American men are
being diagnosed when their tumors are smaller. It is tantalizing to speculate
that if we use the lower PSA reference range of 2.0 ng/mL developed by
WR/CPDR in men between 40 to 49 years old, as discussed earlier, and
encourage screening in these younger African-American men, we can have
even a greater impact.
Finally, I strongly agree with Dr. Powell that based on the DEED data,
we cannot afford to wait to promote early detection in this high-risk population
of African-American men.
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