In a lively session featured at the 32nd Annual Meeting of the American
Society of Clinical Oncology (ASCO), Jerome P. Richie, md, Brigham and
Women's Hospital, Boston, and Steven H. Woolf, md, mph, Medical College
of Virginia, Fairfax, debated the merits of screening for prostate cancer.
Last month, Dr. Ritchie made the case for routine screening. In this issue,
Dr. Woolf, a family physician, argues that currently available data do
not support the value of routine screening.
Primary-care physicians see a different patient population than do oncologists
or urologists and are concerned with preventing a broader range of health
problems, Dr. Woolf said. That is one reason why primary-care practitioners
have a different "take" on the value of routine screening for
Official groups in North America and around the world also have contrasting
viewpoints on this issue, he noted. The American Cancer Society, American
Urological Association, and American College of Radiology all agree on
the need to do regular PSA screening beginning at age 50. However, the
American College of Physicians, American Academy of Family Physicians,
US Preventive Services Task Force, latest Patient Outcomes Research Team
(PORT) of the Agency for Health Care Policy and Research, and several groups
in Canada, Europe, and Australia all do not recommend routine screening.
Why is there so much uncertainty and debate about this issue? Before
any screening test, particularly a cancer screening test, is generally
accepted, some basic criteria must be met: Is the condition serious? Is
screening accurate in detecting the disease? Does early detection improve
outcome? Is screening or treatment harmful? And does screening do more
good than harm? With regard to prostate cancer screening, the answers to
some of these questions are still open, Dr. Woolf asserted.
Is the Condition Serious?
As for whether prostate cancer is a serious condition, evidence from
the United States and other countries clearly shows that this cancer causes
suffering and/or death in a large number of men. However, these men represent
only a subset of the total population with prostate cancer.
"We know from autopsy studies that there is a significant portion
of the population who have latent prostate cancer that progresses slowly
and produces few, if any, clinical symptoms," Dr. Woolf said. Of these
patients, only a subset progress to more aggressive disease, with its potential
for significant morbidity and mortality.
The actual prevalence of latent prostate cancer is debatable. Autopsy
studies suggest that 30% of men over age 50 may have latent cancer,
although the generalizability of these data is questionable. Clearly, however,
a "significant" number of prostate cancers are indolent in nature.
Is Screening Accurate?
With regard to the accuracy of PSA screening, Dr. Woolf noted that the
sensitivity of the test is relatively good. In studies of men with prostate
cancer, 80% have positive PSA results. The positive predictive value
of PSA screening in asymptomatic men is roughly one-third, which means
that one out of three men with a positive PSA actually have prostate cancer.
"The flip side of that is that two-thirds of men with a positive
PSA will not have prostate cancer," Dr. Woolf said. This becomes important
when one considers the potential morbidity associated with further testing
and treatment of this population.
Undoubtedly, the increased effort at screening will lead to the detection
of many latent prostate cancers. Whether these PSA-detected cancers are
clinically significant has been the subject of much debate, however. Recent
evidence indicates that the types of cancers detected by PSA screening
may be more aggressive than those detected on autopsy studies.
Such features as advanced tumor grade and pathologic extension beyond
the prostate capsule are more common in cancers that ultimately produce
clinically significant disease. However, Dr. Woolf made the distinction
between the actual development of clinically significant disease and the
detection of histopathologic characteristics that increase patients' risk
of developing clinically significant disease. Cancers detected by PSA are
more likely to have these features, but whether these patients will actually
develop symptoms is unknown.
Does Early Detection Improve Outcome?
If one accepts, for the purpose of discussion, that the PSA test is
accurate in detecting early prostate cancer, the critical issue, as shown
in Figure 1, is whether treating early
cancer improves outcome, not just whether screening tests can detect early-stage
disease. With respect to breast, colon, or cervical cancer, a large body
of evidence from randomized controlled trials and other types of controlled
outcome studies indicates that early detection and treatment improves outcomes.
What about the evidence that early detection and treatment of prostate
cancer improves outcomes? Currently, there is no direct evidence, Dr. Woolf
said. He noted that the ongoing randomized trials focusing on this issue
will not be completed for many years, and therefore, clinicians must rely
on the indirect evidence available right now. This indirect evidence suggests:
(1) a higher survival rate for patients with early-stage disease; (2) the
types of tumors detected by PSA are more likely to be early-stage disease;
and (3) PSA-detected tumors seem to have features associated with increased
risk for progression.
Lead-Time and Length Bias
Although these available studies suggest that screening may be beneficial,
Dr. Woolf argued that they suffer from numerous methodologic problems.
Two problems that are of particular importance are lead-time bias and length
As shown in Figure 2, for a patient
who develops symptoms at a particular point in life and who will die at
a subsequent point, the goal of screening is to detect the disease before
symptoms develop, initiate early treatment, and thereby prolong the patient's
"In the phenomenon of lead-time bias, we can end up artificially
lengthening the survival of the patient without actually changing the outcome,"
Dr. Woolf said. For example, as shown in Figure
3, a hypothetical patient who develops symptoms at age 55 and dies
at age 60 without cancer screening has a survival of 5 years. If that patient's
cancer is detected at age 50 and early treatment is initiated but he still
dies at age 60, survival will appear to have doubled from 5 to 10 years.
This phenomenon is not necessarily occurring with prostate cancer, but
the extent to which lead-time bias distorts current data is unclear. Thus,
said Dr. Woolf, only controlled studies that collect meaningful outcomes
data, as opposed to stage shifts and 5-year survival rates, can resolve
Some screening trials have found that the percentage of patients with
metastatic prostate cancer has decreased over time since the advent of
routine screening. This has been mistakenly interpreted as evidence that
early detection and treatment are "eliminating" metastatic prostate
cancer. Rather, Dr. Woolf argued, such a finding may only indicate that
there is less evidence of metastases at diagnosis but does not address
patients' ultimate outcome. "Are we simply moving the time of diagnosis
backward...as opposed to actually changing the course of the disease?"
Another phenomenon that occurs commonly with cancer screening is length
bias (Figure 4). If one screens for cancer
at any point in time, one will preferentially detect the slowly growing
tumors and catch only a minority of the aggressive tumors, because they
exist in the screened population for less time.
"The result of that is that your survival rate is artificially
inflated, so [that] you end up with higher survival rates, and a sense
that the types of cancers you're detecting are having a much more favorable
outcome than they actually would have in real life."
1. Woolf SH: Screening for prostate cancer with prostate-specific antigen.
N Engl J Med 333:1401-1405, 1995.
2. Scardino PT: Early detection of prostate cancer. Urol Clin N Am 16:635-655,
3. Catalona WJ, Richie JP, Ahmann FR, et al: Comparison of digital rectal
examination and serum prostate specific antigen in the early detection
of prostate cancer: Results of a multicenter clinical trial of 6,630 men.
J Urol 151:1283-1290, 1994.
4. Catalona WJ, Smith DS, Ratliff TL, et al: Detection of organ-confined
prostate cancer is increased through prostate-specific antigen-based screening.
JAMA 270:948-954, 1993.
5. Albertsen PC, Fryback DG, Storer BE, et al: Long-term survival among
men with conservatively treated localized prostate cancer. JAMA 274:626-631,
6. Johansson J: Expectant management of early stage prostatic cancer:
Swedish experience. J Urol 152:1753-1756, 1994.
7. Gann PH, Hennekens CH, Stampfer MJ: A prospective evaluation of plasma
prostate-specific antigen for detection of prostatic cancer. JAMA 273:289-294,
8. Lerner SP, Seale-Hawkins C, Carlton CE Jr, et al: The risk of dying
of prostate cancer in patients with clinically localized disease. J Urol
9. Hugosson J, Aus G, Bergdahl C, et al: Prostate cancer mortality in
patients surviving more than 10 years after diagnosis. J Urol 154:2115-2117,