The following is Dr. Catalona's response to Dr. Stamey's recent
comments on the usefulness of PSA testing...Ron
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I believe the new Stamey study has some flaws in it and the message
is misleading to men concerning prostate cancer.

I have written a response to this that will soon appear in a journal.
A
draft of that response appears below.

Prostate Cancer Screening

William J. Catalona, M.D.
Professor of Urology, Director, Clinical Prostate Cancer Program,
Robert
H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine,
Northwestern University, Chicago, Illinois, USA

Screening for prostate cancer is controversial. The pro side of the
controversy holds that: (1) prostate cancer is the most common
visceral
cancer in (US) men and the second-leading cause of cancer death; (2)
since there is no cure for advanced prostate cancer and no known means
of preventing prostate cancer, the only hope for reducing suffering
and
death from prostate cancer is to detect it early and treat it
effectively; and (3) since prostate cancer usually produces no
symptoms
until it is too late, it is necessary to pro-actively screen for and
detect it when it is curable. The con side is that: (1) there are
other
important needs for health care resources; (2) the benefits of
prostate
cancer screening have not yet been conclusively demonstrated; (3)
there
are risks associated with treatment; and (4) screening should not be
implemented until there is proof that it does more good than harm.

The goals of screening are to reduce prostate cancer-related suffering
and death by detecting and treating potentially harmful cancers while
they are curable while avoiding causing excessive side effects and
having reasonable economic costs. However, if there were no effective
treatment for prostate cancer, screening could not achieve these
goals.
Recently, a randomized trial has demonstrated that radical
prostatectomy
reduces metastasis and death rates from prostate cancer as compared
with
watchful waiting.1

If screening and treatment were effective, one would expect an initial
increase in incidence rates, as previously undetectable cancers are
detected; a subsequent decline in incidence, as previously occult
cancers are culled from the population; a higher new baseline
incidence
rate, because more of the prevalent cases are detected; detection of
earlier stage disease; a decrease in mortality rates from advanced
cancer; an increase in the "relative" survival rate (survival relative
to other causes of death); detection of cancer at a younger age and
lower PSA levels. All of these trends have been observed.

To prove conclusively that screening is effective, either a randomized
trial or a sustained reduction in national cancer-specific mortality
rates would be required. Even if there were proof, there would remain
questions about which patients benefit; how many cancers must be
detected to save one life; what is the risk-benefit ratio in relation
to
side effects; and what are the economic costs in relation to the
benefits?

The great majority of PSA-detected tumors have the histological
characteristics of clinically important cancers, and most are organ
confined. PSA screening advances the date of diagnosis by 5 to13
years,
and the US prostate cancer-specific mortality rates have decreased by
more than 20% since 1995 in the PSA screening era.2 There are large
ongoing randomized clinical trials, and some smaller studies have
suggested a mortality benefit from screening. These trends have been
interpreted by some cancer epidemiologists as showing the influence of
PSA screening: ".there is little uncertainty that PSA testing has left
its mark on the vital statistics for prostate cancer. Several factors,
especially the decline in the incidence of and mortality from distant
stage disease, hold out the promise that PSA testing may lead to a
sustained decline in prostate cancer mortality."2

Certainly, screening causes some instances of "over detection" of
cancer; however, very few harmless, so-called "autopsy" cancers can be
detected with prostate biopsies. In the US, 17% of men are diagnosed
with prostate cancer during their lifetime and of these men with
prostate cancer, 16% die of their disease. Thus, overall,
approximately
3% of US men die of prostate cancer. It has been implied that this
disparity indicates that most prostate cancers are harmless. The fact
that a man does not die of his cancer does not necessarily mean that
the
cancer was harmless. Some patients are cured of virulent cancers, and
others suffer from advanced disease but die of other causes.

Possible alternative explanations for the current favorable prostate
cancer incidence and mortality trends are lead-time and length-time
bias, improved treatments, the earlier use of hormonal therapy;
misclassification of cause of death, and diet or environmental
factors.
However, it is difficult to discount the importance of early
detection.

With widespread screening, tumors are smaller at the time of diagnosis
now than in the past. With smaller tumors, the "noise"
(BPH/prostatitis)-to-"signal" (cancer) ratio of the PSA level in the
blood increases, and PSA performs less well as a screening test for
cancer. This is especially true in older men. This is the main reason
a
decreasing correlation has been reported between the PSA level and the
volume of the "index" tumor in the prostate gland. However, with early
prostate cancer, the tumor cells are frequently scattered throughout
the
prostate in microscopic foci, and, if one measures only the volume of
the largest "index" tumor, one might miss the correlation between
total
tumor volume and the serum PSA level. However, a direct association
has
been demonstrated between the serum PSA level and the likelihood of
prostate cancer, even at low PSA levels.3

A recent study reported that 15% of men with a normal prostate
examination and a PSA less than 4 ng/ml have cancer detected on
systematic needle biopsies, 3 raising questions about the usefulness
of
PSA testing. Another study reported that PSA in the range below 10
ng/ml
is primarily a marker for BPH (article by Stamey). These reports,
along
with concerns about unnecessary biopsies, the "costs" of screening,
and
possible over treatment, have been the topics of public debate in the
lay media and have created more confusion and controversy than the
information warrants. They could result in men thinking they do not
need
to have annual PSA testing or timely treatment after a prostate cancer
diagnosis. Nothing could be further from the truth.
I believe that several changes should be considered for the future
prostate cancer screening. In 1991, I published the first study
demonstrating that PSA could be used as a first-line screening test
for
prostate cancer, using a PSA cutoff of 4 ng/ml. 4 From preliminary
research, it was clear that no PSA cutoff could completely separate
men
with curable prostate cancer from those with benign enlargement or
inflammation.

Therefore, I initially selected the 4-ng/ml cutoff because I believed
it
would detect many of the dangerous, yet curable, cancers while
limiting
the number of unnecessary biopsies in men without cancer. My PSA study
enrolled 36,000 men for screening and lasted for 12 years. After a few
years, it became apparent that nearly half of the men whose PSA was in
the 2.5 to 4 ng/ml range progressed to PSA levels above 4 ng/ml within
four years. In nearly one-third of these men with rapidly rising PSA
values, the cancer had spread to the margins of the prostate or beyond
by the time the PSA had reached 4 ng/ml. We have subsequently
demonstrated that a PSA cutoff of 4 ng/ml is too high5 and that PSA
velocity during the year before the diagnosis of cancer is strongly
associated with the risk for prostate cancer-specific death.6 These
results indicate that PSA trends are more important than any single
PSA
value in assessing the risk for life-threatening prostate cancer.

Some prostate cancers are highly aggressive but do not produce much
PSA.
They can spread beyond the prostate before the PSA reaches 4 ng/ml.
Catching them in time is a challenge, and the only practical strategy
is
annual screening beginning at an early age with PSA testing and a
digital rectal examination. Therefore, in 1995, I decided to lower the
PSA cutoff for biopsy to 2.5 ng/ml in my PSA study (and personal
practice) and since have demonstrated the usefulness of the 2.5 ng/ml
cutoff. Approximately 25% of men have cancer detected, and the cancer
is
more often organ confined without over detecting harmless cancers.7
Some
have protested that this cutoff means more unnecessary biopsies, but,
in
fact, in many cases it simply means that the biopsy is performed at an
earlier time. The current American Cancer Society and the 2004
National
Comprehensive Cancer Center Network guidelines also recommend
consideration of a biopsy for a PSA above 2.5 ng/ml.

Here is what I recommend for prostate cancer screening: annual PSA and
digital rectal examination beginning at age 40, or earlier in men with
a
family history of early age-at-onset prostate cancer (PSA levels
should
be 0.6 to 0.7 ng/ml in men in their 40s and 50s without prostate
disease); prospectively monitoring PSA velocity; biopsies for men with
a
suspicious digital rectal examination, PSA higher than 2.5 ng/ml, or a
PSA velocity higher than 0.75 ng/ml per year, using 12 core biopsy
protocols under local prostate anesthesia; considering measuring
androgen levels in interpreting PSA results; and using percent free
PSA,
percent complexed PSA, PSA density, and PSA velocity measurements to
determine the need for repeat biopsies.

The most effective and acceptable treatments eradicate the tumor at a
very early stage before it has a chance to spread. Every man hopes to
be
cured with primary treatment without additional therapy. No one wants
to
hear about long-term hormonal therapy, chemotherapy, or harsh
experimental treatments. The risk of unnecessary treatment is low when
good clinical judgment is exercised.

References

1. Holmberg L, Bill-Axelson A, Helgesen F, Salo JO, Folmerz P, Haggman
M, Andersson SO, Spangberg A, Busch C, Nordling S, Palmgren J, Adami
HO,
Johansson JE, Norlen BJ; Scandinavian Prostatic Cancer Group Study
Number 4. A randomized trial comparing radical prostatectomy with
watchful waiting in early prostate cancer. N Engl J Med. 2002;
347:781-9.
2. Hankey BF, Feuer EJ, Clegg LX, Hayes RB, Legler JM, Prorok PC, Ries
LA, Merrill RM, Kaplan RS. Cancer surveillance series: interpreting
trends in prostate cancer--part I: Evidence of the effects of
screening
in recent prostate cancer incidence, mortality, and survival rates. J
Natl Cancer Inst. 1999; 91:1017-24.
3. Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL,
Minasian LM, Ford LG, Lippman SM, Crawford ED, Crowley JJ, Coltman CA
Jr. Prevalence of prostate cancer among men with a prostate-specific
antigen level < or =4.0 ng per milliliter. N Engl J Med. 2004;
350:2239-46.
4. Catalona WJ, Smith DS, Ratliff TL, Dodds KM, Coplen DE, Yuan JJ,
Petros JA, Andriole GL. Measurement of prostate-specific antigen in
serum as a screening test for prostate cancer. N Engl J Med. 1991;
324:1156-61.
5. Punglia RS, D'Amico AV, Catalona WJ, Roehl KA, Kuntz KM. Effect of
verification bias on screening for prostate cancer by measurement of
prostate-specific antigen. N Engl J Med. 2003; 3494): 335-42.
6. D'Amico AV, Chen MH, Roehl KA, Catalona WJ. Preoperative PSA
velocity
and the risk of death from prostate cancer after radical
prostatectomy.
N Engl J Med. 2004; 351:125-35.
7. Krumholtz JS, Carvalhal GF, Ramos CG, Smith DS, Thorson P, Yan Y,
Humphrey PA, Roehl KA, Catalona WJ. Prostate-specific antigen cutoff
of
2.6 ng/mL for prostate cancer screening is associated with favorable
pathologic tumor features. Urology. 2002 60:469-73.