Two Studies Continue Debate on
Prostate Cancer Screening
by David W. Sharp
Screening does tend to attract controversy, and
prostate cancer is no exception. Evidence
that screening for this cancer meets the strict criteria for a
valid screening test (see Science Watch, Nov/Dec, 2008)
has been hard to come by. A systematic review published in 2006
found only two acceptable randomized trials of screening
compared with no screening or routine care. The relative risk
and confidence interval for mortality then was 1.01 (0.80
– 1.29) (D. Ilic, et al., Cochrane Database
Syst. Rev., 3: CD004720, 2006). Many clinicians, patients,
and health economists, among others, will have been hoping that
two major trials reported in the March 26, 2009, issue of the
New England Journal of Medicine would settle the
controversy (paper #10 and G.L. Andriole, et al.,
360[13]: 1310-9, 2009, at #11 with total cites 49 and latest
count 38).
As reported in paper #10, the European Randomized Study of
Screening for Prostate Cancer (ERSPC) was conducted in seven
countries with some variations in methodology between participating
centers. A PSA above 3 or 4 ng/mL was an indication for prostate
biopsy. The principal endpoint was death from prostate cancer.
Cancer was detected in 8.2% of those screened and in 4.8% of
controls. For the first six years of follow-up, mortality rates
from prostate cancer remained much the same in the two groups, but
then a divergence in favor of screening began and the
rate ratio for death from prostate cancer was
significantly reduced at 0.80. A 20% reduction in prostate
cancer mortality sounds important but, put another way, the data
mean that 48 additional men would need to be treated to prevent
1 death from cancer of the prostate. Furthermore, in 75.9% of
the men who did have a biopsy because of a raised PSA , the PSA
result turned out to be a false positive. Overdiagnosis and
overtreatment remain major obstacles in the path to any official
policy of PSA screening. The smaller U.S. Prostate, Lung,
Colorectal, and Ovarian Cancer Screening Trial (PLCO, paper #11)
is looking negative, at least so far. Although screening picked
up prostate cancer at a 22% higher rate, no significant
difference in prostate cancer mortality emerged.
Neither the U.S.A. nor the U.K. has a national screening program
for this cancer. In both countries the emphasis is on full
disclosure of information to men who ask for a PSA test, and last
summer the U.K.’s information pack was altered to take into
account the two papers now under discussion. Nonetheless there is a
wide perception that PSA testing is more established in the U.S.A.
than on the other side of the Atlantic. Surveys suggest that most
men over 40 in the U.S.A. will have had a PSA test (L.E. Ross,
et al., J. Natl. Med. Assoc., 10[4]: 316-24,
2009) and that 87% of U.S. male physicians over 50 seek testing
(E.C. Chan, et al., J. Gen. Intern. Med., 21[3]:
257-9, 2006). This complicates the interpretation of the American
study (#11) because controls can hardly be barred from asking for
the test outside the trial. Indeed, 44% of all those taking part
had already been tested before the trial began and many controls
were tested later. This unavoidable complication of the
trial’s design (known as contamination) could have diluted a
real benefit of screening. Such dilution, however, happened in the
European study also. When the ERSPC data were re-analyzed with
adjustment for both contamination and non-attendance at the initial
screening round, the benefit of screening in respect of prostate
cancer death increased to 29-31% (M.J. Roobol, et al.,
Eur. Urol., 56[4]: 584-91, 2009). Of other explanations
that might account for the apparent lack of screening benefit, the
most important in the opinion of the U.S. trialists (#11) could be
improved treatment for prostate cancer, leading to fewer deaths in
both groups.
To summarize these important trials as positive (#10) and negative
(#11) is probably too simple because both will yield more data with
longer follow-up and more endpoints (a further six years is planned
for PLCO). Indeed, the confidence interval for the principal
endpoint in the "negative" U.S. study encompasses the "positive"
finding in the European one. NEJM’s editorialist,
Dr. Michael J. Barry (360[13]: 1351-4, 2009) questions publication
of this unfinished business, noting that there was neither a clear
declaration of futility in the PLCO trial nor an unambiguous net
benefit in the ERSPC trial." When Science Watch asked
Prof. Fritz. H. Shröder (ERSPC, Erasmus Medical Center,
Rotterdam, Netherlands) why the PLCO And ERSPC findings were
different, he too drew attention to contamination but also noted
the shorter follow-up and smaller sample size of PLCO (ERSPC was
more than twice the size). "The power calculation which was a
crucial issue of discussion with the editors of NEJM, with
respect to the ERSPC paper, is not even mentioned in the PLCO
paper," Schröder told SW. Whether interim findings
should (or, indeed, could) be kept under wraps is often
controversial. With PLCO it was the independent data and safety
monitoring board that urged publication. Either way, evidence from
randomized trials is more reliable than the superficially
persuasive fact that, compared with U.K. experience, prostate
cancer mortality in the U.S.A. fell more rapidly over the decade
1994 to 2004 when PSA testing was introduced into that country
(S.M. Collin, et al., Lancet Oncol., 9[5]:
445-52, 2008).
A former deputy editor of The Lancet, David W.
Sharp, M.A. (Cambridge) is a freelance writer living in
Minchinhampton, U.K.
Medicine
Top 10 Papers
Rank
Paper
Citations
This Period
(Jul-Aug 09)
Rank
Last Period
(May-Jun 09)
1
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pluripotent
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Madison; U. Wisconsin, Madison]
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The ONTARGET Investigators
(S. Yusuf,
et al.), "Telmisartan,
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67
4
4
The ADVANCE Collaborative Group (A.
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blood glucose control and vascular
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2
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62
2
5
J.M. Llovet, et al.,
"Sorafenib in advanced
hepatocellular carcinoma," New
Engl. J. Med., 359(4): 378-90,
24 July 2008. [22 institutions
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51
7
6
R.R. Holman, et al.,
"10-year follow-up of intensive
glucose control in type 2
diabetes," New Engl. J.
Med., 359(15): 1577-89, 9
October 2008. [6 U.K. institutions]
*358FS
45
6
7
R.M. Klevens, et al.,
"Invasive methicillin-resistant
Staphylococcus aureus
infections in the United States,"
JAMA, 298(15): 1763-71, 17
October 2007. [11 U.S.
institutions] *220WF
44
†
8
Cancer Genome Atlas Research
Network (L. Chin, et al.),
"Comprehensive genomic
characterization defines human
glioblastoma genes and core
pathways," Nature,
455(7216): 1061-8, 23 October 2008.
[60 institutions worldwide] *363FG
44
†
9
S.D. Wiviott, et al.,
"Prasugrel versus clopidogrel in
patients with acute coronary
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Med., 357(20): 2001-15, 15
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39
†
10
F.H. Schröder , et
al., "Screening and
prostate-cancer mortality in a
randomized European study," New
Engl. J. Med., 360(13):
1320-8, 26 March 2009. [15
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