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Pre- and postnatal testosterone administration induces proliferative epithelial lesions with neuroendocrine differentiation in the dorsal lobe of the rat prostate

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The Prostate 40:135–136 (1999)
Letter to the Editor
Reply to Labrie et al.
To the Editor:
It is good to see the results of the mortality analysis
of the Quebec Randomized/Controlled Trial (RCT) of
screening [1] in a peer review journal so that all those
who have been awaiting the details can make informed judgments of the strength of the evidence. Any
investigators who find that compliance with the intervention in one arm of an RCT is just 23% are in an
extremely difficult situation. Whilst sympathizing
with this problem, I am very concerned that this report may 1) seriously mislead clinicians by providing
exaggerated estimates of the mortality benefit which
can be achieved by screening for prostate cancer, and
2) lead statisticians, epidemiologists, and clinicians to
lose some of their respect for randomized clinical trials
as the evidential gold standard.
The clear focus of this paper is on complex comparisons of subgroups of men whose comparability is
not justified by randomization. It is simply not correct
to assert that this “first randomized and prospective
study on prostate cancer screening shows a 69% decrease in incidence of deaths due to prostate cancer.”
This 69% reduction is from a nonrandomized comparison and, moreover, one which is, as I shall show
below, subject to serious and substantial selection bias.
It is also false to say that the “analysis is thus made on
an intent-to-treat basis from the time of enrollment”—
false because the analysis is not “intent-to-treat,” and
false too since major problems lie with the identification of the time when the follow-up clock starts ticking. In fact, it is November 15, 1988 for unscreened men
in each arm of the trail, but date of first screen for the
screened men; it is clear that this makes a major difference, since the respective mean follow-up times are
7.4 and 7.5 years for unscreened men in the invited
and control arms but 3.8 and 4.3 years for the two
groups of screened men (Fig. 1A). This is the source of
the most important selection bias in the present analysis: men in the screened cohorts (groups a and c of Fig.
1A) have the additional selection criteria that they
were available for screening and hence were free of
diagnosed prostate cancer at a mean time of around 3
years after the time of enrollment of the unscreened
men (groups b and d). Since rates of death from (prostate) cancer in an initially disease-free population are
© 1999 Wiley-Liss, Inc.
strongly associated with year of follow-up for several
years, the comparisons of prostate cancer mortality in
groups a/b and groups c/d are both subject to large
bias which cannot be quantified using the published
data. However, crude examination of the Scottish survival data for prostate cancer cases diagnosed 1983–
1986 suggests that differences of follow-up could lead
to a 43% reduction in mortality rates in the screened
groups. The fact that the two comparisons (a with b
and c with d) give similar estimates of the benefit of
screening is of no help and no relevance. The quoted
figure of 69% benefit is based on these comparisons, is
subject to unmeasured bias, and should in our opinion
be disregarded.
An “intent-to-screen” analysis is required because
individuals who choose to accept screening differ
from those who do not in many characteristics, including socioeconomic status, perceived health status, and
comorbidity. Analyses which compare “acceptors”
with “nonacceptors” have yielded inflated estimates
of benefit for other cancer screenings [2]. Here [1] the
“intent-to-screen” analysis was conducted with more
scientific rigor, although the poor compliance rate argues against its results giving a meaningful estimate
of the benefit which screening can make. It would
have been sensible to retain the exclusion criteria, especially prior diagnoses of prostate cancer, as is standard for screening trials, and we follow this practice
below, since full data from the excluded men are not
available. The “start-time” problems emerge again,
and examination of them will serve (Table I) to illuminate what we have described above. Analyses of the
data in Figure 1B as rates of death/1,000 men give, as
the authors say, an estimate of 6% benefit in the “invited” arm. However, repeating this analysis as rate/
1,000 person-years (which is preferable) estimates a
4% higher death rate in the invited arm if the personyears of Figure 1A are used. “Correcting” the personyears in groups a and c to take account of the time
from November 15, 1988 to the first screen reconciles
this apparent discrepancy.
*Correspondence to: Freda E. Alexander, Department of Public
Health Sciences, University of Edinburgh Medical School, Edinburgh EH8 9AG, Scotland, UK.
Received 10 March 1999; Accepted 10 March 1999
136
Alexander and Prescott
TABLE I. Intent-to-Screen Analysis
Deaths
Men (deaths/103 men)
Person-years, Figure 1A (deaths/104 person-years)
Corrected person-yearsb (deaths/104 person-years)
Invited
Control
RRa
140
31,290 (4.47)
202,697 (6.91)
228,368 (6.13)
73
15,432 (4.73)
110,067 (6.63)
113,203 (6.45)
0.946
1.041
0.951
a
Risk ratio of invited arm, with control arm as reference.
Multiplying the person-years of Figure 2A in group a by 7.4/3.8 and group c by 7.5/4.3.
b
In their description of the intent-to-screen analysis
in Methods [1], the authors claim to have applied the
method of Cuzick et al. [3] to adjust for noncompliance and contamination; they have not done so. Such
adjustment would have been much more complex
than the example provided [3], since “modelling noncompliance and contamination which occurs during
follow-up is more difficult.” Nevertheless, we believe
the methods of Cuzick et al. [3] could be applied to
these data, with all men entering on November 15,
1988 and changing their status as they receive an invitation to screening and decide whether to accept (invited arm) or find screening for themselves (control
arm). Unless and until we see the results of such
analyses, the scientific community will still have little
guidance from the Quebec study on the effect of prostate cancer screening on mortality from the disease,
and the long history of scientific integrity of the RCT
will be soiled.
Freda E. Alexander*
Robin J. Prescott
Department of Public Health Sciences
University of Edinburgh Medical School
Edinburgh, Scotland, UK
REFERENCES
1. Labrie F, Candas B, Dupont A, Cusan L, Gomez JL, Suburu RE,
Diamond P, Levesque J, Belanger A. Screening decreases
prostate cancer death: first analysis of the 1988 Quebec Prospective Randomized/Controlled Trial. Prostate 1999;38:
83–91.
2. Moss SM, Summerley MC, Thomas BT, Ellman R, Chamberlain
JOP. A case-control evaluation of the effect of breast cancer screening in the United-Kingdom Trial of Early Detection
of Breast Cancer. J Epidemiol Community Health 1992;46:362–
364.
3. Cuzick J, Edwards R, Segnan N. Adjusting for non-compliance
and contamination in randomized clinical trials. Stat Med 1997;
16:1017–1029.
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neuroendocrine, dorsal, induced, pre, administration, rat, lobel, epithelium, lesions, differentiation, testosterone, proliferation, postnatal, prostate
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