2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Table 2. Criteria for Implementation of a Screening Program
Applied to Prostate Cancer Screening*
Criteria for Screening
An important health problem
Recognizable latent or early asymptomatic stage
Available suitable test with agreed-upon cutoff values
Test acceptable to the population
Natural history of the detected lesions understood
Preferential detection of lesions likely to progress
Available, accepted treatment
Available facilities for diagnosis and treatment
Agreed-upon policy on whom to treat
Strong evidence (RCTs) of mortality/morbidity reduction
Benefits proven to outweigh harms
Quality assurance standards in place (including monitoring)
Affordable (cost-effectiveness)
* Adapted from www.screening.nhs.uk/criteria/fileid9287.
no standard clinical policy on whom to treat, strong evidence
(RCTs) of mortality/morbidity reduction does not exist, and
benefits have not been proven to outweigh harms.
Evaluation of PSA Screening for Prostate Cancer:
Prostate Cancer Mortality
Five RCTs of PSA prostate cancer screening (either alone
or in conjunction with another modality) have reported
prostate cancer mortality results. 6 A 2010 meta-analysis of
those studies generated a summary risk ratio of 0.88 (95%
CI: 0.71–1.09), indicating no statistically significant benefit
of PSA screening. 6 The meta-analysis included ERSPC 7 and
PLCO, 8 the two largest and most influential RCTs of prostate
cancer screening. ERSPC, which randomly selected in
excess of 180,000 men ages 50 to 74 from 1991 to 2003,
reported a 20% prostate cancer relative mortality reduction
(95% CI: 0.67–0.98) with screening using the core group of
men ages 55 to 69 (more than 160,000), although the
prostate cancer mortality reduction was not statistically
significant in the entire study population (rate ratio: 0.85,
95% CI: 0.73–1.00). PLCO, which randomly selected almost
77,000 men ages 55 to 74 from 1993 to 2001, reported a
nonsignificant 9% (95% CI: 0.87 to 1.36) increase in prostate
mortality with screening after 13 years of follow-up. Both
trials, however, demonstrated clinically important levels of
harm associated with diagnostic evaluation of positive
screens and treatment of screen-detected prostate cancers.
Neither ERSPC nor PLCO was perfect. As to be expected,
researchers with an a priori belief that prostate cancer
screening is warranted believe that ERSPC’s shortcomings
are not fatal, but those who take a more negative view of
prostate cancer screening feel that PLCO is the stronger of
the two trials. Those who make their decisions based on
systematic evidence reviews, such as the Task Force, look at
the evidence base as a whole and conclude that although a
small benefit of PSA screening may be possible, the harms
that can follow may outweigh that potentially small benefit.
ERPSC was a multicenter trial: Finland, Switzerland,
Italy, the Netherlands, Belgium, Switzerland, Spain, Portugal,
and France participated, although data from the latter
two countries were excluded from the initially published
analyses. Given the unique characteristics of health care in
each country, intervention arm participants had different
experiences and access to different diagnostic evaluation
procedures and treatments. The screening interval varied by
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country (2 to 7 years), as did the use of additional modalities
and the PSA value that defined a positive screen. In the
Netherlands, Belgium, Switzerland, and Spain, randomization
occurred after informed consent was received, but in
Finland, Switzerland, and Italy, potential subjects were
identified using population registries and randomly selected,
and then those selected for screening were asked to
provide written informed consent, thus raising the question
of whether two equivalent arms were produced. A substantial
number of men randomly selected for the control arm
were unaware of their participation in the trial, so they were
less likely to receive cutting-edge treatment, in particular,
radical prostatectomy, because they had no relationship
with the screening centers, which were academic centers. It
has been demonstrated that participants in the screened
arm were more likely to receive therapy with curative
intent. Therefore, it is unclear whether screening led to a
reduction in mortality or whether differences in the treatment
were responsible.
PLCO’s randomization was more likely than ERSPC’s to
have produced equivalent screening arms, as all participants
signed their informed consent forms before they were
randomly selected. Furthermore, all 10 PLCO centers used
the same criterion to define a positive PSA screen, and
control participants knew they were in the trial and had a
relationship with the specialty medical center where the
intervention arm participants were screened. PLCO’s
“Achilles’ heel” was a high rate of PSA screening in the
control arm. The trial had been designed to have 90%
statistical power to detect a 20% reduction in prostate
cancer mortality in the presence of no more than 20%
noncompliance (i.e., screening) in the control arm, but actual
noncompliance, measured annually, was between 40% and
54% at particular screening years. Given that rate of noncompliance,
PLCO’s statistical power was 90% for a mortality
reduction no smaller than 40%, which may be unrealistic
for PSA screening.
Evaluation of PSA Screening for Prostate Cancer:
Harms
Although ERSPC and PLCO came to different conclusions
about whether PSA screening could reduce prostate cancer
mortality, they both did come to the conclusion that screening
could lead to nontrivial levels of adverse events due to
diagnostic evaluation and treatment. They also both indicate
that overdiagnosis occurs with prostate cancer screening.
PSA screening itself, which requires a blood draw, has
infrequent side effects, and the ones that do result—infection
at the draw site, vasovagal reaction, discomfort—are
considered to be minor. However, adverse events associated
with prostatic biopsy are of more concern. In PLCO, almost
13% of men had at least one false-positive PSA exam and of
those, more than 5% had a biopsy dictated by that exam 9 ;at
the Netherlands ERSPC site, 50% of men who had a biopsy
as a result of a positive exam had hematospermia, 23% had
hematuria, and 4% had fever. 10 In addition, there are
reports of a recent and consistent increase in urosepsis with
resistant organisms for men undergoing PSA-motivated
prostatic biopsy. Surveillance, Epidemiology, and End Results
(SEER)-Medicare data indicate that the rate of hospitalization
for biopsy-related infection within 30 days of that
biopsy has quadrupled, from about 0.25% before 2001 to
more than 1% in 2007. 11 Hospitalizations also occur for