CNBH
Association Française d’Urologie
Collège National de Biochimie des Hôpitaux
Société Française de biologie Clinique
Société française de médecine Nucléaire – Groupe de Biologie Spécialisée
GROUPE DE BIOLOGIE DE LA PROSTATE
Niveaux de preuves pour l’utilisation du PSA et des autres
biomarqueurs dans la détection précoce du cancer de la
prostate
Review of evidence for the use of PSA and other
biomarkers in the early detection of prostate cancer
Coordonnateur du groupe de travail: Pierre-Jean Lamy1
pierre-jean.lamy@icm.unicancer.fr
Et
Anne-Sophie Gauchez2 asgauchez@chu-grenoble.fr
Laurent Salomon 3 laurent.salomon@hmn.aphp.fr
Margaret Haugh4 mhaugh@medicom-consult.com
Jocelyn Ceraline5 jocelyn.ceraline@chru-strasbourg.fr
Yvonne Fulla6 yvonne.fulla@gmail.com
1
Agnès Georges7 agnes.georges@chu-bordeaux.fr
Stéphane Larré8 stephanelarre@yahoo.fr
Sylvain Loric9 sylvain.loric@hmn.ap-hop-paris.fr
Elisabeth Luporsi10 e.luporsi@nancy.unicancer.fr
Pierre-Marie Martin11 pierre-marie.martin@mail.ap-hm.fr
Catherine Mazerolles12 mazerolles.c@chu-toulouse.fr
Vincent Molinié13 vincent.molinie@chu-fortdefrance.fr
Pierre Mongiat-Artus14 pierre.mongiat-artus@sls.aphp.fr
Jacques Piffret15 jacques.piffret@orange.fr
François Thuillier16 thuillierfrancois@sfr.fr
Paul Perrin17 paul.perrin@chu-lyon.fr
Xavier Rebillard18 xavier.rebillard@wanadoo.fr, et le groupe de relecture du biologie
de la prostate : Drs, David Azria, Maguy Bernard, Karim Chick, Cyril Clavel,
Stéphane Culine, Olivier Cussenot, Alexandre de la Taille, Aurélien Descazeaud,
David Guenet, François Iborra, Jacques Irani, Igor Latorzeff, Marie-Pierre Moineau,
Didier Peiffert, Pierre Richaud, Jean Marc Riedinger, Pascal Rischmann, François
Rozet, Corinne Sault, Virginie Vlaeminck-Guillem.
1
Biologie Spécialisée et Oncogénétique, CRLC Val d’Aurelle, Montpellier France
2
UMR-S INSERM 1039, Institut de Biologie et de Pathologie CHU Grenoble, France
3
Service d'Urologie, APHP CHU Henri Mondor, Créteil, France
4 MediCom
Consult, Villeurbanne, France
5 UMR_S
1113, FMTS, Université de Strasbourg, Strasbourg, France
6 Société
Française de Médecine Nucléaire, Paris, France
7 Médecine
8 Service
9
Nucléaire, CHU Bordeaux, France
d'urologie, CHU de Reims, Reims, France
Biochimie clinique et génétique, APHP CHU Henri Mondor Créteil, France
10
Service d’Oncologie, Centre Alexis Vautrin, Nancy, France
2
11
Laboratoire de Transfert d’Oncologie Biologie, APHM, Marseille, France
12
Laboratoire d'Anatomie et Cytologie Pathologiques, IUCT Oncopole 1, Toulouse, France
13
Laboratoire d'Anatomie et Cytologie Pathologiques CHU La Meynard Fort de France, France
14
Service d'urologie, APH, CHU Saint-Louis, Paris, France
15
Association Française d’Urologie, Paris, France
16
Société Française de Biologie Clinique, Collège National de Biochimie des Hôpitaux Paris, France
17
Service d'urologie, Hôpital Lyon-Sud, Hospices Civils de Lyon, Lyon
18
Clinique Beausoleil, Montpellier, France
3
RESUME
Contexte: Malgré des preuves contradictoires sur le bénéfice de l'utilisation de
l'antigène prostatique spécifique (PSA) pour la détection précoce du cancer de la
prostate celui-ci est actuellement largement utilisé. De nouveaux biomarqueurs
visant à améliorer la valeur prédictive du PSA sont également utilisés.
Objectif: Examiner systématiquement les données scientifiques sur l'utilisation du
PSA et d'autres biomarqueurs pour la détection précoce du cancer de la prostate.
Acquisition des données: nous avons cherché dans PubMed les essais cliniques et
des études publiés entre 2000 et mai 2013, évaluant le PSA et d'autres
biomarqueurs pour la détection précoce du cancer de la prostate, étude qui
comprenait plus de 200 sujets. Le niveau de preuve de l’utilité clinique a été évalué
en utilisant un système d’évaluation spécifique aux marqueurs tumoraux. Un total de
84 publications, correspondant à 70 essais et études ont été sélectionnés pour cette
revue.
Synthèse: Six essais cliniques randomisés évaluant le PSA ont été identifiés, mais
quatre présentaient des faiblesses méthodologiques. Bien que ces essais aient
inclus un grand nombre de sujets avec un long suivi, leurs résultats présentent des
limites qui sont dues à la contamination (par des dosages antérieurs du PSA) dans le
groupe de contrôle, à la qualité du suivi de ce groupe et de la variabilité dans les
méthodes. Malgré ces limites, nous avons attribué un niveau de preuve IA (le plus
élevé) pour l’utilisation du PSA pour la détection précoce, mais nous ne
recommandons pas son utilisation dans le dépistage de masse. Les biomarqueurs
émergents ont été évalués dans les études cas-témoins et de cohorte prospectives:
PCA3 (n = 3); kallicréines (n = 3); [-2] ProPSA n = 5); oncogènes de fusion (n = 2).
Ces études ont utilisé les résultats des biopsies pour le cancer de la prostate pour
4
déterminer la spécificité et la sensibilité des tests, mais elles n’ont pas évalué l'effet
sur la mortalité. Le niveau de preuve attribué était III-C, insuffisant pour une
utilisation en clinique.
Conclusions: Le PSA peut être utilisé pour la détection précoce du cancer de la
prostate, mais le dépistage de masse n’est pas recommandé. Les études sur
d'autres biomarqueurs suggèrent qu'ils pourraient être utilisés, individuellement ou en
combinaison, pour améliorer la sélection des patients avec des niveaux élevés de
PSA en vue de la réalisation d’une biopsie, mais des essais cliniques évaluant leur
impact sur la gestion du cancer de la prostate et sur la mortalité sont nécessaires.
ABSTRACT
Context: Despite conflicting evidence for the benefit of using of prostate specific
antigen (PSA) screening in the early detection of prostate cancer (PCa), is currently
widely used. New biomarkers aiming to improve the predictive value of PSA are also
used.
Objective: To systematically review the evidence for the use of PSA and other
biomarkers in the early detection of prostate cancer.
Evidence acquisition: We searched PubMed for clinical trials and studies assessing
PSA and other biomarkers in the early detection of prostate cancer, published
between 2000 and May 2013 that included >200 subjects. The level of evidence
(LOE) for clinical utility was evaluated using the tumor marker utility grading system.
A total of 84 publications, corresponding to 70 trials and studies were selected for
inclusion in this review.
5
Evidence synthesis: Six randomised controlled trials (RCTs) assessing PSA were
identified but four were found to have methodological weaknesses. Although these
trials included large numbers of subjects and long-term follow-up, their limitations
include contamination in the control group, lower quality follow-up in this group and
variability in methods. Despite these limitations, we attributed a level of evidence
(LoE) of IA to PSA for early PCa detection, but we do not recommend its use in mass
screening. Emerging biomarkers were assessed in prospective case-control and
cohort studies: PCA3 (n=3); kallikreins (n=3); [-2]proPSA n=5); fusion oncogenes
(n=2). These studies used biopsy results for prostate cancer to determine specificity
and sensitivity, but they did not assess the effect on PCa mortality. The LoE
attributed was III-C.
Conclusions: PSA can be used for early prostate cancer detection but mass
screening is not recommended. Studies on other biomarkers suggest that they could
be used, individually or in combination, to improve the selection of patients with
elevated PSA levels for biopsy, but RCTs assessing their impact on prostate cancer
management and mortality are needed.
6
Message pour les patients: Dans cette étude nous avons recherché quelles sont
les preuves scientifiques pour l’utilisation du PSA et des autres biomarqueurs pour
détecter précocement un cancer de la prostate.
Le PSA reste le marqueur diagnostique standard du cancer de la prostate. Plus le
PSA est élevé plus le risque du cancer est grand. A des niveaux élevés (> 10ng/mL),
il y a un intérêt non discutable de rechercher un cancer par biopsie.
Nous n’avons pas de preuves permettant de valider un dépistage de masse utilisant
le PSA. Pour les autres biomarqueurs, les données suggèrent un intérêt de leur
utilisation dans la sélection des patients avec un PSA élevé qui auraient besoin d’une
biopsie. Néanmoins cela doit être confirmé dans des essais cliniques dédiés.
Patient summary: In this study, we reviewed evidence for the use of PSA and other
biomarkers for the early detection of prostate cancer.
PSA remains the standard diagnostic biomarker in prostate cancer. PSA level is a
continuous risk factor of prostate cancer. At high levels (>10ng/mL) the need for
further investigation, e.g. biopsy is generally accepted.
We did not find any evidence to support mass PSA screening. Data for other
biomarkers suggest that these may have a role to play in selecting subjects with
elevated PSA levels for biopsy but well-designed RCTs assessing their impact on
prostate cancer management are needed.
7
Introduction
Prostate cancer is the second most frequently diagnosed cancer in men worldwide
(899 000 new cases, 13.6% of the total) and the fifth most common cancer overall.
More than 70% of the cases occur in developed countries (644 000 cases). The
incidence of prostate cancer varies worldwide, with the highest rates observed in
Australia/New Zealand (104.2 per 100,000), and the lowest in South-Central Asia
(4.1 per 100 000). Incidence rates are relatively high in some developing regions
such as the Caribbean islands, South America and sub-Saharan Africa. This variation
can be partly explained by differences in prostate specific antigen (PSA) testing and
subsequent biopsies that are more frequently performed in countries with the highest
incidence.
With an estimated 258 000 deaths in 2008, prostate cancer is the sixth cause of
cancer death in men (6.1% of the total). Because PSA testing has a much greater
effect on the incidence of prostate cancer than on its mortality rate, there is less
variation in mortality rates worldwide (10-fold) than observed for incidence (25-fold).
Prostate cancers, which occur mainly in older men, are often slow growing. The
worldwide weighted mean of the age-specific rates (ASR (W)) for prostate cancer
mortality in developed regions is only twice that in developing regions (10.5 vs 5.6,
respectively). These rates are generally higher in predominantly black populations
(Caribbean, 26.3 per 100,000 and sub-Saharan Africa, 18-19 per 100 000), and very
low in Asia (e.g. 2.5 per 100 000 in Eastern Asia) and intermediate in Europe, North
America and Oceania.
In Europe the incidence of prostate cancer is 59.3 per 100 000, with a mortality rate
of 12.0 per 100 000. In France and the UK the mortality rates are similar, 12.7 and
8
13.8 per 100 000, respectively but the incidence is almost twice as high (118.3 and
64.0 per 100 000, respectively). This difference in the apparent incidence of prostate
cancer may be explained by the fact that in France 50% of men ≥50 years have
undergone PSA testing, compared with 10% in the UK.
The impact of PSA testing on the incidence of prostate cancer detection was
demonstrated through the surveillance of the incidence of prostate cancer in the US
[1]. The introduction of PSA testing in the US resulted in an increase in the incidence
of prostate cancer from 140/100 000 in 1987 to 240/100 000 in 1993. After this peak,
there was a reduction in the incidence of detected prostate cancer to 170/100 000,
because there were no more ‘undetected’ cancers, just new cancers developing. This
incidence remains, nevertheless, higher than that prior to the introduction of PSA
testing in 1987.
PSA is a glycoprotein that is produced mainly in the prostate epithelial cells. In
healthy men, PSA is generally concentrated in prostatic tissue and serum PSA levels
are very low. PSA is an organ-specific marker rather than tumour specific and serum
levels can be elevated in the event of various non-malignant (e.g. benign prostatic
hyperplasia (BPH), prostatitis, trauma) and malignant prostatic diseases. Increasing
levels of serum PSA have been shown to be associated with a higher risk of prostate
cancer [2]. However, there is no clear-cut point that can differentiate insignificant
cancers, which are not likely to be life-threatening, from those that are significant and
likely to be life-threatening [2].
Screening can help to detect chronic diseases and cancers in people before they
develop symptoms with the aim of being able to offer treatment before it is too late. In
1968 the World Health Organisation (WHO) commissioned a report on screening
which, at that time, was becoming an important but controversial topic [3]. The report
9
listed criteria for screening. Over the years, other criteria have been proposed but
they are mainly based on the WHO criteria [4]. One of these recent criteria is that
there should be strong scientific evidence that the screening program is effective.
From a public health point-of-view, the aim of prostate cancer screening is to improve
overall survival and from an individual point-of-view, the aim is to increase prostate
cancer disease-free survival and decrease the prostate cancer-specific mortality rate.
In the USA prostate cancer screening began in the eighties when the majority of
patients were diagnosed with advanced prostate cancer and a poor survival rate.
Screening resulted in prostate cancer being detected at earlier stages and therefore
the patients had higher disease-free survival rates. In addition, the lower PSA
threshold introduced and the increased number of biopsy cores resulted in the
detection and treatment of a large number of patients with low-volume and low-grade
tumours [5]. Prostate cancer screening is now widely used in the developed world,
although the scientific evidence supporting its benefits is controversial. One of the
controversies concerns the choice between mass screening, i.e. offering screening to
all men after a certain age, or targeted or individual screening, i.e. proposing
screening to men ‘at risk’, also known as ‘early detection'. Another controversy
concerns the PSA cut-point since many studies have shown that there is a continuum
of prostate cancer risk at all values of PSA and no cut-point with a simultaneously
high specificity and high sensitivity [6, 7]. Even at low PSA levels, e.g. 2.1 ng/mL, the
results from Prostate Cancer Prevention Trial (PCPT) showed a sensitivity of 52.6%
and a specificity of 72.5%. It is possible that some of the emerging biomarkers could
improve the specificity of PSA and other prognostic factors and thus help in the
management decision.
10
As part of an overall review on the role of PSA and other emerging biomarkers in
detection, diagnosis and treatment of prostate cancer, we present here a review of
the literature on the use of PSA and other biomarkers in the early detection of
prostate cancer with an assessment of the level of evidence [8].
Methods
PubMed was searched using combinations of the terms given in Table 1 to identify
publications in English or French and published between 01/01/2000 and 06/05/2013
that evaluated PSA and other biomarkers in prostate cancer. This search was for a
global systematic review to cover the use of biomarkers for early detection,
prognosis, and prediction. In this manuscript only the results for the use of
biomarkers in the early detection of prostate cancer are presented. The titles and
abstracts of the references were screened to identify potentially pertinent references
for the global review. A second screen on the titles and abstracts of references
selected in the first screen was performed to identify potentially pertinent references
for the present analysis on early detection of prostate cancer. Full papers were then
obtained and relevant papers were selected to correspond to the following
categories:

Early detection with PSA in randomised clinical trials (RCTs)

Early detection with PSA in systematic reviews/meta-analyses

Early detection with PSA in ‘real-life’ studies

Early detection with PSA in prospective cohort studies

Early detection with emerging biomarkers

International guidelines for early detection of PSA
11
In addition, the co-authors were asked to provide details of studies they knew about
that had not been detected in the PubMed search and reference lists of included
publications were scanned to identify other studies. Studies were eligible if they
included > 200 men as smaller studies would be underpowered. For PSA, only
randomized clinical trials or prospective cohort studies were included, since we knew
that large randomized clinical trials were available. For the other biomarkers, we
included randomized clinical trials and prospective and retrospective cohort studies.
We did not include studies assessing genetic testing since these require biopsy
tissue and are, therefore, not used in early detection of prostate cancer. The study
characteristics and results were extracted into tables and verified by at least two of
the authors.
Results
A total of 5825 publications were retrieved from the PubMed search and 75 additional
publications were identified either by the authors or in the reference lists of included
studies (Figure 1). A total of 2256 publications were selected after the initial screen
on titles and abstracts; these were then rescreened to select potential publications for
this review on biomarkers in early detection. The PDFs were obtained for 254 articles
for more detailed screening. Finally, 70 studies were selected for inclusion in this
review (Figure 1).
Total PSA in early detection of prostate cancer in RCTs
Although we identified five randomized clinical trials, only two were retained for
analysis because the other trials had major flaws in their design resulting in high risk
of bias. In the Stockholm trial, the participants were not randomly selected and so are
not representative of the population [9, 10]. In addition, this study was carried out
12
many years ago and used diagnostic methods that are no longer used. Both the
Stockholm study and the Norrkoping study reported a 10-fold higher risk of prostate
cancer than the other studies so that their results are not generalizable to other
countries [9-11]. The results from the Norrkoping trial are not comparable with the
other trials because the criteria used was cytology [11]. The study performed in
Quebec was judged to have a risk of bias due to no concealment of allocation and
results not given from an intention-to-treat analysis [12].
The characteristics, quality assessment and results of the two trials included, the
American Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial
and the European Randomized Study of Screening for Prostate Cancer (ERSPC) are
summarized in Tables 2, 3 and 4 [13-40]. The individual countries in the ERSPC trial
had their own specificities in terms of the methods used (Table 2). The PLCO trial did
not compare early detection with no early detection as there was a very high rate of
opportunistic screening in the ‘unscreened’ group. This can be considered as a
comparison of intense screening vs. less intense screening [5, 41]. In contrast, the
ERSPC trial, which was conducted in countries where PSA testing is generally far
less prevalent, reported a reduction in prostate-cancer mortality. Over time, the size
of the reduction has continued to increase; however, the number needed to screen
and the number needed to detect to prevent one death from prostate cancer are
1,055 and 37, respectively [14]. An analysis of the data at 11 years suggest that for
every 1000 men who have a PSA test, 35.1 more cancers will be detected and 1
additional prostate cancer death will be prevented. It was calculated that to detect
these cancers in the screening group, 267 biopsies and 56 prostatectomies would
have to be performed.
13
The 95% confidence interval for prostate cancer mortality for both trials overlap
(0.87–1.36 for PLCO; 0.68–0.91 for ERSPC); the overlap of the 95% confidence
intervals, suggest that the trial results are not heterogeneous.
- LOE for total PSA in early detection of Pca: Ia
- Comments: there is a small effect or no effect on PCa mortality
Total PSA in early detection of prostate cancer: systematic review / metaanalyses
Two systematic reviews of RCTs assessing PSA in early detection have been
published (Table 5) [42, 43]. The methods used in the trials included in these reviews
differed and many methodological concerns were reported. No statistically significant
reduction in prostate cancer-specific mortality was observed: RR=0.88 (95% CI=0.71
– 1.09) and RR=0.95 (95% CI=0.85 – 1.07). There was significant heterogeneity
when all trials were analysed together; this disappeared when the trials judged to be
at a high risk of bias were removed in one of the meta-analysis, but the reduction in
prostate cancer-specific mortality remained non-significant: RR=0.89 (95%CI=0.77 –
1.04) [43]. The authors of one of the reviews concluded that there was no evidence
from randomised clinical trials to support the routine use of screening for prostate
cancer with PSA (with or without digital rectal examination (DRE) [42]. The
conclusions on the other paper were that since any benefits from prostate cancer
screening may take >10 years to accrue, men with a life expectancy of <10-15 years
should be informed that screening for prostate cancer is not beneficial and can be
harmful [43].
Total PSA in early detection of prostate cancer: ‘real-life’ studies
14
Three studies assessing PSA for early detection of prostate cancer in ‘real-life'
settings were identified; one from the US, one from Austria and one from Japan
(Tables 6 and 7). No benefit from PSA was observed in the American study, probably
due to the high contamination rate in the control group [44, 45]. In contrast, in the
Austrian study both the before/after comparison in the region where the screening
was performed and the comparison with the whole country showed a reduction in
prostate cancer-specific mortality; 0.70 (95% CI=0.57-0.87) and 0.92 (95% CI=0.870.97), respectively [46, 47]. In the Japanese study, 44% (1 224/2 775) of men
diagnosed with prostate cancer lived in communities with mass screening and the
prostate cancer-specific mortality rates were 32.9% and 56.4% in the communities
with and without mass screening, respectively [48].
Total PSA in early detection of prostate cancer: prospective cohort studies
We identified six prospective studies that assessed PSA for the early detection of
prostate cancer (Tables 8 and 9) [6, 49-55]. These studies included between 300 and
39 213 participants (median: 12 215) and used different techniques for PSA testing
(different tests and different thresholds) and different biopsy protocols. Most of these
studies confirmed that the risk of prostate cancer increased with increasing PSA
levels, although there was no consensus for the cut-point (Table 9). The authors of
one study suggested that there was a continuum of risk and that this should be
communicated to patients and healthcare professional [6, 50]. The smallest study
reported interim results for 300 subjects with families with BRCA1/2 mutations and
therefore, a genetic predisposition. The authors concluded that the results from the
interim analysis suggested that screening men with a genetic predisposition can
allow clinically significant prostate cancer to be detected. These results need to be
15
confirmed with the analysis of the whole cohort. In June 2013, the study was still
recruiting; 2620 subjects had been recruited [56].
Summary of international guidelines for PSA in the early detection of prostate
cancer
The main recommendations from 13 international clinical practice guidelines,
published from 2006 (one guideline) to 2012 (five guidelines) for PSA testing in the
early detection of prostate cancer are summarised in Table 10 [57-70]. These
guidelines were from the US (n=5), Canada (n=1), Japan (n=1), Europe (n=2), UK
(n=2) France (n=1), and Belgium (n=1). None of the guidelines recommended mass
screening, generally because the cost-benefit has not been demonstrated. The
majority of the guidelines recommended individual testing for early detection in
subjects aged <75 years old (with no comorbidities), with a life expectancy of more
than 10 years or in at-risk subjects (family history, ethnic origins, e.g. Afro-West
Indians, Afro-Americans). They also stress the need for the subjects to be informed
before PSA testing.
The recommendation for early PSA testing in men aged from 40 to 50 years old is
becoming more widespread. The rationale for this is that it can help to evaluate and
stratify the prostate cancer risk and therefore adapt the frequency of future testing
based on the estimate risk of prostate cancer. A PSA level of <1 ng/mL seems to be
generally accepted as a standard to define low risk of prostate cancer and therefore
lower frequency or even stopping subsequent PSA testing.
Summary of studies assessing PSA velocity (PSAV) and doubling time
(PSADT)
16
A total of 1 RCT, 15 retrospective cohort studies and a systematic review were
identified assessing the use of PSAV or PSADT for the early detection of prostate
cancer were identified [50, 71-86]. Data for patients in the RCT (PCPT – Finasteride
vs placebo) [50] suggested that PSAV was correlated with a higher risk of cancer at
biopsy in both the placebo and treatment groups. In the placebo arm, the addition of
PSAV in multivariate analysis that included PSA, led to a very small increase in the
area under the curve of the receiving operating characteristic curve (AUROC) for
predicting positive biopsy (0.702 to 0.709).
Four of the retrospective cohort studies from the Rotterdam and Goteborg ERSPC
study centers concluded that PSAV does not provide any advantage over PSA [7477]. The other 11 retrospective cohort studies concluded that PSAV was correlated
with the risk of prostate cancer on biopsy and there was a correlation with the cancer
stage [71-73, 78-85]. Three of the studies also concluded that there was no
correlation between PSADT and the risk of prostate cancer on biopsy [83-85].
One systematic review [86] analyzed 87 articles. They concluded that here is little
evidence that PSAV and PSADT provide additional information above that provided
by total PSA (tPSA) alone.
LOE for the use of PSAV for predicting positive biopsy: IIa (1 ancillary study of a
RCT).
Harms of PSA-based screening for prostate cancer
Data about the harms of PSA-based screening for prostate cancer were reported by
two of the randomized trials that assess the impact of PSA-based screening on
prostate cancer mortality [14, 37]. A false positive was defined as a positive result
and consequent workup with no histopathologic diagnosis of cancer within one year
17
of the screening test. In the entire ERPSC trial, 75.9% of men that underwent a
biopsy because of an elevated PSA value had a false-positive result [14].
In the PLCO trial, after four PSA tests, men had a 12.9% cumulative risk of receiving
at least one false-positive result (defined as a PSA level of ≥4.0 ng/mL and no
prostate cancer diagnosis after 3 years) [37]. Neither of these trials reported data on
the potential psychological harms of prostate cancer screening, such as anxiety, or
its impact on health-related quality of life.
Summary of studies assessing kallikrein 2 (hK2) in the early detection of
prostate cancer
We did not identify any randomised clinical trials assessing the use of kallikrein 2
(hK2) in the early detection of prostate cancer but we identified three prospective
case-control studies (Table 11) [87-89]. Two of these studies included men who had
been referred for biopsy, and the third included men referred because their PSA was
≥4 ng/mL or between, 3-4 ng/mL and they had an abnormal DRE. In this latter study
the results from multivariate analyses showed that the risk of prostate cancer
increased with increasing concentrations of hK2 and hK2/fPSA [87]. One of the other
studies concluded that hK2 concentrations were statistically different in patients with
biopsy-confirmed prostate cancer while the other did not find a statistically significant
difference [88, 89]. In this latter study the ratios f/tPSAS, hK2/fPSA and hK2/(f/tPSA),
but not hK2/tPSA were all statistically significantly different in patients with prostate
cancer compared with those with BPH [89]. Thus, these studies, with the highest
level of evidence identified, showed conflicting results for hK2 used alone. When
used in combination with other measures of PSA there seemed to be some
advantage, but the level of evidence remained low.
18
In addition, we identified 10 retrospective cohort studies and 3 retrospective casecontrol studies (Table 10). The results from some of these studies suggest that hK2
alone or in combination with other markers offers some advantages over PSA for
selection men for biopsy. However, there are conflicting results from other studies. In
addition, many of these studies assessed hK2 in populations with high rates of
prostate cancer, which makes extrapolation to a population undergoing primary early
detection difficult.
LOE for kallikrein 2 (hK2) in the early detection of prostate cancer: conflicting data
with LOE<II.
Studies assessing emerging biomarkers in early detection of prostate cancer
We identified 28 studies assessing other biomarkers: these studies were either
prospective cohort or case-control studies (Table 12) [90-118]. The biomarkers
assessed most often were PCA3 (prostate cancer antigen 3) and PHI (Prostate
Health Index), a composite biomarker involving total PSA, free PSA and –(2)proPSA,
an isoform of free PSA). Generally, the populations included in the studies had high
rates of prostate cancer, which makes extrapolation to a population undergoing
primary early detection difficult. Many studies included men who had already had a
negative biopsy as well as those undergoing first biopsy. In addition, the biomarkers
were often used in combination with different forms of PSA and included in a logistic
regression model or an artificial neural network. The conclusions of the studies were
heterogeneous.
Sixteen studies assessed the PCA3 score in prostate cancer diagnosis in either
prospective cohort or case-control studies using a variety of methods to determine
the PCA3 concentration (Table 11) [101, 103, 104, 109, 111, 114, 116-118]. Almost
19
all studies suggest that PCA3 performs better than PSA. When compared with other
emerging biomarkers, the results were contradictory for PCA3 being better or not.
The ranges for the positive predictive value (PPV) and the negative predictive value
(NPV) in those that reported these values were 50% to 70% and 35% to 90%,
respectively. The studies used a wide range of PCA3 score cut-offs (Table 12).
These studies do not provide evidence for the use of PCA3 for the early detection of
prostate cancer but the results suggest there may be role for PCA3 in deciding which
men with elevated PSA levels should undergo biopsy.
LOE of PCA3 in patient selection for a second biopsy: II-b
Five studies assessed pro-PSA (Table 12) [99, 102, 107, 112, 113]. These studies
concluded that pro-PSA, in combination with other forms of PSA, could improve the
detection of men more likely to have prostate cancer and thus reduce the number of
unnecessary biopsies. However, the studies reported the AUROC and there were no
clear cut-points. The men included in these studies had a high level of PSA and
therefore had a high risk for prostate cancer; they were not representative of
populations that would be targeted for early detection.
LOE for PHI in patient selection for a second biopsy: II-b
Five studies assessed the role of fusion proteins in men who had undergone PSA
testing and/or biopsy [104-106, 108, 115]. One study reported a positive predictive
value (PPV) of 0.94 and a negative predictive value (NPV) of 0.6 but 70% of the
patients had prostate cancer [104]. Two studies reported that diagnostic accuracy
increased when the fusion proteins were combined with other biomarkers [105, 115].
In one of the other studies all the patients had prostate cancer and in the other the
negative controls were not necessarily biopsy-confirmed [106, 108]. These results do
not support the use of fusion proteins in the early detection of prostate cancer, but
20
they suggest that they could be useful in selecting men with elevated PSA levels for
biopsy. The men included in these studies were pre-selected and therefore the fusion
proteins were not used in the context of early detection screening.
LOE for fusions genes in patient selection for a second biopsy: II-b
Discussion
While the benefit of diagnosing cancer promptly in patients with symptoms with the
hope of avoiding metastatic cancer and being able to provide effective treatment, is
generally accepted, there is more controversy about detecting cancer in
asymptomatic subjects. Cancer detection in asymptomatic subjects can be done
either through mass screen programs in which all subjects are invited to participate,
or through early detection programs in which subjects that may be at risk of
developing a cancer are invited to participate. The discovery that higher PSA levels
were associated with potentially lethal prostate cancer, which could be treated to
increase the likelihood of disease-free survival revolutionized prostate cancer
prognosis. Using lower thresholds results in improved prostate cancer diagnosis and
the detection of earlier-stage tumours with a higher chance of cure when treated.
Following the initial euphoria of this breakthrough, concerns increased about the
over-detection and over-treatment of an increasing number of indolent prostate
tumours that were similar to those found during autopsy of men who died from other
diseases [119]. It has been estimated that the risk of having an indolent prostate
cancer is approximately equal to the patient’s age minus 10, expressed as a
percentage [120]. Thus in Europe, where male life expectancy in 2010 was 72.5
years, this risk is much higher than the lifetime risk of dying of prostate cancer, which
is estimated to be 3% [5, 121]. In a long-term follow-up study of men with low-grade
21
prostate cancer 10-year prostate cancer survival was 97.2% supporting the low risk
of these cancers[122].
In a setting of increased PSA testing, several randomized clinical trials were initiated;
the two biggest were in the US (PLCO) and in Europe (ERSPC). In PLCO annual
PSA testing for six years was accompanied by digital rectal examination (DRE) for
the first four years; in ERSPC which was a ‘federation’ of multiple screening trials in
different countries, the screening frequencies differed between the trials and this was
not always associated with DRE. The results from PLCO did not show a reduction in
prostate-cancer mortality although the rate of prostate cancer detection was higher in
the screening group [123]. However, the control group was ‘contaminated’ by the
high level of non-trial PSA testing in the community. The level of this contamination
was lower in the countries included in the ERSPC study. The high level of prescreening would have reduced the number of men with undetected prostate cancer
that could have been detected in the trials, and would therefore have lowered the
statistical power to detect a reduction in mortality [123].
The latest results from the ERSPC, after 11 years of follow-up, showed a lower rate
of prostate-cancer mortality in the screened group which continues to decrease over
time. It was estimated that 1 055 men would have to be screened to prevent one
prostate-cancer death and to detect 37 prostate cancers [14]. However, this would
result in 267 extra biopsies, 56 prostatectomies and high levels of adverse events
(e.g. incontinence, erectile dysfunction). For comparison, in two breast cancer
screening trials in Sweden and the UK it was estimated that 8.8 and 5.7 breastcancer deaths, respectively would be avoided for every 1 000 women screened with
4.3 and 2.3 per 1000 women over-diagnosed, respectively [124]. This translates to
between 2 and 2.5 lives saved for every over-diagnosed case. In addition, it has
22
been estimated that 12% to 13% of screened men had false-positive results after
three to four screening rounds, and clinically important infections, bleeding, or urinary
retention occurred after 0.5%–1.0% of prostate biopsies [123].
As PSA is expressed by the normal prostate gland, it is not cancer specific
biomarker. PSA levels increase with age as the prostate gland naturally becomes
bigger; levels are high in men with prostate cancer but they are also high in men with
benign prostatic hyperplasia [125]. PSA values are continuous but to be useful in
clinical practice a threshold value needs to be defined. When PSA levels are low, <
4ng/mL the risk of prostate cancer is relatively low and when the levels are high, >
10ng/mL the risk of prostate cancer is high and the clinical management of these
patients is relatively clear. However, in the ‘grey zone’ between these levels there is
uncertainty about the risk of prostate cancer. The positive predictive value (PPV) for
a PSA between 4.0 ng/mL and 10 ng/mL is about 25%, i.e. less than one man in four
will have prostate cancer detected on biopsy, whereas that for a PSA > 10 ng/mL is
between 42% to 64% (refs). In addition almost three out of four cancers detected in
the ‘grey zone’ are organ-confined with a good chance of being cured, whereas this
is less than 50% of those detected with PSA levels >10 ng/mL (ref). Hence, in the
grey zone, many unnecessary biopsies are performed because of the high false
positive rate. Although the threshold used often is 4 ng/mL, some laboratories have
started to use a threshold between 2 and 3 ng/mL, without strong evidence [126,
127]. It is generally accepted that a single test for total PSA with a unique threshold is
not very informative and that it is better to assess its evolution over time, using the
subject as their own control. This approach has been proposed for the early detection
of ovarian cancer. Screening is based on patterns from serial CA-125 values to
predict women at risk of preclinical ovarian cancer [128]. Compared with the use of
23
single fixed cut-off CA-125 measurement, the model was shown to improve
sensitivity for the early detection of ovarian cancer.
Although the World Health Organisation (WHO) has developed international
standards for total and free PSA they are not used. For example, some assays use
the Hybritech® standard that gives levels that are 20% to 30% higher than those
obtained with the WHO international standard. Even with use of the international
standard, quality control shows there is high intra- and inter-assay variability; these
can be about 5% and up to 30%, respectively. In addition to the assay variability
there are a number of factors that are known to affect the real level of PSA in
samples, such as sport (cycling, jogging, horse-riding) sexual intercourse,
manipulation of the prostate after biopsy, inflammatory infections of the urinary tract.
Hence there are guidelines that should be respected to minimise the effect of these
factors, including not to take samples within 48 hours of having practiced sport or
having sexual intercourse and, above all, not to take samples from men with
inflammatory conditions.
The main concerns of the high false positive rate are the cost and the harms that
arise from unnecessary biopsies. Indolent prostate cancers that are either subject to
active surveillance or active treatment result in high costs, both medical and human.
Active surveillance has economic implications for the healthcare system and the
patient and has human costs for the patient and their family with an impact on their
quality of life. The high rate of indolent prostate cancers found that are treated leads
to significant side effects from the treatment and loss of quality of life for the patient
and their partner [129].
The negative predictive value for PSA ≤4 ng/mL was estimated to be 85% in the
PCPT [2]. Among the men with PSA ≤0.5 ng/mL who underwent biopsy, 6.6%
24
(32/449) had prostate cancer and 12.5% of these (4/32) had high grade cancer. The
rate of prostate cancer and high-grade cancers increased up to 26.9% (52/449) and
25% (13/52), respectively in those with PSA between 3.1 and 4.0 ng/mL [2]. These
data show that for all levels of PSA there is a risk of prostate cancer that increases
with the PSA level.
It seems reasonable to think that changes in PSA levels over time, (PSAV or PSADT)
could be a better marker for more aggressive cancer compared with a single
measure of total PSA. However, the results from the studies identified and the metaanalysis do not show they have any advantages over total PSA in the early detection
of prostate cancer.
Although we know from the pre-PSA testing era, when prostate cancer was mainly
diagnosed by DRE, the lesions were frequently high-grade with high mortality rate.
PSA testing has definitely enabled the detection of lower-grade, curable lesions. In
the PSA era, the incidence of prostate cancer has drastically increased with no such
increase in prostate-cancer mortality. Throughout the world, the incidence of prostate
cancer varies widely. It is higher in countries where PSA testing occurs, while
prostate-cancer mortality rates are more homogeneous.
The challenge today is therefore to find a way to reduce the number of unnecessary
biopsies and reduce the detection of indolent prostate cancer, while ensuring that
patients with lesions that require treatment are identified early. In our review we
found many studies that have attempted to increase the PPV by using other
biomarkers for patients with PSA levels in this ‘grey zone’ before deciding to perform
biopsy. However, to date, there have been no randomised controlled trials assessing
these biomarkers. There have been many prospective cohort and case-control
studies performed to assess the advantages of using hK2, fusion proteins, PCA3 and
25
pro-PSA (Tables 11 and 12). Although the results were not always concordant, many
results suggest that these emerging biomarkers could reduce the number of
unnecessary biopsies and improve the identification of men that should undergo
biopsy.
Some studies have evaluated the role of imaging for early detection of prostate
cancer, but this was not the objective of this review. Although prostate ultrasound has
not been shown to be useful, results from prostate magnetic resonance imaging
(RMI) assessment studies look promising for the detection or differentiation of
significant from insignificant prostate cancer [130].
In a setting where there is insufficient evidence to propose mass PSA screening,
there does seem to be some merit to propose individual PSA testing [131]. To identify
men who should be invited to undergo PSA testing, their risk factors should be taken
into consideration [132]. In many guidelines, this approach to early prostate cancer
detection is suggested for men aged between 50 and 70 years with a life expectancy
of at least 10 years, with family history of prostate cancer, of a ‘high-risk’ ethnic and
organochlorine pesticide exposure (e.g. chlordecone) (Table 10) [133]. Although not
within the scope of this review, it will be important to have a management strategy for
those men that are identified as being at risk of having prostate cancer in terms of
biopsy or repeat PSA (and how regularly). Also outside the scope of this review but
essential for the management of men who have positive biopsy results, we need to
have evidence about who should be offered active surveillance and who should be
offered active treatment.
Conclusions
26
PSA has without doubt contributed to improve the prognostic of prostate cancer,
enabling curable cancers to be identified, compared with the pre-PSA era. While it
remains the standard biomarker in prostate cancer, PSA level is a continuous risk
factor. At high levels (> 10ng/mL) the need for further investigation, e.g. biopsy is
generally accepted. However, when the levels are lower, even below the traditional
threshold of 4 ng/mL, other factors (presence of risk factors, results from DRE and
possibly from imaging, such as RMI) need to be taken into consideration in the
decision to propose biopsy with the aim of reducing over-diagnosis. In the current
context where unorganized PSA testing in widely present and where various
biomarkers are being developed for the early detection of prostate cancer, it would
seem useful to suggest an individual management approach, integrating clinical and
biological data in order to obtain a more specific diagnosis and risk assessment. This
approach could be used to choose between prostate biopsy and active surveillance.
Mass screening is not to be recommended currently; it would seem that the future
lies with a personalised, multifactorial approach to early detection of prostate cancer.
Acknowledgment: The authors are grateful to Julie Courraud for editing assistance.
This work was supported by an unconditional grant from Beckman-Coulter and
Hologic and by the scientific societies: Association Française d'Urologie, Collège
national de Biochimie des Hôpitaux, Société Française de Biologie Clinique, Société
Française de Médecine Nucléaire.
27
Identification
Figure 1: Flow diagram of articles identified, screened and selected for inclusion in
current review. A total of 70 trials and studies were included; these correspond to 84
articles as some had more than one publication
Records identified through PubMed
searching
(n = 5825)
Additional records identified
through other sources
(n = 75)
Included
Eligibility
Screening
Records after duplicates removed
(n = 5900)
1st screen for all topics
(n = 5900)
Records excluded
(n = 3644)
2nd screen for early
detection studies
(n = 2256)
Records to be screened
for other topics
(n = 2002)
Full-text articles assessed
for eligibility
(n = 254)
Full-text articles excluded,
with reasons
(n = 174)
 Retrospective (for PSA)
 <200 men
 Not early detection
 Flaws in study design
(n=4)
Studies included in
qualitative synthesis
(n = 70)
28
Tables
Table 1: PubMed search: terms used in combination as either MeSh terms or free text
Prostatic Neoplasms / diagnosis / drug therapy / epidemiology / mortality /
radiotherapy / surgery / therapy
diagnosis / early diagnosis / prognosis
randomized controlled trial / controlled clinical trial / clinical trial / meta-analysis /
practice guideline / multivariate analysis / prognosis / prognostic / evidence-based
medicine*
PSA / pro-PSA / fusion oncogene / human PCA 3 / body mass index / prostatespecific antigen / tumor burden
29
Table 2: Characteristics of randomized clinical trials assessing PSA in the early detection of prostate cancer
Study ID (ref)
/ Dates for
randomisation
and follow-up
Population
included (how
selected,
number, age)
Detection /
screening
test(s)
ERSPC-global
[13, 14, 16,
40] / Varied by
center (see
details below)
182,160 aged
between 50
and 74 years
(162,388 in
core group:
age: 55-69
years) in 8
European
countries from
1993 to 2005
Serum PSA
with
Tandem-R/
Tandem-E
Access
assay
(Hybritech)
Screening
interval = 4
years
(Sweden =
2 years)
External
quality
assessment
(2 samples
6times/year)
Serum
processing
and storage
Definition of
Protocol for
positive for
‘positive’
further workup
Varied by
center but in
2012
publication:
1995-1998:
≥3.4ng/mL
1999-2004:
2.9ng/mL
After 2004:
2.5ng/mL
30
Sextant
prostate
biopsy; lateral
sextant
biopsies
adopted in
June 1996
Biopsy
sample
processing
and storage
and
assessment
Central
guidelines
[134]
Placed in
10%
neutralbuffered
formalin and
sent to lab
in
separatelynumbered
containers
Paraffinblocked and
H&E stain
Semiquantitative
evaluation
of amount
of cancer
Outcomes
measured
Primary:
prostate
cancer
mortality
Secondary:
overall
mortality;
Study ID (ref)
/ Dates for
randomisation
and follow-up
Population
included (how
selected,
number, age)
Detection /
screening
test(s)
Serum
processing
and storage
Definition of
Protocol for
positive for
‘positive’
further workup
ERSPCSweden [1720]/ 1st
Invitation sent
from January
1995December
1996
(Study
became
associate with
ERSPC in
1996 –
without any
changes to
protocol
Follow-up to
31 December
2008
Randomisatio
n before
inclusion
Men in
Goteborg born
between
1/1/30 and
31/12/44:
N=9952 to
screening and
109952 to
control
76.0%
screened
>once
All samples
analysed in
one
laboratory
Prostatus;
Wallac Oy,
Abo,
Finland
Screening
every two
years; in
third round,
men with <1
ng/mL found
in second
round were
not invited
Men ≥70
years no
longer
invited
After clotting,
serum
obtained by
centrifugation
at 3000 g for
20 mins and
stored frozen
at -20°C
within 3h from
sampling
PSA assay
within 2
weeks of
sampling and
<3 of thawing
≥3ng/mL,
lowered to
2.54ng/mL
from the third
round
31
Medical
history; DRE;
TRUS;
laterally
directed
sextant biopsy
Blind review
of all medical
records /
pathology
reports /
autopsy
protocols
Biopsy
sample
processing
and storage
and
assessment
Central
guidelines
[134]
Specimens
stepsectioned in
4 mm
increments
Tumor areas
measured
with 1mm
grid; volume
estimated
(multiplying
the sum of
tumor areas
in
consecutive
sections –
no
correction
for
shrinkage)
Outcomes
measured
Absolute and
relative
reduction in
cumulative
prostatecancer
mortality
Cumulative
incidence of
prostate
cancer
Proportion of
screening
attendees
Study ID (ref)
/ Dates for
randomisation
and follow-up
Population
included (how
selected,
number, age)
Detection /
screening
test(s)
ERSPCNetherlands
[16, 17, 21-25]
/
Randomisatio
n from Nov
1994-March
2000
Using
population
registries in
Rotterdam
and 12
neighbouring
municipalities
men aged 5574 years
21,210 to
screening;
21,166 to
control
94.6%
screened
>once
All samples
analysed in
one
laboratory
(GP Lab)
that covered
Rotterdam
and 7/12 of
the
municipalitie
s (subjects
from the
remaining 5
were not
included for
PSA rates
(only 11
tests)
In 1st round:
PSA-2
(Bayer); in
2nd round:
Hybritech
Tandem E
(BeckmanCoulter)
(after 2000
replaced
with
automated
version
Plus DRE and
Serum
processing
and storage
Definition of
Protocol for
positive for
‘positive’
further workup
Suspicious
finding from
any of the 3
diagnostic
tests
(PSA≥3ng/mL
)
From
November
1997 PSA
threshold:
≥4ng/mL
32
laterally
sextant
needle
biopsies
Biopsy
sample
processing
and storage
and
assessment
Central
guidelines
[134]
Placed in
10%
neutralbuffered
formalin and
sent to lab
in
separatelynumbered
containers
Paraffinblocked and
H&E stain
Semiquantitative
evaluation
of amount
of cancer in
4mm step
sections
Outcomes
measured
Primary
outcome:
prostate
cancer
mortality
(blinded
assessment
by Cause of
Death
Committee)
Study ID (ref)
/ Dates for
randomisation
and follow-up
Population
included (how
selected,
number, age)
Detection /
screening
test(s)
ERSPC-Spain
[17, 26, 27] /
Recruitment
from February
1996-June
1999
4278 men
randomised
(screening:
2416; control:
1862) aged
between 4570 years in
Madrid
Mailed
invitation
(population
registry list)
51.9%
screened
>once
All samples
analysed in
one
laboratory
Screening
interval: 4
years
Serum
processing
and storage
Definition of
Protocol for
positive for
‘positive’
further workup
9 February
1996-12 May
1998: tPSA
>4ng/mL;
12 May 19981 January
2002: tPSA
>2.99ng/mL;
From 1
January 2002present: tPSA
>2.99ng/mL
and tPSA 12.99ng/mL
and f/tPSA
≤20%
33
TRUS-guided
sextant
prostate
biopsy
Biopsy
sample
processing
and storage
and
assessment
Central
guidelines
[134]
Outcomes
measured
Primary:
prostate
cancer
mortality
Study ID (ref)
/ Dates for
randomisation
and follow-up
Population
included (how
selected,
number, age)
Detection /
screening
test(s)
ERSPCBelgium [17,
28, 29] /
Recruitment
from June
1991December
2003
Follow-up until
December
2007 (or up to
10 years)
Population
database of
Antwerp city;
men aged 5574 years
(26.5% of
invited
participated)
Randomisatio
n after
informed
consent
Screening:
5188; control:
5171
90.7%
screened
>once
Initially all
men had
PSA, DRE
and TRUS;
from 1996
only PSA
and DRE
All screening
done at one
centre
Serum
processing
and storage
Definition of
Protocol for
positive for
‘positive’
further workup
1992-94:
suspicious
finding from
any of the 3
diagnostic
tests
(PSA≥10ng/m
L)
1995-97:
same with
threshold at
≥4ng/mL
1999-2003
PSA and DRE
with
threshold:
≥3ng/mL
34
TRUS-guided
prostate
biopsy
Biopsy
sample
processing
and storage
and
assessment
Central
guidelines
[134]
Outcomes
measured
Prostate
cancer
mortality city
population
database;
prostate
cancer
(national and
local cancer
registries)
blinded
assessment
by Cause of
Death
Committee
Study ID (ref)
/ Dates for
randomisation
and follow-up
Population
included (how
selected,
number, age)
Detection /
screening
test(s)
ERSPC-Italy
[17, 30] /
October 1996October 2000
Randomisatio
n before
informed
consent
(Florence
population
registry)
Age 55-69
years
Screening:
7286; control:
7271
49.9%
screened
>once
Screening
interval: 4
years
Serum
processing
and storage
Definition of
Protocol for
positive for
‘positive’
further workup
PSA
>4ng/mL;
PSA
≥2.5ng/mL
35
Initially
sextant
random
biopsy;
currently:
DRE and
TRUS guided
biopsy
(transperineal
)
Biopsy
sample
processing
and storage
and
assessment
Outcomes
measured
Study ID (ref)
/ Dates for
randomisation
and follow-up
Population
included (how
selected,
number, age)
Detection /
screening
test(s)
ERSPCFrance [17] /
Herault: June
2003-March
2005; Tarn:
December
2000-June
2004
Randomisatio
n before
informed
consent
(health
insurance list)
in South-west
France (Tarn
and Herault)
1035 in each
group
Age 55-69
years
Divided into
previously
screened/ no
previous
screen, then
randomised
within
subgroup to
screening or
control
50.1%
(Herault) and
49.0% (Tarn)
screened
>once
Central
testing
(BeckmannHybritech)
Every two
years
Serum
processing
and storage
Definition of
Protocol for
positive for
‘positive’
further workup
PSA >3ng/mL
36
DRE and
TRUS-guided
sextant
biopsy; recall
of those with
high-grade
PIN, a
negative
biopsy with
suspicious
DRE/TRUS or
PSA
>10ng/mL
Biopsy
sample
processing
and storage
and
assessment
Central
guidelines
[134]
Outcomes
measured
Reduction of
prostate
cancer
mortality
Study ID (ref)
/ Dates for
randomisation
and follow-up
Population
included (how
selected,
number, age)
Detection /
screening
test(s)
Serum
processing
and storage
Definition of
Protocol for
positive for
‘positive’
further workup
ERSPCFinland
[17, 31-33] /
January 1996January 1999
Randomisatio
n before
informed
consent
(mailed
invitation)
Men born in
1929-1944 in
the
metropolitan
areas of
Helsinki and
Tampere
Total 79,494
with 30,403 in
screening
group
Mean age in
both groups:
59.6 years
74.4%
screened
>once
Central
testing
tPSA:
Hybritech
Tandem-E
(Beckman
Coulter) and
Delfia
(Wallac)
assays until
June 2001
then
BeckmannCoulter
assay
f/tPSA:
Wallac
ProStatus
(Wallac)
Serum stored
at -80°C
4 aliquots
stored and
since 1998
whole blood
samples also
stored
PSA ≥4ng/mL
PSA 3.03.9ng/mL :
biopsy if
suspicious
DRE (199698) or if
f/tPSA <0.16
(since 1999)
37
DRE, TRUS
and TRUSguided
sextant biopsy
(in 2002 – 1012-core
biopsy) from
focal lesions,
base, central
and apex
Biopsy
sample
processing
and storage
and
assessment
Central
guidelines
[134]
Assessment
done in four
participating
laboratories
Outcomes
measured
Prostate
cancer
mortality
Study ID (ref)
/ Dates for
randomisation
and follow-up
Population
included (how
selected,
number, age)
Detection /
screening
test(s)
Serum
processing
and storage
Definition of
Protocol for
positive for
‘positive’
further workup
ERSPCSwitzerland
[17, 34] /
September
1998-August
2003
Mail invitation
(55-70 years)
in Canton
Aargau
Randomisatio
n after
informed
consent
5150 in both
groups
50.0%
screened
>once
Screening
interval: 4
years
AxSym
(Abbott)
until June
2000 and
Access
(BeckmannCoulter
Hybritech
from July
2000
Serum frozen
at -70°C
within 2h of
blood
sampling
Samples
thawed
immediately
before PSA
test within 2
weeks of
sampling
PSA >3ng/mL
or PSA 13ng/mL and
f/tPSA <20%
38
DRE and
TRUS-guided
transrectal
sextant biopsy
taken laterally
from the
peripheral
zone of the
prostate
Biopsy
sample
processing
and storage
and
assessment
Central
guidelines
[134]
Each biopsy
separately
processed
and
evaluated
All positive
and
suspicious
samples
reviewed by
an
independent
review
pathologist
Outcomes
measured
Study ID (ref)
/ Dates for
randomisation
and follow-up
Population
included (how
selected,
number, age)
Detection /
screening
test(s)
Serum
processing
and storage
Definition of
Protocol for
positive for
‘positive’
further workup
PLCO [35-39]
From
November
1993 to June
2001
Screening
complete by
October 2006
Follow-up: 31
December
2009 or 13
years from
trial entry
76,693 aged
between 55
and 74 years:
38,343
screen;
38,350 control
in 10 centres
across USA
Annual PSA
for 6 years
and DRE for
4 years
Single lab for
testing
using
Tandem-R
until Jan 1
2004 then
Access
Hybridtech
PAS
Centralised
laboratory
Serum frozen
at -70°C or
colder within
2-4 hours of
blood
collection
Shipped
weekly
overnight on
dry ice to
central
laboratory
Spare sample
stored at 70°C for
future
research
PSA:
≥4ng/mL
DRE:
nodularity or
induration, or
investigator
judgement of
suspicion
39
No studyspecific
protocol
Local practice
in each study
center
followed
Certified
tumor
registrars
ascertained
stage,
Gleason
score and
histology
Biopsy
sample
processing
and storage
and
assessment
Outcomes
measured
Primary:
prostate
cancer
mortality
Secondary:
incidence;
staging;
survival
Table 3: PSA in randomized clinical trials: Trial design and quality characteristics
Study ID (ref)
Randomisatio
n methods
Sample size
calculation
ERSPC [13,
14, 16, 40]
Italy, France,
Finland and
Sweden:
randomisation
before
informed
consent using
population
registries –
Belgium,
Netherlands,
Spain and
Switzerland:
mailed
invitation,
then
randomisation
after informed
consent
Power 80% to
detect 25%
reduction in
prostate
cancer
mortality with
10 years
follow-up
Number of
screened/invit
ed (%)
Number of
lost to followup
Excluding
France:
82.6%
underwent
screening at
least once
With France:
63.4%
Median
Blinding of
follow-up time outcome
(min and max) assessors
Contaminatio
n of control
group
Intention to
screen
analysis
Median
screen
interval: 4.02
years
Mean and
median follow
up (as of
2008) for core
group
excluding
France: 10.5
and 11.0 –
including
France: 8.6
and 9.8
Results
available for
Spain and
Netherlands
(others are
on-going)
Spain: in
general
population
aged 55-69
years – 86.8
per 1000
patient-years
Netherlands:
in population
aged 55-69
years – 45 per
1000 patientyears
Yes on core
age group
(55-69 years
old)
40
Yes
PLCO [35-38]
Blocked with
stratification
on center, age
and sex
Power 90%
(one-sided
test) to detect
20% reduction
in prostate
cancer
mortality with
10 years
follow-up
At 10 years,
vital status
known for
67%
(although
23% had not
been enrolled
for 10 years)
11.5 years
(7.2 to 14.8)
41
Cause of
death from
death
certificate and
medical
records in an
‘unbiased’
manner
PSA
Yes
screening:
40% in 1st
year to 52% in
6th year
DRE: from
41% to 46%
Table 4: Results from randomized clinical trials assessing PSA in the early detection of prostate cancer
Study ID (ref)
Number of
screening tests
/ screening rate
Median
screening
interval /
follow-up
% positive
Prostate
cancer
incidence (per
100 000) or
rate (%)
Screening
group = 9.66
Control group
= 5.95
Rate ratio =
1.63 (1.57 –
1.69)
Prostate
Overall
cancer
mortality rate
mortality (n)
(per 100 000)
rate (per
100 000)
ERSPC [14]
mean=2.27/subj 4.02 years
16.7%
Screening
Screening
ect
(excluding
group = 299;
group = 18.2
France);
rate 0.39
Control group
16.6%
Control group = 18.5
(including
= 462 rate =
Rate ratio =
France)
0.50
0.99 (0.97 –
Rate ratio =
1.01)
0.79 (0.68 –
0.91)
p=0.001
NNI = 1055
NND = 37
PLCO [35-39] Range from
Every year /
7.9%
At 7 years:
At 7 years: 50 Screening
40% to 52%
median=11.5
2820 vs 2322; vs 44; rate
group = 2544
years (range
rate ratio =
ratio = 1.13
Control group
7.2-14.8)
1.22 (1.16 –
(0.75 – 1.70)
= 2596
1.29)
At 13 years:
Rate ratio =
At 10 years:
158 vs 145;
0.97 (0.93 –
3452 vs 2974; rate ratio =
1.01)
rate ratio =
1.09 (0.87 –
1.17 (1.11 –
1.36)
1.22)
NNI = number of men needed to be invited to screening to prevent one death from prostate cancer; NND = number of cancers
needed to be detected to prevent one death from prostate cancer
42
43
Table 5: Comparison of two systematic reviews of randomized clinical trials assessing PSA in the early detection of
prostate cancer
Djulbegovic et al 2010 [42]
Ilic et al 2011 [43]
Studies included (no.
ERSPC (72 890 / 89 353)
ERSPC (82 816 / 99 184)
screened / no. control)
PLCO (38 343 / 38 350)
PLCO (38 343 / 38 350)
Quebec (31 133 / 15 353)
Quebec (31 133 / 15 353)
Norrkoping (1 494 / 7 532)
Norrkoping (1 494 / 7 532)
French ERSPC (42 590 / 42 191)
Stockholm (2 374 / 24 772)
Gothenburg (9 952 / 9952)
Total subjects screened /
153 812 / 160 540
156 160 / 185 191
All trials: RR=0.88 (95% CI=0.71-1.09)
All trials: RR=0.95 (95% CI=0.85-1.07)
control for prostate cancerspecific mortality
Prostate cancer-specific
Trials with a low risk of bias: RR=0.89 (95% CI=0.77-1.04)
mortality results
Trials with a high risk of bias: RR=1.05 (95% CI=0.871.25)
44
Djulbegovic et al 2010 [42]
Prostate cancer diagnosis
Ilic et al 2011 [43]
RR=1.46 (95%CI=1.21-1.77)
RR=1.35 (95%CI=1.06-1.72)
‘The existing evidence from RCTs does
‘Prostate cancer screening did not significantly decrease
not support the routine use of screening
prostate cancer-specific mortality’
for prostate cancer with PSA with or
‘Any benefits from prostate cancer screening may take
without DRE’
>10 years to accrue, so men with a life expectance <10-
results
Conclusions
15 years should be informed that screening for prostate
cancer is not beneficial and has harms’
45
Table 6: Characteristics of ‘real-life’ studies on PSA in early detection
Study ID
Population included (how selected,
number, age)
Study design : data sources
Outcomes measured
SeattleConnecticut [44,
45]
● Two fixed cohorts from 1987-97
● Population-based cohorts aged
65-79 (Medicare beneficiaries)
● Seattle: 94 900 Connecticut:
120 621
Observational cohort study
Rate of PCa screening
Medicare denominator and vital statistics
databases, SEER-Medicare linked
database, local SEER registry
PCa mortality
Tyrol [46, 47, 135]
● One region in Austria, Tyrol where
PSA screening is free of charge
to all aged 45-74 since 1988-89
● Control: Austria without Tyrol
where there is no free PSA
screening
● In 1981, MS in 5/70 communities
of Gunma (Japan); in 1986, MS in
22
Observational cohort study
PCa mortality (by 5year categories)
starting at 60
Gunma [48]
Statistics Austria Mortality and Census
data;
Observational cohort study
Cancer register
46
PCa diagnosis
Table 7: Results from ‘real-life’ studies on PSA in early detection
Study ID (ref)
Followup
Seattle15
Connecticut [44, years
45]
PSA screening rates
Prostate cancer
mortality rate (per
100 000)
Seattle: n= 94900 PSA / Seattle: 172.4
person year: 11
Connecticut: 171.1
858/325 873; rate per
100: 36.5
Rate ratio
Seattle/Connecticut
Connecticut: n=
(95%CI°: 1.02 (0.96120621/
1.09)
PSA / person year:
136296/500 547
rate per 100: 27,2
Rate ratio
Seattle/Connecticut
(95%CI) = 1.35 (1.341.36)
47
Comments
No benefit from PSA but in the US PSA is widely
used, so that this non-randomised study is
probably contaminated by the level of non-study
PSA
Study ID (ref)
Followup
PSA screening rates
Prostate cancer
mortality rate (per
100 000)
Comments
Tyrol [46, 47,
135]
18
years
Estimated 75% ≥1 PSA
test
2004-08 compared
with rate in 1989-93:
Tyrol: 0.70 (0.57-0.87)
The observed reduction in mortality was
considered to be too early and is more likely to be
due to the role of PSA in the management of
prostate cancer than the actual impact of early
detection.
Austria-Tyrol: 0.92
(0.87-0.97)
These studies emphasise more the access to PSA
testing and thus patient information in the
screening
Gunma [48]
15
years
ND
ND
1,224/2,775 (44%) of men with PCa lived in MS
communities
48
Table 8: PSA in prospective cohort studies: study characteristics
Study ID /
design (ref)
Rowe et al
2005/
prospective
cohort study
[49]
Population included
(how selected,
number, age)
● Aged 50-65 years
invited by GP
letter to screening
(6 practices in
London, UK)
● 3652 contacted /
775 expressed
interest / 773
accepted and
gave a blood
sample
● 20 min consulting
and consent
Detection /
screening test(s)
Sample
processing
and storage
Single test with
Serum
Access assay for
separated and
tPSA and fPSA
snap-frozen in
(Beckman Coulter) liquid N2
detection limit 0,1 within 3h of
ng/mL)
blood sample
STD: probably
being drawn
Hybritech
113/115
biopsies
perform by
one operator
and all
histology by
one
pathologist
49
Definition
of
positive
If tPSA of
1.1-4.0
ng/mL
and a
f/tPSA of
≤20%
tPSA
≥4ng/mL
DRE and
biopsy
Protocol for
‘positive’
Outcomes
measured
Sextant biopsy
for volume
≤30mL; two
extra cores for
volume 3040mL; ≥40mL
six additional
cores
Primary:
prostate
cancer in
men aged
50-65 with
tPSA of
1.1-4.0
ng/mL and
a f/tPSA of
≤20%
Stat :
Mann Whitney
U test
Comments
Study ID /
design (ref)
Thompson
2007 / RCT)
2
prospective
cohorts / [6,
50]
Population included
(how selected,
number, age)
● 18,882 men
aged ≥55
years,
normal DRE,
PSA<3,
randomised
to finasteride
or placebo
for 7 years.
● Annual PSA
and DRE
biopsy if
DRE
abnormal or
PSA >4
● All
participants
had end-ofstudy biopsy
● In this
analysis:
4,400 from
finasteride
group and
5,587 from
control group
Detection /
screening test(s)
Central lab:
Tandem E assay
(Beckman Coulter)
Sample
processing
and storage
No details
50
Definition
of
positive
PSA >4
or DRE
abnormal
Protocol for
‘positive’
Outcomes
measured
Comments
Biopsy with ≥6
cores
% positive
biopsy;
sensitivity,
specificity,
AUC, other
risk factors
in
univariate
and
multivariate
analyses
Two reports,
one each for
± finasteride
Study ID /
design (ref)
Ishidoya et
al 2008 /
prospective
cohort study
[51]
Population included
(how selected,
number, age)
● 2003 2004
● Four centres
of 11
communities
in North
Japan
● 5548 men
aged 50-79
years
enrolled
● No
conditions for
ineligibility
Detection /
screening test(s)
PSA t and f
measured 3-5h
after collection
(Architect, Abbott)
STD: not specified
(detection limit 0,1
ng/mL)
Sample
processing
and storage
Tested within
3-5h
51
Definition
of
positive
tPSA: >4
ng/mL or
tPSA: 2-4
ng/mL
and
f/tPSA:
≤12%
for biopsy
Protocol for
‘positive’
TRUS-guided
12-core biopsy
(one
pathologist
made
diagnosis
based on
biopsy
specimen
DRE only Gleason
if biopsy
evaluated
Outcomes
measured
Comments
Number of
biopsies
Number of
positive
biopsies
Positive
predictive
value
(PPV)
No DRE in
community
2001 2002
preliminary
screening
for cut off of
ratio f/t 12%
with
sensitivity of
58,3 % and
specificity of
77,8 %
Stat: Stat
view
Study ID /
design (ref)
Antenor
2004 /
Prospective
longitudinal
screening
study [52]
Population included
(how selected,
number, age)
● May 1991November
2001
● 26,111 men
40++, mean
59 (40-96)
● 91 % White
(90 % in
table!!)
● 8 % black
● 2% others
ineligible:
● prostatitis
● urinary
infection
● anterior
biopsy
Detection /
screening test(s)
Sample
processing
and storage
DRE and PSA at
Limitations
6-month (if PSA
(from authors)
‘suspicious’
● only for
or 1 year interval –
white
populati
by
on
Tandem-E PSA
● inadeq
(Hybritech) until
uate
May 2000,
samplin
(detection limit 0,5
g of
ng/mL) then
biopsy
ACCESS analyser
● complia
(Beckmann
nce not
Coulter)
complet
chemiluminescenc
e of
e
subject
+ DRE(detection
limit 0,1 ng/mL)
STD? probably
Hybritech < 20%
WHO
52
Definition
of
positive
Up to
May
1995:
>4.0
ng/mL or
DRE
findings–
after
1995:
>2.5ng/m
L
or DRE
suspiciou
s
Protocol for
‘positive’
Outcomes
measured
TRUS-guided
quadrant
(sextant after
May 1995)
needle biopsy
+ additional for
DRE or US
suspicious
zones
Prostate
cancer by
initial PSA
level
No difference
between 2
groups in
insignificant
cancer
Stat: SPSS
Comments
Study ID /
design (ref)
IMPACT
2010
Ongoing,
multicenter
Prospective
case/control
study [53,
54]
Population included
(how selected,
number, age)
● October
2005 to June
2008
● 300 Men
aged 40-69
recruited
over 33
months in 20
centers in
five countries
● Subjects
recruited by
postal
invitation or
approach of
cancer
genetics
clinics in UK
from families
with
mutations in
BRCA1/2,
● Controls
BRCA1/2
negative (but
from families
with
mutations)
● Eligibility: 40
69 years,
without PC
and with
BRCA1/2
● Inegibility:
PC <5 yrs,
Detection /
screening test(s)
PSA annually
(centralized in
local laboratory)
and analysed at a
central reference
laboratory
(standardization
and Quality
assurance,
methods not
described)
Central histology
review, with a
sample
secondarily
reviewed
Screening:
● PSA < 3
:annual
● PSA > 3
:Biopsy
if negative
and PSA
+50% other
in 1 year
● If
intraepitheli
al or
inconclusiv
e other in 6
weeks
Sample
processing
and storage
Bio-repository
for collection
of blood,
lympho urine
and tissue
For proteomic
metabolomic
and
microarrays
approaches
Definition
of
positive
PSA >3
ng/mL
Protocol for
‘positive’
Outcomes
measured
Comments
Prostate
biopsy (10core
recommended
)
Positive
biopsy rate
Higher
incidence of
PC than in
general
population
but
limitations
by lack of
control
group and
few patients
and the
description
of IMPACT
STUDY
if benign, PSA
at 12 months
re-biopsy if
PSA >50%
higher
repeat biopsy
after 6 weeks if
inconclusive
53
Study ID /
design (ref)
Okihara
2008 /
Prospective
cohort
(‘mass
screening
cohort’) [55]
Population included
(how selected,
number, age)
● Otokuni
district
screening
39,213 male
>55 years
attending
basic health
check
between
1995-2004
(10 years)
●
Detection /
screening test(s)
First, Delfia PSA
assay, cut off 4
(detection limit 1
ng/mL)
second screening
if PSA 4.1 to 10
Sample
processing
and storage
Not indicated
Definition
of
positive
PSA 4.110 ng/mL
Protocol for
‘positive’
First screening % of PCa
PSA > 4
at biopsy
Referral to
central hospital
for secondary
screening:
Biopsy if
PSA > 10 or
between 4-10
With DRE or
TRUS + or
both – with
PSAD > 0.15.
If PSAD < 0,15
again next
year
Biopsy:
transperineal,
systematic
sextant; since
2002 –
additional
sample from
far lateral
region in both
lobes
(systematic
octant biopsy)
54
Outcomes
measured
Comments
Table 9: PSA in prospective cohort studies: study results
Study ID
(ref)
Rowe
2005 [49]
Thomps
on 2007
[6, 50]
Rate of PSA
screening uptake
● 773/3,652
(21.2%)
accepted
● 78.9 %
Caucasian,
10.9 % afro
Caribbean,
5% Asian, 3.4
% Middle
Eastern,
1.8% Oriental
● age: mean
57.9 (50.1 –
64.9)
● Finasteride
group:
4,440/5,676
(78%)
PSA results
Biopsy results
Comments
tPSA <4 ng/mL: 707/773
tPSA <1.1 ng/mL 352/773
tPSA=1.1-3.99 ng/mL: 355/773 eligible for
free PSA
f/tPSA of ≤20%: 137/355
115/137 agree for biopsy
No. biopsy: 115/137
(84%)
PCa detected:
13/115; rate 1 in 8.9
men (11.3%)
At threshold of 3.5 ng/mL
only 1/13 prostate cancer
would be detected
4/13 had
prostatectomy
one was upgraded
of Gleason 6 to 7
Finasteride PSA:
Number (%)
positive biopsy
N=155 (6.2%)
N=164 (15.3%)
N=94 (24.9%)
N=71 (35.9%)
N=98 (52.7%)
N=67 (57.8%)
0-0.5; N=2,489
0.6-1.0; N=1,073
1.1-1.5; N=378
16.-2.0; N=198
2.1-3.0; N=198
>3.0
55
Present method can
reduce mortality PC
particularly in 50 65 years
men
These men would have the
widest range of locally
curative treatment
Not confirmed: overall
incidence of PC if PSA
between 1- 4 because men
with ratio > 20 were not
biopsied
PSA level was a risk factor
for PCa at biopsy in
univariate: OR=3.49
(P<0.001) and multivariate:
OR=3.48 (P<0.001)
Study ID
(ref)
Rate of PSA
screening uptake
● Placebo
group:
5,587/8,575
(65%)
PSA results
Biopsy results
Comments
PSA > 4.0 ng/mL = normal DRE: N=577
(10.3%)
PSA > 4.0 ng/mL = abnormal DRE: N=60
(1.1%)
PSA ≤ 4.0 ng/mL = normal DRE: N=4,453
(79.7%)
PSA ≤ 4.0 ng/mL = abnormal DRE: N=497
(8.9%)
Sensitivity and
specificity for PCa
biopsy:
Cut-point=4.1ng/mL
6.2% false
positive rate, detect
20.5% of cancers.
If lowered to 1.1
ng/mL would detect
83.4% of cancers
but false positive
rate of 61.1%
In this study the authors
recognised they had
selected a healthier, more
compliant population with
generally low PSA levels –
so could affect the
generalizability to the
general population
56
‘Patients and healthcare
professionals must be reeducated that there is a
continuum of risk and no
clearly defined cut-point for
recommending biopsy’
Study ID
(ref)
Ishidoya
2008 [51]
Rate of PSA
screening uptake
● 5,548
subjects
enrolled, 5079 years, no
mean?
● biopsy in 6%
of enrolled
PSA results
Biopsy results
Comments
● tPSA >,337)
● tPSA 2-4ng/mL: 385/5,548 (6.9%); <
2ng/mL: 78.1% (44 ng/mL:14.9 % (826)
with f/tPSA ≤12%: 100/5,548 (1.8% )
● tPSA 4- 10 ng/mL: 6.9% (310)
● tPSA > 10 ng/mL: 1.4 % (75)
Overall 138/332
(42.9%) tPSA
>4ng/mL: 283/385
(73.5%) underwent
biopsy 122/283
were PCa
● effected, %
positive
● Overall: 332,
2.5%
● tPSA 2-4
ng/mL and
f/tPSAt
≤12%: 16/49
(32.7% PPV)
● tPSA 4 10ng/mL:
218, 36.2%
● tPSA >
10ng/mL: 65,
66.2%
f/tPSA ≤12%: detected
PCa in men with PSA 2-4
ng/mL in 16 men / 49,
32.7% Gleason 3 or 4 T1c
to T3, identical to 36.2% in
4-10 ng/mL tPSA
difference in prevalence of
PCa between Japanese
and American or
Europeans
Limitations: sample size
too small and follow up not
long enough
57
Half of patients refused
biopsy
Men with PSA 4-10 ng/mL
used to determine cut point
of f/tPSA of 12% not yet
verified future survey is
expected
Study ID
(ref)
Antenor
2004 [52]
Rate of PSA
screening uptake
● 26,111
enrolled
● mean followup: 51
months ( 0126)
● Age
40-50: 5%
51 60: 51 %
61 70: 33%
>71: 12%
● DRE
normal: 71%
abnormal:
21%
suspicious:
8%
PSA results
Biopsy results
Comments
tPSA
<1.0 ng/mL:12,862 (50%)
tPSA
1.1-2.5 ng/mL: 8,596 (33%)
tPSA
2.6-4.0 ng/mL:2,416 (9%)
tPSA %)
4.1-10.0 ng/mL: 1,866 (7%)
tPSA
>10.0 ng/mL: 351 (1%)
Overall 2,122 (8%)
diagnosed with
prostate cancer
PSA median at Ca
diagnosis 4.3
ng/mL, to Ca
diagnosis 20 ng/mL
% clinically
localized 99%
% organ confined
72%
% Gleason score >
7 biopsy: 15 %
surgery: 26%
RR PCa increased with
PSA level
42% of those with PSA2.64.0 ng/mL increased >4.0
ng/mL vs. 2% and 12% for
<1.0 ng/mL and 1.1-2.5
ng/mL, respectively
Study demonstrates higher
relative risk of cancer if
PSA> 0.7 ng/mL (40 49 yrs
) or PSA >0.9 ng/mL (50
59)
Initial screening PSA
associated with risk of
subsequent prostate
cancer detection
Authors’ Comments:
Study useful for designing
screening protocols
Cost-benefit analysis would
be required
58
Study ID
(ref)
IMPACT
[53, 54]
Rate of PSA
screening uptake
● 99.7%
PSA results
Biopsy results
Comments
Year 1
PSA >3 ng/mL: BRAC1: 6/89; BRAC2:
11/116; Control: 5/95
Overall: 22/300 (7.3%)
Year 2
PSA >3 ng/mL: BRAC1: 0; BRAC2: 5/51;
Control: 1/42
Overall: 6/127 (4.7%)
IMPA BR BR Con ER
CT
CA CA trols SP
1
1
2
C
year
Age
53
52 54 55
66
media
n
%
8.3
6.7 10. 7.4
20.
PSA >
3
1
3
incide 3.3
4.5 3.4 2.1
5.3
nce of
PC
PPV
45.4
66. 36. 40.0 29.
PSA
6
4
2
Year 1
BRAC1: 4/6;
BRAC2: 4/11;
control 2/4
Overall: 10/300
(3.3%)
Year 2
BRAC1: 0; BRAC2:
1/4; control 0
Overall: 1/127
(0.8%)
Interim results; recruitment
to end December 2012
(expected n=1,700); all
subjects will be screened
for 5 years
59
Preliminary data from the
IMPACT study show that
there is a relatively low rate
of biopsy 7% with PSA> 3
but PPV high 48%.
Present study provides
evidence that screening
men with genetic
predisposition detects
clinically significant PC and
support the rationale for
continued screening in
such men
Comparison with ERSPC
PSA ≥ 3ng/mL expected:
recruitment to end
December 2012 n=1,700;
all subjects will be
screened for 5 years in 32
centers through 11
countries
Study ID
(ref)
Otokuni
– Japan
[55]
Rate of PSA
screening uptake
● From 1995 to
2004 more
than two-fold
increase in
number of
PSA
● 39,213
attended
screening
● Between
1995-1998
could not
detect first
time primary
screen, so
only total
number
given, so
estimated
65% uptake
PSA results
Biopsy results
Comments
PSA >4 ng/mL: 2,428 (6%) – 1,633 (67%)
received secondary screening; 1,439 at
central hospital
1st time secondary
screen:
biopsy
recommended:
625/894 (70%)
biopsy done:
606/625 (97%)
prostate cancer:
183/606 (30%)
PSA=4.1-10:
biopsy
recommended:
496/765 (65%)
biopsy done:
482/496 (97%)
prostate cancer:
118/482 (25%)
PSA>10:
biopsy
recommended:
129/129 (100%)
biopsy done.
124/129 (96%)
prostate cancer
65/124 (52%)
Prostate cancer detection
rate 2x higher in those with
PSA>10 ng/mL
60
Table 10: Summary of international guidelines for PSA in the early detection of prostate cancer
Guideline / date
updated (ref)
Recommendations on early screening
Comments
European
Association of
Urology (EAU) /
2012 [63]
‘A baseline PSA determination at age 40 years has been
suggested, upon which the subsequent screening interval
may then be based (GR: B).’
‘A screening interval of 8 years might be enough in men
with initial PSA levels < 1 ng/mL.’
‘PSA testing in men older than 75 years is not
recommended because its early detection would not have
any clinical impact’
European Society
of Medical
Oncology (ESMO)
/ 2010 [70]
‘Decisions on population screening await longer follow-up
and the results of analyses of cost-effectiveness and
quality of life [I, B]’
‘Serum PSA should be measured and digital rectal
examination
(DRE) performed in appropriately counselled patients in
whom
there is clinical suspicion of prostate cancer or in those
who wish to be screened.’
61
Main conclusions on PSA for early detection
1. Not useful in those aged >75 years
(although the rates of prostate cancerspecific mortality in France is highest in
older men)
2. Possible advantage of PSA testing at 40
years old, since the PSA level is not
‘contaminated by BHP
3. If PSA < 1 ng/mL, no retest before 8 years
PSA. This idea of PSA < 1 ng/mL is to be
compared with the results from the study
by Vickers et al (ref) showing that if a man
aged 60 years has a PSA level < 1 ng/mL,
the risk of prostate cancer-specific
mortality is < 0.02%, therefore there is no
need to perform another PSA test.
The results from early detection studies currently
correspond to a short follow-up and report only
cancer-related outcomes. In terms of public
health the important outcomes, are costeffectiveness and quality of life, for which there is
very little data.
It is essential that the patient is involved in the
decision to undergo a PSA test; this test cannot
be undertaken without pre-test information for the
patient
Canadian
guidelines / 2011
[64]
‘the harms and benefits of PCa screening must be
explained to each patient so they understand all the
factors to be considered in the shared decision-making
about screening’
‘Prostate cancer screening should be offered to all men
50 years of age with at least a 10-year life expectancy.’
‘Annual screening has been the standard; however, two
screening studies demonstrate that screening is
beneficial every 2 to 4 years.’
‘If there is a higher risk of PCa, such as family history of
PCa or if the patient is of African descent, screening
should be offered at age 40 years.’
‘there may be benefit in offering a baseline PSA for men
40 to 49 years of age to establish future PCa risk.’
‘Initial screening should include DRE and PSA.’
62
The Canadian guidelines are similar to the French
guidelines: early detection is an individual
decision; involves a DRE and a PSA assay; prior
patient information is essential; is proposed to
men aged ≥ 50 years (or 40 years, if an at-risk
population); only in those with a life expectancy
>10 years.
The concept of an initial test at 40 years old to
evaluate the risk of prostate cancer and therefore
decide how regularly PSA testing should be done
is beginning to seen.
American Cancer
Society / 2010 [57,
69]
‘The American Cancer Society recommends that men
make an informed decision with their doctor about
whether to be tested for prostate cancer.’
‘Research has not yet proven that the potential benefits of
testing outweigh the harms of testing and treatment. The
American Cancer Society believes that men should not
be tested without learning about what we know and don’t
know about the risks and possible benefits of testing and
treatment.’
‘Starting at age 50, men should talk to a doctor about the
pros and cons of testing so they can decide if testing is
the right choice for them.’
‘If they are African American or have a father or brother
who had prostate cancer before age 65, men should have
this talk with a doctor starting at age 45.’
‘If men decide to be tested, they should have the PSA
blood test with or without a rectal exam.’
‘How often they are tested will depend on their PSA level.’
63
No PSA testing without prior patient information
and not in men under 50 years old, except in atrisk populations
Testing based on the PSA level
Frequency of testing dependent on the initial PSA
level
‘In men with a life expectancy<10 years, it is
recommended that general screening for prostate cancer
with total PSA be discouraged, because harms seem to
outweigh potential benefits.’
Type and strength of recommendation. Evidence based:
strong.
Strength of evidence. Moderate: based on five
randomized clinical trials (RCTs) with intermediate to high
risk of bias, moderate follow-up, and limited data on
subgroup populations.
‘In men with a life expectancy>10 years, it is
recommended that physicians discuss with their patients
whether PSA testing for prostate cancer screening is
appropriate for them. PSA testing may save lives but is
associated with harms, including complications, from
American Society
unnecessary biopsy, surgery, or radiation treatment.’
of Clinical
Type and strength of recommendation. Evidence based:
Oncology (ASCO) /
strong.
2012 [59]
Strength of evidence. For benefit, moderate; for harm,
strong: based on five RCTs (and several cohort studies)
with intermediate to high risk of bias, moderate follow-up,
indirect data, inconsistent results, and limited data on
subgroup populations.
‘It is recommended that information written in lay
language be available to clinicians and their patients to
facilitate the discussion of the benefits and harms
associated with PSA testing before the routine ordering of
a PSA test.’
Type and strength of recommendation. Informal
consensus: strong.
Strength of evidence. Indeterminate: evidence was not
systematically reviewed to inform this recommendation;
however, randomized trials are available on the topic.
64
Strong guideline for no PSA testing in men with a
life expectancy of <10 years
For men who are to be screened, prior oral and
written information must be given to them.
U.S. Preventive
Services Task
Force / 2012 [67]
Japanese
Urological
Association (JUA)
/ 2010 [65]
HAS (French) /
February 2012 [62]
‘Prostate cancer is a serious health problem that affects
thousands of men and their families. But before getting a
PSA test, all men deserve to know what the science tells
us about PSA screening: there is a very small potential
benefit and significant potential harms. We encourage
clinicians to consider this evidence and not screen their
patients with a PSA test unless the individual being
screened understands what is known about PSA
screening and makes the personal decision that even a
small possibility of benefit outweighs the known risk of
harms’
‘The Japanese Urological Association (JUA) recommends
prostate-specific antigen (PSA) screening, which can
reduce the risk of death as a result of prostate cancer, for
men at risk of prostate cancer. The recommendation is
based on fact sheets showing the benefits and drawbacks
of screening for prostate cancer. The JUA provides the
best available screening system for men who want to be
screened.’
‘the best available evidence does not support
recommending mass PSA screening for prostate cancer
in the general population’
‘no evidence was found to support recommending PSA
screening in men with a high risk for prostate cancer’
65
The US Preventive Services Task Force
guidelines state that prostate cancer is a public
health problem but that early detection only
provides a small benefit and should only be
proposed after informing the subject about the
benefits and risks
The Japanese Urology Association recommends
early detection, particularly in at-risk subjects.
No recommendations can be formulated for
organised screening in men ‘at-risk’ since there is
no evidence; the two randomised trials (ERSPC
and PCLO) were in the general population.
However, in men ‘at-risk’ early detection of
prostate cancer with a PSA test can be performed
on an individual basis
Conclusions from report by Rachid Salmi [136]:
No reason to question the recommendations from
HAS – the two studies (PLCO and ERSPC) are
too different – the European study is too
heterogeneous for a meta-analysis to be
performed
Centre Fédéral
d’Expertise des
Soins de Santé
(KCE) [61])
National
Comprehensive
Cancer Network
(NCCN) [66]
UK National
Screening
Committee (UK
NSC) [68]
British
Association of
Urological
Surgeons (BAUS)
[60]
American
Urological
Association (AUS)
[58]
Not recommended to install or develop PSA massscreening program
Opportunistic screening for those requesting to be tested,
after receiving sufficient information
Produced in 2006
PSA testing is likely optimal when used for early detection
in high-risk populations instead of general population
screening
Young, healthy, high-risk men will benefit from early
testing
Older men with competing comorbidities should be
carefully selected to avoid over -detection
The UK NSC does not recommend screening men for
prostate cancer.
“… support the idea that men should be aware prostate
cancer can be diagnosed earlier by PSA testing and
biopsy, and that this can save lives. Men should be able
to request and receive prompt PSA testing and
subsequent management.”
Early detection and risk assessment of prostate cancer
should be offered to asymptomatic men 40 years of age
or older who wish to be screened with an estimated life
expectancy of more than 10 years
No mass screening, and individual screening
needs to be evaluated (guidelines produced
before the publication of the results of ERSPC et
PCLO in 2009)
PSA testing is useful for at-risk populations and
for young patients, with comorbidities.
No mass prostate cancer screening organised in
the UK (waiting for the results from the UK
ProTect study in 2014)
However the British urologists recommend
informing men about the benefits of PSA testing
After providing information, PSA testing started in
men >40 years can enable early detection of
prostate cancer and to evaluate the risk of
prostate cancer
NB: NICE have a guideline for diagnosis and treatment of prostate cancer, but they do not cover early detection: in the UK, there is
no organised screening program for prostate cancer but an informed choice program, Prostate Cancer Risk Management, has been
introduced. (Cancer Screening NHS 2012)
66
Table 11: Kallikrein 2 (hK2): Study characteristics and results
Population
included (how
Detection / screening
selected,
test(s)
number, age)
Prospective case-control studies
Nam 2000, /
Serum from
hK2: time-resolved
June 1998324/404 (80%) immunofluorometric
January
consecutive
assay (mouse MAb)
1999 /
patients, in a
fPSA and tPSA:
Toronto,
single center
Immulite
Canada [87]
referred for
chemiluminescence
PSA ≥4 ng/mL system (Diagnostics
or between 3-4 Products Corporation)
ng/mL with
Biopsy: Sextant USabnormal DRE guided; 18-gauge
No information spring-loaded biopsy
on biopsy
device
protocol
Study ID /
place (ref)
Sample
processing
and storage
Plasma
separated
and stored at
-70°C
67
Outcomes
measured
Results
Histological
Cases: Prostate
presence of
cancer: n=159
prostate
Controls
adenocarcinoma
● Normal
at biopsy
prostate:
n=83
● BPH: n=35
● PIN: n=47
hK2 (ng/mL): 1.18
vs 0.53; p=0.0001
hK2/fPSA: 1.17 vs
0.62; p=0.0001
Multivariate
analyses: OR for
prostate cancer
increased with hK2
and hK2/fPSA
Comments
Study ID /
place (ref)
Scorilas
2003 /
January
1992December
1997
/Padova,
Italy [88]
Population
included (how
selected,
number, age)
345 men
undergoing
biopsy
Targeted
population:
BPH: n=174
PCa: n=171
Detection / screening
test(s)
hK2: time-resolved
immunofluorometric
assay
fPSA and tPSA:
Immulite
chemiluminescence
system (Diagnostics
Products Corporation)
No information
on biopsy
protocol
Stephan
2005 / 19972001 / Berlin,
Germany
[89]
475 referred
men for biopsy,
Age: mean=64
(range=43-86)
Targeted
population:
BPH: n=128
PCa: n=347
hK2: Toronto research
assay
fPSA and tPSA:
Immulite
chemiluminescence
system (Diagnostics
Products Corporation)
Sample
processing
and storage
Serum
obtained
under
standardized
conditions,
specimens
were
residuals
from routine
testing,
stored at 70°C until
analysis
ND
No information
on biopsy
protocol
68
Outcomes
measured
?
Results
Cases: Prostate
cancer: n=171
Controls: BPH:
n=174
hK2: statistically
different between
groups
For all tPSA
ranges, hK2 was
not significantly
different for
prostate cancer or
BPH
Ratios f/tPSAS,
hK2/fPSA and
hK2/(f/tPSA) were
all statistically
significantly
different for
prostate cancer or
BPH; hK2/tPSA
was not
Comments
Population
Study ID /
included (how
place (ref)
selected,
number, age)
Retrospective cohort studies
Becker
serum samples
2000a / PCa: from:
1991-1993 /
● healthy
Malmo,
volunteers
Sweden;
(25 female
BPH: 1994and 25 male)
1997 /
● 54 BPH
Michigan, US
patients
[137]
● 57 with
advanced
PCa
● 136 with
localised Pca
● No
information
on biopsy
protocol
Detection / screening
test(s)
hK2 immunofluorometric
assay; analytical
detection limit:
0.01ng/mL; functional
sensitivity: 0.05 ng/mL
antibodies from: Liljas
Clin Chem 1991 and
Lovgren, J, et al
Production of
recombinant PSA and
hK2 and analysis of their
immunologic crossreactivity. Biochem
Biophys Res Comm,
213: 888, 1995
PSA-T and PSA-F:
DELFIA Prostatus PSA
F/T Dual Assay
Sample
processing
and storage
Blood
samples
taken before
any
treatment
BPH and
local PCa:
sera stored
at 4°C for
max 3 days,
then at -20°C
for max 1
week and
then at -80°C
for max 3
years
Advanced
PCa: sera
stored at
-20°C for
max 7 years
Samples
thawed max
3 times prior
to test.
69
Outcomes
measured
Sensitivity and
specificity to
identify pts ±
PCa
Results
Comments
Results for BPH vs
local cancer vs
advanced cancer
hK2 (ng/mL): 0.055
vs 0.085 vs 0.57
p<0.0001 for all
comparisons;
hK2/tPSA: 1.6 vs
1.3 vs 1.4; NS or
slightly significant;
hK2/fPSA: 8.8 vs
13 vs 12 NS or
slightly significant;
hK2 X tPSA/fPSA:
0.34 vs 0.91 vs 5.9;
p<0.0001 for all
comparisons;
Single ,
patients not
recruited
specifically for
this study
hK2 X tPSA/fPSA:
AUC=0.81 p=0.025
Study ID /
place (ref)
Becker
2000b /
Goteborg,
Sweden
(ERSPC)
[138]
Population
included (how
selected,
number, age)
serum samples
from a
randomized
PCa screening
trial (Goteborg
Screening
Study): 5853
out of 9811
accepted to
participate.
This study
involved
samples from
604/611 (92%)
men who had
agreed to
undergo
sextant biopsy
with tPSA ≥3
ng/mL
144/145
samples from
men with PCa
included
Detection / screening
test(s)
hK2 immuno-fluorimetric
assay; In-house
research assay
(functional sensitivity
0.030 ng/mL, crossreactivity with PSA less
than 0.01%)
tPSA and fPSA: DELFIA
ProStatus PSA F/T Dual
Assay
pre-analysis conditions
defined (in house hK2
dosage)
Sample
processing
and storage
Serum
separated
from blood
cells within
3h; frozen &
stored at 20°C;
t-PSA/f-PSA
assays within
2 weeks of
sampling and
3 h of
thawing;
hK2 assay
within 3
years, using
aliquots from
sample at 1st
thawing –
stored at 20°C for max
2 years, and
then at -70°C
without
thawing
70
Outcomes
measured
Sensitivity and
specificity of
biomarker to
predict presence
of PCa at
biopsy,
retrospectively
Results
Comments
604 with tPSA≥3.0
ng/mL: 460 benign
and 144 PC of
which: 541 with
tPSA 3.0 – 10.0
ng/mL; 439 benign
and 102 PCa
AUC
hK2XPSAT/FPSA =
0.807
AUC PSAT = 0.696
Significant
improvement
for sensitivity
and specificity
for PCa by
combining
hK2 with tPSA/f-PSA
Population
Study ID /
included (how
place (ref)
selected,
number, age)
Steuber 2007 Single center
/ 1999-2000 / study
Hamburg,
355 men
Germany
referred for
[139]
TRUS-guided
sextant biopsy
due to PSA ≥4
ng/mL or
abnormal DRE
High number of
men with PCa:
n=234 (66%),
with 50% men
undergoing
repeat biopsy
Biased
population?
TRUS-guided
bilateral
sextant biopsy
of the
peripheral zone
Detection / screening
test(s)
Sample
processing
and storage
hK2: 3-step
immunoassay (details
Becker et al Clin Chem
2000;46:198-206):
analytical detection limit:
0.003ng/mL;
tPSA and fPSA: DELFIA
ProStatus PSA F/T Dual
Assay
Blood taken
before
manipulation;
serum
collected and
immediately
stored at 80°C until
analysis
Outcomes
measured
Results
Comments
Cancer vs no
cancer:
hK2 (ng/mL): 0.074
vs 0.060
hK2 did not
add
diagnostic
information
Univariate OR:
in all patients: 45.9
(1.25-16.87)
p=0.036, (OR
should be 4.59??
but no correction
published)
in patients with
PSA 2.0-9.99
ng/mL: 0.68 (0.0218.9)
hK2 was predictive
in whole cohort but
not in PSA grey
zone (2.0-9.9
ng/mL)
Full model
recommended:
fPSA, fPSA-N,
uPAR(I), suPAR(I–
III),
suPAR(II–III) (full
model) AUC 0.779
71
Study ID /
place (ref)
Lilja2007
(and Vickers
2007) [140,
141]
Population
included (how
selected,
number, age)
Participants
aged <50
years old in a
cardiovascular
prevention
project (MPM)
in Malmo,
Sweden;
participants
were linked to
the Swedish
Cancer
Registry to
identify those
who developed
PCa before
end 1999; 3
controls per
case, matched
by age and
date of PSA
blood sample
No information
on biopsy
protocol
Detection / screening
test(s)
Sample
processing
and storage
hK2 measured with a
research assay with a
functional detection limit
of 0.005 ng/mL and
≤0.01% cross-reaction
with PSA;
t-PSA and f-PSA:
DELFIA Prostatus PSA
F/T Dual Assay
EDTA-anticoagulated
blood, rapidly
centrifuged
and stored at
-20°C until
analysis (not
previously
thawed)
72
Outcomes
measured
Predictive value
of various
markers,
including hK2
for PCa on
biopsy
Results
Comments
A tPSA increase of
1 ng/mL was
associated with an
increase in odds of
cancer of 3.69
(95% CI, 2.99 to
4.56);
(AUC) using 10fold cross
validation for three
models: tPSA,
cPSA, and the
combination of
tPSA, fPSA,
%fPSA, and hK2.
The AUCs were
0.762 (tPSA),
0.763 (cPSA), and
0.759 (combined
markers).
hK2 not evaluated
alone
Malmö
Cohort:
21,277
patients (3350 ans)
462/498 PCa
(93%) and
1222 controls
Authors’
stated :
« additional
markers
added little or
no
discriminative
accuracy [to
tPSA]”
Study ID /
place (ref)
Bangma
2004/
Rotterdam,
Netherlands
(ERSPC)
[142]
Population
included (how
selected,
number, age)
Randomly
selected
samples for
men:150
patients/group
1) normal +
tPSA= 0.99.3ng/mL; PV=
15-40mL
(n=143)
2) BPH +
tPSA= 2.49.6ng/mL;
PV=40-199mL
(n=142)
3) prostate
cancer +
tPSA= 1.410.2ng/mL;
PV=15-122mL
(n=146)
Sextant
biopsies
(number of
cores,
unknown)
Anderson
grading (not
Gleason score)
was used
Detection / screening
test(s)
hK2: Access hK2 test –
detection limit=
0.008ng/mL
tPSA and fPSA: Access
immunoanalyser
(Beckman-Coulter)
Sample
processing
and storage
Archived
samples
stored at 80°C after
having been
processed
within 3-4h of
sampling –
thawed once
73
Outcomes
measured
Results
Comments
Group 1 vs 2 vs 3
hK2: 0.07 vs 0.05
vs 0.04 – all
comparisons
statistically
significant
hK2 X
(tPSA/fPSA): 0.55
vs 0.44 vs 0.31 –
all comparisons
statistically
significant
Levels of
(7,5)proPSA,
hK2 and fPSA
could be used
to distinguish
between BPH
and cancer,
but proPSA
and hK2,
alone or
combined, did
not improve
the specificity
of fPSA for
discriminating
between BPH
and cancer
Study ID /
place (ref)
Becker
2000a /
1995-1996 /
Göteborg,
Sweden
(ERSPC)
[138]
Population
included (how
selected,
number, age)
604 men who
underwent
biopsy for PSA
≥3 ng/mL
Detection / screening
test(s)
hK2: in house research
assay: detection limit=
0.030 ng/mL
fPSA and tPSA: DELFIA
Prostatus PSA F/T Dual
Assay
Sample
processing
and storage
Archived
samples,
processed
within 3-4h of
sampling,
stored at 20°C for up
to 2 years,
thawed and
aliquoted
once and
frozen at 70°C until
analysis
within 3
years for hK2
74
Outcomes
measured
Results
Median serum
concentrations of
hK2 and tPSA were
higher in men with
positive biopsy
than in those with
negative biopsy
In multivariate
analyses, tPSA,
fPSA and hK2 all
contributed
significantly to
prediction of
cancer or benign
results from biopsy:
For benign vs
cancer
hK2 X
(tPSA/fPSA):
tPSA≥3 ng/mL:
0.37 vs 0.67
tPSA 3-10 ng/mL:
0.31 vs 0.57
Comments
Study ID /
place (ref)
Vickers 2008
/ 1995-2005 /
Göteborg,
Sweden
(ERSPC)
[143]
Population
included (how
selected,
number, age)
740 men who
underwent
biopsy for PSA
≥3 ng/mL after
1st round PSA
screening in
ERSPC: 192
(26%) with
prostate cancer
recruitment OK
for PCa
Sextant
biopsies
(number of
cores,
unknown)
Detection / screening
test(s)
hK2: in house research
assay: detection limit=
0.035ng/mL
fPSA and tPSA: DELFIA
Prostatus PSA F/T Dual
Assay
Sample
processing
and storage
Archived
samples,
processed
within 3-4h of
sampling,
stored at 20°C for up
to 2 years,
thawed and
aliquoted
once and
frozen at 70°C until
analysis
75
Outcomes
measured
Results
Comments
hK2 (and tPSA):
significantly higher
in men with cancer
Multivariate
analyses: AUC for
full clinical and
laboratory models
better than basic
models (age +
PSA):
Laboratory model:
0.68 vs 0.83
Clinical model:
0.72 vs 0.84
Developed
nomogram
using a
training set
and an
evaluation set
Study ID /
place (ref)
Benchikh
2010 / 20012005 / Tarn,
France
(ERSPC)
[144]
Population
included (how
selected,
number, age)
262/629 men
who underwent
biopsy for PSA
≥3 ng/mL after
1st round PSA
screening in
ERSPC: 83
with prostate
cancer
11 395 men
between 2001
and 2005 in
ERSPC: subpopulation
4 200 (37%) of
whom 629
(15%) high
PSA: 370
(59%) prostate
biopsy
Sextant 12core biopsies
Detection / screening
test(s)
hK2 and iPSA(intact
PSA): with F(ab’)2
fragments of MAbs – to
reduce non-specific
interference.
fPSA and tPSA: DELFIA
Prostatus PSA F/T Dual
Assay
Sample
processing
and storage
Archived
samples,
processed
within 3-4h of
sampling,
stored at 80°C
shipped on
dry ice to
Memorial
SloanKettering
Cancer
Centre (US)
in 2008 for
hK2 testing,
then shipped
to
Wallenberg
Research
Labs
(Sweden) in
2009 for
fPSA, tPSA
and iPSA
76
Outcomes
measured
Using model
from Rotterdam
ERSPC for
previously
unscreened
men number of
biopsies
avoided
Results
Comments
Biopsy threshold
≥20% cancer risk:
● 492 (49%)
biopsies
avoided
● 61 (19%)
cancers
missed
● 12 (4%)
high-grade
cancers
missed
Using the full
kallikrein
panel with a
risk threshold
of 20% would
reduce biopsy
rates by more
than 50% for
men with
elevated PSA
while missing
only a small
number of
cancers (31
out of 152
low-grade and
3 out of 40
high-grade
cancers).Net
benefit
reported for
biopsy
decision using
an algorithm
with all four
markers
Study ID /
place (ref)
Vickers
2010a
/ 1993-2000 /
Rotterdam,
Netherlands
(ERSPC)
[145]
Population
included (how
selected,
number, age)
2,914
previously
unscreened
men
undergoing
biopsy as a
result of
elevated PSA
(>3 ng/mL) in
the Rotterdam
section of the
ERSPC.
Training set:
n=728; with
cancer = 202
(28%); highgrade disease
= 74 (10%).
Validation set:
n=2,186; with
cancer = 605
(28%); highgrade disease
= 219 (10%).
No details on
biopsy protocol
Detection / screening
test(s)
hK2: in-house research
assay – detection limit=
0.035 ng/mL
fPSA and tPSA: DELFIA
ProStatus PSA F/T Dual
Assay
Sample
processing
and storage
Archived
samples
stored at 80°C after
having been
processed
within 3-4h of
sampling
77
Outcomes
measured
Results
Comments
Full laboratory
(age, PSA, f+iPSA,
hK2) and full
clinical (age, PSA,
DRE, f+iPSA, hK2)
models were
statistically better
than base models
Model for every
1000 men with
elevated PSA, 513
fewer biopsies, but
66 men with cancer
(mostly low-stage,
low-grade) would
be advised against
biopsy
Laboratory models
Base: age, tPSA
0.557 (0.524,
0.590) — Full:
age, tPSA, fPSA,
iPSA, hK2 0.713
(0.682, 0.743)
<0.001
Clinical models
Base: DRE, age,
tPSA 0.585 (0.551,
0.619) Full: DRE,
age, tPSA, fPSA,
iPSA, hK2 0.711
(0.681, 0.741)
a panel of four
kallikreins can
help predict
the result of
initial biopsy
in previously
screened men
with elevated
PSA who
have no
history of
negative
biopsy.
(replicated
study)
Study ID /
place (ref)
Vickers
2010b /
1997-2006 /
Rotterdam,
Netherlands
(ERSPC)
[146]
Population
included (how
selected,
number, age)
1,501 men who
had biopsy
after 2nd or 3rd
round screen;
cancer = 388
(26%)
Detection / screening
test(s)
hK2: in-house research
assay – detection limit=
0.035 ng/mL
fPSA and tPSA: DELFIA
ProStatus PSA F/T Dual
Assay
No details on
biopsy protocol
Sample
processing
and storage
Archived
samples,
processed
within 3-4h of
sampling,
stored at 80°C
shipped on
dry ice to
Malmö in
2005-2007
Retrospective case-control studies
78
Outcomes
measured
Validation of
model developed
for unscreened
men in
previously
screened men
Results
Comments
Full laboratory and
full clinical models
statistically
significantly better
than base model
for predicting any
cancer or highgrade cancer
Model for every
1000 men with
elevated PSA, 362
fewer biopsies, but
47 men with
cancer would be
advised against
biopsy resulting in
4 high-grade being
missed
a panel of four
kallikreins can
predict the
result of
biopsy for
prostate
cancer in men
with elevated
PSA.
Study ID /
place (ref)
Vickers 2007
/ 1981-1982 /
Malmo,
Sweden
[141]
Population
included (how
selected,
number, age)
Participants in
MPM study:
501 cases with
cancer from
Swedish
registry
(31/12/1999),
1292 controls
(age + date of
blood sample)
Analysed for
44-50
(younger) and
~60 (older)
Detection / screening
test(s)
Sample
processing
and storage
hK2 measured with a
research assay with a
functional detection limit
of 0.005 ng/mL and
≤0.01% cross-reaction
with PSA;
PSA-T and PSA-F:
DELFIA Prostatus PSA
F/T Dual Assay
EDTA-anticoagulated
blood, rapidly
centrifuged
and stored at
-20°C until
analysis (not
previously
thawed)
No details on
biopsy protocol
79
Outcomes
measured
Results
Comments
Cases vs
controls:
hK2 (ng/mL)
● younger:
0.038 vs
.032
● older: 0.065
vs 0.037
Univariate OR hK2
● younger:
1.75 (95%
CI: 1.452.11)
● older: 3.09
(95% CI:
1.97-4.85)
Univariate OR
tPSA
● younger:
6.86 (95%
CI: 4.919.60)
● older: 3.27
(95% CI:
2.12-5.05)
Multivariate AUC
with tPSA + fPSA
+ f/tPSA + hK2
0.819 vs 0.758
(older vs younger)
p=0.03
Additional
biomarkers aid
in
discrimination
cancer/non
cancer more
for older men
than for
younger
Population
Study ID /
included (how
place (ref)
selected,
number, age)
Vickers 2011 Participants in
/ 1991-1996 / MDM study
Malmo,
with PSA >3.0
Sweden
ng/mL: 474
Cohort
cases with
design based cancer from
on caseSwedish
control data
registry
[147]
(21/12/2005)
No details on
biopsy protocol
Detection / screening
test(s)
hK2 measured with a
research assay with a
functional detection limit
of 0.005 ng/mL and
≤0.01% cross-reaction
with PSA;
PSA-T and PSA-F:
DELFIA Prostatus PSA
F/T Dual Assay with
WHO 96/670 -(PSAWHO) and WHO 68/668
(fPSA-WHO) standards
For remaining cohort:
PSA level imputed using
described methods
Sample
processing
and storage
EDTA-anticoagulated
blood,
80
Outcomes
measured
Validation of a
previously
published model
developed on
ERSPC
(Rotterdam)
including tPSA,
fPSA, intact PSA
and hK2 + age
Results
Full model was
better than base
model (tPSA +
age);
For prediction of a
prostate cancer,
the base model
(age plus PSA)
had a Cindex of
0.654 (95% CI:
0.621–0.683),
which was
significantly
increased to 0.751
(95% CI: 0.726–
0.777) for the full
model (age plus
kallikrein panel).
hK2 did not seem
to have an
important effect in
the model
Full model without
hK2 0.752 (0.728–
0.782)
Comments
Population
Study ID /
included (how
place (ref)
selected,
number, age)
Becker
Healthy
2000b /
volunteers: 25
Goteborg,
female and 25
Sweden and male
Michigan, US BPH (negative
[137]
biopsy) = 54
localised
cancer = 136
advanced
cancer = 57
Sextant
biopsies
Detection / screening
test(s)
hK2: in-house research
assay, detection limit =
0.05 ng/mL
PSA-T and PSA-F:
DELFIA Prostatus PSA
F/T Dual Assay
Sample
processing
and storage
Blood taken
before any
treatment.
Sera from
BPH and
local cancer
patients
stored at 4°C
≥3 days,
then at -20°C
for max 1
week and
then -80°C
for max 3
years.
Sera from
advanced
cancer
patients
stored at 20°C for max
7 years.
Sera thawed
max 3 times
81
Outcomes
measured
Results
Comments
Sera from healthy
volunteers all
below hK2
detection limit.
With the exception
of hK2/tPSA and
hK2/fPSA (and
fPSA for BPH/local
cancer) singly and
combined the
biomarkers were
statistically
significantly
different for
BPH/local,
BPH/advanced
and
local/advanced
Discrimination
of men with
and without
PCa in a
randomly
selected
population was
improved
by measuring
hK2 in addition
to tPSA and
fPSA
Table 12: Other biomarkers in cohort and case-control studies: study characteristics
Study ID / design
Population
Detection /
Sample
Outcomes
(ref)
included (how
screening
processing
measured
selected,
test(s)
and storage
number, age)
82
Results
Comments
Study ID / design
(ref)
Roobol 2010 /
ERSPC Rotterdam
rescreened cohort,
prospective [95]
Population
included (how
selected,
number, age)
● Men invited
for
rescreening
within ERSPC
Rotterdam
from
September
2007 to
February
2009
● Single centre
● Men with PSA
≥3.0 ng/mL
PSA or PCA3
score ≥10
were invited
to undergo
DRE, TRUS,
and
lateralised
sextant
biopsy
● n=965
including
n=451 with 2
previous
screens; n =
502 with 3
previous
screen and
n=12 with 4
previous
screen
● 1/3 had
Detection /
screening
test(s)
PCA3:
Progensa (in
Radboud
University,
experimental
laboratory)
PSA:
Hybridtech
(in Erasmus
University,
clinical
laboratory)
Sample
processing
and storage
No details
83
Outcomes
measured
Sensitivity,
specificity to
predict cancer;
correlation
between PSA
and PCA3; ROC
analysis
Results
Comments
721 men
biopsied: 122
PCa (16.9%)
PSA (>3.0
ng/mL): 35.2%
with PCa and
69% without
PCa
PCA3 (>35):
68.0% with PCa
and 55.7%
without PCa;
would have
missed 39 PCa
(5 serious) but
avoided 48.3%
biopsies
Poor correlation
between PSA
and PCA3
Cannot
extrapolate
directly since
men had been
pre-screened
with PSA
low level of
disease
PCA3 as a 1st
line screening
test shows
improved
performance
characteristics
and
identification of
serious
disease
compared with
PSA in a prescreened
population.
Study ID / design
(ref)
Crawford 2012 /
prospective cohort
study [91]
Population
included (how
selected,
number, age)
1 962 men
with PSA
(≥2.5ng/mL or
abnormal
DRE) in 50
centres
referred for
transrectal
biopsy (>10
cores)
1913
informative
samples
Detection /
screening
test(s)
PROGENSA
PCA3 assay
Sample
processing
and storage
Post DRE
urine
sample
before
biopsy (first
catch)
Buffered
samples
shipped
with frozen
gel packs
overnight to
central lab
samples
analysed
<48 hours
after
collection
84
Outcomes
measured
Correlation
between PCA3
and
histopathology
and clinical
outcomes
Specificity of
PSA (>2.5ng/mL)
and PCA3 (>35
and >10)
Results
802/1 913 had
positive biopsy
(42%)
PCA3 >35: false
+ve reduced
from 1 089 to
249 (71%); false
–ve increased
from 17 to 413
(2 300%
increase)
PCA>10 false
+ve decreased
to 35.4%, false –
ve increased
5.6%
No correlation
between PSA
and PCA3
PCA3 but not
PSA was
relatively
sensitive to
suspicious
changes found
at biopsy
PCA3 and PSA
were positively
correlated with
increasing
Gleason score
AUC for PCA3
and PSA was
better than PSA
Comments
PCA3 in
conjunction
with PSA could
potentially
significantly
reduce the
number of
unnecessary
biopsies
Study ID / design
(ref)
Ferro 2012 /
prospective cohort
study [92]
Population
included (how
selected,
number, age)
151 men
referred to
one centre for
1st 18-core
transrectal
prostate
biopsy with
PSA between
2 and 20
ng/mL; DRE
negative and
no previous
biopsy 50 yrs,
no previous
surgery, no
treatment
with
5alphareduct
ase inhibitors,
no prostatitis
Detection /
screening
test(s)
Sample
processing
and storage
Outcomes
measured
Results
Comments
PCA3:
PROGENSA
PSA:
Access2
Immunoassa
y System
analyzer
Serum
stored at 80°C until
assay
First catch
urine after
attentive
DRE,
immediately
before
biopsy
Comparison of
Beckman coulter
PHI:
(p2PSA/fPSA)x
tPSA and PCA
score (PCA3
mRNA/PSA
mRNA X 1000 in
identification of
PCa-ve, PCa+ve
and HGPIN
HGPIN: 24%
PCa +ve: 32%
(~90%
significant)
AUC: [-2]proPSA
=0.73; PHI=0.77;
PCA3=0.71
PHI=38.7: 85%
sensitivity; 61%
specificity)
PCA3=32.5:
81%; sensitivity;
57% specificity
[-2]proPSA ,
fPSA, PHI and
PCA3 may be
useful
predictors of
PCa at 1st
biopsy; PCA3
seems to
discriminate
HGPIN from
other noncancer
conditions
85
Study ID / design
(ref)
Perdona 2013 /
prospective cohort
study [94]
Population
included (how
selected,
number, age)
● 160 men
referred to
one centre for
1st prostate
biopsy (8-core
TRUSguided)
Detection /
screening
test(s)
Sample
processing
and storage
Outcomes
measured
Results
Comments
Single
laboratory
PCA3:
PROGENSA
PSA:
Access2
Immunoassa
y System
analyzer
Serum
stored at 80°C until
assay
First catch
urine after
attentive
DRE,
immediately
before
biopsy
Diagnostic
validity by ROC
analyses for
individual
markers and for
model-based
scores
PCa +ve: 29.4%
(46.8% Gleason
≥7)
[-2]proPSA , PHI
and PCA3
significantly
higher for PCa;
fPSA
significantly
lower
Univariable AUC:
PHI=0.71; [2]proPSA =0.68;
PCA3=0.66 (PHI
and PCA3 not
significantly
different)
Combined PHI
and PCA3 better
than single
marker
Individually PHI
and PCA3
showed no
difference in
ability to predict
PCa at 1st
biopsy, but
combined was
better
86
Study ID / design
(ref)
Ochiai 2013 /
prospective cohort
study [93]
Population
included (how
selected,
number, age)
● 633/647 men
with elevated
PSA or
abnormal
DRE referred
to four
centers in
Japan for 8core prostate
biopsy (158
(24.4%) had
previous
negative
biopsy)
Detection /
screening
test(s)
Sample
processing
and storage
PCA3:
PROGENSA
f/tPSA in
men with
PSA 4-10
ng/mL; PV
with US
PSA density
First voided predictive value
urine
of PCA3, PSA,
sample after PV and PASD
DRE
87
Outcomes
measured
Results
Comments
No relation
between PCA3
and PSA
PCa +ve: 41.7%
PCA3
significantly
higher in PCa
+ve
PCA3 <20:
16.0% PCa +ve
PCA3≥50:
60.6% PCa +ve
PCA3=35:
sensitivity=66.5
%; specificity=
71.6%
diagnostic
accuracy=69.7%
AUC:
PCA3=0.748;
PSAD=0.712;
PV=0.706;
PSA=0.583
PCA3 AUC
significantly
better than PSA
but PSAD
multivariate
analysis
PCA3, PSAD,
PV and previous
biopsy all
independent
predictors of
Combined
PSAD and
PCA3 may be
useful to avoid
unnecessary
biopsy
Study ID / design
(ref)
Adam 2011 /
prospective cohort
[90]
Population
included (how
selected,
number, age)
● 105/107 men
referred to
two centres in
South Africa
for first (82%)
or repeat 13core TRUS
biopsy from
July 2009 to
February
2010
Detection /
screening
test(s)
Sample
processing
and storage
PSA:
Beckman
Coulter
Access
Hybridtech
system
PCA3:
PROGENSA
PV: TRUS
Serum
Predictive value
within 24
of markers
hours of
biopsy
First catch
urine after
DRE, within
24 hours of
biopsy
Blinded
assessment
by the same
staff
88
Outcomes
measured
Results
Comments
PCa +ve: 42.9%
Higher PCA3 in
PCa +ve
PCA3>35:
sensitivity
77.7%;
specificity=50%;
NPV=75%;
PPV=54%
PCA3
independent of
PV but PSA
correlated with
PV
Sum of PCA3
and PSA was not
better than PSA
alone
PCA3 performed
best for PSA
‘grey zone’ (4-10
ng/mL)
PCA3 was not
superior to
PSA; could be
useful in men
with higher PV
and PSA
between 4-10
ng/mL
PCA3 score
was higher and
performed
worse in Black
patients
Study ID / design
(ref)
Bollito 2012 /
prospective cohort
[98]
Population
included (how
selected,
number, age)
● 1,246 men
with elevated
PSA and
negative DRE
referred for
first or repeat
biopsy
● 3 centres
Detection /
screening
test(s)
Sample
processing
and storage
PROGENSA
89
Outcomes
measured
Results
Comments
Unvariate and
multivariate for
PSA, fPSA and
PCA3 to predict
PCa +ve biopsy
PCA3 cutoff 3950 best in repeat
biopsy; >39
avoid 51.9%
unnecessary
biopsy – miss
7.8% cancers
>50 avoid 56.5%
unnecessary
biopsy – miss 29
(10.3%) cancers
(5 aggressive)
Cannot be
extrapolated
since this was
an
observational
study on 3,571
men who had
PCA3 test.
Were further
selected for
analysis 1,246
men who
underwent
prostate biopsy
after PCA3 test
(it is not a
diagnostic study
with systematic
PCA3 and
biopsies)
PCA3 >39
useful in repeat
biopsy;
PCA3 not better
than PSA in 1st
biopsy
Study ID / design
(ref)
Hessels 2007 /
prospective cohort
study [104]
Population
included (how
selected,
number, age)
● Men referred
to one clinic
(monocentrique)for
biopsy for
PSA ≥3 ng/mL
or DRE
● n=108;
age?NA PSA
NA
● 72% PCa
(nonrepresentative
of the general
population
(30%)
● >8 biopsies (6
sextant
peripheral
zone and 2
transition
zone +
suspicious
nodule by
DRE)
Detection /
screening
test(s)
Sample
processing
and storage
TMPRSS2ERG fusion
transcript: rtPCR with
SuperScript
II RNase H
Reverse
Transcriptas
e (Invitrogen)
PCA3 as
described in
another
publication:
RT-PCR in
sediments:
normalizatio
n by PSA
First 30ml
Diagnostic
voided urine performance
after DRE,
immediately
cooled on
ice.
Centrifuged
at 4°C to
obtain
sediment –
then snap
frozen in
liquid N2
and stored
at -70°C
90
Outcomes
measured
Results
Comments
Fusion
transcripts:
Sensitivity:0.3
7
Specificity:
0.93
NPV: 0.36
PPV: 0.94
PCA3: (cutoff
58):
Sensitivity:
0.62
Spe: 0.53
NPV: 0.35
PPV: 0.59
Combined with
PCA3:
Sensitivity: 73%
78/108 patients
(72%) had
positive
biopsies ; this
does not
represent the
typical patient
population
having a
prostate biopsy
based on
elevated serum
PSA levels
Study ID / design
(ref)
Laxman 2006 /
prospective cohort
study [106]
Population
included (how
selected,
number, age)
● 19 Men with
localized
prostate
cancer urine
sampling prior
to needle
biopsy (n=11)
or radical
prostatectomy
(n=8)
● n=19; mean
age=60 years
Detection /
screening
test(s)
Sample
processing
and storage
Outcomes
measured
Results
Comments
TMPRSS2ERG fusion
transcript,
PCA3, RTPCR
30ml urine
after DRE,
collected in
cups
containing
DNA/RNA
preservatio
n.
Centrifuged
to obtain
sediment
and stored
at
-20°C until
RNA
extraction
Number positive
8/19 samples
No comparison
with a cohort of
benign cases
Correlation
with the
detection by
FISH on
tissue
samples
(biopsy or
prostatectom
y)
91
Study ID / design
(ref)
Tomlins 2011 /
prospective cohorts
(5) study [115]
Population
included (how
selected,
number, age)
Men
undergoing
needle biopsy
(2 cohorts) or
radical
prostatectomy
(1 cohort)
n= 1312;
median age :
60 in RP
cohort; 62 in
academic
cohort and 65
in community
cohort (all
baseline
characteristic
s are
available in
supplementar
y material)
606/623 (97%)
patients
recruited in 2
centres: 269
PCa (44%)
187 patients
had had
radical
prostatectomy
606 patients
had positive
biopsy
No details on
Detection /
screening
test(s)
Sample
processing
and storage
TMPRSS2:E
RGa, PCA3
and PSA (to
control for
presence of
prostate
cells) using
TMA
Urine
refrigerated
immediately
, and
processed
within 4h,
mixed with
urine
transport
medium
(1:1) and
stored at
-70°C
92
Outcomes
measured
Results
Comments
Fusion in
prostatectomy:
+ve association
with tumour
volume, no. +ve
cores, % cores
with cancer,
greatest cancer
involvement in a
single core; and
maximum
tumour
dimension. Also
difference in
clinically
significant / nonsignficant
cancers
Fusion in
academic
cohort:
+ve association
with no. +ve
cores, % cores
with cancer,
greatest cancer
and involvement
in a single core.
Also difference
in cancer / no
cancer
Fusion in
community
cohort:
Incorporation of
TMPRSS2:ERG
a and PCA3
into PCPT risk
calculator
improved
clinical outcome
for academic
cohort but not
community
cohort
No data
available about
diagnostic
performances of
the sole PCA3
score (only data
about T2:ERG
associated with
PCA3 are
available)
Detection of
TMPRSS2-ERG
was correlated
with tumor
volume
Study ID / design
(ref)
Laxman 2008b /
prospective cohort
study [105]
Population
included (how
selected,
number, age)
● Single centre
● total of 276
men
undergoing
needle biopsy
(n=216) or
radical
prostatectomy
(n=60)
● (but 257
informative
samples),
mean age =
62.8 (see
supplementar
y table S1) ;
mean PSA =
7.9
● analysis on
138 patients
avec PCa (86
biopsies + et
52 radical
prostatectomy
) and 96
patients with ve biopsies
● No details of
biopsy
protocol
Detection /
screening
test(s)
Sample
processing
and storage
RNA and
Transplex
whole
transcriptom
e
amplification
qPCR for 7
biomarkers:
PCA3,
AMACR,
GOLPH2,
ERG,
TMPRSS2:E
RG, TFF3,
SPINK1
First voided Association with
urine after
prostate cancer
DRE,
diagnosis
collected in
cups
containing
DNA/RNA
preservative
s.
Centrifugati
on to obtain
urine
sediments
93
Outcomes
measured
Results
Comments
Univariated
analysis:
OLPH2,
SPINK1, PCA3
and
TMPRSS2:ERG
significantly
associated with
cancer
Multivariated
regression
showed that a
multiplex model
with these
biomarkers were
better than
serum PSA or
PCA3 alone:
● Sensitivity:
0.659
● Specificity:
0.760
● PPV: 79.8%
● NPV: 60.8%
PCA3 alone:
● Sensitivity:
0.75
● Specificity:
0.56
● PPV: 0.71
● NPV: 0.61
● AUC: 0.661
No data about
inclusion criteria
; patients of the
PR group were
included in the
cancer group
when
comparing to
negative biopsy
group
Study ID / design
(ref)
Nguyen 2011 /
prospective case
control study [108]
Population
included (how
selected,
number, age)
● Single
● 3 groups:
PCa-free
(n=44);
confirmed
PCa (n=46);
negative
biopsy (n=11)
● total n=101
● 46 PCa:
● -21 active
surveillance,
● -11
Pretreatment,
● 4 metastatic
● No details of
biopsy
protocol
Detection /
screening
test(s)
Sample
processing
and storage
Outcomes
measured
qPCR for a
panel of
TMPRSS2:E
RG fusion
markers
First voided Number of
urine (10-40 positives
mL) after
attentive
DRE
(females
and postRP subjects
were
exempt
from DRE
as they
have no
prostate),
collected in
cups
containing
DNA/RNA
preservative
s
Low-speed
centrifuge
at 4°C for
sediment
which was
resuspende
d in TRizol
reagent for
either
immediate
94
RNA
extraction
or stored at
-80°C until
Results
No PCa: 0/44
positive
Confirmed PCa:
16/46 (35%)
Negative
biopsy: 2/11
Comments
Study ID / design
(ref)
Groskopf 2006 /
prospective cohort
[101]
Population
included (how
selected,
number, age)
● Single centre
● patients
scheduled for
biopsy
because PSA
>2.5 and/or
‘other risk
factors’ (n=70
but 68
informative
samples;
mean
age=67);
mean PSA =
7.7)
● PCa-free
(n=52)
● Post-RP
(n=21)
● Women (n=6)
● No details of
biopsy
protocol
Detection /
screening
test(s)
Sample
processing
and storage
APTIMA
PCA3 with
probes for
PCA3 and
PAS
First voided
urine (20-30
mL) after an
attentive
DRE, kept
on ice and
processed
with 4h,
shipped
overnight
on cold
packs and
stored at 70°C for <8
months
95
Outcomes
measured
Results
Cut-off: 50x10-3
Pre-biopsy:
AUC=0.746;
Sensitivity=69%,
Specificity=79%
PPV=0.5,
NPV=0.89
(serum PSA
specificity= 28%)
Comments
Study ID / design
(ref)
van Gils 2007 /
prospective cohort
study [117]
Population
included (how
selected,
number, age)
● Men
undergoing
biopsy in 5
centres with
PSA between
3 and 15
● N=583 but
534
informative
samples,
mean
age=64.3
● mean
PSA=7.49
● tPSA and
fPSA
determined as
part of
standard
clinical
practice – all
other data
collected
prospectively
● standard
TRUS biopsy:
8 biopsies (3
from each
peripheral
zones and 2
transition
zone +
suspicious
nodule is
Detection /
screening
test(s)
Sample
processing
and storage
Dual TRFbased qPCR
for PCA3
From men,
first voided
urine after
DRE;
samples
from
community
hospitals (4)
cooled to
4°C;
processed
within 48h;
samples at
university
hospital
processed
within 1h;
centrifuged
to obtain
sediment,
snap-frozen
in liquid N2
and stored
at -70°C
96
Outcomes
measured
Results
PCA3:
AUC=0.66
Serum PSA:
AUC=0.57
Cut-point = 58:
Sensitivity:
65%
Specificity:
66%
PPV:48%
NPV: 80%
PSA with same
sensitivity:
specificity=47%
Higher PCA3
correlated with
high probability
of +ve biopsy
Comments
Study ID / design
(ref)
Hessels 2003 /
prospective cohort
study [103]
Population
included (how
selected,
number, age)
● 2 centres
● Consecutive
men
undergoing
radical
prostatectomy
for
PSA>3ng/mL
● n=108; NA
● Median PSA:
9.15 ng/mL ;
mean PSA:
11.3 ng/mL
● Positive
control group:
8 PR;
Negative
control group
(cancer and
non-prostate
tissue)
● Validation on
a cohort de
108 patients
undergoing
biopsy for
PSA >
3ng/mL (24
with prostate
cancer and 84
without.
● Radical
prostatectomy
samples.
Detection /
screening
test(s)
Sample
processing
and storage
Outcomes
measured
Results
DD3PCA3
transcripts
using timeresolved
florescencebased RTPCR
Voided
urine after
DRE,
cooled on
ice,
centrifuged
for
sediment,
snap-frozen
in liquid N2
and stored
at -70°C
ratio
DD3PCA3/PSA
AUC=0.72 cut
point=200x10-3
Specificity=83%
Sensitivity=67%
NPV=90%
PPV=53%
AUC PSA:0.59
(calculated from
raw data from
Table 1)
97
Comments
Study ID / design
(ref)
Deras 2008 /
prospective cohort
study [100]
Population
included (how
selected,
number, age)
● 4 centres
● Consecutive
men
undergoing
biopsy for
PSA≥2.5
ng/mL, DRE,
family history
or other risk
factor
● N=570; mean
and median
age=64
● Median PSA:
9.15 ng/mL ;
mean PSA:
11.3 ng/mL
● TRUS guided
biopsy with at
least 10 cores
taken
Detection /
screening
test(s)
Sample
processing
and storage
Outcomes
measured
Results
Comments
PCA3 and
PSA mRNA
with
PROGENSA
PCA3 Assay
PSA assays
performed at
each centre
(not
centralised)
Urine
samples
(first
voiding; 2030 mL) after
DRE,
processed
within 4
hours;
mixed with
equal
volume of
stabilisation
buffer,
stored at 70°C until
tested
Biopsy results
PCA3 score <5:
14% biopsy
positive
PCA3 score
>100: 69%
biopsy positive
AUC for whole
population =
0.686
AUC for 1st
biopsy = 0.703
Overall: 37%+ve
biopsy:
Sensitivity=54%
specificity=74%
PSA <4 ng/mL :
26%+ve biopsy:
Sensitivity=50%
specificity=77%
PPV=54%,
NPV=74%
PSA 4-10 ng/mL
: 38%+ve
biopsy:
Sensitivity=53%
specificity=71%
PSA>10 ng/mL:
48%+ve biopsy:
Sensitivity=61%
specificity=80%
AUC PSA for
whole population
=0.547
280/570 had
previous biopsy
98
Study ID / design
(ref)
Van Gils 2007 /
Prospective cohort
[116]
Population
included (how
selected,
number, age)
● Single centre
● Men
undergoing
TRUS-biopsy
for high PSA
or DRE
● N=67; mean
age=64
● Mean PSA:
8.73 ng/mL
● no information
on biopsy
protocol
●
Detection /
screening
test(s)
Sample
processing
and storage
Quantitative
APTIMA
PCA3 test
for PCA3
and PSA for
mRNA
Prostatic
PCA3 and +ve
fluid
biopsy
discharge
during DRE
collected in
EDTA; 1st
voided urine
collected in
two tubes
with EDTA
(sediments)
Cooled to
4°C and
mailed in
cold packs
to central
lab for
processing
within 48h
of collection
99
Outcomes
measured
Results
23/67 (34%) =
+ve biopsy
PCA3 scores for
biopsy –negative
vs. positive:
Prostatic fluid:
18 vs 73;
p<0.001;
AUC=0.76
Urine: 19 vs 48;
p=0.006;
AUC=0.70
Cut off PCA3=66
in prostatic fluid:
sensitivity =65%
specificity =82%
PPV=65%
NPV=82%
(compared with
PSA: sensitivity
=65%, specificity
=64%)
Cut off PCA3=
43 in urine:
sensitivity =61%
specificity =80%
PPV=61%
NPV=80%(comp
ared with PSA:
sensitivity =61%,
specificity =64%)
Comments
Study ID / design
(ref)
Aubin 2011 samples
from RCT
(Dutasteride
REDUCE) [96, 97]
Population
included (how
selected,
number, age)
● Men
participating
in the
REDUCE
RCT
● N=930 /
1072(dutaster
ide/ placebo);
median age:
62 in both
groups
● Median PSA
= 5.3ng/mL
(dutasteride)
and
5.4ng/mL(plac
ebo)
● Ratio of the
selected
population
representative
of the overall
population
● Initial
negative
biopsy (6 – 12
cores)
● Biopsies
during
surveillance
of between 2
and 4 years
(10 cores)
Detection /
screening
test(s)
Sample
processing
and storage
APTIMA
PCA3 test
for PCA3
and PSA
mRNA
Urine
samples
obtained
before
year2 and
year 4
biopsies
after DRE;
stored on
ice and
processed
with 4h of
sampling;
equal
volume of
Gen-Probe
transport
medium,
frozen at 70°C and
shipped on
dry ice to
central lab
Gen Probe
recommend
a maximum
of 1h before
mixing with
the 100
transport
medium
Outcomes
measured
Results
Comments
PCA3
outperformed
PSA, improved
diagnostic
accuracy when
combined with
PSA and other
variables for
men in both
groups
Placebo: PCA3
associated with
+ve biopsy
(p<0.0001);
multivariate
model – AUC =
0.753 (without
PCA3 = 0.717)
Dutasteride:
multivariate
model – AUC =
0.712 (without
PCA3 = 0.660)
PCA3 assay
was better than
PSA for cancer
detection in
men undergoing
dutasteride
treatment and
improved the
diagnostic
accuracy when
combined with
the PSA level
and other
clinical
variables.
No adjustment
needed for men
in placebo
group
Study ID / design
(ref)
Wang 2009 /
Prospective cohort
[118]
Population
included (how
selected,
number, age)
● Single centre
● Men
undergoing
TRUS 12core sextant
biopsy
because of
high PSA,
history of
HGPIN and/or
%fPSA<15%
● N= 192 but
187
informative
samples
mean age: 62
● Mean
PSA=8.7ng/m
L
Detection /
screening
test(s)
Sample
processing
and storage
Outcomes
measured
Results
Gen-Probe
assay
Initial void
after DRE,
processed
with GenProbe
transport
medium
and
transferred
to central
lab <30°C
correlation with
+ve biopsy
Overall
sensitivity and
specificity of
PCA3>35 for
+ve biopsy was
52.9% and 80%;
PPV=69.7;
NPV=66.1%
Logistic
regression after
adjustment
PCA3
independently
associated with
+ve biopsy
(p=0.003)
No. +ve biopsy
increased with
higher PCA3
score range
(p<0.0001)
101
Comments
Study ID / design
(ref)
Shappell 2009 /
prospective cohort
[110]
Ouyang 2009 /
prospective cohort
[109]
Population
included (how
selected,
number, age)
● Single centre
● Men
undergoing
PCA3 testing
and biopsy
within a larger
cohort
● N=35
● No details of
biopsy
protocol
Detection /
screening
test(s)
Sample
processing
and storage
TMA
platform
(Gen-Probe)
Initial void
after DRE,
processed
with GenProbe
transport
medium
and
transferred
to central
lab on cold
packs
● Single centre
● Men
undergoing
biopsy
● N=106 but 92
informative
samples; age
NA
● 43 with; 49
without
● No details of
biopsy
protocol
Quantitative
RT-PCR
Initial void
correlation with
after DRE,
+ve biopsy
urine
centrifuged
immediately
and
sediment
homogenise
d in TRIzol,
transported
to central
lab, stored
at -80°C
102
Outcomes
measured
Results
Comments
9 (38%) had
previous biopsy
PCA3 sensitivity
and specificity
(without
ASAP/HGPIN):
72.7% and
84.2%
Including
ASAP/HGPIN:
72.7% and
79.2%;
PPV=62%;
NPV=86%
Cut-point: 19.9;
AUC=0.67 (for
PSA; AUC=0.59)
Sensitivity=72%;
specificity=59%;
PPV=61%;
NPV=71%
High % of men
with previous
biopsies
Study ID / design
(ref)
Tinzl 2004 /
prospective cohort
[114]
Population
included (how
selected,
number, age)
● Single
● Men referred
for biopsy for
elevated PSA
or DRE
● N=201 but
158
informative
samples; age
66 (64.8 for
PSA mRNA
positive urine)
● No details of
biopsy
protocol
Detection /
screening
test(s)
Sample
processing
and storage
uPM3™
Initial void
assay for
after DRE,
PCA3 mRNA immediately
stabilised,
stored at
4°C and
processed
within 48h.
Centrifugati
on to obtain
sediments
Cells were
harvested
and lysed,
then snapfrozen,
transported
to central
laboratory
on dry ice
103
Outcomes
measured
Results
Comments
uPM3 (cutoff =
0.5): sensitivity:
82%; specificity:
76%; PPV: 69%
NPV: 87%;
AUC=0.87
tPSA (cut
point=4 ng/mL):
sensitivity: 87%;
specificity: 16%;
PPV: 40% NPV:
65%
PCA3 with PSA
4-10 ng/mL :
sensitivity: 84%;
specificity: 80%;
PPV: 67% NPV:
93%
PCA3 with PSA
<4 ng/mL:
sensitivity: 73%;
specificity: 61%;
PPV: 45% NPV:
75%
PCA3 with PSA
>10 ng/mLmL :
sensitivity: 84%;
specificity: 70%;
PPV: 83% NPV:
71%
Several
inconsistencies
between tables
and text or
between tables
Max PSA in the
cohort = 1486!
Study ID / design
(ref)
Sokoll 2008 /
prospective cohort
[111]
Guazzoni 2011 /
prospective cohort
study [102]
Population
included (how
selected,
number, age)
● 2 laboratories
● 72 men with
known biopsy
outcomes
● N=72; median
age: 61.6;
median
PSA=7
● ≥10 biopsies
Detection /
screening
test(s)
Sample
processing
and storage
Outcomes
measured
Gen-Probe
assay for
PSA mRNA
and PCA3
mRNA at two
sites
Specimens
stored at 70°C for up
to
12months
Correlation with
+ve biopsy
● Single centre
● Men referred
for biopsy
with PSA 2.010 ng/mL and
negative DRE
● n=268 (107
(39.9%) with
cancer; age:
63.3
● 12 to 22
biopsies
● Centralised
analyses of
biopsy
samples
Access tPSA
fPSA, and
2ProPSA
assays
Blood
sample
before any
prostatic
manipulatio
n
104
Results
PCA3,
continuous
score: AUC =
0.706 in site 1 &
0.703 in site 2
cut point=35:
68,1% correctly
classified
Regression line
slope (after log
transformation) =
0.9677
Diagnostic
%pPSA OR
accuracy of
(compared with
p2PSA, [base model) =
2]proPSA and
4.889 (2.507Beckman Coulter 9.534); p<0.001
PHI vs
(multivariate
established
analysis)
predictors
AUC = 0.83
(0.78-.89)
Gain in
predictivity =
0.11 (0.06-0.17)
Comments
Additionally
they
demonstrated a
significant
relation
between
Gleason score,
[-2]proPSA (p =
0.002), and PHI
levels( p <
0.001)
Study ID / design
(ref)
Sokoll 2010 /
prospective cohort
study [112]
Population
included (how
selected,
number, age)
● Prior to
prostate
biopsy, in 4
US cancer
centres
● n=566 (245
with cancer)
age: 63.3 vs
60.5 (cancer
vs noncancer)
● ≥10 biopsies
Detection /
screening
test(s)
Sample
processing
and storage
Outcomes
measured
Analysed in
1 laboratory
using
access2
Immunoassa
y System
analyser for
fPSA, tPSA
(commercial
Abs) and [2]proPSA
Beckman
Coulter
Access
p2PSA ( 1st
study with a
completely
automatic
test, PSAT
access
FPSA
access
See [111]
Blood
sampled
before
manipulatio
ns,
processed
and serum
stored at 80°C
Sensitivity of %[- %[-2]proPSA
2]proPSA at fixed and tPSA were
specificity
significantly
higher in cancer
patients; %fPSA
was lower
AUC was higher
when log tPAS,
log %fPSA and
log %[-2]proPSA
were included for
all patients and
in the subgroups
of PSA 2-4
ng/mL, 4-10
ng/mL and 2-10
ng/mL.
105
Results
Comments
%[−2]proPSA
increased with
increasing
Gleason score
(P < 0.001) and
was higher in
aggressive
cancers (P =
0.03).
Study ID / design
(ref)
Stephan 2009 /
prospective cohort
study [113]
Population
included (how
selected,
number, age)
● Men referred
for biopsy in
Berlin,
Germany
2002-2006
● n=586 (311
with cancer);
age: 62.1 vs
67.2 (cancer
vs noncancer)
● 8 to 12
biopsies
Detection /
screening
test(s)
Sample
processing
and storage
Outcomes
measured
Results
Comments
Access2
Immunoassa
y System
analyser for
fPSA, tPSA
(Hybritech
PSA and
free PSA
kits) and [2]proPSA
(RUO p2PSA
kit)
Test used
automated
Access test
Blood
sampled
before
manipulatio
ns, and at
least 3-4
weeks after,
processed
and serum
stored at 80°C
After
thawing at
RT, samples
analysed
within 3
hours
ANN model AUC
0.85 (0.81–0.88)
Sup to logistic
regression
p2PSA was
higher in cancer
patients (10.78
vs 9.71 pg/mL;
p=0.021)
PSA, %fPSA, [2]proPSA and
p2PSA/%fPSA
were
consistently
different
between cancer
and non-cancer
patients for all
tPSA range and
for tPSA 2-10
ng/mL
[-2]proPSA and
p2PSA/ %fPSA
showed their
superiority to
preferentially
detect
aggressive PCa
(P<0.0001–
0.0008).
Gleason
The new marker
p2PSA
significantly
differentiates
between PCa
and NEM in the
0–30 ng/mL
tPSA range
while the ratios
[-2]proPSA
and
p2PSA/%fPSA
discriminate
also in the 2–10
ng/mL tPSA
range.
RAS
106
Study ID / design
(ref)
Catalona 2011 /
multicentre,
prospective doubleblind, case control
trial [99]
Population
included (how
selected,
number, age)
● 1372 men
enrolled in 8
centres from
Oct 2003 to
June 2009
● Only 892
were
analysed who
had no history
of prostate
cancer,
normal DRE,
PSA 2 to 10
ng/mL and 6core or
greater
● Prostate
biopsy in a
prospective
multiinstitutional
trial.
● 121
prospectively
enrolled; 743
prospectively
enrolled
under
separate
protocols; 28
retrospective
samples
● 98% had ≥10
biopsies and
Detection /
screening
test(s)
Sample
processing
and storage
Outcomes
measured
Results
Comments
Access2
Immunoassa
y System
analyser for
fPSA, tPSA
and p2PSA
Duplicate
assay for
p2PSA
(showed
good
correlation r=
0.9985)
Frozen at 70°C <8 h
after
sampling
(which
allowed
accurate
PHI
measureme
nt)
Validation of
prostate health
index (PHI) in
patients with
PSA 2-10 ng/mL
PHI=
p2PSA/fPSA X
PSA1/2
PHI and p2PSA
were significantly
higher in patients
with cancer
PHI use may
avoid
unnecessary
biopsies
An increasing
prostate health
index was
associated with
a 4.7-fold
increased risk
of prostate
cancer and a
1.61-fold
increased risk
of Gleason
score ≥ to
4+3=7 disease
on biopsy
107
Study ID / design
(ref)
Liang 2011 / casecontrol study nested
in the SABOR cohort
[107]
Population
included (how
selected,
number, age)
● Single centre
474/500
(95%)
patients
analysed
● Controls
matched for
age and
ethnic
distribution
with >5 years
follow-up with
no prostate
cancer
detected (not
necessarily
biopsyconfirmed)
● Cases with
PSA
measured
with 2.5 years
before
diagnosis
● n=474 (227
with cancer);
age: 64.1
● 12 biopsies
Detection /
screening
test(s)
Sample
processing
and storage
Test Access
Beckman
Coulter
Quality
control: 20
blinded
duplicate
samples
randomly
mixed
among the
samples
+ PHI
After
clotting for
30 min at
RT and
centrifugatio
n, serum
stored at 80°C
Samples
thawed and
distributed
into smaller
aliquots
108
Outcomes
measured
Results
Comments
AUC (95% CI)
fPSA: 0.76
(0.71..080)
p2PSA: 0.72
(0.67-0.76)
%fPSA: 0.76
(0.72-0.80)
[-2]proPSA :
0.73 (0.68-0.77)
The AUC for
PSA, 0.84 (95%
CI 0.81–0.88),
was higher than
typically
reported
because many
cancer cases
were referred to
biopsy due to
high PSA
(sampling bias)
and not all
controls were
biopsy
confirmed. The
AUCs for the
other markers
decreased for
PSA between 2
to 10 ng/mL vs
the entire PSA
range, although
the study was
not powered to
conduct this
secondary
subgroup
analyses in this
PSA range
Of the new
markers
freePSA and
%freePSA
Only fPSA
retained
independent
diagnostic
usefulness
compared with
traditional risk
factors, but there
were some
biases
REFERENCES
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