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Active Surveillance in prostate cancer
Author
L. Denis
Key words
Prostate Cancer - Screening – Active Surveillance – Watchful Waiting - Overtreatment
Summary
Careful observation of epidemiological data on
incidence of and mortality from prostate cancer
suggest an ever-increasing incidence (number
of new cancers per year) relative to a stable or
slightly declining mortality. This observation
may in part be explained by the ageing of the
male population in Europe, but mostly by overdetection of the disease due to the frequent use
of the Prostate Specific Antigen (PSA) test and
subsequent prostate biopsies.
The results of the European Randomised study
for Screening of Prostate Cancer (ERSPC)
revealed that screening leads to overdetection
of prostate cancer. Approximately half of all
cancers detected by PSA-driven screening are
at low risk of progressing during the lifetime of
the patient and are referred to as either latent
cancer (in the epidemiological setting) or indolent cancer (in the clinical setting).
There is sufficient evidence for managing these
Introduction
Virtually all historical and contemporary evidence
points to unavoidable overdetection of cancer in
screening studies.1 This overdetection should be
constantly on the mind of screening physicians to
avoid subsequent overtreatment.
Epidemiological and clinical data support the AS
option as primary treatment in men with localized
prostate cancer and favourable prognostic factors.2
However, in view of even the slightest chance of
missing the opportunity for potential cure, a meticulous follow-up is recommended to allow changing
management if prognostic factors indicate possible
progression.
The PRIAS study is part of the proposed PROCABIO
project in the Health FP7 programme of the European
Union. This prospective study aims to provide AS in
the context of a scientific study, focused on the iden-
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cancers with a strategy of ‘Active Surveillance’
(AS) rather than any form of aggressive curative
treatment, such as radical prostatectomy and/or
external/internal radiotherapy.
This option for disease management and patient
choice for deferred curative treatment should not
be confused with the frequently used Watchful
Waiting (WW) option. In watchful waiting, curative treatment is avoided because of advanced
age or co-morbidity of the patient, and the
deferred treatment, usually androgen deprivation
treatment (ADT), is intended as palliative treatment when symptomatic progression occurs.
The routine introduction of AS as a primary
treatment option for the management of localised prostate cancer aims to reduce the existing levels of overtreatment. However, carriers
of indolent prostate cancer do remain at some
small risk, and patients are advised to seek careful, scientific medical follow-up.
(BJMO 2007:1;3-7)
tification of new diagnostic or therapeutic biomarkers
in prostate cancer, and the evaluation of PSA kinetics,
velocity and doubling time as possible markers of progressive disease in the follow-up programme.3
What can epidemiological and natural history
studies of prostate cancer teach us?
The introduction of the serum PSA test in the mid
80’s provoked the ever-increasing incidence of prostate cancer in most European countries, along with
an impressive shift towards the detection of cancers
of low grade and stage.2 PSA is still the most effective
biomarker in solid tumours, and despite its non-specificity for prostate cancer and a lot of false positive
and false negative results, remains - together with
its many derivatives - a standard test for measuring the risk of prostate cancer in a given individual.
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Table 1. Incidence and Mortality 2004-2006
in thousands - European Union.25
MEN – Prostate
WOMEN – Breast
Cases
Deaths
Cases
Deaths
2004
202.1
68.2
275.1
88.4
2006
301.5
67.8
319.9
85.3
IARC, 2004-2006
However, its application in population screening,
coupled with increasing indications for and numbers
of TransRectal UltraSound (TRUS) guided biopsies
is directly responsible for a tsunami of newly-diagnosed prostate cancers in Europe.
This fact becomes obvious when comparing the incidence and mortality figures for prostate cancer in the
European Union from 2004 to 2006.4,5 Prostate cancer is the most frequently diagnosed form of cancer
in men, accounting for 24,1% of all cases and is the
third leading cause of death (10,4%) in men. Overall
breast, prostate, colon and lung cancers are the most
common forms of cancer. Together, they count for
more than half of the entire cancer population in the
European Union (25 members in 2006).
Compared to the figures for breast cancer (Table 1),
which increased by approximately 15% over this two
year period, much like other solid tumours, the incidence of prostate cancer increased by an impressive
50%. A small part of the incidence may be due to the
increased life expectancy of the male population, but
these newly detected cancers are identified by the
combination of a PSA test, a set of TRUS-directed
biopsies and dedicated urologists intent on diagnosing prostate cancer in its early stages.
Confirmation came from the ERSPC-released results,
indicating that a large proportion (53%) of newly
found cancers were categorized as ‘overdetection’.6
The major factor leading to this overdetection results
from the detection of small histological cancers and
the ubiquitous preneoplastic, high-grade prostatic
intraepithelial neoplasia (HGPIN) lesions that are
only detectable on autopsy or incidental upon surgery for benign disease of the prostate. These lesions
start in the 3rd decade of life, affect half of all men at
age 50 to reach a staggering 80% at age 80.7,8
Before the PSA era, these foci of cancer were labelled
latent on incidental discovery and classified as T1a
or T1b prostate cancer in the UICC TNM classification.9 The proposed classification by Jewett ended a
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twenty year debate on whether these cancers, detected as incidental findings in the pathology specimen,
required treated. A general consensus developed
among clinicians to follow expectant management
for the T1a lesions, but apply additional treatment
where the tumour volume exceeded more than 5%
of the total specimen.10 Deferred treatment of localised prostate cancer has been a consistent choice in
primary treatment in the European Association of
Urology (EAU) guidelines for low grade, low stage,
localised tumours.11
Defining latent cancer, active surveillance
and watchful waiting
Today the most frequent clinical classification of
prostate cancer is T1c disease. The tumour is impalpable, invisible to imaging and is detected by a set of
core biopsies (minimum of 6) driven by an ‘elevated’
PSA and guided by TRUS. This is where the diagnostic dilemma begins; should a detected cancer be
labelled as indolent and of no consequence to the
patient, or aggressive being a potential lethal threat
to the patient?
If tumour volume exceeds 0.5 cc, is present in more
than two of the core biopsies, is classified as a Gleason
score of more than 3+3 or carries any sign of grade
4 or 5 disease, there is consensus that these cancers
need treatment, and if feasible curative treatment.
Additional prognostic factors, including total PSA
or PSA density are used to confirm the nature of the
cancer. However, PSA in the lower ranges, as clearly
shown in the biopsy results of the Prostate Cancer
Prevention Trial (PCPT) in Table 2, has no clear cutoff value below 4 ng/ml. High-grade prostate cancer
with a possible lethal pathway, even if it takes more
than 10 years, is present in up to 15% of the patients
diagnosed with cancer.12
This explains two clinical facts: a number of the aggressive tumours with PSA above 4 ng/ml, the accepted
‘normal’ value, lead to underdiagnosis in up to 30% of
cases. On the other hand, an indolent cancer meeting
all the criteria for benign disease as presented in Table
3 may still harbour cancer cells, leading to progression
over time in fewer than 5% of cases.
For this reason alone, the trial entry criteria require
willingness and discipline from participants to follow a strict follow-up as outlined in Table 4. This
schedule provides the opportunity choosing curative
treatment, should any signs of progression be noted
on the subsequent check-ups. The patient stops following the schedule if grade 4 or 5 is detected in the
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Table 2. PCa and HGca (>7 Gleason) by PSA level (> 4 ng/ml) in the Prostate Cancer Prevention
Trial study.
PSA ng/ml
Number of men
Number (%)
with prostate cancer
Number (% of cancer) with
high-grade prostate cancer
< 0.5
486
32
(6.6)
4
(12.5)
0.6 – 1.0
791
80
(10.1)
8
(10.0)
1.1 – 2.0
998
170
(17.0)
20
(11.8)
2.1 – 3.0
482
115
(23.9)
22
(19.1)
3.1 – 4.0
193
52
(26.9)
13
(25.0)
Total
2950
449
(15.2)
67
(14.9)
follow-up biopsies, PSA DT is less than 3 years, and
of course, if the patient changes his mind on deferring a curative option in the event the patient or his
treating physician is less than fully confident in the
rationale for the treatment.
Active Surveillance is quite different from the often
discussed watchful waiting. Only healthy people with
a life expectancy of at least 10 years can choose to defer
treatment, as shown in Table 5 at page 6. Watchful
waiting is the preferred treatment term when curative
treatment is not indicated because of co-morbidity or
crippling age, where hormonal treatment would be a
first choice should the cancer cause symptoms.
score, probably the most reliable prognostic factor as
clearly observed in longitudinal studies, has revealed
a gradual shift towards higher Gleason scores.13 This
results in most patients receiving similar Gleason
scores, leading to overtreatment.14
We focus on screening detected prostate cancers, as
the lead and length bias in screening studies favour the
detection of the slow growing tumours. In the ERSPC
study, a comparison of two rounds of screening showed
that indolent cancer was diagnosed in 31.6% of
patients in the first round and in 42.6% in the second,
around four years later. These data suggest that overdetection increases with repeated screening and confirm
the model estimates of 53% of overdetection.15
What can clinical trials tell us?
Of course, stakeholders in this discussion try to
use impressive numbers to convince readers. Based
on the Surveillance Epidemiology and End-Results
(SEER) data, Miller calculated the overtreatment of
the 71,602 men with recorded tumour grade, categorised as low risk and higher risk. He argued that
45% of the lower risk group (10,973 patients) were
potentially over-treated with radiation therapy, while
2,564 patients (10%) were potentially over-treated
with radical prostatectomy.16
Arguments against Active Surveillance are based on
reports that underdiagnosis in a prostate screening
Active Surveillance, no matter how promising as a
choice of treatment, remains a burden for patient
and doctor alike. Scylla and Charybdis, a choice
between the nasty side-effects of curative treatment
and the tiniest chance of missing out on curative
treatment. In particular younger patients with a long
life expectancy fear disease progression.
Adding to the discomfort is the fact that the Gleason
Table 3. Criteria for inclusion in the Active
Surveillance option in the PRIAS trial.
Histology proven adenocarcinoma.
Table 4. Active Surveillance (PRIAS) followup criteria.
Gleason score 3+3=6 (or less).
Minimal number of biopsies.
Maximum one or two cores positive.
Clinical T1c or T2.
PSA test every 3 months for 2 years, if stable, every
6 months thereafter.
Serum PSA level at diagnosis < 10 ng/ml.
PSA D and PSA kinetics (velocity and doubling time)
to evaluate variability in prognosis.
PSA density (PSA D) less than 0,2.
Digital Rectal Examination (DRE) every 6 months.
Patient fit for curative treatment.
Repeat biopsy at 1,4,7 and 10 years. One extra biopsy
if PSA doubling time comes into the 3-10 years range.
Willing to attend follow-up.
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Table 5. Active Surveillance vs.
Watchful Waiting.
Table 6. Expected advantages of Active
Surveillance.
Active Surveillance
Watchful Waiting
Fit patient
Co-morbidity / age
1. Reducing the rampant overtreatment caused by
the overdetection of PCa by screening.
Option cure
Palliation if needed
Indolent tumour
Any tumour
PSA DT
Gleason score > 3+3
Clinical progression
3. Providing a prospective base to study PSA
dynamics to replace unreliable PSA results.
Repetitive biopsies
Symptoms
4. Providing a prospective biorepository for the
development and validation of a new PCa marker
for indolent vs. progressive disease.
population with PSA ranging from 2 to 10 ng/ml
was higher than overdiagnosis in their series (we
prefer the term overdetection).17 Frankly, we cannot
in any way justify the treatment of patients who do
need treatment in the first place.
Excellent studies were performed in Scandinavia,
essentially observations of 223 men with early stage
cancer that did not seek treatment. At 15-year followup, the outcomes were identical to a control group
without prostate cancer. However, at later follow-up,
more cancer-specific deaths occurred in the cancer
group 15-20 years after initial diagnosis.18 Another
study, the Scandinavian Cancer Group Study, compared the long-term outcomes of radical prostatectomy with watchful waiting. A total of 395 men
with early stage prostate cancer (clinical, not through
screening) received surgery or watchful waiting in a
randomised trial (level of evidence 1b). After 8 years,
8.6% of men in the surgery group had died compared
to 14% in the observation group. Although it was calculated that 17 men had to be operated to prevent one
death (maybe 22 for screening), it instilled clinicians
some caution regarding foregoing treatment.19
One of the pioneers and enthusiastic researchers
in Active Surveillance developed a treatment algorithm combining PSA doubling time and followup biopsies. The (ongoing) study involves 299 men
being followed for 8 years. The outcome results are
encouraging; most patients (65%) continue Active
Surveillance. Overall, 85% are alive and only 2 of
299 died of prostate cancer.20
Two new randomized trials have been launched.
The PROTECT treatment trial aims to study the
effectiveness and cost-effectiveness of radical prostatectomy, radical conformal radiotherapy and active
monitoring for PSA detected localised prostate cancer. Effectiveness comprises survival at 5, 10 and 15
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2. Assuring quality of life of PCa carriers by
avoiding unnecessary treatment.
5. Providing evidence based guidelines for the management of early prostate cancer in the PRIAS study.
Europa Uomo, 2007
years, biochemical and clinical disease progression,
impact of treatment and economic evaluation. The
trial is compared to a comparison arm, with the first
analysis expected by 2015.
The National Cancer Institute (USA) has launched
the START trial, a randomised controlled trial to
evaluate active surveillance.
Conclusions
The debate among the different stakeholders will
continue, but the compelling evidence to support
deferred treatment is here to stay.
Quality of life has emerged as a central issue in treatment options, and buying time to delay crippling
treatment looks attractive to a middle-aged male. It
is true that this option requires patients to be well
informed of all aspects of the disease. However, we
are still in great need of adequate models for cancer
progression and are still searching for the Holy Grail,
a reliable, specific biomarker for diagnosis and progression of prostate cancer.
The key messages regarding Active Surveillance as an
equivalent choice in primary treatment of prostate
cancer are presented in Table 6.
References
1. Welch H.G. Should I be tested for Cancer? University of California Press, Berkely – Los Angeles – California, 2004: 224.
2. J. McConnell, L. Denis, H. Akaza, S. Khoury, J. Schalken.
Prostate Cancer. Health Publication, Paris, 2006.
3. Prias study www.prias-project.org
4. P. Boyle, J. Ferlay. Cancer incidence and mortality in
Europe, 2004. Annals of Oncology 2005; 16: 481-488.
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Key messages for clinical practice
1.All cancer screening leads to overdetection. Prostate Cancer is no exception to this rule.
2.Knowledge and insight into the natural history of prostate cancer makes it clear that not all
newly detected cancers need immediate curative treatment.
3.Active Surveillance with an open option to deferred curative treatment is an accepted
primary treatment option for patients and practitioners. Active Surveillance is included
in the Guidelines of the European Association of Urology.
4.A multinational prospective study, PRIAS (www. prias-project.org), provides patients with security
by following PSA dynamics (velocity and doubling time) and PSA density. It provides the scientific community with an established biorepository and test data for the development and validation of new biological markers for diagnosis and prognosis of clinically relevant prostate cancer.
5. J. Ferlay, P. Autier, M. Boniol, M. Heanue, M. Colomber,
P. Boyle. Estimates of the cancer incidence and mortality in
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16. Miller DC et al. Incidence of initial local therapy among
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17. Graif T, Loeb S, Roehl KA et al. Under Diagnosis and Over
Diagnosis of Prostate Cancer: Under Diagnosis and Over
Diagnosis of Prostate Cancer in a Screening Population with
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18. Johansson JE, Andren O, Andersson SO et al. Natural
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19. Bill-Axelson A, Holmberg L, Ruutu M et al. Radical
Prostatectomy Versus Watchful Waiting in Early Prostate
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20. Klotz L. Active Surveillance with Selective Delayed
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Correspondence address
Louis Denis, MD FACS
Lange Gasthuisstraat 35-37
2000 Antwerpen
Tel.: +32.3.223.53.50
Fax.: +32.3.223.53.52
E-mail: [email protected]
Conflicts of interest: no conflicts of financial interest
declared.
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