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ONCH-1579; No. of Pages 7
ARTICLE IN PRESS
Critical Reviews in Oncology/Hematology xxx (2011) xxx–xxx
Defining and predicting indolent and low risk prostate cancer
Chris H. Bangma ∗ , Monique J. Roobol
Department of Urology, Erasmus Medical Centre, Rotterdam, The Netherlands
Accepted 4 October 2011
Contents
1.
2.
3.
4.
5.
6.
7.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Defining indolent PCa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Various aspects of indolence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Focal, insignificant, minimal or indolent? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1. Focal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.2. Insignificant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.3. Minimal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Current nomograms predicting indolent cancer are integrated in risk assessment strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The use of nomograms in the setting of the host . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The implementation phase of nomograms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Improving nomograms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
The early detection of asymptomatic prostate cancer has led to the increased incidence of tumours that are unlikely to become symptomatic
during life, so called indolent cancers. The prediction of low risk and indolent prostate cancer is needed to avoid overtreatment by unnecessary
invasive therapies, and select men for active surveillance. Some of the currently available nomograms predicting these low risk tumours have
been validated in independent populations. However, assessment to the compliance with their treatment advises based on the calculation
of probability are scarce. The ultimate value of nomograms for the urologic practice can only be assessed by analysing their practical
implementation.
© 2011 Published by Elsevier Ireland Ltd.
Keywords: Prostate cancer; Low risk disease; Active surveillance; Nomogram; Indolent disease
1. Introduction
The incidence of prostate cancer is increasing worldwide
[1], likely due to an enhanced awareness of prostate cancer.
∗ Corresponding author at: Department of Urology, Erasmus Medical
Centre University, Room H-1093, PO Box 3040, 3000CA Rotterdam, The
Netherlands. Tel.: +31 10 70 33607; fax: +31 10 70 35838.
E-mail address: [email protected] (C.H. Bangma).
As the first evidence of a reduction of prostate specific mortality by screening of asymptomatic men between 55 and
70 years old was provided by the population based European Randomized study of Screening for Prostate Cancer
(ERSPC) [2], and as in many parts of the world the overall
life expectancy increases, individual men consider prostate
cancer (PCa) screening for their personal benefit. App. 50%
of PCa diagnosed in population based studies show the pathological features of the incidental cancers found at autopsy [3].
1040-8428/$ – see front matter © 2011 Published by Elsevier Ireland Ltd.
doi:10.1016/j.critrevonc.2011.10.003
Please cite this article in press as: Bangma CH, Roobol MJ. Defining and predicting indolent and low risk prostate cancer. Crit Rev
Oncol/Hematol (2011), doi:10.1016/j.critrevonc.2011.10.003
ARTICLE IN PRESS
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C.H. Bangma, M.J. Roobol / Critical Reviews in Oncology/Hematology xxx (2011) xxx–xxx
This implies that a subset of men diagnosed with prostate
cancer do not require any active, invasive treatment during
life. In the ERSPC, over 600 men with these clinically and
pathologically defined low risk PCa features were observed
without primary treatment over a period of ten years [4].
Overall survival was 70%, while none died of PCa.
The diagnosis of these small, well differentiated low
risk tumours (i.e. over diagnosis), is the major drawback of
screening for prostate cancer and the major barrier to implement population based PCa screening programs. Up to now
there still is no parameter that can indicate the risk on an
potential low risk cancer adequately before taking a prostate
biopsy. For the same lack of strong prognostic markers also
over treatment is difficult to avoid.
Various nomograms on the probability of low risk or indolent PCa have been constructed [5], in order to distinguish
these cancers from those that are considered relevant at the
time of diagnosis [6].
Since tumour monitoring with potentially delayed active
invasive therapy (this is: active surveillance (AS)) has been
included in the guidelines of PCa treatment, the selection
of men suitable for an AS strategy based on accurate risk
assessment has become pivotal. Guideline advices might
vary substantially, likely related to the literature information they are based upon, and the cultural background of
the health system, especially regarding the attitude for lawsuit procedures. While the American Urologic Association
(www.auanet.org/guidlines) and the American Cancer Society (www.cancer.org) produced guidelines that define their
low risk categories by PSA and Gleason score only, the
National Comprehensive Cancer Network (NCCN) Clinical
Practice Guidelines in Oncology 2010 created an extra low
risk category in addition to the low risk category adding other
histological features, suggesting an extra safety level for the
application of active surveillance (www.nccn.org). Offering
invasive therapy to all men diagnosed with PCa would be
unacceptable in terms of quality of life and cost efficiency [7].
Active Surveillance however becomes increasingly accepted
by patients and physicians as a treatment option [8].
In this review the stages of the development and use of
nomograms predicting indolent PCa are highlighted.
2. Defining indolent PCa
2.1. Various aspects of indolence
The definition of indolence bears various dimensions.
While for patients the most important aspect is the absence
of symptoms of their prostate tumour over time, the pathologist/biologist will be most interested in the molecular
pathways and genomic background of these cancers, in order
to understand the processes that make these malignancies
within their host into the slow growing tumours they are,
with or without latent metastases. From this biological understanding molecular markers and possibilities for medical
Biological diagnosis
Pathologic
3
Focal
Insignificant
6
4
5
2
1
Minimal
7
clinical diagnosis
Fig. 1. Biological diagnosis: No progression during lifetime, PSADT > 10
years. Clinical diagnosis (at time of tumour diagnosis): PSA < 15,
PSAD < 0.15, number of positive biopsy cores < 3. Pathological diagnosis:
One focus< 5 mm PCa in biopsy. Area 1 = one focus of cancer, PSA < 15,
PSAD < 0.15, progression over time; area 2 = <3 pos cores of cancer,
PSA < 15, PSAD < 0.15, no progression during lifetime; area 3 = one focus
of cancer, no progression during lifetime, PSADT > 10 years, PSA > 15,
PSAD > 0.15; area 4 = one focus of cancer, no progression during lifetime, PSADT > 10 years, PSA < 15, PSAD < 0.15; area 5 = one focus of
cancer, progression over time, PSADT < 10 years, PSA > 15, PSAD > 0.15;
area 6 = 3 or more pos cores, no progression during lifetime, PSADT > 10
years, PSA > 15, PSAD > 0.15; area 7 = <3 pos cores of cancer, PSA < 15,
PSAD < 0.15, progression over time, PSADT < 10 years.
intervention might derive. The clinician then is most focused
on the clinical distinction of indolent cancers from tumours
that are relevant and need immediate treatment. For this, clinicians still use the set of parameters that have been developed
based on the histologic studies of Epstein. Indolence therefore
generally is still being defined by histologic features obtained
in a diagnostic set of prostatic biopsies and can be described
as clinically insignificant. In the near future genetic profiling
of tumours may classify tumours in groups according to prognosis [9], and this genetic analysis of minute tissue volumes
from needle biopsies is currently being validated [10].
2.2. Focal, insignificant, minimal or indolent?
2.2.1. Focal
Fig. 1 is an attempt to combine the various terms and
aspects regarding low risk tumours for a clear understanding of their coherence. The term focal cancer has previously
been used to indicate a single spot of low volume of cancer
in biopsies or surgical specimens (less than 0.5 ml) observed
by the pathologist on histology. Men with these cancers and a
low Gleason score frequently belong to the group of patients
that have a long and protracted course of their malignancy in
the absence of symptoms (indicated by clinically insignificant cancers). Some of these very small cancers nevertheless
have been reported as potentially aggressive [11] due to a
poor tumour differentiation, which shows that not all lowvolume disease is expected to have a benign course. Such
tumours correspond with area 5 in Fig. 1. Tumour size as a
Please cite this article in press as: Bangma CH, Roobol MJ. Defining and predicting indolent and low risk prostate cancer. Crit Rev
Oncol/Hematol (2011), doi:10.1016/j.critrevonc.2011.10.003
ONCH-1579; No. of Pages 7
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C.H. Bangma, M.J. Roobol / Critical Reviews in Oncology/Hematology xxx (2011) xxx–xxx
criteria for minimal or insignificant disease has been defined
differently over time, often as less than 0.2 [12], 0.5 [13],
or 1.0 ml, but always in combination with a Gleason sum 6
or less. Remarkably, these criteria have been validated only
recently in population based series [14]. In the ERSPC data
set, the volume of the index tumours in radical prostatectomy
specimens was correlated with life time risk on symptoms,
showing that for tumour stage less than T2b, and Gleason sum
less than 7 the threshold volume for significance was 1.3 ml
for a single or index lesion, and 2.5 ml of total tumour volume. In fact, nomograms predicting smaller tumours could
be adjusted for this validated threshold.
2.2.2. Insignificant
The cancer growth determines the clinical fate of the
tumour. Tumour growth is by nature continuous, but in case
of indolent tumours expected to be slow. Doubling times of
tumour growth of over 10 years have been measured directly
or indirectly with PSA measurements [15]. It is theoretically
possible that for example multifocal or larger sized tumours
(more than 1.3 ml) exist with a slow biologic growth, in
which case these tumours remain asymptomatic. We know
little about such cancers, as data on the follow-up of such
tumours visualized by ultrasonography [16] or MRI [17] is
only just emerging. And most larger tumours are likely subject to therapeutic interventions, as they are not expected to
remain asymptomatic. These tumours correspond with area
6 in Fig. 1.
2.2.3. Minimal
The clinical diagnosis of indolence, i.e. minimal disease (Fig. 1 lowest circle) uses criteria derived from
autopsy information and radical prostatectomy specimens
described by Epstein already in 1993 [18]. These were
enriched towards clinical Epstein criteria by a combination with parameters like PSA and prostatic volume, and
biopsy pathology parameters [19]. They are: PSA < 10 ng/ml,
PSADensity < 0.15 ng/ml/ml, less than 3 positive cancer
cores, no Gleason 4 or higher, Gleason sum 6 or less, and
less than 50% cancer in a biopsy core. Histologic and clinical
criteria formed the base for the construction of nomograms
that have been improved ever since with the increasing clinical experience. It is likely that sooner or later genomic or
proteomic markers from ongoing research will be added.
Identical criteria have been used to select men for active
surveillance programs. From these programs it is well
known that 30–40% of men show tumour progression or
reclassification during the first four years of follow-up [20].
These are the men that are unlikely to have an overlap
with the slow growing tumours, therefore leaving the areas
1 till 4 in Fig. 1 as the most likely areas to incorporate
real indolent tumours, and generally move from inside to
outside the circles of Fig. 1. There must, however, be some
tumours that are reclassified due to their biopsy results and
might have remained biologically insignificant (area 6), just
as there might be tumours that clinically remain similar
3
to minimal disease, but are biologically active (area 7)
and ultimately even metastasize. Schemes, like Fig. 1, and
generally accepted definitions might support professional
discussions, and the validation of data sets, and they might
help to illustrate the classification changes over time.
3. Current nomograms predicting indolent cancer
are integrated in risk assessment strategies
The development of nomograms to predict the outcome
of disease treatments has been stimulated by the growth of
clinical databases overtime. Nomograms are of interest to
inform patients, and support them making treatment choices.
Nomograms also classify patients in risk groups that are used
to select patients for clinical trials.
Current nomograms for predicting indolent cancer (at the
time cancer has been diagnosed) are based on the histological evaluation of step-sectioned radical prostatectomy
specimens from various populations, being clinical referral
patients or men from the general population in a screening
setting. This histopathological surrogate endpoint has to be
validated over time in active surveillance programs. The difference in study populations between the various nomograms
has been acknowledged as the predominant factor responsible for the differences between the nomograms constructed so
far [21]. This also raises questions about the generalisibility
of nomograms.
The currently available nomograms have been discussed
extensively in a previous paper [5]. The nomogram of Kattan
for the prediction of indolent cancer was initially created in
2003 [22] and updated in 2007 on the website of Memorial
Sloan Kettering Cancer Centre, as it was recognized that the
study population gradually changed in composition during
the last five years (www.mskcc.org).
The Steyerberg nomogram was constructed from 247
stage T1C or T2A patients from the ERSPC with a biopsy
Gleason sum of 6 maximum, number of positive cores less
or equal to 50%, total cancer in biopsy cores less or equal to
20 mm and benign tissue in all cores at least 40 mm. All were
treated with radical prostatectomy [21]. Overall 121 (49%) of
247 patients had indolent cancer in the radical prostatectomy
specimen according to the Epstein criteria. Predictions in men
with screen-detected cancers covered a wide range with 60
of 278 (22%) having probabilities below 30%, and 84 of 278
(30%) with a probability of more than 60% having an indolent cancer. This nomogram could identify about 30% in a
screening population having indolent disease. The concept
of indolent disease was validated in the ERSPC population,
showing 100% cancer specific survival over 8 years followup [4,23]. Thus, in the screening setting it was possible to
predict a high probability of indolent cancer in a third of the
men fulfilling the strict selection criteria for this evaluation.
These two nomograms of Kattan and Steyerberg were
compared and validated in a separate screening cohorts, and
showed an excellent discrimination level expressed as AUC
of 77% [24].
Please cite this article in press as: Bangma CH, Roobol MJ. Defining and predicting indolent and low risk prostate cancer. Crit Rev
Oncol/Hematol (2011), doi:10.1016/j.critrevonc.2011.10.003
ONCH-1579; No. of Pages 7
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C.H. Bangma, M.J. Roobol / Critical Reviews in Oncology/Hematology xxx (2011) xxx–xxx
Recently the Steyerberg nomogram was updated with a
correction factor for the use of 12 or 18 cores prostate biopsy
schemes instead of the 6 core biopsy scheme which was
applied in the development cohort [25].
The Nakanishi nomogram in 2007 restricted the construction of a nomogram to men with only one positive
core on twelve prostatic biopsies [26]. All men underwent
radical prostatectomy, and indolent disease, defined as pathologic organ-confined with a tumour volume <0.5 ml without
Gleason grade 4 or 5 cancer, was found in 52% of cases.
Parameters used were age, PSA, prostate volume, and tumour
length in a biopsy core.
A different approach was chosen for the construction of
the Kattan/Cuzick nomogram, using 10-year disease-specific
survival (and not surgical tumour volume) as a base. In a large
population based cohort of 1911 men who received no initial
active prostate cancer therapy in 6 cancer registries within
England and numerous hospitals in the USA, a nomogram
using grade, PSA and stage was constructed for the prediction
if not treated immediately [23]. The nomogram was validated
in a different cohort of men, showing a concordance index of
0.73, and good calibration.
We have to realize that the construction of nomograms discussed and their individual probability outcome calculated is
likely dependent on the upfront selection of men that undergo
prostate biopsies. As Vickers and Roobol showed for men
that ask themselves whether they have to be screened, when
using risk stratification based on DRE, PSA and prostate volume to select men for biopsies, a large subset of men with
potentially low risk tumours is advised not to follow a diagnostic procedure compared to the situation in which only a
PSA cut-off value is used as a biopsy selection criteria [27].
These men are informed on their very low risk of having a
detectable cancer. Risk based strategies for biopsy, as provided by the ERSPC PCa risk calculator (www.uroweb.org)
or the PTCP risk calculator (www.ptcp.org) will have a direct
effect on the performance of calculators for indolence in men
subsequently diagnosed with cancer. It is likely best to use
the set of ERSPC calculators as a whole, in the geographical
area in which they have been validated (Northern Europe),
while using the PTCP calculator, which also includes information on black Americans, in the USA. Nevertheless, for
white Americans, the ERSPC risk calculator performed better in white Americans compared to the PTCP calculator,
as the ERSPC instrument includes prostate volume in its
calculation of probability [28]. Direct head to head comparisons of the two risk calculators have been published recently
and show that overall the ERSPC risk calculator has better
discriminatory capability [29–31].
4. The use of nomograms in the setting of the host
The use of nomograms has been evaluated by Cooperberg, who reported on the existence of over one hundred
of predicting tools in the field of Urology [32]. On their
implementation in the daily practice it is quoted ‘. . .Clearly,
no risk instrument should be used in isolation to direct
patients towards or away from treatment alternatives. . .’ This
is a serious warning to incorporate various host related factors to take clinical decisions. Factors not measured by current
models are for example: baseline quality of life, comorbidity,
life expectancy, and treatment preference.
The importance of comorbidity for PCa treatment decisions, or even for screening, was recently highlighted by
Albertsen et al. [33], illustrating the influence of the Charlson
et al. score [34] on overall and tumour specific survival. For
example, for men aged 66–75 diagnosed with a PCa staged
T1c with a Gleason sum of 7 or less, a Charlson score of
2 or more increases overall mortality by approximately 3fold over a period of twenty years (10-year mortality rate per
100 from 28.8 to 83.1) compared to a Charlson score of 0.
This while the tumour specific mortality rate remained stable with 4.8–5.3%. Using this comorbidity information for
individual predictions is preferable to overall statistics of life
expectancy on a population level that provide a robust but
only very general impression.
5. The implementation phase of nomograms
In order to implement nomograms into the daily urological
routine, a series of validations needs to be followed after the
initial construction phase. Traditionally, a nomogram would
be tested on an independent but relevant population set, such
as has been performed for the predictive ERSPC risk calculator [35]. Next, an evaluation of the implementation should
take place to analyze the impact of the instrument as a decision tool on the actions taken by patients and physicians. This
phase is rarely completed, however, would provide important information on current questions on the hesitance of
physicians and patients on the use of risk assessment tools.
The compliance with biopsy recommendations provided
by the ERSPC prostate cancer risk calculator was evaluated
by van Vugt et al. (accepted for publication BJUI 2011). In
a setting in which 291 men with a request for PCa screening
agreed to submit themselves to the use of this risk assessment
instrument, 84% were compliant with the advise to biopsy or
to refrain from it. Remarkably the most important reason for
non-compliance of the 31 of 119 men that were advised not
to be biopsied, was the reluctance of the physicians due to the
PSA level as a single parameter. It showed that the traditional
biopsy threshold of PSA over 3 ng/ml overruled the advise
given by the nomogram.
Analysis of the compliance to a risk calculator on the
probability of low risk, or indolent, PCa was also performed by van Vugt [BJUI under review 2011]. In five Dutch
hospitals a prospective analysis was done for nearly 300
men initially selected with: clinical stage T1c, T2a-c, PSA
<20 ng/ml, <50% positive sextant biopsy cores, ≤20 mm cancer, ≥40 mm benign tissue, and Gleason ≤ 3 + 3. An advise
for active surveillance was given when the probability of the
Please cite this article in press as: Bangma CH, Roobol MJ. Defining and predicting indolent and low risk prostate cancer. Crit Rev
Oncol/Hematol (2011), doi:10.1016/j.critrevonc.2011.10.003
ARTICLE IN PRESS
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ERSPC risk calculator exceeded 70%. Of all men included
55% (50/213) were advised AS, and 84% of men was compliant with this advise. Remarkably of those men advised to
follow active treatment, 30% chose active surveillance after
obtaining their probability score, in contrast to the active
treatment recommendation. As a result, this recommendation
is used in the authors’ institute (Erasmus MC, Rotterdam) to
illustrate to the patient eligible for inclusion in the PRIAS
project his probability on an indolent cancer. As the nomogram has been developed on data from the age group 55–74
years old, patients aged 75 or older are not offered active
surveillance (but watchful waiting if conservative treatment
is indicated based on life expectancy). Patients younger than
55 diagnosed with minimal low risk disease often consider a
conservative approach for some years in order to delay potential side effects like erectile dysfunction of invasive treatment.
In the absence of a proper risk calculator for this age group,
an active surveillance strategy can be offered with adequate
data registration.
According to Kattan [in this journal], traditional statistical techniques do not evaluate not clinical consequences,
and therefore are not cable of informing the clinical practice well. Decision curve analysis is used to calculate clinical
net benefit [36]. This decision curve analysis informs about
the clinical value of a model where traditional accuracy
metrics do not working with sensitivity and specificity and
AUC curves [www.decisioncurveanalysis.org]. This method
would not need further data on patient preferences, or costs
of effectiveness.
6. Improving nomograms
Current nomograms on the presence of low risk or indolent
disease still lack the long term clinical follow-up on surveillance. With time, the current AS programs [20,37–40] will
provide this information, improving the accuracy of predictions. New prognostic parameters related to the low volume
low grade tumours found by radical prostatectomy will be
validated and incorporated in the nomograms. Candidate
markers at presence are the kallikreins [41] proPSA [42],
PCA3 [43], or histologic markers [44]. Next to these, imaging is expected to play a larger role in the initial assessment
of risk, as it is to be in the monitoring of men on active
surveillance. In a series of 114 men on active surveillance,
positive MRI lesions had a higher risk of upgrading compared
to men with normal MRI’s [45]. Also parameters in diffusion
weighted MRI changed more in progressors over time, than
in non-progressors [46].
The accuracy of nomograms can not only be improved
based on the addition of new parameters, the sample size
and duration of follow-up, but also by the model used, and
the more accurate measurement of the individual parameters,
that is: cleaner data [47]. Having cleaner data starts at the
time of inclusion with an adequate number of initial biopsies
in relation to the prostatic volume. It is often seen that an
5
inadequate number is corrected by a second biopsy only after
6–12 month, which is then regarded as a ‘follow-up’ restaging
biopsy instead of an ‘inclusion’ biopsy. The evaluation of an
early repeat biopsy is therefore compromised, and the current
value of a repeat biopsy after 3–6 months compared to a
restaging biopsy after 12 months is unknown.
7. Conclusions
Nomograms provide us with tools to inform patients and
physicians more objectively with information on present conditions and future events. They allow us to take a step back
and review the experience of many observers, independent
on the recent individual impressions on a disease. When
complex decisions have to be made using various parameters, nomograms can support balancing the weight of each
individual parameter. However, the definition of thresholds
for treatment advises is still heavily influenced by what we
find ‘acceptable’ as a risk. In the urologic practice we consciously or unconsciously make such decisions permanently.
For example by accepting the predictive performance of a
serum marker or an image report, knowing that their accuracy
is often not higher than 70–80%.
In low risk disease existing nomograms can provide a
probability score for the presence of an indolent disease.
Some nomograms appear to be sufficiently robust to be used
in larger geographical areas outside the population where they
have been raised. Continuous awareness on the conditions in
which they are applied (that is the preselection of the population by other interventions), and the clinical outcome over
time (the maturing of data) is needed to improve the nomograms, and to obtain the best predictive results. There is an
increasing confidence in the use and compliance to treatment
advises by patients as well as physicians.
Conflict of interest
None.
Reviewers
Michael W. Kattan, Ph.D., School of Medicine, Case
Western Reserve University, Department of Epidemiology
and Biostatistics, Center for Clinical, Cleveland, OH, United
States.
James A. Eastham, MD, FACS, Chief, Urology Service,
Memorial Sloan-Kettering Cancer Center, Urology Service,
Surgery, 1275 York Avenue, New York, NY 10065, United
States.
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Oncol/Hematol (2011), doi:10.1016/j.critrevonc.2011.10.003
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Biography
Chris H. Bangma (born 4th January, 1959) was nominated Professor and Chairman of the Department of Urology
at Erasmus University Medical Centre in Rotterdam, The
Netherlands, in 2002. He wrote his Ph.D. thesis on ‘Prostate
Specific Antigen and ultrasonography in detection and
follow-up of prostate cancer’ in 1995, and completed his
professional urologic training at the same institute in 1997.
He was granted a research fellowship on gene therapy for
prostate cancer by the Dutch Cancer Society, and spent a
two-year period at Baylor College of Medicine, Houston,
USA, with Prof Timothy Thompson and Peter Scardino,
and afterwards at the oncology lab of Prof. Bob Pinedo at
the Free University in Amsterdam. Chris Bangma participated in the European Fifth Framework Program from 2000
onwards on the preclinical development of gene therapeutic
7
vectors, followed by coordinating the clinical application in the GIANT consortium within the European Sixth
Framework Program. He has participated to the European
Randomized study on Screening of Prostate Cancer ERSPC
from its start in 1992 as a board member, and has coordinated the P-Mark consortium since 2004 till 2008 under the
umbrella of the Sixth Framework Program for the search
and validation of prognostic serum markers for prostate
cancer. Furthermore, he is PI of the PRIAS (Prostate Cancer International Study of Active Surveillance), PROCABIO
(Prostate Cancer Biomarker research in clinical setting of
Active Surveillance, a European initiative to develop tailored
treatment of prostate cancer by biomarkers), ZonMw Translationeel Gentherapeutisch Onderzoek (Oncolytic adenovirus
therapy as a neoadjuvant treatment for prostate cancer), PRONEST (Prostate Research Organizations-Network of Early
Stage Training, 7th Framework EC, Peoples Pogram), and
PCMM (Prostate Cancer Molecular Medicine, the Dutch
integrated academia–industry program) programs/studies.
Chris has contributed to over 150 peer reviewed papers predominantly in the field of prostate and bladder carcinoma.
Currently he is president of the Dutch Urologic Society.
Please cite this article in press as: Bangma CH, Roobol MJ. Defining and predicting indolent and low risk prostate cancer. Crit Rev
Oncol/Hematol (2011), doi:10.1016/j.critrevonc.2011.10.003