Prostate Cancer is the number one occurring cancer in men in
the U.S. At the same time there is an ongoing debate as to the need to screen
for this cancer. The problem is that most cases of PCa are indolent and will
not be the cause for a man’s demise. On the other hand we know that a
significant number of cases, 5-15% of them, are aggressive and will result in a
very painful death in a short period, two to six years or less. The problem is
that there is no gold standard test to determine which is which.
Various genetic profiles have been proposed wherein they
measure the expression of a panel of genes and then calculate a metric, usually
some number, which if in a certain range means indolent and outside of the
range is aggressive. The problem of course is; what cells are you making this
measurement on? If you are doing it on the encapsulated prostate cells then you
may be missing the already metastasized cells which have moved to the bone.
Now a recent paper by Gulati et al state[1]:
The chance that a prostate cancer
detected by screening is overdiagnosed (ie, it would not have been detected in
the absence of screening) can vary widely depending on the patient’s age and
tumor characteristics. The purpose of this study is to use age, Gleason score,
and prostate-specific antigen (PSA) level to help inform patients with
screen-detected prostate cancers about the chances their cancers were
overdiagnosed.
First I would be concerned with the definition of
overdiagnosed. It states; “it would not have been detected in the absence of
screening”. One should examine this. If one screens and detects a PCa then that
is an overdiagnosis. If, however, one gets a patient who comes into your clinic
with massive back pain and dysuria, then that patient is not overdiagnosed. The
latter patient is however terminal. Thus I would strongly quibble with this
definition of overdiagnosed.
They continue:
A computer microsimulation model
of prostate cancer natural history was used to generate virtual life histories
in the presence and absence of PSA screening, including an indicator of whether
screen detected cancers are overdiagnosed. A logistic regression model was fit
to nonmetastatic patients diagnosed by screening with PSA less than 10ng/mL,
and a nomogram was created to predict the individualized risk of overdiagnosis
given age, Gleason score, and PSA at diagnosis. The calibrated microsimulation
model closely reproduces observed incidence trends in the Surveillance,
Epidemiology, and End Results registries by age, stage, and Gleason score. The
fitted logistic regression predicts risks of overdiagnosis among PSA-detected
patients with an area under the curve of 0.75. Chances of overdiagnosis range
from 2.9% to 88.1%. The chances of overdiagnosis vary considerably by age,
Gleason score, and PSA at diagnosis. The overdiagnosis nomogram presents
tailored estimates of these risks based on patient and tumor information known
at diagnosis and can be used to inform decisions about treating PSA-detected
prostate cancers.
Now I would also have concern as regards to such a model. We
have been examining them in several cancers and they are complex and require
data which we are yet able to provide. Moreover a logistic analysis is rant
with many problems; it merely hypothesizes a relationship based on a correlation
model which may bear no resemblance to reality. In its place one really needs a
tempero-spatial model which includes genetic mutations in some Markov manner.
Also I would be concerned with an overdiagnosis range of from 2.9% to 88.1%.
Now a comment by Rathner in the same issue states as follows[2]:
Using a nomogram that
incorporates age, Gleason score, and prostate-specific antigen (PSA) level at
diagnosis, individual risks that a screen-detected prostate cancer has been
overdiagnosed can be estimated, according to a new study published January 6 in
the Journal of the National Cancer Institute . The authors used a standard
definition of overdiagnosis to refer to a cancer that would not have become
symptomatic or clinically identifiable if it had not been detected by
screening. Overdiagnosed cancers do not pose a risk to the patient and do not
require treatment, which is associated with significant risks of impotence and
incontinence.
Here there is a clarification of overdiagnosed as meaning
indolent. Indolent means slow growing and of de minimis risk of death from the
lesion. However it is highly problematic to make such a determination unless
one uses genetic metrics on a whole body basis. Techniques using exosomes may
be beneficial if the profiles are stable.
Previous studies have estimated
the risk of overdiagnosis for the U.S. population, with results ranging from
23% to 42% of screen detections. However, risks of overdiagnosis can vary
considerably depending on the patient’s age and tumor characteristics,
highlighting the need for a personalized tool to predict the likelihood of
overdiagnosis. … The authors used a microsimulation model to generate virtual
life histories for a representative population of u S men between 1975 and
2005. Men who develop cancer can be detected based on elevated PSA levels or
development of symptoms. ,,,,
A prediction model was then developed to
predict individual chances of overdiagnosis (i.e., the chance that other-cause
death would precede diagnosis in the absence of PSA screening) given
information known at screen detection. The prediction model estimates that the
chances of overdiagnosis range from 2.9% to 88.1% depending on patient age,
PSA, and Gleason score. …
Freidlin and Korn question
whether the Gulati et al model of the risk of overdiagnosis is useful in
guiding treatment decisions of patients with screen-detected prostate cancer:
“...once an individual has been screened and found to have prostate cancer, the
relevant question is the outcomes of various treatments (treatment morbidity,
prostate cancer symptoms and death), and not the probability of an event
[detection of prostate cancer] that could have happened if the individual had
not been screened.”
One then must ask if it is ethical to perform a fully
blinded randomized trial to ascertain the predictions made herein. As much as I
am a fan of models, this is not a phenomenological model. It merely uses data
from previous diagnostic tests to ascertain the importance of certain metrics.
As such it lack what I believe is a sine qua non to approaches like this, a
physical model with predictability.
Now comments in Healio state the following[3]:
Researchers assessed risk for overdiagnosis — defined as a
cancer detected through screening that otherwise would have been asymptomatic
or clinically unapparent— using a microsimulation model of virtual life
histories of men aged 50 to 84 years from 1975 to 2005.
Researchers then applied SEER prostate cancer incidence and PSA
screening data to the virtual models. Results indicated that the odds for
overdiagnosis increased by 12.9% (95% CI, 12.2-13.6) for each additional year
of age at the time of diagnosis.
One of the concerns is that using SEER from 1975 to 2005 may
insert a bias in age since PSA was not used to any extent until 1995 at the
earliest. Thus half the data was without PSA testing and thus the older men may
very well already have PCa.
A Gleason score of at least 7 was
associated with a 19.5% (95% CI, 11.7-26.5) decrease in the risk for
overdiagnosis when compared with a Gleason score of 6 or lower (P<.001). The
odds of overdiagnosis decreased by 16.6% (95% CI, 14.2-18.9) with each
additional 1 ng/mL of serum PSA up to 10 ng/mL.
A Gleason of 7 on biopsy may be
really a Gleason of 8 upon prostatectomy. It may even be higher. PSA is also an
issue related to age, prostate volume, BPH, and the better measurements are
those reflecting temporal changes. Single PSA measures have the same problem as
spot blood pressure measures. Researchers found age to be the most statistically
significant risk. Among men with a Gleason score of 6 or lower and PSA levels
from 4 ng/mL to 4.9 ng/mL, those who were aged 50 to 54 years had an 11.6% risk
for overdiagnosis, whereas those who were aged 70 to 74 years had a 59.9% risk
and those who were aged 80 to 84 years had an 83.4% risk.
Age has always been a significant factor and the results
presented here in my opinion just reiterate that fact.
The question is; does such a nomogram have any clinical
value? That is in my opinion problematic. The handful or so of first line
Urologists at major centers will have thousands of cases where they can
ascertain based on a plethora of data a patient’s prognosis, yet even they are
wont to go too far. Patients, in my opinion, may find such an approach as just
another element to add to an already confusing pile of suggestions.
References
Gulati R et al, Individualized Estimates of Overdiagnosis in
Screen-Detected Prostate Cancer, JNCI J Natl Cancer Inst (2014) doi:
10.1093/jnci/djt367 First published online: January 7, 2014
Rathner, Z., Nomogram to determine individualized estimates
of screen-detected prostate cancer overdiagnosis, JNCI J Natl Cancer Inst
(2014) doi: 10.1093/jnci/dju001 First published online: January 7, 2014
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