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Medical Forum / Diseases and Disorders / Prostate Cancer / June 2005

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Testing for Prostate Cancer Severity

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george conklin - 08 Jun 2005 13:34 GMT
Here is a report from AP.  The medical goal is to find a marker for
significant cancers as opposed to slow-growing cancers of the prostate.
"Statistics from recent studies suggest we have to operate on 19 men to
prevent one death."  The goal is to stop the overtreatment.

------------------------------------

Tests for one blood marker, prostate-specific antigen (PSA), are now used to
help detect prostate malignancy in its early stages. But doctors have found
that many prostate cancers grow so slowly they require no more than watchful
waiting, while others are quickly life-threatening. Unfortunately, right now
there is no test that can tell which cancer requires surgery.

Such a test is needed to avoid unnecessary procedures, Rubin explained.
"Statistics from recent studies suggest that we have to operate on 19 men to
prevent one death, so obviously we are dramatically overtreating," he said.
"The test we want would give more information to a clinician about who could
be treated with just watchful waiting."

AMACR and its relationship to prostate cancer were discovered four years
ago. Rubin, then at the University of Michigan, was the leader of a group
that made one of the first reports on the molecule.

"When you look at prostate cancer, you look at the genes that are most
highly expressed," he said. "This was one of the genes that came up as
highly expressed in cancer cells but not normal cells."

The exact relationship of AMACR to prostate cancer is still unclear, but the
relationship exists, Rubin said. In the study, the risk of death from
prostate cancer for men with low AMACR levels and high Gleason scores -
another measure of prostate cancer severity - was 18-fold greater than for
men without those risk factors.
Leonard Evens - 08 Jun 2005 20:31 GMT
> Here is a report from AP.  The medical goal is to find a marker for
> significant cancers as opposed to slow-growing cancers of the prostate.
[quoted text clipped - 12 lines]
> "Statistics from recent studies suggest that we have to operate on 19 men to
> prevent one death, so obviously we are dramatically overtreating,"

This statement is grossly misleading.  It is based on the latest results
from the Swedish study, which still only involves about a 10 year time
horizon.  Also, it ignores the other increased morbidity statistics for
those followed by watchful waiting as opposed to surgery.

Unfortunately, sometimes people who should know better take a
statistical study designed to investigate one question and try to draw
conclusions from it which the study was not designed for.   This can
often be misleading.

It should be noted that when the first reports of the Swdish study came
out,  critics used the same sort of reasoning to try to conclude that it
didn't whow any advantage in overall mortality or even that those
treated by radical prostatectomy were _more_ likely to die of other
causes.  (It did show a definite advantage with respect to prostate
cancer mortality and similar advantages with respect to progression of
the disease.) The time horizon then was about 6 years.   Now with more
time and data, critics are presumably complaining that the advantage in
overall mortality is not high enough to justify the treatment!

The quoted researcher is trying to dramatize the need to be able to
distinguish cases which "need" treatment from those that don't, and he
is exaggerating one statisitc to do that.   That is unfortunate.
Everyone agrees that there are too many cases of prostate cancer that
are treated unnecessarily.   In present clinical practice, men with
expected life spans  less than ten years are routinely advised to have
their cancers followed by "watchful waiting", followed by hormone
therapy in necessary.  Similarly a few men in their 60s with less
aggressive tumors are advised to do the same.  But generally younger men
are advised to have the cancer treated aggressively in an attempt to
cure it.  As the article notes, there is no way to know whether any
given such man really will be bothered by his cancer during his
lifetime.   Estimates of how many cases are currently treated
unnecessarily vary greatly.  They depend on the criterion chosen for the
meaning of "necessary", and are really just guesses.  The best you can
say is that if you are Swedish, not under 60, and are only interested in
when you will die within ten years, this study shows that radical
prostatectomy will only confer a slight advantage to you in comparision
to watchful waiting followed by hormone therapy if necessary.   It
doesn't address whether you might worry about whether you will die of
prostate cancer,  usually not a pleasant death, or whether or not you
might want to avoid the progression of the disease even if it doesn't
kill you, or whether or not you don't relish hormone therapy.

It is to be hoped that the work described and other similar research
will come up with a definite test to tell whether or not aggressive
treatment is appropriate.  It is also to be hoped that effective methods
with little or no significant side effects will be developed to treat
prostate cancer.  But confusing people with meaningless statistics won't
help anyone.   A real man diagnosed with prostate cancer has to consider
all the facts and all the potential consequences of choosing one mode of
treatment, or possibly no treatment.  Given the large degree of
uncertainty, that is always going to be a difficult choice to make.

> he said.
> "The test we want would give more information to a clinician about who could
[quoted text clipped - 13 lines]
> another measure of prostate cancer severity - was 18-fold greater than for
> men without those risk factors.

Since the great bulk of men who are treated unnecessarily have low to
moderate Gleason scores, that result may or may not have any relevance
except in a limited number of cases.
george conklin - 09 Jun 2005 02:11 GMT
>> Here is a report from AP.  The medical goal is to find a marker for
>> significant cancers as opposed to slow-growing cancers of the prostate.
[quoted text clipped - 23 lines]
> from it which the study was not designed for.   This can often be
> misleading.

  So where are those studies in the USA which are 10 years out now and show
no results with reporting?

  In any case, when all is said and done, we have had surgery for 100 years
now with no evaluation of results.  And it sure looks like any advantages of
current treatments are looking more marginal one would hope.  Maybe after 15
years your idea that differences will emerge may be correct, but no one
knows yet.

  So in 10 more years when more studies are in, if they don't show what you
want them to, you will simply ask for another 20 years worth of studies.
Does this ever end in your mind?
ron - 09 Jun 2005 16:27 GMT
george conklin wrote...snip...
And it sure looks like any advantages of current treatments are looking
more marginal one would hope.

George...That's simply not true.  You have latched onto overall
mortality as the true arbiter of success, and while overall mortality
is easy to grasp, the medical community agrees that it is not a good
measure of success in the case of PCa.  Treatment efficacy of slowly
progressing diseases in elderly populations is poorly measured by
overall or, to a lesser degree,  disease-specific mortality.  At both
the beginning and end of a study of PCa both arms will have zero
difference in mortality (everyone is alive or everyone is dead).  Since
the disease progresses slowly and many people in the study are dieing
of other causes, it is difficult, at best, to discern a significant
difference in mortality somewhere between the beginning and end of the
study.  That's why the majority of investigators prefer disease
progression as an appropriate surrogate endpoint for PCa. Look at the
conclusion from the paper we are discussing (N Engl J Med. 2005 May
12;352(19):1977-84; Radical prostatectomy versus watchful waiting in
early prostate cancer; Bill-Axelson A, Holmberg L, Ruutu M, Haggman M,
Andersson SO, Bratell S, Spangberg A, Busch C, Nordling S, Garmo H,
Palmgren J, Adami HO, Norlen BJ, Johansson JE) and note the word
"substantial".  We agree that many men today are overtreated, but until
there is a way to identify these men or, unless you know that you will
die young, treatment may allow you to live your full allotment of
years...Best wishes and good health, Ron

CONCLUSIONS: Radical prostatectomy reduces disease-specific mortality,
overall mortality, and the risks of metastasis and local progression.
The absolute reduction in the risk of death after 10 years is small,
but the reductions in the risks of metastasis and local tumor
progression are substantial.
george conklin - 09 Jun 2005 19:51 GMT
> george conklin wrote...snip...
> And it sure looks like any advantages of current treatments are looking
[quoted text clipped - 4 lines]
> is easy to grasp, the medical community agrees that it is not a good
> measure of success in the case of PCa.

  That is bullshit.  It merely covers up failure to evaluate and treatment
failures.  After 80 we will all have prostate cancer, and what is it, 8% do
on autopsy before age 30.
Leonard Evens - 09 Jun 2005 21:18 GMT
>>george conklin wrote...snip...
>>And it sure looks like any advantages of current treatments are looking
[quoted text clipped - 8 lines]
> failures.  After 80 we will all have prostate cancer, and what is it, 8% do
> on autopsy before age 30.

this is argument by invective rather than by reasoned discussion.  ron's
points are not addressed.
george conklin - 09 Jun 2005 21:22 GMT
>>>george conklin wrote...snip...
>>>And it sure looks like any advantages of current treatments are looking
[quoted text clipped - 11 lines]
> this is argument by invective rather than by reasoned discussion.  ron's
> points are not addressed.

  Nonsense.  It is the main point your refuse to discuss.  The goal of
treatments is to LIVE longer.  The simple reason why mortality is not
addressed is that the research is so poorly done you have to rely on test
results.  Remember high-dose chemotherapy for breast cancer? The treatments
suppressed the test results but did NOT lenghten life.  And further current
results are long enough out to show that even if current treatments are
doing anything at all, it is so little it is hard to measure yet.  You say
wait another 10 years.  For what?  1% differences?
ron - 10 Jun 2005 22:45 GMT
>    That is bullshit.  It merely covers up failure to evaluate and treatment
> failures.  After 80 we will all have prostate cancer, and what is it, 8% do
> on autopsy before age 30.

from CMAJ 1998;159:685-91

Defining outcome measures has been a particular problem in studies of
prostate cancer. All-cause mortality rates in prostate cancer cohorts
are of limited value because the death rates from prostate cancer and
from other causes in this largely elderly patient group are of
comparable magnitude.21 Thus, differences in the distribution of
coexisting disease in patient cohorts may dramatically affect overall
mortality rates and render comparisons between cohorts meaningless.
Death resulting directly from prostate cancer (cause-specific
mortality) is probably a more objective end-point but is still not
without problems. It is not always possible to ascertain the cause of
death in patients who had advanced prostate cancer. Published studies
often have no explicit criteria for determining that death resulted
from prostate cancer;22 for those that do, the criteria differ from one
study to another.2,3
george conklin - 11 Jun 2005 00:15 GMT
>>    That is bullshit.  It merely covers up failure to evaluate and
>> treatment
[quoted text clipped - 9 lines]
> from other causes in this largely elderly patient group are of
> comparable magnitude.

   This is more nonsense and is being used because real research is not
being done.  If treatment does not extend life, then it is accomplishing
nothing at all except enriching the providers.
Shame.
george conklin - 11 Jun 2005 16:14 GMT
>>    That is bullshit.  It merely covers up failure to evaluate and
>> treatment
[quoted text clipped - 18 lines]
> from prostate cancer;22 for those that do, the criteria differ from one
> study to another.2,3

 Let me add to what I heard at a conference among demographers studying
mortality rates.  The comment accepeted for debate was that what you die of
today is more a function of medical theory than anything else.  Autopsies
are so few now that what is on the death certificiate is highly
questionable.  Doctors in the USA are NOT trained in how to file such
reports.  In Europe they ARE.   And as the article abstract mentions,
criteria for deciding the cause of death differ from one study to another.
In the real world, multiply that by many times.

  In the end, the issue is whether treatments given today extend LIFE.  For
the reasons listed above, doctors have decided that life is not the issue,
only passing the disease onto another group.  So heart specialists want to
pass the blame onto cancer.  Cancer specialists want to pass the blame to
the heart crowd, and everyone wants to blame the patient for not have the
proper lifestyle.  In the end, the revenue keeps coming.
Leonard Evens - 11 Jun 2005 16:40 GMT
>>>   That is bullshit.  It merely covers up failure to evaluate and
>>>treatment
[quoted text clipped - 29 lines]
>
>    In the end, the issue is whether treatments given today extend LIFE.

There are two separate questions here.

First, what should be the criterion for successful treatment of disease?
 It is certainly not true that increasing life expectancy is always the
appropriate criterion.  Quality of life is often equally important and
in some cases may be more important.  Ideally,  physicians should have
information on both matters so they are best able to advise their
patients on treatment decisions.   In my case, for example, minimizing
the risk of advanced prostate cancer was at least as important to me as
any anticipated increase in life expectancy.

The second question is what are appropriate criteria for judging the
success of a treatment method.   I've discussed this matter with a
colleague who is a specialist in mathematical statistics and
considerable experince in biostatistics.   He mentioned that advocates
for using life expectancy are concerned that treatment itself may have
mortaility consequences, so from a statistical point of view, looking at
overall mortality rather than disease specific mortality may be more
appropriate.   But, this argument is more compelling for diseases with
relatively short time horizons.   For diseases with long time horizons,
 the situation is murkier, and this is well understood by experts in
the field.

Ron has raised some specific arguments along this line.  In reasoned
scientific discourse, one would calmly address these arguments rather
than using invective and accusing the medical profession of distorting
the evidence for monetary gain.  Certainly, some physicians are too
concerned with their bottom line.  But those that do the research are
usually a different breed.  They may have biases and vested interests in
one theory or another.  (That would apply both to those whose results
support aggressive treatment and those who are sceptical of such
treatment.)   But I find it implausible that monetary gain is their
primary concern.  If anything, urologists would be better off pushing
hormone therapy on all their patients.  Not only does that provide a
remunerative ready supply of income, but they may also get consulting
fees from drug companies to research particular products.   Keep in mind
also that some of the important research, such as the Swedish study, are
done in countries where physicians are not so influenced by greed.

> For
> the reasons listed above, doctors have decided that life is not the issue,
> only passing the disease onto another group.  So heart specialists want to
> pass the blame onto cancer.  Cancer specialists want to pass the blame to
> the heart crowd, and everyone wants to blame the patient for not have the
> proper lifestyle.  In the end, the revenue keeps coming.
george conklin - 11 Jun 2005 18:57 GMT
>>>>   That is bullshit.  It merely covers up failure to evaluate and
>>>> treatment
[quoted text clipped - 35 lines]
> It is certainly not true that increasing life expectancy is always the
> appropriate criterion.

     In other areas lessened disability is also a high correlate of life
expectancy.  So your false choice below is just that: false choice.

Quality of life is often equally important and
> in some cases may be more important.  Ideally,  physicians should have
> information on both matters so they are best able to advise their patients
> on treatment decisions.

  And of of course it is that information which is what is lacking, since
the research is being resisted, as shown above.

 In my case, for example, minimizing
> the risk of advanced prostate cancer was at least as important to me as
> any anticipated increase in life expectancy.

  Except that may not be the outcomes of current treatments.  No one knows
yet.

> The second question is what are appropriate criteria for judging the
> success of a treatment method.   I've discussed this matter with a
[quoted text clipped - 5 lines]
> But, this argument is more compelling for diseases with relatively short
> time horizons.

  Untrue.  It is even MORE important when treatment outcomes are NOT
immediately visible.  Look at women and high-dose chemotherapy again.  It
turned out the short-term criteria, no visible disease, did NOT lengthen
life, nor, it turns out, offer any improvment over less severe treatments.

For diseases with long time horizons,
>  the situation is murkier, and this is well understood by experts in the
> field.

  No, it is used as an excuse for doing the proper research.  If treatments
were that good, they would have shown mortality differences much more
quickly than previously claimed.

> Ron has raised some specific arguments along this line.  In reasoned
> scientific discourse, one would calmly address these arguments rather than
> using invective and accusing the medical profession of distorting the
> evidence for monetary gain.

  It has been called the prostate industry by others.  It is easy to
collect payment for treatments and virtually impossible to get money to
study outcomes.  This is a moral issue caused by one thing: money.

Certainly, some physicians are too
> concerned with their bottom line.  But those that do the research are
> usually a different breed.  They may have biases and vested interests in
> one theory or another.

  Oh I see.  The guy in the office offering surgery has no interests in HIS
pocketbook?  Are you real?

(That would apply both to those whose results
> support aggressive treatment and those who are sceptical of such
> treatment.)

   Or vice versa.

But I find it implausible that monetary gain is their
> primary concern.  If anything, urologists would be better off pushing
> hormone therapy on all their patients.  Not only does that provide a
> remunerative ready supply of income, but they may also get consulting fees
> from drug companies to research particular products.   Keep in mind also
> that some of the important research, such as the Swedish study, are done
> in countries where physicians are not so influenced by greed.

    You have medical economics to back that up?  I doubt it.  Since many
radial operations fail, the specialists get both:  first the surgery and
then the hormones.  I doubt there is any difference overall.

>> For the reasons listed above, doctors have decided that life is not the
>> issue, only passing the disease onto another group.  So heart specialists
>> want to pass the blame onto cancer.  Cancer specialists want to pass the
>> blame to the heart crowd, and everyone wants to blame the patient for not
>> have the proper lifestyle.  In the end, the revenue keeps coming.

   Surgery does not have to prove to be safe and effective first, like
drugs do.  And we men are paying the price for that lack of oversight.
 
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