Will et al conclude[1]:
Patients had to be medically fit for radical
prostatectomy and to have histologically confirmed, clinically localized
prostate cancer (stage T1-T2NxM0 in the tumor–node–metastasis classification
system according to the American Joint Committee on Cancer) of any grade
diagnosed within the previous 12 months. Patients also had to have a PSA value
of less than 50 ng per milliliter, an age of 75 years or less, negative results
on a bone scan for metastatic disease, and a life expectancy of at least 10
years from the time of randomization. The study sites assessed eligibility on
the basis of locally obtained PSA values and biopsy readings. After
randomization, a central pathologist reviewed the biopsy and
radical-prostatectomy specimens, and a central laboratory measured PSA.[2]….
Among men with localized prostate cancer detected during the early era of PSA
testing, radical prostatectomy did not significantly reduce all-cause or
prostate-cancer mortality, as compared with observation, through at least 12
years of follow-up. Absolute differences were less than 3 percentage points.
Let us first give some substance to the data and terms. This
conclusion may have significant impact on many men who may very well be denied
care under the ACA CCE rules if this paper stands and is interpreted without
comment. Our objective is to analyze the paper to some extant but more
importantly to raise an opinion which may re-interpret the results.
Let us first then define in some detail the AJCC terms[3]
· T1: tumor present, but not detectable
clinically or with imaging
- T1a: tumor was incidentally found in less than 5% of prostate tissue resected (for other reasons)
- T1b: tumor was incidentally found in greater than 5% of prostate tissue resected
- T1c: tumor was found in a needle biopsy performed due to an elevated serum PSA
· T2: the tumor can be felt (palpated)
on examination, but has not spread outside the prostate
- T2a: the tumor is in half or less than half of one of the prostate gland's two lobes
- T2b: the tumor is in more than half of one lobe, but not both
- T2c: the tumor is in both lobes
Will et al go on to describe their patients as follows:
…13,022 men with prostate cancer,
5023 were eligible for enrollment. A total of
731 men (14.6%) agreed to participate and underwent
randomization to
radical prostatectomy (364 men) or
observation (367).
The mean age was 67 years. Nearly one third of the
patients were black; 85% reported full independence in activities of daily
living.
The median PSA value was 7.8 ng per milliliter (mean,
10.1).
About 50% of the men had stage T1c disease (not palpable,
detected by means of PSA testing), and about
25% had histologic scores of 7 or higher on the Gleason
scale;
40% of the men had low-risk,
34% intermediate-risk, and
21% high-risk prostate cancer (about 5% had missing
data).
On the basis of central pathological review, 48% of the
patients had histologic scores of 7 or higher on the Gleason scale, and 66% had
tumors in the intermediate-risk or high-risk categories.
D'Amico tumor risk score is used to differentiate in the
above segmentation (low, intermediate, or high), which was based on tumor
stage, the histologic score assigned by the local study site, and the PSA level[4].
As D’Amico states:
In order to have the multivariable
analysis results of the Cox proportional hazards regression model be applicable
in the clinical setting for an individual patient, risk groups were defined.
These risk groups were established from a review of the literature and were
based on the known prognostic factors:
1.
PSA level,
2.
biopsy Gleason score, and
3.
1992 AJCC T stage.
Patients with AJCC clinical T stage
T1c, T2a and PSA level of 10 ng/mL or less and biopsy Gleason score of 6 or
less have been identified to be at low risk (<25% at 5 years) for
posttherapy PSA failure.
Conversely, patients with AJCC
stage T2c disease or a PSA level of more than 20 ng/mL or a biopsy Gleason
score of 8 or more have a risk higher than 50% at 5 years of posttherapy PSA
failure.
The remaining patients with PSA
levels higher than 10 and 20 ng/mL or lower, a biopsy Gleason score of 7, or
AJCC clinical stage T2b have been found to have an intermediate risk (25%-50%
at 5 years of posttherapy PSA failure).
Patients with AJCC clinical stage
T1a, T1b were not managed using implant therapy because of the significant rate
or urinary incontinence noted17
using this approach in patients with a history of a transurethral
resection of the prostate. Therefore, patients with AJCC clinical stage T1a,
T1b disease managed with RP or RT were excluded from the study to ensure
statistically valid comparisons.
We summarize these categories below:
Factor/Category
|
Stage
|
PSA
|
Gleason
|
Low
|
T1c
or T2a
|
PSA Less Than 10
|
6
|
Intermediate
|
T2b
|
10-20
|
7
|
High
|
T2c
|
PSA More Than 20
|
8
or greater
|
Furthermore from D’Amico et al we have the following:
Specifically, patients with biopsy
Gleason score of 2 through 6 had no statistical difference in their estimates
of PSA failure-free survival across all the treatment modalities evaluated in
this study.
First, the comparison of PSA
outcome for expectant management vs treatment is lacking. This comparison would
be particularly relevant in the low-risk patients where 5-year PSA-progression
rates numerically approximate the 10-year clinical-progression rates noted from
expectant management series
Now returning to Till et al who concludes:
Among men
with clinically localized prostate cancer that had been diagnosed after PSA
testing came into practice, our study showed that radical prostatectomy did not
reduce all-cause or prostate-cancer mortality, as compared with observation,
through at least 12 years of follow-up.
The effect of radical prostatectomy on mortality did not
vary according to age, race, self-reported performance status, or coexisting
conditions, but our findings suggest that it may vary according to PSA value
and possibly tumor risk.
Positive results were from multiple subgroup comparisons;
the tests of interaction typically approached but did not reach significance
and may therefore be due to chance.
Among men with PSA levels of 10 ng per milliliter or
less, all-cause mortality was slightly lower at 12 years in the observation
group than in the radical-prostatectomy group; prostate-cancer mortality in the
observation group was 6%, with a nonsignificant absolute reduction of less than
1.0 percentage point in the radical-prostatectomy group.
Among men with low-risk disease, observation was
associated with a nonsignificant reduction in all-cause and prostate cancer
mortality, with no significant between-group difference in bone metastases.
Among men with a PSA value that was greater than 10 ng
per milliliter and possibly among those with intermediate-risk or high-risk
prostate cancer (as determined according to the PSA value, local histologic
findings, and stage), absolute reductions in all-cause mortality with
radical prostatectomy ranged from 6.7 to 13.2 percentage points.
Thus there appears to be a reduction
in survival. But what does that say? In high risk there very well may already
be a metastasis, especially with such a high Gleason score.
Observations
Let me now make several observations. These are opinions which are subject to some further analysis but they in my opinion present several clear concerns and limitations.
1. No PSA velocity measurements are performed: Namely what if we used PSA velocity as a predictor, not just PSA. Gleason scores are ex post facto. Gleason of 8+ is a significant mortality risk. Gleason of 6- is often rare. One does not record a Gleason 1 score for example and Gleason 3-4 is also infrequent.
1. No PSA velocity measurements are performed: Namely what if we used PSA velocity as a predictor, not just PSA. Gleason scores are ex post facto. Gleason of 8+ is a significant mortality risk. Gleason of 6- is often rare. One does not record a Gleason 1 score for example and Gleason 3-4 is also infrequent.
2. No family histories were used: This is
often the sine qua non determinant. If a 1st degree relative had an aggressive
PCa then there is a high chance that the presenting patient will also have
such. Also this test is free. Why it was not included is a concern.
3. No genetic analyses on tumors: The
aggressiveness of the tumor is often demonstrated by the genes it expresses.
Given the ease to do such tests and the limited numbers of patients it should
have been incumbent on the study to have performed this analysis.
4. No attempt to ascertain PCa stem cell:
As with the genetic study not being done, there also was not attempt to
ascertain any stem cell activity.
5. There is no attempt to define an
aggressive form of PCa. One can admit the existence of indolent and aggressive.
However, identifying what constitutes aggressive is questionable at this time.
We have many genetic markers but there is not a bright line test. One can agree
that a small percent are aggressive, and a large percent is indolent but again
no test exists to determine this. Let us assume 5% are aggressive and 95% indolent.
Further the 95% indolent will have no change in survival due to the PCa.
However the 5% may very well have such a change. Furthermore if to get positive
results from a prostatectomy with aggressive forms we must say perform it when
the PSA velocity hits the 0.7 level, more than likely the patients coming to be
seen are lost to the ravages of the disease, especially since they are
performing tests on PSAs of 10. Thus the sample may be contaminated by results
which fail to show any efficacy. That is 5% of all 3 groups will die and thus
there will be de minimis efficacy. Just as we noted in the faulty prior
studies, the wrong levels may very well have been chose, and thus the wrong
question asked. The question should be; what PSA/PSA velocity tuples provide
significant positive survival efficacy from prostatectomy.
6. What if one used PSA velocity and biopsied when it exceeded
0.7 per year. If that were the case then what percent would have an aggressive
form.
Thus it is our belief that although this paper does provide
some valuable results it fails in our opinion to understand and present many
key factors essential for understanding and treating such a prevalent and
deadly disease. Furthermore the alleged conclusions may actually create in my
opinion a clear and present danger for those patients with family histories and
genetically prone prostate cells. Namely under the new ACA regime, this may
very well be used by the Government for refusal of service and result in
substantial mortality and morbidity.
Now strangely NCI reports on FDA approval of a new test
using percent free PSA but not PSA velocity.[5]
They state:
A PSA test score between 4 and 10 ng/mL often prompts
physicians to recommend a prostate biopsy. Most biopsies from men with PSA
scores in that range, however, reveal no cancer or identify cancers that likely
will never pose a health risk. And biopsies themselves have risks, including
the risk of
life-threatening infection.
The Access Hybritech p2PSA test measures a form of PSA
called [-2]proPSA in the blood. Results from the test are combined with a PSA
score and a measurement of free PSA to calculate
the Prostate Health Index, or phi.
FDA approval was based on a clinical study of nearly 660
men, approximately half of whom had prostate cancer. In the study, the phi score was better able to
distinguish between benign conditions and prostate cancer than the PSA score.
The study also found that the probability of having prostate cancer detected
following a biopsy rose as the phi
score increased.
One does question the “life threatening” issues since in
most cases of competent biopsies with proper preparation and execution the morbidity
is low.
Ultimately, as with the other studies, perhaps the issue is the question which was asked. Perhaps the question should have been:
"What, if any, PSA measurement, Free PSA %, and PSA velocity, combined in some metric, will, with radical prostatectomy, increase survival?"
As with any research the key is always the question, not just the result. All too often failure to pose the proper question just reinforces poor judgement.
But in NEJM there is also an interesting and revealiong editorial piece by Thompson and Tangren which states:
These authors indicate other issues with this study. We believe that valuable that this study may be there are many dimensions that need be addressed. Indeed as Thompson and Tangren state:
Those of us who treat this disease are heartened to see men we treated years or decades ago for aggressive, high-grade cancer who remain cancer-free today.
Indeed, there are the many men with PSA of 10-15 with an indolent disease who will never die from the disease. There are also those men who one year have a PSA of 4 and then next 40, and are dead in three years. It would seem clear we are no dealing with the same disease and until we can determine via defects in pathways and the like what the difference is we are like creatures from Plato trying to identify the type on the basis of shadows on the walls of our caves.
Ultimately, as with the other studies, perhaps the issue is the question which was asked. Perhaps the question should have been:
"What, if any, PSA measurement, Free PSA %, and PSA velocity, combined in some metric, will, with radical prostatectomy, increase survival?"
As with any research the key is always the question, not just the result. All too often failure to pose the proper question just reinforces poor judgement.
But in NEJM there is also an interesting and revealiong editorial piece by Thompson and Tangren which states:
On the other hand, high-grade, aggressive prostate cancers usually
have a lethal course if left untreated. Those of us who treat this
disease are heartened to see men we treated years or decades ago for
aggressive, high-grade cancer who remain cancer-free today. It is these
men who are at greatest risk for death from cancer and who are most
likely to benefit from therapy but whom we must treat effectively.
Effective treatments often require multiple therapeutic approaches; for
example, mortality is reduced among men with high-risk tumors in whom
radiation therapy and surgery are augmented by androgen deprivation.
Prostate
cancer is not a monolithic cancer but a spectrum of disease. The
screening, detection, and treatment we provide must focus on cancers
that matter, and future clinical trials must do so as well.
These authors indicate other issues with this study. We believe that valuable that this study may be there are many dimensions that need be addressed. Indeed as Thompson and Tangren state:
Those of us who treat this disease are heartened to see men we treated years or decades ago for aggressive, high-grade cancer who remain cancer-free today.
Indeed, there are the many men with PSA of 10-15 with an indolent disease who will never die from the disease. There are also those men who one year have a PSA of 4 and then next 40, and are dead in three years. It would seem clear we are no dealing with the same disease and until we can determine via defects in pathways and the like what the difference is we are like creatures from Plato trying to identify the type on the basis of shadows on the walls of our caves.
[1]
Will, T., et al, Radical Prostatectomy versus
Observation for Localized Prostate Cancer, NEJM. July 19, 2012.
[2]
Will, T., et al, Radical Prostatectomy versus
Observation for Localized Prostate Cancer, NEJM. July 19, 2012.
[3]
AJCC 6th Edition, 2002. Note D’Amico used the 5th Edition
and thus we should be aware of a possible change. There was none.
[4] D’Amico
et al, JAMA Network | JAMA: The Journal of the American Medical Association |
Biochemical Outcome After Radical Prostatectomy, External Beam Radiation
Therapy, or Interstitial Radiation Therapy for Clinically Localized Prostate Cancer,
1998.
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