First the NY Times author, one Gina Kolata, states:
"The PSA test, which measures a protein released by prostate cells, does what it is supposed to do — indicates a cancer might be present, leading to biopsies to determine if there is a tumor. But it has been difficult to know whether finding prostate cancer early saves lives. Most of the cancers tend to grow very slowly and are never a threat and, with the faster-growing ones, even early diagnosis might be too late."
The PSA test is not just one test. It is not a black and white thing. It is a process that has evolved over time. There is not a good and bad PSA per se. Admittedly if you are 65 and have a PSA of 60 you are in some trouble. But as we now know a PSA of 2.1 when you are 50 is of concern. But more critically the rate of change in PSA is almost diagnostic. Thus a 25% rate of increase per year should be followed up.
In July 2003 Punglia et al in the New England Journal of Medicine published a study which demonstrated that the then current set point for PSA missed many cancers. They stated:
"Adjusting for verification bias significantly increased the area under the ROC curve (i.e., the overall diagnostic performance) of the PSA test, as compared with an unadjusted analysis (0.86 vs. 0.69, P<0.001, for men less than 60 years of age; 0.72 vs. 0.62, P=0.008, for men 60 years of age or older). If the threshold PSA value for undergoing biopsy were set at 4.1 ng per milliliter, 82 percent of cancers in younger men and 65 percent of cancers in older men would be missed. A digital rectal examination that is abnormal but not suspicious for cancer does not affect the overall performance characteristics of the test….A lower threshold level of PSA for recommending prostate biopsy, particularly in younger men, may improve the clinical value of the PSA test."
They presented the following Figure:
The PSA test has been refined over the period of these studies, the PLCO Study, "Prostate, Lung, Colon, Ovary".
Now to issue two, Let us assume that a biopsy is performed. If a Gleason score of 7 is noted then you best have some attention paid, even a 6 is a problem. You have cancer! It will grow. It may very well kill you! That is if you do not die of something else. The problem is twofold; first, the doubling time of the cancer cells may be short, and second, the metastatic potential could be great. For Prostate cancer has the habit of metting to the bones, especially the spine. Does one want to take that risk?
The European study states the following protocol:
"We identified 182,000 men between the ages of 50 and 74 years through registries in seven European countries for inclusion in our study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, 2006..."
The European trial is akin to a Fire House which uses an answering machine which it checks every three days to see if there is a fire. They then study the town with this Fire House and a town without a Fire House and discover that there is no difference in destroyed houses. Well one would perhaps think that having someone there to answer the phone when it rings and then immediately dispatching a fire engine would improve things.
Let me explain. PSA screening once every year, this is based upon a tumor doubling time of 3 months, a DRE and PSA are performed. If the PSA is measured as per Punglia statistic then we would use 2.6 for men under 60. Punglia states:
"These findings, as well as recent data from a randomized trial showing that prostate-cancer treatment improves disease-free survival, 28 indicate that reduction of the threshold PSA level at which biopsy is recommended to 2.6 ng per milliliter, at least in men under 60 years of age, may be reasonable."
Subsequent studies indicate that the added measurement of velocity or rate of change per year is also critical. Thus a 25% per year rate of change should be used as a way to seek an examination.
The American Group provides the following results:
"From 1993 through 2001, we randomly assigned 76,693 men at 10 U.S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended. The numbers of all cancers and deaths and causes of death were ascertained….In the screening group, rates of compliance were 85% for PSA testing and 86% for digital rectal examination. Rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41 to 46% for digital rectal examination. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16 to 1.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70)."
This American group was one with PSA at 4.0 and a second where PSA may or may not have been used as was a DRE. This is NOT a comparison of two distinct samples. The control group is a mix of anything and everything. Thus there are in my opinion two major faults;
First, the PSA numbers were set too high since we now know they should be set lower.
Second, the Control group was not the untested group as may be inferred, it was unlike the European study which alleges no treatment, and it was tested but just haphazardly.
Thus we have four groups:
Group 1 (American): PSA at 4.0 and DRE annually
Group 2: (American) PSA at 4.0 and DRE haphazardly
Group 3: (European) PSA at 4.0 but only once every 4 years
Group 4: (European) No screening
What is missing is what we now know to be the case. A PSA at 2.0 and an age dependent PSA with velocity measurements.
Thus our conclusion is that the Bayesian analysis, namely determining the probability of death given PSA measurements is or is not independent of the PSA measurement. We believe that the Bayesian approach of using screening at 2.0 under 60 and then testing and addressing a malignancy will reduce the a posteriori mortality. The data assessing that hypothesis appears to bear that out.
The NY Times headline is confusing, and frankly in error. The study proved at best that the specific screening protocol did not result in longer lives. That has been known now for six years! The question is what protocol will prolong life. It is not that PSA does not work; it just does not work as it was being used ten years ago. This study only shows that.
The Times further states:
"In the European study, 48 men were told they had prostate cancer and needlessly treated for it for every man whose death was prevented within a decade after having had a PSA test. Dr. Peter B. Bach, a physician and epidemiologist at Memorial Sloan-Kettering Cancer Center, says one way to think of the data is to suppose he has a PSA test today. It leads to a biopsy that reveals he has prostate cancer, and he is treated for it. There is a one in 50 chance that, in 2019 or later, he will be spared death from a cancer that would otherwise have killed him. And there is a 49 in 50 chance that he will have been treated unnecessarily for a cancer that was never a threat to his life. Prostate cancer treatment can result in impotence and incontinence when surgery is used to destroy the prostate, and, at times, painful defecation or chronic diarrhea when the treatment is radiation."
Again that is not what the data says. The data shows that men were treated and did not die in either case. The two US cases are so overlapping that a bright line is not there and the European cases due to the longer time between screenings also merge to being identical. The statement about impotence and the like are scare statements since we know that if you have cancer and if we do not know the true level of malignancy then we just remove it, we don't want to be sued.
This leads to the final issue, genetic evaluation. Namely as we have discussed elsewhere we believe that genetic testing for predisposition, presence, staging, and prevention is slowly making progress. It is this effort which will eventually bear fruit.
In a 2005 paper in Science by Tomlins et al they state:
"A central aim in cancer research is to identify altered genes that play a causal role in cancer development. Many such genes have been identified through the analysis of recurrent chromosomal rearrangements that are characteristic of leukemias, lymphomas, and sarcomas (1). These rearrangements are of two general types. In the first, the promoter and/ or enhancer elements of one gene are aberrantly juxtaposed to a proto-oncogene, thus causing altered expression of an oncogenic protein. This type of rearrangement is exemplified by the apposition of immunoglobulin (IG) and T cell receptor (TCR) genes to MYC, leading to activation of this oncogene in B and T cell malignancies, respectively (2). In the second, the rearrangement fuses two genes, resulting in the production of a fusion protein that may have a new or altered activity…"
Their conclusion is:
"The existence of recurring gene fusions of TMPRSS2 to the oncogenic ETS family members ERG and ETV1 may have important implications for understanding prostate cancer tumorigenesis and developing novel diagnostics and targeted therapeutics. Several lines of evidence suggest that these rearrangements occur in the majority of prostate cancer samples and drive ETS family member expression. "
Thus gene expression will be essential as a diagnostic tool. In a recent 2008 NEJM article by Zheng et al they state:
"Multiple SNPs in each of the five regions were associated with prostate cancer in single SNP analysis. When the most significant SNP from each of the five regions was selected and included in a multivariate analysis, each SNP remained significant after adjustment for other SNPs and family history. Together, the five SNPs and family history were estimated to account for 46% of the cases of prostate cancer in the Swedish men we studied. The five SNPs plus family history had a cumulative association with prostate cancer ... In men who had any five or more of these factors associated with prostate cancer, the odds ratio for prostate cancer was 9.46 …, as compared with men without any of the factors. The cumulative effect of these variants and family history was independent of serum levels of prostate-specific antigen at diagnosis...SNPs in five chromosomal regions plus a family history of prostate cancer have a cumulative and significant association with prostate cancer."
This further indicates that significant gene progress is being made.
The key fact to take from this exercise is that the results proved something which has some merit. It did not address the true question of what PSA testing if any can reduce mortality. It proved that there was no difference between two sets of PSA testing protocols. However as we have argued one would not have expected a difference. Furthermore the work done since this trial has begun has fine tuned this testing. The true question will ultimately be a genetic question.
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