The following guest blog entry has been kindly provided by Andrew Vickers, PhD, of the Memorial Sloan- Kettering Cancer Center in New York. It is based in part on a presentation he gave at the recent annual meeting of the American Urological Association. Dr Vickers specializes in methodological research with a particular focus on issues related to the diagnosis and treatment of early stage prostate cancer.
The first patient’s question: “My PSA is low, but has been rising over the past few years. Should I consider a biopsy?”
Many groups currently recommend that men who experience a rise in PSA should consider biopsy even if their PSA level is low. As one example, the American Cancer Society suggests that a PSA velocity of 0.35 ng/mL/yr “may be a cause for concern” in men with low PSAs.
This implies that Mr Brown, who had a PSA of 1.6 ng/mL in 2007, and a PSA of 2.0 ng/mL in 2008, should think about a biopsy even though he is below any of the usual PSA cut-points (such as 2.5 or 4 ng/mL).
Now an immediate and obvious problem with such guidelines is that they don’t appear to take into account something known as “measurement error.” For example, different PSA assays can give results that differ by as much as 20 percent, an amount that could easily explain most of Mr Brown’s apparent PSA increase.
A more serious problem with guidelines of this type, however, is that there is actually very little evidence to support them. To obtain suitable evidence, researchers would have to biopsy a very large number of men with low PSAs and then correlate their changes in PSA with the results of their biopsies. This isn’t often done, for ethical reasons. So, researchers who think PSA velocity is potentially important have extrapolated from the available data by assuming, for example, that men who were not biopsied did not have cancer, or that men diagnosed with prostate cancer would have had a positive biopsy (had one been conducted) 10 years before their diagnosis.
Only one study has ever systematically biopsied men with low PSAs and then looked at whether PSA velocity actually predicts whether a man has cancer. This was the Prostate Cancer Prevention Trial, in which all 18,800 men enrolled were biopsied because it was thought that finasteride might lower PSA without lowering the risk of cancer. The conclusions of the authors of this trial were unequivocal: once you took PSA level into account, PSA velocity did not help to identify men who might be more or less appropriate for biopsy.
Other studies in men with higher PSA levels have had similar conclusions; indeed, one study found that men with a rapidly rising PSA were less likely to have prostate cancer, presumably because the rise in PSA was likely due to infection or inflammation of some type.
So, when deciding whether or not to have a biopsy, the two key things to think about are your PSA level and your doctor’s advice. In my and many of my colleagues’ opinion today, PSA velocity is not a relevant risk factor.
The second patient’s question: “My PSA was rising rapidly when I was diagnosed. Does this mean that my cancer is a bad one?”
In recent years we have seen intense interest in how PSA changes over time (PSA velocity). Some researchers have suggested that if PSA is rising rapidly at the time of a positive biopsy — for example, if a man’s PSA rose by more than 2 ng/mL in the year before diagnosis — this is a sign of a particularly aggressive form of cancer. Such cancers, it is claimed, are likely to lead to recurrence and death, even if the patient is treated with surgery or radiotherapy.
Several papers published in major journals, including the New England Journal of Medicine, have indeed reported a statistical association between a rapidly increasing PSA and subsequent risk of death from prostate cancer.
However, the question that research should be addressing is not whether a high PSA velocity is associated with poor outcomes, but whether PSA velocity offers any additional information once you know your stage, your grade and your PSA level. If you think about this carefully, we don’t really need an answer to the question, “Does a high PSA velocity means a bad cancer?” We already know a lot about a specific cancer from the clinical exam and the Gleason grade. What we really want to know is whether, for example, a man with a relatively low-risk cancer — say Gleason 6, with a negative digital rectal exam and a PSA of 5 ng/mL — becomes high-risk if his PSA velocity is, say, 2.2 ng/mL/yr.
As it turns out, there is very little evidence that this is the case. Researchers have looked at several different data sets and, almost without exception, they have found that PSA velocity tells you very little once you take into account other clinical information.
In a typical study, researchers looked to see if PSA velocity predicted which men recur after surgery for prostate cancer. They found, as expected, that men were more likely to recur if they had high PSA, high Gleason grade, or cancer that had spread outside the prostate. But they also found that knowing a man’s PSA velocity did not help you predict what was going to happen to him.
The bottom line is that stage, grade, and PSA remain the best way to understand prostate cancer risk prior to treatment: PSA velocity doesn’t tell us anything more.
For clarity, The “New” Prostate Cancer InfoLink and Dr. Vickers both agree that, by comparison, the role of PSA velocity after first-line treatment is known to be very useful. In particular, it appears to be able to help define those men who are at greatest risk if they have a rising PSA after first-line treatment, and are therefore early candidates for salvage treatment (e.g., external beam radiotherapy after failure of radical prostatectomy).
THE "NEW" PROSTATE CANCER INFOLINK 
[…] and, in modern practice, it frequently affects treatment decisions. The unanswered question, as posed by Vickers and others, is whether the PSAV adds additional knowledge to what we know about patient risk when […]