First introduced in Canada 20 years ago as a test to diagnose prostate cancer, the prostate specific antigen (PSA) blood test has evolved into a measuring tool that’s used at virtually every stage of the disease trajectory. Used intelligently, it can help direct the most appropriate treatment and predict outcomes long before any other measures we currently have to indicate cancer recurrence. But the current controversy about whether routine PSA screening can, in fact, reduce death rates from prostate cancer due to earlier detection and treatment threatens to overshadow its proven benefits in managing the condition.
We’re expecting results from the large European screening trials that are addressing this question within one to four years. Meanwhile, this review showcases the different ways in which we presently rely on PSA.
Treatment options by risk group
There’s no “one size fits all” solution for prostate cancer. Physicians have learned that the likely extent of cancer — and thus the most appropriate treatment — can be accurately predicted based on a combination of baseline (i.e. before any treatment) factors: PSA level, Gleason grade and (to a lesser extent) digital rectal exam (DRE) findings. These factors have led to the widespread use of risk categorization of prostate cancer into the following groups (see chart, page 6):
- Low risk: PSA 10 ng/mL or less; Gleason score less than or equal to 6; stage T1 or T2
- Intermediate risk: PSA between 10 and 20 or a Gleason score of 7, and stage less than T3
- High risk: Any of PSA > 20, Gleason score 8 or greater, or clinical stage T3.
Most Canadian urologists and radiation oncologists agree on the following standard treatment options according to risk groupings:
- Low risk: Radical prostatectomy (RP), brachytherapy or external beam radiation therapy (EBRT). Some lucky guys with early, low-risk prostate cancer can also be managed by active surveillance (see Our Voice, Vol. 3, No. 1, 2007; this issue also contains an article on how to use PSA kinetics [the way PSA changes over time] to monitor men on active surveillance).
- Intermediate risk: Some patients will do well with brachytherapy or RP, while others may be better suited to EBRT.
- High risk: Men in this group have been shown to benefit from combination androgen deprivation therapy (ADT) and EBRT. Selected patients may also be treated with EBRT and brachytherapy (high- or low-dose rate) or RP.
PSA kinetics before treatment
How much PSA rises in the months or years before treatment can predict the likely success of treatment. Several studies have shown that if the PSA is increasing relatively fast — by more than 2 ng/mL in the year before treatment — then there’s less chance of a successful outcome, particularly for men with high-risk cancers. Since fluctuations in PSA from noncancer causes can also lead to a difference of 2 ng/mL, however, it’s preferable to base any concerns about faster PSA velocity on a series of readings. We also have to make sure that an infection or recent biopsy hasn’t artificially caused any PSA rise. If you’re visiting your urologist or oncologist for the first time, it’s useful to bring along any old test results you have so your doctor can look at your PSA history.
PSA response to “before treatment” ADT
Neoadjuvant therapy refers to the use of ADT leading up to radiation or surgery. This approach has been shown to be beneficial, particularly in men with high-risk cancers. Usually, men have a prompt fall in their PSA level within one to two months of starting ADT, and the degree of the response can predict the success of the subsequent EBRT. Men whose PSA falls below 0.1 ng/mL do particularly well, while those whose PSA remains above 1 ng/mL (after three months) have a higher chance of future cancer recurrence. A subgroup of men will have an initial PSA response followed by a small rise in their PSA while still in the neoadjuvant phase (in spite of low testosterone levels from their drug treatment); these men have an increased recurrence and death rate. PSA monitoring in this phase is therefore important —those who are responding poorly to their hormone treatment may benefit from adding an antiandrogen to their LHRH agonist, or from even more aggressive approaches such as chemotherapy as well.
PSA “failure” or relapse
PSA is the most sensitive measure of the success or failure of prostate cancer treatment. After RP, there should be no prostate tissue left, with the exception of any remnants in the seminal vesicles and around the prostate apex. The PSA should be very low — maximum 0.1 ng/mL. The most widely accepted definition of PSA “failure” after RP is a rise to greater than 0.2 ng/mL. Of men who experience such an increase, 50% will develop clinical evidence of cancer recurrence or require ADT within four years.
After EBRT or brachytherapy, the definition of PSA failure is less obvious. This is because the prostate is still in place, and although the cancerous cells are still being killed off over several months, the benign prostate tissue continues to produce declining amounts of PSA for several years before a minimum (“nadir”) PSA level is reached. A typical PSA level four years after EBRT in someone who is cured is about 0.4 ng/mL; after brachytherapy, it’s around 0.05 (the difference between the two treatments is due to a greater amount of benign prostate tissue remaining after EBRT). The level of the nadir reached also predicts future recurrence rates. In our experience in British Columbia, the average nadir of 0.04 ng/mL after brachy-therapy is associated with a 95% seven-year cure rate, whereas with EBRT a nadir of 0.6 ng/mL corresponds with a 75% seven-year cure rate.
We define PSA relapse after radiation (both types) as a PSA that rises to more than 2 ng/mL above the minimum level reached after treatment. As with surgery, if this occurs, clinical evidence of recurrence will likely be picked up within a few years.
PSA bounce
With brachytherapy, and occasionally EBRT, the interpretation of PSA is complicated by the “bounce” phenomenon — a temporary rise in PSA that typically occurs 18 to 36 months after treatment, but may be seen earlier or later. This occurs to some extent in 50% of patients, but only rarely does the PSA rise more than 2 ng/mL. Usually, the PSA reverts to its baseline level within six to 12 months, and then declines to very low levels with more follow-up. Waiting is the best thing to do at this stage, although “doing nothing” can be a source of anxiety for patients. Cancer recurrence is rare after prostate brachytherapy. If your PSA is rising after brachyther-apy, be sure to discuss what this means with your radiation oncologist. Mistakenly assuming that the cancer has recurred may lead to unnecessary hormone treatment.
Post-therapy PSA kinetics: advantages and pitfalls
In cases of relapse, how fast PSA rises, especially the time it takes to double (PSAdt), is a strong prognostic factor for the chance of future metastases and eventual death from prostate cancer. A slow PSAdt (e.g. every 12–24 months) is more often due to a local recurrence of the cancer, whereas a fast PSAdt (faster than six months) usually means the cancer has spread. Men with a fast PSAdt are at risk of dying of prostate cancer within five years, while a slower PSAdt may not affect life expectancy at all. What we don’t know yet is whether men with slow PSAdt even need to have ADT, and whether more aggressive intervention (for example chemotherapy in addition to ADT) will help those with fast PSAdt. A slow PSAdt after surgery tells us that local recurrence of the cancer is likely, in which case salvage radiation therapy can be curative.
PSAdt can be most easily calculated using an online calculator such as www.mskcc.org/mskcc/html/10088.cfm. It’s best to go over the results with your doctor, to be sure you understand them correctly.
There are some pitfalls in looking at post-therapy PSA kinetics. First, for men who also received ADT at the time of primary treatment, when the ADT is discontinued there will be a small rise of PSA, to a level of around 0.5–1 ng/mL. The PSA climb rate may seem fast, but it isn’t due to cancer recurrence. Also, at very low levels of PSA (< 0.5), the calculation of PSAdt may be false, because the lab variation at low levels is more marked. To get around these problems, in my clinic I only use PSA values greater than 1 ng/mL in my calculations of the doubling time.
Metastatic or hormone-resistant cancer
In men who are treated with ADT for metastatic prostate cancer or PSA relapse after primary therapy, once again the PSA response helps to predict the future. Those who achieve a nadir PSA less than 2 ng/mL or whose PSAdt is slower than two months do better. If resistance to the hormone treatment sets in and patients are facing chemotherapy, the rate PSA falls with treatment can be a measure of life expectancy (men whose PSA falls more than 30% live longer than others). However, for some patients there is a “disconnect” between the PSA response, pain relief and survival. Sometimes the PSA response lags behind other traditional endpoints (e.g. general well-being or control of pain from metastases), which makes decision-making purely on a PSA response unwise.
Not perfect, but…
Hopefully, research will soon tell us more about the benefits of routine PSA screening in reducing mortality from prostate cancer. But there’s no doubt that PSA testing has an important role to play in managing men with this disease — in the initial diagnosis, before and after treatment, and in determining relapse.
Dr. Tom Pickles is a Radiation Oncologist at the British Columbia Cancer Agency (BCCA) and Clinical Professor at the University of British Columbia, in Vancouver.
