PSA as a Marker for Disease Progression
PSA is produced by all prostate cells, not just prostate cancer cells. At this point in your journey, your cancer cells have either been removed or effectively killed after being bombarded with radiation. But some cells might have been able to spread outside the treatment areas before they could be removed or killed. These cells at some point begin to multiply and produce enough PSA that it can again become detectable by our lab tests.
Therefore, PSA is not really a marker for disease progression, but a marker for prostate cell activity. Because the two correlate well after initial treatment for local therapy, tracking the rise of PSA in this setting is an important way of understanding how your prostate cancer is progressing.
However, in order to determine whether your PSA is rising, you need to first determine where it is rising from. Often, imaging tests will not be able to determine this when the PSA is at very low levels. Tests such as bone scans, Prostascint scans, and CT/MRI scans in this setting are often negative and thus most decisions on the next therapy (ie radiation or hormonal therapy) are based on probabilities of cure with radiation rather than by seeing the cancer on scans. Prostascint scans in this setting are often not very helpful, given their high false positive and false negative rates, and thus can be misleading.
After prostatectomy, the PSA drops to “undetectable levels,” typically given as < 0.05 or < 0.1, depending on the lab. This is effectively 0, but by definition we can never be certain that there isn’t something there that we’re just not picking up. By contrast, because normal healthy prostate tissue isn’t always killed by radiation therapy, the PSA level doesn’t drop to 0 with this treatment. Rather, a different low point is seen in each case, and that low point, or nadir, becomes the benchmark by which to measure a rise in PSA.
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Because the starting point is different whether you had surgery or radiation therapy, there are two different definitions for disease recurrence as measured by PSA following initial therapy.
In the post-prostatectomy setting, the most widely accepted definition of a recurrence is a PSA > 0.2 ng/mL that is seen to be rising on at least two separate occasions at least two weeks apart and measured by the same lab. In the post-radiation therapy setting, the most widely accepted definition is a PSA that is seen to be rising from nadir in at least three consecutive tests conducted at least two weeks apart and measured by the same lab. It’s important to always use the same lab for all of your PSA tests because PSA values can fluctuate somewhat from lab to lab.
The reason that we need to look for confirmation from multiple tests following radiation is that the PSA can “bounce” or jump up for a short period after radiation therapy, and will then come back down to its normal level. If we relied only on the one elevated PSA, it’s possible that we will have tested during a bounce phase, and the results will therefore be misleading. This PSA bounce typically occurs between 12 months and 2 years following the end of initial therapy.
If your PSA is rising but doesn’t quite reach these definitions, your doctor might be tempted to start initiating further therapy anyway. Remember that PSA is only one of many factors that help to determine your prognosis after treatment. The original clinical stage of disease, your pre-diagnostic PSA, and your overall health and life expectancy are also key factors in assessing the aggressiveness of your disease, so be prepared to discuss treatment options even if you don’t fit the classical categories for PSA rise after initial therapy.
On the other hand, if your PSA is rising and you do fit the categories defined above, that doesn’t necessarily mean that your situation is dire. What researchers have been finding over the past few years is that universal PSA cut-offs might not be sufficient for truly understanding how prostate cancer grows.
Suppose one man underwent intensity-modulated radiation therapy (IMRT), and his PSA nadir was 0.15 ng/mL. Over the course of nine months, it slowly creeps up until it hits 0.45. But his brother, who also underwent IMRT, nadired at 0.32 ng/mL. If after the same progression over the course of nine months his PSA also rose to 0.45, are they now in the same place? Or is there some significance to the fact that one man’s PSA rose much more rapidly than his brother’s?
The rate at which your PSA rises after prostatectomy or radiation therapy can be a very significant factor in determining how aggressive your cancer is, and can therefore be useful in determining how aggressively it might need to be treated.
When looking at PSA velocity in a few hundred men who had undergone either prostatectomy or radiation therapy, researchers found that men whose PSA doubled in under three months had the most aggressive tumors and were more likely to die from their disease, whereas those whose PSA doubled in more than ten months had the least aggressive tumors and were less likely to die from their disease.
If we go back to our two hypothetical cases, although both have a PSA of 0.45 ng/mL, the first one, whose PSA rise represents a doubling within nine months after treatment, would likely be considered for an aggressive therapeutic regimen. And the second case with the smaller rise in PSA? He might be watched closely to see how rapidly his PSA rises, and to determine when it might be time to intervene.
However, PSA doubling time or velocity does not always remain the same over time. So even if you have a very slowly rising PSA now, continued monitoring with your doctor is important. Also, if you’ve consistently kept to a very low PSA rate after treatment, any rise will likely be seen as a signal that the tumor might be starting to grow again.
Measuring and using PSA velocity is an art, not a science. There’s no magic number of times that your PSA has to be tested in order to determine the rate of rise, although most researchers would agree that more frequent tests over longer periods of time will likely give a better sense of how your tumor is growing.
Ultimately, PSA is only one of many factors that can influence the decision to pursue additional treatments. You and your doctors will need to weigh all of the different factors before deciding on the course that’s right for you.
What to Consider When Your PSA Is Rising After Initial Treatment
Below is a list of questions to ask when your PSA is rising after initial treatment.
- What does it mean that my PSA level is rising?
- What is my PSA level now and how will we monitor changes over time?
- Can we chart the velocity or doubling time of my PSA? What can this tell us about my prognosis?
- Am I a candidate for local “salvage” prostatectomy or radiation? Why or why not?
- Should I get a bone scan to see if the cancer has spread to my bones?
- If you recommend that I initiate androgen deprivation therapy (“hormone therapy”), how will this benefit me and slow down the growth of the cancer cells? Is this the optimal time to initiate this treatment?
- What are the benefits and drawbacks/side effects of hormone therapy? Are there things that I can do to minimize the side effects?
- If I initiate hormone therapy, will this make my PSA drop back to zero? Will we monitor my PSA over time to see if it’s working?
- How long do the treatment effects of hormone therapy last?
- If the hormone therapy stops working, what treatment options remain?
- Are there dietary changes that I could or should make to optimize my treatment?
- Should we add a medical oncologist to my treatment team to gain an additional perspective on treating my disease?
- Should I consider joining a clinical trial?
The list below of important issues is by no means exhaustive, and there might be other points that you want to think about as well. The goal is to help you focus on what you need to know about each stage of disease so you can hold meaningful, regular dialogues with all members of your health care team as you find the treatment path that’s right for you.
- Following surgery (radical prostatectomy), your PSA should be undetectable after about a month. That means zero PSA, not within the “normal” range of 0-4 ng/mL. After radiation therapy, your PSA will likely not be zero, but it should be close, and the lowest it goes is called the nadir. The most widely accepted definition of a cancer recurrence after surgery is a PSA > 0.2 ng/mL that has risen on at least two separate occasions at least two weeks apart and measured by the same lab. In the post-radiation therapy setting, the most widely accepted definition is a PSA that has risen from the nadir in at least three consecutive tests conducted at least two weeks apart and measured by the same lab. Some believe that failure after radiation is not clear until the PSA has risen 2 points above its lowest value after radiation. Either way, it’s important to always use the same lab for all of your PSA tests because PSA values can fluctuate somewhat from lab to lab. Defining failure after other forms of therapy like seeds or cryotherapy is more challenging, but similar to that used with external beam radiation.
- One of the most important questions after surgery to ask is whether you may benefit from additional therapy like adjuvant radiation. The decision to use radiation to lower your risk of recurrence and dying from prostate cancer after surgery is based on whether the cancer has spread to your seminal vesicles, whether there were positive margins, and whether the cancer spread beyond the prostate capsule. In addition, it is important to allow time to recover your urinary function before considering radiation therapy after surgery, as radiation in this setting increases the risk of urinary strictures, leakage, and frequency. There is currently an ongoing debate about doing radiation early or waiting until the PSA has begun to rise in men with these high risk features, given these toxicities.
- PSA velocity or PSA doubling time, both of which measure the rate at which your PSA rises, can be a very significant factor in determining is the aggressiveness of your cancer. Men with a shorter PSA doubling time or a more rapid PSA velocity after initial therapy tend to have more aggressive disease, and are therefore more likely to need more aggressive therapies. Likewise, men who have recurrence quickly after surgery (ie within 3 years) have a higher risk of aggressive disease.
- If your PSA starts to rise after you’ve undergone prostatectomy,“salvage” radiation therapy might be a good option to explore, and has been shown to improve outcomes over time. With this approach, external beam radiation is delivered to the area immediately surrounding where the prostate was (the prostate bed), in the hopes of eradicating any remaining prostate cells that have been left behind. It is not known if hormonal therapies can improve outcomes with salvage radiation and clinical trials are ongoing to look at this. Other trials are looking at other more aggressive experimental systemic therapies in this setting.
- If your PSA rises and you were initially treated with radiation therapy, surgery may be an option. With 3D conformal radiotherapy, IMRT, and brachytherapy, local tissue damage is often kept at a minimum, and surgeons at some of the larger cancer centers have been seeing improved results with “salvage” prostatectomy. But even under the best of circumstances, post-radiation surgery is a very difficult operation to perform, and few surgeons across the country perform it regularly.
- Regular monitoring of PSA levels after primary therapy is key, as is prompt initiation of treatment upon disease recurrence. The earlier the treatment is begun, the better the likelihood of improved results.
- Androgen deprivation therapy (“hormone therapy”) is a key treatment strategy for prostate cancer that has recurred following local treatment. The goal of all hormone therapies is to stop the production and/or interfere with the effects of testosterone which fuels the growth of prostate cancer cells. However, because not all prostate cancer cells are sensitive to increases or decreases in testosterone levels, hormone therapy is a treatment for prostate cancer but does not cure the disease. The decision to start testosterone blocking therapies is individualized, based on your PSA, the PSA doubling time, whether the cancer has spread visibly or caused symptoms, and the risks of harm with this therapy.
- There are several approaches to blocking the secretion of testosterone including treatment with drugs known as LHRH agonists and/or the surgical removal of the testes.
- Antiandrogens block the action of testosterone by preventing the active form of testosterone known as DHT from entering the central part of the prostate cancer cell; without DHT, the growth of prostate cancer cells is halted.
- Testosterone is the primary male hormone, playing an important role in establishing and maintaining the typical male characteristics, such as body hair growth, muscle mass, sexual desire, and erectile function. Most men who are on hormone therapy experience at least some of the effects related to the loss of testosterone, but the degree to which you will be affected by any one drug regimen is impossible to predict. Side effects from testosterone lowering therapies include hot flashes, breast enlargement or tenderness, loss of bone mineral density and fracture, increased weight gain (especially around the midsection), higher cholesterol, a higher risk of diabetes, and a slightly higher risk of heart problems like heart attacks and chest pains. Some men complain of mood problems and depression during this time as well. Don’t be afraid to discuss these issues with your doctors. For all of these reasons, a healthy lifestyle as described in other sections, is vital to doing well with hormonal therapies over time.
- LHRH agonists, the most commonly used drug class for hormone therapy, are given in the form of regular shots: once a month, once every three months, once every four or six months, or once per year. These long-acting drugs are injected under the skin and release the drug slowly over time. There are newer agents called LHRH antagonists that also lower testosterone and may be used.
- Antiandrogens can be helpful in preventing the “flare” reaction associated with LHRH agonists resulting from an initial transient rise in testosterone. Their use for at least the first 4 weeks of LHRH therapy can relieve the symptoms often seen from the flare reaction, ranging from bone pain to urinary frequency or difficulty. You should ask your doctor whether continuing these pills for longer term cancer control will be beneficial to your individual case. There is some information to suggest that combination testosterone blockade and testosterone lowering therapy may be better than either one alone for long term control, but at the cost of additional side effects like breast tenderness and enlargement, cost, and hot flashes.
- With intermittent hormone therapy, the LHRH agonist is used for six to twelve months, during which time a low PSA level is maintained. The drug is stopped until the PSA rises to a predetermined level, at which point the drug is restarted. During the “drug holidays” in between cycles, sexual function and other important quality of life measures might return. Recent large studies have shown that the intermittent and continuous approaches are equivalent in terms of long-term survival in patients without metastatic disease. However, once the cancer has spread, continuous androgen deprivation therapy improves survival relative to intermittent hormone therapy and remains the standard of care.
- Deferring hormone therapy until metastatic disease can be detected might be an appropriate option for some men. In such cases, the goal would be to reserve an effective, albeit temporary, treatment option until it’s clearly needed.
- Hormone therapy typically is effective for only a few years, but this period can range from several months to many decades. For many men taking an antiandrogen in combination with an LHRH agonist, stopping the antiandrogen, called antiandrogen withdrawal, is the most common first step in secondary hormone therapy. Switching to a different antiandrogen might also offer an extra few months of benefit, and a drug known as ketoconazole can be used to block the small amounts of testosterone produced by the adrenal glands from being released. As newer, more effective hormonal therapies are developed, many of the secondary hormonal manipulations using ketoconazole and older estrogenic medications will likely fall out of favor.
- When the PSA is rising or cancer spreading despite a low level of testosterone, prostate cancer is called castration-resistant, or hormone-refractory. Despite this name, some hormonal therapies (see above) may still work. But prostate cancer in this setting will inevitably progress and become more aggressive and resistant, and you should be prepared to discuss more aggressive treatment strategies with your doctor. This is the time when a medical oncologist, if not already involved in your care, gets involved. These doctors specialize in “systemic” treatments for prostate cancer, which is useful at this time given that your disease is typically systemic, meaning that it is not confined to only one location. Cancer cells in this situation have typically spread through the blood stream or lymphatics to other places in the body, and localized treatments are rarely helpful except in circumstances where urination becomes difficult. You should talk to your doctor about these systemic therapies, when to start chemotherapy, and clinical trials that may be available.
- Carefully review the side effect profile of the different therapy regimens, and discuss with your health care team potential ways to minimize the effects. In the end, it’s important that you not only understand the value of the therapy in the management of your prostate cancer, but also that you learn how to live your life as best as possible while fighting the disease.
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