What to Consider When Your PSA Is Rising After Initial Treatment

For the majority of men, prostate cancer is treatable and curable and does not recur after local definitive therapy with surgery or radiation. However, this next section summarizes key points to consider when your PSA is rising after undergoing initial treatment. About 25-33% of men with prostate cancer will experience a recurrence of their cancer after surgery or radiation. Some of these men can still be cured with radiation after surgery, or with other local therapies after radiation. However, some men develop a form of prostate cancer that, while not curable, remains TREATABLE for a very long time.

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 again?
  • What is my PSA level now and how will we monitor changes over time?
  • Can we (should 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.

  1. Following surgery (radical prostatectomy), your PSA should be undetectable after about a month. That means zero PSA, not 0-4 ng/dl. However, some men will have a very low non-rising PSA after surgery, which can sometimes be related to normal prostate tissue left behind. This is uncommon, and referred to as benign regeneration. However, the most widely accepted definition of a cancer recurrence 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 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 radiation.
  2. 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.
  3. 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 (i.e. within 3 years) have a higher risk of aggressive disease.
  4. 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.
  5. 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.
  6. 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.
  7. 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 on starting testosterone lowering or 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.
  8. There are several approaches to blocking the secretion of testosterone including the surgical removal of the testes, drugs known as LHRH agonists, and estrogens.
  9. 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.
  10. 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, and 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.
  11. 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.
  12. 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.
  13. 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. However, the clinical benefits of this approach remain unclear, and large clinical trials are currently underway to evaluate its use in this setting.
  14. 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.
  15. Hormone therapy typically is effective for only a few years, but this period can range from several months to many decades. For many men who were using an antiandrogen in combination with an LHRH agonist, stopping the antiandrogen, or antiandrogen withdrawal, is the most common first step in secondary hormone therapy. Switching to a different antiandrogen might also be able to offer an extra few months of benefit, and drugs known as ketoconazole can be used to block the small amounts of testosterone produced by the adrenal glands from being released. An older estrogenic medication, DES, can also be useful when other hormonal therapies stop working. As DES can increase your risk of blood clots, using a blood thinner like Coumadin/warfarin with DES is recommended if possible. There are many trials of newer hormonal therapies in this setting and trial participation is encouraged.
  16. 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.
  17. Carefully review the side effect profile of the different hormone 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.