What to Ask When Your PSA Is Rising After Initial Treatment

For the majority of men, prostate cancer is treatable and curable and does not come back after initial treatment. However, 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 additional treatment, but 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?
• 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 an imaging scan to see if the cancer has spread outside the prostate area?
• 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 or other lifestyle changes that I could 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?

There’s more to know about rising PSA after treatment.

The goal is to help you focus on what you need to know about rising PSA levels 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. Here are some questions you may have about the complexities of treatment in these cases—and some answers that will help prepare you for the ongoing discussions and decisions to be made to keep your prostate cancer under control.

1. What should my PSA level be after treatment?

Following surgery (radical prostatectomy), your PSA number should be undetectable after about a month. This is effectively zero PSA, but may not get all the way to zero, given the sensitivity of the test and the fact that other proteins may be misread as “PSA proteins.” The most widely accepted definition of a prostate cancer recurrence after surgery is a PSA of 0.2 ng/mL or greater on at least two separate occasions.

If you’ve had radiation therapy, your PSA will likely not drop to zero, as there is some normal, healthy prostate tissue that remains after treatment. Instead, there is a different low PSA level for each patient, called a nadir. The most widely accepted definition is a PSA that has risen from nadir by 2 ng/mL or more. Either way, it’s important to always use the same lab, if possible, for all of your PSA tests because PSA values can fluctuate somewhat from lab to lab. Defining failure after other forms of therapy like brachytherapy seeds or cryotherapy is more challenging, but similar to that used with external radiation.

If your PSA is rising but doesn’t quite meet these definitions, your doctor may recommend an evaluation to see whether your prostate cancer has recurred.

2. Do I need additional treatment after prostate surgery?

After surgery, one of the most important questions to ask is whether you may benefit from additional therapy, such as “adjuvant” radiation (started 4-6 months after surgery without waiting for a rise in PSA). 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 to this region increases the risk of urinary strictures, leakage, and high urination frequency.
Many, but not all men, often can safely avoid adjuvant radiation therapy, and closely monitor their PSA to determine if they will need early “salvage” radiation therapy (given only if the PSA level rises).

3. What does ‘PSA velocity’ mean?

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 soon after surgery (i.e. within 18 months) have a higher risk of aggressive disease.

4. What happens if my PSA rises after surgery?

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), with the aim of eradicating any remaining prostate cells that have been left behind. Depending on your PSA level, the addition of hormone therapy can improve outcomes with salvage radiation; for details, please see “Therapies for Locally Recurrent Prostate Cancer” in PCF’s Prostate Cancer Patient Guide. Clinical trials are investigating more aggressive systemic therapies.

5. Can I have radiation therapy first, and then surgery? [alternate: If radiation therapy doesn’t work, can we try surgery after?]

With modern radiation therapy techniques, 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 performed after radiation. 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. Why do I need to keep getting my PSA checked after treatment?

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. What is hormone therapy for prostate cancer?

Hormone therapy (also called “androgen deprivation therapy”) is a key treatment strategy for prostate cancer that has recurred following treatment for localized disease. Testosterone is a male hormone that fuels the growth of prostate cancer cells. The goal of hormone therapy is to stop the production and/or interfere with the effects of testosterone. However, not all prostate cancer cells are sensitive to decreases in testosterone levels, and, over time, the cancer can adapt to survive in a low-testosterone environment. Therefore, hormone therapy is a treatment for prostate cancer but does not cure the disease. The decision to start hormone therapy is individualized, based on your PSA, the PSA doubling time, whether the cancer has spread visibly or caused symptoms, and the potential side effects and risks involved with this type of therapy.

8. Are there different types of hormone therapy for prostate cancer?

Yes. There are several different ways to block the secretion of testosterone, including the surgical removal of the testes, drugs known as LHRH agonists, and drugs called LHRH antagonists. These are considered “standard” hormone therapy. Another class of medications that can be used in combination with standard hormone therapy is called antiandrogens.

In the past decade, several newer drugs that work in different ways to lower testosterone and decrease its effects in the body (abiraterone, apalutamide, darolutamide, and enzalutamide) have been approved for certain states of advanced prostate cancer.

9. How does hormone therapy for prostate cancer work?

LHRH, or luteinizing-hormone releasing hormone, is one of the key hormones released by the body that initiates the production of testosterone.

LHRH Agonists: One of the most common hormone therapies in prostate cancer involves blocking the release of LHRH through the use of agonists (substances that initiate a response). LHRH agonists cause a “testosterone flare” reaction, which is an initial transient rise in testosterone that happens over the first week or two after the first treatment.

LHRH Antagonists: These are a class of medications that can block LHRH from stimulating testosterone production without causing an initial testosterone surge.

10. What are the side effects of hormone therapy for prostate cancer?

Testosterone is the primary male hormone and plays an important role in establishing and maintaining the male sex characteristics, such as body hair, muscle mass, sexual desire, and erectile function. Most men who are on hormone therapy experience at least some 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 (potentially leading to fractures), weight gain (especially around the midsection), higher cholesterol, and a higher risk of diabetes and heart attack. Some men experience fatigue, memory loss, and/or depression. Don’t be afraid to discuss these issues with your doctors. Maintaining a healthy lifestyle through good nutrition and exercise can help reduce the impact of these side effects.

11. How are hormone therapies for prostate cancer administered?

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. LHRH antagonists include degarelix (a monthly injection) and relugolix, an oral form.

12. What are antiandrogens, and should they be part of my treatment plan?

Antiandrogens can be helpful in preventing the “flare” reaction associated with LHRH agonists resulting from an initial transient rise in testosterone. They can help block the action of testosterone in prostate cancer cells. Their use for at least the first 4 weeks of LHRH agonist 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 might be beneficial for you.

13. What is intermittent hormone therapy?

With intermittent hormone therapy, the LHRH agonist is used for 6–12 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, this approach is not right for all patients, and a patient-by-patient approach should be used based on response to and tolerability of hormone therapy.

14. Can I delay hormone therapy?

Deferring hormone therapy until metastatic disease (sites of prostate cancer outside the prostate region) 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. How long will hormone therapy keep my cancer in check?

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 or antagonist, stopping the antiandrogen, or antiandrogen withdrawal, is the most common first step in secondary hormone therapy. Between 10%–30% of men will respond to anti-androgen withdrawal, which lasts on average 3 to 5 months. However, inevitably, additional therapies will need to be added even if this withdrawal response occurs. Continuing the LHRH agonist or antagonist and adding a new therapy in combination can improve survival and maintain or improve quality of life.

16. What if my PSA rises while I’m on hormone therapy?

When the PSA is rising or cancer is 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 may progress and become more aggressive and resistant, and you should be prepared to discuss additional 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 medical, “systemic” treatments for prostate cancer, which is useful at this time given that your disease is typically metastatic, 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 where you are having symptoms, such as problems with urination.

Fortunately, more and more treatments for metastatic castration-resistant prostate cancer have become available in recent years, including certain newer androgen directed therapies, taxane chemotherapy, immunotherapy, PARP inhibitors, and, in 2022, lutetium-PSMA radionuclide therapy. Additional tests are required for some of these treatments to see if your particular type of prostate cancer is likely to respond. See Chapter 5 in PCF’s Prostate Cancer Patient Guide for more details.

Also, ask your doctor about whether a clinical trial might be right for you.

17. I’m worried about all the side effects from prostate cancer medications. What can I do?

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.