That’s usually of small comfort to the patient whose PSA has risen. It’s emotionally traumatic to go through treatment for prostate cancer, thinking it is cured, and then learn that it might have come back. For many men, it’s as if they’re dealing with another diagnosis of cancer, except this time it’s much worse because there is less likelihood of getting cured. A man’s confidence and sense of safety may be shattered, especially because the popular misconception is that when prostate cancer recurs, it is deadly.
Which brings me back to my patient’s question: “Am I going to die?”
The simple answer is yes, eventually — we all do — but you may not die from prostate cancer. Of course, with prostate cancer, nothing is simple. This may be one disease, but it can appear in multiple forms, so every diagnosis or recurrence requires individualized assessment and intervention. To start thinking about the salient issues, see “Four key questions.”
Four key questions
If your PSA rises after prostate cancer treatment, answering four key questions will help you and your doctor determine next steps:
- What were your risk characteristics, such as Gleason score, PSA, and cancer stage, at the time of diagnosis? (See Table 1.)
- What type of treatment did you have? That will help determine your next treatment options.
- How long has it been since you underwent initial therapy for prostate cancer? This helps indicate how aggressive follow-up treatment needs to be.
- How fast is your PSA rising, as determined from several evaluations?
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In practical terms, biochemical recurrence means that you are now dealing with a chronic disease, like diabetes, so that your clinical monitoring will have to increase and you may need to choose or adjust treatment to meet new challenges. Unfortunately, we don’t yet have sufficient research to provide clear guidance about when a second therapy (referred to as salvage therapy) should be considered after biochemical recurrence, and which type of salvage therapy is most effective in particular circumstances. (Salvage therapy is a terrible term, but I use it in this article because it is the standard name for follow-up therapy.)
For those who have already suffered a biochemical recurrence after being treated for prostate cancer — or dread each follow-up blood test because it might signal such a recurrence — this article explains what a rising PSA after treatment really means and what your treatment options are.
Table 1: Predictors of biochemical recurrence at time of diagnosis
Although a number of clinical factors contribute to your risk of relapse after treatment, the parameters below provide a simpler assessment of your chances of biochemical recurrence, based on your clinical profile at the time of diagnosis. For more sophisticated estimates, based on specific risk factors, see Figures 1 through 3.
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| Low risk (33% chance of biochemical recurrence within five years) | Gleason score less than or equal to 6
andPSA less than or equal to 10 ng/ml
andCancer stage T1c or T2a |
| Intermediate risk (50% chance of biochemical recurrence within five years) | Gleason score of 7 (if 3+4)
and/orPSA greater than 10 but no greater than 20 ng/ml
and/orCancer stage T2b |
| High risk (85% chance of biochemical recurrence within five years) | Gleason score of 7 (if 4+3), or 8 or more
and/orPSA greater than 20 ng/ml
and/orCancer stage T2c or more |
Defining biochemical recurrence
As you are probably aware, both normal prostate cells and prostate cancer cells manufacture PSA. That is why the PSA level should fall to undetectable levels in men treated with radical prostatectomy, in which the prostate is removed, but is not likely to drop to zero in men treated with radiation therapy, even when treatment is successful. This is because after radiation therapy the prostate gland remains intact and can recover some function. This is also true if you received hormone therapy as part of your radiation treatment: As you recover, testosterone levels rise, and so does your PSA.
The real challenge is defining what constitutes a biochemical recurrence after a particular type of therapy. There is no consensus on this issue, but the working guidelines are summarized in Table 2.
Table 2: Guidelines for determining biochemical recurrence
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| Initial therapy | PSA threshold | Comments |
| Radical prostatectomy | 0.2 ng/ml on at least two successive tests | Some physicians continue to use a higher threshold of 0.4 ng/ml or greater |
| Radiation therapy (external beam or brachytherapy) | Three successive elevations in PSA compared to nadir (low point), regardless of actual reading, according to the American Society for Therapeutic Radiology and Oncology | Many oncologists use a working definition that biochemical recurrence has occurred if PSA levels are greater than 1–2 ng/ml 12 to 18 months following initial treatment.
Ideally, post-treatment PSA levels should be less than 0.5 ng/ml, but this is rare; levels of 0.6–1.4 ng/ml may occur.
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| Neoadjuvant hormone therapy and radiation therapy | Unknown |
Further muddying the water, it is not clear what PSA levels should be in men who have undergone neoadjuvant hormone therapy in addition to radiation therapy. Hormone therapy suppresses levels of testosterone; once the therapy is stopped, testosterone levels rise, and PSA generally increases rapidly until the hormonal environment stabilizes.
Moreover, some men who have undergone external beam radiation therapy or implantation of radioactive seeds (brachytherapy) experience a phenomenon known as PSA bounce, a temporary spike in PSA that does not necessarily indicate recurrence. Studies offer varying conclusions about how common this phenomenon is, probably because they use different definitions of what constitutes a “bounce.” Until more is known, if you have had some form of radiation therapy for prostate cancer and experience a spike in your PSA level, it is wise to ask your physician whether this could be a PSA bounce.
A common challenge
Rising PSA after initial treatment often comes as a shock to the person affected, but it’s actually a common problem. Studies indicate that biochemical recurrence affects roughly 15%–30% of men initially thought to be curable with localized treatment of prostate cancer. Certainly if you find yourself in this situation, you are not alone.
For example, a study published in the Journal of Urology, which followed 3,478 men who underwent radical prostatectomy for prostate cancer, found that 32% were likely to suffer a biochemical recurrence within 10 years. (The study actually followed patients an average of a little more than five years, but used actuarial tables to predict outcome at 10 years.) Another study, published in the Journal of the American Medical Association, examined the outcomes for 1,997 men who underwent radical prostatectomy and were followed for an average of a little more than five years, and found that 15% experienced biochemical recurrence in that time. (For further details about these studies, see “Biochemical recurrence after surgery,” below.)
Biochemical recurrence after surgery
Pound CR, Partin AW, Eisenberger MA, et al. Natural History of Progression after PSA Elevation Following Radical Prostatectomy. Journal of the American Medical Association 1999;281:1591–7. PMID: 10235151.
Roehl KA, Han M, Ramos CG, et al. Cancer Progression and Survival Rates Following Anatomical Radical Retropubic Prostatectomy in 3,478 Consecutive Patients: Long-Term Results. Journal of Urology 2004;172:910–14. PMID: 15310996.
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Other studies indicate that a similar (or perhaps slightly higher) percentage of men treated with radiation therapy will experience a biochemical recurrence (see “Biochemical recurrence after radiation therapy,” below). For example, a study of 1,449 men with prostate cancer treated with brachytherapy, published in the Journal of Urology, found that anywhere from 19% to 26% experienced biochemical recurrence within 12 years, depending on the definition of recurrence. It should be noted that nearly half the men were also treated with either neoadjuvant hormone therapy or a combination of brachytherapy and external beam radiation therapy, which may have increased the success of treatment or delayed recurrence. And a study comparing the outcomes of 393 men who received different doses of external beam radiation therapy for prostate cancer, published in the Journal of the American Medical Association, found that 19.6% of those who underwent high-dose radiation therapy experienced biochemical recurrence within five years, while 38.6% of those who underwent conventional-dose radiation therapy did.
Biochemical recurrence after radiation therapy
Potters L, Morgenstern C, Calugara E, et al. 12-Year Outcomes Following Permanent Prostate Brachytherapy in Patients with Clinically Localized Prostate Cancer. Journal of Urology2005;173:1562–6. PMID: 15821486.
Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of Conventional-Dose vs High-Dose Conformal Radiation Therapy in Clinically Localized Adenocarcinoma of the Prostate: A Randomized Controlled Trial. Journal of the American Medical Association 2005;294:1233–9. PMID: 16160131.
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Assessing your personal risk
Several factors contribute to your risk profile. One important factor is whether you have localized or more advanced disease at the time of biochemical recurrence. As indicated in Table 1, your pretreatment numbers such as Gleason score and pathological cancer stage will provide some indication of whether the recurrence is local or metastatic. Also important is how much the PSA increased within a given time period (known as the PSA velocity) before treatment, and how long it takes for PSA to double in value (known as PSA doubling time) after treatment.
For example, two studies that looked at the relationship between PSA velocity and post-treatment outcomes in men treated for early-stage prostate cancer found that men with a PSA velocity of 2 ng/ml or less in the year before diagnosis had a much better prognosis than those whose PSA velocity was greater than 2 ng/ml per year (see “PSA velocity and prognosis,” below). In a study of 1,095 men treated with surgery, published in the New England Journal of Medicine, investigators found that men with a PSA velocity greater than 2 ng/ml in the year preceding diagnosis were 50% more likely to experience biochemical recurrence than the men whose PSA velocity was less than that. These men were also likely to experience biochemical recurrence faster and faced a greater likelihood of dying from prostate cancer than the other men. In the second study, involving 358 men treated with external beam radiation therapy, published in the Journal of the American Medical Association, researchers found that men with a PSA velocity greater than 2 ng/ml in the year preceding diagnosis were 80% more likely to experience biochemical recurrence than the others, and less likely to survive (see Table 3). Similarly, post-treatment PSA doubling time can also be used to assess the likelihood that disease is local or metastatic and provide insight into prognosis.
Table 3: PSA velocity before diagnosis and estimated chances of survival
An analysis of PSA velocity in the year preceding diagnosis reveals that it can predict the likelihood of survival seven years after external beam radiation therapy. (Similar findings have been reported for an analysis of men who underwent radical prostatectomy.)
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| Overall risk profile (based on PSA, Gleason score, cancer stage) | When PSA velocity is less than or equal to 2 ng/ml per year | When PSA velocity is greater than 2 ng/ml per year |
| Low risk | 100% | 81% |
| High risk | 96% | 76% |
| Source: Journal of the American Medical Association, July 27, 2005. |
When the post-treatment PSA level doubles in less than six months, for example, and certainly when it doubles in less than three months, the cancer has most likely spread and therefore requires systemic treatment. Research has also shown that the length of time it takes PSA to double can be used to estimate likelihood of whether disease will become clinically evident (detected by symptoms and scans) following biochemical recurrence (see Table 4).
Table 4: PSA doubling time and outcome five years after biochemical recurrence
A study involving 2,809 men who were treated with surgery and subsequently experienced biochemical recurrence (defined as a PSA of 0.4 ng/ml or more) found a clear relationship between PSA doubling time and eventual clinical outcomes.
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| PSA doubling time | Percentage of men without prostate cancer* |
| Less than 6 months | 38% |
| 6–11 months | 46% |
| 12 months–9 years, 11 months | 62% |
| 10 years or more | 87% |
*No clinical indication of local or systemic disease, based on digital rectal examination, transrectal ultrasonography, biopsy, or bone scan.
Source: Mayo Clinical Proceedings, June 2001.
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Of course, estimates of average likelihood of progression are simply that — estimates — and may not indicate what is going on in your own case. So to better determine whether your cancer recurrence is localized to the prostate or has spread elsewhere, your doctor will not only look at your pretreatment numbers, but also restage the disease by repeating some of the tests you had at the time of your initial diagnosis. You will likely undergo a bone scan and an abdominal pelvic CT scan. You may also undergo a ProstaScint scan, which uses monoclonal antibodies tagged with a radioisotope to identify metastatic prostate cancer in lymph nodes and other areas in the pelvis. It’s important to note, however, that not all doctors recommend such tests because in most men who experience rising PSA, these scans will usually not reveal any clinical evidence of metastases.
PSA velocity and prognosis
D’Amico AV, Chen MH, Roehl KA, Catalona WJ. Preoperative PSA Velocity and the Risk of Death from Prostate Cancer After Radical Prostatectomy. New England Journal of Medicine2004;351:125–35. PMID: 15247353.
D’Amico AV, Renshaw AA, Sussman B, Chen MH. Pretreatment PSA Velocity and Risk of Death from Prostate Cancer Following External Beam Radiation Therapy. Journal of the American Medical Association 2005;294:440–7. PMID: 16046650.
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Knowing whether and when to act
If your PSA indicates that biochemical recurrence has occurred — or if you are tracking your PSA closely, to determine whether you may need to consider treatment — you probably want to know what your options are. But as you evaluate options, consider not only what to do, but whether and when to act.
Unfortunately, experts don’t agree about when salvage treatment for recurrent prostate cancer should begin, or which salvage treatments are best. Of course, if you experience biochemical recurrence and the cancer appears aggressive — as indicated by your pretreatment risk profile (see Table 1) or a PSA doubling time of less than six months — your physician is likely to recommend immediate treatment, probably with hormone therapy, to delay metastases.
But many other men will find themselves in a gray area, with clinical profiles and PSA doubling times that are not sufficient to trigger immediate salvage therapy. If you are in this category, your physician may recommend waiting to treat until your PSA rises to a particular level. That means you may have more frequent PSA testing, which can be nerve-racking but is necessary to detect progression earlier. (For more insight into what this feels like, see “A couple’s story: Tracking PSA,” below.)
Although many men diagnosed with biochemical recurrence will want to take immediate action to stop the cancer, going ahead with therapy for the sake of simply doing something may cause more harm than good. The risks and complications of surgery or radiation, already high when delivered after an initial diagnosis of prostate cancer, may become even greater when these therapies are delivered as salvage after biochemical recurrence. Data are sparse on the side effects of salvage therapy, simply because not many studies have been done on the topic, but I always advise patients in this situation to consider that any complications of the initial therapy may be increased if their abdominal and pelvic areas are subjected to a second therapy. For example, some research indicates that the likelihood of developing urinary incontinence after prostatectomy is greater following salvage treatment (where it may affect 20%–60% of men) than when it is the first mode of treatment (where it may affect 2%–15% of men).
It’s also wise to consider the impact of further treatment if you have other diseases besides prostate cancer, such as diabetes, cardiovascular disease, or a pulmonary disease such as emphysema. If you do, it is likely that you are on medications for these disorders, and are already dealing with significant health challenges and risks. Undergoing additional treatment for prostate cancer may add to these risks, or may require that you readjust medications you are taking.
Finally, remember that you have time to make an informed decision about whether and when to undergo additional treatment for prostate cancer following biochemical recurrence. The evidence shows that you can expect to live for many more years. For example, the Journal of the American Medical Association study cited earlier, which reported that 15% of men experienced biochemical recurrence in a little over five years, also analyzed what happened to the men afterward. The authors found that it took an average of eight years for the cancer to metastasize to the bones, and the men survived another five years after that — for a total of 13 years, on average, after biochemical recurrence.
Remember that average survival times are based on studies of men treated in the past, and sometimes as long as 10 or 20 years ago. What’s more, some of these studies (including the Journal of the American Medical Association study cited above) included men who did not undergo further treatment after biochemical recurrence occurred. It’s likely that these men would have survived for a longer time if they had received additional treatment after biochemical recurrence was detected (although longer survival would come at the cost of treatment side effects). For these reasons, the “average” chances may be much better for a man treated today. And such averages can never predict what will happen in your particular case. That’s why, when I talk with patients about studies like this one, I encourage them to make decisions based on their own risk profile. As shown in Figures 1 through 3, your particular risk will vary, depending on factors such as PSA level at diagnosis, PSA doubling time, and Gleason score. Finally, when it comes to evaluating your options, much will depend on whether you were treated initially with surgery or radiation therapy, with or without hormone therapy.
Options for men who had surgery
How long after treatment it took for the PSA to rise and how quickly it rose provide important clues to whether it’s likely that your cancer is localized or metastatic. Generally speaking, the prognosis is worse for men whose PSA never becomes undetectable after surgery, or rises quickly a short time after treatment. Prognosis is better for men whose PSA rises slowly and begins to rise a long time after treatment. A few scenarios will help clarify what the options are in each situation.
Some men learn right away that they have residual disease. The surgeon sends any tissue excised during the operation to a pathologist for analysis. If the pathologist finds positive margins — meaning that he found cancer cells at the borders, or margins, of the excised tissue — this means that you may need to undergo radiation treatment to eradicate the cells remaining in the prostate area.
Scenario 1. Sometimes the PSA level never becomes undetectable after a prostatectomy. This situation, which is fortunately rare but among the most challenging to treat, means either that some cancer cells remained in the prostatic fossa (tissue left behind during surgery in the area once occupied by the prostate gland), or — more likely — that micrometastases had already spread beyond the prostate. A man in this situation may need additional therapy right away. The options offered may be radiation or hormone therapy, or both, or an investigational therapy.
Scenario 2. Sometimes the PSA falls to undetectable levels for several months following radical prostatectomy, and then begins to creep up. Typically, a man in this situation learns during one of his follow-up tests that he has experienced a biochemical recurrence. If the PSA level rises within the first year after surgery, it usually indicates metastatic disease. The treatment option most often offered is hormone therapy (either intermittent or continuous).
Scenario 3. The PSA does not begin to rise until a year or more after surgery. This is more likely to indicate localized disease, although it is possible that the disease has spread. Your treatment options depend on the PSA doubling time — how quickly PSA is increasing. If your PSA doubles in less than six months, and certainly less than three months, your doctor may recommend treating the area again, but this time with radiation or hormone therapy, in order to eradicate the disease.
Scenario 4. The PSA rises a year or more after surgery, but the doubling time is slow (a year or longer). This is probably the best scenario of all, as it indicates that the cancer may be localized and not aggressive. In this situation, you may opt for active surveillance — monitoring PSA and periodically having other tests, but not necessarily choosing an active intervention right away.
Salvage options after radical prostatectomy
Most men who experience a biochemical recurrence after prostatectomy and decide to undergo treatment have three options. The best strategy depends on your risk profile and comfort with side effects.
Radiation therapy
Many men opt to undergo salvage radiation therapy. Although few studies have been done to evaluate long-term results, many men do respond to salvage treatment. One study involving 368 men who had initially undergone radical prostatectomy, for example, found that five years after undergoing salvage radiation therapy, 46% remained free of biochemical recurrence, and 92% were still alive; at eight years, 35% remained free of biochemical recurrence, and 80% were still alive. Other studies have reported that salvage radiation therapy is likely to be most effective in men whose Gleason score, PSA level and doubling time, and other clinical features indicate less aggressive disease (see “For more information: Salvage radiation therapy,” below).
Side effects. Be aware that radiation therapy delivered after a prostatectomy markedly increases the likelihood of impotence and may increase the likelihood of incontinence. If you are already incontinent after surgery, then having radiation therapy is likely to make the problem permanent. For that reason, most men who become incontinent after surgery will wait until they regain control over their bladder or rectum before undergoing postoperative radiation therapy.
For more information: Salvage radiation therapy
Buskirk SJ, Pisansky TM, Schild SE, et al. Salvage Radiotherapy for Isolated Prostate Specific Antigen Increase after Radical Prostatectomy: Evaluation of Prognostic Factors and Creation of Prognostic Scoring System. Journal of Urology 2006;176:985–90. PMID: 16890677.
Sengupta S, Christensen CM, Zincke H, et al. Detectable Prostate Specific Antigen Between 60 and 120 Days Following Radical Prostatectomy for Prostate Cancer: Natural History and Prognostic Significance. Journal of Urology 2006;176:559–63. PMID: 16813889.
Stephenson AJ, Shariat SF, Zelefsky MJ, et al. Salvage Radiotherapy for Recurrent Prostate Cancer after Radical Prostatectomy. Journal of the American Medical Association2004;291:1325–32. PMID: 15026399.
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Radiation with hormone therapy
Another option is to undergo hormone treatment while undergoing salvage radiation therapy, because this may increase the effectiveness of radiation therapy.
Hormone therapy
If the PSA doubling time is less than six months, indicating that the cancer is aggressive, radiation therapy may not be adequate, as it is likely the cancer has already spread. In that case, a better option is a full course of hormone therapy, which can delay the time of onset to bone metastasis.
But other considerations also come into play. If you are sexually active and want to remain so, hormone therapy may not be the right option for you. Or you can opt for erectile-sparing hormone therapy, which involves a single agent like bicalutamide (Casodex), or bicalutamide and finasteride (Proscar) (see “For more information: Erectile-sparing hormone therapy,” below). Another option is to go on intermittent hormone therapy, in effect taking occasional “holidays” from treatment. This allows men to recover some quality of life while at the same time reducing levels of testosterone, which fuels the cancer.
If you are elderly (defined as having less than 10 years of life expectancy), you may not want the full spectrum of hormone therapy because it causes other complications.
For more information: Erectile-sparing hormone therapy
Boccardo F, Rubagotti A, Barichello M, et al. Bicalutamide Monotherapy Versus Flutamide Plus Goserelin in Prostate Cancer Patients. Journal of Clinical Oncology 1999;17:2027–38. PMID: 10561254.
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Salvage options after radiation therapy
If your initial cancer treatment was radiation therapy and you experience a biochemical recurrence, the salvage treatment you choose depends on whether you received external beam radiation therapy or brachytherapy, as well as whether you also received hormone therapy.
Salvage prostatectomy
When one of my patients experiences biochemical recurrence following radiation therapy, the first question I expect to hear is, “Can we just go in and take it out?” Salvage prostatectomy is a possibility for some men, but it is not used often, simply because it’s such a difficult operation. Radiation therapy causes scar formation and the development of fibrous tissue in the treated area, so that a surgeon may be unable to distinguish among different types of tissue. It may be difficult, for example, to distinguish the specific boundaries of the rectum and the bladder because of prior radiation scarring. Some highly skilled surgeons can perform a salvage prostatectomy, but the larger consideration is whether it is worth doing at all.
One could make a strong argument that in most cases, rising PSA after radiation therapy indicates systemic disease, and any type of local therapy — even salvage prostatectomy — is not going to solve the larger problem of cancer cells that have metastasized elsewhere. For those cells, you need hormone therapy.
Salvage radiation therapy
In certain unusual circumstances, if recurrent cancer is found only in a limited part of the prostate gland, it may be possible to place radioactive seeds in the area to eradicate the cancer. The techniques for performing this are still under investigation, and long-term data on effectiveness are not yet available. Be aware that it is not known whether this additional radiation will increase the risk of other types of cancers.
Cryotherapy
Another option, also appropriate only when a localized area of cancer is found, is cryotherapy. This freezes the prostate gland to kill any remaining cancer cells. This highly specialized treatment is not practiced widely, and substantial complications have been reported.
Metastatic disease: Hormone therapy
If your doctor determines that you have a metastatic rather than a localized recurrence, hormone therapy is your best option — and it is appropriate whether you initially underwent a radical prostatectomy or radiation therapy. Before a man who has experienced biochemical recurrence decides to have hormone therapy, however, the first question is whether he has had it before. Some men who were at intermediate or high risk of relapse (see Table 1) and decided to have radiation therapy initially probably also had hormone therapy beforehand because this increases the chances that initial therapy will succeed. If the patient had a hard time of it, in terms of side effects, he may not want to consider hormone therapy again.
Hormone therapy works by reducing testosterone levels. Because testosterone fuels the growth and development of prostate cancer, reducing levels of this fuel helps stop cancer from progressing — or at least slows the rate of progression.
Hope for the future
Experiencing biochemical recurrence can be emotionally devastating — there’s no doubt about it. But research continues about how best to treat men who experience a relapse following initial therapy for prostate cancer, and it is likely that new therapies will emerge in the coming years. In the meantime, stay informed about your treatment options and work with your doctor to determine whether it’s time to consider some type of salvage therapy.
