Managing the Patient With a Rising PSA Following ADT

Although prostate cancer is initially responsive to hormone manipulation, the responsiveness of tumor cells to ADT in patients with metastatic disease begins to wane rather quickly, with a median time to disease progression of less than 2 years,^[37,38] and a median survival of 12-16 months from the time that androgen independence is established.^[38]
                       
Unfortunately, the natural history of these patients is poorly understood. Numerous factors such as the lactate dehydrogenase, alkaline phosphatase, hemoglobin, and Eastern Cooperative Oncology Group or Karnofsky performance status have been used to predict prognosis,^[39,40] while others have suggested that a detailed PSA history alone may be enough to stratify risk and predict prognosis.^[41]

Because the velocity of PSA changes may be different before and after ADT, reflecting changes in tumor kinetics after treatment, intermediate end points based on the ratio of the post- to pre-ADT slope are being considered in clinical trials as an end point for comparing systemic therapy in patients with the "lethal phenotype" (ie, PSA doubling time < 3 months).

Nevertheless, until PSA doubling time and/or calculated pre- and post-ADT PSA velocities as predictors of survival in patients are widely accepted, a 50% decline in PSA is typically considered the benchmark for response to ADT, while PSA increases of a minimum of 5 ng/mL with two consecutive increases of 25% after ADT indicate clinical disease progression.^[2,38,42]

Treatment Strategies

Castrate patients with a rising PSA present unique and complex challenges for the treating physician. Frequently, ADT continues to be employed while additional therapeutic strategies are explored. At this stage of disease, the establishment of a true multidisciplinary care team is essential, including the coordinated involvement of a urologist, an oncologist, and a radiologic imaging specialist.

Before any additional therapeutic regimens can be considered, maintenance of castrate levels of testosterone (< 50 ng/mL) should be confirmed, as the presence of a rising PSA may in fact indicate that ADT is not sufficiently suppressing testosterone production and/or action and that additional androgen suppression therapy is warranted.^[2]
                       
Even if androgen independence is established despite castrate levels of testosterone and the rising PSA levels indicate biochemical failure, the tumor might respond to secondary hormonal manipulation.

In patients who had been treated with an antiandrogen, withdrawal of the agent while maintaining castrate levels of testosterone has been associated with PSA responses, as well as with symptomatic and objective responses, in about 25% of patients. The duration of response is typically 3-4 months, but some cases have lasted for several years.^[2] This response has been noted with flutamide, bicalutamide, and nilutamide^[43] and may result from mutations of androgen receptors.^[44]

Thus, a trial of antiandrogen withdrawal may be reasonable for certain patients, particularly before initiating more toxic therapy. Although it is unclear whether the same antiandrogen would still be effective if reintroduced at a later point, cross-reactivity generally does not exist among the antiandrogens: both bicalutamide and nilutamide have shown some activity as secondary antiandrogens following resistance to flutamide.^[45-47]
                       
Adrenal androgen inhibitors, most commonly ketoconazole, also have a role as second-line hormonal agents. Approximately 10% of circulating androgens derive from the adrenal glands, and a higher proportion of adrenal androgens may be in prostate cancer cells.^[2] Ketoconazole has been shown to decrease serum PSA by 50% with high doses^[48] and low doses,^[49] but the duration of response is short, with one study finding a median PSA response duration of only 3.5 months.

Similarly, glucocorticoids have also shown some effect in patients with AIPC. In several trials comparing hydrocortisone alone with hydrocortisone and a study treatment, disease response was seen in the hydrocortisone-alone arms.^[50-53] However, as with ketoconazole, the duration of response tends to be rather short and further progression of disease is rapidly seen.

A more promising approach has been seen with chemotherapeutic agents. Chemotherapy with cytotoxic agents historically has had a minor role in the treatment of prostate cancer. In 1985, Eisenberger and colleagues reviewed 17 randomized clinical trials and found complete and partial response rates in only 4.5% of patients.^[54] In 1993, in another large review, the overall response rate with chemotherapy was 8.7%.^[55]

Switching tactics, researchers began to measure quality-of-life parameters in this population, and the use of mitoxantrone showed significant palliative benefits,^[51] which led to its approval by FDA for use in patients with AIPC. Unfortunately, aside from its palliative benefits, it has shown only modest activity in measurable disease and lacks the ability to confer a significant survival advantage in patients with AIPC.^[52]
                       
By contrast, two phase 3 trials with docetaxel, one pairing with prednisone and the other pairing with estramustine, showed significant improvement in both survival and palliation in patients with AIPC when compared with the standard mitoxantrone/prednisone regimen.^[56,57] These trials led to the recent approval by FDA of docetaxel in combination with prednisone every 3 weeks in patients with AIPC.

Newer agents targeting apoptosis, growth factors, angiogenesis, tumor-associated antigens, and protein degradation pathways are also being studied, many in combination with various chemotherapeutic regimens. The ability of docetaxel and, potentially, other agents to slow disease progression and improve survival in patients with AIPC indicates that the natural history of prostate cancer can be altered even in late stages of disease.

Unfortunately, these data also indicate that there is no clear standard of care for the large number of men who will develop a rising PSA while on ADT. Those patients who are symptomatic should undergo radiographic studies to assess for metastatic disease, and a full evaluation of known prognostic factors can give insight into a patient's future clinical course. Most importantly, patients should be evaluated for inclusion into a clinical trial, as there remains much to learn about the optimal treatment of patients with AIPC.

The algorithm in Figure 2 suggests an approach that can be taken when deciding how to manage patients with rising PSA despite ADT.

Figure 2. Suggested algorithm for approaching the patient with a rising PSA despite ADT.

Handling relapse after Prostate Cancer Treatment - 2

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
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.
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.

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 Urology 2005;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.

How to handle a relapse after treatment for prostate cancer - Part One

Marc B. Garnick, M.D., discusses what biochemical recurrence means and what your options are

“Am I going to die?”

This is the first question a patient usually asks me when a follow-up blood test reveals that his prostate-specific antigen (PSA) level has risen after he has already undergone treatment for prostate cancer (usually a radical prostatectomy or radiation therapy).

The fear is understandable: When PSA levels rise to a certain threshold after prostate cancer treatment, the patient has suffered what is known technically as a biochemical recurrence, sometimes also referred to as a biochemical relapse or stage D1.5 disease.

Whatever term is used, it means that prostate cancer remains within the prostate after radiation therapy, that it survived outside the excised area after radical prostatectomy, or that it has reappeared in metastatic form in other tissues and organs.

In most cases the cancer remains at a microscopic level, and many years will pass before any physical evidence of it is detectable on a clinical exam or any abnormalities are seen on a bone scan or CT scan.  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?

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.)

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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 ____________________________________________________________________________________________________________

Low risk (33% chance of biochemical recurrence within five years)

Gleason score less than or equal to 6 and PSA less than or equal to 10 ng/ml and Cancer stage T1c or T2a.

</></></> Intermediate risk
(50% chance of biochemical recurrence
within five years)
 
Gleason score of 7 (if 3+4)

and/or PSA greater than 10 but no greater
than 20 ng/ml

and/or Cancer stage T2b.
</></></> High risk
(85% chance of biochemical recurrence within
five years)
Gleason score of 7 (if 4+3), or 8 or more

and/or PSA greater than 20 ng/ml

and/or Cancer stage T2c or more
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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 — the next article in this series explains what a rising PSA after treatment really means and what your treatment options are.

The PSA Test. Is It Worth It?

Sunday March 22, 2009

The results of two large research studies that sought to evaluate the worth of the PSA test were recently published in the New England Journal of Medicine.

Both studies looked back over a number of years to determine whether men who had undergone PSA and digital rectal exam screening for prostate cancer actually had lower rates of death from prostate cancer than men who hadn't undergone any screening.

One of the studies, which was based in Europe, found that, yes, men who had undergone prostate cancer screening did have lowered rates of death from prostate cancer (up to 20% lower).

However, it was also found that, in order to prevent one death from prostate cancer, approximately 1400 men would have to undergo prostate cancer screening. Furthermore, a certain percentage of men who undergo screening eventually proceed to more invasive testing such as prostate biopsy, which has its own set of risks and complications.

So far, most of the editorials and opinions in the American media have focused on the fact that a large number of men need to be screened and tested for prostate cancer in order to save even one life from prostate cancer. This is true, but the results of these studies really don't change what doctors have been saying all along - that the PSA test is imperfect, but still the best that is available (when used with regular digital rectal exams) for early detection of prostate cancer.

In my opinion, the PSA test should be interpreted with a more nuanced approach. Other indicators such as the PSA velocity, the PSA density, and the percent-free PSA have been shown to be useful for determining which elevated PSA levels are the most likely to represent prostate cancer that is the most dangerous.

Abandoning the PSA test because of its imperfections is unwise and very unlikely to happen until a proven superior test is developed.

Here are links to the two studies that were recently published in the NEJM.

The American trial and the European trial.

What to Consider When Your PSA Is Rising After Initial Treatment

This section summarizes key points to consider when your PSA is rising after undergoing initial treatment. The list 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) In the post-prostatectomy setting, the most widely accepted definition of a recurrence is a PSA > 0.3 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. 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.

2) 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.

3) If your PSA starts to rise after you’ve undergone prostatectomy, "salvage" radiation therapy might be a good option to explore. With this approach, external beam radiation is delivered to the area immediately surrounding where the prostate was, in the hopes of eradicating any remaining prostate cells that have been left behind.

4) 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.

5) 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.

6) 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.

7) There are several approaches to blocking the secretion of testosterone including the surgical removal of the testes, drugs known as LHRH agonists, and estrogens.

8) 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.

9) 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.

10) 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 months, or once per year. These long-acting drugs are injected under the skin and release the drug slowly over time.

11) 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.

12) 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.

13) 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.

14) Hormone therapy typically is effective for only a few years. 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 or aminoglutethimide can be used to block the small amounts of testosterone produced by the adrenal glands from being released.

15) 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.

(http://www.prostatecancerfoundation.org/)