Treatment of Hormone Resistant Prostate Cancer

The following are treatment options for castrate-resistant prostate cancer (also called hormone-refractory prostate cancer). The types of treatments given are based on the unique needs of the person with cancer.

Hormonal therapy

 

Some form of hormonal therapy must always be continued even if the cancer is growing despite the hormonal therapy. If all hormonal therapy is stopped, the cancer is likely to grow very rapidly.

If a man is only taking an LHRH agonist, an anti-androgen (usually bicalutamide) will be added when there are signs of hormone-refractory growth (usually a rising PSA). The LHRH is not stopped. The PSA will often come down for a period of weeks or months before rising again. When it rises, the anti-androgen is stopped but the LHRH is continued.

Chemotherapy

 

Chemotherapy has an important role in the treatment of castrate-resistant or hormone-refractory prostate cancer.

The most common chemotherapy drugs used to treat prostate cancer are:

• docetaxel (Taxotere)
• mitoxantrone (Novantrone)
• cabazitaxel (Jevtana)

The most common chemotherapy combinations used are:

• docetaxel and prednisone – This combination reduces pain, improves quality of life and increases survival.
• mitoxantrone (Novantrone) and prednisone (Deltasone) – This combination reduces pain and improves quality of life.
• cabazitaxel (Jevtana) and prednisone – This combination prolongs survival in castrate-resistant prostate cancer.

Radiation therapy

 

Radiation therapy may be offered for hormone-refractory prostate cancer, either to relieve the urinary symptoms caused by the prostate tumour or to relieve the pain of bone metastases. The types of radiation therapy used is external beam radiation therapy:

• short course of treatment (1–10 treatments) to relieve bone pain
• not given for 4–6 weeks after a transurethral resection of the prostate (TURP), to reduce the risk of scarring in the urethra (urethral stricture)

Bisphosphonates

 

Bisphosphonates are drugs that strengthen bone. A bisphosphonate is used in combination with other standard treatments for hormone-refractory prostate cancer.

The type of bisphosphonate used with hormone-refractory prostate cancer is zoledronic acid (Zometa). It decreases bone-related complications in men with prostate cancer.

Biological therapy

 

A RANK ligand inhibitor is biological therapy in which a monoclonal antibody blocks the action of RANK ligand (a protein that promotes bone resorption). This helps to strengthen bone. The RANK ligand inhibitor denosumab is better than zoledronic acid in decreasing time to bone-related events in prostate cancer. It has recently been approved for use in men with prostate cancer in Canada.

 

 

Surgery

Transurethral resection of the prostate (TURP) may be offered for hormone-refractory prostate cancer. This type of surgery is used to relieve urinary symptoms caused by the prostate tumour (palliative surgery).

Clinical trials

 

Men with prostate cancer may be offered the opportunity to participate in clinical trials.

References

Cancer information / Cancer type / Prostate / Treatment / Castrate-resistant prostate cancer

American Cancer Society. Prostate cancer overview. (2011, May 4). Detailed Guide: Prostate Cancer. Atlanta, GA: American Cancer Society. Retrieved from: http://www.cancer.org/.

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de Bono,J.S., Oudard,S., Ozguroglu, M., et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. (2010, October 2). Lancet. New York, NY: Elsevier, Inc. Retrieved from: http://www.thelancet.com/journals/lancet/issue/current.

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Fizazi K, Carducci M, Smith M,et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. (2011, March 5). Lancet. New York, NY: Elsevier, Inc. Retrieved from: http://www.thelancet.com/journals/lancet/issue/current.

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Prostate Cancer Treatment (PDQ®). National Cancer Institute. (2010, August). National Cancer Institute (NCI). Bethesda, MD: National Cancer Institute. Retrieved from: http://www.cancer.gov.

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Prostate cancer. National Comprehensive Cancer Network. (2010). NCCN Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network (NCCN).

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Ross, P. L., Carroll, P. R., Small, E. J., et al. Prostate. Ko, A. H., Dollinger, M., & Rosenbaum, E. (2008). Everyone's Guide to Cancer Therapy: How Cancer is Diagnosed, Treated and Managed Day to Day. (5th Edition). Kansas City: Andrews McMeel Publishing. pp. 789-806.

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Zelefsky MJ., Eastham JA, Sartor OA, et al. Cancers of the genitourinary system: cancer of the prostate. Devita, V. T., Jr., Lawrence, T. S., & Rosenberg, S. A. (2008). Cancer: Principles & Practice of Oncology. (8th Edition). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. 40.6: 1392-1451.

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Source - Canadian Cancer Society:

http://www.cancer.ca/en/cancer-information/cancer-type/prostate/treatment/castrate-resistant-prostate-cancer/?region=on

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
</></></>________________________________________________________________________________________________

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.

Drug Shows Activity In Men With Advanced Prostate Cancer

ScienceDaily (Apr. 8, 2009) — A new multi-center study shows that an experimental drug lowers prostate specific antigen (PSA) levels – a marker for tumor growth – in men with advanced prostate cancer for whom traditional treatment options have failed. The study, led by researchers at Memorial Sloan-Kettering Cancer Center (MSKCC), is published in Science Express, the online version of the journal Science.

Most men with metastatic prostate cancer eventually build up resistance to the drugs that lower or block male hormones and develop a more aggressive form of the illness called castration-resistant prostate cancer (CRPC), or hormone-refractory disease. According to the study's findings, investigators studied two novel compounds, RD162 and MDV3100, and not only gained an understanding of their novel mechanism of action, but found that these agents showed activity in CRPC cells in culture and in mice.

The study also reports on a Phase 1/2 trial of MDV3100 in 30 patients with advanced CRPC and found that 22 out of 30 men showed declining PSA levels, and 13 out of 30 men (43 percent) had PSA levels fall by more than half.

Several years ago, the senior author of the study, Charles Sawyers, MD, and his colleagues at the University of California, Los Angeles (UCLA), uncovered a potential reason why metastatic prostate cancer patients eventually relapse with CRPC. This insight was used to discover RD162 and MDV3100.

"It's gratifying to know that our hypotheses about why men develop resistance to currently available treatments are confirmed and, most importantly, that there are already patients who are benefiting from our research," said Dr. Sawyers, Chair of the Human Oncology and Pathogenesis Program at MSKCC and a Howard Hughes Medical Institute investigator.

Current treatments for men who have advanced prostate cancers inhibit the activity of male hormones that help drive tumor growth. Many of these drugs disrupt the androgen (male hormone) receptor, which helps regulate cell proliferation, but tumors eventually become resistant to the drugs by expressing higher levels of the receptor. Preclinical studies by Dr. Sawyers and others have demonstrated that CRPC cells have increased expression of the androgen receptor and that overexpression of this receptor may contribute to the progression of disease.

Based on this information, Dr. Sawyers initiated a collaboration with Michael Jung, PhD, Professor of Chemistry at UCLA, that led to the discovery of a number of nonsteroidal, small molecule antiandrogen compounds, including MDV3100, which has been shown to retain its anticancer activity, even when the receptor's expression is elevated.

"The discovery and initial development of this drug was a collaborative effort all done in the academic setting, without reliance on the engine of the pharmaceutical industry that typically drives drug development," said Dr. Sawyers.

Dr. Jung's group synthesized the compounds, which Dr. Sawyers' team then evaluated using prostate cancer mouse models engineered to highly express the androgen receptor, mimic progression to castration-resistant disease, and reflect the biology of clinical drug resistance.

According to the new study, the team of researchers tested various compounds to block the androgen receptor in CRPC cells. They chose to further evaluate the drug RD162 and a closely related compound, MDV3100. According to their findings, both drugs inhibit the androgen receptor function by impairing the receptor's ability to enter a CRPC cell's nucleus (called nuclear translocation), blocking it from binding to the DNA of its target genes, and preventing the cell from growing.

They found that both compounds worked well in cells in culture, shrank tumors in mice, maintained tumor shrinkage for months, and prevented the androgen receptor from activating additional genes later in the process, or "downstream." Other currently approved drugs cannot disable the receptor in such a way.

The biopharmaceutical company Medivation, Inc., licensed RD162 and MDV3100 from UCLA in 2006 and has already completed enrollment in the first human trial of oral MDV3100 – a Phase 1/2 clinical trial, which was led by investigators at MSKCC and conducted through the Prostate Cancer Clinical Trials Consortium.

The Consortium is sponsored by the Department of Defense and the Prostate Cancer Foundation. The trial enrolled men with metastatic, castration-resistant prostate cancer who relapsed after treatment with conventional hormone therapy and demonstrated anti-prostate cancer effects beginning with the first patient treated with MDV3100 at the lowest dose. Further positive results from an additional 110 patients who received the drug at higher doses were recently reported at the ASCO Genitourinary Cancers Symposium in February 2009.

"The declines in PSA levels observed thus far and the general tolerability of this treatment are encouraging," said Howard Scher, MD, a study co-author and Chief of the Genitourinary Oncology Service at MSKCC. "I am looking forward to continuing the study of this drug, which has the potential to be a powerful tool in a limited arsenal of treatments against this deadly form of the disease." A Phase 3 trial is planned to begin later this year.

The study was supported in part by the Prostate Cancer Foundation, the National Cancer Institute, and a Prostate Cancer Research Program Clinical Consortium Award.

Hormone (Androgen Deprivation) Therapy

Hormone therapy is also called androgen deprivation therapy (ADT) or androgen suppression therapy. The goal is to reduce levels of the male hormones, called androgens, in the body. The main androgens are testosterone and dihydrotestosterone (DHT). Androgens, produced mainly in the testicles, stimulate prostate cancer cells to grow. Lowering androgen levels often makes prostate cancers shrink or grow more slowly. However, hormone therapy does not cure prostate cancer.


Hormone therapy may be used in several situations:

* If you are not able to have surgery or radiation or can't be cured by these treatments because the cancer has already spread beyond the prostate gland
* If your cancer remains or comes back after treatment with surgery or radiation therapy
* As an addition to radiation therapy as initial treatment if you are at high risk for cancer recurrence
* Before surgery or radiation to try and shrink the cancer to make other treatments more effective

Types of Hormone Therapy

There are several types of hormone therapy used to treat prostate cancer.

Orchiectomy (surgical castration): Even though this is a type of surgery, its main effect is as a form of hormone therapy. In this operation, the surgeon removes the testicles, where more than 90% of the androgens, mostly testosterone, are made. With this source removed, most prostate cancers stop growing or shrink for a time.

This is done as a simple outpatient procedure. It is probably the least expensive and simplest way to reduce androgen levels in the body. But unlike some of the other methods of lowering androgen levels, it is permanent, and many men have trouble accepting the removal of their testicles. Some men having the procedure are concerned about how it will look. If wanted, artificial silicone sacs filled with saline (salt water) can be inserted into the scrotum. These look and feel like testicles.

Possible side effects of orchiectomy are generally related to changing levels of hormones in the body. About 90% of men who have had this operation have reduced or absent libido (sexual desire) and impotence. Some men also experience:

* Hot flashes (these may go away with time)
* Breast tenderness and growth of breast tissue
* Osteoporosis (bone thinning) which can lead to broken bones
* Anemia (low red blood cell counts)
* Decreased mental acuity (sharpness)
* Loss of muscle mass
* Weight gain
* Fatigue
* Decrease in HDL ("good") cholesterol
* Depression

Many of these side effects can be prevented or treated. For example, sometimes the hot flashes will be helped by treatment with antidepressants. Brief radiation treatment to the breasts before surgery can help prevent their enlargement.

Men getting this treatment should be watched and treated for osteoporosis to help prevent broken bones. There are several different drugs available. Exercise is a good way to reduce fatigue, weight gain, and the chance of loss of bone and muscle mass. If anemia occurs, it is often very mild and usually doesn't cause symptoms. Depression can be treated by antidepressants and/or counseling.

Luteinizing hormone-releasing hormone (LHRH) analogs: Even though LHRH analogs (also called LHRH agonists) cost more and require more frequent doctor visits, most men choose this method over orchiectomy. These drugs lower testosterone levels just as well as orchiectomy by lowering the levels of androgens (mainly testosterone) made by your testicles.

LHRH analogs are injected or placed as small implants under the skin. They are given either monthly or every 3, 4, 6, or 12 months. The LHRH analogs available in the United States include leuprolide (Lupron, Viadur, Eligard), goserelin (Zoladex), and triptorelin (Trelstar).

Possible side effects of LHRH analogs such as hot flashes, osteoporosis, and others are similar to those of orchiectomy (see above), and are largely due to low testosterone levels.

When LHRH analogs are first given, testosterone production increases briefly before falling to very low levels. This effect is called flare and results from the complex way in which LHRH analogs work. Men whose cancer has spread to the bones may experience bone pain. If the cancer has spread to the spine, even a short-term increase in growth could compress the spinal cord and cause pain or paralysis. Flare can be avoided by giving drugs called anti-androgens for a few weeks when starting treatment with LHRH analogs. (For more on anti-androgens, see below.)

Luteinizing hormone-releasing hormone (LHRH) antagonists: A newer drug, abarelix (Plenaxis), is an LHRH antagonist. It is thought to work like LHRH agonists, but it appears to reduce testosterone levels more quickly and does not cause tumor flare like the LHRH agonists do.

A small percentage of men (fewer than 5%) have serious allergic reactions to the drug. Because of this, it is only approved for use in men who have serious symptoms from advanced prostate cancer and who cannot or refuse to take other forms of hormone therapy.

The possible side effects are similar to those with orchiectomy (see above) or LHRH agonists.

Abarelix is given only in qualified doctors' offices. It is injected into the buttocks every 2 weeks for the first month, then every 4 weeks. You will be asked to remain in the office for 30 minutes after the injection to make sure you are not having an allergic reaction.

Anti-androgens: Anti-androgens block the body's ability to use any androgens. Even after orchiectomy or during treatment with LHRH analogs, a small amount of androgens is still made by the adrenal glands.

Drugs of this type, such as flutamide (Eulexin), bicalutamide (Casodex), and nilutamide (Nilandron), are taken daily as pills.

Anti-androgens are not often used by themselves (see below). An anti-androgen may be added if treatment with orchiectomy or an LHRH analog is no longer working by itself.

Anti-androgen treatment may be combined with orchiectomy or LHRH analogs as first-line hormone therapy. This is called combined androgen blockade (CAB). There is still some debate as to whether CAB is more effective in this setting than using orchiectomy or an LHRH analog alone. If there is a benefit, it appears to be small.

Some doctors are testing the use of anti-androgens instead of orchiectomy or LHRH analogs. Several recent studies have compared the effectiveness of anti-androgens alone with that of LHRH agonists. Most found no difference in survival rates, but a few found anti-androgens to be slightly less effective.

If hormone therapy including an anti-androgen stops working, some men seem to benefit for a short time from simply stopping the anti-androgen. Doctors call this the "anti-androgen withdrawal" effect, although they are not sure why it happens.

Side effects of anti-androgens in patients already being treated by orchiectomy or with LHRH agonists are usually not serious. Diarrhea is the major side effect, although nausea, liver problems, and tiredness can also occur.

The major difference from LHRH agonists and orchiectomy is that anti-androgens may have fewer sexual side effects. When these drugs are used alone libido and potency can often be maintained.

Other androgen-suppressing drugs: Estrogens were once the main alternative to orchiectomy for men with advanced prostate cancer. Because of their possible side effects (including blood clots and breast enlargement), estrogens have been largely replaced by LHRH analogs and anti-androgens. Still, estrogens may be tried if androgen deprivation is no longer working.

Ketoconazole (Nizoral), first used for treating fungal infections, blocks production of androgens and is sometimes used.


Current Controversies in Hormone Therapy

There are many issues around hormone therapy that not all doctors agree on, such as the best time to start and stop it and the best way to give it. Studies looking at these issues are now under way. A few of the issues are discussed here.

Early vs. delayed treatment: Some doctors think that hormone therapy works better if it is started as soon as possible if the cancer has reached an advanced stage (for example, when it has spread to lymph nodes), if it is large (T3) or has a high Gleason score, or if the PSA starts rising after initial therapy, even though the patient feels well. Some studies have shown that hormone treatment may slow down the disease and perhaps even lengthen patient survival. But not all doctors agree with this approach. Some are waiting for more evidence of benefit. They feel that because of the likely side effects and the chance that the cancer could become resistant to therapy sooner, treatment should not be started until symptoms from the disease appear. Studies addressing these questions are now under way.

Intermittent vs. continuous hormone therapy: Nearly all prostate cancers treated with hormone therapy become resistant to this treatment over a period of months or years. Some doctors believe that constant androgen suppression may not be needed, so they advise intermittent (on-again, off-again) treatment.

In one form of intermittent therapy, androgen suppression is stopped once the blood PSA level drops to a very low level. If the PSA level begins to rise, the drugs are started again. Another form of intermittent therapy involves using androgen suppression for fixed periods of time -- for example, 6 months on followed by 6 months off.

Clinical trials of intermittent hormonal therapy are still in progress. It is too early to say whether this new approach is better or worse than continuous hormonal therapy. However, one advantage of intermittent treatment is that for a while some men are able to avoid the side effects of hormonal therapy such as impotence, hot flashes, and loss of sex drive.

Combined androgen blockade (CAB): Some doctors treat patients with both androgen deprivation (orchiectomy or an LHRH agonist) and an anti-androgen. But most doctors are not convinced there's enough evidence that this combined therapy is better than one drug alone.

Triple androgen blockade (TAB): Some doctors have suggested taking combined therapy one step further, by adding a drug called a 5-alpha reductase inhibitor -- either finasteride (Proscar, Propecia) or dutasteride (Avodart) -- to the combined androgen blockade. There is very little evidence to support the use of this "triple androgen blockade" at this time.

Last Revised: 08/25/2008

Treatment for Advanced Cancer

I came across the following in my research and it gave me some reason to pause and reconsider the way forward!

I'm due to see my Urologist on 14 February, we'll have a bit to talk about I think. On 8 February, I am due to have my next PSA test - hoping that the result is a continued improvement.

After 3 months [almost] on Hormone Therapy, I have seen my PSA level drop from '84.8' to '12' and [hopefully] to zero [or close to it] - this time.

Advanced Cancer

Patients with advanced prostate cancer are generally men who have extensive disease in the pelvis [No], metastases in the lymph nodes [No] or bone [No] or a PSA level greater than 50 ng/mL [Yes, 84.8 ... hmm, definitely me] or men in whom local treatment has failed [No].

Bilateral orchidectomy is the gold standard for testosterone reduction. However, although it offers immediate relief from metastatic pain and eliminates problems of compliance, orchidectomy is psychologically unacceptable to most men. Hormone therapy is the mainstay of treatment in this group.

When hormone therapy is commenced, the vast majority of patients get excellent initial symptomatic relief, even in the presence of painful metastases. Regular PSA measurements are the best way to monitor response. Some patients elect to delay hormone therapy in the interest of avoiding side effects. These men may have had a PSA recurrence after failed initial therapy or be older asymptomatic men with metastatic disease.

In patients who have less advanced disease the cancer ultimately becomes refractory [resistant] to hormone therapy' (after three to five years, or even longer).

Most patients who develop hormone refractory disease die within 12 months.

Which hormones should be used?

Leuprorelin acetate (Lucrin) and goserelin acetate (Zoladex), which are LHRH analogues, are commonly used for chemical castration. However, these agents cause an initial testosterone flare that should be prevented with concomitant use of an antiandrogen for the first two to four weeksí duration. LHRH analogues are available in monthly, three-monthly and, more recently, four-monthly depot preparations.

The nonsteroidal antiandrogens flutamide (Eulexin, Flutamin, Fugerel), bicalutamide (Cosudex) and nilutamide (Anandron) have similar action. These agents are generally used in association with LHRH analogues, but can be used alone in sexually active men to sometimes prevent impotence. Careful monitoring of liver function tests is essential in patients taking antiandrogens.

Cyproterone acetate (Androcur, Cyprone, Procur) is a steroidal antiandrogen that can be used alone or with LHRH analogues. Oestrogens have fallen out of favour because of their cardiovascular side effects.


Should hormones be commenced immediately or later, or intermittently?

Immediate hormone therapy is appropriate for symptomatic patients; however, its timing in asymptomatic patients remains controversial. There is increasing evidence to suggest that earlier use of hormone therapy improves survival, but this benefit must be balanced against side effects.

Most patients choose immediate therapy, although older asymptomatic patients may choose delayed therapy after informed consent. Patients with a PSA recurrence after previous failed surgery or radiotherapy often opt for a period of observation to ascertain the rate of PSA rise prior to commencing hormone therapy.

The use of intermittent hormone therapy has become increasingly popular in patients with less advanced disease. Although the benefits of intermittent therapy are less proven, it clearly improves quality of life in patients with less advanced disease who are destined to use hormones for very long periods.

The aim of this therapy is to depress PSA to undetectable levels, wait until it rises again to a predetermined level (such as 10 ng/mL), then commence a further pulse of hormones. This approach gives patients longer periods free of side effects of hormone therapy, such as impotence, depression, lethargy and osteoporosis.

How should hormone therapy be monitored?

Hormonal therapy is best monitored by regular measurement of PSA levels. To assess effectiveness in suppressing testosterone, a serum testosterone can be used and, if not completely suppressed, an anti-androgen can be added. A combination of castration (medical or surgical) and anti-androgen therapy may be used to block both testicular and adrenal androgen activity.

Since the results of major trials have recently become available, enthusiasm for this combination has decreased, but it still tends to be used in young men with early metastatic disease.


How should side effects of hormone therapy be managed?

The side effects of hormones must be managed individually. Hot flushes may be treated with cyproterone, clonidine (Catapres 100) or oestrogen; lethargy may be improved by giving hormones intermittently. Osteoporosis may develop in patients destined to use hormone therapy for long periods; in this group, bone density should be checked at 12 months and therapy such as intravenous or oral bisphosphonates should be used if significant deminerali-sation is present.


What can we do when hormones no longer work?

When hormone therapy fails, most treatment is palliative. Serum testosterone should always be checked to ensure hor-mone therapy has been achieving castrate levels of testosterone. Therapeutic options include:

Localised radiotherapy or strontium-89 (Metastron) radiotherapy to painful metastatic deposits - second-line hormone therapy - chemotherapy - cyclophosphamide (Cycloblastin, Endoxan-Asta), mitozantrone hydrochloride (Mitozantrone Injection, Novantrone, Onkotrone), docetaxel (Taxotere) - corticosteroids and pain relief.

A team approach to palliation is important to provide maximal quality of life in men who have hormone refractory cancer, and may include antidepressants, psychological support and hospice services. Promising new approaches include gene therapy, antiangiogenesis drugs such as thalidomide, immunological approaches, and growth factor blocking drugs.


Conclusion

It is mandatory to tailor therapy for prostate cancer to the individual. Modern treatments, including newer surgical techniques and improved conformal delivery of radiotherapy, have resulted in a significant decrease in side effects and improved outcomes. Further knowledge about biochemical markers, the results of new and improved techniques and more established results of known treatments will help us to individualise treatment, resulting in better control of the disease and fewer side effects.

Source: St Vincent's

Hormone Resistant Cancer

What happens if my prostate cancer stops responding to the hormone treatment? This was the question that had begun to enter my thoughts. As a result, I decided to research this possibility and found some very useful information which I now share with you the reader.

"When prostate cancer advances to later stages, it can become resistant, or refractory, to first-line treatments.

As prostate cancer tends to advance, men will get some kind of what is called hormone therapy, androgen deprivation therapy, hormone manipulation, many different names where basically we attempt to suppress the testosterone stimulation for the prostate. Although most prostate cancers, more than 90 percent, are sensitive to this hormone change, at some point the prostate cancer for some reason that's still unclear to us, adapts.

At that point it's no longer sensitive to the suppression of the hormones or testosterone. And that's when it's called 'hormone refractory prostate cancer'.

There are many types of hormonal therapies. Even when the cancer has become resistant to some hormonal treatments, others may still be effective.

In patients that have hormone refractory prostate cancer, they continue on their hormonal therapy. Many of those patients will undergo a secondary hormonal manipulation.

In men, there are two main producers of testosterone, the testes and the adrenal glands. By late-state disease, patients have most likely had their testicles surgically removed. Another type of hormone therapy uses drugs to inhibit testosterone release by the adrenal glands.

Secondary hormone manipulations include medications, such as ketoconazole, which is an antifungal agent, but given at higher doses, it can actually suppress the hormones that are produced by the adrenal gland, so many patients can undergo a secondary manipulation, for example, with ketoconazole and steroids.

Hormone therapy at any stage of prostate cancer can affect a patient's quality of life.

Patients complain very frequently of hot flashes or hot flushes. People have different names for it and essentially it's like going through menopause for women. The second thing that can happen is they can lose bone mass and muscle, which can be very distressing to men, particularly younger men who are diagnosed with the disease. And then the last thing some patients complain that they actually don't feel as sharp. They don't think as clearly.

The survival rate for hormonal refractory prostate cancer is approximately two years. However, recent studies have shown that chemotherapy may extend the lifespan of some patients by over 20 percent.

There are two large, actually very well done studies that looked at using docetaxel; the trade name for that is Taxotere. One was a trial called TAX-327, which was an industry-sponsored trial looking at giving docetaxel plus steroid, called prednisone, and that was compared to the previously FDA-approved regimen, which was something called mitoxantrone and prednisone. And what you saw was actually about a two to three month difference in overall survival -- between those patients that got docetaxel at every three weeks compared to the previous FDA-approved chemotherapy regimen.

The second study, known as SWOG-9916, focused on docetaxel and another chemotherapy drug called estramustine.

The combination of docetaxel and the estramustine phosphate were compared to at the time the standard, which was mitoxantrone and prednisone. And again, survival benefit was shown in the chemotherapeutic arm of docetaxel and estramustine phosphate over mitoxantrone. And again, it was about a 25 percent improvement in patient survival.

Estramustine, however, may be associated with series side effects including blood disorders and abnormal clotting.

The problem with that regimen though is the estramustine phosphate does have thromboembolic and hematologic toxicities that make that not the clearest choice for patients with advanced prostate cancer.

Radiation therapy can also be used in advanced prostate cancer.

Radiation therapy is very commonly used, not only for localized therapy, but for therapy for patients who have prostate cancer that has already spread, symptomatic relief. For instance, if you have a spread of cancer to your back or to your rib or somewhere painful in your bone, it's very common to use radiation therapy. That's in a palliation sense.

Advanced prostate is an incurable disease. However, emerging therapies are helping patients live longer lives.

We now have effective chemotherapy that for the first shows survival benefit. I think that most people who treat prostate cancer believe, especially in the advanced stages, that we're not there yet with a cure for these advanced hormone refractory patients. We have probably the first piece of the puzzle with some new chemotherapy that shows survival advantage".

Source: Your Health Portal