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Advanced Prostate Cancer and Its Treatment

(revised December 2001)

This sheet has been developed to provide you with general information on the different treatments available at UCSF for advanced prostate cancer. We define "advanced" prostate cancer as prostate cancer that requires additional therapy beyond surgery and/or radiation. The treatment options available to you will depend on what kind of treatment you have already had and what your current condition is.

Many of the following treatments are options for patients with metastatic prostate cancer. The term "metastatic" means that the prostate cancer has metastasized or spread outside of the prostate to a distant site, such as bone or lymph nodes. Patients who have no evidence of disease at distant sites but whose PSA (prostate specific antigen: a blood test which usually is increased with active prostate cancer) is rising may also be candidates for some of the treatments described.

I. Hormonal Therapy for Prostate Cancer

For patients with metastatic disease, for some patients who choose to not have radiation or surgery, and for some patients with a climbing PSA after radiation or surgery, hormone therapy is frequently the first treatment offered. The reason is that the male hormone testosterone causes the growth of prostate cancer. Testosterone is mostly produced by the testicles, and a smaller supply comes from the adrenal glands.

There are two treatments that reduce the supply of testosterone from the testicles to the prostate tumor. One method is an orchiectomy. This is the surgical removal of the testicles. The other approach is a monthly injection of Lupron or Zoladex, medications which stop the production of testosterone. Both Lupron and Zoladex are also available in a 3 or 4-month preparation. The side effects of both the orchiectomy and Lupron/Zoladex are hot flashes, and, in virtually all patients, low sexual desire and impotence (inability to have an erection). There can be muscle loss, weight gain, anemia (a lowering of the red blood cells which can contribute to fatigue), and in some patients on long-term therapy, osteoporosis or thinning of the bone. There are some medications that may help decrease hot flashes. Medications exist to treat anemia and osteoporosis. The impact that hormone treatments have on an individual's sex life is equally as important as other side effects, and we hope to provide an open, supportive environment for you to discuss this if you wish. There is also a very helpful booklet provided by the American Cancer Society called Sexuality and Cancer: For the Man Who Has Cancer, and His Partner. We have copies of this booklet available upon request. There are also resources within the University to discuss treatments for impotence.

In addition to the injections or surgery, you may also be started on an oral medication called flutamide (Eulexin) or bicalutamide (Casodex), which will block the uptake of testosterone by the tumor cells, regardless of where it was produced (testicles or adrenal glands). While debate remains, many physicians who treat prostate cancer feel that these two drugs are equivalent. A third pill called nilutamide (Nilandron) is on the market, although we tend not to use it because of potential side effects.

The side effects from Eulexin may include mild stomach distress, such as diarrhea. Eulexin, Casodex and Nilandron can make blood tests that measure liver function (liver enzymes) abnormally high, and, on rare occasions, the drug may need to be stopped because of this. The liver enzymes return to normal (in the vast majority of patients) once the drug is discontinued. Because of this, we recommend checking blood tests that measure the liver enzymes one month after starting Eulexin, Casodex or Nilandron, and then once every 3 months. Diarrhea and abnormalities in liver enzymes occur in less than 5-10% of patients.

While most patients stay on these drugs indefinitely, some patients are treated with "intermittent" therapy. This involves taking Lupron or Zoladex plus Eulexin, Nilandron or Casodex until the PSA falls to its lowest point and for a total of 9 to 12 months. The drugs are then stopped, with careful PSA monitoring (usually once every 1 or 2 months). When the PSA starts to climb and reaches about half of the previous highest PSA level, the drugs are started again until the PSA again falls, and so on. This is an unproven approach, but its benefits include being off hormone therapy for up to 12 months at a stretch, and possibly prolonging the time to when the cancer becomes resistant to hormones.

Alternative ways of administering hormonal therapy are also utilized. When Casodex is given at high dose (3 pills a day instead of 1), two studies have shown that it may be equivalent to the use of a Lupron shot plus low-dose Casodex. These studies suggested that there may be fewer side-effects with this approach, although confirmatory studies are needed.

Osteoporosis: Long-term hormone therapy can cause osteoporosis. Zoledronate is a drug given by vein over 20 minutes once every four weeks, which stabilizes bone, and may help prevent bone loss in patients receiving hormonal therapy. Zoledronate may also be able to slow the progression of prostate cancer, and is available on a study to patients who are on hormonal therapy and have a rising PSA, but do not have evidence of spread of prostate cancer to the bones or elsewhere. The purpose of the study is to see if Zoledronate helps prevent bone metastases. Patients are randomly assigned to receive Zoledronate at the time of study entry, or at the time of disease progression. Zoledronate is easily administered and side effects are minimal.

II. The Next Step After Hormonal Therapy: Eulexin/Casodex/Nilandron Discontinuation

Once hormonal therapy becomes ineffective, the next therapy consists of stopping Eulexin, Casodex or Nilandron. When you were started on Eulexin, Casodex or Nilandron, the drug was effective in slowing the tumor growth by blocking the use of the male hormone testosterone by the tumor. However, after the tumor has been treated for a period of time (usually more than 6-8 months) with Eulexin, Casodex or Nilandron, in some patients the Eulexin, Casodex or Nilandron not only stop working, but serve to "add fuel to the fire" and feed the cancer. For this reason, approximately 20% of patients will have an improvement in their disease when the Eulexin, Casodex or Nilandron is stopped. The Lupron or Zoladex injections should not be stopped. Improvement in the disease is usually manifested as a decrease in PSA, usually within 4 to 6 weeks of discontinuation of the Eulexin, Nilandron or Casodex. In order to determine if you are having a response, a PSA will be drawn the day you stop taking Eulexin, Nilandron or Casodex, and again 2 and 4 weeks later (and sometimes 6 weeks later). If your PSA declines or remains stable, no further treatment is undertaken until the PSA starts to climb. PSA levels are checked monthly. Responses to Eulexin, Nilandron or Casodex discontinuation last an average of 3-5 months, although in some patients responses have lasted over 2 years.

III. Options After Stopping Eulexin/Casodex/Nilandron

If your tumor continues growing after stopping Casodex or Eulexin or Nilandron, treatment options again depend on certain characteristics of your disease. Three large categories can be considered: 1) additional hormones, 2) investigational therapy, and 3) chemotherapy. These options will be discussed with you when you reach that point. The treatment of advanced prostate cancer is constantly changing, so specific recommendations will be made at the time your PSA rises.

Some of the therapies available are described in this handout as a starting point. We will discuss with you the relative benefits and side effects of each therapy, and provide you with additional written information about the therapies you are interested in pursuing. Which therapy is best for you will depend on your wishes and the therapies medically best suited for you. In addition, since some of our therapies are investigational in nature, there may be restrictions placed by the National Cancer Institute, the FDA, or the sponsor of the trial on the situations in which a given treatment can and cannot be used.

1. Additional Hormone Therapy

a) Ketoconazole (Nizoral) or Aminoglutethamide (Cytadren). These drugs are another form of hormonal therapy, which is ideal for patients who may be unable to tolerate more aggressive treatment, who have minimal symptoms, or who wish first to be treated with less aggressive treatment. They work by shutting down testosterone production from the adrenal glands. About 50-60% of patients will benefit from this therapy. This therapy is relatively easy to take (pills) and has modest side effects. About 15% of patients have nausea, and 5% will have abnormalities of blood tests that measure the liver's function (liver enzymes), although both go away if the drug is discontinued.

Rarely, patients will develop rashes, more commonly with Cytadren. Patients on Nizoral have noticed a sensation of "sticky skin." In addition to making testosterone, the adrenal glands serve to balance minerals and fluids in the body by producing the hormone hydrocortisone. For this reason, all patients on Cytadren or Nizoral also receive hydrocortisone (2 pills in the morning and 1 pill at night) to make up for what the body normally produces.

b) PC-SPES: PC-SPES is an herbal preparation taken in the form of capsules. It is not known how it works, although one of the ways might be through a hormone mechanism similar to a female hormone, estrogen. We have shown that PC-SPES has some anti-cancer activity both in patients previously untreated with hormones, as well as in patients whose cancer has grown despite hormone therapy. Usually, PC-SPES has only minor side effects, but there are potential serious side effects (including blood clots in the legs or lungs in 5% of patients) that are not well understood. For this reason, a low dose of Coumadin (a blood thinner) is often given along with PC-SPES. If PC-SPES is an option for you, a separate information sheet on PC-SPES will be provided to you.

c) DES: DES is an older estrogen treatment for prostate cancer that is being re-examined. It is also given given in oral form, and has similar side effects to PC-SPES. DES is also given along with a blood thinner.

2. Investigational Therapy

a) Immune Therapy. Several agents exist that have the potential of stimulating your immune system to fight cancer. These treatments are usually well tolerated, but it is not yet known how effective they are.

1) Dendritic Cell Therapy. This therapy uses cells collected from your blood and treated in the laboratory to stimulate an anti-prostate cancer immune response. These dendritic cells are powerful immune system cells which are then injected back into your body (by vein) every 2 weeks for a total of 3 infusions. No significant side effects have been observed with this treatment, and strong immune responses have been observed. This therapy is available for patients with a rising PSA after surgery or radiation therapy. The current clinical trial combines this therapy with another form of immune therapy, antibodies to Vascular Endothelial Growth Factor (VEGF), a protein involved in new blood vessel formation for tumors.

2) CTLA-4 is an antibody that helps to turn on T cells in your body. T cells are powerful immune cells that can attack prostate cancer. This therapy is injected by vein into your body on just one occasion. Anti-CTLA-4 in combination with other immune therapy is being developed.

3) Vaccine Trials. Vaccination is a general term for injecting substances under your skin to boost an immune response, in this case, against cancer cells. Our current trial uses a vaccine called GVAX prostate cancer cell lines (cells grown in a dish that are used to study cancer drugs) that have been modified to produce an immune-stimulating protein called GM-CSF. This trial is for patients who have metastatic prostate cancer but who have no symptoms from their disease.

4) Low-Dose Stem Cell Transplant is a form of bone marrow transplant in which stem cells (cells capable of producing all of your blood cells) are collected by vein from a brother or sister, who must be a perfect immune system match to you. After you have received low doses of chemotherapy to suppress your immune system, your sibling's cells are infused by vein into you. It is hoped that these cells will form a new immune system that attacks the prostate cancer. This treatment has been used successfully in some patients with other cancers, but has not been used yet in prostate cancer. Major life-threatening side effects of the treatment are severe rash, diarrhea, infections, and damage to the liver. This is a complicated and aggressive treatment, and if you are interested, we will discuss it with you in great detail.

b) Growth Inhibitors

1) Rosiglitazone is a drug used to treat diabetes that can cause growth arrest of prostate cancer cells. The current study treats men with an elevated PSA (no metastases) and no prior hormone therapy. Patients are randomized to receive rosiglitazone at the time of study entry, or later, at the time of disease progression.

2) Herceptin. Herceptin is a new drug which is FDA approved for the treatment of breast cancer, but has not been extensively tested in prostate cancer. Herceptin is an antibody that blocks the function of the HER2 protein. The HER2 protein, when present on cancer cells, appears to make them more aggressive. Some patients with prostate cancer may have the HER2 protein on the surface of their cancer cells, so it is hoped that Herceptin may be able to control prostate cancer growth as well. In this study Herceptin will be given intravenously each week, and in addition patients will receive the chemotherapy drugs Taxotere and Estramustine. There is evidence that Herceptin is more effective when it is combined with chemotherapy. This treatment is available for patients who have metastatic hormone resistant prostate cancer.

3) IRESSA (ZD1839) is an experimental drug that blocks the function of the epidermal growth factor receptor (EGFR), a protein in cancer cells important in stimulating their growth. The drug has shown some effectiveness against prostate cancer in previous studies, and is given by pill form. The most common side effects may be lowered blood counts, rash, or diarrhea. This treatment is available for patients with hormone resistant prostate cancer. IRESSA alone is available for patients without metastases, whereas IRESSA given in combination with estramustine/docetaxel chemotherapy is available for patients with metastatic hormone resistant prostate cancer.

4) Gleevec is a pill which inhibits a protein called PDGF. It has had dramatic effects in certain chronic leukemias and rare gastrointestinal tumors. Gleevec is being tested in two groups of patients: men with a climbing PSA after prostatectomy or radiation therapy, and men with a climbing PSA (but negative scans) despite hormone therapy. Gleevec is also being used in men with metastatic hormone-resistant prostate cancer, in combination with estramustine/taxotere chemotherapy.

c) Anti-Angiogenesis Therapy

This refers to treatment targeted at stopping new blood vessel formation which is important for cancer growth. We are using a monoclonal antibody -- the anti-VEGF antibody -- to try to achieve this. This antibody is being used in combination with dendritic cells, or in combination with chemotherapy.

3. "Conventional" Chemotherapy

There are new ways of combining drugs which directly kill prostate cancer cells (chemotherapy), that look very promising. We refer to these as "conventional" because they consist of FDA-approved chemotherapy drugs which are commonly used for prostate cancer. In some situations these drugs are being combined with new (investigational) agents.

a) Estramustine (Emcyt) and Docetaxel (Taxotere). Taxotere is a standard chemotherapy drug given by vein in the outpatient setting. Estramustine is an oral (pill) form of chemotherapy. Taxotere is given once every three weeks. Estramustine is taken three times a day for five days every three weeks. The main side effect of this treatment is lowering of the blood counts. Other side effects include hair loss and mild fatigue. Rarely estramustine may cause blood clots, and you will take a blood thinner (Coumadin) to prevent this from happening. This regimen has become one of the standard treatments for metastatic hormone resistant prostate cancer. Approximately 50-70% of patients will have a lowering of PSA with this therapy, and 20-30% of patients will have measurable tumors (e.g., enlarged lymph nodes) get smaller.

b) Mitoxantrone (Novantrone) is given by IV injection over 10-30 minutes in the outpatient infusion center every 3 weeks. This drug has received FDA approval for the treatment of prostate cancer. Its primary role is in controlling pain. It is often combined with a steroid called Prednisone.

c) AC uses drugs called Adriamycin (A) and Cytoxan (C), and has also shown very good results in patients once hormonal therapy is no longer effective. This requires intravenous (IV) infusion of these two drugs over 2-4 hours every 21 days, also in our outpatient infusion center. One day after the IV infusion you will be started on daily shots of G-CSF under the skin for at least 10 days. We can teach you, or a companion, to give yourself the shot, or we can arrange to have it done in a doctor's office or hospital close to your home. This drug stimulates your body to make more white blood cells, which may be decreased by the chemotherapy you receive. A decrease in the number of white blood cells in your body may put you at risk for infections. Besides decreasing your white blood cells, the drugs can also decrease the number of platelets, which are the blood cells that prevent you from bleeding too easily. Your blood counts will be closely monitored, and treatment will be held if your counts are too low. Fatigue is also a possibility. Nausea and vomiting is very uncommon. Hair loss is common, but hair regrows when treatment is stopped.

Please note that this is only a very general information sheet, and that new treatments are continuously added to our list. We will be providing you with considerably more information as we discuss your treatment options. Our primary commitment is to your well being. Please let us know if there is more information that you need. Should you have additional questions, please feel free to contact us at 415-353-7171.

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