After Androgen Deprivation
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 Introduction

Androgen Deprivation (ADT) can be an effective treatment for controlling prostate cancer for many years in most men. When ADT is no longer effective, you may be told that your cancer is “androgen-independent”, “hormone-resistant”, “hormone-refractory” or “castrate-resistant”. The terms all have similar meaning. For consistency, we will refer to CRPC.

The nadir PSA is an important prognostic marker. Stewart, et al. concluded: “A PSA nadir of greater than 0.2 ng/mL, after 8 months of ADT given for postoperative or postradiation PSA failure, is significantly associated with prostate cancer specific mortality.”[1]

When a prostate cancer patient becomes castrate resistant, the cancer journey becomes more involved. It requires more time devoted to treatment choices, treatment monitoring, and treatment side effects. It is important to investigate each treatment carefully so that you understand what to expect regarding signs of response, signs of failure, side-effects and potential drug interactions.

Our Insights article Empowerment In Advanced & Hormone Refractory PC provides many suggestions that may help you to get the most benefit from your treatment choices. The first suggestion is to review all medical records and keep a detailed log to allow you to correlate treatments with evidence of response and impact of side-effects. The article should help you understand how to identify and select the next treatment. It suggests ways to learn how to give the treatment the best chance of success and how to minimize side-effects. It may also help you deal with the emotional issues that you face along the way.

 

Is your cancer really CRPC?

The first step is to recheck the PSA value to verify that it is rising and also check the testosterone to verify a castrate level of less than 50ng/mL (1.725 nM/L) or preferably less than 20 ng/mL (0.69 nM/L). If your testosterone is not at castrate level, a change in the type of androgen deprivation or the frequency should be considered. If testosterone is at castrate level, your cancer should be restaged before selecting the next option.

 

How is CRPC restaged?

PSA is the most prominent laboratory marker but there are also tests like prostatic acid phosphatase (PAP), chromogranin-A (CGA), and neuron-specific enolase (NSE) tests that are useful in some patients. The chromogranin-A and NSE represent markers of neuroendocrine differentiation which may provide an indication of very aggressive disease.

Radiographic tests that are useful to detect metastases include bone scans, CAT scans, and MRI’s. Most metastases occur in the bone (over 90% of patients with far advanced cancer will have bone metastases). The second most common site of metastases is in the lymph nodes. When lymph nodes are involved and able to be detected with CT and/or MRI testing, the most common locations are near the aorta, in the abdomen, deep in the pelvis, or in the chest.

 

What is Small Cell?

Elevation of chromogranin-A and NSE in the blood may result from an underlying small cell component to a patient’s disease.  Small cell prostate cancer should be considered in patients who do not respond to ADT, have high Gleason scores of 9-10, or have rapidly progressive disease. A biopsy of accessible lesions can be considered for confirmation. When small cell is confirmed treatment with chemotherapy regimens such as either cisplatin or carboplatin combined with etoposide may provide better results.

 

What about symptoms?

In evaluating your situation with your physician, you should be conscious of any symptoms. Is there pain or swelling of your extremities that could be edema from lymph node involvement? Are you experiencing appetite or weight loss, fatigue, or loss of energy? Prostate cancer symptoms in the CRPC disease state relate to either general elements related to tumor bulk (fatigue, loss of appetite, or weight loss), or symptoms of metastases to bone (bone pain).

 

What are the options if the PSA rises while on androgen deprivation?

It is important to understand that patients respond differently to different treatments. An effective treatment for some may provide no response for you and vice versa. Since some of the treatments below can first result in a short term PSA increase (flare), it is advisable to try a treatment for at least a couple of months. If you are not one who responds favorably or if you encounter intolerable side-effects, you should probably discontinue the treatment and try something else.

 

What secondary hormone manipulations can be considered?

  • Antiandrogen administration – If an LHRH drug has been the only treatment, adding an antiandrogen (flutamide, bicalutamide, nilutamide) may provide a response by blocking the ability of the cancer cells to use the testosterone produced from the adrenal androgens.
  • Antiandrogen withdrawal – If an antiandrogen has been used with or without an LHRH drug, a mutation of the androgen receptors may be allowing the antiandrogen to stimulate cancer growth. Discontinuing the antiandrogen may provide a favorable response. If successful, a different antiandrogen might also be tried.
    See: Anti-androgen Withdrawal Response (AAWR).
    Note: A similar withdrawal response may also result from discontinuing Megace if it has been used to reduce hot flashes.
  • Adrenal suppressants (ketoconazole, aminoglutethimide) block the production of androgens that are produced by the adrenal glands and further lower testosterone. A substantial number of patients will respond to ketoconazole, and sometimes for a long period of time. Note: Ketoconazole requires careful administration and monitoring because it alters the effect of many other medications.
    See: High Dose Ketoconazole Plus Hydrocortisone (HDK+ HC)
  • Glucocorticoids (ex. dexamethasone, prednisone, hydrocortisone) produce some anti-angiogenesis activity and also suppress the pituitary’s ACTH (adrenocorticotropic hormone), which leads to a suppression of adrenal androgens such as DHEA and androstenedione. Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant. It is 20 to 30 times more potent than the naturally occurring hormone cortisol and 4 to 5 times more potent than prednisone.
  • 5-alpha reductase inhibitors (finasteride and dutasteride) have shown some response in patients who have castrate testosterone. They decrease dihydrotestosterone and also induce fairly substantial increases in estrogen levels in the blood.
  • Estrogens (ex. DES, fosfestrol, estramustine, estradiol patches) were once used as a primary treatment for prostate cancer but the use was largely discontinued due to side-effects of blood clots and strokes. The development of anticoagulant drugs allows estrogens to again be considered as an option.
  • Abiraterone (Zytiga®) is a novel, targeted, oral androgen biosynthesis inhibitor that prevents cancer cells from producing their own testosterone. It is presently only approved for after chemotherapy.  However, this is an artificial distinction since it will be effective before chemotherapy as well.  However, at a price of $5,000 per month insurance companies will probably restrict payment to after chemotherapy to save themselves money.

Except for abiraterone, these are discussed in detail in our 2005 Insights article: Hormone-Refractory Prostate Cancer: A Continuum of Diseases and Options by Oliver Sartor, MD.

 

Is immune therapy an option?

  • Provenge – is approved by the FDA as an autologous cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic CRPC. A patient’s white blood cells are used to trigger the patient’s own immune system to fight the cancer itself. Since immunotherapy takes some time to work, an immediate PSA response will probably not be seen in most men. For more info, see:
    PROVENGE® Approved in the U.S.A.
    www.provenge.com
  • Other immune therapies – a number of treatment alternatives are being reviewed and have been used to benefit some patients, including: Low-Dose Cyclophosphamide, Leukine, ipilimumab (MDX-010), GVAX. For more info, see:
    Immunotherapy And Advanced Prostate Cancer
    Immune Treatment for PSA-Relapsed Prostate Cancer

What about docetaxel?

Docetaxel –Two clinical trials demonstrated an improvement in overall survival. These trials reported an average survival advantage of only 2.5 months. Many logically ask, “With such a small survival advantage why should I bother?” First, the survival advantage is probably larger than what was reported because men who were not in the docetaxel arm were allowed to cross over and receive docetaxel when their cancer progressed.  So, in a sense, the trial was a study of men who got immediate docetaxel compared to men who got delayed docetaxel.

At the 2010 PCRI Conference, Dr. Vogelzang addressed this issue of survival in a different way. He pointed out that despite the chemo side-effects, quality of life was better. He also pointed out that there is a smaller group of men who benefit with dramatically longer survival. For example, at the same conference, Dr. Scholz pointed out that a 30% PSA decline within 3 months powerfully predicts for much dramatically improved survival. The patients whose PSA dropped to less than 4.0 had a huge survival advantage of about 20 months.

 

Related Resources

 

What else to consider?

  • Thalidomide exerts some antiangiogenic activities after it is converted to various metabolites. Antiangiogenesis agents, like thalidomide may not show a lot of PSA decline but there may be PSA stability and failure to progress. Revlimid®, a second generation of thalidomide is a less toxic alternative.
  • Bisphosphonates (zoledronate) if bone metastatic – has been shown to prevent disease-related skeletal complications in addition to reverse osteoporosis caused by androgen deprivation. Denosumab (a monoclonal antibody) was approved by the FDA on 2010. It may be slightly more potent than the bisphosphonates.
  • External-beam radiation therapy can be used to treat specific metastatic sites identified by imaging. This can be beneficial to relieve pain but has not been proven to extend survival.
  • Bone-seeking radiopharmaceuticals (samarium-153, strontium-89) – target widely metastatic and painful skeletal involvement as they “seek out” and radiate areas of increased bone metabolism that characteristically occurs with metastasis. However, because of their wide ranging impact long term bone marrow suppression with low platelet counts and anemia is a risk. See: Bone-Targeted Therapy for Advanced Prostate Cancer.
  • Experimental therapies – Patients are encouraged to investigate Clinical Trials.

 

Related Resources

Booklet “Living with Advanced Prostate Cancer When PSA Rises During Hormone Therapy (2005)”. You can obtain a copy by calling the PCRI office.

A mail list for men with confirmed HRPC – www.hormonerefractorypca.org

References:
1 Stewart, A.J., Scher, H.I., Chen, M.H., et al: Prostate-specific antigen nadir and cancer-specific mortality following hormonal therapy for prostate-specific antigen failure. J Clin Oncol, 23: 6556, 2005 Abstract

 

 

Page updated 8/1/11