Many commonly prescribed second-line hormone therapies are not formally approved for advanced prostate cancer, but many doctors believe that they can control PSA and perhaps extend life for many men. However, each of the second-line therapies has unique side effects themselves.

Use an experienced prostate cancer oncologist so they are familiar with the potential “off label” uses of some treatments.

  • Antiandrogen withdrawal
    [AAW] (stopping the drug) is considered an excellent first option for men who have been taking an anti-androgen drug such as Casodex, Eulexin, Nilutamide or Androcur. There are no side effects associated with AWW, but its response is often short-lived and PSA begins rising again.
  • For those men who have not taken antiandrogen drugs, adding them to the ADT protocol can help suppress the cancer because they block cells from metabolizing the androgens. Possible side effects of antiandrogens can include liver damage, hot flashes, breast growth and tenderness, loss of ejaculate, breast cysts, and the loss of libido. Men who only took an antiandrogen drug (antiandrogen mono-therapy) can add a GnRH agonist [Firmagon].
  • Estrogens can also control testosterone levels in the blood, and may even directly kill castrate resistant cancer cells. Problems with estrogen therapy include risk of developing blood clots, increased risk for cardiac events, and breast growth and associated pain. Estrogen therapy may be administered via injections, IV, pills, gels, or patches. The optimum method is by patches because it allows superior dosing control and avoids any stomach-related complications.

CAUTION- Men who have a family history of breast cancer or have an increased risk of developing Melanoma proceed with great caution before beginning an estrogen regime. These men should make sure that their doctor knows of the increase in their risks as well as undergoing genetic screening and testing for the BRCA mutation before starting an estrogen regime.

CAUTION — Diethylstilbestrol (DES), which is an inexpensive synthetic form of estrogen, is thought to cause blood clots, which can kill you. If you do use any estrogen, especially DES, be sure that you also have your doctor prescribe an anticoagulation medication, possibly Coumadin or Heparin.  Do not take aspirin or aspirin-related medications while taking any anti-coagulation medication.

  • Ketoconazole (Nizoral) (Keto) is an antifungal drug that has been shown to be effective by temporarily decreasing testosterone levels. Normally administered in higher doses (200mg to 800mg/day) together with hydrocortisone, it can produce an effective, albeit temporary, hormone blockade. Since it has a different action than ADT or anti-androgens, it also blocks the androgens that are generated in the adrenal gland. However, Keto can cause nausea, vomiting and abdominal pain. If high doses create bothersome quality of life (QOL) issues, it is possible to take it at lower doses and still receive a benefit. Keto must be taken with an acid stomach (drink orange juice along with the pill), and it must be taken religiously every eight hours without fail. Do not drink grapefruit juice with keto as it nullifies much of keto’s action.

Keto can be toxic to the liver so bilirubin and albumin levels in your blood must be monitored on a regular basis. Some doctors will administer drug called Ursodial to protect the liver.

Keto has a similar mode of action as the newer, FDA approved drug abiraterone (Zytiga).  A question has been raised if prior exposure to Keto will prevent abiraterone from being effective.  A study found that a significant proportion of the men with prior Keto exposure still demonstrated a clinical response to Zytiga. So, if you have already had Keto in your treatment protocol you should still try Zytiga as a treatment.

However, if you have not started Keto you should discuss with your doctor the risks of possibly interfering with future treatments of abiraterone. ( ) Citation re Keto and abiraterone: J Clin Oncol 32, 2014 (suppl 4; abstr 53), Won Kim, John Wilton, Li Zhang, Amy M. Lin, Lawrence Fong, Terence W. Friedlander, Andrew Caleb Hsieh, Rahul Raj Aggarwal, Tammy J. Rodvelt, Allison Morse, Jeffrey Bozeman, Vivian K. Weinberg, Arturo Molina, James Mohler, Gerald J. Fetterly, Russell Zelig Szmulewitz, Eric Jay Small, Charles J. Ryan)

Other second-line hormone therapies include:

  • Leukine, a granulocyte macrophage colony-stimulating factor (GM-CSF), is a hormone therapy that has no effect on a man’s testosterone production. It works by increasing overall production of white blood cells and increasing their biological activity.

Dr. Eric Small has reported (Rini, etaL Journal of Clinical Oncology) on using Leukine to treat men with advanced prostate cancer. Dr. Small found that Leukine slowed and sometimes even arrested the progression of prostate cancer cells. (

There have been reports of a mild skin reaction to Leukine. Over the counter treatments such as Claritin or Benadryl usually resolves these issues.

  • Celebrex, which is used to treat arthritis, blocks a protein called “akt.” Akt, when inhibited, causes the death of prostate cancer cells. Celebrex has fallen into some disfavor by the rheumatology community because it has been reported to increase the risks of strokes. Discuss this issue with your doctor to see if it may be a good alternative for you.
  • Revlimid (lenalidomide) is approved to treat Multiple Myeloma and has also been used by some of the “out of the box” oncologists to treat advanced prostate cancer. However, a recent clinical trial using Revlimid with taxotere and prednisone was halted early because it did not significantly increase the overall survival of men with castrate resistant prostate cancer. However, the actual implications of this trial, specific to using Revlimid alone as a second line treatment, is not clear because it was not tested as part of the study.
  • Low dose Thalidomide (30 mg) along with 300 mg of vitamin B 6 (to prevent peripheral neuropathy) taken daily also appears to have an anti-prostate cancer effect. But there are no formal studies to support this observation.