8 Ways Hormone Therapy Treats Prostate Cancer

Man receiving hormone injections
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One of the unique characteristics of prostate cancer is how quickly it responds to testosterone withdrawal. This “Achilles' Heel” of prostate cancer was discovered when surgical removal of the testicles was first shown to induce cancer remissions back in the 1940s. Subsequently in 1985, Lupron, an injectable medicine that works by fooling the testicles into ceasing testosterone production, came on the market.

Surgical removal of the testicles has been declining in popularity ever since.

Hormone Therapy for Prostate Cancer

Hormone therapy for prostate cancer has a variety of different terminologies, such as androgen deprivation therapy (ADT), hormone blockade (HB), and testosterone inactivating pharmaceuticals (TIP). I like to call it TIP because I think testosterone inactivation is the most accurate description of how these hormonal treatments actually function. The testosterone inactivating pharmaceuticals fall into three broad categories:

  1. Lupron-like medications that function by blocking luteinizing hormone (LH). Luteinizing hormone comes from the pituitary gland and travels through the blood to stimulate the testicles to manufacture testosterone. When LH levels are reduced, testosterone levels drop. There are two types of injectable drugs that block LH, the agonists and antagonists. The agonists are called Lupron, Eligard, Trelstar and Zoladex. There is only one antagonist, Firmagon. All these agents eliminate most, but not all, testosterone in the blood. Residual amounts of testosterone come from the adrenal glands, which are independent of the effects of LH.
  1. Anti-androgen pills chemically “block” testosterone’s biologic activity without eliminating it from the blood. They have fewer side effects and are occasionally substituted for Lupron-like drugs in frail or elderly men. However, they are less potent as anticancer agents. The trade names of the FDA-approved antiandrogens are Casodex, Flutamide, and Nilutamide. Their generic names are bicalutamide, eulexin and nilandron respectively. The anti-androgens are commonly used along with Lupron-like drugs to counteract the testosterone “flare” that lasts for 10 days or so after the first injection (Firmagon does not cause a testosterone flare). Many doctors stop the anti-androgens after a month, once the flare period has passed. Other doctors believe that the anti-androgens should be continued for the duration of the hormonal therapy, to block the small amounts of testosterone produced by the adrenal glands.
  1. Zytiga and Xtandi are FDA-approved for hormone-resistant disease. Prostate cancer cells that become resistant to Lupron-like drugs have developed the capacity to manufacture their own testosterone (instead of feeding on testosterone in the blood that originates from the testicles). Zytiga works inside the cancer cell to block the synthesis of testosterone. Xtandi prevents testosterone from activating the receptors that turn on cell growth. The side effects of Zytiga and Xtandi, with some exceptions, are very similar to that of the Lupron-like drugs.

The overall anticancer efficacy of TIP is improved by prolonging therapy over a longer period of time.  However, longer treatment is associated with an increased incidence of side effects. The duration of TIP, therefore, is adjusted in accordance with each patient’s specific needs.

Administering Hormone Therapy

The following list presents eight different ways that TIP is commonly administered to men with prostate cancer:

1. A Short Course of TIP for Intermediate-Risk Disease

In 2013, Memorial Sloan Kettering published a retrospective evaluation of 1,000 men with Intermediate-Risk disease treated with radiation and six months of TIP in the journal of European Urology. The TIP-treated men had lower relapse rates and improved survival. The only exception was a subgroup of men with only a single intermediate risk factor, men with so called favorable Intermediate-Risk. This favorable subgroup was characterized as having less than 50 percent of their biopsy-cores positive and a Gleason grade of 3 + 4 rather than 4 + 3. The study reported that this subgroup of men is just as likely to do well with radiation alone and could forgo TIP altogether. Men with newly-diagnosed, Intermediate-Risk disease who are undergoing radiation are recommended to begin TIP two months before starting radiation and continue for a total of six months of therapy.

2. Longer TIP for Men with Newly-Diagnosed High-Risk Disease

Men with newly-diagnosed, High-Risk disease who undergo radiation are typically treated with TIP for 18 months. Treatment starts two months before radiation and continues during and after the radiation. The most famous study evaluating the benefit of long-term TIP was performed by Dr. Bolla in Europe. Dr. Bolla prospectively evaluated the survival rates of men treated with radiation who had TIP for 36 months, comparing them with men treated with radiation without TIP. Ten years after the radiation was completed, the mortality rate from cancer in the TIP-treated men was only 10 percent compared to 30 percent in the men who did not receive TIP.  In another study, Dr. Bolla compared short-term TIP with long-term TIP in 970 men treated with radiation who had an average PSA of 18. Half of the men in the study were treated with hormone therapy for six months and the other half were treated for three years. The 5-year mortality with 6 months of TIP was 19 percent compared to 15 percent when the TIP was continued for three years.   

3. Intermittent TIP for PSA-Relapsed Disease

TIP is considered the standard treatment for relapsed disease. A typical intermittent protocol consists of TIP administered for six to nine months followed by treatment holiday. After TIP is stopped, the testosterone recovers and the PSA begins to rise. A second cycle of TIP is started when the PSA rises back to the original PSA baseline, or up into the 3 to 6 range, whichever is lower.

Several clinical trials have investigated the safety of using intermittent TIP. Dr. Laurence Klotz conducted a huge prospective trial involving close to 1400 men with PSA-relapsed disease. The men were divided into two groups; 690 received intermittent TIP for 8 months; another 696 men were given TIP continuously. In the men receiving TIP intermittently, the PSA was allowed to rise as high as 10 during the holiday period after which the next cycle of TIP was started. The study showed equal survival between the two groups. The average time to TIP resistance was identical—ten years in both groups. The men on intermittent therapy were on “holiday” from TIP 73 percent of the time. 

4. Continuous TIP for Metastatic Disease

Men with metastatic prostate cancer remain on TIP indefinitely with occasional exceptions. Patients often question why TIP is continued after the development of hormone resistance. The prevailing belief is that continued therapy is beneficial because prostate cancer is multi-clonal. That means that even in a man who has developed a hormone-resistant clone, other clones may exist that are still hormone sensitive. So TIP is continued indefinitely so that the dormant hormone sensitive clones don’t start proliferating.

5. Zytiga and Xtandi for Advanced Disease

Lupron works for an average of 2-6 years in men with metastatic disease and for more than ten years in men without metastasis. When Lupron stops working, other hormonal agents such as Zytiga or Xtandi should be considered. These designer drugs exploit a relatively recent discovery, that hormone resistance occurs because prostate cancer cells figure out how to manufacture their own testosterone (instead of feeding on testosterone originating from the testicles and getting to the prostate cancer cells via the bloodstream). Zytiga works inside the cancer cell to block the synthesis of testosterone. Xtandi prevents testosterone from activating the receptors that turn on cell growth.

6. Reducing the Side Effects of Radiation 

TIP not only kills prostate cancer cells, it also kills prostate gland cells, leading to shrinkage the prostate gland. This can be advantageous prior to radiation, particularly seed radiation, because it enables that radiation therapist to administer the radiation to a smaller target area. Men who have three or four months of TIP usually experience a 25 to 50 percent reduction in prostate size. The shrinking effect of TIP on the prostate gland allows some men with large prostates to undergo seed implantation when otherwise they would be ineligible. Otherwise, many men with excessively enlarged prostates would be ineligible for seed implantation.

7. Intermittent TIP for Men with Newly-Diagnosed Disease

TIP can be used as primary therapy, instead of surgery or radiation in men with newly-diagnosed, Intermediate-Risk prostate cancer. Back in the 1990s, Prostate Oncology Specialists published an article reporting the outcome of 73 men who used TIP as primary therapy. Their average PSA was 9. The average Gleason was seven. Most of the men had cancer that could be felt by digital rectal examination. Over the next 12 years 21 of these men (29 percent) never needed any further therapy. Twenty-four men (33 percent) required periodic retreatment with TIP to keep their PSA levels less than five. Twenty-eight men (38 percent), rather than continuing on intermittent TIP, decided to have local therapy such as surgery, seeds or radiation. The delayed treatment with radiation or surgery was performed an average of five and a half years after the first cycle of TIP. Of these 28 men who underwent delayed local therapy, only three developed a PSA relapse and none have developed metastasis or died of prostate cancer.

8. TIP Added to Surgery

TIP can be used after surgery to improve cure rates in men with newly-diagnosed, High-Risk disease. However, using TIP in this fashion is controversial. Why? Some studies using only three months of TIP showed no improvement in cure rates. Subsequent studies, however, using TIP for a more extended duration, do show improved survival. The most compelling one was published in the May 2011 issue of the Journal of Clinical Oncology. Dr. Tanya Dorff reported on 351 men, who were treated with two years of Casodex and Zoladex right after surgery. After five years, the relapse rate was less than 10 percent. Multiple other studies show that without TIP the five-year relapse rate after surgery for High-Risk prostate cancer is about 50 percent.

Lupron by Itself Can Be Considered 'Standard' TIP

Most of the largest prospective randomized trials evaluating TIP have been done using one of the Lupron-like drugs by itself as a single agent. However, other trials have evaluated milder agents, such as Casodex, or treatment with multiple agents in combination.

The conclusion of all these studies taken together is exactly what you would expect: More intense therapy has a greater anticancer effect as well as more side effects. Milder agents used for a shorter time period have fewer side effects. No specific agent or combination of agents is ideal for everyone. The guidelines listed above are merely that—guidelines.

The intensity and duration of TIP selected has to be personalized in accordance with individual circumstances of each man’s cancer, his age as well as his overall health status. In some cases, the initially proposed protocol may be changed if the initial type of TIP selected results in an unexpectedly poor response. Unexpectedly mild or severe side effects may also lead to an increase or a decrease in TIP’s intensity or duration respectively.

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