Hormone Therapy in the Recurrent Setting
In select men who undergo surgery or radiation therapy, the best salvage treatment option may not be more local therapy, but rather hormonal therapy. This has been shown to be beneficial especially in men who have lymph node involvement that was found at time of surgery. In addition, after radiation therapy when the PSA is rising, but there is no evidence of disease within the prostate by imaging or a repeat biopsy, initiation of hormone therapy alone may be most appropriate.
Treating Advanced Prostate Cancer
We typically refer to Advanced Disease as the state of prostate cancer that has grown beyond the prostate and is unlikely to be cured with surgery or radiation alone. After a man experiences PSA Progression after surgery or radiation, hormonal therapy is often given at some point, and often for many years. Some men will not require any therapy, however, if their PSA doubling time is quite prolonged. However, many men will continue to progress at some point despite the above hormonal treatments and require more aggressive therapy. This comes in the form of additional second and third-line hormonal therapies, chemotherapy, immunotherapy, bone-targeted agents, and investigational agents (many are in trials right now from new hormonal therapies to prostate cancer vaccines to bone-targeting drugs).
Prostate cancer cells are like other living organisms—they need fuel to grow and survive. Because the hormone testosterone serves as the main fuel for prostate cancer cell growth, it’s a common target for therapeutic intervention in men with the disease.
Hormone therapy, also known as androgen-deprivation therapy or ADT, is designed to stop testosterone from being released or to prevent it from acting on prostate cancer cells. Although hormone therapy plays an important role in men with advancing prostate cancer, it is increasingly being used before, during, or after local treatment as well.
The majority of cells in prostate cancer tumors respond to the removal of testosterone. But some cells gain the ability to grow in a low-testosterone environment and remain unaffected by hormone therapy. As these hormone-independent cells continue to grow unchecked, hormone therapies have less and less of an effect on the growth of the tumor over time.
For this reason, hormone therapy is not a perfect strategy in the fight against prostate cancer, and it does not cure the disease. It also carries some unwanted toxicities. But it remains an important step in the process of managing advancing disease, and it will likely be a part of every man’s therapeutic regimen at some point during his fight against recurrent or advanced prostate cancer.
The timing of when to start hormone therapy once the PSA begins to rise is an individual decision and one that should be discussed with your doctor.
Types of Hormone Therapy
The most common types of hormone therapy are described below. Although each option is effective at controlling prostate cancer growth, the loss of testosterone confers significant side effects in nearly all men. These side effects range from hot flashes and loss of bone density to mood swings, weight gain, and erectile dysfunction. Learn more about the side effects of hormone therapy—and how to manage or minimize them.
Orchiectomy—About 90% of testosterone is produced by the testicles. So orchiectomy—the surgical removal of the testicles—is an effective solution to blocking testosterone release. This approach has been used successfully since the 1940s. Because it’s permanent and irreversible, most men opt for drug therapy instead.
For those who choose this option, the procedure is typically done on an outpatient basis in the urologist’s office. Recovery tends to be rather quick and no further hormone therapy is needed, making it a very attractive choice for someone who prefers a low-cost, one-time procedure.
LHRH Agonists—LHRH, or luteinizing-hormone releasing hormone, is one of the key hormones released by the body before testosterone is produced. (Note that LHRH is sometimes called GnRH, or gonadotropin-releasing hormone.)
Blocking the release of LHRH through the use of LHRH agonists or LHRH analogues is one of the most common hormone therapies used in men with prostate cancer. Drugs in this class, including leuprolide (Eligard, Lupron, and Viadur), goserelin (Zoladex), and triptorelin (Trelstar), are given in the form of regular shots: once a month, once every three, four, or six months, or once per year.
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LHRH Antagonists—A newer class of medications can block LHRH (GnRH) from stimulating testosterone production without causing an initial testosterone surge. This class includes degarelix, which is given monthly to men as an alternative to orchiectomy or LHRH agonists.
LHRH agonists cause what is known as a “flare” reaction because of an initial transient rise in testosterone over the first three weeks after the shot is given. This can result in a variety of symptoms, ranging from bone pain to urinary frequency or difficulty. Fortunately, this can be prevented.
Anti-androgens such as bicalutamide (Casodex), flutamide (Eulexin), and nilutamide (Nilandron) can help block the action of testosterone in prostate cancer cells. They are often added to the LHRH agonist to prevent flare reactions.
Although the sexual side effects of the anti-androgens when given alone are typically far fewer compared with the LHRH agonists, anti-androgens might not be as effective as orchiectomy or LHRH agonists, and they are not the optimal choice for men with documented metastatic prostate cancer.
When used in combination with LHRH agonists, anti-androgens tend to increase the risk of hot flashes and breast tenderness, and they can rarely result in liver injury. Your liver function tests should be monitored while you take these medications.
In addition, nilutamide is known to cause visual light-dark adaptation problems and—rarely—cause inflammation and scarring in the lungs. If you develop a persistent cough or persistent shortness of breath while on nilutamide, you should contact your doctor.
Newer hormonal medications that inhibit the synthesis of androgen (abiraterone) and block androgen receptor signaling (enzalutamide) are now FDA-approved for the treatment of metastatic prostate cancer, however they are still under investigation for use earlier in the disease, like when the PSA begins to rise.
Importantly, many plant-based and complementary medicines can have estrogen-like properties and can interfere with the effectiveness of your hormone therapy, so be sure that your doctor has a complete list of all drugs—including the “non-traditional” ones—so that he or she can better monitor the effects of your therapy on the progression of your disease.
For a man starting hormonal therapy, visits are usually timed with the LHRH injection, along with PSA and other lab checkups such as the testosterone levels and liver and kidney function tests. There is a wide variety of practice patterns, but typically, checking bone mineral density before starting hormonal therapy and once per year to assess the loss of bone density is reasonable given that there are medications that can be used to reduce the risk of fracture.
Anti-Androgen Therapy for Hormone-Refractory Prostate Cancer
The most common types of initial hormone therapy are described above. These include orchiectomy, LHRH agonists or antagonists, and antiandrogens.
These initial hormone therapies are typically effective for only a few years. This is because prostate cancer cells often evolve ways to thrive despite the low androgen environment produced by hormone therapy. For instance, tumors may evolve to produce their own androgens, upregulate the androgen receptor, or acquire mutations in the androgen receptor that allow sufficient activity with little or no androgens. In these cases, because prostate cancer cells still rely on the androgen receptor pathway to survive and grow, a number of “secondary” hormone approaches can be used to keep the tumor from spreading.
For many men who were using an antiandrogen in combination with an LHRH agonist, stopping the antiandrogen, or antiandrogen withdrawal, is the most common first step in secondary hormone therapy. About 10-30% of men will experience this anti-androgen withdrawal, which lasts on average 3-5 months, during which time additional therapies are not needed. However, inevitably, additional therapies will be needed even if this withdrawal response occurs. Switching to a different antiandrogen might also be able to offer an extra few months of benefit before other therapeutic approaches are required.
Another option is to block the release of testosterone from the adrenal glands, small organs that sit on top of the kidneys. Only about 10% of the circulating testosterone is produced by these two glands, so few therapeutic interventions focus on them until it becomes important that every last bit of the hormone is removed. The commonly used drugs used for this purpose, ketoconazole and the newer agent abiraterone acetate (Zytiga), are typically administered in conjunction with steroids to avoid the effects seen when the adrenal glands are shut down. Abiraterone acetate plus low-dose steroids (prednisone) has been shown to prolong life when given to men with hormone therapy refractive prostate cancer, and has been FDA-approved for use either before or after chemotherapy with docetaxel. Although this medication is generally well-tolerated, side effects may include fatigue, high blood pressure, and electrolyte or liver abnormalities and patients need to be monitored regularly.
Enzalutamide is a nonsteroidal antiandrogen that acts by blocking the activation of the androgen receptor by androgens. Enzalutamide has received FDA approval for the treatment of men with hormone therapy refractive prostate cancer, either before or after chemotherapy with docetaxel. Side effects are mild but include fatigue, diarrhea, hot flushes, headache, and very rarely seizures. Importantly, enzalutamide treatment does not require simultaneous steroid treatment and therefore the steroid side effects can be avoided. Thus, enzalutamide is a new treatment option for men in the post-docetaxel metastatic hormone-refractory setting and is also a reasonable choice in men who are not candidates for chemotherapy.
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