Hormone Therapy in Prostate Cancer

Hormone Therapy

The approach taken in the treatment of prostate cancer will depend on several factors, including the clinical presentation, Gleason score, and PSA (2). For patients with metastatic spread of prostate cancer, such as the patient in this case, the treatment of choice is androgen-deprivation therapy (ADT) (2,3). ADT has been reported to lead to remission in as many as 80% of patients with advanced prostate carcinoma (3,4). ADT is used in advanced prostate cancer to relieve pain, prevent pathologic fractures, and prevent neurologic complications (4). Typically, androgen deprivation is achieved through 3 mechanisms in prostate carcinoma patients, gonadotrophin-releasing hormone (GnRH) agonists, antiandrogens, and GnRH antagonists.

GnRH agonists (goserelin, leuprorelin, and triptorelin) are considered the leading approach to ADT in prostate carcinoma (5). GnRH is released in pulses from the hypothalamus to stimulate pituitary release of luteinizing hormone, which, in turn, stimulates the secretion of testosterone in the testes (5,6). GnRH agonists decrease testosterone levels by overstimulation, downregulation, and eventually receptor desensitization (5–7). There is, however, an initial flare or surge in testosterone production before suppression is effected (5). Unfortunately, testosterone suppression also increases the risk of osteoporosis and fracture (loss of bone mineral density), diabetes (altered glucose tolerance), and cardiovascular disease (7). Some of the more common adverse effects of ADT include weight gain, erectile dysfunction, decreased libido, gynecomastia, insomnia, sweats or chills, and gastrointestinal disturbances (7).

Antiandrogens (bicalutamide, flutamide, and nilutamide) are nonsteroidal inhibitors of androgen receptors (6,7). The advantage of this class of ADT medications is that testosterone levels are not suppressed, and thus the associated risks discussed above are largely avoided (6,7). That is, antiandrogens inhibit conversion of testosterone to dihydrotestosterine (metabolite) and prevent both from binding to the androgen receptor, without suppressing serum testosterone levels. The flare in serum testosterone associated with GnRH agonists means that they should be avoided as monotherapy in patients with severe pain or neurologic problems. Antiandrogens can be used as adjunctive therapy to block the flare (4).

GnRH antagonists (degarelix) have only recently received attention in the literature. GnRH agonists can cause an early increase in testosterone levels which, in turn, can promote tumor spread and worsen symptoms (2). GnRH antagonists can be used before the GnRH agonist therapy to block testosterone increases (2,7). GnRH antagonists can also be used as an alternative approach to androgen deprivation by inhibiting gonadotrophin production, leading to a reduction in the synthesis of androgens in the testes (7).

Bone Scan

ADT has been shown to result in remission in as many as 80% of patients, which is reflected in a median period of 12–33 mo of progression-free survival (4,6). That is, ADT prevents the progression of metastatic spread. Typically the nuclear medicine bone scan will demonstrate partial improvement or stabilization (nonprogression) of metastatic disease in response to ADT, but it is a rare occurrence for the bone scan to revert to normal (4). This observation reflects the fact that ADT rarely provides an overall cure and the likelihood of cure is inversely proportional to the extent of disease at the time of commencement of ADT. Another reason for the infrequency of a completely normal follow-up bone scan is that remodeling of bone in response to healing will mimic metastatic progression. The reversion to normal in this case is remarkable given the advanced stage of disease (Gleason score of 9) and extent of metastatic disease at the commencement of ADT.

After the progression-free survival period, there will be transformation of the disease to an androgen-independent phenotype that will not respond to ADT (6). At this point, alternative therapy (e.g., docetaxel) may be indicated. The mean patient survival (from commencement of ADT) is 23–37 mo (6). Androgen-independent disease is marked by disease progression despite testosterone levels below castrate levels (<50 ng/mL).