Hormonal Therapy (or more properly androgen deprivation therapy or androgen blockade) is based on the fact that lowering a man's blood level of testosterone will arrest the cancer (anywhere in the body) in 80% of the men for an average of two years. Hormone therapy may be combined with radiation and is used in men with advanced disease or metastatic.
The timing of hormone therapy is still under study (see here and here). For men with cancer that has spread to the bone (metastatic disease or stage IV or Stage D2) hormone therapy is the treatment of choice. If the cancer is extremely sensitive to hormones, the PSA will fall to extremely low levels and this predicts for a better survival (go here)
Lowering a man's testosterone level can be done 3 ways:
Gonadotropin-releasing hormone analogs: the most common of the synthetic hormonal blocking drugs are Lupron (injection 22.5mg/ q 3 mos or 30 mg q 4 mos; leuprolide or Eligard), Zoladex (10.8 mg sc. q 3 mos; goserelin) or Trelstar LA (11.25mg triptorelin) which turn off testicular production of testosterone by inhibiting the production of the pituitary hormone (gonadotropin) which normally drives the testicles to produce testosterone. (these drugs are obviously of no use in a man who has had an orchiectomy.) A pure GnRH antagonist, Abarelix did not work out. (When first started on these injections the patient's testosterone initially goes higher which can temporarily worsen the disease, called a flare, and can be prevented by taking an androgen blocker, as below, for the first two weeks.)
Nonsteroidal antiandrogens: the other category of drugs, Eulexin (two - 125mg caps three times a day (6 pills so 750mg/day); flutamide), Casodex (one 50mg caps a day; bicalutamide) or Nilandron (300mg a day; nilutamide) are called anti-androgens and block the effects of testosterone at the androgen receptor level. and prevent the normal androgenic response. These drugs will block other androgens (e.g. those produced in the adrenal gland) and have an added benefit to patients who are already on Lupron or have had an orchiectomy.
Combining both categories of drugs is called TAB (or total
androgen blockade) and has a slightly higher response rate and duration than
just using one type of drug. (There is controversy about whether the additional benefit is
worth the added expense.) Other drugs that inhibit adrenal production of androgens
(ketaconazole or aminoglutethamide) are available and drugs that interfere with conversion
of tamoxifen to DHT (5 alpha reductase inhibitors like Proscar or finasteride) may be
useful. Other herbal estrogen combinations (like PC-SPES) is being studied.
There has been interest in cycling the hormonal therapy (called a Lupron holiday, where
the treatments are stopped intermittently, see data.) For up
to date reviews see the online reviews list above and for more information about
combinations, triple therapy or intermittent therapy see the studies below:
|antiandrogen therapy withdrawal||21%|
|from the NCI:
Hormonal treatment is the mainstay of therapy for distant metastatic prostate cancer. Cure is rarely, if ever, possible, but striking subjective or objective responses to treatment occur in the majority of patients. Initial results from a randomized study of immediate hormonal treatment (orchiectomy or LHRH analogue) versus deferred treatment (watchful waiting with hormonal therapy at progression) in men with locally advanced or asymptomatic metastatic prostate cancer showed better overall survival and prostate cancer-specific survival with the immediate treatment.
Approaches using LHRH agonists and/or antiandrogens in patients with stage IV prostate cancer have produced response rates similar to standard hormonal treatments. Based on the fact that the adrenal glands continue to produce androgens after surgical or medical castration, case series studies were performed in which antiandrogen therapy was added to castration. Promising results from such case series led to widespread use of the strategy, known as "maximal androgen blockage" (MAB) or "complete androgen blockade." However, subsequent randomized controlled trials cast doubt on the efficacy of adding an antiandrogen to castration. In a large randomized controlled trial comparing treatment with bilateral orchiectomy plus either the antiandrogen flutamide or placebo, there was no difference in overall survival. Although it has been suggested that MAB may improve the more subjective end point of response rate, prospectively assessed quality of life was worse in the flutamide arm than in the placebo arm, primarily due to more diarrhea and worse emotional function in the flutamide-treated groupA meta-analysis of 22 randomized trials of 5,710 patients comparing conventional surgical or medical castration to MAB - castration plus prolonged use of an antiandrogen such as flutamide, cyproterone acetate, or nilutamide - showed no significant improvement in survival associated with MAB.
A large proportion of men experience hot flushes after bilateral orchiectomy or treatment with LHRH agonists. These hot flushes can persist for years. Varying levels of success in the management of these symptoms have been reported with DES, clonidine, cyproterone acetate, or medroxyprogesterone acetate (Megace).
After tumor progression on 1 form of hormonal manipulation develops, an objective tumor response to any other form is uncommon. However, some studies suggest that withdrawal of flutamide (with or without aminoglutethimide administration) may be associated with a decline in PSA values and that 1 may need to monitor for this response before initiating new therapy.Chemotherapy may be appropriate in selected patients, but remains under evaluation. To date, no evidence exists that indicates chemotherapy prolongs survival.Low-dose prednisone may palliate symptoms in about a third of the cases.
Hormone therapy complications
Maximum androgen blockade in advanced prostate cancer: a meta-analysis of published randomized controlled trials using nonsteroidal antiandrogens.
Caubet To assess the survival benefit of maximum androgen blockade (MAB) using nonsteroidal antiandrogens (NSAAs) through meta-analysis of published randomized controlled trials (RCTs). METHODS: All RCTs comparing treatment with NSAA plus either luteinizing hormone-releasing hormone (LHRH) or orchiectomy versus treatment with LHRH or orchiectomy alone were included if the necessary statistical summaries were present in the publication. This meta-analysis supports a beneficial effect for MAB using NSAAs compared with castration alone, and sensitivity analyses suggest that the design of future trials should carefully address issues of patient characterization, randomization blinding, and other study quality issues.
Lancet 1995 Jul 29;346(8970):265-9
Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Prostate Cancer Trialists' Collaborative Group.
A systematic overview, or meta-analysis, of the randomised evidence on maximum androgen blockade (MAB) in advanced prostate cancer identified 25 trials that compared conventional castration (surgical or medical) versus MAB (castration plus prolonged use of an antiandrogen such as flutamide, cyproterone acetate, or nilutamide). Individual patient data were obtained from 22 of the trials. Median follow-up was 40 months, during which 57% of patients died (3283/5710). Crude mortality rates were 58% for castration alone and 56% for MAB. Life-table estimates of the corresponding 5-year survival rates were 22.8% and 26.2%, representing a non-significant improvement of 3.5% (95% CI 0-7%). Logrank time-to-death analyses found no significant heterogeneity between trials (or between the effects of different types of MAB) and no significant evidence of additional benefit in an overview of all these MAB trial results (2p > 0.1). The currently available evidence from randomised trials does not show that MAB results in longer survival than conventional castration.
Urol Clin North Am 1991 Feb;18(1):15-24
Advanced prostatic carcinoma. Early versus late endocrine therapy.
Kozlowski. Since the landmark observations of Huggins and Hodges in 1941, androgen deprivation has been the mainstay of treatment for advanced-stage prostate cancer. Although early, poorly controlled studies suggested enhanced survival with hormonal therapy, this view fell into disfavor as a result of the observations of the first and second VACURG studies. Recently, there has been a proliferation of experimental and clinical data supporting early androgen deprivation, including a reanalysis of the VACURG data, which suggests a survival advantage for younger patients with stage D disease and high-grade tumors who undergo androgen-ablative therapy at the time of diagnosis. The risk-benefit analysis presented in this review is strongly supportive of early hormonal therapy. Finally, long-term survival of patients with metastatic prostate cancer will require the development of novel treatment strategies effective against androgen-resistant tumor cells and their use in concert with early androgen deprivation.
Eur Urol 1999;35 Suppl 1:32-6
Intermittent complete androgen blockade in metastatic prostate cancer.
Rambeaud. Intermittent hormonal treatment of prostate cancer was first developed based upon experimental study results. Using the Shionogi mouse breast cancer model, it was shown that the tumor grows rapidly in the presence of androgens, then undergoes apoptotic regression when androgens are removed. This apoptotic potential can be reinduced several times by cyclic replacement and withdrawal of androgens. In most of the clinical studies a protocol is used in which the patient receives 36 weeks of androgen deprivation. For those patients whose prostate-specific antigen (PSA) drops to less than 4 ng/ml within 32 weeks of therapy, the androgen withdrawal is stopped at 36 weeks, and not reintroduced until PSA increases to 20 ng/ml. This cycle is then repeated until the patient's tumor becomes hormone-sensitive. These studies demonstrated that the androgen-dependent state of prostate cancer can be maintained during a course of intermittent androgen suppression, supporting the possibility of multiple apoptotic regressions under well-regulated conditions. Oliver et al. in 1997, conducted a retrospective study of 20 patients and concluded that intermittent androgen deprivation reduced induction of hormone-resistant prostate cancer, with no acute or major risk associated with the use of intermittent androgen suppression.
Urology 1998 Sep;52(3):353-9
Current status of intermittent androgen suppression in the treatment of prostate cancer.
Theyer. Treatment of advanced prostate cancer by continuous androgen suppression results in excellent short-term response but poor long-term survival. Intermittent androgen suppression (IAS) aims to maintain androgen responsiveness of tumor cells by regular cycles of treatment cessations and tumor regrowth to specific prostate-specific antigen limits. First clinical trials demonstrate consistent responses and improved quality of life in most patients on androgen suppression retreatment for up to five cycles, with mean off-treatment periods of approximately 5 to 16 months. Most patients with metastatic disease exhibit early disease progression or androgen independency under IAS, but a subgroup including patients with metastatic disease respond to a single androgen suppression cycle with off-treatment times for up to 48 months. In conclusion, IAS improves the quality of life in patients with primarily hormone-dependent tumors without adverse effects and seems to be most effective in patients with prostate cancer with asymptomatic biochemical progression and low tumor burden.
Treatment of localized prostate cancer with
intermittent triple androgen blockade: preliminary results in 110 consecutive