There are four therapeutic approaches for androgen axis blockade in current clinical use: ablation of androgen sources, inhibition of androgen synthesis, antiandrogens, and inhibition of luteinizing hormone–releasing hormone (LHRH) or luteinizing hormone (LH) release ( Table: Therapeutic Approaches to Androgen Deprivation Therapy ).
Table: Therapeutic Approaches to Androgen Deprivation Therapy[*]
DES, diethylstilbestrol; LH, luteinizing hormone; LHRH, luteinizing hormone–releasing hormone.
* Several agents have multiple mechanisms of action.
Ablation of Androgen Sources
Bilateral orchiectomy quickly reduces circulating testosterone levels to less than 50 ng/dL, which, on the basis of this procedure, is considered the castrate range. Within 24 hours of surgical castration, testosterone levels are reduced by more than 90%. The Veterans Administration Cooperative Urological Research Group (VACURG) conducted a series of large clinical trials, demonstrating the clinical effectiveness of surgical castration in reducing pain and performance status in men with advanced disease.
Scrotal (Simple) Orchiectomy
A straightforward outpatient procedure, the simple scrotal orchiectomy can be performed under local anesthesia. At the level of the external ring, each spermatic cord is grasped and infiltrated with 10 mL of 1% lidocaine without epinephrine. This cord block can be performed before the formal skin preparation and draping. After infiltration of the skin overlying the median raphe with 1% lidocaine, a 6- to 8-cm incision is made directly over the median raphe. After the skin incision, electrocautery is used exclusively to transect the other tissue layers, reducing the risk of scrotal hematoma formation. The incision is directed into one hemiscrotum, where the tunica vaginalis is divided and the testicle delivered through the wound. The cord is mobilized above the testicle but below the level of the external ring. The cord structures are divided into two or three equal components, and the cord is ligated with nonabsorbable sutures. I favor double ligation of the proximal cord with two sutures, one of which is a suture ligature. The cord is transected relatively close to the ligatures to limit the amount of nonviable tissue distal to the ligature. Care is taken to examine for any bleeding as a scrotal hematoma after scrotal orchiectomy can be dramatically large. The identical procedure is performed on the contralateral side. The dartos is then reapproximated in the midline, closing each semiscrotal incision at the same time in one layer. The skin is closed with interrupted absorbable sutures. Drains are not used for clean scrotal wounds. Scrotal supports are used for the first several days after surgery, and ice is applied for symptomatic relief.
Subcapsular orchiectomy has been advocated as a technique of androgen deprivation therapy (ADT) that avoids the psychological consequences of an empty scrotum. Because this approach relies on the complete removal of all intratesticular tissue and Leydig cells, it is more dependent on technique to achieve ADT than a simple orchiectomy is. In a properly performed operation, however, the hormonal and cancer responses are indistinguishable from those of a simple, complete orchiectomy.
Antiandrogens
Cyproterone Acetate
The classic steroidal antiandrogen with direct androgen receptor–blocking effects, cyproterone acetate also rapidly lowers testosterone levels to 70% to 80% through its progestational central inhibition. An oral agent, the recommended dose is 100 mg, two to three times per day. Side effects are consistent with the hypogonadal state and include loss of libido, erectile dysfunction, and lassitude. Severe cardiovascular complications can occur in up to 10% of patients, limiting the use of cyproterone acetate. Gynecomastia occurs in less than 20% of men. Rare cases of fulminant hepatotoxicity have been reported. It has been used at doses of 50 to 100 mg/day for the treatment of hot flashes.
Nonsteroidal Antiandrogens
By blocking the testosterone feedback centrally, the nonsteroidal antiandrogens cause LH and testosterone levels to increase. Testosterone levels reach about 1.5 times the normal levels of hormonally intact men. This allows antiandrogen activity without inducing hypogonadism; potency, therefore, can be preserved. However, in clinical trials specifically examining erectile functioning and sexual activity in men receiving flutamide monotherapy, long-term preservation of those domains was only 20%, not much different from men undergoing surgical castration. The peripheral aromatization of increased testosterone to estradiol has been demonstrated after antiandrogen administration, leading to the widely recognized gynecomastia and mastodynia associated with these agents. Gastrointestinal toxicity, most notably diarrhea, is more common with flutamide than with the other nonsteroidal antiandrogens. Liver toxicity, ranging from reversible hepatitis to fulminant hepatic failure, is associated with all nonsteroidal antiandrogens, and periodic monitoring of liver function is required.
Antiandrogen Withdrawal Phenomenon
Patients treated with a combination of an antiandrogen and an luteinizing hormone–releasing hormone agonist can experience a decline in prostate specific antigen (PSA) level and even objective responses with the withdrawal of the antiandrogen from the combination. On the basis of this response, it appears that the antiandrogen is actually exerting agonistic activity on prostate cancer cells. This phenomenon, first described with flutamide has now been demonstrated with all antiandrogens, including cyproterone acetate as well as DES and progestational agents. Declines in prostate specific antigen level are seen within 4 weeks with flutamide withdrawal and within 6 weeks with bicalutamide and nilutamide withdrawal. Between 15% and 30% of patients may have declines in PSA level of more than 50% after antiandrogen withdrawal and have a median duration of 3.5 to 5 months. Objective, measurable tumor responses are observed less commonly. Overall survival has not been shown to be increased in those demonstrating the antiandrogen withdrawal phenomenon compared with those who have not. Clinical trial designs of novel agents must take this phenomenon into consideration, given the possible confounding effects. Prospective criteria to predict who will demonstrate this response have not been established, but it has been recognized that those with rapid PSA responses after androgen ablation have higher rates of antiandrogen withdrawal phenomenon.
It has been postulated that mutations in the androgen receptor may underlie this phenomenon, allowing the antiandrogen to behave like an activator of the androgen receptor. The widely used prostate cancer cell line LNCaP expresses an androgen receptor with a specific point mutation that causes cell proliferation in the presence of hydroxyflutamide; the identical mutation was found in human tumor samples from patients who had remarkable declines in prostate specific antigen level after antiandrogen withdrawal. Similar point mutations in the androgen receptor have been described for bicalutamide to act as an agonist; the structural basis of this mutation, resolved by x-ray crystallography, demonstrates the ability of bicalutamide to bind to the mutant androgen receptor in a fashion similar to dihydrotestosterone (DHT) to the wild-type androgen receptor.
Flutamide
A nonsteroidal antiandrogen, flutamide was the first “pure” antiandrogen. Because of the short half-life (6 hours) of the active metabolite, 2-hydroxyflutamide, this oral agent requires a three-times-a-day dosing schedule, 250 mg per dose. Elimination of hydroxyflutamide is by renal excretion. Unlike with the steroidal antiandrogens, there are no associated side effects of fluid retention or thromboembolism. In a randomized, double-blind study comparing flutamide with DES (3 mg/day) in metastatic prostate cancer, overall survival was significantly shorter with flutamide (28.5 months) than with DES (43.2 months).
A nonsteroidal antiandrogen with a long serum half-life (6 days), bicalutamide has a once-per-day dosing schedule and therefore is likely to have better compliance. It is the most potent of the nonsteroidal antiandrogens and the best tolerated. The pharmacokinetics of bicalutamide are not affected by age, renal insufficiency, or moderate hepatic impairment. The R isomer of bicalutamide has about a 30-fold higher binding affinity to the androgen receptor compared with the S isomer and functionally processes the antiandrogen activity. Like the other antiandrogens, bicalutamide is associated with maintenance of serum testosterone levels; in the majority of patients, these remain within the normal range.
Bicalutamide as monotherapy has been most extensively studied, and like the inferiority of flutamide monotherapy to DES, bicalutamide monotherapy at a dose of 50 mg/day was inferior to castration in survival of men with metastatic disease. At higher dose of 150 mg/day, however, bicalutamide monotherapy appears to have efficacy equivalent to that of medical or surgical castration in men with metastatic or locally advanced disease. In these large phase III studies, bicalutamide monotherapy (150 mg/day) had significantly better quality of life in the domains of sexual interest and physical capacity. There was, however, a high rate of gynecomastia (66.2%) and breast pain (72.8%). Of more concern, in men with low-risk, localized prostate cancer, bicalutamide was associated with significantly worse overall survival compared with those on watchful waiting.
The plasma half-life of nilutamide is 56 hours, and elimination is by hepatic clearance employing the cytochrome P-450 system. Because steady-state plasma levels are achieved in 14 days on once-per-day dosing, dosing recommendations are a single 300-mg daily dose for the first month of treatment followed by a single 150-mg daily dose. About one quarter of men receiving nilutamide therapy will note a delayed adaptation to darkness after exposure to bright illumination. In approximately 1% of patients, nilutamide is also associated with interstitial pneumonitis, which can progress to pulmonary fibrosis. The early effects are usually reversible with cessation of nilutamide. In a small study, there was a suggestion of a role for nilutamide as an effective secondary hormonal agent.
Inhibition of LHRH
LHRH Agonists
The LHRH agonists exploit the desensitization of luteinizing hormone–releasing hormone receptors in the anterior pituitary after chronic exposure to LHRH, thereby shutting down the production of LH and, ultimately, testosterone. The clinical utility of the current LHRH agonists is based on the creation of analogs of native LHRH by amino acid substitutions, particularly position 6 in the peptide, increasing their potency and half-lives ( Table: Structure of LHRH and Therapeutic Analogs ). Pharmacologic depot preparations and osmotic pump devices allow dosing to extend from 28 days to 1 year, respectively ( Table: LHRH Agonists Approved for the Treatment of Prostate Cancer ). In a review of 24 trials involving more than 6600 patients, survival after therapy with an LHRH agonist was equivalent to that of orchiectomy.
Table: Structure of LHRH and Therapeutic Analogs
| Amino acid number |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
9 |
10 |
| Native LHRH |
(pyro)Glu- |
His- |
Trp- |
Ser- |
Try- |
Gly- |
Leu- |
Arg- |
Pro- |
Gly-NH2 |
| Leuprolide |
(pyro)Glu- |
His- |
Trp- |
Ser- |
Try- |
D-Leu- |
Leu- |
Arg- |
Pro- |
Ethylamide |
| Goserelin |
(pyro)Glu- |
His- |
Trp- |
Ser- |
Try- |
D-Ser(tBu)- |
Leu- |
Arg- |
Pro- |
Gly-NH2 |
| Triptorelin |
(pyro)Glu- |
His- |
Trp- |
Ser- |
Try- |
D-Trp- |
Leu- |
Arg- |
Pro- |
Gly-NH2 |
| Histrelin |
(pyro)Glu- |
His- |
Trp- |
Ser- |
Try- |
D-His(Imbzl) |
Leu- |
Arg- |
Pro- |
N-Et-NH2 |
LHRH, luteinizing hormone–releasing hormone.
Table: LHRH Agonists Approved for the Treatment of Prostate Cancer
LHRH, luteinizing hormone–releasing hormone.
The initial exposure to more potent agonists of LHRH results in a flare of LH and testosterone levels. This phenomenon is seen with all available LHRH preparations and can result in a severe, life-threatening exacerbation of symptoms. The flare, associated with up to a 10-fold increase in luteinizing hormone, may last 10 to 20 days. Fortunately, the co-administration of an antiandrogen functionally blocks the increased levels of testosterone. Although it had been argued that the administration of the antiandrogen should precede the administration of the LHRH agonist by a week, others have found no differences in prostate specific antigen levels with the simultaneous administration of both agents. Given the predictable length of the flare phenomenon, co-administration of antiandrogens is required for only 21 to 28 days.
LHRH Antagonists
The LHRH antagonists bind immediately and competitively to the LHRH receptors in the pituitary, reducing LH concentrations by 84% within 24 hours of administration. The direct antagonistic activity eliminates the LH and testosterone flare, which is a major therapeutic advantage of these agents; there is no need for antiandrogen co-administration. Hormonally naive patients with impending spinal cord compression or severe bone pain for whom surgical castration is not appropriate may uniquely benefit from this class of agents; clinical response has been observed with the LHRH antagonist cetrorelix.
In clinical trials of the luteinizing hormone–releasing hormone antagonist abarelix, testosterone levels dropped quickly, with 34.5%, 60.5%, and 98.1% of men chemically castrate at 2, 4, and 28 days, respectively. Compared with an LHRH agonist and an antiandrogen, abarelix monotherapy was equally effective in achieving castrate levels of testosterone. Ninety percent of men with symptomatic prostate cancer treated in an open-label fashion had improvements in pain or disease-related problems.
Many of the first- and second-generation antagonists induced significant histamine-mediated side effects, complications not as often observed in third- and fourth-generation agents. Nevertheless, severe allergic reactions can occur, even after previously uneventful treatment. Abarelix is approved in the United States for the treatment of advanced prostate cancer in patients who cannot take other hormonal therapies and have refused surgical castration. Given the rare but serious allergic reactions, patients must be monitored for at least 30 minutes after administration.
FSH levels are only partially suppressed by LHRH agonists, and FSH levels are significantly elevated after surgical castration, given the loss of inhibitory feedback. LHRH antagonists reduce both LH and FSH levels. In an androgen-insensitive prostate cancer xenograft model, cetrorelix significantly reduced tumor growth, suggesting that other factors stimulate tumor growth. In men with disease progression after surgical castration, treatment with abarelix reduced FSH levels by nearly 90% but did not meet criteria for PSA response.
Inhibition of Androgen Synthesis
Aminoglutethimide inhibits the conversion of cholesterol to pregnenolone, an early step in steroidogenesis. Given its inhibition of a very proximal step in adrenal function, aminoglutethimide blocks production of aldosterone and cortisol. As the medical version of a total adrenalectomy, the use of this agent requires replacement of cortisone and fludrocortisone. Side effects include anorexia, nausea, rash, lethargy, vertigo, hypothyroidism, and nystagmus. Clinical responses have been observed in a subset of patients with androgen-refractory prostate cancer treated with aminoglutethimide plus cortisone. In the PSA era, 37% of patients had more than a 50% decline in PSA level with treatment by aminoglutethimide (1000 mg/day) and hydrocortisone acetate (40 mg/day), with median response times lasting 9 months.
An orally active, broad-spectrum azole antifungal agent, ketoconazole interferes with two cytochrome P-450–dependent pathways: inhibition of 14-methylation in the conversion of lanosterol to cholesterol and blockade of 17,20-desmolase, affecting the conversion of C21 to C19 steroids. On the basis of the observation that some patients taking the drug developed gynecomastia, investigations of its effects on steroid synthesis demonstrated loss of adrenal steroid synthesis and testosterone synthesis by Leydig cells. The effects were rapid, with testosterone levels dropping to the castrate level within 4 hours of administration in some cases; the effects were also immediately reversible, indicating that dosing must be continuous to maintain low testosterone levels (400 mg every 8 hours).
Early experience with ketoconazole in the treatment of prostate cancer showed this agent to be tolerable, durable, and effective and palliative for those whose first-line androgen ablation therapy had failed. Although it is effective in rapidly bringing testosterone levels into the castrate range, with continuous treatment with ketoconazole in the otherwise hormonally intact individual (no other surgical or chemical ADT), testosterone levels begin to rise and can reach low-normal ranges within 5 months of therapy. Therefore, ketoconazole is currently used for men with androgen-refractory prostate cancer, often as the first or second agent in so-called secondary hormonal manipulation. In addition to gynecomastia (caused by alterations in testosterone-to-estradiol ratios), ketoconazole is associated with lethargy, weakness, hepatic dysfunction, visual disturbance, and nausea. Because of the adrenal suppression, ketoconazole is usually given with hydrocortisone (20 mg, twice per day).
Mechanisms of androgen axis blockade
There are four general forms of androgen deprivation therapy: ablation of androgen sources, inhibition of androgen synthesis, antiandrogens, and inhibition of LHRH or LH.
Bilateral orchiectomy reduces testosterone by 90% within 24 hours of surgery.
Nonsteroidal antiandrogens cause LH and testosterone levels to increase.
Serious liver toxicity is a possible side effect of all antiandrogens.
Antiandrogens can act agonistic on some tumors; antiandrogen withdrawal results in decline of PSA level in 15% to 30% of patients.
Bicalutamide 150-mg monotherapy appears to have efficacy equivalent to that of medical or surgical castration for locally advanced or metastatic prostate cancer.
All LHRH agonists induce a testosterone increase on initial exposure. Co-administration of an antiandrogen functionally blocks the effects of testosterone.
