a.prostate cancer–specific death was more common in the continuous ADT arm.
b.death unrelated to prostate cancer was more common in the intermittent ADT arm.
c.attrition from the intermittent arm was rare throughout the cycles.
d.duration of intermittent ADT progressively shortened over time.
e.quality of life was not improved in the intermittent arm.
.There is general consensus that ADT should always be initiated in a hormonally intact patient in which of the following clinical settings?
a.Before radical prostatectomy with a clinical T2 tumor
b.In all clinical stages of men undergoing external beam radiation therapy
c.In those with clinically localized prostate cancer who do not want local treatment
d.In those with symptomatic metastatic disease
e.In those with high-grade prostatic intraepithelial neoplasia (PIN) on needle biopsy who refuse a subsequent biopsy
Answers
1.e. Negative feedback on luteinizing hormone (LH) secretion by the pituitary. After the success of surgical castration in treating prostate cancer, the first central inhibition of the hypothalamic-pituitary-gonadal axis exploited the potent negative feedback of estrogen on LH secretion. Estradiol is a thousandfold more potent at suppressing LH and FSH secretion by the pituitary compared with testosterone. Although estrogen has some direct cytotoxic effects on prostate cancer cells, this is not its primary mode of action. All antiandrogens competitively bind to the androgen receptor.
Aminoglutethimide inhibits the conversion of cholesterol to pregnenolone, an early step in steroidogenesis. The LHRH agonists desensitize LHRH receptors in the anterior pituitary.
2.c. LH increases, testosterone increases, estrogen increases. Unlike the steroidal antiandrogens, such as cyproterone acetate, which have central progestational inhibitory effects, the nonsteroidal antiandrogens simply block androgen receptors, including those in the hypothalamic-pituitary axis. Because those central androgen receptors no longer sense the normal negative feedback exerted by testosterone, both LH levels and—as the normal
testicular response to increased LH—testosterone levels increase. Peripheral conversion of this excessive testosterone also increases estrogen levels, leading to the gynecomastia and mastodynia associated with the nonsteroidal antiandrogens.
3.d. Direct inhibition of androgen receptor–mediated pathways. There are four therapeutic approaches for androgen axis blockade in current clinical use. All current forms of androgen deprivation therapy function by reducing the ability of androgen to activate the androgen receptor, whether through lowering levels of androgen or by blocking androgen–androgen receptor binding. Therefore, the androgen receptor is not directly affected by androgen deprivation therapy, leading many to hypothesize that hormone-refractory prostate cancer is a reactivation of androgen receptor–mediated pathways.
4.b. Allow long-term maintenance of erectile function and sexual activity at rates similar to men undergoing surgical castration. By blocking testosterone feedback centrally, the nonsteroidal antiandrogens cause LH and testosterone levels to increase, allowing antiandrogen activity without inducing hypogonadism and potency can be preserved. In clinical trials specifically examining erectile function and sexual activity in men on antiandrogen monotherapy, however, long-term preservation of those domains was 20% and not significantly different from that in men undergoing surgical castration. All antiandrogens can act agonistically on prostate cancer cells and, when used in combination with LHRH agonists, withdrawal of the antiandrogen can lead to declines in PSA and even objective responses. The common gastrointestinal toxicity is diarrhea, most often seen with flutamide. Liver toxicity, ranging from reversible hepatitis to fulminant hepatic failure, is associated with all nonsteroidal antiandrogens and requires periodic monitoring of liver function tests. The steroidal antiandrogen cyproterone acetate is associated with fluid retention and thromboembolism.
5.d. Nilutamide. About one quarter of men on nilutamide therapy will note a delayed adaptation to darkness after exposure to bright illumination, and in approximately 1% of patients, nilutamide is also associated with interstitial pneumonitis, which can progress to pulmonary fibrosis. Hydroxyflutamide is the active metabolite of flutamide. Cyproterone acetate is a steroidal antiandrogen.
6.d. Widespread use of orally effective LHRH agonists has been limited by
severe allergic reactions in some patients, even after previously uneventful treatment. The LHRH agonists exploit the desensitization of LHRH receptors in the anterior pituitary following chronic exposure to LHRH, thereby shutting down the production of LH and, ultimately, testosterone. Analogues of native LHRH increase their potency and halflives. The initial flare in LH and testosterone may last 10 to 20 days, and co-administration of an antiandrogen is required for only 21 to 28 days.
Survival after therapy with an LHRH agonist was equivalent to that for orchiectomy. The clinical utility of the first LHRH agonists was hampered by their short half-lives, requiring daily dosing. The LHRH antagonist abarelix has been associated with severe allergic reactions: All LHRH agonists are administered either IM or subcutaneously. LHRH can be used without combination with an antiandrogen.
7.e. The maintenance of a detectable PSA. The odds ratio of progressing to androgen-refractory progression at 24 months after starting ADT was 15-fold higher in those who did not achieve an undetectable PSA. The magnitude and rapidity of PSA decline, the pre-ADT PSA doubling time, and pretreatment testosterone levels are all associated with the ability to predict the response of to ADT. For each unit increase in Gleason score, the cumulative hazard of castration-resistant progression was nearly 70%.
8.c. Erectile dysfunction after surgical castration or use of an LHRH is common but not inevitable: Although 1 in 5 men maintain some sexual activity, only 1 in 20 maintain high levels of sexual interest (libido). The loss of sexual functioning is not inevitable with surgical or chemical castration, with up to 20% of men able to maintain some sexual activity.
Libido is more severely compromised, with approximately 5% maintaining a high level of sexual interest. More than half of men undergoing ADT meet the bone mineral density criteria for osteopenia or osteoporosis; it is estimated osteopenia will develop in the average man within 4 years of initiating ADT. Hot flashes are among the most common side effects of ADT, affecting between 50% and 80% of patients. Hot flashes should be treated only in those who find them bothersome. Loss of muscle mass and increase in percent fat body mass are common in men undergoing ADT. Prophylactic radiation therapy (10 Gy) has been used to prevent or reduce gynecomastia and mastodynia, but it has no benefit once these side effects have already occurred.
9.a. Positive surgical margin rates are significantly reduced with ADT-
treated patients. In both nonrandomized and randomized clinical trials, the pathological positive surgical margin rate is significantly reduced. In one study, the positive surgical margin rate fell from nearly 50% in hormonally intact patients to 15% in ADT-treated patients. Despite this improvement, there has not been a corresponding significant reduction in biochemical (PSA) progression in ADT-treatment patients, a finding in four separate prospective randomized studies. The benefit of ADT in men with locally advanced disease and/or high-grade disease has been in combination with external beam radiation therapy. There is no evidence that any form of 3- month neoadjuvant ADT before radical prostatectomy reduces biochemical failure rates.
.e. Using cyproterone acetate has a slightly worse outcome. In studies of combined androgen blockade using the steroidal antiandrogen cyproterone acetate compared to LHRH agonists alone, the outcomes were slightly worse with the combination, suggesting increased non–prostate cancer deaths with this agent. Combined androgen blockade is designed to block the possible contribution of adrenal androgens to prostate cancer progression. Combined androgen blockade uses an antiandrogen along with an LHRH agonist: Addition of an antiandrogen at the time of PSA rise (evidence of hormonerefractory disease) is considered secondary hormonal manipulation. Several clinical trials have shown a slight but significant survival advantage for combined androgen blockade. A landmark randomized clinical trial comparing surgical castration alone with surgical castration combined with flutamide did not show a significant benefit in men with minimal metastatic disease.
.d. Does not prevent the emergence of castration-resistant prostate cancer.
The timing of the initiation of ADT has not prevented the development of
castration-resistant prostate cancer. Although early ADT may provide an overall survival advantage in certain clinical disease states, in most studies there is no significant overall survival advantage. Indeed, in localized, low-risk prostate cancer, early ADT is associated with an increase in overall death rates. The natural history of disease progression after biochemical failure following radical prostatectomy is protracted: Median time to bone metastases is 10 years.
.b. A significant overall survival benefit of immediate ADT has been demonstrated in men who have also undergone subsequent radical prostatectomy. A randomized prospective study of men with positive
1.Antiandrogens bind to the androgen receptor in a competitive fashion. They are either steroidal or nonsteroidal.
2.Steroidal antiandrogens suppress LH release. Thus the steroidal antiandrogens block the effects of testosterone on the receptor as well as lower testosterone through their progestational central inhibition effect. The nonsteroidal antiandrogens simply block androgen receptors
3.When performing an orchiectomy, double-ligating the transected segments of the cord with one being a transfixion suture is advised.
4.Initial exposure to LHRH agonists results in a flare of testosterone that may last for up to 20 days; the clinical effects of the flare may be blocked by the simultaneous administration of an antiandrogen. The two drugs should be administered together, and the antiandrogen therapy should be continued for 3 weeks.
5.After 4 years of androgen deprivation, the average man is osteopenic.
6.Hot flashes may be treated with megestrol, 20 mg twice daily.
7.Androgen deprivation therapy may result in bone loss, sexual dysfunction, hot flashes, decreased cognitive function, loss of muscle mass, increase in body fat, anemia, gynecomastia, diabetes, and increased cardiovascular mortality.
8.Twenty percent of individuals with metastatic prostate cancer die of nonprostate cancer causes.
9.Bilateral orchiectomy reduces testosterone by 90% within 24 hours.
10.The androgen receptor remains responsive to androgen even in the castration-resistant state; therefore, androgen deprivation therapy should be continued in the patient who has castration-resistant prostate cancer.
11.The steroid synthesis inhibitors aminoglutethimide, ketoconazole, and abiraterone require simultaneous glucocorticoid replacement. Aminoglutethimide requires mineral corticoid replacement as well, whereas abiraterone results in increased mineral corticoid production that may result in hypokalemia and hypertension.
12.Intermittent androgen deprivation therapy compared with continuous therapy is not superior and may be worse.
13.Many men with prostate cancer will never require androgen deprivation therapy because of the protracted course of the disease.
14.Estradiol is a thousandfold more potent at suppressing LH and folliclestimulating hormone (FSH) secretion by the pituitary compared to testosterone.
15.Therapies that block the androgen receptor but do not lower testosterone, such as nonsteroidal antiandrogens, may produce excessive amounts of testosterone, which is peripherally converted to estrogens, leading to the gynecomastia and mastodynia.
16.All antiandrogens can act agonistically on prostate cancer cells and, when used in combination with LHRH agonists, withdrawal of the antiandrogen can lead to declines in PSA and even objective responses.
17.The LHRH agonists exploit the desensitization of LHRH receptors in the anterior pituitary following chronic exposure to LHRH, thereby shutting down the production of LH and, ultimately, testosterone.
18.Prophylactic radiation therapy (10 Gy) has been used to prevent or reduce gynecomastia and mastodynia, but it has no benefit once these side effects have already occurred. Once they are present, a simple mastectomy may be required in some men for cosmetic and symptomatic relief.
19.A clinical trial comparing surgical castration alone with surgical castration combined with flutamide did not show a significant benefit in men with minimal metastatic disease.
20.Although early ADT may provide an overall survival advantage in certain clinical disease states, in most studies there is no significant overall survival advantage. Indeed, in localized, low-risk prostate cancer, early ADT is associated with an increase in overall death rates.
21.The benefits of ADT in combination with external beam radiation therapy are limited to men with locally advanced and/or high-grade disease.