Chapter 63: Natural Products in Cancer Chemotherapy: Hormones and Related Agents

In acute lymphoblastic or undifferentiated leukemia of childhood, glucocorticoids may produce prompt clinical improvement and objective hematological remissions in ≤30% of children. Although these responses frequently are characterized by complete disappearance of all detectable leukemic cells from the peripheral blood and bone marrow, the duration of remission is brief. Remissions occur more rapidly with glucocorticoids than with antimetabolites, and there is no evidence of cross-resistance to unrelated agents. For these reasons, therapy is initiated with prednisone and vincristine, often followed by an anthracycline or methotrexate, and l-asparaginase. Glucocorticoids are a valuable component of curative regimens for other lymphoid malignancies, including Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and chronic lymphocytic leukemia (CLL). Glucocorticoids are extremely helpful in controlling auto-immune hemolytic anemia and thrombocytopenia associated with CLL.

The glucocorticoids, particularly dexamethasone, are used in conjunction with radiotherapy to reduce edema related to tumors in critical areas such as the superior mediastinum, brain, and spinal cord. Doses of 4-6 mg every 6 hours have dramatic effects in restoring neurological function in patients with cerebral metastases, but these effects are temporary. Acute changes in dexamethasone dosage can lead to a rapid recrudescence of symptoms. Dexamethasone should not be discontinued abruptly in patients receiving radiotherapy or chemotherapy for brain metastases. Gradual tapering of the dosage may be undertaken if a clinical response to definitive antitumor therapy has been achieved. The antitumor effects of glucocorticoids are mediated by their binding to the glucocorticoid receptor, which activates a program of gene expression that leads to apoptosis.

Several glucocorticoids are available and at equivalent dosages exert similar effects (see Chapter 42). Prednisone, e.g., usually is administered orally in doses as high as 60-100 mg, or even higher, for the first few days and gradually reduced to levels of 20-40 mg/day. A continuous attempt should be made to establish the lowest possible dosage required to control the manifestations of the disease. These agents, when used chronically, exert a wide range of side effects, including glucose intolerance, immunosuppression, osteoporosis, and psychosis (see Chapter 42). Dexamethasone is the preferred agent for remission induction in multiple myeloma, usually in combination with melphalan, anthracyclines, vincristine, bortezomib, or thalidomide.

Medroxyprogesterone (depo-provera, others) can be administered intramuscularly in doses of 400-1000 mg weekly. An alternative and more commonly used oral agent is megestrol acetate (megace, others; 40-320 mg daily in divided doses). Hydroxyprogesterone (not available in the U.S.) usually is administered intramuscularly in doses of 1000 mg one or more times weekly. Beneficial effects have been observed in approximately one-third of patients with endometrial cancer. The response of breast cancer to megestrol is predicted by both the presence of estrogen receptors (ERs) and the evidence of response to a prior hormonal treatment. The effect of progestin therapy in breast cancer appears to be dose dependent, with some patients demonstrating second responses following escalation of megestrol to 1600 mg/day. Clinical use of progestins in breast cancer has been largely superseded by the advent of tamoxifen and the aromatase inhibitors (AIs). Responses to progestational agents also have been reported in metastatic carcinomas of the prostate and kidney.

Responses to hormonal therapy may not be apparent clinically or by imaging for 8-12 weeks. If the disease responds or remains stable on a given treatment, the medication typically should be continued until the disease progresses or unwanted toxicities develop. The duration of an induced remission in patients with metastatic disease averages 6-12 months but sometimes can last for many years.

There are two subtypes of estrogen receptors: ERα and ERβ, which have different tissue distributions and can either homo- or heterodimerize. Binding of estradiol and SERMs to the estrogen-binding sites of the ERs initiates a change in conformation of the ER, dissociation of the ER from heat-shock proteins, and inhibition of ER dimerization. Dimerization facilitates the binding of the ER to specific DNA estrogen-response elements (EREs) in the vicinity of estrogen-regulated genes. Co-regulator proteins interact with the receptor to act as co-repressors or co-activators of gene expression. At least 50 transcriptional activating factors transduce and modulate the effects of estrogen on target genes. Differences in tissue distribution of ER subtypes, the function of co-regulator proteins, and the various transcriptional activating factors likely explain the variability of response to tamoxifen in hormone receptor–positive (ER⁺) breast cancer and its agonist and antagonist activities in noncancerous tissues. Other organs displaying agonist effects of tamoxifen include the uterine endometrium (endometrial hypertrophy, vaginal bleeding, and endometrial cancer), the coagulation system (thromboembolism), bone metabolism (increase in bone mineral density [BMD]), and liver (alterations of blood lipid profile).

Tamoxifen is readily absorbed following oral administration, with peak concentrations measurable after 3-7 hours and steady-state levels being reached at 4-6 weeks. Metabolism of tamoxifen is complex and principally involves CYPs 3A4/5, and 2D6 in the formation of N-desmethyl tamoxifen, and CYP2D6 to form 4-hydroxytamoxifen, a more potent metabolite (Figure 63–1). Both metabolites can be further converted to 4-hydroxy-N-desmethyltamoxifen, which retains high affinity for the ER. The parent drug has a terminal t_1/2 of 7 days; the t_1/2 of N-desmethyltamoxifen and 4-hydroxytamoxifen are significantly longer (14 days). After enterohepatic circulation, glucuronides and other metabolites are excreted in the stool; excretion in the urine is minimal.

Tamoxifen is used for the endocrine treatment of women with ER⁺ metastatic breast cancer or following primary tumor excision as adjuvant therapy. For the adjuvant treatment of premenopausal women, tamoxifen is given for 5 years, or in postmenopausal women, for 2 years, followed by an AI. In patients with high risk of recurrence, it may be sequenced after adjuvant chemotherapy. Tamoxifen is used in premenopausal women with ER⁺ tumors. Disease response rates are similar to those seen in postmenopausal patients. Alternative or additional anti-estrogen strategies in premenopausal women include oophorectomy or gonadotropin-releasing hormone analogs. The combination of tamoxifen and a gonadotropin-releasing hormone analog in premenopausal women (to reduce high estrogen levels resulting from tamoxifen effects on the gonadal-pituitary axis) yields better response rates and improved overall survival than either drug alone (Klijn et al., 2000).

The nolvadex Adjuvant Trial Organization (NATO) study indicated an overall disease-free survival advantage for patients receiving tamoxifen versus placebo. Five years of adjuvant therapy with tamoxifen yielded superior results compared to 1 or 2 years of therapy (Swedish Breast Cancer Cooperative Group, 1996; Early Breast Cancer Trialists' Collaborative Group, 1998). Therefore, although the optimal duration of tamoxifen has not been fully determined, randomized trials have demonstrated superiority of 5 years over shorter durations. One clinical trial evaluating the administration of tamoxifen for >5 years failed to show benefit of continued therapy and a trend toward worse outcomes in women who received tamoxifen therapy over a longer duration (Fisher et al., 2001).

Tamoxifen also has shown effectiveness (a 40-50% reduction in tumor incidence) in initial trials for preventing breast cancer in women at increased risk (Vogel et al, 2010). These studies were prompted by preclinical experiments showing prevention of tumors in animal models and also by the observation of reduced contralateral new primary breast tumors in women receiving adjuvant tamoxifen for early-stage breast cancer (Early Breast Cancer Trialists' Collaborative Group, 1998; Fisher et al., 2001). Tamoxifen only reduces ER+ tumors without affecting ER-negative tumors, which contribute disproportionately to breast cancer mortality.

Tamoxifen also increases the incidence of endometrial cancer by 2- to 3-fold, particularly in postmenopausal women who receive 20 mg/day for ≥2 years. In general, tamoxifen-associated endometrial cancers are reported as low-grade and early-stage tumors. Standard practice guidelines from the National Comprehensive Cancer Network alert physicians to the evaluation of abnormal vaginal bleeding in women with an intact uterus.

Tamoxifen increases the risk of thromboembolic events, which increase with the age of a patient and also in the perioperative period. Hence, it often is recommended to discontinue tamoxifen prior to elective surgery. Because tamoxifen is associated with thromboembolism, some authorities suggest that the pretreatment evaluation of breast cancer patients should include screening for coagulation abnormalities (factor V Leiden, protein C, antithrombin III defects) and for a history of thromboembolic disease. Presence of these risk factors should lead to exclusion of women from treatment. Note that no clear causative association between the presence of the factor V Leiden mutation and tamoxifen-induced thromboembolism has been found (Abramson, 2006).

Like estrogen, tamoxifen is a hepatic carcinogen in animals, although increases in primary hepatocellular carcinoma have not been reported in patients on the drug. Tamoxifen causes retinal deposits, decreased visual acuity, and cataracts in occasional patients, although the frequency of these changes is more common in patients on high doses of drug.

In addition to its ability to prevent recurrence or the development of primary breast cancer, tamoxifen has other end-organ benefits related to its partial estrogenic action. For example, it may slow the development of osteoporosis in postmenopausal women. Like certain estrogens, tamoxifen lowers total serum cholesterol, low-density-lipoprotein cholesterol, and lipoproteins and raises apolipoprotein A-I levels, potentially decreasing the risk of myocardial infarction.

Tamoxifen Resistance. Despite its benefits, initial or acquired resistance to tamoxifen frequently occurs (Moy and Goss, 2006). Polymorphisms in CYP2D6 that reduce its activity lead to lower plasma levels of 4-OH tamoxifen, a potent metabolite, and are associated with higher risks of disease relapse and a lower incidence of hot flashes (Goetz et al., 2005). CYP2D6 is responsible for the activation of tamoxifen to its active metabolite endoxifen (Figure 63–1). Cross-talk between the ER and HER2/neu pathway also has been implicated in tamoxifen resistance. The paired box 2 gene product (PAX2) has been identified as a crucial mediator of ER repression of ErbB2 by tamoxifen (Hurtado et al., 2008). Interactions between PAX2 and the ER co-activator AIB-1/SRC-3 determine tamoxifen response in breast cancer cells.

In preclinical models, toremifene has activity against breast cancer cells in vitro and in vivo similar to that of tamoxifen. Unlike tamoxifen, however, toremifene is not hepatocarcinogenic in experimental animals. Two adjuvant studies have compared efficacy of these two agents and, in particular, long-term tolerability and safety, in early-stage breast cancer. There were no significant differences in efficacy or tolerability after a median follow-up of 4.4 years, and the number of subsequent second cancers was similar (Howell et al., 2004a). However, in vitro in a low-estrogen environment, toremifene has less estrogen agonist effect than tamoxifen. This may make toremifene more effective in combination with an AI than tamoxifen, and this possibility is the subject of ongoing clinical trials.

Mechanism of Action. Fulvestrant is a steroidal anti-estrogen that binds to the ER with an affinity >100 times that of tamoxifen. The drug inhibits the binding of estrogen but also alters the receptor structure such that the receptor is targeted for proteasomal degradation; fulvestrant also may inhibit receptor dimerization. Unlike tamoxifen, which stabilizes or even increases ER expression, fulvestrant reduces the number of ER molecules in cells, both in vitro and in vivo; as a consequence of this ER downregulation, the drug abolishes ER-mediated transcription of estrogen-dependent genes (Howell et al., 2004b).

Absorption, Fate, and Excretion. Maximum plasma concentrations are reached ~7 days after intramuscular administration of fulvestrant and are maintained over 1 month. The plasma t_1/2 is ~40 days. Steady-state concentrations are reached after three to six monthly injections. There is extensive and rapid distribution and extensive protein binding of this highly lipophilic drug.

Various pathways, similar to those of steroid metabolism (oxidation, aromatic hydroxylation, and conjugation), extensively metabolize fulvestrant. CYP3A4 appears to be the only CYP isoenzyme involved in the metabolism of fulvestrant. However, several preclinical and clinical studies indicate that fulvestrant is not subject to CYP3A4 interactions that might affect its pharmacokinetics, safety, or efficacy; however, the effects of strong CYP3A4 inhibitors have not been studied. The putative metabolites possess no estrogenic activity, and only the 17-keto compound demonstrates a level of anti-estrogenic activity, which is ~22% that of fulvestrant. Less than 1% of the parent drug is excreted intact in the urine.

Dosing. The approved dosing for fulvestrant is 250 mg by intramuscular injection monthly. Because pharmacokinetic data have shown that it takes ~3-6 months for fulvestrant to reach steady-state levels with monthly dosing, alternative regimens have been studied. A loading dose regimen of 500 mg on day 0, 250 mg on days 14 and 28, and then 250 mg each month (McCormack and Sapunar, 2008) yields maximum fulvestrant concentrations in plasma an average of 12 days after the first dose and maintains those levels thereafter.

Therapeutic Uses. Fulvestrant is used in postmenopausal women as anti-estrogen therapy of hormone receptor–positive metastatic breast cancer after progression on first-line anti-estrogen therapy such as tamoxifen (Strasser-Weippl and Goss, 2004). Fulvestrant is at least as effective in this setting as the third-generation AI anastrozole.

Fulvestrant 250 mg (administered as a once-monthly 5-mL intramuscular injection) also has been compared with tamoxifen 20 mg (orally once daily) in a trial of postmenopausal women with ER⁺ and/or PR⁺ or ER/PR-unknown metastatic breast cancer who had not previously received endocrine or chemotherapy. In patients with ER⁺ and/or PR⁺ disease, there was no difference between fulvestrant and tamoxifen in time to disease progression or overall response rate (Vergote and Robertson, 2004). The long time to steady-state plasma levels for fulvestrant has brought into question the results of studies that lacked a loading dose, and trials are in progress to test the relative efficacy of giving an initial loading dose followed by regular monthly injections.

Toxicity and Adverse Effects. Fulvestrant generally is well tolerated, the most common adverse effects being nausea, asthenia, pain, vasodilation (hot flashes), and headache. The risk of injection site reactions, seen in ~7% of patients, is reduced by giving the injection slowly. In the study comparing anastrozole and fulvestrant in tamoxifen-resistant patients, the drugs had equivalent quality-of-life outcome measures (Vergote and Robertson, 2004).

Mechanism of Action. Anastrozole, like letrozole, binds competitively and specifically to the heme of the CYP19. Anastrozole, 1 mg or 10 mg, administered once daily for 28 days, reduces total body androgen aromatization by 96.7% or 98.1%, respectively. In addition, anastrozole reduces aromatization in large, ER⁺ breast tumors.

Absorption, Fate, and Excretion. Anastrozole is absorbed rapidly after oral administration, reaching maximal plasma concentrations after 2 hours. Repeated dosing increases plasma concentrations of anastrozole, and steady-state is attained after 7 days. Although a high-fat breakfast slows absorption, the meal does not significantly alter the ultimate steady-state concentration achieved with multiple dosing. Anastrozole is metabolized by N-dealkylation, hydroxylation, and glucuronidation. The main metabolite of anastrozole is a triazole. In addition, several other metabolites with no pharmacological activity are formed. Less than 10% of the drug is excreted as the unmetabolized parent compound. The principal excretory pathway is via the liver and biliary tract. The elimination t_1/2 is ~50 hours. The pharmacokinetics of anastrozole, which can be affected by drug interactions via the CYP system, are not altered by co-administration of tamoxifen or cimetidine (Köberle and Thürlimann, 2001).

Therapeutic Uses. Anastrozole (arimidex), 1 mg administered orally once daily, is approved for upfront adjuvant hormonal therapy in postmenopausal women with early-stage breast cancer and as treatment for advanced breast cancer. In early-stage breast cancer, anastrozole is significantly more effective than tamoxifen in delaying time to tumor recurrence and decreasing the odds of a primary contralateral tumor (Baum et al., 2002). In advanced breast cancer, the results of two large, randomized trials in postmenopausal women with disease progression while taking tamoxifen showed a statistically significant survival advantage with anastrozole 1 mg/day versus megestrol acetate 40 mg four times daily. In another phase III clinical trial on women with ER⁺ or PR⁺ metastatic breast cancer, anastrozole showed a statistically significant advantage over tamoxifen in median time to disease progression (Bonneterre et al., 2001).

Adverse Effects and Toxicity. Compared to tamoxifen, anastrozole has been associated with a significantly lower incidence of vaginal bleeding, vaginal discharge, hot flashes, endometrial cancer, ischemic cerebrovascular events, venous thromboembolic events, and deep venous thrombosis, including pulmonary embolism. Anastrozole is associated with a higher incidence of musculoskeletal disorders and fracture than tamoxifen. In the advanced disease setting, anastrozole is as well tolerated as megestrol and causes less weight gain. In addition, anastrozole is as well tolerated as tamoxifen, with a low rate of withdrawal due to drug-related adverse events (2%).

The estrogen depletion caused by anastrozole and other AIs raises the concern of bone loss. Compared with tamoxifen, treatment with anastrozole results in significantly lower BMD in the lumbar spine and total hip (Eastell et al., 2008). Bisphosphonates prevent AI-induced bone loss in postmenopausal women (Brufsky et al., 2007).

Anastrozole has no clinically significant effect on adrenal glucocorticoid or mineralocorticoid synthesis in postmenopausal women. Anastrozole also does not affect ACTH-stimulated release of cortisol or aldosterone, plasma concentrations of FSH or LH in postmenopausal women, or TSH levels.

Actions. In postmenopausal women with primary breast cancer, letrozole inhibits estrogen aromatization by 99% and reduces local aromatization within the tumors. The drug has no significant effect on the synthesis of adrenal steroids or thyroid hormone and does not alter levels of a range of other hormones. Letrozole also reduces cellular markers of proliferation to a significantly greater extent than tamoxifen in human estrogen-dependent tumors that overexpress HER1 and HER2/neu.

Letrozole increases the levels of bone resorption markers in healthy postmenopausal women and in those with a history of breast disease but without current active disease. Letrozole has not demonstrated a consistent effect on serum lipid levels in healthy women or postmenopausal women with breast cancer.

Absorption, Fate, and Excretion. Letrozole is rapidly absorbed after oral administration, and maximum plasma levels are reached ~1 hour after ingestion. Letrozole has a bioavailability of 99.9%. Steady-state plasma concentrations of letrozole are reached after 2-6 weeks of treatment. Following metabolism by CYP2A6 and CYP3A4, letrozole is eliminated as an inactive carbinol metabolite mainly via the kidneys. The total body clearance is low (2.2 L/h); the elimination t_1/2 is ~41 hours.

Therapeutic Uses. The usual dose of letrozole (femara) is 2.5 mg administered orally once daily. In early-stage breast cancer, extending adjuvant endocrine therapy with letrozole (beyond the standard 5-year period of tamoxifen) improves disease-free survival compared with placebo and improves overall survival in the subset of patients with positive axillary nodes (Goss et al., 2004). Furthermore, upfront letrozole is significantly more effective than upfront tamoxifen in terms of time to tumor recurrence and odds of a primary contralateral tumor (Thürlimann et al., 2005).

In advanced breast cancer, letrozole is superior to tamoxifen as first-line treatment; time to disease progression is significantly longer and objective response rate is significantly greater with letrozole, but median overall survival is similar between groups (Mouridsen et al., 2003). As second-line therapy of advanced breast cancer that has progressed on tamoxifen or after oophorectomy, letrozole has efficacy equal to that of anastrozole and similar to or better than that of megestrol.

Adverse Effects and Toxicity. Letrozole is well tolerated; the most common treatment-related adverse events are hot flashes, nausea, and hair thinning. In patients with tumors that progressed on anti-estrogen therapy, letrozole was tolerated at least as well as, or better than, megestrol. In the trial of extended adjuvant therapy, adverse events reported more frequently with letrozole than placebo were hot flashes, arthralgia, myalgia, and arthritis, but patients discontinued letrozole no more frequently than placebo in this double-blind trial. Letrozole has a low overall incidence of cardiovascular side effects (Mouridsen et al., 2007).

A greater number of new diagnoses of osteoporosis occurred among women receiving letrozole. Compared with tamoxifen, the use of upfront letrozole results in significantly more clinical fractures. Bisphosphonates prevent letrozole-induced bone loss in postmenopausal women (Brufsky et al., 2007).

Mechanism of Action. In contrast to the reversible competitive inhibitors of aromatase (anastrozole and letrozole), exemestane irreversibly inactivates the enzyme and is referred to as a "suicide substrate." Doses of 25 mg/day inhibit aromatase activity by 98% and lower plasma estrone and estradiol levels by ~90% in postmenopausal women.

Absorption, Fate, and Excretion. Exemestane is rapidly absorbed from the GI tract, reaching maximum plasma levels after 2 hours. Its absorption is increased by 40% after a high-fat meal. Exemestane is highly protein bound in plasma and has a terminal t_1/2 of ~24 hours. It is extensively metabolized in the liver to inactive metabolites. A key metabolite, 17-hydroxyexemestane, which is formed by reduction of the 17-oxo group via 17-β-hydroxysteroid dehydrogenase, has weak androgenic activity, which also could contribute to antitumor activity. The elimination t_1/2 of the parent drug is 24 hours. Although significant quantities of active metabolites are excreted in the urine, no dosage adjustments are recommended in patients with renal dysfunction.

Therapeutic Uses. Exemestane (aromasin), 25 mg administered orally once daily, is approved for disease progression in postmenopausal women who completed 2-3 years of adjuvant tamoxifen based on results from a randomized clinical trial in women with ER⁺ breast cancer. Women who had completed 2-3 years of adjuvant tamoxifen were randomized to complete a total of 5 years of adjuvant treatment with tamoxifen or exemestane (Coombes et al., 2004). The unadjusted hazard ratio in the exemestane group versus the tamoxifen group was 0.68, representing a 32% reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7% at 3 years after randomization. Overall survival was not significantly different in the two groups.

In advanced breast cancer, exemestane improves time to disease progression compared with tamoxifen as first-line treatment (Paridaens et al., 2008). Exemestane also has been evaluated in a phase III trial against megestrol in women with disease progressing on prior anti-estrogen therapy. Patients receiving exemestane had a similar response rate but improved time to disease progression and time to treatment failure and had a longer duration of survival compared with those taking megestrol acetate. Responses to treatment also have been shown in women with disease progressing on prior nonsteroidal AIs.

Clinical Toxicity. Exemestane generally is well tolerated. Discontinuations due to toxicity are uncommon (2.8%). Hot flashes, nausea, fatigue, increased sweating, peripheral edema, and increased appetite have been reported. In the trial comparing exemestane to tamoxifen in early-stage breast cancer, exemestane caused more frequent arthralgia and diarrhea but less frequent vaginal bleeding and muscle cramps. Visual disturbances and clinical fractures were more common with exemestane (Coombes et al., 2004).

Whether exemestane negatively affects long-term bone metabolism remains to be determined. The drug has less androgenic activity than formestane but otherwise has a similar toxicity profile.

The duration of response to ADT for patients with metastatic disease is variable but typically lasts 14-20 months (Crawford et al., 1989; Eisenberger et al., 1998). Disease progression despite ADT signifies a castration-resistant state. However, many men respond to secondary hormonal manipulations. Despite castrate levels of testosterone, low-level androgen (DHEA) synthesis from the adrenal glands may permit the continued androgen-driven growth of prostate cancer cells. Therefore, anti-androgens (which competitively bind the androgen receptor [AR]), inhibitors of steroidogenesis (such as ketoconazole), and estrogens frequently are employed as secondary hormone therapies. Unlike the nearly universal response to ADT, only the minority of patients experience symptomatic relief or tumor regression when treated with secondary hormone therapies. When patients become refractory to further hormonal therapies, their disease is considered androgen independent. In these patients, the next treatment option usually is cytotoxic chemotherapy; docetaxel has a proven survival benefit, with average overall survival of 18 months (Petrylak et al., 2004; Tannock et al., 2004).

Common side effects of androgen deprivation include vasomotor flashing, loss of libido, impotence, gynecomastia, fatigue, anemia, weight gain, decreased insulin sensitivity, altered lipid profiles, osteoporosis and fractures, and loss of muscle mass (Saylor and Smith, 2009). The spectrum of side effects of GnRH agonists is distinct from the metabolic syndrome (Smith, 2008). ADT is associated with an increased risk of diabetes and coronary heart disease (Keating et al., 2006). However, retrospective analyses have not revealed a compelling increase in cardiovascular mortality due to GnRH agonists (Efstathiou et al., 2008; Efstathiou et al., 2009). Skeletal-related events due to ADT, including fractures, may be mitigated by bisphosphonate therapy, such as zoledronic acid (zometa) (Saad et al., 2002) or inhibitors of osteoclast activation, such as denosumab (Smith et al., 2009).

Anti-androgens, when compared with GnRH agonists, cause more gynecomastia, mastodynia, and hepatotoxicity but less vasomotor flashing, and loss of bone mineral density (BMD) (McLeod, 1997). Estrogens cause a hypercoagulable state and increase cardiovascular mortality in prostate cancer patients and are no longer standard treatment options (Byar and Corle, 1988).

During the transient rise in LH, the resultant testosterone surge may induce an acute stimulation of prostate cancer growth and a "flare" of symptoms from metastatic deposits. Patients may experience an increase in bone pain or obstructive bladder symptoms lasting for 2-3 weeks (Waxman et al., 1985). The flare phenomenon can be effectively counteracted with concurrent administration of 2-4 weeks of oral anti-androgen therapy, which may inhibit the action of the increased serum testosterone levels (Kuhn et al., 1989).

Leuprolide and goserelin have been compared with orchiectomy in randomized trials. A meta-analysis of 10 such randomized trials found equivalence in overall survival, progression-related outcomes, and time to treatment failure (Kaisary et al., 1991; Seidenfeld et al., 2000; Turkes et al., 1987; Vogelzang et al., 1995).

Combined androgen blockade (CAB) requires administration of ADT with an anti-androgen. The theoretical advantage is that the GnRH agonist will deplete testicular androgens, while the anti-androgen component competes at the receptor with residual androgens made by the adrenal glands. CAB provides maximal relief of androgen stimulation. Numerous large trials have compared CAB with ADT monotherapy, with variable results. Several meta-analyses of these trials suggest a benefit for CAB in 5-year survival but not at earlier time points (Samson et al., 2002; Schmitt et al., 1999). Toxicity and costs associated with CAB are higher than with ADT alone.

GnRH antagonists have been developed to suppress testosterone while avoiding the flare phenomenon of GnRH agonists. Other than avoidance of the initial flare, GnRH antagonist therapy offers no apparent advantage compared with GnRH agonists. The first available GnRH antagonist, abarelix (plenaxis), rapidly achieves medical castration (Trachtenberg et al., 2002). However, local reactions and anaphylaxis have discouraged its clinical acceptance and have led to its withdrawal from the market. A second GnRH antagonist, degarelix, is not associated with systemic allergic reactions and is approved for prostate cancer in the U.S. (Klotz et al., 2008).

Mechanism of Action of Nonsteroidal Anti-Androgens. The nonsteroidal anti-androgens are taken orally and inhibit ligand binding and consequent AR translocation from the cytoplasm to the nucleus.

Flutamide. Flutamide has a t_1/2 of 5 hours and therefore is given as a 250-mg dose every 8 hours. Its major metabolite, hydroxyflutamide, is biologically active; there are at least five other minor metabolites (Luo et al., 1997). The common side effects include diarrhea, breast tenderness, and nipple tenderness. Less commonly, nausea, vomiting, and hepatotoxicity occur (Wysowski and Fourcroy, 1996; Wysowski et al., 1993).

Bicalutamide. Bicalutamide (casodex, others) has a serum t_1/2 of 5-6 days and is taken once daily at a dosage of 50 mg/day when given with a GnRH agonist. Both enantiomers of bicalutamide undergo glucuronidation to inactive metabolites, and the parent compounds and metabolites are eliminated in bile and urine. The elimination t_1/2 of bicalutamide is increased in severe hepatic insufficiency and is unchanged in renal insufficiency.

Bicalutamide is well tolerated at higher doses with rare additional side effects. Daily bicalutamide (either low or high dose) is significantly inferior compared with surgical or medical castration (Bales and Chodak, 1996; Tyrrell et al., 1998). Although the ease of administration and favorable toxicity are attractive, concerns about inferior survival has limited the use of bicalutamide monotherapy.

Nilutamide. Nilutamide (niladron) is a second-generation anti-androgen with an elimination t_1/2 of 45 hours, allowing once-daily administration at 150 mg/day. Common side effects include mild nausea, alcohol intolerance (5-20%), and diminished ocular adaptation to darkness (25-40%); rarely, interstitial pneumonitis occurs (Decensi et al., 1991; Pfitzenmeyer et al., 1992). It is metabolized to five known products that are all excreted in the urine. Nilutamide appears to offer no benefit over the first-generation drugs above and has the least favorable toxicity profile (Dole and Holdsworth, 1997).

Estrogens. High estrogen levels can reduce testosterone to castrate levels in 1-2 weeks via negative feedback on the hypothalamic– pituitary axis. Estrogen also may compete with androgens for steroid hormone receptors and may thereby exert a cytotoxic effect on prostate cancer cells (Landström et al., 1994). Numerous estrogenic compounds have been tested in prostate cancer. Estrogens are associated with increased myocardial infarctions, strokes, and pulmonary emboli and increased mortality, as well as impotence, loss of libido, and lethargy. One benefit is that estrogens prevent bone loss (Scherr et al., 2002).

Most early studies on the use of estrogens used DES and were conducted between 1960 and 1975 by the Veterans Administration Cooperative Urological Research Group (VACURG). Two studies compared orchiectomy to different doses of DES to placebo (Byar, 1973; Byar and Corle, 1988). DES was as effective as orchiectomy for metastatic prostate cancer but was associated with an increase in cardiovascular events, including myocardial infarction, cerebrovascular accident, and pulmonary embolism (Bailar and Byar, 1970; Byar, 1973; de Voogt et al., 1986; Waymont et al., 1992). Due to its cardiovascular toxicity and unacceptable mortality at any dose level, DES is not indicated for prostate cancer treatment and is not available in North America for that purpose. Other synthetic estrogens have a similar associated cardiovascular toxicity to that of DES but without the efficacy. These compounds include conjugated estrogens (premarin, others), ethinyl estradiol, medroxyprogesterone acetate (provera, others), and chlorotrianisene (no longer marketed in the U.S.).

Inhibitors of Steroidogenesis. In the castrate state, AR signaling, despite low steroid levels, supports continued prostate cancer growth. AR signaling may occur due to androgens produced from nongonadal sources, AR gene mutations, or AR gene amplification. Nongonadal sources of androgens include the adrenal glands and the prostate cancer cells themselves (Figure 63–4). Androstenedione, produced by the adrenal glands, is converted to testosterone in peripheral tissues and tumors (Stanbrough et al., 2006). Intratumoral de novo androgen synthesis also may provide sufficient androgen for AR-driven cell proliferation (Montgomery et al., 2008).

Ketoconazole is an antifungal agent that interrupts the synthesis of an essential fungal membrane sterol. In an unrelated action, ketoconazole inhibits both testicular and adrenal steroidogenesis by blocking CYPs, primarily CYP17 (17α-hydroxylase). Ketoconazole is administered off label as secondary hormone therapy to reduce adrenal androgen synthesis in castration-resistant prostate cancer (Small et al., 2004). Ketoconazole causes significant diarrhea and hepatic enzyme elevations that limit its use as initial hormone therapy. Consequent poor patient adherence deters from its efficacy. Ketoconazole is given in doses of 200 mg or 400 mg three times daily. Hydrocortisone supplementation is co-administered to compensate for inhibition of adrenal steroidogenesis at the 400-mg dose level. A related compound, itraconazole, inhibits the activation of Smoothened (SMO), a component of the Hedgehog (Hh) signaling pathway (Kim et al., 2010), which is overly active in certain cancers. Thus, this class of antifungal agents may act by several distinct mechanisms and prove useful in treating other cancers.

Abiraterone is an irreversible inhibitor of both 17α-hydroxylase and C-17,20-lyase CYP17 activity, with greater potency and selectivity compared with ketoconazole. The parent compound, abiraterone acetate, is orally bioavailable and has been well tolerated in castration-resistant prostate cancer patients as secondary hormone therapy in phase I and II studies (Attard et al., 2009; Attard et al., 2008). With continuous administration, abiraterone increases ACTH levels, resulting in mineralocorticoid excess. Therefore, abiraterone acetate is administered with daily low-dose glucocorticoids, such as prednisone. Ongoing phase III trials will evaluate the efficacy and appropriate timing of abiraterone therapy for prostate cancer patients.