Goodman and Gilman Manual of Pharmacology and Therapeutics

Section VIII
Chemotherapy of Neoplastic Diseases

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

The growth of a number of cancers is hormone-dependent or regulated by hormones. Glucocorticoids are used for their antiproliferative and lympholytic properties and to ameliorate untoward responses to other treatments. Estrogen, androgen, and GnRH analogs and antagonists are effective in extending survival and delaying or preventing tumor recurrence of both breast and prostate cancer. These molecules interrupt the stimulatory axis created by systemic pools of androgens and estrogens, inhibit hormone production or hormone binding to receptors, and ultimately block expression of genes that promote tumor growth and survival.


The pharmacology, major therapeutic uses, and toxic effects of the glucocorticoids are discussed in Chapter 42. Only the applications of these drugs in the treatment of neoplastic disease are considered here.

Glucocorticoids act by binding to a specific physiological receptor that translocates to the nucleus and induces antiproliferative and apoptotic responses in sensitive cells. Because of their lympholytic effects and their ability to suppress mitosis in lymphocytes, glucocorticoids are used as cytotoxic agents in the treatment of acute leukemia in children and malignant lymphoma in children and adults. In acute lymphoblastic or undifferentiated leukemia of childhood, glucocorticoids may produce prompt clinical improvement and objective hematological remissions in ≤30% of children. However, 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. Thus, therapy is initiated with prednisoneand 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 disease, non-Hodgkin lymphoma, multiple myeloma, and chronic lymphocytic leukemia (CLL). Glucocorticoids are extremely helpful in controlling autoimmune hemolytic anemia and thrombocytopenia associated with CLL.

A number of 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, for the first few days and gradually reduced to levels of 20-40 mg/day, using the lowest possible effective dose. Side effects of these agents include glucose intolerance, immunosuppression, osteoporosis, and psychosis (seeChapter 42). Dexamethasone is the preferred agent for remission induction in multiple myeloma, usually in combination with melphalan, anthracyclines, vincristine, bortezomib, or thalidomide. 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 h 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.


Progestational agents (see Chapters 40 and 66) are used as second-line hormonal therapy for metastatic hormone-dependent breast cancer and in the management of endometrial carcinoma previously treated by surgery and radiotherapy. In addition, progestins stimulate appetite and restore a sense of well-being in cachectic patients with advanced stages of cancer and AIDS.

Medroxyprogesterone (DEPO-PROVERA, others) can be administered intramuscularly in doses of 400-1000 mg weekly. An alternative 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 1 or more times weekly. Beneficial effects have been observed in 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).


The pharmacology of the estrogens and androgens appears in Chapters 4041, and 66. These agents are of value in certain neoplastic diseases, notably those of the prostate and mammary gland, because these organs are dependent on hormones for their growth, function, and morphological integrity.

High doses of estrogen have long been recognized as effective treatment of breast cancer. Paradoxically, anti-estrogens also are effective. Thus, because of equivalent efficacy and more favorable side effects, anti-estrogens such as tamoxifen and the AIs have replaced estrogens or androgens for breast cancer. The presence of the ERs and progesterone receptors (PRs) on tumor tissue serves as a biomarker for response to hormonal therapy in breast cancer and identifies the subset of patients with a ≥60% likelihood of responding. The response rate to anti-estrogen treatment is somewhat lower in the subset of patients with tumors that are ER+ or PR+ but also positive for human epidermal growth factor receptors HER1/neu amplification. In contrast, ER-negative and PR-negative carcinomas do not respond to hormonal therapy. Responses to hormonal therapy may not be apparent clinically or by imaging for 8-12 weeks. 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.


Anti-estrogen approaches for the therapy of hormone receptor–positive breast cancer include the use of selective estrogen-receptor modulators (SERMs), selective estrogen-receptor downregulators (SERDs), and AIs (Table 63–1).

Table 63–1

Clinical Uses for Anti-Estrogen Therapy in ER+ Breast Cancer



SERMs bind to the ER and exert either estrogenic or anti-estrogenic effects, depending on the specific organ. Tamoxifen citrate is the most widely studied anti-estrogenic treatment in breast cancer. However tamoxifen also exerts estrogenic agonist effects on non-breast tissues, which influences the overall therapeutic index of the drug. Therefore, several novel anti-estrogen compounds that offer the potential for enhanced efficacy and reduced toxicity compared with tamoxifen have been developed. These novel anti-estrogens can be divided into tamoxifen analogs (e.g., toremifene [FARESTON], droloxifene, idoxifene), “fixed ring” compounds (e.g., raloxifene [EVISTA], lasofoxifene, arzoxifene, miproxifene, levormeloxifene, EM652), and the SERDs (e.g., fulvestrant [FASLODEX], SR 16234, and ZK 191703, the latter also termed “pure anti-estrogens”).


Tamoxifen was developed as an oral contraceptive but instead was found to induce ovulation and to have antiproliferative effects on estrogen-dependent breast cancer cell lines. Tamoxifen is prescribed for the prevention of breast cancer in high-risk patients, for the adjuvant therapy of early-stage breast cancer, and for the therapy of advanced breast cancer. It also prevents the development of breast cancer in women at high risk based on a strong family history, prior nonmalignant breast pathology, or inheritance of the BRCA1 or BRCA2genes.

Mechanism of Action. Tamoxifen is a competitive inhibitor of estradiol binding to the ER. There are 2 subtypes of ERs: 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. 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 (tamoxifen lowers total serum cholesterol, low-density-lipoprotein cholesterol, and lipoproteins and raises apolipoprotein A-I levels).

ADME. Tamoxifen is readily absorbed following oral administration, with peak concentrations measurable after 3-7 h 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 t1/2 of 7 days; the t1/2 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.


Figure 63–1 Tamoxifen and its metabolites.

Therapeutic Uses. The usual oral dose of tamoxifen in the U.S. is 20 mg once a day. 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, tamoxifen may be sequenced after adjuvant chemotherapy. Tamoxifen is used in premenopausal women with ER+ tumors. Alternative or additional anti-estrogen strategies in premenopausal women include oophorectomy or gonadotropin-releasing hormone analogs. The combination of tamoxifen and a GnRH 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. Tamoxifen also has shown effectiveness (a 40-50% reduction in tumor incidence) in initial trials for preventing breast cancer in women at increased risk. Tamoxifen only reduces ER+ tumors without affecting ER-negative tumors, which contribute disproportionately to breast cancer mortality.

Toxicity. The common adverse reactions to tamoxifen include vasomotor symptoms (hot flashes), atrophy of the lining of the vagina, hair loss, nausea, and vomiting. Menstrual irregularities, vaginal bleeding and discharge, pruritus vulvae, and dermatitis occur with increasing severity in postmenopausal women. 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. 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. Tamoxifen causes retinal deposits, decreased visual acuity, and cataracts, although the frequency of these changes is more common in patients on high doses of drug.

Tamoxifen Resistance. Initial or acquired resistance to tamoxifen frequently occurs. CYP2D6 is required for the activation of tamoxifen to its active metabolite endoxifen (see Figure 63–1). Polymorphisms in CYP2D6 that reduce its activity lead to lower plasma levels of the potent metabolites 4-OH tamoxifen and endoxifen, and are associated with higher risks of disease relapse and a lower incidence of hot flashes. Crosstalk 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. Interactions between PAX2 and the ER co-activator AIB-1/SRC-3 determine tamoxifen response in breast cancer cells.


Toremifene (FARESTON) is a triphenylethylene derivative of tamoxifen and has a similar pharmacological profile. Toremifene is indicated for the treatment of breast cancer in women with tumors that are ER+ or of unknown receptor status.


SERDs, also termed “pure anti-estrogens,” include fulvestrant and a host of agents in experimental trials (RU 58668, SR 16234, ZD 164384, and ZK 191703). SERDs, unlike SERMs, are devoid of any estrogen agonist activity.


Fulvestrant (FASLODEX) is approved for postmenopausal women with hormone receptor–positive metastatic breast cancer that has progressed on tamoxifen.

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; as a consequence of this ER downregulation, the drug abolishes ER-mediated transcription of estrogen-dependent genes.

ADME and Dosing. Peak plasma concentrations are reached ~7 days after intramuscular administration of fulvestrant and are maintained over 1 month. The plasma t1/2 is ~40 days. Steady-state concentrations are reached after 3-6 monthly injections. There is rapid distribution and extensive protein binding of this highly lipophilic drug. Various pathways, similar to those of steroid metabolism (oxidation, aromatic hydroxylation, and conjugation), metabolize fulvestrant. CYP3A4 appears to be the only CYP isoenzyme involved in the metabolism of fulvestrant. The putative metabolites possess no estrogenic activity, and only the 17-keto compound demonstrates a level of anti-estrogenic activity (~22% that of fulvestrant). Less than 1% of the parent drug is excreted intact in the urine.

The approved dosing for fulvestrant is 250 mg by intramuscular injection monthly. Because 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 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. Fulvestrant is at least as effective in this setting as the third-generation AI anastrozole.

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 tamoxifen-resistant patients, anastrozole and fulvestrant produce equivalent quality-of-life outcome measures.


Aromatase converts androgens to estrogens (e.g., androstenedione to estrone). Aromatase inhibitors (AIs; Figure 63–2) block this enzymatic activity, reducing estrogen production. AIs now are considered the standard of care for adjuvant treatment of postmenopausal women with hormone receptor–positive breast cancer, either as initial therapy or sequenced after tamoxifen.


Figure 63–2 Aromatase and its Inhibitors. Aromatase tri-hydroxylates the methyl group at C19, eliminating it as formate and aromatizing the A ring of the androgen substrate. Type 1 aromatase inhibitors are steroidal analogs of androstenedione that bind covalently and irreversibly to the steroid substrate site on the enzyme and are known as aromatase inactivators. Type 2 inhibitors are nonsteroidal, bind reversibly to the heme group of the enzyme, and produce reversible inhibition.

Aromatase (CYP19A1) is responsible for the conversion of adrenal androgens and gonadal androstenedione and testosterone to the estrogens, estrone (E1) and estradiol (E2), respectively (Figures 63–2 and63–3). In postmenopausal women, this conversion is the primary source of circulating estrogens, while estrogen production in premenopausal women primarily is from the ovaries. In postmenopausal women, AIs can suppress most peripheral aromatase activity, leading to profound estrogen deprivation. AIs are classified as first, second, or third generation. In addition, they are further classified as type 1 (steroidal) or type 2 (nonsteroidal) AIs according to their structure and mechanism of action. Type 1 inhibitors are steroidal analogs of androstenedione (see Figure 63–2) that bind covalently and irreversibly to the same site on the aromatase molecule. Thus, they commonly are known as aromatase inactivators. Type 2 inhibitors are nonsteroidal and bind reversibly to the heme group of the enzyme, producing reversible inhibition.


Figure 63–3 Steroid synthesis pathways. The shaded area contains the pathways used by the adrenal glands and gonads. Enzymes are labeled in green, inhibitors in red. A, aromatase; 3β, 3β,-hydroxysteroid dehydrogenase; 5α-R, 5α-reductase; 11β, 11β-hydroxylase; 17, 20, C-17, 20-lyase (also CYP17); 17α, 17α-hydroxylase (CYP17); 17βR, 17β-reductase; 18, aldosterone synthase; 21, 21-hydroxylase.


The third-generation inhibitors include the type 1 steroidal agent exemestane and the type 2 nonsteroidal imidazoles anastrozole and letrozole. Third-generation AIs are used as part of the treatment of early-stage and advanced breast cancer in postmenopausal women.


Anastrozole is a potent and selective triazole AI. Anastrozole, like letrozole, binds competitively and specifically to the heme of the CYP19. Anastrozole, 1 mg, administered once daily for 28 days, reduces total body androgen aromatization by 96.7% Anastrozole also reduces aromatization in large ER+ breast tumors.

ADME. Anastrozole is absorbed rapidly after oral administration. Steady-state is attained after 7 days of repeated dosing. Anastrozole is metabolized by N-dealkylation, hydroxylation, and glucuronidation. The main metabolite of anastrozole is a triazole. 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 t1/2 is ~50 h. The pharmacokinetics of anastrozole, which can be affected by drug interactions via the CYP system, are not altered by coadministration of tamoxifen or cimetidine.

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. In advanced breast cancer, postmenopausal women with disease progression while taking tamoxifen showed a statistically significant survival advantage with anastrozole 1 mg/day versus megestrol acetate 40 mg 4 times daily. Women with ER+ or PR+ metastatic breast cancer, anastrozole showed a statistically significant advantage over tamoxifen in median time to disease progression.

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 advanced disease, anastrozole is as well tolerated as megestrol and causes less weight gain. 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. Bisphosphonates prevent AI-induced bone loss in postmenopausal women.


Letrozole is approved for upfront adjuvant hormonal therapy in postmenopausal women with early-stage breast cancer and as treatment for advanced breast cancer. 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 more than tamoxifen in human estrogen-dependent tumors that overexpress HER1 and HER2/neu.

ADME. Letrozole is rapidly absorbed after oral administration, with 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 metabolite mainly via the kidneys with a t1/2 ~41 h.

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. Furthermore, upfront letrozole is significantly more effective than upfront tamoxifen in terms of time to tumor recurrence and odds of a primary contralateral tumor. 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. 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 the trial of extended adjuvant therapy, adverse events were hot flashes, arthralgia, myalgia, and arthritis. Letrozole has a low overall incidence of cardiovascular side effects. Compared with tamoxifen, the use of upfront letrozole results in significantly more clinical fractures. Bisphosphonates prevent letrozole-induced bone loss in postmenopausal women.


Exemestane is a more potent, orally administered analog of the natural aromatase substrate, androstenedione, and lowers estrogen levels more effectively than does its predecessor, formestane. Exemestane irreversibly inactivates aromatase and is 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.

ADME. Orally administered exemestane is rapidly absorbed from the GI tract; its absorption is increased by 40% after a high-fat meal. Exemestane has a terminal t1/2 of ~24 h. It is extensively metabolized in the liver, ultimately to inactive metabolites. One metabolite, 17-hydroxyexemestane, has weak androgenic activity that could contribute to antitumor activity. Although 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 complete 2-3 years of adjuvant tamoxifen (based on a clinical trial in women with ER+ breast cancer). In advanced breast cancer, exemestane improves time to disease progression compared with tamoxifen as first-line treatment. 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 a longer duration of survival compared with those taking megestrol acetate.

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. Compared 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.


Androgens stimulate the growth of normal and cancerous prostate cells. Androgen deprivation therapy (ADT) is the mainstay of treatment for patients with advanced prostate cancer.

Localized prostate cancer frequently is curable with surgery or radiation therapy. However, when distant metastases are present, hormone therapy is the primary treatment. ADT is the standard first-line treatment. ADT is accomplished via surgical castration (bilateral orchiectomy) or medical castration (using gonadotropin-releasing hormone [GnRH] agonists or antagonists). Other hormone therapy approaches are used in second-line treatment and include anti-androgens, estrogens, and inhibitors of steroidogenesis. ADT is not a curative treatment. ADT can alleviate cancer-related symptoms and normalize serum prostate-specific antigen (PSA) in >90% of patients. ADT provides important quality-of-life benefits, including reduction of bone pain and reduction of rates of pathological fracture, spinal cord compression, and ureteral obstruction. It also prolongs survival.

The duration of response to ADT for patients with metastatic disease is variable but typically lasts 14-20 months. Disease progression despite ADT signifies a castration-resistant state. 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 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.

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. ADT is associated with an increased risk of diabetes and coronary heart disease. However, retrospective analyses have not revealed a compelling increase in cardiovascular mortality due to GnRH agonists. Skeletal-related events due to ADT may be mitigated by bisphosphonate therapy, such as zoledronic acid (ZOMETA) or inhibitors of osteoclast activation, such as denosumab. Anti-androgens, when compared with GnRH agonists, cause more gynecomastia, mastodynia, and hepatotoxicity but less vasomotor flashing, and loss of BMD. Estrogens cause a hypercoagulable state and increase cardiovascular mortality in prostate cancer patients and are no longer standard treatment options.


The most common form of ADT involves chemical suppression of the pituitary gland with GnRH agonists. Synthetic GnRH analogs (Table 63–2) have greater receptor affinity and reduced susceptibility to enzymatic degradation than the naturally occurring GnRH molecule and are 100-fold more potent. Several long-acting preparations are available in doses that are approved for 3-, 4-, and 6-month administrations.

Table 63–2

Structures of GnRH and Decapeptide GnRH Analogs


GnRH agonists bind to GnRH receptors on pituitary gonadotropin-producing cells, causing an initial release of both LH and FSH and a subsequent increase in testosterone production from testicular Leydig cells. After ~1 week of therapy, GnRH receptors are downregulated on the gonadotropin-producing cells, causing a decline in the pituitary response. The fall in serum LH leads to a decrease in testosterone production to castrate levels within 3-4 weeks of the first treatment. Subsequent treatments maintain testosterone at castrate levels.

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. 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. Besides avoidance of the initial flare, GnRH antagonist therapy offers no apparent advantage compared with GnRH agonists. The GnRH antagonist, degarelix, is not associated with systemic allergic reactions and is approved for prostate cancer in the U.S.

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. Several trials suggest a benefit for CAB in 5-year survival but not at earlier time points. Toxicity and costs associated with CAB are higher than with ADT alone.


Anti-androgens bind to ARs and competitively inhibit the binding of testosterone and dihydrotestosterone. Unlike castration, anti-androgen therapy by itself does not decrease LH production; therefore, testosterone levels are normal or increased. Men treated with anti-androgen monotherapy maintain some degree of potency and libido and do not have the same spectrum of side effects seen with castration. Currently, anti-androgen monotherapy is not indicated as first-line treatment for patients with advanced prostate cancer. Anti-androgens most commonly are used in clinical practice as secondary hormone therapy or in CAB.

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.

AVAILABLE ANTI-ANDROGENS. Anti-androgens are classified as steroidal, including cyproterone and megestrol, or nonsteroidal, including flutamide, bicalutamide (CASODEX, others), and nilutamide (NILANDRON). Cyproterone is associated with liver toxicity and has inferior efficacy compared with other forms of ADT. Cyproterone is not available in the U.S. Neither bicalutamide nor flutamide is approved as monotherapy at any dose for treatment of prostate cancer in the U.S.

Flutamide. Flutamide is given as a 250-mg dose every 8 h. It has a t1/2 of 5 h; its major metabolite, hydroxyflutamide, is biologically active. Common side effects include diarrhea, breast tenderness, and nipple tenderness. Less commonly, nausea, vomiting, and hepatotoxicity occur.

Bicalutamide. Bicalutamide (CASODEX, others) is taken once daily at a dosage of 50 mg/day when given with a GnRH agonist; it has a t1/2 of 5-6 days. Both enantiomers of bicalutamide undergo glucuronidation to inactive metabolites, and the parent compounds and metabolites are eliminated in bile and urine. The elimination t1/2 of bicalutamide is increased in severe hepatic insufficiency and is unchanged in renal insufficiency. Bicalutamide is well tolerated at higher doses. Daily bicalutamide is significantly inferior compared with surgical or medical castration.

Nilutamide. Nilutamide (NILANDRON) is a second-generation anti-androgen that is taken once-daily administration at 150 mg/day. It has an elimination t1/2 of 45 h and is metabolized to 5 products that are all excreted in the urine. Common side effects include mild nausea, alcohol intolerance (5-20%), and diminished ocular adaptation to darkness (25-40%); rarely, interstitial pneumonitis occurs. Nilutamide appears to offer no benefit over the first-generation drugs above and has the least favorable toxicity profile.


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. Estrogens are associated with increased myocardial infarctions, strokes, and pulmonary emboli and increased mortality, as well as impotence, and lethargy. One benefit is that estrogens prevent bone loss.


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 (see Figure 63–3). Androstenedione, produced by the adrenal glands, is converted to testosterone in peripheral tissues and tumors. Intratumoral de novo androgen synthesis also may provide sufficient androgen for AR-driven cell proliferation. Thus, inhibitors of androgen synthesis may be useful secondary therapy in reducing AR signaling.

Ketoconazole. Ketoconazole is an antifungal agent that also 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. Diarrhea and hepatic enzyme elevations limit its use as initial hormone therapy; consequent poor patient compliance reduces its efficacy. Ketoconazole is given in doses of 200 mg or 400 mg 3 times daily. Hydrocortisone (400-mg dose) is coadministered to compensate for inhibition of adrenal steroidogenesis. A related compound, itraconazole, inhibits the activation of Smoothened (SMO), a component of the Hedgehog (Hh) signaling pathway, 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. Abiraterone is an irreversible inhibitor of 17α-hydroxylase and C-17,20-lyase (CYP17) activity, with greater potency and selectivity than ketoconazole. The prodrug abiraterone acetate (ZYTIGA) is approved for use with prednisone in metastatic castration-resistant prostate cancer. With continuous administration, abiraterone increases ACTH levels, resulting in mineralocorticoid excess. Recommended oral dose of abiraterone acetate is 1000 mg administered once daily (on an empty stomach) with 5 mg prednisone administered twice daily. Side effects include joint swelling, hypokalemia, hot flush, diarrhea, cough, hypertension, arrhythmia, urinary frequency, dyspepsia, and upper respiratory tract infection.