■ High doses of methotrexate coupled with leucovorin rescue can be used to treat methotrexate-resistant tumors. This technique can be potentially harmful in that failure to give sufficient leucovorin at the right time can be lethal.
■ Cytarabine, a pyrimidine analog, undergoes intracellular activation followed by incorporation into DNA, where it acts to inhibit DNA synthesis.
■ Fluorouracil, a uracil analog, undergoes intracellular activation, after which it inhibits thymidylate synthetase, thereby depriving cells of thymidylate needed to make DNA.
■ Antitumor antibiotics are used to treat cancer, not infections.
■ Antitumor antibiotics fall into two major groups: anthra- cyclines (which damage the heart) and nonanthracyclines (which don’t).
■ Doxorubicin is an anthracycline-type antitumor antibiotic.
To reduce the risk of heart failure, the cumulative lifetime dose should be kept below 550 mg/m2. The risk can be further reduced with dexrazoxane, a drug that helps protect the heart from doxorubicin.
■ Doxorubicin is a planar molecule that intercalates DNA, thereby distorting DNA structure. As a result, DNA
polymerase and RNA polymerase are unable to use DNA as a template, and hence synthesis of DNA, RNA, and proteins is disrupted. Doxorubicin also disrupts the function of topoisomerase II, thereby causing strand breakage. This may be the primary mechanism of cell kill.
■ Vincristine and vinblastine block assembly of the micro- tubules that move chromosomes during cell division.
Accordingly, the drugs are M-phase specific.
■ Vincristine is toxic to peripheral nerves, but does not significantly suppress bone marrow function. Because it spares bone marrow, vincristine can be safely combined with drugs that suppress bone marrow.
■ In contrast to vincristine, vinblastine causes significant bone marrow suppression, but is relatively harmless to peripheral nerves.
■ Asparaginase converts asparagine into aspartic acid and thereby deprives cells of asparagine needed to make proteins. Cytotoxicity is limited primarily to leukemic lymphoblasts because these cells are unable to manufacture their own asparagine as normal cells do.
Please visit http://evolve.elsevier.com/Lehne for chapter- specific NCLEX® examination review questions.
103 Anticancer Drugs II: Hormonal
Agents, Targeted Drugs, and Other Noncytotoxic Anticancer Drugs
DRUGS FOR BREAST CANCER, p. 1246 Antiestrogens, p. 1246
Tamoxifen, p. 1246 Toremifene, p. 1249 Fulvestrant, p. 1249 Aromatase Inhibitors, p. 1249
Anastrozole, p. 1249 Letrozole, p. 1250 Exemestane, p. 1250 Trastuzumab, p. 1250
Ado-Trastuzumab Emtansine, p. 1251 Pertuzumab, p. 1251
Lapatinib, p. 1251
Palbociclib and Ribociclib, p. 1252
Cytotoxic Drugs (Chemotherapy), p. 1252 Denosumab and Bisphosphonates for
Skeletal-Related Events, p. 1252
Zoledronate and Other Bisphosphonates, p. 1252 Denosumab, p. 1253
DRUGS FOR PROSTATE CANCER, p. 1253 Androgen Deprivation Therapy, p. 1254
Gonadotropin-Releasing Hormone Agonists, p. 1254
Gonadotropin-Releasing Hormone Antagonists, p. 1255
Androgen Receptor Blockers, p. 1256 Abiraterone, a CYP17 Inhibitor, p. 1256 Ketoconazole, p. 1257
Other Drugs for Prostate Cancer, p. 1257 Sipuleucel-T, p. 1257
Cytotoxic Drugs, p. 1257
TARGETED ANTICANCER DRUGS, p. 1258
Kinase Inhibitors, p. 1258
EGFR Tyrosine Kinase Inhibitors, p. 1258 BCR-ABL Tyrosine Kinase Inhibitors, p. 1262 Multi-Tyrosine Kinase Inhibitors, p. 1263 mTOR Kinase Inhibitors, p. 1264
BRAF V600E Kinase Inhibitors, p. 1264 ALK Inhibitors, p. 1264
Other Targeted Drugs, p. 1264 CD-Directed Antibodies, p. 1264
Brentuximab Vedotin, an Antibody-Drug Conjugate, p. 1265
Angiogenesis Inhibitors, p. 1266 Proteasome Inhibitors, p. 1267
Histone Deacetylase Inhibitors, p. 1267 Ipilimumab, p. 1267
IMMUNOSTIMULANTS, p. 1267 Interferon Alfa-2B, p. 1267
Aldesleukin (Interleukin-2), p. 1268 BCG Vaccine, p. 1268
OTHER NONCYTOTOXIC ANTICANCER DRUGS, p. 1268
Glucocorticoids, p. 1268 Retinoids, p. 1269
Alitretinoin, p. 1269 Bexarotene, p. 1269 Tretinoin, p. 1269 Progestins, p. 1269 Key Points, p. 1270
In addition, many of the drugs discussed in this chapter lack the serious toxicities associated with cytotoxic agents, including bone marrow suppression, stomatitis, alopecia, and severe nausea and vomiting. Nonetheless, most of these drugs have severe toxicities of their own, and many are included in the list of drugs identified as hazardous by the National Institute for Occupational Safety and Health Hazardous (NIOSH).
NIOSH requires special handling of drugs identified as hazard- ous. See Chapter 3, Table 3.1, for administration and handling In this chapter, we continue our discussion of anticancer agents,
focusing on two large groups of drugs: hormonal agents and targeted drugs. The hormonal agents, used primarily for breast cancer and prostate cancer, mimic or suppress the actions of endogenous hormones. The so-called targeted drugs bind with specific molecular targets on cancer cells and thereby suppress tumor growth and promote cell death. Unlike the cytotoxic agents discussed in Chapter 102, many of which are cell-cycle phase specific, the drugs addressed here lack phase specificity.
postmenopausal patients, aromatase inhibitors are more effec- tive, both in the metastatic and adjuvant settings. There is a wealth of data showing that adjuvant hormonal therapy can reduce tumor recurrence and prolong life.
In addition to chemotherapy and hormonal therapy, six other drugs—trastuzumab [Herceptin], ado-trastuzumab emtansine [Kadcyla], pertuzumab [Perjeta], lapatinib [Tykerb], palbociclib [Ibrance], and ribociclib [Kisquali]—can be used for adjuvant treatment. Trastuzumab, pertuzumab, and ado-trastuzumab emtansine block receptors known as human epidermal growth factor receptor 2 (HER2). In addition, when ado-trastuzumab emtansine binds with HER2 receptors, it releases cytotoxic catabolites that cause cell apoptosis. Lapatinib inhibits two enzymes, known as HER2 tyrosine kinase and epidermal growth factor receptor (EGFR) tyrosine kinase. These drugs are indicated only for cancers that are HER2 positive. Palbociclib and ribociclib differ from the others, as they are indicated for HER2-negative cancer. These drugs work by inhibition of cyclin-dependent kinases 4 and 6, which leads to a decrease in malignant cellular growth. Lastly, patients may take deno- sumab [Xgeva] or zoledronate [Zometa] to minimize hyper- calcemia (caused by bone metastases) and fractures (caused by bone metastases as well as hormonal therapy).
What about breast cancer prevention? Currently, two drugs are approved for preventing breast cancer in women at high risk. Both drugs are selective estrogen receptor modulators, or SERMS. One of the drugs—raloxifene [Evista]—is approved only for postmenopausal women. The other drug—tamoxifen [Soltamox]—is approved for premenopausal and postmeno- pausal women. In clinical trials, these drugs reduced the risk of breast cancer by about 50%. Raloxifene is discussed in Chapter 75. Tamoxifen is discussed next. Another drug—exemestane [Aromasin] (discussed later in this chapter)—can also prevent breast cancer, but it is not yet approved for this use.
guidelines. Nurses should take proper precautions when handling the medications listed in the following box.
Safety Alert
HAZARDOUS DRUGS REQUIRING SPECIAL HANDLING
Ado-trastuzumab emtansine Afatinib
Anastrozole Axitinib Bortezomib Bosutinib Brentuximab Cabozantinib Carfilzomib Crizotinib Dabrafenib Degarelix Docetaxel Eribulin Erlotinib Estramustine Everolimus Exemestane Flutamide Fulvestrant
Goserelin Histrelin Imatinib Ixazomib Letrozole Leuprolide Megestrol Nilotinib Pazopanib Pertuzumab Ponatinib Regorafenib Sorafenib Sunitinib Tamoxifen Toremifene Trametinib Vandetanib Vemurafenib
DRUGS FOR BREAST CANCER
Breast cancer is second only to skin cancer as the most common cancer among women in the United States. In 2017, an estimated 289,120 new cases were diagnosed and 40,610 were expected to be fatal. Fortunately, this death rate has been decreasing, thanks to earlier detection and improved treatment.
Principal treatment modalities are surgery, radiation, cytotoxic drugs (chemotherapy), and hormonal drugs. Surgery and radiation are considered primary therapy; chemotherapy and hormonal therapy are used as adjuvants. For a woman with early breast cancer, treatment typically consists of surgery (using total mastectomy or partial mastectomy [lumpectomy]) followed by local radiation. After that, chemotherapy is used to kill cells left behind after surgery and radiation and to kill cells that may have metastasized to other sites. Finally, hormonal agents are taken for several years to reduce recurrence. Increas- ingly, chemotherapy is used before surgery—so-called neoad- juvant therapy—to shrink large tumors and thereby permit lumpectomy in women who would otherwise require mastec- tomy. Drugs for adjuvant therapy are shown in Table 103.1.
Hormonal agents for breast cancer fall into two major groups:
antiestrogens (e.g., tamoxifen [Soltamox]) and aromatase inhibitors (e.g., anastrozole [Arimidex]). Antiestrogens block receptors for estrogen, whereas aromatase inhibitors block estrogen biosynthesis. In both cases, tumor cells are deprived of the estrogen they need for growth. However, there is a caveat: For these drugs to work, tumor cells must have estrogen receptors (ERs). Fortunately, the majority of breast cancers are ER positive. For years, tamoxifen had been the hormonal agent of choice. However, recent data have shown that, in
Safety Alert
HEALTH RISKS WITH BREAST CANCER PREVENTION DRUGS
Selective estrogen receptor modulators pose a risk of thrombosis, and tamoxifen also poses a risk of endometrial cancer.
ANTIESTROGENS
Antiestrogens are drugs that block ERs, and hence work only against cells that are ER positive. Benefits derive from depriving tumor cells of the growth-promoting influence of estrogen.
Three antiestrogens—tamoxifen, toremifene, and fulvestrant—
are approved for adjuvant treatment. Of these, tamoxifen is by far the most widely used.
Tamoxifen
Tamoxifen [Soltamox] is considered the gold standard for endocrine treatment of breast cancer. The drug is approved for treating established disease and for primary prevention in women at high risk. As discussed under Mechanism of Action in Breast Cancer, tamoxifen is a prodrug that must be converted to active metabolites.
Generic Name Brand Name Route Mechanism Indications Major Adverse Effects HORMONAL THERAPIES
Antiestrogens
Tamoxifen Soltamox PO Blockade of estrogen
receptors
ER-positive breast cancer in pre- and
postmenopausal women
Increased risk of endometrial cancer and thrombosis Hot flashes, fluid retention,
vaginal discharge, nausea, vomiting, and menstrual irregularities
Toremifene Fareston PO Blockade of estrogen
receptors
ER-positive breast cancer in postmenopausal women only
Fulvestrant Faslodex IM Blockade of estrogen
receptors
ER-positive breast cancer in postmenopausal women only Aromatase Inhibitors
Anastrozole Arimidex PO Inhibition of estrogen
synthesis
ER-positive breast cancer in postmenopausal women only
Musculoskeletal pain, osteoporosis and related fractures
Letrozole Femara PO
Exemestane Aromasin PO
OTHER DRUGS FOR BREAST CANCER Anti-HER2 Antibodies
Trastuzumab Herceptin IV Blockade of HER2
receptors
HER2-positive breast cancer in pre- and postmenopausal women
Cardiotoxicity and hypersensitivity reactions
Ado-trastuzumab Kadcyla IV Blockade of HER2
receptors
HER2-positive breast cancer
Hepatotoxicity, cardiotoxicity, neurotoxicity
Pertuzumab Perjeta IV Blockade of HER2
receptors
HER2-positive breast cancer
Cardiotoxicity, hypersensitivity reactions
Kinase Inhibitors
Lapatinib Tykerb PO Inhibits HER2 tyrosine
kinase and EGFR tyrosine kinase
HER2-positive breast cancer in pre- and postmenopausal women
Diarrhea, hepatotoxicity, cardiotoxicity, interstitial lung disease
Palbociclib Ibrance PO Inhibits cyclin-dependent
kinase 4 and 6
ER-positive, HER2- negative breast cancer in pre- and
postmenopausal women
Bone marrow suppression, pulmonary embolism, peripheral neuropathy
Ribociclib Kisqali PO Inhibits cyclin-dependent
kinase 4 and 6
ER-positive, HER2- negative breast cancer in pre- and
postmenopausal women
Severe hypokalemia, neutropenia, hepatotoxicity
Cytotoxic Drugs (Representative Agents) Doxorubicin plus
cyclophosphamide
Adriamycin;
Cytoxan, Neosar
IV Direct cell kill by DNA intercalation, topoisomerase II inhibition, and DNA alkylation
Breast cancer in all women, regardless of ER, HER2, or menopausal status
Together, these drugs can cause cardiotoxicity, bone marrow suppression, alopecia, oral and GI ulceration, and hemorrhagic cystitis
Paclitaxel Taxol ,
Abraxane
IV Direct cell kill by mitotic arrest
Breast cancer in all women, regardless of ER, HER2, or menopausal status
Bone marrow suppression, peripheral neuropathy, alopecia, cardiotoxicity, muscle and joint pain Severe hypersensitivity
reactions with Taxol , but not Abraxane
Eribulin Halaven IV Direct cell kill by
mitotic arrest
Breast cancer in all women, regardless of ER, HER2, or menopausal status
Bone marrow suppression, peripheral neuropathy TABLE 103.1 ■ Drugs for Adjuvant Therapy of Breast Cancer
Continued
Generic Name Brand Name Route Mechanism Indications Major Adverse Effects Drugs to Delay Skeletal Events
Zoledronate Zometaa IV Inhibits osteoclast
function
Hypercalcemia of malignancy, prevention of malignancy-related skeletal events
Kidney damage, osteonecrosis of the jaw, rare atrial fibrillation
Denosumab Xgevab SubQ Inhibits osteoclast
function and production
Hypercalcemia of malignancy, prevention of malignancy-related skeletal events
Hypocalcemia, serious infections, skin reactions, osteonecrosis of the jaw TABLE 103.1 ■ Drugs for Adjuvant Therapy of Breast Cancer—cont’d
EGFR, Epidermal growth factor receptor; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IM, intramuscular; IV, intravenous; PO, oral; SubQ, subcutaneous.
aZoledronate is also available as Reclast for treating osteoporosis and Paget’s disease.
bDenosumab is also available as Prolia for treating postmenopausal osteoporosis.
Overview of Actions
Tamoxifen blocks ERs in some tissues and activates them in others. Receptor blockade underlies benefits in breast cancer but also underlies some adverse effects (especially hot flashes).
Receptor activation leads to other beneficial effects (increased bone mineral density, reduction of low-density lipoprotein cholesterol, elevation of high-density lipoprotein cholesterol) as well as certain adverse effects (endometrial cancer and blood clots). Because tamoxifen can cause receptor activation as well as blockade, the drug is often classified as a SERM.
Mechanism of Action in Breast Cancer
Tamoxifen is a prodrug that undergoes hepatic conversion to active metabolites. These metabolites then block ERs on breast cancer cells and thereby prevent receptor activation by estradiol, the principal endogenous estrogen. Estrogen acts on tumor cells to stimulate growth and proliferation. Hence, in the absence of estradiol’s influence, the rate of tumor cell proliferation declines. Tumors regress in size as the rate of cell death outpaces new cell production. Obviously, if treatment is to be effective, target cells must be ER positive.
Use for Treatment of Breast Cancer
Tamoxifen has two treatment applications: (1) as adjuvant therapy to suppress growth of residual cancer cells following surgery and (2) treatment of metastatic disease. Efficacy as adjuvant therapy has been evaluated in 55 randomized trials involving more than 37,000 women. Treatment for 1, 2, and 5 years decreased tumor recurrence by 21%, 29%, and 47%, respectively. The ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial, first published in 2013, revealed that continuing tamoxifen for 10 years can almost halve breast cancer mortality in the second decade after diagnosis. Benefits were limited almost entirely to women with ER-positive cancer. Tamoxi- fen can be used in both premenopausal and postmenopausal women.
Use for Prevention of Breast Cancer
Tamoxifen is approved for reducing the development of breast cancer in healthy women at high risk. Approval was based on results of the Breast Cancer Prevention Trial, which enrolled 13,388 otherwise healthy women who had risk factors for breast cancer (e.g., age older than 60, family history of breast cancer, failure to give birth before age 30, a breast biopsy
showing atypical hyperplasia). Half of the participants received tamoxifen (20 mg PO daily) and half received placebo. After an average follow-up time of 4 years, daily tamoxifen reduced the incidence of breast cancer by 44%. Unfortunately, tamoxifen increased the incidence of endometrial cancer, pulmonary embolism, and deep vein thrombosis. Hence, women considering tamoxifen for chemoprevention must carefully weigh the benefits of treatment (reduced risk of breast cancer) against the risks (increased risk of endometrial cancer and thrombo- embolic events). According to guidelines issued in 2013 by the U.S. Preventive Services Task Force (USPSTF), tamoxifen chemoprevention is appropriate only for women at high risk and not for women at lower risk.
To help determine who is at high risk for breast cancer, the National Cancer Institute has created an Internet-based Breast Cancer Risk Assessment Tool. You can access the tool at www.cancer.gov/bcrisktool.
Pharmacokinetics
Tamoxifen is readily absorbed following oral administration.
In the liver, CYP2D6 (the 2D6 isoenzyme of cytochrome P450) converts tamoxifen into two active metabolites: 4-hydroxy- N-desmethyltamoxifen (endoxifen) and 4-hydroxytamoxifen.
The half-lives of tamoxifen and its metabolites range from 1 to 2 weeks. Because clearance is slow, once-daily dosing is adequate. When treatment is stopped, tamoxifen and its metabolites can be detected in serum for weeks.
Not surprisingly, benefits of tamoxifen are greatly reduced in women with an inherited deficiency in the gene that codes for CYP2D6. In one study, the cancer recurrence rate in poor metabolizers was 9.5 times higher than in good metaboliz- ers. Between 8% and 10% of Caucasian women have gene variants that prevent them from converting tamoxifen to its active metabolites. However, at this time, the U.S. Food and Drug Administration (FDA) neither requires nor recommends testing for variants in the CYP2D6 gene, although a test kit is available.
Adverse Effects
The most common adverse effects are hot flashes, fluid retention, vaginal discharge, nausea, vomiting, and menstrual irregularities.
In women with bone metastases, tamoxifen may cause transient hypercalcemia and a flare in bone pain. Because of its estrogen agonist actions, tamoxifen poses a small risk of thromboembolic
events, including deep vein thrombosis, pulmonary embolism, and stroke.
Perhaps the biggest concern is endometrial cancer. Tamoxi- fen acts as an estrogen agonist at receptors in the uterus, causing proliferation of endometrial tissue. Proliferation initially results in endometrial hyperplasia and may eventually lead to endo- metrial cancer. In women taking tamoxifen to treat breast cancer, the benefits clearly outweigh this risk. However, in women taking the drug to prevent breast cancer, the risk/benefit balance is less obvious. In postmenopausal women, endometrial cancer is usually caught early, due to abnormal menstrual bleeding.
Tamoxifen can harm the developing fetus, and hence is classified in FDA Pregnancy Risk Category D.a Accordingly, women using the drug should avoid getting pregnant.
Interaction With CYP2D6 Inhibitors
Inhibitors of CYP2D6 can prevent activation of tamoxifen and can thereby negate the benefits of treatment. Put another way, when tamoxifen is combined with a CYP2D6 inhibitor, the risk of breast cancer recurrence is greater than when tamoxifen is used alone. Accordingly, women using tamoxifen should avoid strong CYP2D6 inhibitors. Important among these are fluoxetine [Prozac], paroxetine [Paxil, Pexeva], and sertraline [Zoloft]—selective serotonin reuptake inhibitors (SSRIs) taken by many women to suppress tamoxifen-induced hot flashes.
Fortunately, alternatives with less effect on CYP2D6 are avail- able. Among these are escitalopram [Lexapro, Cipralex ] (an SSRI) and venlafaxine [Effexor XR] (a serotonin/norepinephrine reuptake inhibitor).
Dosage and Administration
The usual dosage for adjuvant treatment of breast cancer is 20 mg PO once a day. Larger doses do not increase benefits. In most cases, treatment should continue for 5 years. The dosage for prevention of breast cancer in high-risk women is 20 mg PO daily for 5 to 10 years. There are no data to indicate that extending treatment beyond 10 years increases benefits.
Toremifene
Actions and Use
Toremifene [Fareston] is an antiestrogen indicated for metastatic breast cancer in postmenopausal women with ER-positive tumors or tumors for which ER status is unknown. The drug is a structural analog of tamoxifen and shares most of that drug’s properties. Like tamoxifen, toremifene is a SERM with antiestrogenic actions in some tissues and estrogenic actions in others. In women with breast cancer, toremifene blocks ERs on tumor cells, thereby depriving them of estrogen’s growth-promoting effects. In clinical trials, toremifene was about as effective as tamoxifen: With both drugs, the response rate in metastatic disease was about 20%, and median survival time was about 30 months. In a crossover study, most patients who failed to respond to tamoxifen also failed to respond to toremifene. The recommended dosage is 60 mg PO once a day.
Pharmacokinetics
Toremifene is well absorbed following oral administration. Plasma levels peak in 3 hours. The drug undergoes extensive hepatic metabolism, primarily by CYP3A4 (the 3A4 isoenzyme of cytochrome P450). Metabolites are excreted in the feces. The half-life is prolonged (about 5 days) owing to enterohepatic recirculation. As with tamoxifen, drugs that induce CYP3A4 will reduce toremifene levels, and drugs that inhibit the enzyme will raise toremifene levels.
Adverse Effects
Adverse effects are like those of tamoxifen. Hot flashes are most common.
Other common reactions are sweating, nausea, and vaginal discharge. Patients
may also experience dizziness, vomiting, and vaginal bleeding. Hypercal- cemia may occur in women with bone metastases. There is a small risk of thromboembolic events. Cataracts and elevation of liver enzymes have been reported.
Toremifene prolongs the QT interval and thereby poses a risk of potentially fatal dysrhythmias. To reduce risk, toremifene should be avoided in patients with hypokalemia, hypomagnesemia, or pre-existing QT prolongation, and in those taking other QT drugs.
Like tamoxifen, toremifene activates ERs in the uterus. As a result, the drug can promote uterine hyperplasia and uterine cancer.
Fulvestrant
Actions and Use
Fulvestrant [Faslodex] is an antiestrogen indicated for metastatic ER-positive breast cancer in postmenopausal women. Unlike tamoxifen and toremifene, which block some ERs and activate others, fulvestrant is a pure estrogen receptor antagonist. As with other antiestrogens, benefits derive from depriving breast cancer cells of required hormonal stimulation.
Pharmacokinetics
Plasma levels peak about 7 days after IM injection and remain therapeutic for at least 1 month. Steady-state levels are reached after three to six monthly doses. The drug undergoes hepatic metabolism followed by renal excretion.
The apparent half-life is 40 days.
Adverse Effects and Drug Interactions
Fulvestrant is generally well tolerated. The most common adverse effects are GI disturbances, hot flashes, headache, pharyngitis, and bone and back pain.
Thromboembolism can occur but is uncommon. In contrast to tamoxifen, fulvestrant poses no risk of endometrial cancer. In clinical trials, injection-site reactions (inflammation; mild, transient pain) developed in 7% of women receiving a single 5-mL injection and in 27% of women receiving two 2.5-mL injections. Fulvestrant has no known drug interactions.
Preparations, Dosage, and Administration
Fulvestrant is supplied in solution (50 mg/mL) for administration by slow IM injection (1 to 2 minutes). The dosage is 500 mg on days 1, 15, and 29, followed by 500 mg once a month thereafter. Each dose is administered as two 5-mL injections, one into each buttock.
AROMATASE INHIBITORS
The aromatase inhibitors are used to treat ER-positive breast cancer in postmenopausal women. These drugs block the production of estrogen from androgenic precursors and thereby deprive breast cancer cells of the estrogen they need for growth.
Aromatase inhibitors do not block production of estrogen by the ovaries, and hence are of little benefit in premenopausal women. In fact, aromatase inhibitors may cause a compensatory rise in estradiol in premenopausal patients. Aromatase inhibitors are more effective than tamoxifen and have a different toxicity profile. Unlike tamoxifen, aromatase inhibitors pose no risk of endometrial cancer and only rarely cause thromboembolism.
However, they can increase the risk of fractures and have been associated with moderate to severe myalgias.
Anastrozole
Mechanism, Use, and Dosage
Anastrozole [Arimidex] is approved for first-line oral therapy of postmenopausal women with early or advanced ER-positive breast cancer. The drug works by depriving breast cancer cells of estrogen. In postmenopausal women, the major source of estrogen is adrenal androgens, which are converted into estrogen by the enzyme aromatase in peripheral tissues. Anastrozole inhibits aromatase and thereby reduces estrogen production.
With regular use, the drug lowers estrogen to undetectable
aAs of 2020, the FDA will no longer use Pregnancy Risk Categories. Please refer to Chapter 9 for more information.
poses no risk of endometrial cancer. However, it can cause osteoporosis, fractures and, rarely, thromboembolism. Osteoporosis can be managed with denosumab [Prolia] or a bisphosphonate (e.g., zoledronate [Zometa]). No significant drug interactions have been reported.
Exemestane
Exemestane [Aromasin] is indicated for oral therapy of (1) advanced ER-positive breast cancer in postmenopausal women whose disease has progressed despite treatment with tamoxifen and (2) early ER-positive breast cancer in post- menopausal women who have received 2 to 3 years of tamoxifen therapy and then are switched to adjuvant exemestane to complete a 5-year course of treatment. Like anastrozole, exemestane inhibits aromatase and thereby reduces estrogen levels. A dosage of 25 mg once daily (administered after a meal) reduces circulating estrogen by 85% to 95%. In the absence of sufficient estrogen, estrogen-dependent tumors cannot thrive. In clinical trials, the objective response rate was about 25%.
In addition to treating breast cancer, exemestane can be effective for breast cancer prevention, as shown in the Mammary Prevention 3 trial. The trial enrolled 4560 postmenopausal women at high risk for breast cancer and randomized them to receive exemestane or placebo. After a median follow-up of 35 months, the incidence of invasive breast cancer was 65% lower in the exemestane group. If exemestane is approved for breast cancer prevention, it will become an attractive alternative to raloxifene and tamoxifen.
Exemestane is rapidly absorbed following oral dosing and is widely distributed to tissues. In the liver, the drug undergoes extensive metabolism, mainly by CYP3A4. Excretion is via the urine and feces. Its half-life is about 24 hours.
Exemestane is generally well tolerated. The most common adverse effects are fatigue, nausea, hot flashes, depression, and weight gain. Like anastrozole and letrozole, exemestane often causes musculoskeletal pain. Increased risk of osteoporosis and fractures is a concern. Women at high risk of osteoporosis can be treated with denosumab [Prolia] or a bisphosphonate (e.g., zoledronate [Zometa]).
Drugs that induce CYP3A4 (e.g., phenytoin, phenobarbital, rifampin, St.
John’s wort) can cause a significant drop in exemestane levels. Accordingly, if these drugs are combined, the exemestane dosage may need to increase.
TRASTUZUMAB
Actions and Use
Trastuzumab [Herceptin] is a monoclonal antibody originally approved for HER2-positive metastatic breast cancer and for adjuvant therapy of HER2-positive breast cancer and HER2- positive metastatic gastric cancer. Discussion here is limited to breast cancer.
Trastuzumab is effective only against tumors that overexpress human epidermal growth factor receptor 2, a transmembrane receptor that helps regulate cell growth. Trastuzumab binds with HER2 and thereby (1) inhibits cell proliferation and (2) promotes antibody-dependent cell death. Between 25% and 30% of metastatic breast cancers produce excessive HER2.
High numbers of HER2 receptors are associated with unusually aggressive tumor growth. For treatment of breast cancer, trastuzumab may be used (1) alone in women who failed to respond to prior chemotherapy, (2) in combination with paclitaxel as first-line therapy, and (3) for adjuvant treatment as part of a regimen containing doxorubicin, cyclophosphamide, and paclitaxel.
Adverse Effects
The principal concern with trastuzumab is cardiotoxicity, manifesting as ventricular dysfunction and congestive heart failure. In clinical trials, the incidence of symptomatic heart failure was 7% with trastuzumab alone and 28% when trastu- zumab was combined with doxorubicin, a drug with prominent cardiotoxic actions. Combining trastuzumab with paclitaxel can also result in cardiac damage. Because of cardiotoxicity, levels. In women with estrogen-dependent cancer, estrogen
deprivation can arrest tumor growth and may cause outright cell death. In clinical trials, anastrozole was not effective in women with ER-negative tumors or in women who did not respond initially to tamoxifen. The recommended dosage is 1 mg PO once a day. Treatment duration typically ranges from 2 to 5 years. Anastrozole may be used as initial therapy or as a follow-up to therapy with tamoxifen.
Adverse Effects
Anastrozole is generally well tolerated. In clinical trials, about 5% of patients withdrew because of adverse effects. At a daily dose of 1 mg, the most common adverse effects are musculo- skeletal pain, asthenia, headache, and menopausal symptoms, including hot flashes, vaginal dryness, and GI disturbances.
Other reactions include anorexia, vomiting, diarrhea, constipa- tion, dyspnea, peripheral edema, vaginal hemorrhage, and hypertension.
Up to 50% of women experience musculoskeletal pain, often described with the statement, “Every bone in my body hurts.” The cause may be estrogen deprivation. Persistent or severe pain drives about 5% of users to discontinue treatment.
For women who choose to continue anastrozole, pain can often be managed with a mild analgesic (e.g., acetaminophen, ibuprofen). High-dose vitamin D may help too.
Estrogen depletion increases the risk of osteoporosis and related fractures. To reduce bone loss, women should ensure adequate intake of calcium and vitamin D. Women at high risk should take a bisphosphonate (e.g., zoledronate [Zometa]) or denosumab [Prolia].
Comparison With Tamoxifen
As shown in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, which enrolled postmenopausal women with early breast cancer, anastrozole is more effective than tamoxifen and causes fewer adverse effects. After a median follow-up of 5.6 years, cancer recurred in 13% fewer of the women who took anastrozole, and the time to cancer recurrence was longer.
Regarding side effects, anastrozole is less likely to cause hot flashes, weight gain, or vaginal bleeding—although it may cause more nausea and irritability. In contrast to tamoxifen, anastrozole is devoid of all estrogenic activity, and hence does not promote endometrial cancer or thromboembolic events—
although it does increase the risk of fractures. Because of their superior efficacy and tolerability, aromatase inhibitors have replaced tamoxifen as the drug of first choice for treating ER-positive breast cancer in postmenopausal women.
Letrozole
Letrozole [Femara], a selective aromatase inhibitor, is indicated for (1) first-line therapy of early and advanced ER-positive breast cancer in postmenopausal women and (2) extended adjuvant therapy of early breast cancer following 5 years of adjuvant therapy with tamoxifen. Like anastrozole, letrozole blocks conversion of androgens into estrogens and thereby deprives breast cancer cells of estrogen’s growth-promoting influence. In one study of women with advanced breast cancer, letrozole (2.5 mg/day) was more effective than tamoxifen (20 mg/day): The objective response rate with letrozole was higher (30% vs. 20%), and the time to tumor progression was longer (9.4 months vs. 6 months). In women with early breast cancer who have received 5 years of tamoxifen therapy, following with letrozole reduces the risk of recurrence.
Letrozole’s most common adverse effects are musculoskeletal pain and nausea.
Other reactions include headache, arthralgia, fatigue, constipation, dyspnea, cough, vomiting, diarrhea, and hot flashes. Extremely low doses are embryotoxic and fetotoxic in animals. Like anastrozole, and unlike tamoxifen, letrozole
The most common reactions include nausea, fatigue, musculoskeletal pain, headache, and constipation. Other common, but more serious, reactions include thrombocyto- penia, increases in liver function test results, anemia, and hypokalemia.
Like trastuzumab, ado-trastuzumab emtansine can cause potentially fatal hypersensitivity reactions, infusion reactions, and pulmonary events. If a patient experienced trastuzumab- related infusion reactions, ado-trastuzumab emtansine should be avoided.
Dosage and Administration
Treatment consists of a 3.6-mg/kg IV infusion every 3 weeks until disease progression or toxicity is noted. The first infusion should be administered over 90 minutes. If this is well tolerated, subsequent infusions can be given over 30 minutes. If signs of toxicity are observed, the dose may be decreased or held until improvement is seen.
PERTUZUMAB
Pertuzumab [Perjeta] is used in combination with trastuzumab and docetaxel for the treatment of women with HER2-positive metastatic breast cancer who have not received prior therapy for metastatic disease. Like trastuzumab, pertuzumab is an antibody that blocks HER2 receptors, resulting in cell growth arrest and cell death.
Adverse effects include infusion-related reactions. Patients should be closely monitored for 60 minutes after the first infusion and for 30 minutes after subsequent infusions. Other adverse effects include cardiotoxicity, diarrhea, leukopenia, and neuropathy. Oligohydramnios has been reported in pregnancy, thus pregnant women should avoid use of pertuzumab.
Pertuzumab is administered intravenously. The initial dose is 840 mg given over 60 minutes. This is followed every 3 weeks by additional infusions of 420 mg given over 30 to 60 minutes.
LAPATINIB
Actions and Use
Lapatinib [Tykerb] is an oral inhibitor of two enzymes—HER2 tyrosine kinase and EGFR tyrosine kinase—that are involved in cell signal transduction.
Enzyme inhibition results in apoptosis and suppression of tumor cell growth.
Lapatinib is approved for treating advanced HER2-positive breast cancer, but only in combination with either (1) capecitabine (in patients who have received prior therapy with multiple drugs, including an anthracycline, a taxane, and trastuzumab) or (2) letrozole (in postmenopausal women for whom estrogen deprivation therapy is indicated). EGFR tyrosine kinase is discussed further later in this chapter under EGFR Tyrosine Kinase Inhibitors.
Adverse Effects
The most common adverse effects of lapatinib plus capecitabine are GI disturbances (diarrhea, nausea, vomiting), fatigue, rash, and palmar-plantar erythrodysesthesia (swelling and numbness of the hands and feet). The most common adverse effects of lapatinib plus letrozole are diarrhea, rash, nausea, and fatigue. Diarrhea occurs in 65% of patients and is the most common reason for stopping treatment. Like other HER2 inhibitors, lapatinib may pose a risk of cardiotoxicity. Accordingly, the drug should be used with caution in patients with existing cardiac impairment. Rarely, letrozole has been associated with severe liver injury. Liver function tests should be performed at baseline and periodically throughout treatment. When used alone and together with other drugs, letrozole has been associated with interstitial lung disease and pneumonitis. In laboratory animals, giving letrozole during pregnancy resulted in death of the pups a few days after birth. Women using the drug should avoid getting pregnant.
trastuzumab should be used with caution in women with pre- existing heart disease. Concurrent use with doxorubicin and other anthracyclines should generally be avoided. In contrast to the cytotoxic anticancer drugs, trastuzumab does not cause bone marrow suppression or alopecia.
Many patients experience a flu-like syndrome, which also occurs with other monoclonal antibodies. Symptoms include chills, fever, pain, weakness, nausea, vomiting, and headache.
The syndrome develops in 40% of patients receiving their first infusion, and then diminishes with subsequent infusions.
Safety Alert
TRASTUZUMAB
Trastuzumab can cause potentially fatal hypersensitivity reac- tions, infusion reactions, and pulmonary events. Symptoms include urticaria, bronchospasm, angioedema, hypotension, dyspnea, wheezing, pleural effusions, pulmonary edema, and hypoxia requiring oxygen. Most severe reactions developed in association with the first dose, either during the infusion or by 12 hours after. If symptoms develop during the infusion, the infusion should be stopped.
Dosage and Administration
Treatment consists of a loading dose (4 mg/kg infused over at least 90 minutes) followed by weekly maintenance doses for 12 to 18 weeks (2 mg/kg infused over 30 minutes). An alternative regimen uses a larger loading dose (8 mg/
kg) and larger but less frequent maintenance doses (6 mg/kg every 3 weeks).
ADO-TRASTUZUMAB EMTANSINE
Actions and Use
Ado-trastuzumab emtansine [Kadcyla] is a monoclonal anti- body approved for HER2-positive metastatic breast cancer in patients previously treated with trastuzumab and/or a taxane (see Chapter 102).
Like trastuzumab, ado-trastuzumab emtansine is effective only against tumors that overexpress human epidermal growth factor receptor 2. Ado-trastuzumab emtansine binds with HER2 and releases cytotoxic catabolites, thereby (1) inhibiting the cell cycle and (2) promoting cell death. In addition, ado- trastuzumab emtansine inhibits HER2 receptor signaling and shedding of HER2 in breast cancer cells.
Adverse Effects
Ado-trastuzumab emtansine can cause hepatotoxicity, cardio- toxicity, and neurotoxicity. Serious hepatotoxicity, including liver failure and death, has been reported. Liver function tests should be obtained before each dose. Left ventricular dysfunc- tion was seen in 1.8% of patients. Ejection fraction should be monitored at regular intervals. The incidence of neurotoxicity, expressed as peripheral neuropathy, was 2.2%.
Ado-trastuzumab emtansine can also cause embryo-fetal toxicity. Because exposure can result in birth defects or death of the fetus, ado-trastuzumab emtansine is classified in FDA Pregnancy Risk Category Db and should be avoided by pregnant women and nursing mothers.
bAs of 2020, the FDA will no longer use Pregnancy Risk Categories. Please refer to Chapter 9 for more information.
otherwise require a mastectomy. When used after surgery, chemotherapy can kill cancer cells that remain in the breast, as well as cells that may have metastasized to distant sites. A common regimen for breast cancer consists of doxorubicin (an anthracycline-type anticancer antibiotic) plus cyclophos- phamide (an alkylating agent) followed by paclitaxel (a mitotic inhibitor).
DENOSUMAB AND BISPHOSPHONATES FOR SKELETAL-RELATED EVENTS
Women with breast cancer are at risk for skeletal-related events (SREs), especially hypercalcemia and fractures. There are two causes: the cancer itself and the drugs used for treatment. In breast cancer, most metastases occur in bone. These metastases promote hypercalcemia by increasing the activity of osteoclasts, the cells that promote bone resorption. Not only does resorption promote hypercalcemia, it also weakens bone and thereby increases the risk of fractures. Fracture risk is further increased by the use of antiestrogens and aromatase inhibitors. As we discussed in Chapter 61, estrogens promote bone health by inhibiting bone resorption and promoting bone deposition.
Hence, by removing the influence of estrogen, the antiestrogens and aromatase inhibitors accelerate bone resorption and reduce bone deposition. Both actions weaken bone and thereby increase the risk of fractures. To reduce the risk of SREs, we can treat patients with denosumab or a bisphosphonate (usually zoledronate).
Zoledronate and Other Bisphosphonates
In women with breast cancer, bisphosphonates can help preserve bone integrity and can thereby decrease the risk of hypercal- cemia and fractures. Benefits derive from inhibiting the activity of osteoclasts. At this time, two bisphosphonates—zoledronate [Zometa] and pamidronate—are approved for hypercalcemia of malignancy, and both are also approved for managing osteolytic bone metastases. Compared with pamidronate, zoledronate has three advantages: onset is faster, duration is longer, and infusion time is shorter (15 minutes vs. 2 to 4 hours). Accordingly, zoledronate is generally preferred to pamidronate. Principal adverse effects of the bisphosphonates are kidney damage and osteonecrosis of the jaw.
In addition to reducing fractures and hypercalcemia, bisphosphonates may actually prevent metastases and prolong life. These benefits were discovered somewhat by accident.
In women with breast cancer, bisphosphonates were originally employed to suppress bone resorption caused by metastases.
While using bisphosphonates for this purpose, researchers noted something surprising: Bisphosphonates appeared to reduce the incidence of new bony metastases. Results of a follow-up study confirmed the original observation: In women with breast cancer, treatment with a bisphosphonate reduced metastases to bone and prolonged survival.
How do bisphosphonates suppress metastases? When cancer cells spread to bone, they stimulate the activity of osteoclasts, the cells responsible for bone resorption. In turn, osteoclasts release growth factors that stimulate the cancer cells, thereby setting up a self-reinforcing cycle. Bisphosphonates interrupt the cycle by inhibiting osteoclast function and blocking tumor adhesion to bone.
Drug Interactions
Lapatinib is metabolized by CYP3A4, and hence CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s wort) can lower lapatinib levels, and CYP3A4 inhibitors (e.g., ketoconazole, itra- conazole, erythromycin, indinavir, nelfinavir) can raise lapatinib levels. If possible, CYP3A4 inducers and inhibitors should be avoided.
Preparations, Dosage, and Administration
Lapatinib [Tykerb] is supplied in 250-mg tablets for oral dosing without food (either 1 hour before a meal or 1 hour after). Two dosing regimens are used:
• Lapatinib with capecitabine—The recommended dosage is 1250 mg (5 tablets) taken once every day, along with capecitabine
• Lapatinib with letrozole—The recommended dosage is 1500 mg (6 tablets) taken once every day, along with letrozole (2.5 mg) taken once every day.
PALBOCICLIB AND RIBOCICLIB
Actions and Use
Because palbociclib [Ibrance] and ribociclib [Kisquali] are both oral inhibitors of cyclin-dependent kinases (CDKs) 4 and 6, we will discuss them together. Cyclin-dependent kinases are proteins that play an important role in cell division and progression through the cell cycle. When CDK 4/6 dysregulation occurs, this can promote initial tumor growth and contribute to further tumor spread. In patients with estrogen receptor–
positive breast cancers, the signals from the receptors upregulate CDK4/6 pathways. Hence, palbociclib and ribociclib are indicated for the treatment of ER-positive breast cancer.
Palbociclib is used in conjunction with letrozole in postmeno- pausal women and with fulvestrant in women with disease progression following endocrine therapy. Ribociclib is combined with letrozole for treatment in postmenopausal women.
Adverse Effects
The most common adverse effects of palbociclib are neutro- penia, infections, and fatigue. The most common adverse effects of ribociclib are neutropenia, nausea, diarrhea, and fatigue. In addition, ribociclib can cause QT prolongation and hepatotoxic- ity. Accordingly, the drug should be used with caution in patients with existing hepatic impairment. The effects of letrozole were discussed previously.
Preparations, Dosage, and Administration
Palbociclib [Ibrance] is supplied in 75-, 100-, and 125-mg tablets for oral dosing. Two dosing regimens are used:
• Palbociclib with letrozole (for women who are post- menopausal)—The recommended dosage is 125 mg taken once every day, along with letrozole.
• Palbociclib with fulvestrant (for women who have progression after treatment with endocrine therapy)—
125 mg daily with fulvestrant.
Ribociclib [Kisquali] is supplied in 200-mg tablets. The recom- mended dosage is 600 mg taken once every day for 21 days to be used with letrozole.
CYTOTOXIC DRUGS (CHEMOTHERAPY)
Cytotoxic drugs may be used before breast surgery or after.
When used before surgery, chemotherapy can shrink large tumors, thereby permitting lumpectomy in women who would
of the jaw. The pharmacology of denosumab is presented in Chapter 75.
DRUGS FOR PROSTATE CANCER
Cancer of the prostate is the most common cancer among men in the United States. In 2017, an estimated 161,360 new cases were diagnosed, and 26,730 were fatal. For men with localized prostate cancer, the preferred treatments are surgery and radia- tion, with or without adjunctive use of drugs. For men with metastatic prostate cancer, drug therapy and castration are the only options. Among the drugs employed, agents for androgen deprivation therapy (ADT) comprise the largest and most widely used group. The only other choices are cytotoxic drugs and a new immunotherapy known as sipuleucel-T [Provenge].
As with breast cancer, most metastases (65% to 75%) go to bone. To minimize hypercalcemia and fractures caused by bone metastases, men may take zoledronate [Zometa] or denosumab [Xgeva] (see earlier discussion of breast cancer). The drugs used to treat prostate cancer are shown in Table 103.2.
The basic pharmacology of the bisphosphonates is discussed in Chapter 75.
Denosumab
Denosumab, marketed as Xgeva, is indicated for preventing (delaying) SREs in patients with breast cancer and other solid tumors that have metastasized to bone. Benefits derive from inhibiting the formation and function of osteoclasts. Efficacy was demonstrated in three double-blind trials that compared denosumab with zoledronate. One trial enrolled patients with breast cancer, one enrolled patients with prostate cancer, and one enrolled patients with other cancers, including multiple myeloma, kidney cancer, small cell lung cancer, and non–small cell lung cancer. Patients received either denosumab (120 mg subQ every 4 weeks) or zoledronate (4 mg IV every 4 weeks).
In patients with breast cancer or prostate cancer, denosumab was superior to zoledronate at delaying SREs. In patients with other cancers, denosumab was equal to zoledronate at delaying SREs. Principal adverse effects of denosumab are hypocal- cemia, serious infections, skin reactions, and osteonecrosis
Generic Name Brand Name Route Major Adverse Effects DRUGS FOR ANDROGEN DEPRIVATION THERAPY
GnRH Agonistsa
Leuprolide Lupron , Lupron Depot IM Hot flashes, erectile dysfunction, decreased libido, decreased muscle mass, gynecomastia, osteoporosis
Eligard SubQ
Triptorelin Trelstar IM
Goserelin Zoladex SubQ
Histrelin Vantas SubQ implant
GnRH Antagonist
Degarelix Firmagon SubQ Same as the GnRH agonists plus hepatotoxicity
Androgen Receptor Blockers
Flutamide Generic only PO Same as the GnRH agonists plus hepatotoxicity
Bicalutamide Casodex PO Same as the GnRH agonists plus hepatotoxicity
Enzalutamide Xtandi PO Same as the GnRH agonists plus PRES
Nilutamide Nilandron, Anandron PO Same as the GnRH agonists plus hepatotoxicity and interstitial pneumonitis CYP17 Inhibitor
Abiraterone Zytiga PO Same as the GnRH agonists plus hepatotoxicity, edema, hypertension,
hypokalemia, glucocorticoid insufficiency OTHER DRUGS FOR PROSTATE CANCER
Immunotherapy
Sipuleucel-T Provenge IV Infusion reactions, fatigue, fever
Cytotoxic Drugs
Cabazitaxel Jevtana IV Neutropenia, hypersensitivity reactions, diarrhea
Docetaxel Taxotere IV Neutropenia, anemia, hypersensitivity reactions, fluid retention
Estramustine Emcyt PO Gynecomastia, thrombosis
Drugs to Delay Skeletal Events
Zoledronate Zometab IV Kidney damage, osteonecrosis of the jaw, rare atrial fibrillation
Denosumab Xgevac SubQ Hypocalcemia, serious infections, skin reactions, osteonecrosis of the jaw TABLE 103.2 ■ Drugs for Prostate Cancer
aGonadotropin-releasing hormone agonists, also known as luteinizing hormone–releasing hormone (LHRH) agonists.
bZoledronate is also available as Reclast for treating osteoporosis and Paget’s disease.
cDenosumab is also available as Prolia for treating postmenopausal osteoporosis.
GnRH, Gonadotropin-releasing hormone; PRES, posterior reversible encelphalopathy syndrome.
It is important to note that leuprolide does not decrease production of androgens made by the adrenal glands or by the prostate cancer itself. As noted, these nontesticular sources account for about 10% of the androgens in circulation. Hence, even though production of testicular androgens is essentially eliminated, adrenal and prostatic androgens can still provide some support for prostate cancer cells.
Co-treatment With an Androgen Receptor Blocker. In patients receiving leuprolide, an androgen receptor blocker can help in two ways. Specifically, (1) it can prevent cancer cells from undergoing increased stimulation during the initial phase of GnRH therapy, when androgen production is increased;
and (2) it can block the effects of adrenal and prostatic andro- gens, whose production is not reduced by GnRH agonists. The current trend is to use an androgen receptor blocker during the first weeks of leuprolide therapy (to prevent leuprolide- induced tumor flare), after which the drug is discontinued unless there is tumor progression despite continued leuprolide treatment.
Adverse Effects. Leuprolide is generally well tolerated.
Hot flashes are the most common adverse effect, but these usually decline as treatment continues. Reduced testosterone may also lead to erectile dysfunction, loss of libido, gyneco- mastia, reduced muscle mass, new-onset diabetes, myocardial infarction, and stroke. During the initial weeks of treatment, elevation of testosterone levels may aggravate bone pain and urinary obstruction caused by prostate cancer. As a result, patients with vertebral metastases or pre-existing obstruction of the urinary tract may find treatment intolerable. As noted, concurrent treatment with an androgen receptor blocker can minimize these problems.
By suppressing testosterone production, leuprolide may increase the risk of osteoporosis and related fractures. Bone loss can be minimized by consuming adequate calcium and vitamin D and by performing regular weight-bearing exercise. In addition, a bisphosphonate (e.g., zoledronate [Zometa]) or denosumab [Xgeva] can be used to preserve bone and reduce fracture risk (see previous discussion of breast cancer).
Preparations, Dosage, and Administration. Leuprolide is supplied in two basic formulations for parenteral dosing:
• Leuprolide short-acting injection [Lupron ] is supplied as a 5-mg/
mL solution for subQ administration. The recommended dosage is 1 mg once a day.
• Leuprolide depot injection is available in single-dose kits under two brand names: Lupron Depot (for IM injection) and Eligard (for subQ injection). With either product, the dosage is 7.5 mg once a month, 22.5 mg every 3 months, 30 mg every 4 months, or 45 mg every 6 months.
Triptorelin, Goserelin, Histrelin
Triptorelin, goserelin, and histrelin are GnRH analogs indicated for palliative treatment of advanced prostate cancer. All three have the same mechanism and adverse effects of leuprolide, our prototype GnRH agonist. Preparations, dosage, and administration are as follows:
• Triptorelin [Trelstar] is administered by IM injection. The recommended dosage is 3.75 mg once a month, 11.25 mg once every 3 months, or 22.5 mg once every 6 months.
• Goserelin [Zoladex] is formulated as pellets (3.6 mg and 10.8 mg) for subQ implantation in the upper abdominal wall. The 3.6-mg pellets are implanted every 4 weeks, and the 10.8-mg pellets are implanted every 12 weeks.
• Histrelin [Vantas] is formulated as a 50-mg pellet for subQ implantation in the inner aspect of the upper arm once every 12 months.
ANDROGEN DEPRIVATION THERAPY
The term androgen deprivation therapy refers to the use of castration and/or drugs to deprive prostate cancers of the andro- gens they need for growth. By implementing ADT, we can slow disease progression and increase comfort. Initially, ADT was reserved for patients with metastatic disease. However, ADT is now used as an adjuvant in earlier-stage disease. Unfortunately, the benefits of ADT are time limited: After 18 to 24 months of treatment, disease progression often resumes. Side effects of ADT include hot flashes, reduced libido, erectile dysfunction, gynecomastia, decreased muscle mass, and decreased bone mass with associated increased risk of fractures.
Where do androgens come from, and how can we reduce their influence? About 90% of circulating androgens are produced by the testes. The remaining 10% are produced by the adrenal glands and by the prostate cancer itself. Accordingly, we can reduce the influence of androgens in three ways. Specifi- cally, we can block testosterone receptors with drugs; we can lower testosterone production with drugs; and we can lower testosterone production by castration. Drug therapy is more effective than castration because castration eliminates only testicular androgens, leaving androgen synthesis by the adrenal glands and cancer cells intact. In contrast, by using drugs to block testosterone receptors and testosterone synthesis, we can reduce the influence of testosterone from all sources (testes, adrenal glands, prostate cancer).
Gonadotropin-Releasing Hormone Agonists
The gonadotropin-releasing hormone (GnRH) agonists suppress production of androgens by the testes—but not by the adrenal glands and prostate cancer cells. Currently, four GnRH agonists are available: leuprolide, triptorelin, goserelin, and histrelin.
All four are indicated for cancer of the prostate. In addition, leuprolide is used for endometriosis (see Chapter 63).
Leuprolide
Therapeutic Use. Leuprolide [Eligard, Lupron , Lupron Depot] is a synthetic analog of GnRH, also known as luteinizing hormone–releasing hormone (LHRH). Leuprolide is indicated for advanced carcinoma of the prostate. Palliation is the primary benefit. For patients with prostate cancer, leuprolide represents an alternative to orchiectomy (surgical castration). Leuprolide may be administered daily (subQ); monthly (IM); or every 3, 4, or 6 months (IM).
Mechanism of Action. Cells of the prostate, both normal and neoplastic, are androgen dependent. Leuprolide provides palliation by suppressing androgen production in the testes.
During the initial phase of treatment, leuprolide mimics GnRH.
That is, the drug acts on the pituitary to stimulate release of interstitial cell–stimulating hormone (ICSH), which acts on the testes to increase production of testosterone. As a result, there may be a transient “flare” in prostate cancer symptoms.
However, with continuous exposure to leuprolide, GnRH receptors in the pituitary become desensitized. As a result, release of ICSH declines, causing testosterone production to decline too. After several weeks of treatment, testosterone levels are equivalent to those seen after surgical castration. Because leuprolide therapy mimics the effects of orchiectomy, treatment is often referred to as chemical castration.
follicle-stimulating hormone, which in turn deprives the testes of the stimulus they need for testosterone production. In clinical trials, patients received an initial 240-mg dose followed by monthly maintenance 80-mg doses. Testosterone levels fell rapidly to those produced by castration and then remained low for at least 12 months. Because degarelix works through direct blockade of GnRH receptors, the drug does not cause the initial surge in testosterone production seen with GnRH agonists, and hence there is no early tumor flare.
Degarelix is administered subQ, and absorption is slow.
Plasma levels peak in 2 days. Elimination is primarily by peptide bond hydrolysis, a process that occurs in the liver but does not involve cytochrome P450 enzymes. The drug’s half-life is long: 53 days.
As with other drugs for ADT, major side effects are hot flashes, reduced libido, erectile dysfunction, gynecomastia, decreased muscle mass, and decreased bone mass with
Gonadotropin-Releasing Hormone Antagonists
Like the GnRH agonists, the GnRH antagonists suppress production of androgens by the testes. However, in contrast to the GnRH agonists, the GnRH antagonists do not produce an initial tumor flare. Currently, only one GnRH antagonist—
degarelix—is available.
Degarelix
Degarelix [Firmagon] is a synthetic decapeptide GnRH antagonist indicated for palliative therapy of advanced prostate cancer in men who are not candidates for a GnRH agonist and who do not want surgical castration. Benefits derive from suppressing testosterone production by the testes. The underlying mechanism is blockade of GnRH receptors in the anterior pituitary, which decreases release of luteinizing hormone and
Prototype Drugs
HORMONAL, TARGETED, AND OTHER ANTICANCER DRUGS Drugs for Breast Cancer
Antiestrogen Tamoxifen
Aromatase Inhibitor Anastrozole
HER2 Antagonist Trastuzumab Cytotoxic Drugs
Doxorubicin/cyclophosphamide Paclitaxel
Drugs to Delay Skeletal Events Denosumab
Zoledronate
Drugs for Prostate Cancer
Gonadotropin-Releasing Hormone Agonist Leuprolide
Gonadotropin-Releasing Hormone Antagonist Degarelix
Androgen Receptor Blocker Flutamide
CYP17 Inhibitor Abiraterone
Patient-Specific Immunotherapy Sipuleucel-T
Cytotoxic Drugs Docetaxel Cabazitaxel
Drugs to Delay Skeletal Events Denosumab
Zoledronate Targeted Drugs
EGFR Tyrosine Kinase Inhibitor Cetuximab
BRC-ABL Tyrosine Kinase Inhibitor Imatinib
BRAF V600E Kinase Inhibitor Vemurafenib
CD-Directed Antibody Rituximab
PD-Directed Antibody Nivolumab
Angiogenesis Inhibitor Bevacizumab
Proteasome Inhibitor Bortezomib
Immunostimulants Interferon
Interferon alfa-2a
Other Noncytotoxic Drugs Glucocorticoid
Prednisone
PD, Programmed death.
