Anastrozole

Mechanism of Action
Anastrozole is a selective nonsteroidal aromatase inhibitor. Many breast cancers have estrogen receptors; the growth of these tumors is stimulated by estrogen. In postmenopausal women, the main source of estrogen is the conversion of adrenal androgen to estrogen (primarily estradiol) by aro-matase in the peripheral tissues, such as the adipose tissue.

Indications
Treatment of advanced breast cancer in postmenopausal women whose disease has progressed after tamoxifen therapy.

Metabolism/Excretion
Metabolized by the hepatic system and excreted in the urine. Half-life: 7 days.

Dosage Range
Adult: For breast cancer, 1 mg/day.
Pediatric: Safety and efficacy not established.

Drug Preparation/Stability
Available in 1-mg tablets.

Drug Administration
PO

Drug Interaction
None known

Side Effects and Toxicities
¨ Cardiac: Chest pain, peripheral edema
¨ CNS: Dizziness, depression, headache
¨ Cutaneous: Rash
¨ GI: Vomiting, diarrhea, constipation, abdominal pain, anorexia, dry mouth
¨ Other: Bone pain, pharyngitis, increased cough, pelvic pain

Special Considerations
Replacement therapy with glucocorticoids or mineralocorti-coids is not necessary with anastrozole because it does not affect cortisol or aldosterone secretion.

Anastrozole

Mechanism of Action
Anastrozole is a selective nonsteroidal aromatase inhibitor. Many breast cancers have estrogen receptors; the growth of these tumors is stimulated by estrogen. In postmenopausal women, the main source of estrogen is the conversion of adrenal androgen to estrogen (primarily estradiol) by aro-matase in the peripheral tissues, such as the adipose tissue.

Indications
Treatment of advanced breast cancer in postmenopausal women whose disease has progressed after tamoxifen therapy.

Metabolism/Excretion
Metabolized by the hepatic system and excreted in the urine. Half-life: 7 days.
Dosage Range
¨ Adult: For breast cancer, 1 mg/day.
¨ Pediatric: Safety and efficacy not established.

Drug Preparation/Stability
Available in 1-mg tablets.

Drug Administration
PO

Drug Interaction
None known

Side Effects and Toxicities
¨ Cardiac: Chest pain, peripheral edema
¨ CNS: Dizziness, depression, headache
¨ Cutaneous: Rash
¨ GI: Vomiting, diarrhea, constipation, abdominal pain, anorexia, dry mouth
¨ Other: Bone pain, pharyngitis, increased cough, pelvic pain

Special Considerations
Replacement therapy with glucocorticoids or mineralocorti-coids is not necessary with anastrozole because it does not affect cortisol or aldosterone secretion.

Aminoglutethimide

Mechanism of Action
Inhibits adrenocortical steroid synthesis by blocking the production of adrenal glucocorticoids, mineralocorticoids, estrogens, and androgens.

Indications
Suppression of adrenal function in patients with Cushing's syndrome. Unlabeled use: To cause “chemical adrenalectomy” in patients with advanced breast cancer and patients with metastatic prostate cancer.

Metabolism/Excretion
Well absorbed orally and excreted in the urine. Half-life: 11 to 16 hours.

Dosage Range
¨ Adult: Initial dose is 250 mg/day PO at 6-hour intervals. If cortisol suppression is not adequate, the dosagemay be increased in increments of 250 mg/day at 1- to 2-week intervals to a total daily dose of 2 g. If adverse side effects occur, including extreme drowsiness or a skin rash that persists for 5 days or longer or becomes severe, or if the patient develops excessively low cortisol levels, reduce the dose or discontinue the drug.
¨ Pediatric: Safety and efficacy not established.

Drug Preparation/Stability
Available in 250-mg scored tablets. Protect tablets from light and dispense from a light-resistant container. Do not store above 30°C.

Drug Administration
Per Oral

Drug Interaction
¨ Decreased effectiveness of warfarin, so dose may need to be increased.
¨ Enhanced metabolism of dexamethasone, so hydro-cortisone should be used for replacement.

Side Effects and Toxicities

• Cardiac: Orthostatic hypotension, tachycardia (rare)
• CNS: Drowsiness, headache
• Cutaneous: Morbiliform rash, pruritus (may be due to allergic or hypersensitivity reactions)
• Endocrine: Adrenal insufficiency was noted in Cush-ing's syndrome patients who were treated for at least 4 weeks. Occasional masculinization and hirsutism in women; precocious sexual development in men.
• GI: Nausea and anorexia
• Other: Fever, myalgia
• Special Considerations
• Avoid in patients who have hypersensitivity to the drug.
• Monitor adrenocortical function. If hypofunction occurs, give supplements such as hydrocortisone. Avoid dexamethasone.
• Monitor blood pressure at regular intervals because of the potential for hypotension. Advise patients to watch for signs of hypotension (e.g., weakness and dizziness) and teach the appropriate measures to be taken should they occur.
• Warn patients that drowsiness may occur and that they should not engage in activities that may be hazardous because of decreased alertness.
• Inform patients that effects may be potentiated by alcohol.

Amifostine

Mechanism of Action

Amifostine is dephosphorylated at the tissue site by alkaline phosphatase to form free thiol. Once inside the cell, the free thiol binds with and neutralizes the reactive species of cis-platin. It also acts as a potent scavenger of oxygen free radicals. This action is important because free radicals can damage cell membranes, DNA, and other important cell components, which will lead to cell death.

Indications
Used to reduce the cumulative renal toxicity associated with cisplatin-based therapies in advanced ovarian cancer or non-small cell lung cancer. It is also indicated to alleviate moderate xerostomia associated with radiation therapy.
Metabolism/Excretion
Rapidly cleared from the plasma. Elimination half-life: about 88 minutes. Excreted by the renal system.

Dosage Range
¨ With cisplatin therapy: 910 mg/m2 given as a 15-minute infusion once a day 30 minutes before the cisplatin-based treatment.
¨ For moderate xerostomia: 200 mg/m2 given as a 3-minute IV infusion starting 15 to 30 minutes before standard fraction radiation therapy.
¨ Use in children, elderly patients, and patients with pre-existing cardiovascular or cerebrovascular conditions has not been evaluated.

Drug Preparation/Stability
Supplied as a sterile lyophilized powder in 10-mL single-use vials. Each vial contains 500 mg of the drug and 500 mg of mannitol. When stored in the refrigerator at 2° to 8°C, theunused vial is chemically and physically stable for 15 months. Reconstitute the drug with 9.5 mL of sterile 0.9% sodium chloride solution, resulting in a formulation containing 50 mg of amifostine and 50 mg of mannitol/mL. The reconstituted solution can be further diluted with sterile sodium chloride solution for dosage adjustment and should be adjusted to equal a 50-mL solution. Reconstituted ami-fostine is stable for 5 hours at room temperature (15° to 25°C) or for up to 24 hours under refrigeration (2° to 8°C).

Drug Administration
¨ Before cisplatin treatment: give as a 15-minute IV infusion 30 minutes before chemotherapy. The patient should be adequately hydrated and maintained in a supine position. Monitor blood pressure every 5 minutes during the infusion.
¨ Before radiation: give as a 3-minute IV infusion. Patients should be well hydrated before the infusion. Give antiemetics before and in conjunction with the drug. Monitor blood pressure before and after the infusion.

Drug Interaction
None known. Use caution in patients taking antihyperten-sive drugs or other drugs that could potentiate hypotension. Contraindicated in patients sensitive to mannitol or am-inothiol compounds.

Side Effects and Toxicities
¨ Cardiac: Transient reduction in systolic blood pressure
¨ GI: Nausea and vomiting, which can be severe. Can be relieved with an antiemetic regimen containing dexametha-sone (20 mg) and a serotonin 5-HT3 receptor antagonist.
¨ Other: Hypocalcemia, fever, chills, dyspnea, skin rashes, urticaria, sneezing, sleepiness, flushing, hiccups, and chills

Special Considerations
¨ Ensure that the patient is sufficiently hydrated before treatment. Do not administer to patients who are dehydrated or are taking antihypertensive therapy that cannot be interrupted for 24 hours.
¨ Maintain the patient in a supine position during the infusion.
¨ Obtain a baseline blood pressure, and monitor blood pressure every 5 minutes during and 5 minutes after the infusion is completed. If the blood pressure drops below the threshold level, it may be necessary to interrupt the infusion. Restart the infusion if the blood pressure returns to threshold within 5 minutes and the patient is asymptomatic. Refer to the following manufacturer's guidelines for interruption of infusion in relation to blood pressure thresholds.

¨ Infuse the drug within 15 minutes; a longer infusion period increases the incidence of side effects.
¨ Administer antiemetics before and in conjunction with amifostine. Monitor fluid balance, especially when severe emesis occurs.

Altretamine

Mechanism of Action
Unknown

Indications

• Palliative treatment for recurrent or persistent ovarian cancer after first-line therapy with cisplatin or alkylating agent; use as a single agent
• Lymphoma, lung cancer

Metabolism/Excretion

Undergoes rapid and extensive metabolism in the liver and is excreted by the kidneys. Half-life: 0.5 to 3.0 hours.

Dosage Range

• Adult: Given for 14 or 21 days in a 28-day cycle at a dosage of 260 mg/m2 per day. Therapy may be temporarily discontinued (for more than 14 days) and subsequently restarted at 200 mg/kg per day for any of the following: GI intolerance unresponsive to symptomatic measures; WBC count <2000/mm3>
• Pediatric: Safety and efficacy not established.

Drug Preparation/Stability
Available in 50- and 100-mg capsules. No stability data available.

Drug Administration
Give the total daily dose in four divided PO doses after meals and at bedtime.

Drug Interaction
Concurrent therapy with monoamine oxidase inhibitors may cause severe orthostatic hypotension.

Side Effects and Toxicities

• CNS: Peripheral neuropathy, mood disorders, disorders of consciousness, ataxia, vertigo
• GI: Nausea and vomiting
• GU: Elevated serum creatinine and BUN levels
• Hematologic: Leukopenia, thrombocytopenia, anemia
• Special Considerations
• Do not give to patients with known hypersensitivity to the drug, severe bone marrow depression, or severe neurologic toxicity.
• If patients who have been heavily treated with cis-platin or alkylating agents and have cisplatin-induced toxicity are given altretamine, monitor their neurologic function before each course of treatment.
• Obtain peripheral blood counts before initiation of treatment.
• Administer antiemetics to patients receiving high-dose courses. For nausea and vomiting not controlled by anti-emetics,the dose should be reduced or discontinued according to the patient's tolerance.

Aldesleukin

Mechanism of Action
Inhibits tumor growth; exerts immunologic effects by activating the cellular immunity to increase lymphocytes, eosinophils, platelets, and cytokines, including tumor necrosis factor, interleukin-1, and gamma interferon.

Indications
Metastatic renal cell carcinoma in adults.
Metabolism/Excretion
Metabolized in the kidney; excreted in the urine. Serum half-life: 13 minutes after IV administration. Eliminated in 85 minutes.

Dosage Range
¨ Adult: 600,000 IU/kg (0.037 mg/kg) given every 8 hours by a 15-minute IV infusion for a total of 14 doses. After 9 days of rest, repeat the schedule for another 14 doses, for a maximum of 28 doses per cycle. Doses may be held for toxicities. Retreatment may be given if response to treatment is noted after 4 weeks. The patient should have a rest period of at least 7 weeks from the date of discharge before retreatment.

¨ Pediatric: Safety and efficacy not established.
Drug Preparation/Stability
Supplied in powder for injection: single-use, preservative-free vials contain 22 million IU (1.3 mg) of aldesleukin. Reconstitute with 1.2 mL sterile water for injection. When reconstituted, each milliliter contains 18 million IU (1.1 mg) of aldesleukin. Do not reconstitute with bacteriostatic water or sodium chloride. Store powder and reconstituted solution in the refrigerator at 2° to 8°C (36° to 46°F). Do not shake or freeze. Discard unused portions. Administer reconstituted solution within 48 hours.

Drug Administration

Drug Interaction :
¨ Interactions possible with concomitant administration of psychotropic drugs.
¨ Increased toxicity noted with nephrotoxic (aminoglyco-sides, indomethacin), myelotoxic (chemotherapy), cardiotoxic (doxorubicin), or hepatotoxic drugs (methotrexate, asparaginase).
¨ Decreased effectiveness with concomitant administration of glucocorticoids.
¨ Increased hypotensive effects with concomitant administration of antihypertensives.

Side Effects and Toxicities :
¨ Constitutional: Fever, chills, pain, fatigue, weakness, malaise, weight gain, weight loss, headache
¨ CNS: Mental status changes, dizziness, sensory dysfunction
¨ GI: Nausea, vomiting, diarrhea, stomatitis, anorexia, GI bleeding, dyspepsia, constipation
¨ GU: Oliguria, anuria, BUN and serum creatinine elevation, proteinuria, hematuria
¨ Hematologic: Elevated bilirubin, transaminase, and alkaline phosphatase, anemia, thrombocytopenia, leukopenia, coagulation disorders, leukocytosis, eosinophilia; hypomagnesemia, acidosis, hypocalcemia, hypophosphatemia, hypokalemia, hyperuricemia, hypoalbuminemia, hypoproteinemia
¨ Integumentary: Pruritus, erythema, rash, dry skin, ex-foliative dermatitis
¨ Musculoskeletal: Arthralgia, myalgia
¨ Pulmonary and cardiovascular: Congestion, dyspnea, pulmonary edema, respiratory failure, tachypnea, pleural effusion, wheezing; hypotension, sinus tachycardia, arrhythmias, bradycardia
¨ Other: Jaundice, edema, infection

Special Considerations
¨ Contraindicated in patients with known allergy to aldesleukin or any component of the product; abnormal thallium stress test or pulmonary function test results; or organ allografts. Contraindicated in patients who have experienced the following toxicities during a previous treatment: sustained ventricular tachycardia (more thanfive beats); cardiac rhythm disturbances not controlled by or unresponsive to management; recurrent chest pain with ECG changes, consistent with angina or myocardial in-farction; intubation required for more than 72 hours; pericardial tamponade; renal dysfunction requiring dialysis for more than 72 hours; coma or toxic psychosis lasting more than 48 hours; repetitive or difficult-to-control seizures; bowel ischemia or perforation; or GI bleeding requiring surgery.

¨ Patients should have normal cardiac, pulmonary, hepatic, and CNS function before start of treatment.
¨ Assess for capillary leak syndrome, characterized by hypotension, hypoperfusion, edema, and effusions. Frequently monitor blood pressure, pulse, mental status, weight, and urine output. May need to administer dopamine (1 to 5 mcg/kg/min) to patients with capillary leak syndrome.
¨ Obtain laboratory tests (CBC with differential, blood chemistries, including renal and liver function tests) before and daily during therapy. Obtain a baseline chest x-ray, pulmonary function test with arterial blood gases, and stress thallium study. Repeat studies during therapy when clinically indicated.
¨ If adverse events occur that require dosage modifications, withhold treatment rather than decreasing dosage.

The Cell Cycle

The cell cycle is the cornerstone of cell division and proliferation. Both normal and malignant cells undergo this process, which may last for approximately 25 to 30 hours. There are five phases to the process. In the first phase, Gap 0 (G0), a cell can stay in a dormant or latent state for months or even years until stimulated to move forward in the cycle. Because certain cells divide more rapidly than others, some rest in the G0 phase for a brief period, whereas others bypassthe G0 phase and enter the second phase, the Gap 1 (G1) phase, directly if the body needs the immediate production of a certain cell. The G1 phase occurs after mitosis, the birth of two daughter cells. During this phase, the cell synthesizes RNA and the proteins needed for DNA synthesis. The time a cell spends in this phase varies and can last from hours to days, depending on the cell type. After RNA and protein syn-theses occur, the cell then enters the third phase, the synthesis (S) phase, when RNA, protein, and DNA syntheses occur and DNA replicates.

DNA is an essential nucleic acid composed of deoxyribose, a phosphate, and four nitrogenous bases: adenine, guanine, cytosine, and thymine. Adenine and guanine are the purines, and cytosine and thymine are the pyrimidines. Chemical reactions occur between the two purines and also between the two pyrimidines, leading to the formation of the double-stranded DNA helix, which serves as the genetic template of the cell.

Generally, the S phase lasts 8 to 12 hours. The cell then enters the fourth phase, Gap 2 (G2), when more RNA and protein syntheses take place in preparation for mitosis. This phase tends to last 2 to 4 hours; then the cell enters the fifth or mitosis (M) phase. The M phase consists of the following orchestrated subphases: prophase, metaphase, anaphase,and telophase. As the cell progresses through these subphases, the cytoplasm and nucleus divide so that replication of the cell results in the birth of two daughter cells.

It is not clearly understood how the body maintains normal cellular homeostasis. What has been postulated is that the body possesses a feedback system that signals a cell to enter the G1 phase of the cell life cycle in response to cell death. In patients with cancer, this feedback system is dysfunctional, and the cancer cell enters the cell cycle independently of the body's feedback system.

Chemotherapy

Chemotherapy is the use of cytotoxic agents to destroy cancer cells. Chemotherapy dates back to the 1500s, when heavy metals were used systemically to treat cancers, and severe toxicity and limited cure were reported. Since then, a vast spectrum of antineoplastic drugs has been discovered to achieve cure, control, and palliation of many cancers. The new and improved changes in the drug approval process of the Food and Drug Administration have speeded the entry of novel drugs that have made chemotherapy a vital part of the cancer armamentarium. Chemotherapy remains the primary treatment for some malignancies and an adjunct to other treatment modalities (surgery, radiation, and immunotherapy). Unlike surgery and radiation, chemotherapy is distinguished by its systemic effects. Most of the drugs are transported by the bloodstream; most do not cross the blood–brain barrier and therefore cannot reach the central nervous system.

To achieve the above goals, chemotherapeutic drugs (as single agents or in combination) may be used in the following strategies:
Adjuvant: A short course of high-dose, usually combination drugs is given after radiation or surgery to destroy residual tumor cells.
Consolidation: Chemotherapy is given after induction therapy has achieved a complete remission; the regimen is repeated to increase the cure rate or to prolong patient survival.

Induction: This term is commonly used in the treatment of hematologic malignancies. It refers to the use of usuallya combination of high-dose drugs to induce a complete response when initiating a curative regimen.
Intensification: After complete remission is achieved, the same agents used for induction are given at higher doses, or different agents are given at high doses to effect a better cure rate or a longer remission.
Maintenance: Single or combination, low-dose cytotoxic drugs are used on a long-term basis in patients who are in complete remission to delay regrowth of residual cancer cells.

Neoadjuvant: Adjuvant chemotherapeutic drugs are used during the pre- or perioperative period.
Palliative: Chemotherapy is given to control symptoms, provide comfort, and improve quality of life if cure is impossible.
Salvage: A potentially curative high-dose regimen is given to a patient whose symptoms have recurred or whose treatment has failed with another regimen.
The human body is composed of an intricate network of nondividing and dividing cells organized into various tissues that perform specific functions. Nondividing cells, such as striated muscle cells and neurons, are highly differentiated and do not need to replicate to maintain their function. Dividing cells, such as germ, epithelial, and bone marrow stem cells, must replicate to maintain their function.

The body regulates all replication of dividing cells by maintaining a balance between the birth and death of cells. The body's maintenance of this homeostasis depends on the synthesis of trigger proteins, or signals, in response to cell death. This synthesis stimulates the entry and movement of dividing cells through the process of cell division.