Antineoplastic and Biologic Therapy

Question 1

What is the designation for the initial phase of the cell cycle?

Answer 1

The initial phase of the cell cycle is the resting phase and is designated G₀

Question 2

What occurs during phase 2 of the cell cycle?

Answer 2

Phase 2 of the cell cycle is designated G₁ and cell division occurs. Protein synthesis for RNA occurs during this phase.

Question 3

What occurs during the S phase of the cell cycle?

Answer 3

Enzymes for synthesis of DNA are activated during the S phase of the cell cycle.

Question 4

What occurs during the G2 phase of the cell cycle?

Answer 4

DNA synthesis stops while RNA synthesis and protein synthesis continue while the cell prepares for mitosis.

Question 5

What occurs during the M phase of the cell cycle?

Answer 5

Mitosis occurs during the final stage of the cell cycle, the M phase, and usually lasts 30-90 minutes.

Question 6

What is the mechanism of action of antimetabolites?

Answer 6

Antimetabolites are cell cycle-specific agents that act in the S phase and interfere with DNA and RNA synthesis by blocking the production of essential enzymes and preventing cell division.

Question 7

gemcitabine (Gemzar)

Answer 7

Antineoplastic (antimetabolite)

pH 2.7-3.3

ACTIONS

A nucleoside metabolic inhibitor with antineoplastic activity. Metabolized intracellularly to two active nucleosides. Cell phase specific, these nucleosides induce internucleosomal DNA fragmentation, primarily killing cells undergoing DNA synthesis (S-phase) and also blocking the progression of cells through the G 1 /S-phase boundary. Very little is bound to plasma protein. Volume of distribution is increased by infusion length. Half-life is shorter (42 to 94 minutes) with a short infusion (less than 70 minutes), and longer (245 to 638 minutes) with a long infusion (more than 70 minutes). Half-life is slightly longer and rate of clearance is lower in women and in the elderly, resulting in higher concentrations for any given dose. Primarily excreted in urine.

INDICATIONS AND USES

First-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas in patients previously treated with fluorouracil. ■ First-line treatment in combination with cisplatin for the treatment of inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) non–small-cell lung cancer. ■ First-line treatment in combination with paclitaxel for treatment of metastatic breast cancer after failure of previous anthracycline chemotherapy unless anthracyclines (e.g., doxorubicin [Adriamycin], idarubicin [Idamycin]) were clinically contraindicated. ■ Treatment in combination with carboplatin for patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.

Question 8

What are the indications for Gemcitabine?

Answer 8

Pancreatic CA (w/paclitaxel) , unresectable non-small cell lung CA (w/cisplatin), metastatic breast CA (w/paclitaxel)

Question 9

What is the dose-limiting toxicity of Gemcitabine?

Answer 9

Myelosuppression with a nadir of 7 to 14 days.

Question 10

What is the emetic risk of Gemcitabine?

Answer 10

Low (10-30%)

Question 11

What is the mechanism of action of methotrexate?

Answer 11

Methotrexate is a folic acid antagonist that interferes with the synthesis of purine and thymidylate. It is cell cycle specific in the S phase

Question 12

Why should urine be alkanized when high doses of methotrexate are given?

Answer 12

Methotrexate can crystallize and precipitate in acidic solution and can cause renal damage in urine with a low pH.

Question 13

What medication is given following high doses of methotrexate?

Answer 13

Leucovorin (folic acid) is usually given as a resue agent within 24 to 36 hours. The purpose of leucovorin is to reduce bone marrow toxicity.

Question 14

fluorouracil (5-FU)

Answer 14

Antineoplastic (antimetabolite)

pH 9.5

ACTIONS

An antimetabolite. A fluorinated pyrimidine antagonist, cell cycle specific, that interferes with the synthesis of DNA and RNA. Through various chemical processes this deprivation acts more quickly on rapidly growing cells and causes their death. Distributes into tumors, intestinal mucosa, bone marrow, liver, and readily crosses the blood-brain barrier into cerebrospinal fluid and brain tissue. Metabolized by the liver within 3 hours. Half-life is approximately 16 minutes. Excretion is through the urine and as respiratory CO 2 .

INDICATIONS AND USES

To suppress or slow neoplastic growth. Palliative treatment of cancers of the breast, colon, pancreas, rectum, and stomach. May be used alone or in combination with other agents.

SIDE EFFECTS

Abnormal bromsulphalein (BSP), prothrombin, total protein, sedimentation rate; alopecia (reversible), anaphylaxis, bleeding, bone marrow suppression (agranulocytosis, anemia, leukopenia, pancytopenia, thrombocytopenia), cerebellar syndrome, cramps, dermatitis, diarrhea, disorientation, dry lips, erythema, esophagopharyngitis and stomatitis (may lead to sloughing and ulceration), euphoria, frequent stools, GI ulceration and bleeding, headache, hemorrhage from any site, increased skin pigmentation, infection, lacrimal duct stenosis, mouth soreness and ulceration, myocardial ischemia, nail changes, nausea, palmar-plantar erythrodysesthesia syndrome (tingling of hands and feet followed by pain, redness, and swelling), photophobia, photosensitivity, pneumopathy (cough, shortness of breath), thrombophlebitis, visual changes, vomiting (intractable). Diarrhea and stomatitis are most common and may be more severe with a prolonged duration in patients on combination therapy. Pseudomembranous colitis has been reported.

Question 15

What are side effects of 5-FU?

Answer 15

Anorexia, fatigue, alopecia, and photosensitivity. The patient should be instructed to avoid exposure to direct sunlight, to wear long sleeves and pants outdoors, and to use SPF 15 or higher sunscreen.

Question 16

Cyclophosphamide (Cytoxan)

Answer 16

Antineoplastic (alkylating agent/nitrogen mustard)

pH 3-7.5

ACTIONS

An alkylating agent of the nitrogen mustard group with antitumor activity; cell cycle phase nonspecific, but most effective in S phase. Cyclophosphamide is a prodrug that is activated by hepatic microsomal enzymes. It is thought to prevent cell division by cross-linking DNA strands and preventing DNA synthesis. Elimination half-life is 3 to 12 hours. Metabolized in the liver, it or its metabolites are excreted in the urine. Secreted in breast milk.

INDICATIONS AND USES

Although effective alone in susceptible malignancies, cyclophosphamide is more frequently used concurrently or sequentially with other antineoplastic agents. Cyclophosphamide has been used in the treatment of the following malignancies: malignant lymphomas (e.g., Hodgkin’s disease, lymphocytic lymphoma, mixed-cell–type lymphomas, histiocytic lymphoma, Burkitt’s lymphoma), multiple myeloma, leukemias (e.g., chronic lymphocytic leukemia, chronic granulocytic leukemia, acute myelogenous and monocytic leukemia, acute lymphoblastic [stem cell] leukemia in children), mycosis fungoides, neuroblastoma, adenocarcinoma of the ovary, retinoblastoma, and carcinoma of the breast. ■ Adjuvant treatment of operable node-positive breast cancer in combination with doxorubicin and docetaxel. ■ Used orally to treat many other indications, including biopsy-proven nephrotic syndrome, in pediatric patients when disease fails to respond to primary therapy or when primary therapy causes intolerable side effects.

Question 17

Carboplatin (Paraplatin)

Answer 17

Antineoplastic (ankylating agent)

pH 5-7

ACTIONS

An alkylating agent. Better tolerated by patients, carboplatin causes less nausea and vomiting, less neurotoxicity, and less nephrotoxicity than cisplatin. Myelosuppression is generally reversible and manageable with antibiotics and transfusions. Produces interstrand DNA cross-links and is cell-cycle nonspecific. Not bound to plasma proteins. Half-life is 2.6 to 5.9 hours. Majority of carboplatin is excreted in the urine within 24 hours.

INDICATIONS AND USES

Initial treatment of advanced ovarian cancer in combination with other approved chemotherapeutic agents (e.g., cyclophosphamide). ■ Palliative treatment of recurrent ovarian cancer after prior chemotherapy, including patients treated with cisplatin.

Question 18

Cisplatin (Platinol)

Answer 18

Antineoplastic (alkylating agent)

pH 3.5-4.5

PRECAUTIONS

Hydrate patient with 1-2 L of infusion fluid for 8 to 12 hours before adminstration.

Ototoxicity is cumulative; test hearing before administration and regularly during treatment.

INDICATIONS AND USES

Treatment of metastatic testicular tumors; used in combination therapy with other approved chemotherapy agents in patients who have already received appropriate surgical and/or radiotherapeutic procedures. ■ Treatment of metastatic ovarian tumors; used in combination therapy with other approved chemotherapy agents in patients who have already received appropriate surgical and/or radiotherapeutic procedures. ■ Used as a single agent as secondary treatment in patients with metastatic ovarian tumors refractory to standard chemotherapy who have not previously received cisplatin therapy. ■ Used as a single agent for treatment of patients with transitional cell bladder cancer that is no longer amenable to local treatment such as surgery and/or radiotherapy. ■ Is used in specific combinations with other chemotherapeutic drugs.

Question 19

There are two main types of drugs used for cancer treatment that interfere specifically with the cell cycle. Name and describe the mechanism of action of each and give some specific examples of drugs utilized.

Answer 19

The two main types of cell cycle-specific drugs used in cancer treatment are either antimetabolites or vinca alkaloids.

· Antimetabolites act during the S phase of cell replication by suppressing DNA synthesis and therefore protein synthesis as well. These agents can have some side effects on the blood or gastrointestinal system; they include drugs such as methotrexate, cytarabine, and fluorouracil. ·

The vinca alkaloids obtained from plants act to prevent cell division during any phase of the cell cycle (except the resting stage) by blocking both DNA and RNA synthesis and binding to the tubules. They can have neurological side effects; these agents include vinblastine, vincristine, and vinorelbine.

Question 20

Decarbazine (DTIC)

Answer 20

Ankylating agent. Irritant, indicated to treat melanoma, soft tissue sarcomas, neuroblastoma and Hodgkin’s disease

Question 21

Ifosfamide (Ifex)

Answer 21

Antineoplastic (alkylating agent/nitrogen mustard)

pH 6

ACTIONS An alkylating agent. Chemically related to the nitrogen mustards and a synthetic analog of cyclophosphamide. A prodrug that requires activation by hepatic cytochrome P 450 isoenzymes to exert its cytotoxic activity. Exact mechanism of action not determined, but its cytotoxic action is primarily through DNA cross-links caused by alkylation by isophosphoramide mustard at guanine N7 positions. The formation of inter-and intra-strand cross-links in the DNA results in cell death. Distribution takes place with minimal tissue binding and little plasma protein binding. Extensively bound by red blood cells. Extensively metabolized in the liver by cytochrome P 450 isoenzymes (considerable individual variation). Elimination half-life for a usual dose is about 7 hours. Half-life is extended with larger doses. Ifosfamide and its metabolites are excreted in urine. Secreted in breast milk.

INDICATIONS AND USES Used in combination with other specific antineoplastic agents for third-line chemotherapy of germ cell testicular cancer. Should be used in combination with mesna for prophylaxis of hemorrhagic cystitis.

Question 22

Mechlorethamine hydrochloride (Mustargen)

Answer 22

Antineoplastic(Alkylating agent/nitrogen mustard)

pH 3 to 5

ACTIONS An alkylating agent, cell cycle phase–nonspecific, with antitumor activity. It has a selective cytotoxic effect on rapidly growing cells. Palliative, not curative, in its effects; regression in the size of malignant tumor may occur; pain and fever subside; appetite, strength, and a sense of well-being are increased. Rapidly metabolized. Excreted in changed form in the urine.

INDICATIONS AND USES Used intravenously for the palliative treatment of Hodgkin’s disease (Stages III and IV), lymphosarcoma, chronic myelocytic or chronic lymphocytic leukemia, polycythemia vera, mycosis fungoides, and bronchogenic carcinoma. ■ Used intrapleurally, intraperitoneally, or intrapericardially for the palliative treatment of metastatic carcinoma resulting in effusion.

Question 23

Thiotepa (Thioplex)

Answer 23

Thiotepa (Thioplex)—Non-vesicant, used before bone marrow transplantation, and to treat Hodgkin’s disease, lymphoma, or brain, breast, ovarian or bladder cancers

Question 24

vinblastine

Answer 24

Antineoplastic (miitic inhibitor -vinca alkaloid).

ACTIONS An alkaloid of the periwinkle plant with antitumor activity. Cell cycle–specific for M phase. Thought to interfere with the metabolic pathways of amino acids. Sometimes pharmacologically effective without any noticeable improvement in symptoms of malignancy. Cell energy production and synthesis of nucleic acid may also be inhibited. Half-life is 24.8 hours. Metabolism mediated by the hepatic cytochrome P 450 isoenzymes in the CYP 3A subfamily. Some excretion through bile and urine.

INDICATIONS AND USES To suppress or retard neoplastic growth. Remission and probable cure have been achieved with bleomycin and cisplatin in testicular malignancies. Response has been noted in Hodgkin’s disease, non-Hodgkin’s lymphomas, choriocarcinoma, Kaposi’s sarcoma, mycosis fungoides, breast and renal cell malignancies. ■ Used to treat many other malignancies.

Question 25

Vincristine

Answer 25

Antineoplastic (miitic inhibitor -vinca alkaloid).

INDICATIONS AND USES

Treatment of acute leukemia. ■ Useful in combination with other oncolytic agents for Hodgkin’s disease, non-Hodgkin’s malignant lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms’ tumor.

Question 26

Vinorelbine

Answer 26

Antineoplastic (mitotic inhibitor-vinca alkaloid).

INDICATIONS AND USES

Treatment of unresectable advanced non–small-cell lung cancer (ANSCLC), in ambulatory patients. Used as a single agent or in combination with cisplatin. ■ Indicated as a single agent or in combination with cisplatin in patients with Stage IV NSCLC and in combination with cisplatin in patients with Stage III NSCLC.

Question 27

methotrexate

Answer 27

Antineoplastic (antimetabolite)

pH 8.5

ACTIONS

An antimetabolite and folic acid antagonist. Inhibits dihydrofolic acid reductase. Cell cycle–specific for the S phase. It interferes with DNA synthesis, repair, and cellular replication. Rapidly proliferating tissues are more sensitive to this effect. Widely distributed and is approximately 50% protein bound. Undergoes some hepatic and intracellular metabolism. Half-life is dose dependent and is 3 to 10 hours in patients receiving low-dose antineoplastic therapy and 8 to 15 hours in patients receiving high-dose methotrexate therapy. 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. Clearance rates decrease with higher doses. Does not cross blood-brain barrier. Secreted in breast milk.

INDICATIONS AND USES

Used for life-threatening neoplastic disease alone or in combination with other anticancer agents in the treatment of acute lymphocytic leukemia, breast cancer, epidermal tumors of the head and neck, small-cell and squamous cell lung cancer, non-Hodgkin’s lymphoma, advanced mycosis fungoides (cutaneous T-cell lymphoma). ■ Severe disabling psoriasis or rheumatoid arthritis unresponsive to other treatment. Diagnosis of psoriasis should be established by biopsy and/or dermatology consultation before use. ■ To prolong relapse-free survival in patients with nonmetastatic osteosarcoma who have undergone surgical resection or amputation of the primary tumor. Given as a high-dose regimen with leucovorin rescue in combination with other chemotherapeutic agents. ■ Given PO or IM for early-stage mycosis fungoides, trophoblastic diseases (gestation choriocarcinoma, chorioadenoma destruens, and hydatidiform mole), polyarticular-course juvenile rheumatoid arthritis, rheumatoid arthritis, and other diagnoses, and given intrathecally for treatment and prophylaxis of meningeal leukemia.

Question 28

Define the cell cycle and give a brief explanation of each of its stages.

Answer 28

The cell cycle is the series of phases that both normal and cancer cells go through. Cells in the body normally divide and enter a resting phase, where they usually remain unless they need to replicate as a result of damage or death. There are five stages in the cell cycle:

· G0 -A dormant stage where the cell is not multiplying.

· G1 -Stage where replication is begun through ribonucleic acid (RNA) and protein synthesis.

· S -Deoxyribonucleic acid (DNA) is synthesized.

· G2 -The mitotic spindle is manufactured; also called premitosis. ·

M -Mitosis or actual cells divide and multiply.

Question 29

Give a brief explanation of what happens to the normal cell cycle when cancer cells develop.

Answer 29

The control mechanism preventing uncontrolled cell division in normal cells is not operating properly in cancerous cells. Therefore, the cancer cells keep dividing regardless of need, and they form cell masses or tumors, which can also push into other areas of the body resulting in what is known as metastases. Many cancer cells are actively dividing, some cells may be in a resting phase, and some of the cancer cells are immature. An immature cell is one that is not differentiated into a specific type of cell. The number of cells in a tumor mass is called the tumor burden.

Question 30

Explain the primary purpose of administering antineoplastic agents to patients. Describe the two basic types of antineoplastic agents.

Answer 30

While there are a number of different types of antineoplastic drugs now available, the basic purpose of all of them is to prevent cancer cells from dividing by disrupting the cell division process at some point or destroying some component involved in cell division. Many of the agents also have the same effects on normal cells so the key is to either begin therapy early or target the therapy during a time of heavy cell replication. There are two types of antineoplastic agents, ones that are cell cycle-specific and those that are cell cycle-nonspecific.

· The cell cycle-specific agents either inhibit or interfere with some part of the cell cycle, and are therefore most effective during heavy replication.

· The nonspecific agents target the cells in a resting phase by mechanisms such as chromosomal damage, destruction of DNA, prevention of RNA transcription or other nonselective actions.

Question 31

There are two main types of drugs used for cancer treatment that interfere specifically with the cell cycle. Name and describe the mechanism of action of each and give some specific examples of drugs utilized.

Answer 31

The two main types of cell cycle-specific drugs used in cancer treatment are either antimetabolites or vinca alkaloids.

· Antimetabolites act during the S phase of cell replication by suppressing DNA synthesis and therefore protein synthesis as well. These agents can have some side effects on the blood or gastrointestinal system; they include drugs such as methotrexate, cytarabine, and fluorouracil. ·

The vinca alkaloids obtained from plants act to prevent cell division during any phase of the cell cycle (except the resting stage) by blocking both DNA and RNA synthesis and binding to the tubules. They can have neurological side effects; these agents include vinblastine, vincristine, and vinorelbine.

Question 32

List and describe the mechanism of action of the most common cell cycle-nonspecific agents to treat cancer. Give some specific examples.

Answer 32

There are a number of types of agents that act on cells when they are not actively dividing. These include most alkylating agents, antitumor antibiotics, and nitrosoureas as well as some miscellaneous drugs and biologic agents. The first three types of agents are drugs that interfere in some way with either DNA or RNA.

· Alkylating agents such as cisplatin and cyclophosphamide interfere with replication of deoxyribonucleic acid.

· Antitumor antibiotics employ several different mechanisms to either interfere with RNA synthesis or to suppress or actually react with DNA. Some examples of antitumor antibiotics include bleomycin, doxorubicin hydrochloride, and mitomycin C.

· Nitrosoureas such as carmustine and streptozocin also inhibit DNA replication and repair.

Question 33

Some chemotherapeutic agents have strict dosage and lifetime cumulative dosage requirements. Explain what category these agents generally fall into and why.

Answer 33

The dosage of chemotherapeutic agents usually needs to be monitored because of the more severe side effects of bone marrow suppression, cardiotoxicity or other toxicities, or the possibility of a hypersensitivity reaction that could result in anaphylaxis. Some of the antitumor antibiotics have strict dosage and lifetime cumulative dosage requirements. Antibiotics can lose their effectiveness if given in excessive amounts. Drugs that suppress the bone marrow, such as Cerubidine, Adriamycin, or Mutamycin, typically have these strict dosage requirements including lifetime limits.

Question 34

Explain the unique considerations of administering plicamycin as a chemotherapeutic agent.

Answer 34

Plicamycin (Mithracin) is generally given to a patient to control the hypercalcemia that accompanies malignant disease by continuous or intermittent infusion. It inhibits bone reabsorption and reduces serum calcium levels. Therefore, in addition to the possible side effects of bone marrow suppression, renal or liver toxicity, and others, actual hypocalcemia might occur if excessive amounts are given. Symptoms might include muscle cramps, weakness, a tingling in the legs or arms, or most importantly facial redness, nosebleeds, and phlebitis. Facial flushing is an early indication of hemorrhage. Be sure to monitor CBCs and electrolyte levels. The health care provider should give no more than a dosage of 25 microgram per kg per day for 3 to 4 days each week to control hypercalcemia. If Mithracin is used to treat testicular cancer, it may be administered for up to 10 days.

Question 35

Explain the unique characteristics of doxorubicin liposome injection (Doxil) and its administration.

Answer 35

Doxorubicin liposome injection (Doxil) had been prepared as a liposome suspension and is therefore an irritant. It is also not compatible with 0.9% saline solutions and must instead be given by intermittent infusion in 5% dextrose in water only. The patient should expect their urine to be red in color for the first few voidings after administration. Doxil may not be well tolerated and in addition to a number of common side effects of chemotherapy it specifically can cause skin or blood side effects. Do not exceed a total cumulative dose of 550 mg/ m2.

Question 36

There are a variety of possible side effects and risks associated with antineoplastic therapy. Give the types of risks and some examples.

Answer 36

Some of the most important immediate side effects of antineoplastic therapy include allergic reactions, inflammation of the blood vessels, leaking of fluid from the blood vessels into the surrounding tissues, and gastrointestinal problems. All of these must be closely monitored. Later, a number of delayed effects can occur including baldness, suppression of the bone marrow, gastrointestinal problems such as diarrhea, nausea and vomiting, reproductive or sexual issues, changes in ability to taste, increase in mucous, and the possibility of developing psychosocial problems. Toxicity can develop in a number of bodily systems including in the bone marrow, the cardiovascular system, kidneys, the bladder, the liver, the lungs, or the nervous system.

Question 37

List and define the types of hematologic complications that might occur with chemotherapy. Explain what symptoms need to be monitored and how they might be alleviated.

Answer 37

The main three types of hematologic complications found during chemotherapy administration are neutropenia, thrombocytopenia, and anemia. In neutropenia there is a decreased white blood cell count with a concurrent decrease in the neutrophil (ANC) count, which predisposes the patient to infection. Therefore, symptoms such as fever and purulent damage and WBC and ANC counts should be monitored, and antibiotics given if infection is confirmed. Thrombocytopenia is defined as a decrease in platelet count which may result in an increased susceptibility to bleeding. Attention should be paid to bleeding gums or nosebleeds, blood in the urine or stools, easy bruising, or a large spleen or liver. Pressure should be applied to the bleeding and the physician contacted. If the oxygen-carrying capacity of the blood is decreased because the number of red blood cells is low, a condition called anemia may result. The patient might have a number of cardiac or fatigue-type symptoms. If abnormal hemoglobin or hematocrit is obtained, red blood cells, oxygen, or erythropoietin may be indicated.

Question 38

Explain the types of gastrointestinal complications that can occur with chemotherapy, the major risks involved, and types of therapy.

Answer 38

Common gastrointestinal complications of chemotherapy include nausea and vomiting, anorexia, diarrhea, and sometimes constipation. The major risk involved if the first three occur is the possibility of dehydration and insufficient nutritional status. If diarrhea occurs, electrolyte imbalance can also occur. If nausea and vomiting occur, use of antiemetics is usually indicated. If the patient becomes anorexic, high protein or high calorie foods may be prescribed as well as nutritional supplements, appetite stimulants, or even administration of total nutrition parenterally. Serum electrolytes should be monitored, antidiarrheal agents administered, and a high protein, high fluid diet prescribed. Fluid intake also needs to be increased if constipation occurs and a diet high in fiber and bulk prescribed.

Question 39

Many chemotherapeutic agents adversely affect renal function. Name some of these agents and explain the precautions that should be taken when administering these.

Answer 39

Chemotherapeutic agents that are known to often specifically affect renal function including toxicity, hemorrhagic cystitis, and frequent or burning urination. With these drugs, the patient should be given adequate hydration before and after drug administration and they should be encouraged to increase their oral fluid intake and empty their bladder every 4 hours. Laboratory results that should be monitored include BUN, serum creatinine, creatinine clearance, urinalysis and uric acid. The nitrosoureas, which are irritants, often cause renal toxicity, and in the case of streptozocin the urine should be monitored for protein. High dosages of methotrexate, an antimetabolite, often cause renal problems and need to be reversed within 24 hours with leucovorin calcium rescue.

Question 40

Often antineoplastic agents given to cancer patients may actually be administered as part of an investigational protocol. For drugs (or devices) used in clinical investigations, explain the possible phases.

Answer 40

Clinical investigations are divided into 4 distinct phases.

· For drugs, phase I is designed merely to determine the highest tolerated dose of the drug including toxicities and to examine the pharmacology involved; subjects may be normal individuals.

· Phase II for an antitumor drug would involve looking at more defined doses or administration schedules to further evaluate antitumor activity or toxicity.

· In phase III, the investigational drug is compared to existing drug protocols, after which the drug can be marketed if the Food and Drug Administration finds favorable results.

· Phase IV are trials that give more information about prolonged use of the agent after it has been marketed. In a hospital or other institution where trials are performed, they are internally monitored by the Institutional Review Board.

Question 41

List the 7 most common alkylating agents for cancer treatment today by generic and brand name. Give their category type and indications for use.

Answer 41

· Carboplatin (Paraplatin)—Non-vesicant, indicated for solid tumors such as brain tumors, before bone marrow transplantation, and in a number of other cancers

· Cisplatin (Platinol)—An irritant and also a vesicant in high concentration, used to treat neuroblastoma, Wilms’ tumor, multiple myeloma, lymphoma, plus other cancers

· Cyclophosphamide (Cytoxan)—Non-vesicant, again used to prepare for bone marrow transplantation, and to treat lymphocytic leukemia, Hodgkin’s and non-Hodgkin’s lymphoma, myeloma, mycosis fungoides, and other tumors

· Decarbazine (DTIC)—Irritant, indicated to treat melanoma, soft tissue sarcomas, neuroblastoma and Hodgkin’s disease

· Ifosfamide (Ifex)—Non-vesicant, for treatment of lung, hormone-associated cancers, sarcoma, or non-Hodgkin’s lymphoma

· Mechlorethamine hydrochloride (Mustargen)—Vesicant, for treatment of chronic lymphocytic or myelogenous leukemia or Hodgkin’s disease

· Thiotepa (Thioplex)—Non-vesicant, used before bone marrow transplantation, and to treat Hodgkin’s disease, lymphoma, or brain, breast, ovarian or bladder cancers

Question 42

List the three commonly utilized vinca alkaloids and explain the nature of their drug specificity, their category, indications for use and the most important side effects to consider.

Answer 42

Vinca, or plant-derived, alkaloids inhibit mitosis and are therefore agents that inhibit cell division. There are 3 vinca alkaloids, all vesicants, which are commonly administered. These are vinblastine (Velban), vincristine (Oncovin), and vinorelbine (Navelbine). ·

Currently, vinblastine is indicated for histiocytosis, Hodgkin’s disease, Kaposi’s sarcoma, testicular cancer and squamous cell head or neck carcinoma.

· Vincristine is used to treat a number of leukemias and lymphomas as well as melanoma, sarcoma, Wilms’ tumor, multiple myeloma, neuroblastoma, breast and small cell lung carcinoma.

· Vinorelbine is normally used to treat either breast cancer or non-small cell lung cancer.

Each of these agents can cause neurological complications among other side effects. Vinblastine and vinorelbine can also suppress the bone marrow.

Question 43

List the 8 commonly used types of antitumor antibiotics by generic and brand name. Give their category type and their major indications for use.

Answer 43

Bleomycin (Blenoxane)—A non-vesicant, used to treat Hodgkin’s disease, non-Hodgkin’s lymphoma, head and neck squamous cell carcinomas, and various cancers of the reproductive system.

Dactinomycin (Cosmegen)—Vesicant, for treating Wilms’ tumor, choriocarcinoma, several connective tissue-derived tumors, or testicular tumors.

Daunorubicin hydrochloride (Cerubidine)—Vesicant, used to treat leukemias, especially in children, or non-Hodgkin’s lymphoma.

Doxorubicin hydrochloride (Adriamycin)—Vesicant, indicated for acute myeloid or lymphocytic leukemias, Hodgkin’s disease, small cell lung carcinoma, multiple myeloma, and a variety of other cancers.

Doxorubicin Liposome Injection (Doxil)—Irritant, used to treat Kaposi’s sarcoma and cancer of the ovaries.

Mitomycin (Mutamycin)—Vesicant, for treatment of a wide range of systemic cancers.

Mitoxantrone hydrochloride (Novantrone)—Vesicant, indicated primarily for treatment of breast cancer, lymphoma or acute nonlymphocytic leukemia.

Plicamycin (Mithracin)—Irritant, used mostly to treat testicular cancer, and the high levels of calcium that may be associated with malignant disease.

Question 44

There are a few cell cycle-nonspecific antitumor agents besides alkylating agents and antitumor antibiotics. Name their pharmacologic classifications and give examples. Indicate when they are used.

Answer 44

Besides alkylating agents and antitumor antibiotics, nitrosoureas and taxanes are sometimes administered. These agents are not cell cycle specific.

· The nitrosoureas include carmustine (BCNU) and streptozocin (Zanosar). BCNU is an irritant and is before bone marrow transplantation, in Hodgkin’s and non-Hodgkin’s lymphoma, melanoma, myeloma and tumors of the central nervous system.

· Taxanes are another classification of agent employed; the most common is docetaxel (Taxotere), which is again an irritant and is indicated for non-small cell lung cancer, ovarian cancer that has metastasized, and cancers of the breast, head and neck regions.

Question 45

Currently there are also some antitumor agents that act by cell cycle-specific modes that are either of miscellaneous or unique classifications. List them, their classification, and their indications.

Answer 45

At present, there are three common cell cycle-specific agents that one would put in a miscellaneous category. They are asparaginase (Elspar) which is primarily used to treat acute lymphocytic leukemia, irinotecan (Camptosar), commonly used to treat colon or rectal cancer, and paclitaxel (Taxol). Taxol, which can be an irritant, is employed to treat a number of types of cancers, including metastatic ovarian, breast, lung, head, and neck carcinomas as well Kaposi’s sarcoma. Another drug called etoposide (VP-16, VePesid) is classified as an epipodophyllotoxin and is commonly used to treat lymphomas and leukemias as well as myeloma, small cell lung cancer, and breast and testicular cancer. Topotecan or Hycamtin is classified as a camptothecin, and it used to treat acute lymphocytic leukemia, metastatic ovarian cancer, some solid tumors as well as non-small cell lung carcinoma.

Question 46

Explain what a nomogram chart is and how it is utilized for antitumor treatment administration. Give a formula for using this chart.

Answer 46

A nomogram chart is a method of calculating body surface area (BSA). There are different charts for adults versus children and infants. BSA in m2 (square meters) is determined from the nomogram chart by drawing a line between two scales for height and weight through a scale for body surface area in the middle. The point where the drawn line intersects the body surface scale gives the BSA. Then the antitumor treatment dose is determined by the formula:

Treatment dose (in mg) = Body surface area (in m2) x dose ordered (in mg/ m2)

There is also usually lifetime dosage limit for these drugs, which can be calculated by:

Lifetime dose (in mg) = Body surface area (in m2) x recommended limit (in mg/ m2)

Question 47

List the various antimetabolites that are currently used for cancer treatment by both generic and brand name. Explain their basic method of action and give indications for each.

Answer 47

There are five main antimetabolites currently used to treat neoplasms. Each one acts by inhibiting either DNA or protein synthesis by a replacement type of reaction during the actual cell division cycle. Several of these agents are used to treat lymphomas or leukemias, including cytarabine (cytosine arabinoside or Cytosar-U), fludarabine (Fludara), and methotrexate (Mexate-AQ). Methotrexate is indicated for treatment of other cancers as well, including osteogenic sarcoma, gestational trophoblastic tumors, and breast, cervical, lung, head and neck cancers. Two other antimetabolites are also currently used; they are fluorouracil (5-FU) and gemcitabine (Gemzar). Both are employed to treat breast, ovarian, and pancreatic cancer. 5-FU is sometimes used for gastrointestinal tract or liver cancer as well and Gemzar may be given to lung cancer patients. All of these agents are non-vesicants.

Question 48

Define biotherapy and immunotherapy. Describe the most important biologic agents used in cancer therapy.

Answer 48

Biotherapy is the use of some type of substance obtained or derived from an actual biologic source. Immunotherapy is a form of treatment that utilizes the body’s immune processes in some manner. For cancer therapy, commonly employed immunotherapeutic agents fall into three types, interferons, interleukins, and monoclonal antibodies.

· Interferons are antiviral substances produced in mammals.

Interleukins act by regulating the immune cascade sequence at some point. · A commonly administered interleukin is interleukin-2 (aldesleukin, Proleukin), which is used to treat renal cell carcinoma or metastatic melanoma; one must watch for flu-like symptoms, bone marrow suppression or other side effects.

· Monoclonal antibodies have been specifically engineered to react with a particular antigen usually specific to one type of cancer. Currently employed monoclonal antibodies include rituximab (Rituxan), indicated to target CD20 + (a B cell marker) non-Hodgkin’s lymphoma, and trastuzumab (Herceptin), which recognizes the HER-2 protein found in some breast carcinomas.

Question 49

List the three types of biologic agents currently used as cancer treatments, explain their methods of action, and give examples.

Answer 49

The three classes of biologic agents used at present in cancer treatment are hematopoietic growth factors, interferons and interleukins, and monoclonal antibodies.

· Hematopoietic growth factors are involved in the development of red blood cells.

· Interferons and interleukins both have effects on the immune system that can be antiviral or in some way immunomodulatory. Interleukins such as interleukin-2 can actually interfere with tumor cell development and spread.

· Monoclonal antibodies are highly specific antibodies that have been developed and isolated to react with specific tumor-associated antigens. These include rituximab and trastuzumab.

Question 50

Discuss the indications and considerations for the infusion of monoclonal antibodies such as Remicade.

Answer 50

Monoclonal antibodies, such as infliximab (Remicade ®), bevacizumab (Avastin ®), and cetuximab (Erbitux ®), are synthesized using DNA technology. Monoclonal antibodies, which are immunosuppressives, are used in the treatment of many types of cancer (usually in combination with other drugs), inflammatory diseases (such as rheumatoid arthritis), multiple sclerosis, and organ transplantation. For cancer treatments, monoclonal antibodies target cancer cells rather than all body cells; however, monoclonal antibodies are associated with a wide range of adverse effects, such as flu-like symptoms (fever, chills, respiratory infections). Primary adverse effects vary according to the specific drug. For example, infliximab may cause headache, rash, GI upset, and upper and lower respiratory infection. Bevacizumab may cause DVT, hypertension, GI upset, leukopenia, hypokalemia, and proteinuria. Patients receiving intravenous infusions of monoclonal antibodies are at increased risk of severe allergic reactions to the drugs. To reduce risk, patients may be premedicated with acetaminophen and diphenhydramine. These same drugs as well as corticosteroids and epinephrine may be used to treat allergic reactions.

Question 51

Discuss the indications and considerations for the infusion of B-cell inhibitors such as Rituxan.

Answer 51

B-cell inhibitors, such as rituximab (Rituxan ®) and tositumomab, are monoclonal antibodies that target and bind to CD20 antigens on B lymphocyte cells (both normal and malignant) and result in destruction of the cell. B-cell inhibitors are used in the treatment of non-Hodgkin’s lymphoma because > 90% of B-cell NH lymphomas express the CD20 antigens, so destruction of these cells decreases the malignant cells. In other diseases, such as rheumatoid arthritis, the destruction of B-cells decreases the production of autoantibodies, reducing the effects of the disease. Rituximab may cause tumor lysis syndrome with acute renal failure, respiratory distress syndrome, flu-like symptoms, dyspnea, bronchospasm, and pulmonary infiltrates. Tositumomab may cause flu-like symptoms, headache, rash, infection, and hypertension. As with other monoclonal antibodies, patients who are to receive B-cell inhibitors per IV infusion should be premedicated with acetaminophen and diphenhydramine to prevent severe and sometimes fatal allergic reactions.

Question 52

Discuss the indications and considerations for the infusion of T-cell inhibitors such as Orencia.

Answer 52

T-cell inhibitors, such as abatacept (Orencia ®), are immunomodulating drugs that inhibit T-cell activation. Abatacept is used primarily in the treatment of rheumatoid arthritis and may be used in conjunction with other DMARDs or by itself if DMARDs have been infective. Intravenous infusions are given initially and at 2-week intervals for the first month of treatment and then once a month, with dosage according to patient’s weight in Kg. The infusion is usually per intravenous infusion administered over a 30-minute period with an IV filter in place. Adverse effects include cold and flu-like symptoms, and hypertension. Patients should not receive vaccinations while being treated with T-cell inhibitors, especially live vaccines, and should not receive anakinra, TNF-blocking drugs, or echinacea because of increased risk of infection. Because of the risk (rare) of severe allergic reactions, patients should be premedicated with acetaminophen and diphenhydramine.

Question 53

Indicate the purpose of administering immune modulator reagents and give specific examples.

Answer 53

Immune modulator agents can be compounds that stimulate or suppress the immune system, or they may be targeted monoclonal antibodies. The most common immunostimulant is probably immune globulin IV (Sandoglobulin is a commercial name), which is used to restore immunoglobulin G levels. There are several agents available that suppress the immune system. These include aldesleukin (Interleukin-2 Recombinant), often given to patients with cancer or some other type of immune malfunction, azathioprine sodium (Imuran), and cyclosporine (Sandimmune IV), which is administered before transplantation surgery. Monoclonal antibodies are antibodies that are isolated or produced with a targeted specificity. Today they are used to treat a number of diseases, including alemtuzumab (Campath), which is employed to treat leukemia.