ANTINEOPLASTIC AGENTS

CLINICAL PHARMACOLOGY & THERAPEUTICS III

READING ASSIGNMENT
Chapter 45 Pages 493 - 511

OBJECTIVES
1. Evaluate the categories of antineoplastic agents. 2. Dissect the nomenclature of monoclonal antibodies to facilitate the comprehension of agent source and application. 3. Discuss the principles of chemotherapy, cellular effects, and limitations. 4. Evaluate the development of chemotherapy regimens in managing neoplastic processes. 5. Gain insight into the development of drug resistance .

6. Assess toxicities associated with antineoplastic therapies. 7. Relate the key components of antineoplastic therapy both acute and long term to a primary care provider. 8. Discuss advantages & disadvantages of oral antineoplastic agents and review the indications and side effects of multiple agents. 9. Note various supportive agents in antineoplastic therapies. 10. Review the role of hormone agents in managing disease.

ANTINEOPLASTIC AGENTS
Cytotoxic Agents Targeted Anticancer Drugs

Nonspecifically inhibit DNA replication or mitosis.

Inhibit specific proteins involved in tumor cell growth

Monoclonal Antibodies Inhibitors of protein kinases linked to growth factor receptors

MONOCLONAL ANTIBODIES
Names end in MAB Letter preceding indicates source for AB:
O is for mouse U for human XI is chimeric

Internal letter indicates therapeutic use:

TU for tumor VI for virus C or CI for circulation

LIMITATIONS OF CHEMOTHERAPY
1. Tumor cell resistance 2. Production of host toxicity 3. Inability to suppress metastasis.

CYTOTOXIC ANTINEOPLASTIC AGENTS

Cell cycle specific Cell cycle non-specific

Drugs that act during a specific phase of the cell cycle. DNA synthesis inhibitors, mitotic inhibitors

Drugs that are active throughout the cell cycle. DNA alkylating agents, DNA intercalating agents

PRINCIPLES OF CANCER THERAPY

Antineoplastic agents are used to treat hematologic malignancies, lesions that cannot be surgically removed or to eliminate micro metastasis.

Agents may be used curative or palliative dependent upon the disease and staging.
Some agents are administered prophylactically.

CHEMO REGIMENS
Designed to optimize the synergistic effects of agents while minimizing the toxicity. Induction:
Produce a rapid reduction in tumor cell burden. Produce a symptomatic response in the patient

Consolidation:
Completes or extends the initial remission Often a different combination of agents.

Maintenance:
Sustain the remission Less frequent administration of different classes of drugs from above

MOST COMPLICATED FORM OF DRUG THERAPY IN USE TODAY

Intermittent administration of multiple drugs.
Allows for recovery of bone marrow and normal host cells to recover between courses. Reduces levels of toxicity.

Based on clinical trials.

Phase I-IV
Drug kinetics, tumor cell cycle kinetics, drug toxicity

Determine tolerances Identifies toxicities Determine efficacy

First line drugs used for initial treatment Subsequent regimens determined by tolerances, toxicities

DRUG RESISTANCE
Major cause of cancer treatment failure. Tumor cell resistance can be innate or acquired. Failure of agents to reach target or ineffective dosing. Acquired drug resistance can result from genomic mutations or abnormal gene expression occurring during uncontrolled replication of tumor cells.

TOXICITIES
Myelosuppression
Most agents impact marrow function

Cardiac toxicity

Nadir events occur 7-10 days post exposure. Recovery is dependent on agent.
Growth factors have impacted practice

Anthracyclines, taxanes, Herceptin

Dose dependent

Renal toxicity
Cisplatin

Nausea/vomiting Pulmonary
Bleomycin, BCNU
5FU, Camptosar
Leucovorin

Serotonin antagonists Rx

Neurotoxicity

Mannitol, fluid hydration Sodium thiosulfate

Stomatitis/Diarrhea

Hemorrhagic cystitits
Ifosfamide, cytoxan
Mesna

Multiple agents (Platinol, vincristine, paclitaxel)

Alopecia

REALITIES
Therapeutic decisions related to management of hematologic or solid tumor malignancies is deferred to specialists such as oncologists. Even if working in Heme/onc practice therapeutic decisions are based on ASCO guidelines and typically made by physician. Some patients Rx w/oral agents may potentially be seen in PCP As PCP you will see patients post induction or consolidation therapies.

Patients on hormonal therapy will often be seen in PCP offices. Patients may present many years after exposure to agents w/sxs of toxicities from exposure to various agents.

Maintenance therapies are intermittent and as such may pose opportunities for PCP

ORAL CHEMOAGENTS
The chief advantage of oral chemotherapy is the convenience
Without having to go to a clinic or hospital and sit through sometimes hours of IV infusions.

Another great benefit to oral chemotherapy is that it gives the patient a degree of control.
Control is a major issue with chemo patients.

 A drawback to oral chemotherapy is that oral chemo drugs have all the same side effects.
Nausea is sometimes worsened due to gastric absorption Vomiting may prevent absorption.

Other drawbacks to oral chemotherapy include:

variable absorption, unpredictable and incomplete bioavailability, and uncertainty about patient compliance.

CYCLOPHOSPHAMIDE (CYTOXAN)
IV or PO Side Effects:
Alopecia, nausea and vomiting, Stomatitis Anorexia

Indications:
breast cancer, leukemia, cutaneous T-cell lymphoma, lung cancer, multiple myeloma and ovarian cancer.

ETOPOSIDE (TOPOSAR)
Side effects may include increased risk of infection, hair loss, loss of appetite, nausea and vomiting. Indications:
prostate cancer, Kaposi's sarcoma, small cell lung cancer and lymphoma.

IDARUBICIN (IDAMYCIN)
Indications:
breast cancer acute nonlymphocytic leukemia.

Side effects:
Leukopenia, nausea and vomiting, skin rash hair loss

VINORELBINE (NAVELBINE)
IV & PO preparations Indications:
non-small cell lung cancer breast cancer.

Side effects can include constipation, fatigue and weakness, increased risk of infection and nausea and vomiting.

IMATINIB (GLEEVEC)
Indications:
chronic myeloid leukemia GIST

Side Effects:
The drug may cause weight gain, diarrhea, muscle aches, fatigue, stomach pain and skin rash.

METHOTREXATE
IV & PO formulations Indications:
ALL Breast cancers Non-Hodgkins Lymphoma Osteosarcoma Leptomenigeal carcinomatosis Rheumatoid dz, psoriasis

Side effects:
Nausea/vomiting Diarrhea Myelosuppression Oral ulcers Hepatotoxicity Renal toxicity

MERCAPTOPURINE
Indications:
ALL Crohn's disease ulcerative colitis Typically combined w/thioguanine

Side effects:
Nausea/vomiting/diarrhea darkening of the skin alopecia rash myelosuppression hepatotoxicity anorexia

THIOGUANINE
Indication: Complications:
Amenorrhea Sterility in males Birth defects headache

Leukemia

Side effects:

Myelosupression darkening of the skin Anorexia stomatitis fatigue Dysuria/ hematuria GI BLEED n/v, diarrhea swelling of the feet and/or legs cough Hepatotoxicity arthralgia

HYDROXYUREA
Indications:
melanoma chronic myelocytic leukemia (CML;) recurrent, metastatic, or inoperable ovarian cancer to control primary squamous cell carcinoma to prevent crises and decrease the need for blood transfusions in sickle cell anemia Malignant gliomas Polycythemia Psoriasis

side effects:

Nausea/vomiting/diarrhea constipation drowsiness rash purple, blue, or black discoloration of the skin or nails paraesthesia Stomatitis foul-smelling substance oozing from the skin swelling of the hands, feet, ankles, or lower legs

CHLORAMBUCIL
Indications:
chronic lymphocytic leukemia (CLL). non-Hodgkin's lymphoma (NHL) Hodgkin's disease

Side Effects:

Nausea/vomiting stomatitis Myelosuppression Amenorrhea Skin rash GI Bleed Dysuria, red or dark urine Cough & congestion difficulty breathing seizures Jaundice hepatotoxicity

THALIDOMIDE
Side effects: Indications: Sedation, dizziness multiple myeloma Confusion, anxiety, depression or mood skin symptoms of erythema changes nodosum leprosum (ENL; episodes difficulty falling asleep or staying asleep of skin sores, fever, and nerve Arthralgias headache damage that occur in people with GI c/o Hansen's disease [leprosy]). dry mouth, dry skin, itching Myelodysplastic syndrome Tardive dyskinesia complications of human swelling of the hands, feet, ankles, or immunodeficiency virus (HIV) lower legs Erectile dysfunction aphthous stomatitis , rash HIV-associated diarrhea, blistering and peeling skin HIV-associated wasting swelling of the face, throat, tongue, lips, or eyes syndrome, difficulty swallowing or breathing Kaposi's sarcoma chronic graft myelosuppression versus host disease arrhythmia Crohn's disease seizures

OTHER ORAL AGENTS

Topotecan hydrochloride (Hycamtin) Sorafenib tosylate (Nexavar) Lenalidomide (Revlimid) Dasatinib (Sprycel) Sunitinib malate (Sutent) Erlotinib (Tarceva) Nilotinib (Tasigna) Temozolomide (Temodar) Lapatinib (Tykerb)

SUPPORTIVE AGENTS
Allopurinol: Inhibits the synthesis of uric acid (complication from rapid cell kill w/induction therapy for acute leukemia). Mesna: IV or PO (liquid). Provides protection of bladder wall following administration of Ifosfamide. Leucovorin: Cytoprotective. Protects cells of GI tract from effects of 5FU. Steroids: Therapeutic, anti-emetic Ondansetron: Potent antiemetic Colony Stimulating Factors: Neulasta, Neupogen, Leukine; Epogen, Procrit, Aranesp; n-plate, Promacta, Neumega

HORMONAL AGENTS
Breast cancer: Estrogen antagonist (Tamoxifen), Aromatase inhibitors:
anastrozole (Arimidex) exemestane (Aromasin) letrozole (Femara)

Prostate cancer: Androgen antagonists [flutamide (Eulexin), bicalutamide (Casodex), and nilutamide (Nilandron)], are taken daily as pills.
Luteinizing hormone-releasing hormone (LHRH) analogs [(Lupron, Eligard), goserelin (Zoladex), triptorelin (Trelstar), and histrelin (Vantas)].

THE FUTURE
New agents are constantly under investigation. Immunomodulating agents, biologicals, and protein bound agents reduce toxicities but are much more expensive.