CHEMOTHERAPY Dr M Torfehnezhad Pediatrician Definition Chemotherapy The

CHEMOTHERAPY Dr. M. Torfehnezhad Pediatrician

Definition: Chemotherapy • The treatment of cancer using specific chemical agents or drugs that are destructive to malignant cells and tissues. The term comes from two words that mean "chemical" and "treatment. " Cytotoxic • literally translated means ‘toxic to cells’.

The Cell Cycle

Mitosis

Cell Biology: Mitosis l. A cell in mitosis

Normal Cell Characteristics: l Metabolism. Strictly controlled & predictable l Maturation & Specialisation. Occurrs before dividing. Strictly controlled. l Reproduction = Cell death l Contact Inhibition. Mechanism for switching off division when in contact with different cells l Recognition. Like cells stay together.

Cancer Cell Characteristics: l Unchecked & Uncontrolled Growth l Loss of contact inhibition l Loss of capacity to differentiate l Increased growth fraction l Chromosomal Instability l Capacity to metastasise l Altered biochemical properties

Chemotherapy and Cancer Cells Cell Cycle specific : Most active against cells in a specific phase therefore need prolonged exposure or repeated doses. Cell Cycle Non-specific: Most effective against actively dividing cells

Chemotherapy may be used conventionally to: l Cure patients l Prolong survival l Palliative care symptom control

Chemotherapy Combination Therapy. Prevents resistance. Adjuvant Therapy. Administered after primary therapy e. g. Surgery Neo adjuvant Therapy: Given before surgery to reduce tumour size.

Chemotherapy Over 50 different chemotherapy drugs Administered as an outpatient or inpatient depending on toxicity Modes of administration include: l l l Oral e. g. Methotrexate, Hydroxyurea IV: Canula/Indwelling Central Venous Catheter Sub cut Intracavity e. g pelvic cavity, bladder Intrathecal. Can be fatal if wrong drug administered!

Intrathecal Chemotherapy

Drugs Used in Cancer Chemotherapy l Cytotoxic Agents Alkylating Agents l Antimetabolites l Cytotoxic antibiotics l Plant derivatives l l Hormones l Suppress nat’l hormone secr’n or antagonize hormone action l Misc (mostly target oncogene products)

Rand 50. 3

Alkylating Agents l Contain chemical groups that bind cell nucleophiles

Alkylating Agents l Cisplatin (Platinol), Mechlorethamine (Mustargen) and Cytoxan are commonly used agents in this category l Carboplatin- more myelotoxic l Action: substitutes an alkyl chemical structure for a hydrogen atom in the DNA l This results in a cross-linking of each strand of DNA, thus preventing cell division

Alkylating Agents, con’t l Effective against lymphomas, leukemias, myelomas, ovarian, testicular, breast, and pancreatic cancers l Cause bone marrow suppression, alteration in mucous membranes, severe N&V, alopecia

Alkylating Agents, con’t l Can also cause ototoxicity and nephrotoxicity. Be sure the patient is well hydrated before receiving these agents

Cyclophosphamide l Most common l Prodrug – liver metab by CYP P 450 MFO’s l Effects lymphocytes l Also immunosuppressant l Oral or IV usually l SE’s: n/v, bone marrow dpression, l Cytoxan cause hemorrhagic cystitis (give MESNA to protect the bladder)

Antimetabolites l These drugs have a structure similar to a necessary building block for the formation of DNA. l These drugs are accepted by the cell as the necessary ingredient for cell growth, but because it is an imposter, it interferes with the production of DNA.

Antimetabolites l Kill cells in S phase l Three main groups Folate antagonists l Pyr analogs l Pur analogs l

Folic Acid Analogs l Folic acid essential for synth purines, and thymidylate

Methotrexate l Higher affinity for enz than does FH 2 l Inhib’n DNA synth

Pyrimidine Analogs l 5 -Fluorouracil Competitive inhibitor for thymidylate synthetase active site l Decr’d DNA synthesis l

l Gemcitabine l Inhib’s ribonucleotide reductase decr’d nucleotide synth

l Cytosine l arabinoside (cytarabine) Inhibits DNA polymerase l Gemcitabine l Fewer SE’s – ara. C analog

Purine Analogs l 6 -Mercaptopurine, l 6 -Thioguanine Inhibit enz’s necessary for purine synth l Fludarabine Converted to triphosphate l Mech action sim to ara-C l l Pentostatin l Inhibits adenosine deaminase l l Catalyzes adenosine inosine Interferes w/ purinemetab, cell prolif’n

Antibiotic Antineoplastic Agents l These agents actually bind DNA, thus inhibiting DNA and RNA synthesis and therefore inhibiting cell growth. l Sadly, these drugs have great potential to cause irreversible cardiomyopathies. l Doxorubicin (Adriamycin) is used for acute leukemias, soft tissue/bone cancers, lymphomas, and breast cancer

Antibiotic Agents, con’t l Adriamycin is also a potent vessicant (will cause tissue necrosis if it infiltrates) l Most dangerous side effect is decreased ejection fraction (normal is 70%). Must do baseline CV assessment prior to beginning Adriamycin (EKG, echo, angiography). l Must reduce the dose of chemo at the first sign of heart failure

Antibiotic agents, con’t l Other side effects include stomatitis, alopecia, bone marrow suppression, hepatic impairment.

Antibiotic agents, con’t l Dactinomycin l l Interferes w/ RNA polymerase movement decr’d transcr’n Bleomycin Glycopeptide l Chelates Fe, which interacts w/ O 2 l Gen’n superoxide and/or hydroxyl radicals l Radicals degrade DNA fragmentation, release of free bases l Most effective in G 2, also active against cells in G 0 l Little myelosuppression BUT pulmonary fibrosis l

Mitotic Inhibitors l These drugs are also called Vinca. Alkaloids l Work by inhibiting mitosis during cell division l Vinblastine (Velban) and Vincristine (Oncovin) are commonly used agents for ALL, lymphomas, rhabdomyosarcoma)

Mitotic Inhibitors, con’t l Neurotoxicity is a specific side effect for this classification of drugs. Peripheral neuropathy, alteration in bowel and bladder tone (including paralytic ileus), headache, tingling of fingers/hands/toes, ataxia. l Constipation is common due to effects on the autonomic nervous system

Vinca Alkaloids

l Etoposide, teniposide From mandrake root l Inhibit mitoch function, nucleoside transport, topoisomerase II l l Campothecins: irinotecan, topotecan Irinotecan requires hydrolysis active form l Bind, inhibit topoisomerase II l

Hormonal Agents l Used to treat neoplasms that are sensitive to hormonal growth controls of the body. l They interfere with growth-stimulating receptors on target tissues. l Corticosteroids are considered hormonal agents. They retard lymphocytic proliferation, so they help with lymphocytic leukemias and lymphomas.

Hormonal Agents, con’t l Corticosteroids also decrease edema associated with tumor growth, especially in or around the brain, spinal cord, and mediastinum. Will decrease cerebral edema. l Androgens (testosterone) may be used to treat advanced breast cancer

Hormonal Agents, con’t l Anti-Estrogen drugs (Tamoxifen) block the uptake of estrogen and therefore are good for tumors that contain high concentrations of estrogen receptors l Estrogen may be used to treat androgensensitive cancers, such as prostate cancer l Progestins (Depo-Provera and Megace) are used to treat endometrial cancer

Chemotherapy Side Effects l Chemotherapy targets cells which are dividing rapidly. l Chemotherapy cannot distinguish between normal cells and cancer cells l Healthy Cells which have a high rate of growth and multiplication include cells of the bone marrow, hair, GI mucosa and skin.

l Side effects greatest in other rapidlydividing cells Bone marrow toxicity l Impaired wound healing l Hair follicle damage l Gi epith damage l Growth in children l Gametes l Fetus l l May themselves be carcinogenic

Chemotherapy Side effects contd… l Side effects may be drug specific e. g. anthracyclines and cardiotoxicity, vinca alkaloids and neuropathy/constipation, bleomycin and pulmonary fibrosis l Severity of side effects varies between drugs. l Side effects often occur 7 -14 days post treatment.

Side Effects: Acute Tumour Lysis Syndrome. l A Metabolic Emergency. l Occurrs due to rapid cell lysis (death) & large amounts of cell metabolites in blood. l If untreated can lead to acute renal failure, cardiac arrest and death.

Side Effects: Acute Neutropenic Sepsis: Occurs due to Bone Marrow Failure and poor immune response to infection. Predisposing factors include: Neutropenia Underlying disease Chemotherapy Venous access devices

Neutropenic Sepsis l Severe overwhelming infection where inadequate blood flow to the tissues results in cellular dysfunction and, if not reversed, eventual organ failure. l Most common micro organism is gram negative l Mortality rate 40 -90%

Side Effects: Acute Haemorrhage • Invading tumours e. g gastric MALT lymphomas • Haemorrhagic Cystitis related to high dose Cyclophosphomide Anaphylactic Reaction

Side Effects: Bone Marrow Neutropenia: Increased risk of infection. Anaemia: Tiredness, lethargy & breathlessness Thrombocytopenia: Increased risk of bleeding

Side Effects: Gastro-Intestinal l Nausea & Vomiting l Diarrhoea & constipation l Loss of appetite l Taste Changes l Mucositis

Side Effects l Example of Grade 4 Mucositis

Side Effects: Body Image l Hair Loss l Weight Loss/ Weight Gain l Long term central venous catheters l Skin changes (colour, rashes, sensitivity to sunshine, dry)

Side Effects: Other l Fatigue: Often multi-factorial l Peripheral neuropathy l Altered Kidney Function l Changes in hearing (high dose Cisplatin) l Cardiac Toxicity (Doxorubicin/ Idarubicin) l Late Effects: Infertility, secondary malignancy, growth retardation.

Key Points: l Chemotherapy is a major treatment in curing or prolonging survival in cancer patients l It has a wide range of side effects depending on the drugs given. l Nurses have a key role to play in caring for a patient receiving chemotherapy l Safety issues are paramount in administration.

Summary: The potential benefit to the patient of treatment as an option must always outweigh the toxic effects.

Thank You

NCCN 2012 Recommendations by Risk Category High (>90% emetic risk) Including AC containing regimens Three-drug combination of a HT 3 serotonin receptor antagonist, (palonosetron preferred-NCCN) dexamethasone, and aprepitant Moderate (>30% to 90% emetic risk) Two-drug combination of a HT 3 serotonin receptor antagonist and dexamethasone (+/-aprepitant for selected patients) Thank You ﺷﺎﺩ ﺑﺎﺷیﺪ Low (10% to 30% emetic risk) Dexamethasone 8 -12 mg Minimal (<10% emetic risk No antiemetic routinely