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." CCytotoxic literally translated means ‘toxic to cells’.

The Cell Cycle

Mitosis

Cell Biology: Mitosis A cell in mitosis

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

Cancer Cell Characteristics: Unchecked & Uncontrolled Growth Loss of contact inhibition Loss of capacity to differentiate Increased growth fraction Chromosomal Instability Capacity to metastasise 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 Chemotherapy may be used conventionally to: Cure patients Prolong survival 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: 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 Cytotoxic Agents Alkylating Agents Antimetabolites Cytotoxic antibiotics Plant derivatives Hormones Suppress nat’l hormone secr’n or antagonize hormone action Misc (mostly target oncogene products)

Rand 50.3

Alkylating Agents Contain chemical groups that bind cell nucleophiles

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

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

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

Cyclophosphamide Most common Prodrug – liver metab by CYP P450 MFO’s Effects lymphocytes Also immunosuppressant Oral or IV usually SE’s: n/v, bone marrow dpression, Cytoxan can cause hemorrhagic cystitis (give MESNA to protect the bladder)

Antimetabolites These drugs have a structure similar to a necessary building block for the formation of DNA. 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 Kill cells in S phase Three main groups Folate antagonists Pyr analogs Pur analogs

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

Methotrexate Higher affinity for enz than does FH2  Inhib’n DNA synth

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

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

Cytosine arabinoside (cytarabine) Inhibits DNA polymerase Gemcitabine – araC analog Fewer SE’s

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

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

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

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

Antibiotic agents, con’t Dactinomycin Interferes w/ RNA polymerase movement  decr’d transcr’n Bleomycin Glycopeptide Chelates Fe, which interacts w/ O2  Gen’n superoxide and/or hydroxyl radicals Radicals degrade DNA  fragmentation, release of free bases Most effective in G2, also active against cells in G0 Little myelosuppression BUT pulmonary fibrosis

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

Mitotic Inhibitors, con’t 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. Constipation is common due to effects on the autonomic nervous system

Vinca Alkaloids

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

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

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

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

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

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

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

Side Effects: Acute Tumour Lysis Syndrome. A Metabolic Emergency. Occurrs due to rapid cell lysis (death) & large amounts of cell metabolites in blood. 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 Severe overwhelming infection where inadequate blood flow to the tissues results in cellular dysfunction and, if not reversed, eventual organ failure. Most common micro organism is gram negative 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 Nausea & Vomiting Diarrhoea & constipation Loss of appetite Taste Changes Mucositis

Side Effects Example of Grade 4 Mucositis

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

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

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

NCCN2012 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) Low (10% to 30% emetic risk) Dexamethasone 8-12 mg Minimal (<10% emetic risk No antiemetic routinely Thank You شاد باشید