CHEMOTHERAPY

2. CHEMOTHERAPY Dr.M.Torfehnezhad Pediatrician

3. 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’.

4. The Cell Cycle The Cell Cycle

5. Mitosis

6. Cell Biology: Mitosis A cell in mitosis

7. 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.

8. 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

9. 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

10. Chemotherapy Chemotherapy may be used conventionally to: • Cure patients • Prolong survival • Palliative care symptom control

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

12. 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!

13. Intrathecal Chemotherapy

14. 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)

15. Rand 50.3

16. Alkylating Agents • Contain chemical groups that bind cell nucleophiles

17. 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

18. 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

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

20. 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)

21. 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.

22. Antimetabolites • Kill cells in S phase • Three main groups • Folate antagonists • Pyr analogs • Pur analogs

23. Folic Acid Analogs • Folic acid essential for synth purines, and thymidylate

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

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

26. Gemcitabine • Inhib’s ribonucleotide reductase  decr’d nucleotide synth

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

28. 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

29. 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

30. 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

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

32. Antibioticagents,con’t • Dactinomycin • Interferes w/ RNA polymerase movement  decr’dtranscr’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

33. 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)

34. 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

35. Vinca Alkaloids

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

37. 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.

38. 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

39. 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

40. 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.

41. 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

42. 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.

43. 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.

44. 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

45. 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%

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

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

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

49. Side Effects • Example of Grade 4 Mucositis

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