Principle of chemotherapy for phar student .pptx

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1. Introduction to The Principles of Chemotherapy Abinet Abebe (B.pharm, Msc in Clinical Pharmacy) Department of Clinical Pharmacy and Pharmacy Practice School of Pharmacy, CHMS , Mizan Tepi University [email protected] 1

2. Objectives 2 Upon completion of this topic, you will be able to :- Understand the basic principles of cancer chemotherapy Describe goals of chemotherapy Describe cycles of chemotherapy Know principles of combination chemotherapy Describe how to dose chemotherapy and necessary measures to admintser chemotherapy Describe the different classes of chemotherapeutic agents Understand administration issues and safety of chemotherapy

3. Introduction The term cancer ( neoplasm, tumor, or malignancy) is a group of more than 100 different diseases which can develop almost anywhere in the body Cancer is a disease characterized by uncontrolled, uncoordinated and undesirable cell division Common characteristics of all cancerous cells: uncontrolled growth, potential for invading local tissues and spreading to other parts of the body( metastases) 3

4. If cancer cells are allowed to grow uncontrollably, they can eventually result in the death of the patient Tumor metastasize to distant sites generally have a greater effect than the primary tumor on the frequency of complications and the patient’s quality of life and mortality Cancer can be prevented by avoiding known risk factors, use of vaccines and chemoprevention in high-risk patients 4

5. Tumor types Benign – non cancerous and not an immediate threat to life, even though treatment may required for health Malignant –tend to worsen and cause death, invasive and metastasis 5

6. Intro,…….. Cancer can be categorized based on functions/locations of cells from which they originate Carcinoma : a tumor derived from epithelial cells, cells that line the surface of skin, internal organs and glands Usually form solid tumors Most common type, accounts for 80-90% of all cancer cases . E.g Prostate cancer, Breast cancer, Lung cancer, and colorectal cancer 6

7. Intro,……. Sarcoma : a tumor derived from bone, fat or connective tissues E.g Osteosarcoma , Fibrosarcoma Leukemia – a cancer of blood cells or their precursors. B egins when healthy blood cells change and grow uncontrollably E.g ALL, CLL, AML,CML 7

8. Lymphoma –a cancer of bone marrow derived cells that affects the lymphatic system . E.g :- Hodgkin lymphoma and non-Hodgkin lymphoma . Myelomas – is a type of blood cancer that involves the over production of plasma cells and the antibody producing cells that develop from B-lymphocytes in the bone marrow E.g :- IgG myeloma, multiple myeloma 8

9. Characteristics of cancer cells Excessive autonomous cell growth Tumor cells produce growth factors that stimulate their own proliferation Invasiveness :- Ability to grow into adjacent tissue Ability to metastasize : Spread to new sites and form new growths Defective differentiation and immortality U ncontrolled proliferation ( i.e. differentiated cells don't divide) F ailure of cancer cells to undergo programmed cell death . 9

10. Etiology Cancers arise from the transformation of a single normal cell . Damage or mutation to the cell’s DNA is caused by an initial event which include; lifestyle, environmental , or occupational factors, as well as some medical therapies (e.g ., cytotoxic chemotherapy , radiation therapy) and hereditary factors . Cigarette smoking is the single largest factor that contributes to cancer development and approximately 30% of deaths per year. Other preventable causes, including physical inactivity, obesity, and nutrition cause an additional 30% of cancer deaths per year 10

11. Etiology A. Genetics Cancer is a genetic disease, two gene classes, oncogenes and tumor suppressor genes , are important in pathogenesis of cancer. Damage to cellular DNA can result in mutations that lead to the development of oncogenes and loss or inactivation of tumor suppressor genes. Genetic mutations : responsible for generation of malignant cells. ` 11

12. Two major categories of mutated genes are: Oncogenes and tumor suppressor genes Oncogenesis Abnormal forms of normal genes (proto-oncogenes ) that regulate cell growth . Oncogenes are genes whose overactivity or presence in certain forms can lead to the development of cancer. Oncogenes arise from normal genes called proto-oncogenes through genetic alterations such as chromosomal translocations, deletions, insertions, and point mutations 12

13. Mutation of these genes may result in direct and continuous stimulation of the molecular biologic pathways that control cellular growth and division.. For example, ras gene encodes Ras protein , which regulates cell division. Mutations may result in the inappropriate activation of the Ras protein, leading to uncontrolled cell growth and division 13

14. Tumor suppressor genes I nherent genes that play role in cell division, DNA repair, and are critical for detecting inappropriate growth signals in cells If these genes, as a result of inherited or acquired mutations , become unable to function, genetic mutations in other genes can proceed unchecked, leading to neoplastic transformation 14

15. Another important regulatory protein, p53 P revents replication of damaged DNA in normal cells and promotes cell death (apoptosis) in cells with abnormal DNA. Inactive or altered p53 allows cells with abnormal DNA to survive and divide. The p53 gene is defective in many human cancers. 15

16. B. Viruses Viruses contribute to the pathogenesis of human malignancies through the integration of viral genetic elements into the host DNA. These new genes are expressed by the host; they may affect cell growth or division, or disrupt normal host genes required for control of cell growth and division . 16

17. Alternatively, viral infection may result in immune dysfunction , leading to decreased immune surveillance for early tumors . Examples: H uman papillomavirus : C ervical cancer Epstein-Barr: nasopharyngeal carcinoma Hepatitis B virus: hepatocellular carcinoma HIV: Kaposi's sarcoma. 17

18. Immune system dysfunction as a result of genetic mutation, acquired disease, aging, or immunosuppressants interferes with normal immune surveillance of early tumors and results in higher rates of cancer. Known cancer-associated immune disorders include immune deficiency secondary to : Immunosuppressant's HIV infection ( Kaposi's sarcoma) R heumatologic conditions, such as Rheumatoid arthiritis 18

19. C. Occupational and Environmental Carcinogens Smoking L ung , mouth, pharynx, larynx, esophagus, urinary bladder , pancreas , and kidney cancers . Lifestyle Diet, alcohol consumption, reproductive behavior, exposure to sunlight, etc . 19

20. D. Radiation Carcinogenesis can result from ionizing radiation and may develop from 2 different mechanisms: Direct ionization – damages DNA and other molecules can cause direct somatic mutations Secondary effectors such as oxygen radicals can be formed by interaction with ionizing radiation. Oxygen free radicals can damage and kill cells and also induce mutations . 20

21. Pathogenesis of Neoplasia Carcinogenesis is the process by which normal cells are transformed into cancer cells It is a multistep process that includes initiation, promotion, conversion, and progression In carcinogenesis, normal mechanisms such as apoptosis and senescence (aging) do not function properly and cannot control excessive cell division, because of abnormalities in the proto-oncogenes and tumor suppressor genes Cancer development can begin with a brief exposure (hours or days ) of a cell to a carcinogen (a chemical, virus or radiation ) 21

22. Mutations occurs up on exposure of cell to a carcinogen, this mutations is inherited by at least one cell division ( initiation ) This mutation mainly lead to: A ctivation of proto-oncogene into oncogenes leading to uncontrolled cell proliferation and/or I nactivation of tumor suppressor genes (leading to resistance to apoptosis.) 22

23. Initiation Point at which an irreversible alteration , usually genetic , is introduced into a target cell . Has the following characteristics : is essentially irreversible caused only by carcinogenic compounds occurs rapidly after carcinogen exposure alone does not result in tumor formation 23

24. Promotion Initiated tissue or organ develop focal proliferations Requires the presence of continuous stimulation. Has the following characteristics: Reversible acts only after exposure to an initiating agent is not carcinogenic in itself Promotion could be affected by chemoprevention strategies (strategies to lower cancer risk ), changes in lifestyle and diet 24

25. Transformation T he altered cell becomes cancerous ( conversion or transformation). Depending on the cancer, 5 to 20 years may elapse between the initiation and the development of a clinically detectable cancer Progression The final stage, which involves further genetic alterations that lead to increased cell proliferation. The critical elements of this phase include invasion into local tissues and the development of metastases 25

26. 26 Cell Cycle Cancer cells, like normal cells, proceed through a specific and orderly set of events during cellular replication referred to as the cell cycle The cell cycle contains four phases (M, G1, S , and G2), each responsible for a different task necessary for cell division During the first activity phase , M phase , the cell undergoes mitosis, the process of cell division . After mitosis, the cell enters the first gap or resting phase (G1).

27. 27 During the G1 resting (or gap) phase, the cell makes the enzymes necessary for DNA synthesis. The synthesis of DNA occurs during the S phase . After S phase, the cell enters a second resting phase (G2). RNA and other proteins are synthesized to prepare for cell division during M phase . Cells that complete mitosis may either continue to proceed through the cell cycle to divide again , differentiate or mature into specialized cells and eventually die, or enter a third resting phase called G0

28. Mitotic Cycle 28

29. Reading Assignment Risk factors for cancer Screening and prevention of cancer Diagnosis of Cancer Staging of Cancer 29

30. Cancer Treatment Treatment possibilities for cancer, often in combination, either simultaneously or sequentially include:- Surgery Often the first line of treatment for many solid tumors. Sufficient to cure the patient if cancer is detected at early stage Radiation The goal of radiation is to kill the cancer cells directly by damaging them with high energy beams. . 30

31. Chemotherapy A term used for a wide array of drugs used to kill cancer cells. Hormonal Treatment These drugs are designed to prevent cancer cell growth by preventing the cells from receiving signals necessary for their continued growth and division 31

32. Some cancers where chemotherapy works very well: Childhood leukemia Retinoblastoma Osteosarcoma Testicular cancer Hodgkin’s Disease Some lymphomas Some early breast cancers 32

33. Cancers that are very difficult to treat with chemotherapeutics (need surgery or radiotherapy first): Colon Lung Late stage breast cancer Pancreatic cancer 33

34. Problems associated with chemotherapy: Resistance to chemotherapy Resistance to chemotherapy may develop by several mechanisms: A. Decrease in the amount of drug uptake by cancer cells E.g. Methotrexate B . Increase in the amount of drug removed by cancer cells . E.g. Vinblastine, doxorubicin , bleomycin, etopside 34

35. C. Decrease or alteration in target molecule sensitivity, this is caused by mutation in the molecule targeted by the drug E.g. Methotrexate, Mercaptopurine, doxorubicin D. Increase in DNA repair ability of the cell via an increased expression of DNA repairing enzymes . E.g. Alkylating agent 35

36. 36 Hallmarks of anti-cancer drug resistance

37. Cancer Response Cure Cure from cancer is considered when a patient is entirely free of disease and has the same life expectancy as someone without cancer Complete Response When a patient experiences complete disappearance of all cancer without evidence of new disease for at least one month after treatment 37

38. Partial Response When a patient experiences a decrease in their tumor size or other disease markers and has no evidence of any new disease for at least one month Progressive Disease When a patient experiences an increase in tumor size or they develop new lesions while receiving treatment Stable Disease When a patient's tumor neither grows nor shrinks : It is the zone between partial response and progression. 38

39. Response to chemotherapy 39 RECIST(Response Evaluation Criteria in Solid Tumors

40. Survival Endpoints Disease-free survival H ow long a patient survives without the cancer Progression-free survival H ow long a patient survives without disease progression 40

41. Principles of Chemotherapy Chemotherapy is term used for drugs used to kill cancer cells It is intended to be either cytostatic (preventing cell division) or cytocidal (causing cell death). Most chemotherapy agents are cytocidal and bring about cell death or apoptosis by interfering with cellular processes, such as DNA replication, RNA function, and mitosis. Two fundamental principles of chemotherapy are the “ cell kill model ” and Gompertzian tumor growth kinetics . 41

42. The Cell Kill Model States that a certain percentage of cancer cells will be killed with each cycle of chemotherapy, assuming that all the cells are actively dividing, consistently sensitive to treatment , and growing at a constant rate. However, all tumor cells are not actively dividing, and cells can become insensitive to chemotherapy, so this model has limitations. 42

43. Gompertzian Tumor Growth Kinetics States that tumors grow fastest when small, and tumors given less time to recover can be more effectively destroyed. This principle has led to the use of dose-dense chemotherapy that includes shorter cycle intervals so that the actively dividing cells can be killed before they have a chance to divide. 43

44. Goals of Cancer Chemotherapy The main goals of treatment depend on the cancer stage, cancer type and patient factors, such as comorbidities . Goals To cure the cancer To control the cancer To relieve symptoms caused by the cancer 44

45. 45 Types of chemotherapy Primary induction chemotherapy When surgery isn't an option and chemotherapy used on its own . Adjuvant chemotherapy When the most appropriate course of action is s urgery but it is followed by chemotherapy The goal is to prevent recurrence by administering chemotherapy to kill microscopic cells not removed during surgery that travelled to other parts of the body and prolong survival

46. 46 Neoadjuvant chemotherapy Chemotherapy given before surgery to de –bulk the tumour, making its removal easier This decrease the tumor burden to be removed (which may result in a shorter surgical procedure or less physical disfigurement to the patient) and make the surgery easier to perform because the tumor has shrunk away from vital organs or vessels.

47. 47 Consolidation or intensification chemotherapy Chemotherapy that is given to sustain a remission once remission is achieved Maintenance chemotherapy C hemo given at lower doses to assist in prolonging remission. It is only used for certain types of cancer like acute lymphocytic leukemia

48. 48 Palliative : Chemotherapy given to control symptoms or prolong life in a patient in whom cure is unlikely . Salvage: A potentially curative, high-dose, usually combination, regimen given in a patient who has failed or recurred following a different curative regimen .

49. 49 Chemotherapy c ycles Many chemotherapy agents have significant organ toxicities that preclude using steadily increasing doses to treat the cancer. The doses of chemotherapy must be given at a frequency that allows the patient to recover from the toxicity of the chemotherapy Each period of chemotherapy dosing is referred to as a cycle Cycles are courses of chemotherapy and defined by number of days. Cycles may be the same each time or vary based on toxicity concerns or the protocol being used

50. 50 Dose-Dense Chemotherapy (DDC) The dose density of chemotherapy refers to shortening of the period between cycles of chemotherapy. This accomplish two things: First, tumor has less time between cycles to grow Second, patients receive the total number of required cycles in a shorter time period.

51. 51 Thus dose-dense chemotherapy; Shortens the time between cycles Shorten the overall time of therapy Decrease amount of time tumor can grow between cycles, But it usually requires the use of colony -stimulating factors (CSFs) to shorten the length of neutropenia . Dose-Intense Chemotherapy (DIC) Involves increasing the total dose of chemo given during a fixed cycle period.

52. 52 Compared with conventional chemotherapy doses, dose dense chemotherapy is an important predictor of clinical outcomes, improved disease free and overall survival without increasing toxicity . [Marc L citron, 2008]

53. 53 Combination of chemotherapy Basic Principles Single drugs at tolerable doses rarely able to cure cancers Combinations of chemotherapeutic agents are often used to take advantage of: Different mechanisms of action to avoid resistance Different toxicity profiles, and Possible synergistic actions

54. Combination chemotherapy accomplishes three important objectives not possible with single-agent therapy: It provides maximum cell kill within the range of toxicity tolerated by the host for each drug; It offers a broader range of coverage of resistant cell lines in a heterogeneous tumor population; It prevents or slows development of new drug-resistant cell lines. 54

55. Selection of drugs for combination The following principles have been established to guide drug selection in combination regimens : Drugs known to be active as single agents should be selected for combinations . Drugs with different mechanisms of action should be combined in order to allow for additive or synergistic effects Drugs with differing dose-limiting toxicities should be combined to allow each drug to be given at full dose 55

56. Cont… Drugs should be used in their optimal dose and schedule This maximize cell kill and avoid unnecessary toxicity, drug resistance . Drugs with different patterns of resistance should be combined to minimize cross-resistance . 56

57. Dosing of Chemotherapy 57 Chemotherapeutic agents typically have a very narrow therapeutic index. If too much is administered, the patient may suffer from fatal toxicities. If too little is given, the desired effect on cancer cells may not be achieved.

58. Administration of dose-dense chemotherapy regimens often requires the use of colony-stimulating factors ( eg , filgrastin or granulocyte colony-stimulating factor to be administered. These agents shorten the duration and severity of neutropenia . When a chemotherapy regimen is used as palliative therapy, the dosages of chemotherapy may be decreased based on toxicity or the interval between cycles may be lengthened to maintain quality of life. 58

59. Patient and tumor biology also affect how cancer therapy is dosed. Patients with a uridine diphosphate glucuronosyl transferease 1A1 enzyme (UGT1A1* 28) deficiency can have life threatening diarrhea and complications from Irinotecan related to a decreased ability to metabolize the parent drug. The patient may have a blood test before irinotecan therapy to determine if this genetic mutation is present. 59

60. Measurements n ecessary to administer c hemotherapy A white blood cell count (WBC ) > 2,500 cells/mm3 or ANC of >1,000 cells/mm3 a platelet count of >75,000 cells/mm3 However , these parameters may not apply when the cancer is of the bone marrow such as with leukemia. 60

61. Renal Function Creatinine clearance is the most often used measure used to estimate glomerular filtration rate (GFR) and estimate renal function. The Cockcroft-Gault equation is arguably still the most common equation used to calculate creatinine clearance for drug dosing , although some use the Jelliffe equation instead . 61

62. Renal Function Calculations Cockcroft-Gault equation for CrCl : CrCl (mL/min) = [(140-age) x (weight in kg)] [(72) x (serum creatinine in mg/dL)] x 0.85 if female Jelliffe equation for CrCl : Male CrCl (mL/min/1.73 m2) = 98 - 0.8 (age in years - 20) serum creatinine in mg/dL Female CrCl (mL/min/1.73 m2)= 88 - 0.7 (age in years - 20) serum creatinine in mg/dL 62

63. Calculation Body Weight Calculating ideal body weight in kg (IBW ): Males : IBW = 50 + (2.3 x height in inches over 5 feet) Females : IBW = 45.5 + (2.3 x height in inches over 5 feet ) Calculating adjusted body weight in kg ( ABW) ABW = IBW + 0.4 x (actual weight - IBW) Or ABW = (IBW + actual weight ) / 2 63

64. 64 In the early days most chemotherapy was given at fixed doses or doses based on body weight. Today , most chemotherapeutic agents are dosed by body surface area Dubois equation for BSA: BSA(m2) = 0.007184 x weight (kg)0.425 x height (cm)0.725

65. Cumulative Dosing- Anthracyclines • Toxicity increases as their cumulative dose increases. • The cumulative dose of all anthracyclines has to be taken into consideration and tracked. • Anthracyclines – doxorubicin, daunorubicin , epirubicin , idarubicin or mitoxantrone – direct toxicity to cardiac muscle in a cumulative dose – risk for cardiomyopathy and congestive heart failure . – The damage is permanent – changing to a different anthracycline won't help prevent it. 65

66. With cumulative doses of doxorubicin over 450 to 550 mg/square meter, the incidence of congestive heart failure is significant, and at higher doses the incidence climbs steeply . Factors: age Both very young children and the elderly are at higher risk even with lower cumulative doses Delayed toxicity …..children (extended lifespan). 66

67. Continued monitoring after completion for all pediatric patients that have received anthracyclines. Combinations Paclitaxel increases exposure to doxorubicin when it is administered immediately before doxorubicin. I nfused them 24 hours apart. 67

68. Classes o f c hemotherapeutic a gents 68 Antitumor drugs may be placed into one of three classes based on the relationship of the effect to the mitotic cycle of the cell: Cell cycle active, phase specific Cell cycle active, phase non-specific Non-cell cycle active

69. Cell cycle and effects of cytotoxic drugs on phases of the cell cycle 69

70. CLASSES OF CHEMOTHERAPEUTIC AGENTS 70

71. 71

72. Reading Assignment - Classes of chemotherapeutic agents - Targeted therapy 72

73. 73 Thank You !!!!