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PRINCIPLES OF CANCER CHEMOTHERAPY: A DEEP INSIGHT

PRINCIPLES OF CANCER CHEMOTHERAPY: A DEEP INSIGHT. PRESENTER DETAILS: VISHNU.R.NAIR, 5 TH YEAR PHARM.D, NATIONAL COLLEGE OF PHARMACY(NCP). PRINCIPLES OF ONCOLOGY. Under “PRINCIPLES OF ONCOLOGY”  the following will be discussed : CANCER DEFINITION FEATURES OF CANCER CELLS(SUMMARIZED)

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PRINCIPLES OF CANCER CHEMOTHERAPY: A DEEP INSIGHT

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  1. PRINCIPLES OF CANCER CHEMOTHERAPY: A DEEP INSIGHT PRESENTER DETAILS: VISHNU.R.NAIR, 5TH YEAR PHARM.D, NATIONAL COLLEGE OF PHARMACY(NCP).

  2. PRINCIPLES OF ONCOLOGY

  3. Under “PRINCIPLES OF ONCOLOGY”  the following will be discussed: • CANCER DEFINITION • FEATURES OF CANCER CELLS(SUMMARIZED) • TYPES OF CANCER • ETIOLOGY • DIAGNOSTIC PARAMETERS ENUMERATION • CANCER STAGING.

  4. CANCER DEFINITION

  5. “CANCER refers to a HETEROGENOUS group of diseases, that are caused by an IMPAIRMENT of NORMAL FUNCTIONING of GENES, leading to GENETIC DAMAGE”

  6. FEATURES OF CANCER CELLS(SUMMARIZED)

  7. Cancer cells are also known as “TUMORS”/ “NEOPLASMS” • Single abnormal cell continues to divide INDEFINITELY  causes TUMORS • The unique features of cancer cells can be explained under the heading “CARCINOGENESIS” CARCINOGENESIS: • Process of cancer formation • Occurs in the following stages: • INITIATION: • Normal cells  exposed to CARCINOGEN  causes GENETIC DAMAGE to cell B. PROMOTION: - Alteration in environment  allows growth of mutated cells (preferentially over normal cells)  results in mutated cells becoming “CANCEROUS”.

  8. C. PROGRESSION: • Increased proliferation of cancer cells  allows invasion into local tissue  results in METASTASIS!

  9. TYPES OF CANCERS

  10. Tumors can either be BENIGN or MALIGNANT • BENIGN TUMORS: • Slow-growing • Resemble normal cells • Localized • Less harmful! • MALIGNANT TUMORS: • Proliferate rapidly • Have a typical appearance • Invade & destroy surrounding tissues • Harmful!!

  11. Malignant tumors are further classified according to the origin of tumor cell development: • SOLID TUMORS: • Include: • CARCINOMAS: • Tumors of EPITHELIAL CELLS • Eg: Breast, colon, lung cancers ii. SARCOMAS: • Tumors of connective tissue • Eg: Osteosarcoma, leiomyosarcoma

  12. B. HEMATOLOGICAL MALIGNANCIES: • Include: • LYMPHOMAS: • Tumors of LYMPHATIC SYSTEM • Eg: HL, NHL, etc ii. LEUKEMIAS: • Tumors of BLOOD-FORMING ELEMENTS • Classified as ACUTE/CHRONIC & MYELOID/LYMPHOID

  13. WHAT CAUSES CANCERS??

  14. Causes include: • VIRUSES: • Include: • EBV • HBV • HPV B. ENVIRONMENTAL & OCCUPATIONAL EXPOSURES: • Include: • Ionizing radiations • UV-radiations • Exposure to chemicals like vinyl chloride, benzene, asbestos, etc.

  15. C. LIFESTYLE FACTORS: • Include: • High-fat diet • Low-fiber diet • Tobacco usage • Ethanol usage. D. MEDICATIONS: • Include: • Alkylating agents • Immunosuppressants.

  16. E. GENETIC FACTORS: • Includes: • Inherited mutations • Oncogenes • Defective tumor-suppressing genes.

  17. CANCER DIAGNOSTIC MEASURES

  18. Include: • WARNING SIGNS & SYMPTOMS: Include: • Unexplained weight loss • Fatigue • Fever • Pain • Skin changes • Sore, that does not heal • White patches/ spots in mouth/on tongue • Unusual bleeding/discharge • Recent change in wart/mole • Thickening or lump in breast/ other body part, etc.

  19. B. TUMOR MARKERS: • Biochemical indicators of presence of NEOPLASTIC PROLIFERATION • Detected in serum, plasma/ other body fluids • Examples include: • CARCINOEMBRYONIC ANTIGEN(CEA) : For COLORECTAL CANCER • ALPHA-FETOPROTEIN(AFP): For HCC/ HEPATOBLASTOMA • PROSTATE-SPECIFIC ANTIGEN(PSA): For PROSTATE CANCER. C. TUMOR BIOPSY D. IMAGING STUDIES: Include: • Radiograph • MRI-Scan • PET • CT-Scan.

  20. E. OTHER LABORATORY TESTS: Include: • CBCs • Blood chemistries, etc.

  21. CANCER STAGING

  22. Refers to “CATEGORIZING of patients, with respect to extent of their disease” • Helps to determine PROGNOSIS & TREATMENT • There are 2 different staging systems currently employed: • TNM CLASSIFICATION: • “T’: • Indicates TUMOR SIZE • Classified from 0 to 4 • 0 : Indicates “absence of tumor” ii. “N”: • Indicates PRESENCE & EXTENT OF REGIONAL LYMPH NODE SPREAD • Classified from 0(no lymph node involvement) to 3(extensive involvement).

  23. iii. “M”: • Indicates presence/absence of METASTASES • Classified as 0(absence) OR 1(presence of metastases). B. AJCC STAGING: • Developed by American Joint Committee on Cancer • Classifies cancers as stages 0 to IV • Higher number indicates: • Larger tumors • Extensive nodal involvement • With/without metastases • Worsening prognosis.

  24. CELL LIFE-CYCLE: A BRIEF INSIGHT

  25. Includes: • PHASES OF CELL-CYCLE • CELL-GROWTH KINETICS(THEORIES INVOLVED) • TUMOR CELL BURDEN(HYPOTHESIS INVOLVED) • PHASE-SPECIFIC ANTITUMOR AGENTS • PHASE-NONSPECIFIC ANTITUMOR AGENTS • CELL-CYCLE NONSPECIFIC AGENTS

  26. CELL-CYCLE PHASES

  27. Useful to get an insight into activity of chemotherapeutic agents • Include: • M-PHASE(MITOSIS): • In this phase  cell divides into 2 daughter cells B. G1-PHASE: • Also known as “POSTMITOTIC GAP” • In this phase  RNA & proteins required for specialized cell functions  synthesized for DNA synthesis. C. S-PHASE: - In this phase DNA synthesis & replication occurs.

  28. D. G2-PHASE: • Also known as “PRE-MITOTIC/ POST-SYNTHETIC GAP” • In this phase  RNA & enzymes “TOPOISOMERASE I & II” produced  helps in cell duplication E. G0-PHASE: • Also known as “RESTING PHASE” • In this phase  CELL DOESN’T DIVIDE! • Cells in this phase  GENERALLY INSENSITIVE TO CHEMOTHERAPY! • Some of the cells in this phase  re-enter the actively –dividing cell-cycle, by strategic chemotherapeutic regimen(known as RECRUITMENT!) • In the process of RECRUITMENT  a large number of actively-dividing cells are killed  thus facilitates G0 cells re-entry!!!!!!!

  29. CELL-GROWTH KINETICS(THEORIES INVOLVED)

  30. There are some terminologies that describe cell-growth kinetics • Include: • CELL-GROWTH FRACTION: • “Proportion of cells(inside the tumor), that are dividing/preparing to divide” • As tumor enlarges  large number of cells may not be able to obtain sufficient nutrients & blood supply for replication  GROWTH FRACTION REDUCES!! B. CELL-CYCLE TIME: • “Average time for a cell(that has just completed MITOSIS), to grow & again divide & again pass through mitosis” • Time varies, according to each individual tumor

  31. C. TUMOR DOUBLING TIME: • “Time required for tumor to DOUBLE IN SIZE!” • As tumor gets larger  fewer cells gets nutrients & blood supply for growth  few cells only actively divide  DOUBLING TIME GETS LONGER!! - The GOMPERTZIAN GROWTH CURVE illustrates these cell-growth concepts!!

  32. TUMOR CELL BURDEN(HYPOTHESIS INVOLVED)

  33. Refers to “NUMBER OF TUMOR CELLS IN THE BODY” • A large number of cells are required to produce symptoms & be clinically detectable(Approx. 109 cells!) • According to CELL-KILL HYPOTHESIS : • “Certain PERCENTAGE of TUMOR CELLS will be killed with each course of cancer chemotherapy” • Since tumor cells are killed  cells in G0-phase may be recruited into G1-Phase  results in TUMOR REGROWTH • Thus  REPEATED CYCLES of CHEMOTHERAPY required to achieve a complete response/remission! • Percentage of cells killed  depends on CHEMOTHERAPY DOSE! • In theory  tumor burden WOULD NEVER REACH ABSOLUTE ZERO(since only a percentage of cells are killed with each cycle) • Less than 104 cells may depend on elimination by host’s immune system!

  34. PHASE-SPECIFIC CHEMOTHERAPEUTIC AGENTS

  35. Most active against cells, that ARE IN A SPECIFIC PHASE OF CELL-CYCLE • Most effective against tumors with a HIGH GROWTH FRACTION • Giving such drugs as CONTIINUOUS I.V INFUSION / by MULTIPLE REPEATED DOSES  increase likelihood of targeting majority of cells in the specific phase at any one time! • Also known as “SCHEDULE-DEPENDANT AGENTS” • Include: • M-PHASE: Mitotic inhibitors(vinca alkaloids, taxanes) • G1-PHASE: Asparaginase, prednisone • S-PHASE: Antimetabolites • G2-PHASE: Bleomycin, etoposide.

  36. PHASE-NONSPECIFIC CHEMOTHERAPEUTIC AGENTS

  37. Effective, while cells are in the active cycle, regardless of particular phase • Usually show activity against SLOW-GROWING TUMORS • Given as SINGLE BOLUS DOSES (since their activity is independent of cell-cycle) • Also known as “DOSE-DEPENDENT AGENTS” • Examples include: • ALKYLATING AGENTS • ANTITUMOR ANTIBIOTICS.

  38. CELL-CYCLE NONSPECIFIC CHEMOTHERAPEUTIC AGENTS

  39. Effective in ALL PHASES, including G0!!! • Examples include: • Carmustine • Lomustine • Radiation therapy.

  40. CHEMOTHERAPY: PRINCIPLES INVOLVED

  41. Includes the following headings: • OBJECTIVES OF CHEMOTHERAPY • CHEMOTHERAPY DOSING • DOSING ADJUSTMENTS • COMBINATION CHEMOTHERAPY • ADMINISTRATION PRINCIPLES • RESPONSE TO CHEMOTHERAPY • FACTORS AFFECTING CHEMOTHERAPY RESPONSE

  42. OBJECTIVES OF CHEMOTHERAPY

  43. Objectives depend on nature of cancer/tumor • FOR HEMATOLOGICAL MALIGNANCIES: • Several chemotherapy phases will be required • With aggressive therapy for a prolonged period  CURE may be obtained! • For LEUKEMIAS  objectives of therapy include: • REMISSION INDUCTION: Therapy, with the intention of MAXIMUM KILL • CONSOLIDATION THERAPY: • Also known as post-remission therapy • Intends to lower tumor cell burden below 103! • Aims to eradicate any clinically undetectable disease

  44. iii. MAINTENANCE THERAPY: • Therapy given in LOW DOSES • Major objective is to maintain/prolong REMISSION! B. FOR SOLID TUMORS: • One/ more strategies may be used, depending on whether surgery/radiation is required along with chemotherapy OR not • Consists of 2 types: • ADJUVANT CHEMOTHERAPY: • In this  chemotherapy is given AFTER SURGERY to eliminate any remaining disease or so ii. NEOADJUVANT CHEMOTHERAPY: - In this  chemotherapy is given BEFORE SURGERY/RADIATION, to reduce tumor burden!

  45. C. PALLIATIVE THERAPY: • Given in the following conditions: • Complete tumor eradication is unlikely • Patient refuses aggressive therapy • Can be given, to: • Reduce tumor size • Control growth • Reduce symptoms. D. SALVAGE CHEMOTHERAPY: - Given to assist in remission, on NON-EFFECTIVENESS OF PREVIOUS CHEMOTHERAPIES!

  46. CHEMOTHERAPY DOSING

  47. Dosing can be done, based on: • Body weight • BSA • AUC • BSA is most frequently used! • BSA  correlates with C.O  C.O determines hepatic & renal blood flow  thus affects drug elimination  thus frequently used! • In children (especially infants/ children of weight < 10-12 kg)  usage of BSA  can OVERESTIMATE PATIENT’S SIZE  leads to OVERDOSING OF THERAPY  can lead to TOXICITIES! • In such cases  dosing is based on BODY WEIGHT(in kilograms).

  48. DOSING ADJUSTMENTS

  49. Dosing adjustments may be required for KIDNEY/LIVER DYSFUNCTION • Doses can also be adjusted, based on HEMATOLOGIC/ NON-HEMATOLOGIC TOXICITIES

  50. COMBINATION CHEMOTHERAPY

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