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Training on Cancer for Medical Representatives of Pharma Company

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  • Four simplified steps for normal cell growth and differentiation:)An extracellular growth factor binds to a specific receptor on the plasma membrane )The growth factor receptor is transiently activated, leading to a cascade of signaling cellular events, many of which involve signal-transducing proteins on the plasma membrane )The signal/message is transmitted from the plasma membrane via the cytosol to the nucleus via secondary messengers )Nuclear regulatory machinery is induced/activated to initiate cell replication and transcription.
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    • 1. Cancer May 2003Dr Anshu P Gokarn
    • 2. To understand oncology we shall discuss thefollowing …...I. What is cancer ?II. How cells continue dividing in an uncontrolled manner in cancer. Normal cell cycle Abnormalities associated with normal processIII. Factors that control cancer Natural factors Risk factors CarcinogensIV. Types of cancersV. Treatment available for cancerVI. Latest Treatment availableDr Anshu P Gokarn
    • 3. PART I Basics of cancerDr Anshu P Gokarn
    • 4. CANCER (Neoplasm) - What is it?  New Growth  Definition : An abnormal mass of tissue, excessive growth, uncoordinated with normal tissue and persistent growth even after the cessation of evoking stimuli.Fundamental to origin of all Cancers is :“Loss of responsiveness to normal growth control mechanisms” Dr Anshu P Gokarn
    • 5. Neoplasms – TheirCharacteristics  Enjoy a certain degree of autonomy  Parasitic in nature (regardless of local environment or host nutritional status)  Require endocrine support of host  Dependent on host for blood supply and nutrition Dr Anshu P Gokarn
    • 6. Part IIDr Anshu P Gokarn
    • 7. Dr Anshu P Gokarn
    • 8. CELL DIVISION Proliferating cells enter cell cycle which is : G1 Phase Pre nucleic acid synthesis interval S1 Phase Synthesis of DNA occurs G2 Phase Post synthetic interval M Phase Mitosis occurs, two G1 cells produced; which either directly enter next cycle or pass into non proliferating phase G0 G1 G2 Non-proliferating cells; a fraction of these are colonogenic – may remain quiet for G 0 Phase some time but can be recruited in cell cycle if stimulated later Dr Anshu P Gokarn
    • 9. Normal cell cycleInterphase – cell carries out it’s normal activity but is resting from dividing Also called growth phase or metabolic phase Prepares for next cell division Is divided into three stagesG1 phase - (cells metabolically active, synthesize proteins rapidly, grow vigorously) Lasts from minutes to hours or even yearsG0 phase - Cells cease to divide permanently.S Phase - DNA replication occurs . Two future cells will receive identical copies of the genetic materialG2 phase - Final phase. Enzymes and other proteins needed for division are synthesized and moved to their proper sitesM phase - Mitosis –Prophase, metaphase, anaphase and telophase occurs Cytokinesis – division of cytoplasm – Dr Anshu P Gokarn
    • 10. Dr Anshu P Gokarn
    • 11. How cancer develops Normal cell Transformation carcinogen Step 1 Initiation (change in cellular genetic material primes the cell to become cancerous) Step II Promotion (cell becomes cancerous) Normal feedback mechanisms mediating cell growth are defective. Faulty cells contact-signaling process (transduction defect) Dr Anshu P Gokarn
    • 12. Progression of a normal cell to cancer Tumour formation is a multi-step process Genes mutation occursGenetic changes confer a selective growth or survival advantage No response to normal regulatory signalsGrow in an uncontrolled manner, resulting in malignant disease Dr Anshu P Gokarn
    • 13. Cell transformation from normal to cancer Dead cell apoptosis DNA repair Mutation Repair absent or faulty Cancer cell Dr Anshu P Gokarn
    • 14. Part III  A. Molecular basis of cancer  B. Carcinogens  C. The risk factors involvedDr Anshu P Gokarn
    • 15. Dr Anshu P Gokarn
    • 16. How normal cell proliferation occurs : Growth factor binds to specific receptor Activates several signal transducing proteins on the inner surface of the plasma membrane Signal reaches nucleus via 2nd messengers Activation of Nuclear Regulatory Factors initiate DNA transcription (via transcription factors). Cell enters cell division. Alterations/Mutations in any of these steps cause Cancer Dr Anshu P Gokarn
    • 17. Some more factors… Systems that regulate apoptosis may be altered to cause cancer. Cell adhesion proteins can also undergo mutation and contribute to metastasis. Several genes altered during conversion of a cell from normal to malignant. Dr Anshu P Gokarn
    • 18. Carcinogenic genesGenes may be either : Effectors of transformation also known as Oncogenes(eg. signal pathway molecules) or Facilitators of transformation – also known as tumor suppressor genes They cause increase occurrence of mutations in other genes e.g. p53 gene DNA repair genes Apoptosis genes Telomerase genesDr Anshu P Gokarn
    • 19. Some cell cycle regulators 1. Integral membrane tyrosine kinases ( erbB and others ) 2. growth factors ( sis and hst ) 3. ras and src gene families 4. Membrane associated tyrosine kinases, serine- threonine kinases ( mos and raf ) 5. nuclear oncoproteinsThese proteins are expressed in most cells, but when a mutation occurs, this expression is abnormal and cancer can arise. Dr Anshu P Gokarn
    • 20. Cellular genes controlling malignancyProtooncogenes – Tumor suppressorPositively influence genes – negatively influence cellgrowth growth Mutation Oncogenes cancer Dr Anshu P Gokarn
    • 21. Proto-oncogenes  Control cell proliferation and differentiation  Expressed in all subcellular compartments (nucleus, cytoplasm, cell surface)  Act as protein kinases, growth factors, growth factor receptors, or membrane associated signal transducers  Mutations in proto-oncogenes alter the normal structure and/or expression patternDr Anshu P Gokarn
    • 22. Oncogenes Mutated types of normal Wild Type Genes (proto-oncogenes) promote cancer development Act in a dominant fashion – a mutation is needed in only a single allele for activation – also referred to as gain of function mutations For oncogenes to be tumorigenic, they must be activated in some way. Three known mechanisms of transforming oncogene activation: translocations amplification point mutations Dr Anshu P Gokarn
    • 23. Oncogene mechanisms of activation Changes to oncogenes confer advantage to affected cells leading to transformation. Categorized into two groups Changes to the structure of an oncogene results in an abnormal gene product (protein) with abnormal function Changes to the regulation of gene expression which results in excessive or inappropriate production of the structurally normal growth-promoting protein Dr Anshu P Gokarn
    • 24. Oncogene mechanisms of action Extracellular growth factor Growth factor receptor Signal transduced and transmitted via cytosol to the nucleusCell replication and transcription Dr Anshu P Gokarn
    • 25. Normal regulation of a gene that promotes cell division Dr Anshu P Gokarn
    • 26. Growth Factors Mutations of genes encoding growth factors can render them oncogenic (eg platelet derived growth factor). Tumors possessing receptors for PDGF are subject to autocrine stimulation Growth factor gene itself may not be altered / mutated but the products of other oncogenes such as ras cause over-expression of growth-factor genes. Large number of growth-factors eg. TGF-α produced. TGF-α binds to endothelial growth factor to induce cell proliferation Whole process occurs outside the cell Dr Anshu P Gokarn
    • 27. Growth Factor Receptor  Mutations/Pathologic over-expression of growth factor receptors have been detected in several tumors.  Over-expression : eg. EGF receptor family  c-erb B-1 is over expressed in squamous cell carcinoma of lungs  c-erb B-2 in breast cancers, adino-carcinoma of lungs, ovaries and salivary glands.  HER-2 and PDGF are amplified in human cancer cells. These are the other types which can be over- expressed.Dr Anshu P Gokarn
    • 28. Cytoplasmic Oncogenes Two important members in this category are c-ras and c-abl ras Gene Family includes k-ras, h-ras and m-ras Mutations in these three members of the ras gene family – quite common Structure of ras eg. k-ras mutation prevalent in pancreatic cancer & colonic cancer. Mutation in all three types in thyroid cancerDr Anshu P Gokarn
    • 29. Cytoplasmic Oncogenes abl Gene altered in 90% of CML Gene activated by chromosomal rearrangement with another gene called bcr resultng in expression of hybrid bcrabl protein eg. Philadelphia Chromosome (reciprocal translocation of long arm f chromosome 22 occurs) abl possesses tyrosine kinase activity which is activated in the bcrabl fusion protein.Dr Anshu P Gokarn
    • 30. Nuclear Oncogenes Bind to DNA elements in the promotors of specific genes, enhancing (or occassionally inhibiting) gene expression Eg. eos, jun, erb A, mic Mic gene family consists of c-mic, N-mic and L-mic – c-mic plays a part in regulating apoptosis Alterations in mic and bcl-2 (other oncogene indicated in apoptosis) affects the balance between cell division an death Combined with aberrant growth stimuli, it may result in growth of malignant cells.Dr Anshu P Gokarn
    • 31. Tumor Suppressor Genes Have normal, diverse functions to regulate cell growth in a negative fashion (restrain neoplastic growth; act as cellular “brakes”) Act in a recessive fashion – physical or functional loss of both alleles frees the cell from constraints imposed by their protein products – also referred to as loss of function mutations Signal transduction regulation--NF1 Transcription regulation--Rb and p53 Cell surface/cell matrix molecules--NF2, APC, and DCC – regulate cell adhesionDr Anshu P Gokarn
    • 32. Tumor Suppressor Genes Products of TSGs receive and process growth inhibitory signals from their surroundings. The result is the same as for unchecked stimulation of cell growth: neoplastic growth deregulation Some products are responsible for normal cell morphology, cell-cell interactions, and cell-matrix interactions Dr Anshu P Gokarn
    • 33. Tumor Suppressor Genes Mechanisms of inactivation – Structural inactivation  Deletions  Insertions  Inactivating point mutations – Functional inactivation (analogous to regulatory alterations as seen in oncogenes: normal gene, abnormal function eg Rb) In one clonal population it is possible to find a combination of two mechanisms of inactivation, a different one for each alleleDr Anshu P Gokarn
    • 34. The p53 gene….. Tumor suppressor gene, present in most human cancersFunction of p53 gene : To halt the cell in its cycle before DNA replication of the chromosomal DNA has been damaged. This pause allows time for DNA repair, preventing mutations from becoming permanent.Uses Ex: to assess cancer origin, to define cancer cell immuno-phenotype, to detect cellular products( hormones, cytokines, etc. ), to predict tumor behavior with specific markers. Dr Anshu P Gokarn
    • 35. The role of p53 in development of cancerIn normal cells, p53regulates cell growth bycontrolling cell proliferationand cell death.Mutations in p53 lead toloss of growth suppressivefunctions, leading touncontrolled growth. Dr Anshu P Gokarn
    • 36. Growth Inhibitory Factors Mutations in genes encoding soluble factors that bind to cell membrane, transmit growth inhibitory signals, favour uncontrolled cell growth eg. Breast cancer – 1 (brca-1 protein) Increased mutations of brca-1 have increased risk of breast and ovarian cancersDr Anshu P Gokarn
    • 37. DNA Repair Genes “Humans literally swim in a sea of environmental carcinogens.” Cells can repair damage caused by ionizing radiation, sunlight, dietary/chemical carcinogens and replication errors which occur spontaneously in dividing cells. If errors accumulate, cells are at risk of neoplastic transformation Dr Anshu P Gokarn
    • 38. Apoptosis Regulating Genes Apoptosis is programmed cell death There are both proapoptotic genes (cell death agonists such as bax, bcl-xS, bad, bid) and antiapoptotic genes (cell death antagonists such as bcl-2, bcl-xL) The prototypic gene in this category is bcl- 2Dr Anshu P Gokarn
    • 39. Cancer: apoptosis Apoptosis (programmed or physiological cell death) Process in which single cells are removed from midst of living tissue without disturbing architecture or function or eliciting an inflammatory response. Normal inbuilt response is present in its genetic material. Deregulated apoptosis : pathogenesis of neoplasms Apoptosis : End result of chemotherapeutic drug action Dr Anshu P Gokarn
    • 40. bcl-2 family Antiapoptosis Proapoptosis (Death antagonists) (Death agonists) bcl-2 ba x Cell accumulation ApoptosisDr Anshu P Gokarn
    • 41. bcl-2 family Antiapoptosis Proapoptosis(Death antagonists) (Death agonists) bax bcl-2 bcl-xS bcl-xL bad bidDr Anshu P Gokarn
    • 42. Telomerase Genes  With each cell division, shortening of specific tracts of DNA at the ends of chromosomes occurs  These tracts are called telomeres  Telomeres are composed of repetitive DNA sequences  Once shortened beyond a certain point, cells die  Telomere shortening, therefore, acts as a clock that counts cell divisionsDr Anshu P Gokarn
    • 43. Telomerase Genes  In germ cells, telomere shortening is prevented by the enzyme complex telomerase  Telomerase adds back any repetitive telomere sequences lost after a cell division  Most somatic cells lack telomerase  For a cell to divide indefinitely, it must prevent telomere shortening  Tumor cells do this by activating telomerase Dr Anshu P Gokarn
    • 44. Molecular Basis of MultistepCarcinogenesis  No single gene can transform cells in Normal cell proliferation vitro  Every human cancer analyzed reveals multiple genetic alterations involving activation of several oncogenes and loss of two or more tumor suppressor genes.  The specific temporal order of mutations determines the propensity for tumor development Dr Anshu P Gokarn Aggressive cancer cell
    • 45. Localization and function of cancer associated genesDr Anshu P Gokarn
    • 46. How cancer develops (The Pathological changes) Stages of development of cancer Dr Anshu P Gokarn
    • 47. Cancer :Initiation to metastasis Dr Anshu P Gokarn
    • 48. Dr Anshu P Gokarn
    • 49. CarcinogenCarcinogen are chemicals that cause cancerCarcinogen may be:Environmental / Industrial Benzene leukemia Vinyl chloride liver Asbestos lung, pluera Arsenic lungAssociated with lifestyle Alcohol esophagus, mouth and throat Betel nuts mouth, throat Tobacco head, neck, lung, esophagus, bladder Dr Anshu P Gokarn
    • 50. CarcinogensDrug induced Alkylating agents leukemia, bladder DES liver, vagina (if exposed before birth) Oxymetholone liver Susceptible cell + carcinogen cancerous cellDr Anshu P Gokarn
    • 51. Dr Anshu P Gokarn
    • 52. Risk Factors Family history Ex: breast cancer, colorectal cancer Chromosomal abnormalities ex : Down’s Syndrome with acute leukemia Environmental factors Ex : UV radiation / sunlight --- skin cancer ionizing radiation / atomic bomb explosion ---- leukemia smoking ---- lung cancerDr Anshu P Gokarn
    • 53. Risk factors DietEx : 1. Smoked / pickled food cancer stomach more 2. High fiber diet - less colorectal cancer AlcoholEx: liver cancer Occupational hazardEx :asbestos with lung cancer Geographic location :Ex : Japanese : colon / breast cancer - less stomach cancer ---- - more Dr Anshu P Gokarn
    • 54. Risk Factors Viral infection Ex: cytomegalovirus : Kaposi’s sarcoma Hepatitis B virus : liver cancer HIV virus : lymphomasParasitic infectionEx: schistosoma : bladder cancerImmune statusEx : immunosuprressants / immunosuppressed status More chances Dr Anshu P Gokarn
    • 55. PART IVDr Anshu P Gokarn
    • 56. Types of tumors  Benign tumor Tumor is localized,cannot spread to other sites,amenable to local surgical removal,patients life is not at danger, capsule present  Malignant tumor c/a cancer Adhere to any part that they seize in an obstinate manner Lesion can invade / destroy surrounding areas, can metastasize, patient’s life is at risk Capsule is absentDr Anshu P Gokarn
    • 57. Characteristics of benign and malignant tumors  Differentiation (lack of differentiation a hallmark of malignant cells)  Rate of growth ( in malignant tumors correlates with their level of differentiation)  Local invasion (most benign tumors have a fibrous capsule around them which separates them from the host tissue)  metastasis Dr Anshu P Gokarn
    • 58. Comparison characteristics Benign malignant Well differentiated. Lack of differentiation1.Differentiation Structure typical of Structure atypical tissue of origin Progressive / slow Erratic/ slow to rapid2. Rate of growth Standstill / regression Cohesive and expansile; Locally invasive; well demarcated;no invades surrounding3. Local invasion infiltration into tissue surrounding Dr Anshu P Gokarn
    • 59. comparisoncharacteristics benign malignant4. Metastasis Absent Frequently present5. Bleeding Absent present6. survival No threat to life Serious threat to life Dr Anshu P Gokarn
    • 60. Benign tumorDr Anshu P Gokarn
    • 61. Malignant tumor (spreading)Dr Anshu P Gokarn
    • 62. Structure of a tumor Stroma (blood vessels, connective tissue) Parenchyma (Decides the biological behaviour)Dr Anshu P Gokarn
    • 63. Structure of a tumorDr Anshu P Gokarn
    • 64. Dr Anshu P Gokarn
    • 65. Nomenclature Benign  Fibrous – fibroma  Cartilagenous – chondroma  Epithelial -- microscopic / macroscopic appearance/ cell of origin Ex: Adenoma -- generally displays glandular appearance Papilloma – located on the surface finger like processes Polyp --- mass projecting above mucosal surface ex: gut Cystadenoma -- hollow cystic massesDr Anshu P Gokarn
    • 66. Nomenclature Malignant  Arising from mesenchyme --- sarcomas Fibrous tissue --- fibrosarcoma Chondrocytes --- chondrosarcoma  Arising from epithelium ----carcinomas squamous cell carcinoma adenocarcinomaDr Anshu P Gokarn
    • 67. Nomenclature Melanoma in skin  Poorly differentiated carcinoma  Mixed Tumors ex: salivary glands Exceptions to the rule  Lymphoma  Melanoma  Mesothelioma malignant  seminomaDr Anshu P Gokarn
    • 68. Nomenclature Malignant  Arising from white blood cells Leukemias Ex : Acute Lymphoblastic Leukemia  Arising from monocytes, macrophages Lymphomas Ex : Hodgkin’s diseaseDr Anshu P Gokarn
    • 69. NomenclatureLung cancer- Tumors arising from the respiratory epithelium(bronchi, bronchioles, alveoli) Treatment Decisions Of Lung Cancers Depends On The Histological Appearance of the tumors Dr Anshu P Gokarn
    • 70. According to WHO classification……Four major cell types make 88% of all primary lungneoplasmsThey are:Squamous / epidermoid carcinomaSmall cell also called as oat cell carcinomaAdenocarcinoma (including bronchioalveolar)Large cell (large cell anaplastic) carcinoma The remainder include undifferentiated carcinomas, carcinoids, bronchial gland tumors (including adenoid cystic and mucoepidermoid carcinomas) and the rarer tumors.Dr Anshu P Gokarn
    • 71. Differences between Small cell type and Non- small cell type Small cell type Non small cell type  (scant cytoplasm,small  (Abundant cytoplasm, hyperchromatic nuclei, pleomorphic nuclei, indistinct nucleoli, diffuse prominent nucleoli, sheets of cells glandular/squamous architecture)  At presentation they have spread so much that surgery  Localized not helpful.  Managed primarily by  Amenable to surgery and chemotherapy and/or radiotherapy but not radiotherapy. chemotherapy. Dr Anshu P Gokarn
    • 72. Benign Neoplasms of the Lung Represents less than 5 % of all primary tumors  Bronchial adenomas  Hamartomas  Chondromas  Fibromas  Lipomas  Haemangiomas etc.Dr Anshu P Gokarn
    • 73. Cancer of stomach 85% of stomach cancers are adenocarcinomas 15% - lymphomas / leiomyosarcomas Adenocarcinomas --- Diffuse type (individual cells infiltrate and thicken the stomach Intestinal type (neoplastic cells form gland like tubular structure) Dr Anshu P Gokarn
    • 74. Tumors of the small intestine Benign tumorsAdenomas – Islet cell adenoma (From the pancreas) Brunner’s gland adenoma( from the duodenal mucosal glands)Polypoid adenomasLeiomyomas – from smooth muscle of the intestineLipomas – In the distal ileum and at ileocecal valveAngiomas – They cause intestinal bleeding Dr Anshu P Gokarn
    • 75. Tumors of the small intestine Contd…..Malignant tumors Ampullary carcinomas – arise from biliary / pancreatic ducts Adenocarcinomas – Most common carcinoma of small bowel (50% incidence) Lymphomas – may be primary / secondary  Primary -ex : Non-Hodgkin’s Lymphoma, Involves the ileum, duodenum and jejunum in decreasing order of frequency.  Secondary lymphomas – involvement of the intestine by a lymphoid malignancy extending from involved retroperitoneal or mesenteric lymph nodes Carcinoid Tumors – From distal duodenum to the ascending colon Leiomyosarcomas Dr Anshu P Gokarn
    • 76. Tumors of the liver Benign liver tumors Hepatocellular adenomas – In right lobe of the liver Focal nodular hyperplasia- predominantly in women Solid tumor in the right lobe with a fibrous core Hemangioma Malignant tumors Hepatocellular carcinomas Dr Anshu P Gokarn
    • 77. Breast cancer Ductal adenocarcinoma - most common Lobular carcinoma - the second malignant breast tumour Medullary carcinoma is rare Hyperplasia is a proliferation without criteria of malignancy Fibroadenomas are benign breast tumours Dr Anshu P Gokarn
    • 78. Solid tumors Comprise a group of malignancies arising from the various systems or organs with distinct behaviour patterns, requiring different management Multimodal approach followed in management of solid tumors Surgery - the primary modality for most of the solid tumors Radiotherapy also can be used as a primary modality followed by adjuvant therapy Dr Anshu P Gokarn
    • 79. Solid tumors Contd….. Chemotherapy systemic, local or regionalRegional chemotherapy - intra-tumoral, intracavitary or intra-arterialSystemic chemotherapy – to prevent early disseminated aggressive lesionsDr Anshu P Gokarn
    • 80. Dr Anshu P Gokarn
    • 81. Various types of cancers  Haematological malignancies Acute Lymphocytic Leukemia Multiple myeloma Acute Granulocytic leukemia Hodgkin’s Disease Acute myelomonocytic Low grade(nodular) leukemia lymphomas Chronic granulocytic leukemia High grade lymphomas Chronic Lymphocytic Burkitt’s tumor leukemia Mycosis Fungoides Dr Anshu P Gokarn
    • 82. Various types of tumors Solid tumors Adrenocortical carcinoma  Head and neck Bronchogenic carcinoma squamous cell small cell or oat cell  Hepatocellular Squamous cell, large cell carcinoma anaplastic and  Malignant insulinoma adenocarcinoma or islet cell carcinoma  Malignant melanoma Cervix squamous cell  Ovary Colon carcinoma  Pancreatic Endometrial carcinoma adenocarcinoma Gastric adenocarcinoma  Prostate Dr Anshu P Gokarn
    • 83. Various types of cancers  Pediatric solid tumors  Wilm’s tumor  Ewing’s sarcoma  Embryonal Rhabdomyosarcoma  Retinoblastoma  Neuroblastoma  Osteogenic sarcomaDr Anshu P Gokarn
    • 84. Dr Anshu P Gokarn
    • 85. Metastases  Development of secondary implants discontinuous with the primary tumor, possibly in remote areas.  Not all cancerous cells have an equal ability to metastasize Ex:  basal cell carcinoma and cancers of CNS invade locally but rarely metastasize  Bone sarcomas have already metastasized to lungs at discoveryDr Anshu P Gokarn
    • 86. MetastasesOccurs by following routes1. Hematogenous2. Lymphatic3. Seeding of cancer cells4. Direct implantation Common sites of metastases Dr Anshu P Gokarn
    • 87. Metastases Hematogenous Favoured by sarcomas (carcinomas are by no means shy about using it ! ) Liver and lungs – most frequently affected Spread by this route very fast Some tumors have propensity to invade veins Dr Anshu P Gokarn
    • 88. MetastasesLymphatic spread More typical of carcinomas Pattern of lymph node involvement depends on site of involvement, natural lymphatic pathways for drainageex: lung carcinomas of respiratory passage first metastasize to the regional bronchial lymph nodes; then to tracheo - bronchial / hilar lymph nodes Cells may traverse all the lymph nodes to enter the vascular compartment Dr Anshu P Gokarn
    • 89. MetastasesSeeding of cancers Invasion of natural body cavities Ex: carcinoma of colon can penetrate wall of the gut and reimplant at distant sites. Cancer ovary disseminates through peritoneal cavityDirect spread With surgeon’s gloves Or With surgical instruments Rarely seen in practiceDr Anshu P Gokarn
    • 90.  What happens to the patient ?Dr Anshu P Gokarn
    • 91. Signs and symptoms Pain Loss of weight / muscle wasting Loss of appetite/anaemia Ulceration at the site Bleeding Rapid growth in size Immunosuppression –repeated infections Depending on the location of the tumor pitutary adenoma - hypopituitarism Renal carcinoma - renal ischaemia/hypertension Hormone production --Neoplasm of endocrinal gland Dr Anshu P Gokarn
    • 92. Signs andsymptoms Dr Anshu P Gokarn
    • 93. Diagnosis of cancer History Age Sex Family, personal history Geographic location Screening Radiological examination ---- MRI CT- Scan X ray chest Dr Anshu P Gokarn
    • 94. Diagnosis of cancerScreening To detect possibility of cancer Early detectionDisadvantage Though not definitive reduction in number of deaths Costly Psychological or physical repurcussions High number of false positive/ false negative results seen Dr Anshu P Gokarn
    • 95. Diagnosis of cancerScreening tests widely usedIn women Pap staining --- cancer cervix Mammogram – breast cancerIn men Prostate specific antigen ---- prostate cancerOther testsXray chestSputum cytology lung cancerStool examination for occult blood rectal cancerRectal examination rectal cancerpelvic examination cervical cancer Dr Anshu P Gokarn
    • 96. Diagnosis of cancer Molecular / Morphologic methodsTissue Biopsy Indicated almost all types of cancers Advantages Invasive method but highly diagnostic Disadvantage Margins may not be representative / centre may be necrotic . Selection of appropriate site necessary Dr Anshu P Gokarn
    • 97. Diagnosis of cancer Frozen section biopsy Advantages  determines nature of lesion  Helps evaluate the margins of excised cancer  Quick method  Patient spared the trauma of repeated operationDr Anshu P Gokarn
    • 98. Diagnosis of cancerFine needle aspiration cytology Indicated For readily palpable lesions of breast, thyroid,lymph nodes, salivary glands Advantages : obviates need for surgery Deeper structures can be examined Disadvantages Sampling errors due to small sample size may occur Dr Anshu P Gokarn
    • 99. Diagnosis of cancer Cytologic smears  Indicated in: Carcinoma cervix, endometrial carcinoma, bronchogenic carcinoma,bladder, prostate,joints,, abdominal tumors, pleural tumors  Advantages 100 % true positive diagnosisDr Anshu P Gokarn
    • 100. Diagnosis of cancer Biochemical methods 1. Biochemical assays Indications  To determine prognosis  To detect new cases  Tumor associated enzymes  Hormones  Tumor markers : alpha fetoprotein, carcinoembryonic antigen 2. RadioimmunoassayDr Anshu P Gokarn
    • 101. Tumor Markers Normal metabolic constituents / biochemical products found in abnormal amount / at inappropriate time of life Aids in detecting viable tumor tissue in the bloodEx : Fetal proteins re-expressed in adult life Tumor markers used to monitor progress of individual patients of malignancyEx : alpha-fetoprotein for testicular tumors Dr Anshu P Gokarn
    • 102. Radioimmunoassay Highly specific antibodies raised against tumor antigens and labelled with flourescein stain /. Used in immunohistochemical techniques to detect tumor cell products such as enzymes, hormones, receptors Used to differentiate between benign and malignant tumors To differentiate between histological subtype of similar tumors To select the most appropriate therapy Dr Anshu P Gokarn
    • 103. Dr Anshu P Gokarn
    • 104. Grading of cancer  Grading Helps to estimate  The aggressiveness of the tumor  Level of malignancy  To predict the prognosis Done depending on the degree of anaplasia Grade I -- IVDr Anshu P Gokarn
    • 105. Staging Based on size of primary lesion Extent of spread to regional lymph nodes Presence/absence of lymph nodes CT Scan/ MRI/Exploratory laparotomy to conduct staging Of more value than gradingDr Anshu P Gokarn
    • 106. Staging Method TNM classification T = extent of primary tumor N = regional lymph node involvement M = Metastases Dr Anshu P Gokarn
    • 107. TNM classification  T0 ---- excised tumor  T1,T2,T3, – increase in size of primary lesion  N0, N1,N2,N3—indicate advancing nodal involvement  M0, M1 – Presence/ Absence of metastases Dr Anshu P Gokarn
    • 108. TNM Classification: ex: Breast cancer Primary Tumor  TX primary tumor cannot be assessed  TO No evidence of primary tumor  Tis Carcinoma in situ: intraductal carcinoma, lobular carcinoma in situ or Pagets disease of the nipple with no tumor  T1 tumor 2 cm or less in greatest diameter  T1a 0.5 cm or less in greatest diameter  T1b > 0.5 cm but < 1 cm in greatest diameter  T1c > 1cm but < 2 cm in greatest diameter  T2 Tumor > 2cm but < 5 cm in greatest diameter.  T3 Tumor>5 cm in greatest diameter.  T4 Tumor any size with direct extension into chest wall of skin  T4a Extension to chest wall .  T4b Oedema  T4c Both(T4a and T4b)  T4d Inflammatory carcinoma Dr Anshu P Gokarn
    • 109. TNM Classification: ex: Breast cancer Regional Lymph Nodes  NX Regional lymph nodes cannot be assessed (ex: previously removed)  N0 No regional Lymph Node metastasis  N1 Metastasis to ipsilateral axillary lymph nodes fixed to one another or to other structures.  N3 Metastases to ipsilateral internal mammary node(s) Distant Metastases  MX Presence of distant metastases cannot be assessed  M0 No distant metastases  M1 Distant metastases Dr Anshu P Gokarn
    • 110. Investigations to define TNM classification Tumor  Palpation  Inspection including endoscopy  Radiology  Cytology / aspiration /biopsy Nodes  Palpation  Aspiration  Biopsy  Radiology (CT scanning) Dr Anshu P Gokarn
    • 111. Investigations to define TNM status Metastases  Biochemical screening(ex : liver function tests)  Radionuclide scans(ex : liver,brain, bones)  Ultrasound of liver  Radiology (Xray chest, CT scan- liver, brain, thorax)  Laparoscopy  LaparotomyDr Anshu P Gokarn
    • 112. PART - VDr Anshu P Gokarn
    • 113. Cancer treatment Types :  Radiotherapy  Chemotherapy  Immunotherapy  Endocrine Therapy  SurgeryDr Anshu P Gokarn
    • 114. ChemotherapyThe treatment of cancer with drugs which killmalignant cells or modify their growth and leavehost cells unharmed or at least recoverable.AIMTo Cure Or Prolong RemissionPalliationAdjuvant Chemotherapy – drugs are used to mopup any residual malignant cells (micrometastases)after surgery or radio-therapy.Dr Anshu P Gokarn
    • 115. Purine Pyrimidine PALA-I nhibits pyrimidine synthesis synthesis synthesisPentosan- Inhibitsadenisine deaminase Hydroxyurea- inhibits ribonucleotide reductase6-mercaptopurine, 6- Ribonucleotide thioguanine 5-Fluorouracil- inhibits TMPInhibits purine ring Deoxyribonucleotides s synthesis biosynthesis Gemcitabine,Cytarabine,FludaraInhibits nucleotide bine, -Inhibits DNA synthesis bioconversions DNAMethotrexate- inhibits Platinum analogues,alkylatingdihydrofolate reduction- agents,Mitomycin,,cisplatin,blocks TMP and purine Procarbazine,Dacarbazine- forms RNA adducts with DNAsynthesis L-asparginase- deaminatesCamptothecin,Etoposide,T asparagine- inhibits proteineniposide,Daunorubicin – Proteins synthesisblocks topoisomerasefunction Paclitaxel, Vinca alkaloids, Enzymes microtubules colchicine- inhibits function of microtubule Dr Anshu P Gokarn
    • 116. Anti tumor drug action to the cycleDNA synthesis (G2) Premitotic (S) interval S-Phase specific Cytosine arabinoside (M) Mitosis Hydroxurea Vincristine, vinblastine, S Phase specific, self Paclitaxel limiting 6 Mercaptopurine Methtrexate G 0 (resting (G 1) phase)Dr Anshu P Gokarn
    • 117. Anti tumor drug action to the cycle Phase Non-Specific  Alkylating drugs  Nitrosoureas,  Anti tumor antibiotics  Procarbazine,  Cis-platinum,  DacarbazineDr Anshu P Gokarn
    • 118. Treatment Of CancerDRUG ACTION Cycle Specific : only active cycling cells killed Toxicity is generally expressed in S -phase e.g. anti-metabolite Cycle Non-Specific : kills cells in both resting or active cycling phase (i.e. tumor with low growth fraction - e.g. solid tumors). Non cycling cells are allowed to re-enter the cycle between drug courses. e.g. alkylating agents; doxorubicin; anthracyclines; MOPP regime Dr Anshu P Gokarn
    • 119. Alkylating agents  Nitrogen mustards ex: Mechlorethanamine, cyclophosphamide, Melphalan, Uracil mustard, Chlorambucil  Ethylenimines ex: Triethylenemelamine (TEM) Triethylene Thiophosphamide (Thio-TEPA)  Alkyl Sulfonates ex: BusulfanDr Anshu P Gokarn
    • 120. Alkylating agents Mechanism of action  Cells are destroyed by alkylation  Alkyl groups are added to constituents of DNA inhibiting DNA synthesis  Interference with the replication and transcription of Messenger RNA occurs Indications  Hodgkin’s disease  Lymphomas, chronic leukemias  Bronchial, ovarian carcinoma  seminomasDr Anshu P Gokarn
    • 121. Alkylating agents - Cyclophosphamide  Mechanism of action similar but thrombocytopenia is less severe while alopecia like side effects are more.  The drug does not produce any CNS side effects.  Essential component for various drug combinations for Non-Hodgkin’s lymphoma.  Administered by both oral and Intravenous route  Can be given as single agent for Burkitt’s Lymphoma Dr Anshu P Gokarn
    • 122. Alkylating agents (busulfan)  More effective on the myeloid series of cells  Causes depression of platelet and granulocyte production Indication  In chronic myeloid leukemiaDr Anshu P Gokarn
    • 123. Nitrosureas EX: carmustine, Lomustine, Streptozotocin Alkylates the DNA and kills cells in all phases of cell cycle Have high lipophilicity , so can be given in Brain malignancies. Indicated in gastrointestinal neoplasms and brain tumors. Significant response in Hodgkin’s disease May cause renal failure and myelosuppression. Streptozotocin does not cause myelosuppression.Dr Anshu P Gokarn
    • 124. AntimetabolitesII) Folic acid antagonistsEx: methotrexate Purine analoguesEx : 6- mercaptopurine, Azathioprine Pyrimidine analoguesEx : cytosine arabinoside, 5- fluorouracil Dr Anshu P Gokarn
    • 125. Antimetabolites Mechanism of action  Blocks the action of the metabolite by preventing the combination of the metabolite with it’s enzyme Or  Itself combines with the enzyme to get transformed into a metabolically inactive compound which is harmful to the cellDr Anshu P Gokarn
    • 126. Antimetabolites Folic acid antagonists : Methotrexate Folic acid Methotrexate TetraHydrofolic Folate reductase + acid No THF synthesis DNA synthesis No DNA synthesis Indications  Acute Lymphatic Leukemia  Choriocarcinoma  Soft tissue sarcoma  Breast cancer  Acute Myeloid LeukemiaDr Anshu P Gokarn
    • 127. Antimetabolites: (Purine antagonists)  Interferes with the synthesis and interconversion of purines 6- Mercaptopurine 6-mercaptopurine ribonuclideinhibits inhibits Purines synthesis DNA Dr Anshu P Gokarn
    • 128. Purine antagonists Indications  Acute Leukemia mainly in children  Choriocarcinoma  Chronic Myelogenous leukemia (CML)Dr Anshu P Gokarn
    • 129. Pyrimidine antagonists(5- Fluorouracil) Fluorinated analogue of pyrimidine Binds to thymidylate synthetase to prevent the production of thymine(basic component of DNA) Incorporates in place of uracil in RNAIndications Carcinoma of colon, ovaries, rectum, stomach, breastCytosine arabinoside Pyrimidine analogue used in inducing remission in acute myeloid leukemia Dr Anshu P Gokarn
    • 130. ProcarbazineMechanism of action Undergoes metabolic activation to generate the cytotoxic reactants which methylate DNA. Exposure to Procarbazine leads to damage of the DNA, RNA and the protein synthesis which occurs in vivoIndications Used in combination with other drugs of the MOPP regime in Hodgkin’s disease. Has shown activity against brain tumors, small cell carcinoma of the lung, myeloma and melanoma Dr Anshu P Gokarn
    • 131. Hydroxyurea Mechanism of action  Interferes with the activity of ribonucleoside diphosphate reductase .  This enzyme converts ribonucleotide to deoxyribonucleotides and is the rate limiting step in the biosynthesis of DNA. Indication  Used as a myelosuppressant in myeloproliferative disorders ex: chronic granulocytic leukemia, polycythemia vera and essential thrombocytosisDr Anshu P Gokarn
    • 132. Gemcitabine : newer antimetabolite. Mechanism of action Weak inhibitor of DNA polymerase Potent inhibitor of ribonucleotide reductase Incorporates into DNA and leads to DNA strand termination. Indications First line therapy in pancreatic acncer and non small cell lung cancerDr Anshu P Gokarn
    • 133. Radioactive isotopes Radiations emitted by these isotopes produce ionization in the cells thereby disrupting the cellular metabolism. Cell destruction follows Indications Radioactive iodine for thyroid cancer Radioactive gold for malignant pleural/ peritoneal effusions, in prostatic / pelvic cancersEx : Radioiodine, Radiogold, RadiophosphorusDr Anshu P Gokarn
    • 134. AntibioticsMechanism of action Blocking DNA dependent RNA synthesis (actinomycin D, Rubidomycin) Causing breaks in single / double stranded DNA (bleomycin)IndicationsActinomycin D - Wilm’s tumor, choriocarcinoma ,Hodgkin’s lymphomaMitomycin ---- CML, Hodgkin’s DiseaseRubidomycin --acute leukemia in childrenDoxorubicin ---Remission in ALL, lymphoblasticlymphosarcoma Dr Anshu P Gokarn
    • 135. Antibiotics (contd…..) Bleomycin ---- epidermoid carcinoma of skin, respiratory passage, oral cavity, Mithramycin --embryonal cell carcinoma of testes, in hypercalcaemia due to malignancy, Paget’ disease Mitoxantrone Analogue of doxorubicin Has low cardiotoxicity potential Indicated in acute granulocytic leukemia, breast cancer.Dr Anshu P Gokarn
    • 136. Antimitotic plant products (Vinca alkaloids)Act by:Inhibiting mitosisBinds to tubulin and prevents the formation of mitotic spindleUsesVinblastine inHodgkin’s disease(remission in 50- 60% cases)Methotrexate resistant choriocarcinoma, lymphosarcomaVincristine inAcute Lymphatic LeukemiaVinorelbine inNon small cell lung carcinomas along with cisplatinIn breast cancerCauses lesser neurotoxicity and modest thrombocytopeniathan other vinca alkaloids. Dr Anshu P Gokarn
    • 137. Antimitotic plant products (Paclitaxel)Mechanism of actionBinds to microtubules and inhibits their depolymerization(molecular disassembly) into tubulin.Paclitaxel blocks a cells ability to break down the mitoticspindle during mitosis (cell division)Paclitaxel inhibits mitosis but unlike vinca alkaloids promotesmicrotubule formation.IndicationsIn Cisplastin resistant tumors of ovaryCancers of breast, lung, oesophagus, head and neck Dr Anshu P Gokarn
    • 138. DocetaxelMechanism of ActionLike paclitaxel, it prevents the breakdown of mitotic spindleClinical trials indicate its about twice as effective as paclitaxelIndication:Breast cancerNon small cell Lung cancerOther uses:Head and neck cancer, Small cell lung cancerMesothelioma, Ovarian cancer, Prostate cancerOrothelial transitional cell cancer Dr Anshu P Gokarn
    • 139. Natural Products (Camptothecins)Irinotecan, Topotecan Combines with the Topo-isomerase I and inhibits its function An intermediate complex formed creating single stranded DNA break(cleavable complex) This relieves the DNA torsion Camptothecins stabilize the cleavable complex Accumalation of single stranded breaks in DNA which after series of reactions becomes irreversible leading to cell death Active in S phaseIndications Ovarian cancer, Small cell lung cancer, Colon cancer Dr Anshu P Gokarn
    • 140. Natural Products (Epipodophyllotoxins)Etoposide Form a ternary complex with Topoisomerase II and DNA Results in double stranded DNA breaks and resealing of the break that follows the binding of DNA with Topoisomerase is inhibited Enzyme remains bound to the free end of the broken DNA strand leading to accumalation of DNA breaks and cell death. Cells in S /G2 phase most susceptibleIndications In testicular cancer, small cell lung, breast cancers. Hodgkin’s disease, Non- Hodgkin’s Lymphoma, Acute granulocytic Leukemia, Kaposi’s sarcoma Dr Anshu P Gokarn
    • 141. Hormones and Hormone antagonistsMechanism of action Act in a different manner from the cytotoxic drugs and can be combined with them in certain malignancies Are slow in their effect Inhibit cell growth and differentiationEx androgens in breast cancer estrogens in prostate cancer Stimulation of differentiation of cells which regain the body’s ability to respond to regulatory mechanismEx: estrogens in breast cancer in postmenopausal women Dr Anshu P Gokarn
    • 142. Hormone and hormone antagonists Selective lysis of leukemic lymphocytesEx : in ALL (Acute Lymphocytic Leukemia) Inhibition of circulating concentration of a substance which stimulates the malignant cellsEx: Thyroxine suppresses thyroid cancers by inhibiting TSH levels Androgens in Mammary tumors in post-menopausal women Particularly useful in bone metastases because they promote recalcification Flutamide Nonsteroidal compound used in metastatic cancer o prostate Dr Anshu P Gokarn
    • 143. Hormones and hormone antagonistsTamoxifen Nonsteroidal oestrogen it competes with the circulating estrogen for binding to estrogen receptors At low concentrations – estrogen receptor positive cells are blocked by the drug (cytostatic effect) At higher concentrations – (cytotoxic effects) Estrogen receptor positive/ negative cells are destroyed.Indication Postmenopausal women with breast cancer Dr Anshu P Gokarn
    • 144. Hormone and hormone antagonistsSteroids Direct lympholytic effect Suppress mitosis in lymphocytes (due to this effect used in ALL / Malignant lymphoma) Prevents accelerated erythrocyte destruction (prevents anaemia ) Counter haemolytic/Haemorrhagic) complications due to thrombocytopenia in CML/ CLL In cerebral edema due to intracranial tumors metastases To control hypercalcemia due to certain tumors or following drug therapy In combination with cytotoxic drugs to produce symptomatic relief and sense of well being Dr Anshu P Gokarn
    • 145. L- Asparginase Acts by depleting asparginase from the host and denying the malignant cells the metabolite Indications  In reticulum cell carcinoma  Lymphoblastic leukemia CisPlatinum  Gets converted into active form in the cell  Behaves like alkylating agent and attacks the DNA Indications  Ovarian and testicular tumorsDr Anshu P Gokarn
    • 146. Newer agents : Carboplatin Mechanism of action is similar to cisplatin.However: Carboplatin is less reactive than cisplatin. Relatively well tolerated in clinical practice. Carboplatin is an effective remedy in patients with responsive tumors but unable to tolerate cisplatin because of impaired renal function, refractory nausea, significant hearing impairment, or neuropathy.. Can be used in high dose therapy.Indications In bladder cancer, head and neck cancer. Dr Anshu P Gokarn
    • 147. Newer agents : Oxaliplatin Unlike carboplatin and cisplatin it has a high volume of distribution. Unlike cisplatin, oxaliplatin in combination with 5-FU is active in colorectal cancer. Oxaliplatin, does not yield a cross-resistance. Less toxic than cisplatin Indications Ovarian cancer, germ cell cancer, cervical cancer, colorectal cancer.Dr Anshu P Gokarn
    • 148. Newer agents : Nedaplatin Nedaplatin – A recent addition to platinum compounds. Along with 5FU effective in squamous cell carcinoma of oral region.1 Indicated in head and neck, testicular, lung, oesophageal, ovarian, and cervical cancer. 2 Yields cross resistance with other platinum compounds .2 Less toxic than cisplatin.21. Ita M et al. Oral Oncol 2003 Feb;39(2): 144-92. Desoize B, Madoulet CCrit Rev Oncol Hematol 2002 Jun;42(3):317-25 Dr Anshu P Gokarn
    • 149. Drugs commonly used to treat major types of cancer: Hematological Malignancy Leukemia: (ALL)Cancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityAcute Induction: Daunorubicin ThioguanineLymphocytic Vincristine + Doxorubicin TeniposideLeukemia prednisone Cyclophaosphamide Methotrexate for cytarabineIncidence : 2.1% CNS prophylaxisof all cancers Maintenance –and cancer Methotrexate +deaths mercaptopurine Dr Anshu P Gokarn
    • 150. Drugs commonly used to treat major types of cancer: Hematological MalignancyLeukemia: (Acute granulocytic Leukemia) Cancer Type/ Drugs used Alternative/ Other drugs with Incidence secondary drugs reported activity Acute Doxorubicin or Amsacrine Azacitidine granulocytic daunorubicin + Mitoxantrone Mercaptopurine leukemia cytarabine Etoposide OR Cytarabine + Thioguanine OR Cytarabine, vincristine + Prednisone Dr Anshu P Gokarn
    • 151. Drugs commonly used to treat major types of cancer: Hematological Malignancy Leukemia: AMLCancer Type/ Drugs used Alternative/ Other drugs withIncidence secondary drugs reported activityAcute Doxorubicin / Etoposidemyelomonocytic daunorubicin +or monocytic cytarabineleukemia OR Cytarabine + thioguanine OR citarabine, vincristine + prednisone Dr Anshu P Gokarn
    • 152. Drugs commonly used to treat major types of cancer: Leukemia and Multiplemyeloma Leukemia : CLLCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityChronic Hydroxyurea Busulfan MercaptopurineGranulocytic Interferon alpha PlicamycinleukemiaChronic Chlorambucil PrednisoneLymphocytic CyclophosphamideLeukemia Dr Anshu P Gokarn
    • 153. Drugs commonly used to treat major types of cancer: Hematological malignancy Multiple MyelomaCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityMultiple Myeloma Melphalan OR Doxorubicin Vincristine+ Cyclophosphamide vincristine doxorubicin+ + Prednisone Dexamethasone Dr Anshu P Gokarn
    • 154. Drugs commonly used to treat major types of cancer: Hematological MalignancyCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityHodgkin’s disease ABVD MOPP Lomustine (Doxorubicin, regime(chlormusti Carmustine bleomycin, ne, vincristine,Incidence: Chlorambucil vinblastine, procarazine,0.5% of all cancers Thiotepa dacarbazine) prednisone)and 0.3% of cancer Etoposidedeaths Dr Anshu P Gokarn
    • 155. Drugs commonly used to treat major types of cancer: Hematological MalignancyCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityNodular lymphoma Cyclophosphamid fludarabine Lomustine(Non Hodgkin’s e, vincristine, CarmustineLymphoma) prednisone Interferon alpha 2.4% of all cancersBurkitt’s tumor cyclophosphamid carmustine methotrexate(Non Hodgkin’s eLymphoma)2.4% of all cancersMycosis fungoides Methotrexate Mechlorethamine Dr Anshu P Gokarn
    • 156. Drugs commonly used in Pediatric solid tumors, brain tumors, germ cell tumors and sarcomasCancer Type/ Incidence Drugs used Alternative / Other drugs secondary with reported drugs activityWilm’s Tumor Dactinomycin + Doxorubicin CyclophosIncidence: 1.6% of all vincristine -phamidecancers and 1.8% ofcancer deathsEwing’s sarcoma Cyclophosphamide+ Dactinomycin0.2% of all cancers doxorubicin+ vincristineEmbryonal Doxorubicin Dactinomycin Thioteparhabdomyosarcoma Cyclophosphamide Methotrexate Vincristine alternating with cisplatin + etoposide Dr Anshu P Gokarn
    • 157. Drugs commonly used to treat major types of cancerCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityRetinoblastoma cyclophosphamide CarboplatinNeuroblastoma Cyclophosphamide Doxorubicin Etoposide OR vincristine Cisplatin or carboplatin Vinblastine PrednisoneOsteogenic Doxorubicin+ Cisplatin or Melphalansarcoma cisplatin, Methotrexate + Mitomycin0.2 % of all folinic acidcancers Dr Anshu P Gokarn
    • 158. Drugs commonly used to treat major types of cancer: solid tumorsCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityAdrenocortical mitotanecarcinomaBladder Cisplatin or Methotrexate , Fluorouracil,Incidence: 4.6% of doxorubicin vinblastine, cyclophosphamideall cancers and Thiotepa mitomycin3.4% of all cancer Methotrexatedeaths vinblastineColon carcinoma Fluorouracil mitomycin Tegafur11.6% of ll cancers Semustine Doxorubicin Dr Anshu P Gokarn
    • 159. Drugs commonly used to treat major types of cancer: solid tumorsCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityBronchogenic Doxorubicin+ Etoposide + Procarbazine,carcinoma small cyclophosphamide+ cisplain Altretaminecell or ‘oat cel’ vincristineOR Paclitaxel16.8% of all Cyclophosphamidecancers + lomustine+ methotrexateSquamous cell, Cisplatin + Methtrexate, Mitomycinlarge cell vincristine OR cyclophosphamideanaplastic and cisplatin + Methotrexateadenocarcinoma etoposide16.8% of allcancers Dr Anshu P Gokarn
    • 160. Drugs commonly used to treat major types of cancer: solid tumorsCancer Type/ Incidence Drugs used Alternative / Other drugs with secondary reported activity drugsEndometrial carcinoma Megestrol OR Doxorubicin Fluorouracil,1.5% of all cancers and Medroxyprogest cyclophosphamide0.7% of all cancer deaths eroneGastric adenocarcinoma Fluorouracil Semustine, Tegafur5% of all cancer deaths Mitomycin mitomycinand 5.8% of cancer DoxorubicindeathsHepatocellular Doxorubicin Fluorouracil, Tegafurcarcinoma etoposide0.5% of all cancer deaths cisplatin Dr Anshu P Gokarn
    • 161. Drugs commonly used to treat major types of cancer: solid tumorsCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityCervix squamous Cisplatin Bleomycin,mitom Methotrexate,cell ycin, Fluorouracil,1.8% of all cancers Vincristine,and 1.2 % of Cyclophosphamidecancer deaths doxorubicinHead and Neck Cisplatin+ Bleomycin Methotrexate, Vinblastinecancer OR methotrexate OR Paclitaxel Epirubicin fluorouracil+ leucovorin Doxorubicin carboplatinMalignant Streptozotocin + DacarbazineInsulinoma doxorubicin OR2.7% of all cancers fluorouraciland 4.2 5 of allcancer deaths Dr Anshu P Gokarn
    • 162. Drugs commonly used to treat major types of cancers Solid tumorsCancer Type/ Incidence Drugs used Alternative / Other drugs with secondary reported activity drugsMalignant Melanoma Dacarbazine Cisplastin Hydroxycarbamide1.5% of all cancers and Semustine0.8% of all deathsOvary Cisplatin + Doxorubicin FluorouracilChloraIncidence: 2.3% of all cyclophosphamide OR mbucil, Thiotepacancers and 2.7% of + Doxorubicin altretamine Melphalan,cancer deathsProstate Stilbestrol Cyclophosph EstramustineIncidence: 5% of all amidecancers and 6.2% of Doxorubicincancer deaths Dr Anshu P Gokarn
    • 163. Nonmelanoma skin cancer:Incidence : 12.2% of all cancers Cancer Type/ Incidence Drugs used 1. Basal cell carcinoma 5 Fluorouracil – tretament of superficial variety Intralesional intereferon useful 2. Squamous cell carcinoma 13 Cis retinoic acid -1 mg orally daily + interferon (3 million units s.c.) Combinations with cisplatin may help in few cases Dr Anshu P Gokarn
    • 164. Likely therapies in future for malignant melanoma  Melanomas often express cell-surface antigens which may be recognized by host immune cells.  Number of such antigens present such as:  MAGEs – 1,-2,-3  Tyrosinase –an enzyme involved in melanin synthesis  MART antigen  These antigens may make it possible to develop vaccination strategies against melanoma. Dr Anshu P Gokarn
    • 165. Drugs commonly used to treat major types of cancer: solid tumorsCancer Type/ Incidence Drugs used Alternative / Other drugs secondary drugs with reported activityPancreatic Fluorouracil Mitomycin Tegafuradenocarcinoma Doxorubicin2.7% of all cancer deathsSarcomas(Bone) Doxorubicin + Cyclophosphamide0.2% of all cancer and Dacrabazine Vincristinemethotrcancer deaths exate IfosfamideTesticular Vinblastine + Melphalan0.5% of all cancers and 1 Ifosfamide+ Doxorubicin% of cancer deaths cisplatin OR Bleomycin etoposide+ bleomycin+ cisplatin Dr Anshu P Gokarn
    • 166. Drugs commonly used to treat major types of cancer: solid tumorsCancer Type/ Drugs used Alternative / Other drugs withIncidence secondary drugs reported activityBrain neoplasms Carmustine or PCV(Procarbazine Plicamycin1.3% of all cancers lomustine +Lomustine+Vincri stine)Choriocarcinoma Methotrexate OR Chlorambucil Dactinomycin Etoposide+ cisplatinRenal cell Medroxyprogester Vinblastine Interferon alpha1.6% of all cancers oneand 1.8% of allcancer deaths Dr Anshu P Gokarn
    • 167. Drugs commonly used to treat major types of cancer: solid tumorsCancer Type/ Drugs used Alternative / Other drugsIncidence secondary drugs with reported activityBreast CMF+ P Doxorubicin+ Vinblastine, (cyclophosphamide, vincristine if CMF thiotepa, methotrexate, fluorouracil + P used as Melphalan,Incidence: , prednisone) OR primary otherwise Mitomycin11.1 % of all Doxorubicin combination ofcancers and drugs not used0.3% of cancer Cyclophosphamide previously/ singledeaths Additive (where agents not used hormones indicated): previously Stilbesterol, testolactone,tamoxifen,me gestrol, depending on menopausal and tumor hormone receptor status Dr Anshu P Gokarn
    • 168. Drugs commonly used to treat major types of cancer: solid tumors Cancer Type/ Drugs used Other drugs with Incidence reported activity Thyroid cis[platin 0.4% of all cancers doxorubicin Larynx Cisplatin+ Bleomycin OR Vinblastine methotrexate oR 0.8% of all cancers fluorouracil Dr Anshu P Gokarn
    • 169. Drugs commonly used to treat major types of cancer: solid tumors Cancer Type/ Drugs used Other drugs with Incidence reported activity Salivary glands Cisplatin+ Bleomycin Vinblastine 0.1% of all cancers OR methotrexate oR fluorouracil Gall Bladder Radiotherapy has 0.5% of al cancers not yielded good results Esophagus Cisplatin 2.2 % of all Paclitaxel cancers Dr Anshu P Gokarn
    • 170.  PART - VIDr Anshu P Gokarn
    • 171. Newer approaches to cancer Therapy  Measuring initial tumor growth factors or oncogenes helps in: 1. Selecting the patients for more intensive therapy. Ex: epidermal growth factor receptor in bladder and breast cancer. Nuclear oncoprotein p53 in breast cancer. 2. Helps in identifying patients who may show relapse or good response. Dr Anshu P Gokarn
    • 172. Newer approaches to cancer therapy In Cytotoxic treatment  Most of the drugs interfere with DNA metabolism  Additionally they possess activity on the newer targets for therapy.  Major advances with germ cell tumor, lymphomas and leukemias but less success with common solid tumors like lung, breast and colorectal cancer Dr Anshu P Gokarn
    • 173. Advances in Cytotoxic Drug TreatmentDr Anshu P Gokarn
    • 174. Newer approaches to cancer therapy  1. Topoisomerase inhibitors What are Topoisomerases ?  Nuclear enzymes involved in multiple cellular processes like DNA replication and separations of daughter chromosomes.  Are of two types – Type I and Type II Dr Anshu P Gokarn
    • 175. Type II Topoisomerase inhibitors Act mainly by inhibiting Topoisomerase II Drug in this class:  Epipodophyllotoxins (Etoposide) – In Lung cancer  Anthracyclines (Doxorubicin) – In breast cancer  Amsacrine derivatives  Anthrapyrazole group (CI-941) Dr Anshu P Gokarn
    • 176. Topoisomerase Type I inhibitors Less widely available Ex: Camptothecin Unaceeptable gastroinrestinal toxicity observed Newer types being developed Ex: Analogue of camptothecin – 9 amino- camptothecin Has significant activity in colon cancer xenografts an area where Topoisomerase II inhibitors have minimal impact. Dr Anshu P Gokarn
    • 177. Newer approaches to cancer therapy 2. New Antimetabolites: Gemcitabine  Anti-Folates like methotreaxte have been the most widely used till date.  Nowadays drugs which inhibit thmidylate synthase being developed.  Recently Gemcitabine developed  Gemcitabine gets converted to metabolites that inhibit DNA polymerase.  Active on Non Small Cell Lung cancer and breast cancer. Dr Anshu P Gokarn
    • 178. Newer approaches to cancer therapy 3. Modulation of drug resistance  Normally mdr1 gene encodes a glycoprotein which acts as an energy dependent efflux pump for many cytotoxic drugs.  Many new drugs modulate this glycoprotein  Ex: antiestrogens  These drugs modify the activity of p- glycoprotein which is present in the renal and biliary canaliculi. Suppression of this p-glycoprotein may lead to altered pharmacokinetics of the cytotoxic drug. Dr Anshu P Gokarn
    • 179. Dr Anshu P Gokarn
    • 180. New Drug Targets Inhibitors of Signal Transduction and second messenger systems Angiogenesis Receptor targeting Monoclonal Antibodies Immunotherapy agianst Tumor antigens or mutant oncogenes Molecular targets Dr Anshu P Gokarn
    • 181. Molecular Therapy……… Drugs developed using past paradigms attack both cancerous and healthy cells, often causing devastating short- and long-term side effects. Moreover, individual patient responses to conventional agents vary, even in cases where cancers appear to be identical Molecularly targeted therapies hold the promise of being more highly selective, drastically reducing the incidence of side effects in patients. Dr Anshu P Gokarn
    • 182. Research Avenues for Molecular Targeting Influence the cancer cell to re-regulate itself, or assume a more normal state. Turn on self-destruct pathways that cause a cancer cell to commit suicideStimulate the bodys immunesystem to reject the cancer Prevent the cell from acquiring the capacity to repeatedly replicate itself. Interfere with a cells capacity to use surrounding tissue to support its growth - e.g., through angiogenesis Dr Anshu P Gokarn
    • 183. Application of gene therapy to cancer Strategy: to introduce novel genes into cancer cells to convert them into "foreign" tissue grafts so they will be rejected by the patients own immune system. Following gene therapy, the cancer cells will be recognised as a genetically unrelated graft in the cancer patients and therefore will be rejected by the patients own immune system. Two Phase I clinical trials employing this strategy had been completed. Preliminary results are encouraging. A Phase 2 clinical trial is presently in progress. Dr Anshu P Gokarn
    • 184. Gene Therapy (contd……) Novel non-viral gene delivery lipid vehicles to deliver genes to cancer cells are also being designed and synthesized by this research group. The aim is to improve the efficiency of which cancer cells can take up novel exogeneous genes. Dr Anshu P Gokarn
    • 185. Gene Therapy (contd…..)Techniques that are possible 1. Immunomodulation by using tumor infiltrating lymphocytes This strategy mostly used in malignant Melanoma. 2. Certain genes are transcribed in malignant and fetal tissues but are not transcribed in adult tissue Ex: α fetoprotein in hepatomas and germ cell tumors Carcinoembryonic antigen in a range of adenocarcinomas particularly colonic tumor Vectors used to construct promoters of these particular proteins. Dr Anshu P Gokarn
    • 186. Oligonucleotides Involves down regulation of expression of important genes such as oncogenes which may be overexpressed in cancer cells. Achieved by three techniques1. Antisense approach2. Targeting specific mRNAs3. Antigene approach aimed at blocking transcription at its genetic location. Dr Anshu P Gokarn
    • 187. Antisense approach: Principle Translation is inhibited by degradation of mRNA by RNAase H OR Inhibition of binding of ribosomal subunits. Dr Anshu P Gokarn
    • 188. Antisense approach Normal flow of genetic information where a gene is transcripted into an mRNA and translated into a corresponding protein Antisense oligonucleotide hybridization to the complementary target and causes a block of protein translation Antisense oligonucleotides are taken up by the cell, hybridize to their target mRNA and block protein expression Dr Anshu P Gokarn
    • 189. Inhibitors of signal transduction and second messenger systems Mutation (ras) Over-expression of growth factor G proteins regulating receptors adenylate cyclase Increased intracellular signalling by second messenger systems like protein kinase C/ C-AMP dependent protein kinase Trials on for Bryostatin – antagonises protein kinase CC-AMP analogues ex: 8 Chlorocyclic AMP– inhibits tumor growth with little tissue toxicity Dr Anshu P Gokarn
    • 190. Inhibitors of signal transduction and second messenger systems  Activation of Tyrosine kinases has a transforming role.  Epidermal growth factors inhibitors ex: tyrosine analogues, may be useful. Dr Anshu P Gokarn
    • 191. What is a telomere The DNA molecule of a typical chromosome contains a linear array of genes (encoding proteins and RNAs) interspersed with non-coding DNA. Included in the non-coding DNA are:1. long stretches that make up the centromere and2. long stretches at the ends of the chromosome, the telomeres.When telomeres are completely or almost completely lost, cells mayreach a point at which they crash and die. Dr Anshu P Gokarn
    • 192. Telomerase Inhibitors Telomerase is the enzyme that replenishes shortened telomeres and allows cells to reproduce indefinitely. Found in only a few normal human cells, telomerase is present in as many as 90% of human cancers. This makes telomerase an attractive candidate for highly selective cancer drugs Certain normal human cells can only undergo 30-50 doublings before their telomeres are too short and doubling stops. Cancer cells must undergo about 80 doublings before a tumor mass is large enough to be detected Dr Anshu P Gokarn
    • 193. Telomerase Inhibitors B.-S. Herbert, A. E. Pitts, et al. at the University of Texas Southwestern Medical Center have shown that inhibitors of telomerase can remortalize transformed human breast epithelial cells and human prostate cancer cells in culture, ultimately leading to their cell death. The telomerase inhibitors used in this study are 2-0- MeRNA oligonucleotides directed towards the essential RNA component (hTR) of human telomerase. Dr Anshu P Gokarn
    • 194. Receptor Targeting External domain of the receptor – the new target Recombinant DNA technology used Either single molecule prepared or fusion protein with other molecule prepared. High specificity and affinity provided Ex: IL-6 receptor in Myeloma IL-2 receptor in lymphomas C-erb-2 / epidermal growth factor receptor – breast cancer. In fusion proteins – anticancer component provided by diphtheria / pseudomonas exotoxin Phase I studies in bladder cancer Dr Anshu P Gokarn
    • 195. Angiogenesis inhibitorsTumor invasiveness and metastasisrequire neovascularization (formation ofnew blood vessels)Tumor cells cannot grow as a massabove 2 to 3 mm because diffusion isinsufficient for oxygen and glucoserequirements, unless the tumor induces ablood supply. AngiogenesisMechanism of induction of a new bloodsupply from pre-existing vascular bed Drugs which inhibit angiogenesis are angiogenesis inhibitors Dr Anshu P Gokarn
    • 196. Angiogenesis inhibitors….. Like:  Suramin analogues  Antibodies to proliferating endothelium  Angioinhibins  Collagenase inhibitorsAngiogenesis inhibitors can be used with hypoxically active drugs for better effects. Hypoxically active drugs – drugs activated under reducingconditions to generate toxic metabolites that can bind to DNA and Dr Anshu P Gokarn generate strand breaks.
    • 197. Angiogenesis inhibitors in clinical trials Thalidomide and TNP-470, a synthetic analogue of fumagillin have shown efficacy in Kaposi,s sarcoma. 2- methoxyestradiol – in phase I trial for Breast cancer; has shown efficacy against melanoma. Thrombospondin 1 in basal cell and squamous cell carcinoma Col –III is a synthetic metalloproteinase inhibitor (in phase I trial) SU 6668 inhibits VEGF, FGF, and EGF receptor signalling. (in phase II trial ) Dr Anshu P Gokarn
    • 198. Common targets for angiogenesis inhibitorsAttack Points for angiogenesis inhibitors include specific cell surface and intracellular targets 1. Initial drugs including pentosan polysulphate, were heparin like. 2.Blocking a receptor’s autophosphorylation interferes with subsequent signal transmission 3. Some occupy a particular growth factor 4. Blocks cell surface proton pumps which interferes with several receptors. 5. Proliferating endothelial cells require specific cell surface contacts such as those mediated by Integrin αγβ3 6. Blockade of the process may induce endothelial cell death. 7. Body has its own tissue inhibitors of Dr Anshu P Gokarn matrix metalloproteinases(TIMPs)
    • 199. Newer developments in monoclonal Antibodies  Two step strategy used  Initially antibody allowed to localize itself for several days.  Then second binding protein which recognizes the first and has the therapeutic agent attached is administered.Ex: biotin on the first antibody and streptavidin asthe second protein. Dr Anshu P Gokarn
    • 200. Dr Anshu P Gokarn
    • 201. Monoclonal antibodies Rituximab and Trastuzumab are monoclonal antibodies approved by FDA Rituxan – for treatment of B-cell Non-Hodgkin’s Lymphoma that has not responded to chemotherapy. Herceptin – in treatment of metastatic breast cancer These antibodies are also being tested in lymphomas, leukemias, colorectal cancer, lung cancer, brain tumors ,and prostate cancers. Dr Anshu P Gokarn
    • 202. ADEPT MechanismADEPT – Antibody dependent enzyme prodrug therapyToxin is generated by1 enzyme attached to the antibody from a nontoxic Step an Step 2precursor.Advantage is that cytotoxic drug produced locally that will be active againsttumor cels that have not bound the antibody well. Repeated daily doses can begiven Dr Anshu P Gokarn
    • 203. Immunotherapy Antibodies designed specially to recognize a specific cancer When coupled with natural toxins, drugs or radioactive substances, the antibodies will seek out their target cancer cells and deliver their lethal load Alternatively toxins combined with lymphokines and routed to cells equipped with receptors for Lymphokines. Dr Anshu P Gokarn
    • 204. Immunotherapy against tumor antigens or mutant oncogenes Endogenous antigens presented by HLA class I molecules. Selective loss of HLA (Human leukocyte antigens) alleles occurs in many epithelial tumors. Upregulation of HLA with combined therapy with interferons may prove to be beneficial. Beneficial specially when vaccine technology is used for immunization against tumor antigens or mutant oncogenes like p 53, H-ras, mutant K- ras. Dr Anshu P Gokarn
    • 205. Dr Anshu P Gokarn
    • 206. Vaccines in cancer Dendritic cells are potent initiators of anti-tumor responses. They involve the activation of cytotoxic T cells which eliminate the tumor cells. Dendritic cells are being primed with Tumour cell lysates, tumour peptides, or DNA, to induce tumour-specific immunity against various human cancers. These DCs are expected to be valuable tool in the immunotherapeutic treatment of patients with metastatic tumor Dr Anshu P Gokarn
    • 207. Smart drugs searching out problem cells Specially designed toxins are linked with agents that bind selectively with components on the surface of cancer cells . A single piece molecule with two step mode of action has been developed One component of the molecule carries the tumor identifier and the other carries the active agent. Two tumor cell identifiers (IL-13 and SS1) are being developed to selectively seek out, recognize, attach to and deliver active drug to destroy cancer cells while leaving healthy cells intact. Dr Anshu P Gokarn
    • 208. Neopharm ,FDA and Nationalcancer institute have developedtwo highly selective tumor targetingagents1.Tumor targeted cytotoxin calledas IL-13-PE38 Normal cell Antimesothelin monoclonal2.antibody called as SS1-PE 38The PE-38 component of both thedrugs is a naturally occuringcytotoxin.It destroys the cancer cell after it is Cancer cellintroduced into the cell. Dr Anshu P Gokarn
    • 209. IL-13 targets receptors in thekidney , brain, berast, head andneck and Kaposi’s sarcomaSS1 seeks out and attaches tosites normally present in largenumbers on the surface ofspecific cancer cells.IL13-PE38 (delivered systemically)- fro treating renal cancerIL13-PE38 (delivered intratumorally)- for treating glioblastoma (braincancer)SS1-PE38(delivered systemically)- antimesothelin monoclonal antibodydelivery system Dr Anshu P Gokarn
    • 210. Rasburicase – approved by the FDAAnticancer therapy leads to tumor lysisLeads to accumalation of uric acid in plasmaLeads to tumor lysis syndrome which may lead to acute renalfailure.Rasburicase helps convert uric acid into a solublebyproduct(allantoin) which is readily excreted by the kidneys. Dr Anshu P Gokarn
    • 211. Biological Response Modifiers They are antibodies, cytokines and other immune system substances that can be produced in the laboratory for use in cancer treatment. They include:1. Interferons2. Interleukins3. Colony stimulating factors4. Monoclonal antibodies and5. Vaccines Dr Anshu P Gokarn
    • 212. Interferons They are cytokines which occur naturally in the body. Three major types:1. Interferon alpha2. Interferon beta3. Interferon gamma They improve the way a cancer patients immune system reacts to cancer cells. Additionally they also slow their growth or promote their development into more normal behaviour. Interferon Alpha used in – hairy cell leukemia, malignant melanoma, CML, AIDS related Kaposi’s sarcoma. May also be useful in metastatic kidney cancer and Non- Hodgkin’s Lymphoma Dr Anshu P Gokarn
    • 213. Biological Response Modifierslevamisole Acts by modulating cell mediated immune response Restores/ augments cutaneous delayed hypersensitive responseBCG Boost’s the production of antibodies Direct injection of tuberculosis bacteria into Melanoma decreases the size of tumor Dr Anshu P Gokarn
    • 214. Interleukins Interleukins are also cytokines produced naturally in the body IL-2 (Aldesleukin) is the most widely used It stimulates the growth and activity of many immune cells like lymphocytes that can destroy cancer cells. IL-2 indicated in metastatic kidney cancer and metastatic melanoma Dr Anshu P Gokarn
    • 215. Colony Stimulating Factors(CSF) Also called as Haematopoeitic growth factors They encourage the bone marrow stem cells to divide and develop into white blood cells, platelets and red blood cells. CSF are particularly useful when combined with high dose chemotherapy Some ex; G-CSF (Filrastim) and GM-CSF(sargramostin) Dr Anshu P Gokarn
    • 216. Imatinib Mesylate Inhibits specific protein tyrosinekinase which is targeted to plateletderived growth factor. It specifically inhibits constitutivelyactive fusion protein arising from thePhiladelphia chromosome of CML andc-kit(CD117) in GISTImpairs BCR-ABL mediated transfer of phosphates to itssubstrates.BCR-ABL is a protein unique to leukemia cells and its tyrosine kinase activity is essential for its ability to induce leukemia BCR-AABL mutation is present in almost all patients with CML, Dr Anshu P Gokarn
    • 217. What are protein Kinases?  Enzymes that transfer phosphate from adenosine triphosphate to specific amino acids on substrate proteins (Phosphorylation).  Phosphorylation of these proteins leads to activation of signal transduction pathways.  Signal transduction pathways play a critical role in cell growth, differentiation and death.Several protein kinases are deregulated and overexpressed inhuman cancers and serve as an attractive target for anticancertherapy. Dr Anshu P Gokarn
    • 218. Disrupted regulation of oncogene : bcrabl gene responsible for CML Dr Anshu P Gokarn
    • 219. Mechanism of action of BCR-ABL and of its inhibition by Imatinib BCR-ABL oncoprotein with a molecule of adenosine triphosphate in the kinase pocket.Substrate activated by one of its tyrosine residues Imatinib ocupies the kinas epocket, action of BCR-AABl is inhibited. Phosporylation is prevented Dr Anshu P Gokarn
    • 220. Imatinib Mesylate(ST1571)Indicated in :1.CML in blast crisis, in accelerated phase,or in chronic phase after interferon alphatherapy2.In unresectable and/ or metastaticmalignant gastrointestinal stromaltumor(GIST). Dr Anshu P Gokarn
    • 221. Points where imatinib scores over other conventional therapy Conventionally hydroxyurea or interferon alpha is used. However cytogenic response is faster with imatinib than with interferon alpha.1 Phosphorylation of BCR-ABL substrates reduced markedly in leukemic cells.1 Mild to moderate side effects which are reversible on cessation of treatment.1 Oral therapy may improve patient compliance. With interferon resistant chronic phase CML had a complete haematologic response and almost half had a major cytogenic response. So it is drug of choice in interferon resistant CML.1 Can be combined with farnesyltransferases may also be useful.1 1. Savage D, Karen H et al. N Eng J Med, 346(9);2002 Feb Dr Anshu P Gokarn
    • 222. Points where imatinib scores over other conventional therapy  Long plasma half life so convenient once daily dosing. Useful in patients with relapses after allograft transplantation2. At a dose of 400 mg, twice daily it is well tolerated during the first 8 weeks, side effects diminish with continuing treatment.3 A possible additive effect of INF and imatinib suggest that a concurrent use of these agents may also be effective than single use particularly in advanced stages of CML where imatinib has activity but resistance develops.42. (Olavarria E et al. Blood 2002 May 15;99(10) :3861-2)3. Oosterom Van et al. Lancet 2001, 358(9291): 1421-34. Talpaz M. Semin Hematol 2001 Jul;38(3 suppl 8):22-7 Dr Anshu P Gokarn
    • 223. Some newer agents in cancer Irinotecan – A topoisomerase inhibitor indicated in colon cancer, non small cell lung cancer, gastric, breast, cervix and lymphoma. Topotecan – Topoisomerase I inhibitor – small cell lung cancer, non small cell lung cancer, ovarion, sarcoma and lung cancer. Ralitrexed – Thymidylate synthetase – colorectal, non small cell lung cancer. Docetaxel – Tubulin interactive agent – breast, ovary, non small cell lung cancer, pancreas and Cholangiosarcoma. Gemcitabine - an antimetabolite - indicated in pancreatic cancer and non small cell lung cancer. Dr Anshu P Gokarn
    • 224. All-transretinoic acid Elicits differentiation. Promotes remission of malignant melanoma and renal cell carcinoma even after failure of standard chemotherapy. 13 – cis retinoic acid prevents occurrence of 2nd primary tumors in patients with head and neck cancer.Dr Anshu P Gokarn
    • 225. Dacarbazine  Inhibits the RNA and protein synthesis (Other alkylating agents act on DNA)  Indicated in malignant melanoma. Leucovorin  Enhances thymidylate synthase enzyme inhibition.  Increases the cytotoxic effect of 5FUDr Anshu P Gokarn
    • 226. Bicalutamide INDICATIONS Along with a luteinizing hormone releasing hormone analogue for the treatment of stage D2 metastatic carcinoma of the prostate. MECHANISM OF ACTION A nonsteroidal antiandrogen it competetively inhibits the action of androgens by binding to cytosol androgen receptors in the target tissue. Prostatic carcinoma is known to be androgen sensitive and responds to tretament that counteracts the effect of androgen. Dr Anshu P Gokarn
    • 227. Bicalutamide Bicalutamide 150mg as immediate therapy, either alone or as adjuvant to treatment of curative intent, significantly reduces the risk of disease progression in patients with early prostate cancer . Eur Urol 2002 Sep;42(3):204 ; . Iversen P et al May Cause less bone loss than androgen deprivation therapy. Urology 2002 Sep;60: 79-85; Smith MR Long term therapy well tolerated with a predicatble side effect profile. Urologt 2002 Sep;60: 64 -71. Iverson P Evidence supports th euse of bicalutamide 150 mg, both as immediate monotherapy and as adjuvant therapy in early stage prostate cancer Urologt 2002 Sep;60: 64 -71. Iverson P Dr Anshu P Gokarn
    • 228. Bicalutamide Bicalutamide has significant reduction of 42% in the risk of objective progression compared with patients who receive placebo plus standard care. (Urology 2002 Sep;60: 13-20;Macleod DG ) Risk of Prostate specific antigen progression is also significantly reduced by 59%. (Urology 2002 Sep;60: 13-20;Macleod DG ) The R- isomer analogs of bicalutamide exhibit higher Androgen receptor binding affinity and more potent functional activity than their corresponding sulphone analogues.( He Y et al.Eur J Med Chem 2002 Jul;37(8)):619 Dr Anshu P Gokarn
    • 229. Bicalutamide Represents an alternative therapy to castration and has favourable tolerability profile. A prospective randomized trial demonstrates that immediate therapy with bicalutamide significantly reduces the risk of objective disease progression inpatients with localized or locally advanced prostate cancer Combined androgen blockade with bicalutamide is associated with a similar survival outcome to combined androgen blockade with flutamide and is better tolerated Expert Opin Pharmacotherap 2002 Sep;3(9): 1313-28. Schellhammer PF Dr Anshu P Gokarn
    • 230. Bicalutamide Bicalutamide is not associated with interstitial Pneumonitis and difficulty with light/dark adaptation seen with nilutamide and in 50 mg/ day dosage causes lesser incidence of diarrhoea than flutamide 750 mg/day Changes in hepatic function are mild and transient. Stav SY Harefuah 2002 apr;14(4);379-83. At a dose of 25 mg/day is an effective drug in the treatment of patients with hirsuitism. Gynecol Endocrinol 202 Feb:16(10:63-6 Bicalutamide decreases pain and improves symptoms in patients with prostate cancer in whom first line hormonal therapy failed. (Kucuk O et al.Urology 2001 jul;58(1)): 53-8) Once Daily oral Therapy can improve patient compliance Dr Anshu P Gokarn
    • 231. Pegylated LiposomalDoxorubicin Indication 1. For the treatment of metastatic carcinoma of the ovary in patients with disease that is refractory to both paclitaxel- and platinum-based chemotherapy regimens. 2. In AIDS related Kaposi’s sarcoma Mechanism of Action It binds to DNA and inhibit the nucleic acid synthesis Dr Anshu P Gokarn
    • 232. Pegylated Liposomal doxorubicin Liposomes -microscopic vesicles composed of a phospholipid bilayer capable of encapsulating active drugs. Formulated with surface-bound methoxypolyethylene glycol (pegylation) Pegylation protects liposomes from detection by the mononuclear phagocyte system (MPS) Increase blood circulation time. Dr Anshu P Gokarn
    • 233. CapecitabineIndications In metastatic colorectal and breast cancer.Mechanism of action Inhibits the formation of thymidylate from 2-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division interfere with RNA processing and protein synthesis Capecitabine is extensively metabolized enzymatically to 5-FU in tumors Dr Anshu P Gokarn
    • 234. Capecitabine Patients receiving concomitant capecitabine and oral coumarin- derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. Does not interact with cytochrome P450 enzyme system . New orally administered fluoropyrimidine carbamate. Rationally designed to exert its effect by tumor selective activation. As effective as combination of leucovorin and 5FU Significantly less toxic than 5FU Dr Anshu P Gokarn
    • 235. LetrozoleMechanism of action Time to progression Selective Non steroidal Aromatase inhibitor. Acts by reducing circulating levels of oestradiol in post- menopausal women with breast cancer.Indication Metastatic Breast cancer which is not responding to tamoxifen and other antiestrogen therapy (exemestane, anastrozole) In uterine cancer Dr Anshu P Gokarn
    • 236. Clodronic acidMechanism of action:Bisphosphonate , inhibits bone resorption.Binds strongly with the hydroxyapatite crystals in bone matrix.Action predominant at the sites of increased bone turnover.Inhibits the formation and dissolution of crystalsAdditionally:Directly inhibits the mature osteoclast function.Promotes osteoclast apoptosis.Interferes with osteoblast mediated osteoclast activation.Inhibits tumor induced bone resorption.Reduces calcium flow from resorbing bone into the blood Dr Anshu P Gokarn
    • 237. Clodronic acidIndicationsTo prevent metastatic bone disease in cancer patientsApproximately 60 – 80% breast cancer patients develop bonemetastases.Results in weakened bone structure and pain.Clodronate reduces pain and fracture rate.Reduces incidence of spinal cord compression.Drugs and therapy Perspectives,15(10): 1-4,2000Should be considered where analgesics and radiotherapyineffective to prevent bone metastasesWong R et al. Cochrane database Syst rev 2002;(2):CD002068 Dr Anshu P Gokarn
    • 238. Zoledronic acid A new generation bisphosphonate. A higher response rate in hypercalcemia of malignancy compared to pamidronate disodium. Dose adjustments are not necessary in mild to moderate renal impairment prior to initiation of therapy. Dr Anshu P Gokarn
    • 239. Reovirus therapy demonstrates activity against lymphoid malignancies Reuters Health, January 3, 2003  Human Reovirus infects and destroys neoplastic cells harboring an activated ras signaling pathway. (as seen in solid tumors)  Now, preclinical studies demonstrate the efficacy of human reovirus in human lymphoid tumors.  Human reovirus infects and destroys the diffuse large B cell lymphoma and Burkitt’s lymphoma cell lines. (Tumors where ras activation is rare)Dr Anshu P Gokarn
    • 240. Antiviral chemotherapy – Attractive target for chemotherapy  Antiretroviral drugs( the protease inhibitors) used for HIV decreases incidence of Kaposis sarcoma, and regresses established lesions.  Study of 47,000 HIV-infected persons carried out at the Cancer Epidemiology Unit in Oxford, England, found a decrease of approximately 66 percent in the number of cases. Mariusz J.S. Sapijaszko, and Roy C. Grekin, The 2001 Skin Cancer Foundation Journal. Dr Anshu P Gokarn
    • 241. Antiviral Therapy –High potential area Human papillomaviruses types 6 or 11 are aetiological agents of recurrent respiratory papillomatosis. Disease characterized by benign exophytic tumours usually on the vocal cords. Adjunct medical treatments, include indole-3-carbinol or its dimer diindolylmethane and interferon Auborn KJ . Therapy for recurrent respiratory papillomatosis. Antivir Ther 2002 Mar;7(1):1-9 Also associated with development of genital cancers (ex: cervical carcinoma) Dr Anshu P Gokarn
    • 242. Combination chemotherapy Simultaneous administration of more than one drug disrupts the cells metabolism at more than one site and has more profound effects on the tumor metabolism Ex: MOPP regimen in Hodgkin’s diseaseDr Anshu P Gokarn
    • 243. Adverse effects of chemotherapy Nausea & Vomiting Bone marrow & lymphoreticular system : pancytopenia & immunosuppression-leading to opportunistic microbial infection Gut epithelium & other mucosal surfaces- diarrhoea, mouth ulcers Alopecia Dr Anshu P Gokarn
    • 244. Adverse effects to chemotherapy Delayed wound healing Local toxicity, if extravasation occurs Various organ damages Sterility, teratogenesis, mutagenicity Second cancers as in treatment with antimetabolites /alkylating agents /doxorubicin Urate -nephropathy Hazards to staff handling cytotoxic agents Dr Anshu P Gokarn
    • 245. Principles of chemotherapy Chose appropriate drugs (cycle specific/ non-specific), or drugs found empirically effective Use Combination Of Drugs Repeat courses of high dose chemotherapy with intervals for recovery of normal tissue rather than continuous low dose therapy. Use adjuvant therapy to eliminate micro-metastases Recognize contradictions include very advanced disease & existing bone marrow depression Should reach target at high enough concentration, for long enough time and at right stage of cycle. Dr Anshu P Gokarn
    • 246. Principles of Chemotherapy Cell destruction follows 1st Order Kinetics So, in presence of multiple cancerous cells, necessary to use several drugs & repeated administration to the limit of patients tolerance. In case complete cell-kill not possible without unacceptable risk, use of adjunct therapy Dr Anshu P Gokarn
    • 247. Principles of Adjuvant therapyAim : to remove cancer cells that are present but are undetectable at early stages of growth : when tumor cells are more sensitive & rapidly growing To eliminate micro metastases Used in tumors that multiply rapidly – e.g. breast cancers Types : - Cytotoxic - Endocrine Dr Anshu P Gokarn
    • 248. Assessing response to Treatment Complete response No new lesions Complete disappearance of all known disease Partial response 50% reduction in the size of tumor No new lesions No response No change Increase of less than 25%/decrease of no greater than 25 % in size of tumor No new lesions Progressive disease New lesions Increase in size by at least 25 %Dr Anshu P Gokarn
    • 249. Supportive treatment To relieve the patients discomfort  Analgesics ex : morphine  Antiemetics Ex: ondansetron  Antidepressants  Laxatives  Appetite stimulantsDr Anshu P Gokarn
    • 250. Complications of cancer Paraneoplastic syndromes symptoms caused by the products of the cancer and not by the tumor itself. Cancer emergencies  Pleural effusion  Spinal cord compression  Cardiac tamponade  Hypercalcemic syndrome  Superior vena cava syndromeDr Anshu P Gokarn
    • 251. Cancer SurvivalSurvival Inversely related to initial number of leukemic cells / number remaining after treatment Single leukemic cell can multiply and eventually kill the host. Dr Anshu P Gokarn
    • 252. Queries ? anshu.gokarn@gmail.comDr Anshu P Gokarn