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Oncology seminar
- 2. Out line of Presentation • • • • • • • • • • • Introduction Epidemiology Cancer Etiology Cancer Biology Cancer Risk Assessment Cancer Screening Diagnosis Staging Surgical Approach to Cancer Therapy Chemotherapy Radiation Therapy Sunday, December 08, 2013 Oncology
- 3. INTRODUCTION • Tumor - “abnormal mass of tissues the growth of which exceeds and is uncontrolled with that of normal tissues” Wills • Cancer – ”Karanikos” Sunday, December 08, 2013 Oncology
- 4. Epidemiology • In 2008 - 1.44 million new cases in US. • 565,650 – died in US • Global Statistics on Cancer Incidence -10.9 million new cancer cases in 2002. -Lung cancer is the leading cancer in the world. - Breast cancer - the second most common Sunday, December 08, 2013 Oncology
- 5. Sunday, December 08, 2013 Oncology
- 6. Sunday, December 08, 2013 Oncology
- 7. Cancer Etiology • • • • Genetic disease Somatic mutation Germ line mutation Hereditary cancer Sunday, December 08, 2013 Oncology
- 8. • factors may suggest hereditary cancer 1. Tumor development at a much younger age than usual 2. Presence of bilateral disease 3. Presence of multiple primary malignancies 4. Presentation of a cancer in the less affected sex 5. Clustering of the same cancer type in relatives 6. Occurrence of cancer in association with other conditions such as mental retardation or pathognomonic skin lesions Sunday, December 08, 2013 Oncology
- 9. • Importance of knowing hereditary cancer – Examples • P53 and li-fraumani syndrome • RB1 Gene and Hereditary Retinoblastoma • BRCA1, BRCA2, and Hereditary Breast-Ovarian Cancer Syndrome • APC Gene and Familial Adenomatous Polyposis Sunday, December 08, 2013 Oncology
- 10. Carcinogens • Environmental factors - 60 to 90% • Three types - Chemical, Physical, or Viral • Chemicals carcinogens • Three groups 1.genotoxins . 2. co carcinogens-potentiate genotoxins. 3.Tumor promoters. • IARC - 4 Groups • E.g. of Proven carcinogens - aflatoxins ,tobaco ,aresnic ,benzene etc Sunday, December 08, 2013 Oncology
- 11. Physical Carcinogen • Mechanism - Induction of inflammation and cell proliferation - Induce DNA damage • Radiation - Best known physical carcinogen • Ionizing -DNA break( deletion ,gene rearrangement -Direct effect -Indirect effect -Bystander effect • Non-ionizing -UV light-skin cancer Sunday, December 08, 2013 Oncology
- 12. Viral Carcinogens • 15 % cancers world wide • Mechanism -Insertional mutagenesis -Expression of oncogenes -Alteration of immune system • DNA virus -Have their own Oncogen -Oncoprotiens –bind cellular genes-p53.RB -activate cellular genes-IL-5,C—MYC,H-ras -E.g.- HPV, HBV, EBV Sunday, December 08, 2013 Oncology
- 13. • RNA virus - Are retroiviruses -They have no their own oncogenes -Transform host proto oncogene E.G-HTLV-1 Sunday, December 08, 2013 Oncology
- 14. Cancer Biology Sunday, December 08, 2013 Oncology
- 15. TUMORIOGENESIS • • • • • • • Phenotipicaly Genetically Initiation A single cell or clone Field effect Promotion Progression – From benign lesion to CIN to invasive lesion – Accumulate genetic changes Sunday, December 08, 2013 Oncology
- 16. Sunday, December 08, 2013 Oncology
- 17. Sunday, December 08, 2013 Oncology
- 18. Tumor growth Sunday, December 08, 2013 Oncology
- 19. • • • • Oncogen Tumor suppressor gene Proapoptotic genes Oncogenes -Proto-oncogenes →oncogenes -Three letter abbr - e.g. myc ,ras, prefix v or c -Can be activated by translocation (e.g., abl), -Promoter insertion e.g., c-myc, -Mutation - e.g., ras, -Amplification (e.g., HER-2/ neu). Sunday, December 08, 2013 Oncology
- 20. Sunday, December 08, 2013 Oncology
- 21. Function of Oncogenes • Promote growth – Growth factors- PDGF, FBGF. – GF receptors- e.g., HER2, HER1 • Intracellular signal transduction molecules (e.g., ras). • Nuclear transcription factors e.g., c-myc. Sunday, December 08, 2013 Oncology
- 22. Sunday, December 08, 2013 Oncology
- 23. Tumor Suppressor Genes • • • • p53, pRB. APC TGF-B Function -Arrest cell cycle -Induce apoptosis -Activate other genes Sunday, December 08, 2013 Oncology
- 24. Sunday, December 08, 2013 Oncology
- 25. Evasion of Apoptosis • Two path ways -Death receptor path way - Fas(CD95) -The mitochondrial Path way Stimulus - DNA damage, free radicals, withdrawal of GFs • E.g. – Loss of CD 95 In HCC Sunday, December 08, 2013 Oncology
- 26. Sunday, December 08, 2013 Oncology
- 27. Cancer Invasion • Carcinoma insitu • Invasive cancer • Steps -Loss of adhesion – cadherins -Attachemement to ECM -Degradation of ECM -locomotion Sunday, December 08, 2013 Oncology
- 28. Sunday, December 08, 2013 Oncology
- 29. ANGIOGENESIS • Proangiogenic factors- VEGF, FGF • Antiangiogenic factors- Thrombospondin 1, Angiostatin • Source –tumor cells-RAS,myc,HER2/NEU ,endothelial cells ,Inflammatory cells Effect - nutrition, metastasis -Remval of Primary Tumor Sunday, December 08, 2013 Oncology
- 30. Metastasis • Hematogenous • lymphatic • seeding in to body cavities. Prerequisites -Access to circulation -survive in the circulation. -Extravasate -Initiate growth in the new tissues Organ specific metastasis - mechanical -Seed and soil theory Dormancy. Sunday, December 08, 2013 Oncology
- 31. Sunday, December 08, 2013 Oncology
- 32. Cancer Risk Assessment • Initial evaluation of any patient • Cancer screening - genetic counseling and testing • Component -Complete history -Hx of environmental exposure -Detailed family history -Personal history -Age, race - E.g.-GAIL model for breast cancer Sunday, December 08, 2013 Oncology
- 33. Cancer Screenings Early detection Criteria for screening • The Disease -Recognizable early stage -Treatment at an early stage more effective than at a later Stage -Prevalence Sunday, December 08, 2013 Oncology
- 34. • The Test - Sensitive and specific -Acceptable to the screened population -Safe -Inexpensive • The Programme • Intensive screening Sunday, December 08, 2013 Oncology
- 35. Cancer Diagnosis • The Definitive - Biopsy of the lesion - histology, grade • Open biopsy -Inscisional or Excisional -More tissue for histologic Dx • CORE Biopsy • FNAC Sunday, December 08, 2013 Oncology
- 36. Staging • Anatomic extent of tumor in an individual patients • Importance - To predict prognosis - Selection of Therapy -Evaluation of Treatment -Exchange of information among Treatment centers Sunday, December 08, 2013 Oncology
- 37. • TNM Staging - Before definitive therapy - 4 month - Microscopically confirmed Cancer - cTNM , pTNM, aTNM, rTNM - Multiple Tumors - T2(5), T2(m) - Unknown Primary - Paired Organs - Stage Grouping Sunday, December 08, 2013 Oncology
- 38. • cTNM Primary tumor(T) -P/E , Imaging studies, Endoscopy -Size ,Extent, Multiplicity - Tx, T0, T is - T1, T2 , T3 • Regional LN ( N ) -Based on size -Characteristics, and location. -NX ,N0 - N1 ,N2 , N3 • M - distant metastasis - clinical examination - M0 , M x Sunday, December 08, 2013 Oncology
- 39. Surgical Approach to Cancer Therapy • • • • • • • Prevention Diagnosis Staging Treatment Palliation Rehabilitation Surgeons Role Sunday, December 08, 2013 Oncology
- 40. • Management of Primary Tumor -Goal of surgical mx- oncologic cure -Operable - negative surgical margin - Inoperable - positive surgical margin • Radical vs conservative management • Appropriate surgical margin Sunday, December 08, 2013 Oncology
- 41. Breast Cancer Sunday, December 08, 2013 Oncology
- 42. Surgical Management of the Regional Lymph Node Basin • Cancers • Soft tissue sarcomas • Methods -Enbloc Removal of Primary Tumor With the LN - Separate Incision • Advantage Clinically Negative Node • Lymphatic mapping and Sentinnel LN Biopsy - Identification Rate - False Negative Rate - Advantage Sunday, December 08, 2013 Oncology
- 43. Sunday, December 08, 2013 Oncology
- 44. Surgical Management of Distant Metastases • Mostly non curative • Curable in isolated metastasis • Survival rates depends on - Disease free interval - Natural history o f metastatic disease • The goal is to resect the metastases with negative margins Sunday, December 08, 2013 Oncology
- 45. Principles of Chemotherapy • Fractional cell kill - Constant percentage of cells killed - E.g. 1012 tumor cells, treated with a dose that result in 3 log kill 1012 → 109 cells • • • • Selection of chemotherapeutic agent Conventional dose High dose Cyclic Therapy Sunday, December 08, 2013 Oncology
- 46. Sunday, December 08, 2013 Oncology
- 47. • End Point of Drug Action - Metastatic Disease - Localized Tumors - Adjuvant Therapy -Sensitizes Tumors to radiation -As part of adjuvant therapy -Palliative therapy • Classification -Cell-cycle phase–nonspecific agents -Cell-cycle phase–nonspecific agents Sunday, December 08, 2013 Oncology
- 48. • Agents Alkylating agents - Kill cells in any phase of the cycle - MOA : cross linking the DNA strands and direct damage to the DNA - Three Groups –Classic ,, miscellaneous DNA Binding Agents - Classic - Cylophosphamide, Busulfan , Chlorambucil - Nitrosureas- Streptozocin ,Carmustine - miscellaneous- cisplatin, Carboplatin - Toxicity : Sunday, December 08, 2013 Oncology
- 49. Antimetabolites - cell-cycle–specific agents - Effective in tumors with high growth fraction -MOA : analogues of naturally occuring metabolities involved in DNA synthesis -Eg. - Folic acid Analogue - Methotrexate , - Pyrimidine Analogue- 5-FU - Purine Analogue - Azathioprine , Mercaptopurine -Toxicity: Sunday, December 08, 2013 Oncology
- 50. • Plant Alkaloids - Derived from vinca rosea plant - Act by binding to tubulin in the S phase - Eg. - Vincristin, vinblastin - Toxicity: • Combination therapy: - Maximizes Cell kill -Broader Range of Coverage of Resistant cell lines -Delays the emergence of Drug-Resistant cell lines Sunday, December 08, 2013 Oncology
- 51. Response evaluation -Complete response -Partial response -Minimal response -Progressive disease Sunday, December 08, 2013 Oncology
- 52. Radiation Therapy • Ectro magnetic Waves -Penetrate Tissues Deep • Particulate - electrons, superficial lesion • Biologic bases -DNA breaks, cross linking - Indirectly ionizing - X-ray ,Gamma rays - Directly ionizing - Electrons, Neutrons • Factors Influence Cell Killing -Tissue Factor - Physical Parameter of Radiation Sunday, December 08, 2013 Oncology
- 53. Factors influence cell killing Sunday, December 08, 2013 Oncology
- 54. • Radiation sentisizers - Metronidazole , misonidazole - Thymidine analogue - iododeoxy uridine. - 5 FU, actinomicin D Sunday, December 08, 2013 Oncology
- 55. • Planning therapy -Define Target - Shield -Homologues delivery -Fraction Dose • Conventional fractionation - 1.8-2 Gy/d,5 day /wk for 3-7 wks • Ways of delivery -Tele Therapy -Brachy Therapy -Systemic Therapy • Preop or post op Sunday, December 08, 2013 Oncology
- 56. • Indication - Component of Curative Therapy -Palliation - Prevent Development of Disease • Toxicity- Acute and Chronic Sunday, December 08, 2013 Oncology
- 57. • Other Option of Therapy - Hormonal - Targeted Therapy - Gene Therapy Sunday, December 08, 2013 Oncology
- 58. REFFERENCE • SCWARTZ PRINCIPLES OF SURGERY • ROBINS PHOLOGIC BASES OF DISEASE • INTERNET THNK YOU Sunday, December 08, 2013 Oncology
Editor's Notes
- Figure 6-26 A-D, Schematic illustration of the sequence of events in the invasion of epithelial basement membranes by tumor cells. Tumor cells detach from each other because of reduced adhesiveness, then attach to the basement membrane via the laminin receptors and secrete proteolytic enzymes, including type IV collagenase and plasminogen activator. Degradation of the basement membrane and tumor cell migration follow.
- genetic model for colorectal tumorigenesis. Tumorigenesis proceeds through a series of genetic alterations involving oncogenes and tumor-suppressor genes. In general, the three stages of adenomas represent tumors of increasing size, dysplasia, and villous content. Individuals with familial adenomatouspolyposis (FAP) inherit a mutation on chromosome arm 5q. In tumors arising in individuals without polyposis, the same region may be lost or mutated at a relatively early stage of tumorigenesis. A ras gene mutation (usually K-ras) occurs in one cell of a pre-existing small adenoma which, through clonal expansion, produces a larger and more dysplastic tumor. The chromosome arms most frequently deleted include 5q, 17p, and 18q. Allelic deletions of chromosome arms 17p and 18q usually occur at a later stage of tumorigenesis than do deletions of chromosome arm 5q or ras gene mutations. The order of these changes varies, however, and accumulation of these changes, rather than their order of appearance, seems most important. Tumors continue to progress once carcinomas have formed, and the accumulated chromosomal alterations correlate with the ability of the carcinomas to metastasize and cause death. DCC = deleted in colorectal cancer gene.(Modified with permission from Fearon et al.6 Copyright Elsevier.)
- Figure 6-29 Tumor progression and generation of heterogeneity. New subclones arise from the descendants of the original transformed cell by multiple mutations, as illustrated in Figure 6-27. With progression the tumor mass becomes enriched for variants that are more adept at evading host defenses and are likely to be more aggressive
- Gompertzian tumor growth. The growth fraction of a tumor declines exponentially over time (top). The growth rate of a tumor peaks before it is clinically detectable (middle). Tumor size increases slowly, goes through an exponential phase, and slows again as the tumor reaches the size at which limitation of nutrients or auto- or host regulatory influences can occur. The maximum growth rate occurs at 1/e, the point at which the tumor is about 37% of its maximum size (marked with an X). Tumor becomes detectable at a burden of about 109 (1 cm3) cells and kills the patient at a tumor cell burden of about 1012 (1 kg). Efforts to treat the tumor and reduce its size can result in an increase in the growth fraction and an increase in growth rate
- io
- The probabilities of tumor control and of complications at different doses. A. At lower doses, the probability of complications is low, with a moderate chance of tumor control. B. Increasing the dose may gain a higher chance of tumor control at the price of significantly higher complication risks. (Modified from Eisbruch et al, 240 with permission.)