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INTRODUCTION TO CLINICAL ONCOLOGY

INTRODUCTION TO CLINICAL ONCOLOGY. Başak Oyan-Uluç, MD Yeditepe University Hospital Department of Medical Oncology. What is Cancer?. Population of clonal (identical) cells Genetically modified cell Unregulated cell growth Inhibited cell death. BIOLOGY OF CANCER. Secondary genetic change

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INTRODUCTION TO CLINICAL ONCOLOGY

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  1. INTRODUCTION TO CLINICAL ONCOLOGY Başak Oyan-Uluç, MD Yeditepe University Hospital Department of Medical Oncology

  2. What is Cancer? • Population of clonal (identical) cells • Genetically modified cell • Unregulated cell growth • Inhibited cell death

  3. BIOLOGY OF CANCER

  4. Secondarygenetic change (eg, dysfunction of p53or overexpression of bcl-2) Normalcell Initialgenetic change (eg, loss of function of pRb or overexpression of c-myc) Subsequentgenetic change Further alterationsin phenotype(eg, invasivenessand metastasis) Increase incell proliferation Decreasein apoptoticcell death Tumorigenesis Kastan MB. Cancer: Principles & Practice of Oncology. 5th ed. 1997;121-134.

  5. Precancerous conditions • Polyps (eg, adenomatous polyps) • Neoplasia (eg, prostatic intraepithelial neoplasia) • Carcinoma in situ Stedman’s Medical Dictionary. 26th ed. 1995;1182,1405, 279.

  6. Emergence of tumor cell heterogeneity Primary Neoplasm Metastases TRANSFORMATION TUMOR EVOLUTION METASTASIS TUMOR EVOLUTION AND PROGRESSION AND PROGRESSION

  7. Pathogenesis MOTILITY & INVASION TRANSFORMATION ANGIOGENESIS Capillaries,Venules, Lymnphatics ARREST INCAPILLARY BEDS EMBOLISM &CIRCULATION ADHERENCE TRANSPORT Multicell aggregates(Lymphocyte, platelets) EXTRAVASATIONINTO ORGANPARENCHYMA METASTASES RESPONSE TOMICROENVIRONMENT METASTASIS OFMETASTASES TUMOR CELLPROLIFERATION& ANGIOGENESIS

  8. Host influences on metastatic disease • Anatomical factors • Organ microenvironment • Angiogenic factors • Immune response Fidler IJ. Cancer: Principles & Practice of Oncology. 5th ed. 1997;135-147.

  9. Angiogenesis • Establishment of a capillary network from the surrounding host tissue • A series of processes originating from microvascular endothelial cells • Mediated by multiple molecules released by both tumor and host cells like; • Vascular endothelial growth factor (VEGF) • Fibroblastic growth factor (FGF) Fidler IJ. Cancer: Principles & Practice of Oncology. 5th ed. 1997;135-147.

  10. Carcinogenesis • Duration: Depends of cancer type • Carcinogenesis: 10-20 years Limited stage: 5-10 years Disseminated stage: 1-5 years

  11. The doubling process Malignanttransformation 4 cells Doubling Doubling 2 cancercells Dividing Normalcell 8 cells 1 million cells(20 doublings)undetectable Doubling 16 cells 1 trillion cells(40 doublings – 2 lb/1kg) 1 billion cells(30 doublings)lump appears 41 – 43doublings— Death

  12. 1012 Number ofcancer cells Diagnosticthreshold(1cm) 109 time Undetectablecancer Detectablecancer Limit ofclinicaldetection Hostdeath Tumor growth and detection

  13. Classification of Cancer • Type of tissue in which cancer originates • Epithelial -> Carcinoma • %80-90 of all cancers • Connective and supportive tissue -> Sarcoma • Hematopoietic system • Leukemia • Lymphoma • Myeloma • Other tissue • Primary site

  14. Epidemiology

  15. How frequent is the cancer? • Worldwide incidence • 2012: 14 million new cancer cases/year • Lung cancer: 1.8 million/year (%13) • 2025: 19 million new cancer cases/year • 2035: 24 million new cancer cases/year • Cancer mortality: • 2012: 8.2 million/year • 2035: 13 million/year • Total cost of cancer in the world in 2010: 1.16 trillion $ ACS, 2006

  16. Cancer in the world

  17. Second Rank in Causes of Death Total death rates, USA Heart disease Cancer CVA COPD Accident Diabetes Mellitus Pneumonia Alzheimer Nephritis Septicemia ACS 2006

  18. Change in the US Death Rates* by Cause, 1950 & 2003 Rate Per 100,000 1950 2003 HeartDiseases CerebrovascularDiseases Pneumonia/Influenza Cancer * Age-adjusted to 2000 US standard population. Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised. 2003 Mortality Data: US Mortality Public Use Data Tape, 2003, NCHS, Centers for Disease Control and Prevention, 2006

  19. Change in US Death Rates* from 1991 to 2006 Rate Per 100,000 1991 2006 * Age-adjusted to 2000 US standard population. Sources: US Mortality Data, National Center for Health Statistics, Centers for Disease Control and Prevention, 2009.

  20. 2009 Estimated Cancer Cases* Men766,130 Women713,220 • 27% Breast • 14% Lung & bronchus • 10% Colon & rectum • 6% Uterine corpus • 4% Non-Hodgkin lymphoma • 4% Melanoma of skin • 4% Thyroid • 3% Kidney & renal pelvis • 3% Ovary • 3% Pancreas • 22% All Other Sites Prostate 25% Lung & bronchus 15% Colon & rectum 10% Urinary bladder 7% Melanoma of skin 5% Non-Hodgkin 5% lymphoma Kidney & renal pelvis 5% Leukemia 3% Oral cavity 3% Pancreas 3% All Other Sites 19% *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2009.

  21. 2009 Estimated Cancer Deaths* Women269,800 Men292,540 • 26% Lung & bronchus • 15% Breast • 9% Colon & rectum • 6% Pancreas • 5% Ovary • 4% Non-Hodgkin lymphoma • 3% Leukemia • 3% Uterine corpus • 2% Liver & intrahepatic bile duct • 2% Brain/ONS • 25% All other sites Lung & bronchus 30% Prostate 9% Colon & rectum 9% Pancreas 6% Leukemia 4% Liver & intrahepatic 4%bile duct Esophagus 4% Urinary bladder 3% Non-Hodgkin lymp 3% Kidney & renal pelvis 3% All other sites 25% ONS=Other nervous system. Source: American Cancer Society, 2009.

  22. Cancer Incidence Rates* by Sex,1975-2005 Rate Per 100,000 Men Both Sexes Women Overall incidence rates decrease from 1999-2005 *Age-adjusted to the 2000 US standard population and adjusted for delays in reporting. Source: Surveillance, Epidemiology, and End Results Program, Delay-adjusted Incidence database: SEER Incidence Delay-adjusted Rates, 9 Registries, 1975-2005, National Cancer Institute, 2008.

  23. Cancer Incidence Rates* Among Men, 1975-2005 Rate Per 100,000 Prostate: Increase due to PSA screening Lung: Incidence decline Colon: Incidence decline Prostate Lung & bronchus Colon and rectum Urinary bladder Non-Hodgkin lymphoma Melanoma of the skin *Age-adjusted to the 2000 US standard population and adjusted for delays in reporting. Source: Surveillance, Epidemiology, and End Results Program, Delay-adjusted Incidence database: SEER Incidence Delay-adjusted Rates, 9 Registries, 1975-2005, National Cancer Institute, 2008.

  24. Cancer Incidence Rates* Among Women, 1975-2005 Rate Per 100,000 Breast: Decrease due to mamographic screening and reduction in use of HRT. Lung: Slight increase Colon: Rapid decrease Breast Colon and rectum Lung & bronchus Uterine Corpus Ovary Non-Hodgkin lymphoma *Age-adjusted to the 2000 US standard population and adjusted for delays in reporting. Source: Surveillance, Epidemiology, and End Results Program, Delay-adjusted Incidence database: SEER Incidence Delay-adjusted Rates, 9 Registries, 1975-2005, National Cancer Institute, 2008.

  25. Cancer Death Rates* by Sex,1975-2005 Rate Per 100,000 Men Both Sexes Women *Age-adjusted to the 2000 US standard population. Source: US Mortality Data 1960-2005, National Center for Health Statistics, Centers for Disease Control and Prevention, 2008.

  26. Cancer Death Rates* Among Men,1930-2005 Rate Per 100,000 Lung & bronchus Stomach Prostate Colon & rectum Pancreas Leukemia Liver *Age-adjusted to the 2000 US standard population. Source: US Mortality Data 1960-2005, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2008.

  27. Cancer Death Rates* Among Women,1930-2005 Rate Per 100,000 Lung & bronchus Uterus Breast Colon & rectum Stomach Ovary Pancreas *Age-adjusted to the 2000 US standard population. Source: US Mortality Data 1960-2005, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2008.

  28. Lifetime Probability of Developing Cancer, Men, 2003-2005* Site Risk All sites† 1 in 2 Prostate 1 in 6 Lung and bronchus 1 in 13 Colon and rectum 1 in 18 Urinary bladder‡ 1 in 27 Melanoma§ 1 in 39 Non-Hodgkin lymphoma 1 in 45 Kidney 1 in 57 Leukemia 1 in 67 Oral Cavity 1 in 72 Stomach 1 in 90 * For those free of cancer at beginning of age interval. Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.3.0 Statistical Research and Applications Branch, NCI, 2008. http://srab.cancer.gov/devcan

  29. Lifetime Probability of Developing Cancer, Women, US, 2003-2005* Site Risk All sites†1 in 3 Breast 1 in 8 Lung & bronchus 1 in 16 Colon & rectum 1 in 20 Uterine corpus 1 in 40 Non-Hodgkin lymphoma 1 in 53 Urinary bladder‡ 1 in 84 Melanoma§ 1 in 58 Ovary 1 in 72 Pancreas 1 in 75 Uterine cervix 1 in 145 * For those free of cancer at beginning of age interval. Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.3.0 Statistical Research and Applications Branch, NCI, 2008. http://srab.cancer.gov/devcan

  30. Five-year Relative Survival (%)* during Three Time Periods By Cancer Site, USA 1975-2004 Site 1984-1986 1996-2004 1975-1977 • All sites 50 54 66 • Breast (female) 75 79 89 • Colon 52 59 65 • Leukemia 35 42 51 • Lung and bronchus 13 13 16 • Melanoma 82 87 92 • Non-Hodgkin lymphoma 48 53 65 • Ovary 37 40 46 • Pancreas 3 3 5 • Prostate 69 76 99 • Rectum 49 57 67 • Urinary bladder 74 78 81 *5-year relative survival rates based on follow up of patients through 2005. Source: Surveillance, Epidemiology, and End Results Program, 1975-2005, Division of Cancer Control and Population Sciences, National Cancer Institute, 2008.

  31. Cancer in Turkey • Data from 13 cities (50% of the population) • Incidence (2008): 226/100.000 • Male: 280/100.000 • Female: 172/100.000 • New cancer diagnosis each year: 175.000 • Cause of death (2012) 1. Cardiovascular 38 % 2. Cancer 21%

  32. Camcer incidence in Turkey Men Women

  33. ETIOLOGY • 80% of cancers are caused by: • living habits (smoking, alcohol and diet) • environmental carcinogens

  34. Etiology of Cancer • Smoking • Alcohol • Diet • Ionizing radiation, radon • Environmental (asbestosis, UV lights, air pollution) • Chemical carcinogens – Benzene, asbestosis • Viruses – Hepatitis B,C • Bacteria- H. pylori • Immune insufficiency • Genetic- Congenital or acquired

  35. Smoking • Responsible from 30% of all cancer deaths • Risk of lung cancer is increased 10-20 times in smokers compared to non-smokers • Deaths related to lung cancer is due to smoking in >90% of the cases • 6000 deaths/year is related to passive smoking.

  36. Smoking-related cancers Major cause • Lung • Larynx • Oral cavity • Esophagus Contributory factor • Pancreas • Bladder • Kidney • Stomach • Uterine cervix Blum A, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;545-557.

  37. Alcohol-related cancers Although not a carcinogen, it causes cancer by increasing the permeability to carcinogens in mucosa. • Cancer of the esophagus • Head and neck cancer • Colon cancer • Liver cancer (by causing cirrhosis) • Pancreatic cancer • Breast cancer Trichopoulos D, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;231-257.

  38. Ionizing Radiation • Atomic bomb • Leukemia • Breast cancer • Radon • Formed by underground nuclear fission and comes to surface in some regions • Increase risk of lung cancer and other cancers • Radiotherapy • Breast cancer, leukemia, thyroid cancer, etc

  39. Environmental exposure • Asbestos-related cancers • Solar ultraviolet radiation • Electromagnetic fields • Unclear relationship to malignancy

  40. Diet • Lipids: Breast, colon • High caloric intake: Breast, endometrium, prostate, colon, biliary tract • Animal protein: Breast, endometrium, colon • Alcohol: oral cavity, esophagus, larynx, liver • Salt-preserved and smoked food: esophagus, gastric • Foods with nitrate and nitrite: Gastric, colon • Obesity and no regular exercise

  41. Virus-related cancers Agents • Hepatitis B • Hepatitis C • HTLV-1 • HPV • Epstein-Barr Site of Cancer Liver Liver Adult T-cell leukemia or lymphoma Uterine cervix, oropharyngeal cancer Burkitt’s lymphoma, nasopharynx,Hodgkin’s disease Adapted from Trichopoulos D, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;249.

  42. Bacteria- and parasite-related cancers Agents Helicobacter pylori Schistosoma haematobium Opisthorchis viverrini Site of Cancer Stomach Urinary bladder Liver Adapted from Trichopoulos D, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;249.

  43. Iatrogenic contributors Pharmaceuticals Agents Site of Cancer Cancer chemotherapeutics Bone marrow Immunosuppressive drugs Reticuloendothelial system Exogenous hormonesMenopausal estrogens Endometrium, breastDiethylstilbestrol Vagina, cervix uteriAnabolic steroids LiverOral contraceptives LiverTamoxifen Endometrium Phenacetin analgesics Kidney, pelvis Adapted from Trichopoulos D, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;249.

  44. Occupational-related cancers Industries Associated with Exposure to Carcinogens Industry Carcinogen Cancer Shipbuilding, demolition, insulation Asbestos Lung, pleura, peritoneum Varnish, glue Benzene Leukemia Pesticides, smelting Arsenic Lung, skin, liver Mineral refining and manufacturing Nickel, chromium Lung Furniture manufacturing Wood dusts Nasal passages Petroleum products Polycyclic hydrocarbons Lung Rubber manufacturing/dye workers Aromatic amines Bladder Vinyl chloride Vinyl chloride Liver Radium Radium Bone Petroleum refining/coal Coal tar products, mineral Skin hydrogenation oils Bal DG, et al. American Cancer Society Textbook of Clinical Oncology. 2nd ed. 1995;48.

  45. Genetic risk factor:Mechanisms of cancer predisposition • Germline tumor suppressor gene inactivation • Germline oncogene activation • DNA repair defects Bale AE, Li FP. Cancer: Principles & Practice of Oncology. 5th ed. 1997;285-293.

  46. Genetic risk factors:Characteristics of cancer families • Family history of cancer • Cancer appears earlier in life • Multiple and bilateral tumors • May include rare tumor types (eg, retinoblastoma) • Multisystem involvement Bale AE, Li FP. Cancer: Principles & Practice of Oncology. 5th ed. 1997;285-293.

  47. Familial cancer syndromes Familial Cancer Syndrome Site of Cancer Neurofibromatosis type 1 CNS, neurofibrosarcomas,pheochromocytomas, leukemia Neurofibromatosis type 2 CNS, spine von Hippel-Lindau disease CNS, renal cell, spine, pancreas, adrenal glands Li-Fraumeni syndrome CNS, breast, head and neck, soft tissue, osteosarcoma, adrenal cortical carcinomas, leukemia Wilms’ tumor gene Wilms’ tumor Basal cell carcinoma syndrome Skin, CNS, ovary Bale AE, Li FP. Cancer: Principles & Practice of Oncology. 5th ed. 1997;285-293. Linehan WM, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1253-1271.

  48. Familial cancer syndromes Familial Cancer Syndrome Site of Cancer Familial adenomatous polyposis Colorectal, jaw, skull, skin, coli stomach, CNS Hereditary nonpolyposis colorectal Colorectal, endometrium Cowden’s syndrome Thyroid, stomach, breast, ovary BRCA-1 Breast, ovary BRCA-2 Breast (female and male) Bale AE, Li FP. Cancer: Principles & Practice of Oncology. 5th ed. 1997;285-293. Safai B. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1883-1933. Cohen AM, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1144-1197. Dickson RB, Lippman ME. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1541-1557.

  49. Approach to Patients with Cancer • Diagnosis • Staging • Treatment: Depends on • Stage • Performance status of the patient • Goal of therapy • Cure (Early stage) • Palliation (Advanced stage) • Anticipated survival duration • Anticipated benefit • Response evaluation • Evaluation of toxicity

  50. Staging • Mostly TNM staging • T: Tumor size • T1, T2, T3, T4 • N: Lymph node • N1-3 • M: metastasis • M0, M1

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