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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 Tumorigenesis Normal cell Initial genetic change Secondary genetic change (eg, loss of function of pRb or overexpression of c-myc) (eg, dysfunction of p53 or overexpression of bcl-2) Increase in cell proliferation Decrease in apoptotic cell death Subsequent genetic change Further alterations in phenotype (eg, invasiveness and metastasis) Kastan MB. Cancer: Principles & Practice of Oncology. 5th ed. 1997;121-134. Precancerous conditions • Polyps (eg, adenomatous polyps) • Neoplasia (eg, prostatic intraepithelial neoplasia) • Carcinoma in situ Stedman’s Medical Dictionary. 26th ed. 1995;1182,1405, 279. Emergence of tumor cell heterogeneity Primary Neoplasm TRANSFORMATION TUMOR EVOLUTION AND PROGRESSION Metastases METASTASIS TUMOR EVOLUTION AND PROGRESSION Pathogenesis MOTILITY & INVASION TRANSFORMATION ANGIOGENESIS Capillaries, Venules, Lymnphatics ADHERENCE ARREST IN CAPILLARY BEDS EMBOLISM & CIRCULATION TRANSPORT Multicell aggregates (Lymphocyte, platelets) EXTRAVASATION INTO ORGAN PARENCHYMA METASTASES RESPONSE TO MICROENVIRONMENT METASTASIS OF METASTASES TUMOR CELL PROLIFERATION & ANGIOGENESIS 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. 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. Carcinogenesis • Duration: Depends of cancer type • Carcinogenesis: 10-20 years Limited stage: 5-10 years Disseminated stage: 1-5 years The doubling process Malignant transformation Dividing Normal cell 4 cells Doubling Doubling 2 cancer cells 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 – 43 doublings — Death Tumor growth and detection Number of cancer cells 1012 Diagnostic threshold (1cm) 109 time Undetectable cancer Detectable cancer Limit of clinical detection Host death Classification of Cancer I. Type of tissue in which cancer originates • Epithelial -> Carcinoma • • • Connective and supportive tissue -> Sarcoma Hematopoietic system • • • • %80-90 of all cancers Leukemia Lymphoma Myeloma Other tissue II. Primary site Epidemiology 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 Cancer in the world Second Rank in Causes of Death Total death rates, USA Heart disease 28,0 Cancer 22,7 CVA 6,4 COPD 5,2 Accident 4,5 Diabetes Mellitus 3,0 Pneumonia 2,7 Alzheimer 2,6 Nephritis 1,7 Septicemia 1,4 ACS 2006 Change in the US Death Rates* by Cause, 1950 & 2003 Rate Per 100,000 600 586,8 1950 500 2003 400 300 231,6 193,9 180,7 200 100 53,3 190,1 48,1 21,9 0 Heart Diseases Cerebrovascular Diseases 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 Change in US Death Rates* from 1991 to 2006 Rate Per 100,000 400 1991 313,0 2006 300 215,1 200,2 200 180,7 100 63,3 43,6 34,8 17,8 0 Heart diseases Cerebrovascular diseases Influenza & pneumonia Cancer * Age-adjusted to 2000 US standard population. Sources: US Mortality Data, National Center for Health Statistics, Centers for Disease Control and Prevention, 2009. 2009 Estimated Cancer Cases* Men 766,130 Women 713,220 Prostate 25% •27% Breast Lung & bronchus 15% •14% Lung & bronchus Colon & rectum 10% •10% Colon & rectum Urinary bladder 7% • 6% Uterine corpus Melanoma of skin 5% • 4% Non-Hodgkin lymphoma 5% Non-Hodgkin lymphoma • 4% Melanoma of skin Kidney & renal pelvis 5% • 4% Leukemia 3% • 3% Kidney & renal pelvis Oral cavity 3% • 3% Ovary Pancreas 3% • 3% Pancreas 19% •22% All Other Sites All Other Sites *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2009. Thyroid 2009 Estimated Cancer Deaths* Lung & bronchus 30% Men 292,540 Women 269,800 •26% Lung & bronchus Prostate 9% •15% Breast Colon & rectum 9% • 9% Colon & rectum Pancreas 6% • 6% Pancreas Leukemia 4% • 5% Ovary Liver & intrahepatic bile duct 4% • 4% Non-Hodgkin lymphoma Esophagus 4% • 3% Leukemia Urinary bladder 3% • 3% Uterine corpus • 2% Liver & intrahepatic bile duct • 2% Brain/ONS •25% All other sites Non-Hodgkin lymp 3% Kidney & renal pelvis 3% All other sites 25% ONS=Other nervous system. Source: American Cancer Society, 2009. Cancer Incidence Rates* by Sex,1975-2005 700 Rate Per 100,000 Men 600 Both Sexes 500 400 Women 300 200 Overall incidence rates decrease from 1999-2005 100 0 1975 1978 1981 1984 1987 1990 1993 1996 *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. 1999 2002 2005 Cancer Death Rates* Among Men,1930-2005 100 Rate Per 100,000 Lung & bronchus 80 60 Stomach Prostate 40 Colon & rectum 20 *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. 2005 2000 1995 1990 1985 1980 1975 1970 1965 1960 Liver 1955 1950 1945 1940 1935 Leukemia 1930 0 Pancreas Cancer Death Rates* Among Women, 1930-2005 100 Rate Per 100,000 80 60 Lung & bronchus 40 Uterus Breast Colon & rectum Stomach 20 Ovary *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. 2005 2000 1995 1990 1985 1980 1975 1970 1965 1960 1955 1950 1945 1940 1935 Pancreas 1930 0 Lifetime Probability of Developing Cancer, Men, 2003-2005* Site Risk All sites† Prostate 1 in 2 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. † All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder. ‡ Includes invasive and in situ cancer cases, § Statistic for white men. 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 Lifetime Probability of Developing Cancer, Women, US, 2003-2005* Site Risk All sites† Breast 1 in 3 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. † All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder. ‡ Includes invasive and in situ cancer cases, § Statistic for white women. 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 Five-year Relative Survival (%)* during Three Time Periods By Cancer Site, USA 1975-2004 Site 1975-1977 1984-1986 1996-2004 • 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. Cancer in Turkey • Data from 13 cities (50% of the population) • Incidence (2008): 226/100.000 – Male: – Female: 280/100.000 172/100.000 • New cancer diagnosis each year: 175.000 • Cause of death (2012) 1. Cardiovascular 2. Cancer 38 % 21% Camcer incidence in Turkey Men Women ETIOLOGY 80% of cancers are caused by: • living habits (smoking, alcohol and diet) • environmental carcinogens 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 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. 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. 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. 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 Environmental exposure • Asbestos-related cancers • Solar ultraviolet radiation • Electromagnetic fields – Unclear relationship to malignancy 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 Virus-related cancers Agents Site of Cancer • Hepatitis B Liver • Hepatitis C Liver • HTLV-1 Adult T-cell leukemia or lymphoma • HPV Uterine cervix, oropharyngeal cancer • Epstein-Barr Burkitt’s lymphoma, nasopharynx, Hodgkin’s disease Adapted from Trichopoulos D, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;249. Bacteria- and parasite-related cancers Agents Site of Cancer Helicobacter pylori Stomach Schistosoma haematobium Urinary bladder Opisthorchis viverrini Liver Adapted from Trichopoulos D, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;249. Iatrogenic contributors Pharmaceuticals Agents Site of Cancer Cancer chemotherapeutics Bone marrow Immunosuppressive drugs Reticuloendothelial system Exogenous hormones Menopausal estrogens Diethylstilbestrol Anabolic steroids Oral contraceptives Tamoxifen Endometrium, breast Vagina, cervix uteri Liver Liver Endometrium Phenacetin analgesics Kidney, pelvis Adapted from Trichopoulos D, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;249. 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. 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. 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. 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. Familial cancer syndromes Familial Cancer Syndrome Site of Cancer Familial adenomatous polyposis coli Colorectal, jaw, skull, skin, 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. 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 Staging • Mostly TNM staging – T: Tumor size • T1, T2, T3, T4 – N: Lymph node • N1-3 – M: metastasis • M0, M1 Staging • Mainly 4 stages according to TNM classification – – – – Stage 1: Early stage Stage 2: Early stage Stage 3: Locally advanced stage Stage 4: Metastatic Goals of therapy • Curable tumors: Complete remission (CR) • Non-curable tumors and patients receiving palliative treatment: – – – – Partial response or stabile disease Symptom control Quality of life Prolongation of survival Approach to Patients with Cancer • Diagnosis • Staging • Goal of therapy – Cure (Early stage) – Palliation (Advanced stage) • Treatment: Depends on – Stage – Performance status of the patient – Survival duration – Anticipated benefit • Response evaluation • Evaluation of toxicity Treatment modalities • Surgery • Radiotherapy • Chemotherapy • Immunotherapy (monoclonal antibodies, cancer vaccines, cytokines, extracorporeal photopheresis) • Hormonal therapy • Differentiating agents • Targetted therapies • Stem cell transplantaion • Photodynamic therapies • Radioisotope treatment • Gene therapy Conclusion • Cancer is uncontrolled proliferation of genetically modified cells. • Cancer is second cause of death. • 80% of cancers are related to lifestyle (smoking, alcohol, diet) and environmental carcinogens. • Changes in life style and early diagnosis would significantly decrease cancer incidence and mortality. • Multidisiplinary approach is required in treatment of cancer.