1. INTRODUCTION TO CLINICAL ONCOLOGY Ba ş ak 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. Kastan MB. Cancer: Principles & Practice of Oncology. 5th ed. 1997;121-134. Initial genetic change (eg, loss of function of pRb or overexpression of c-myc) Decrease in apoptotic cell death Subsequent genetic change Normal cell Increase in cell proliferation Secondary genetic change (eg, dysfunction of p53 or overexpression of bcl-2) Further alterations in phenotype (eg, invasiveness and metastasis) Tumorigenesis

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

6. Emergence of tumor cell heterogeneity Primary NeoplasmMetastases TRANSFORMATIONTUMOR EVOLUTIONMETASTASISTUMOR EVOLUTION AND PROGRESSIONAND PROGRESSION

7. Pathogenesis TRANSFORMATIONANGIOGENESIS MOTILITY & INVASION Capillaries, Venules, Lymnphatics ADHERENCE ARREST IN CAPILLARY BEDS EMBOLISM & CIRCULATION EXTRAVASATION INTO ORGAN PARENCHYMA RESPONSE TO MICROENVIRONMENT TUMOR CELL PROLIFERATION & ANGIOGENESIS METASTASES METASTASIS OF METASTASES TRANSPORT Multicell aggregates (Lymphocyte, platelets)

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

9. Angiogenesis Fidler IJ. Cancer: Principles & Practice of Oncology. 5th ed. 1997;135-147. 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)

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 Normal cell Dividing Malignant transformation 2 cancer cells Doubling 4 cells Doubling 8 cells Doubling 16 cells 1 million cells (20 doublings) undetectable 1 billion cells (30 doublings) lump appears 1 trillion cells (40 doublings – 2 lb/1kg) 41 – 43 doublings — Death

12. Tumor growth and detection 10 12 10 9 time Diagnostic threshold (1cm) Undetectable cancer Detectable cancer Limit of clinical detection Host death Number of cancer cells

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

18. Change in the US Death Rates* by Cause, 1950 & 2003 * 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 Heart Diseases Cerebrovascular Diseases Pneumonia/ Influenza Cancer 1950 2003 Rate Per 100,000

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

20. 2009 Estimated Cancer Cases* *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2009. Men 766,130 Women 713,220 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 Prostate25% Lung & bronchus15% Colon & rectum10% Urinary bladder7% Melanoma of skin5% Non-Hodgkin5% lymphoma Kidney & renal pelvis5% Leukemia 3% Oral cavity3% Pancreas3% All Other Sites19%

21. 2009 Estimated Cancer Deaths* ONS=Other nervous system. Source: American Cancer Society, 2009. Men 292,540 Women 269,800 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% Prostate9% Colon & rectum 9% Pancreas6% Leukemia4% Liver & intrahepatic4% bile duct Esophagus4% Urinary bladder3% Non-Hodgkin lymp 3% Kidney & renal pelvis3% All other sites 25%

22. Cancer Incidence Rates* by Sex,1975-2005 *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. Both Sexes Men Women Rate Per 100,000 Overall incidence rates decrease from 1999-2005

23. Cancer Death Rates* Among Men,1930-2005 *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. Lung & bronchus Colon & rectum Stomach Rate Per 100,000 Prostate Pancreas LiverLeukemia

24. Cancer Death Rates* Among Women, 1930-2005 *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. Lung & bronchus Colon & rectum Uterus Stomach Breast Ovary Pancreas Rate Per 100,000

25. * 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 Lifetime Probability of Developing Cancer, Men, 2003-2005* † All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder. Site Risk All sites † 1 in 2 Prostate1 in 6 Lung and bronchus1 in 13 Colon and rectum1 in 18 Urinary bladder ‡ 1 in 27 Melanoma § 1 in 39 Non-Hodgkin lymphoma1 in 45 Kidney1 in 57 Leukemia1 in 67 Oral Cavity1 in 72 Stomach1 in 90 ‡ Includes invasive and in situ cancer cases, § Statistic for white men.

26. 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 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 * 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.

27. Five-year Relative Survival (%)* during Three Time Periods By Cancer Site, USA 1975-2004 *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. Site 1975-1977 1984-1986 1996-2004 All sites505466 Breast (female)757989 Colon 525965 Leukemia354251 Lung and bronchus131316 Melanoma828792 Non-Hodgkin lymphoma485365 Ovary3740 46 Pancreas33 5 Prostate697699 Rectum495767 Urinary bladder747881

28. 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. Cancer21%

29. Camcer incidence in Turkey WomenMen

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

31. 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

32. 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.

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

34. 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 Alcohol-related cancers Trichopoulos D, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;231-257.

35. 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

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

37. 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

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

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

40. Pharmaceuticals AgentsSite of Cancer Cancer chemotherapeuticsBone marrow Immunosuppressive drugsReticuloendothelial system Exogenous hormones Menopausal estrogensEndometrium, breast DiethylstilbestrolVagina, cervix uteri Anabolic steroidsLiver Oral contraceptivesLiver TamoxifenEndometrium Phenacetin analgesicsKidney, pelvis Iatrogenic contributors Adapted from Trichopoulos D, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;249.

41. Industries Associated with Exposure to Carcinogens IndustryCarcinogenCancer Shipbuilding, demolition, insulationAsbestosLung, pleura, peritoneum Varnish, glueBenzeneLeukemia Pesticides, smeltingArsenicLung, skin, liver Mineral refining and manufacturingNickel, chromiumLung Furniture manufacturingWood dustsNasal passages Petroleum productsPolycyclic hydrocarbonsLung Rubber manufacturing/dye workersAromatic aminesBladder Vinyl chlorideVinyl chlorideLiver RadiumRadiumBone Petroleum refining/coal Coal tar products, mineral Skin hydrogenation oils Occupational-related cancers Bal DG, et al. American Cancer Society Textbook of Clinical Oncology. 2nd ed. 1995;48.

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

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

44. Familial Cancer SyndromeSite of Cancer Neurofibromatosis type 1 CNS, neurofibrosarcomas, pheochromocytomas, leukemia Neurofibromatosis type 2CNS, spine von Hippel-Lindau diseaseCNS, renal cell, spine, pancreas, adrenal glands Li-Fraumeni syndromeCNS, breast, head and neck, soft tissue, osteosarcoma, adrenal cortical carcinomas, leukemia Wilms’ tumor geneWilms’ tumor Basal cell carcinoma syndromeSkin, CNS, ovary Familial cancer syndromes 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.

45. Familial Cancer SyndromeSite of Cancer Familial adenomatous polyposis Colorectal, jaw, skull, skin, coli stomach, CNS Hereditary nonpolyposis colorectal Colorectal, endometrium Cowden’s syndromeThyroid, stomach, breast, ovary BRCA-1Breast, ovary BRCA-2Breast (female and male) Familial cancer syndromes 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.

46. 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

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

48. Staging Mainly 4 stages according to TNM classification –Stage 1: Early stage –Stage 2: Early stage –Stage 3: Locally advanced stage –Stage 4: Metastatic

49. 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

50. 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

51. 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

52. 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.