Download Cancer What, Why, Who,When….

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.