INTRODUCTION TO INTRODUCTION TO

CLINICAL ONCOLOGYCLINICAL ONCOLOGY

Başak Oyan-Uluç, MDYeditepe 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

Kastan MB. Cancer: Principles & Practice of Oncology. 5th ed. 1997;121-134.

Initialgenetic change

(eg, loss of function of pRb or overexpression of c-myc)

Decreasein apoptoticcell death

Subsequentgenetic change

Normalcell

Increase incell proliferation

Secondarygenetic change

(eg, dysfunction of p53or overexpression of bcl-2)

Further alterationsin phenotype(eg, invasivenessand metastasis)

Tumorigenesis

• Polyps (eg, adenomatous polyps)

• Neoplasia (eg, prostatic intraepithelial neoplasia)

• Carcinoma in situ

Precancerous conditions

Stedman’s Medical Dictionary. 26th ed. 1995;1182,1405, 279.

Emergence of tumor cell heterogeneity

Primary NeoplasmPrimary Neoplasm MetastasesMetastases

TRANSFORMATIONTRANSFORMATION TUMOR EVOLUTIONTUMOR EVOLUTION METASTASISMETASTASIS TUMOR EVOLUTIONTUMOR EVOLUTIONAND PROGRESSIONAND PROGRESSION AND PROGRESSIONAND PROGRESSION

Pathogenesis

TRANSFORMATION ANGIOGENESISMOTILITY & INVASION

Capillaries,Venules, Lymnphatics

ADHERENCE

ARREST INCAPILLARY BEDS EMBOLISM &

CIRCULATION

EXTRAVASATIONINTO ORGAN

PARENCHYMA RESPONSE TOMICROENVIRONMENT

TUMOR CELLPROLIFERATION& ANGIOGENESIS

METASTASES

METASTASIS OFMETASTASES

TRANSPORT

Multicell aggregates(Lymphocyte, platelets)

• 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.

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)

Carcinogenesis

• Duration: Depends of cancer type

• Carcinogenesis: 10-20 years

Limited stage: 5-10 years

Disseminated stage: 1-5 years

The doubling process

NormalNormalcellcell

DividingDividing

MalignantMalignanttransformationtransformation

2 cancer2 cancercellscells

DoublingDoubling 4 cells4 cells

DoublingDoubling

8 cells8 cells

DoublingDoubling

16 cells16 cells

1 million cells1 million cells(20 doublings)(20 doublings)undetectableundetectable

1 billion cells1 billion cells(30 doublings)(30 doublings)lump appearslump appears

1 trillion cells1 trillion cells(40 doublings – 2 lb/1kg)(40 doublings – 2 lb/1kg)

41 – 4341 – 43doublingsdoublings— Death— Death

Tumor growth and detection

10101212

101099

timetime

DiagnosticDiagnosticthresholdthreshold

(1cm)(1cm)

UndetectableUndetectablecancercancer

DetectableDetectablecancercancer

Limit ofLimit ofclinicalclinical

detectiondetection

HostHostdeathdeath

Nu

mb

er o

fN

um

ber

of

can

cer

cells

can

cer

cells

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

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

ACS 2006

Second Rank in Causes of Death

1,4

1,7

2,6

2,7

3,0

4,5

5,2

6,4

22,7

28,0

Total death rates, USA

Heart disease

Cancer

CVA

COPD

Accident

Diabetes Mellitus

Pneumonia

Alzheimer

Nephritis

Septicemia

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

21,9

180,7

48,1

586,8

193,9

53,3

190,1

231,6

0

100

200

300

400

500

600

HeartDiseases

CerebrovascularDiseases

Pneumonia/Influenza

Cancer

1950

2003

Rate Per 100,000

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.

17,8

63,3

34,8

313,0

215,1

43,6

180,7200,2

0

100

200

300

400

Heart diseases Cerebrovasculardiseases

Influenza &pneumonia

Cancer

1991

2006

Rate Per 100,000

2009 Estimated Cancer Cases*

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2009.

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-Hodgkin5% lymphoma

Kidney & renal pelvis 5%

Leukemia 3%

Oral cavity 3%

Pancreas 3%

All Other Sites 19%

2009 Estimated Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society, 2009.

Men292,540

Women269,800

•26% Lung & bronchus

•15% Breast

• 9% Colon & rectum

• 6% Pancreas

• 5% Ovary

• 4% Non-Hodgkin lymphoma

• 3% Leukemia

• 3% Uterine corpus

• 2% Liver & intrahepaticbile 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%

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.

0

100

200

300

400

500

600

700

1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 2005

Both Sexes

Men

Women

Rate Per 100,000

Overall incidence rates decrease from 1999-2005

Cancer Incidence Rates* Among Men, 1975-2005

0

50

100

150

200

250

1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 2005

Prostate

Lung & bronchus

Colon and rectum

Urinary bladder

Non-Hodgkin lymphoma

Rate Per 100,000

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.

Prostate: Increase due to PSA screening

Lung: Incidence decline

Colon: Incidence decline

Cancer Incidence Rates* Among Women, 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.

0

50

100

150

200

250

1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 2005

Colon and rectum

Rate Per 100,000

Breast

Lung & bronchus

Uterine CorpusOvary

Non-Hodgkin lymphoma

Breast: Decrease due to mamographic screening and reduction in use of HRT.

Lung: Slight increase

Colon: Rapid decrease

Cancer Death Rates* by Sex,1975-2005

*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.

0

50

100

150

200

250

300

1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 2005

Men

Both Sexes

Rate Per 100,000

Women

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.

0

20

40

60

80

100

1930

1935

1940

1945

1950

1955

1960

1965

1970

1975

1980

1985

1990

1995

2000

2005

Lung & bronchus

Colon & rectum

Stomach

Rate Per 100,000

Prostate

Pancreas

LiverLeukemia

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.

0

20

40

60

80

100

1930

1935

1940

1945

1950

1955

1960

1965

1970

1975

1980

1985

1990

1995

2000

2005

Lung & bronchus

Colon & rectum

Uterus

Stomach

Breast

Ovary

Pancreas

Rate Per 100,000

* 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 RiskAll 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

‡ Includes invasive and in situ cancer cases, § Statistic for white men.

Lifetime Probability of Developing Cancer, Women, US, 2003-2005*

Site RiskAll 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.

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 andPopulation Sciences, National Cancer Institute, 2008.

 

 

 

Site 1975-1977 1984-1986 1996-2004

• All sites 50 5466

• Breast (female) 75 7989

• Colon 52 5965

• Leukemia 35 4251

• Lung and bronchus 13 1316

• Melanoma 82 8792

• Non-Hodgkin lymphoma 48 5365

• Ovary 37 40 46

• Pancreas 3 3 5

• Prostate 69 7699

• Rectum 49 5767

• Urinary bladder 74 7881

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%

Camcer incidence in Turkey

WomenMen

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.

Major causeMajor cause• Lung• Larynx• Oral cavity• Esophagus

Contributory factorContributory factor• Pancreas• Bladder• Kidney• Stomach• Uterine cervix

Smoking-related cancers

Blum A, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;545-557.

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.

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

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

Liver

Adult T-cell leukemia or lymphoma

Uterine cervix, oropharyngeal cancer

Burkitt’s lymphoma, nasopharynx,Hodgkin’s disease

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

Pharmaceuticals

Agents Site of Cancer

Cancer chemotherapeutics Bone marrow

Immunosuppressive drugs Reticuloendothelial system

Exogenous hormones

Menopausal estrogens Endometrium, breast

Diethylstilbestrol Vagina, cervix uteri

Anabolic steroids Liver

Oral contraceptives Liver

Tamoxifen Endometrium

Phenacetin analgesics Kidney, pelvis

Iatrogenic contributors

Adapted from Trichopoulos D, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;249.

Industries Associated with Exposure to CarcinogensIndustries Associated with Exposure to Carcinogens

IndustryIndustry CarcinogenCarcinogen CancerCancer

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

Occupational-related cancers

Bal DG, et al. American Cancer Society Textbook of Clinical Oncology. 2nd ed. 1995;48.

• 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.

• 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.

Familial Cancer SyndromeFamilial Cancer Syndrome Site of CancerSite 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

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.

Familial Cancer SyndromeFamilial Cancer Syndrome Site of CancerSite 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)

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.

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.