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Lung Cancer
Summary: Content of Lung Cancer
Tutorial
∙Statistics in the United States
∙Anatomy of the lungs and respiratory
system
∙Lung cancer types
∙Lung cancer progression
∙Staging
∙Symptoms
∙Risk factors / risk reduction factors
∙Screening
∙Treatment
∙Clinical Trials
∙Current state of lung cancer research
∙References
www.physics.byu.edu
Summary: Statistics
∙ Statistics in the
United States
∙Incidence by race
∙Death by race
∙Incidence according to
geographical
location
∙ Death according to
geographical location
∙ Comparison of incidence
and death rates
between men and
women
Top Ten Cancers in the U.S.
Lung Cancer Statistics
Lung cancer is the leading cause of
cancer death among men and women
∙ 60% of all people diagnosed with
lung cancer die within one year
∙ 1 in 12 men will be diagnosed with
lung cancer, and a 1in 16 women
∙16% of people diagnosed with nonsmall call lung cancer survive to 5
years
∙Survival rate has remained steady
10 years
∙6.95% of people born today will be
diagnosed with lung cancer
∙ 70% of lung cancers are diagnosed
after the age of 60
89,575
108,355
87,897
68,431
Lung Cancer Incidence According to
Race in the U.S.
www.cdc.gov 2005
∙ Currently the highest incidence rate among African Americans
∙ Caucasians> American Indian/Alaskan Natives Asians/ Pacific Islanders > Hispanics
Lung Cancer Death According to Race
in the U.S.
www.cdc.gov 2004
∙ Death rate highest among African Americans.
∙ Caucasians> American Indians/Alaskan natives > Asians/Pacific Islanders > Hispanics
Lung Cancer Incidence- Geographical
Location in the U.S.
∙ Lowest Incidence in
UT, and NM
∙ Highest Incidence
in WV, KY and TN
∙ Colorado is in the
lowest bracket
for incidence.
www.cdc.gov 2005
Lung Cancer Deaths- Geographical
Location in the U.S.
∙ Death rate does not
perfectly correlate
with incidence rate
∙ Lowest death rates
in UT and NM
∙ Highest death rates
are in MO, AR, LA,
WV, KY, TN and MS
∙ Colorado is in the
lowest bracket for
death rate
www.cdc.gov 2005
Lung Cancer Rates for Men
∙ Rates for both
death and
mortality is ↓
for men.
www.seer.cancer.gov
Lung Cancer Rates for Women
∙ From 1975 –
2000 both
incidence and
death rates ↑.
∙ Rates appear to
be leveling off.
www.seer.cancer.gov
Summary: Content of Lung Cancer
Tutorial
∙Statistics in the United States
∙Anatomy of the lungs and respiratory
system
∙Lung cancer types
∙Lung cancer progression
∙Staging
∙Symptoms
∙Risk factors / risk reduction factors
∙Screening
∙Treatment
∙Clinical Trials
∙Current state of lung cancer research
∙References
www.physics.byu.edu
Summary: Anatomy of the Lungs and
Respiratory System
∙ Basic Respiratory
Anatomy
∙ Detailed anatomy of the
lungs
∙ Lung function
Basic Respiratory Anatomy
∙Food and air pass through
the pharynx
∙ Air then passes through
the larynx and down
through the trachea
into the lungs
Lungdisease.about.com
Detailed Anatomy of the Lungs
www.daviddarling.info/encyclopedia/L/lungs.html
∙ Trachea leads to the
bronchi (carina is
where the trachea
splits into the right
and left bronchi)
(not shown)
∙ Bronchi go to
secondary and
tertiary bronchi
∙ Tertiary bronchi lead
to the bronchioles
∙ Bronchioles end with
alveoli
Lung Function
∙ Oxygen enters through
mouth/nose
∙ Travels to the lungs
∙ Oxygen extracted and
sent through body via
the blood stream
∙ Carbon dioxide brought
to lungs via blood
stream and exhaled
www.daviddarling.info/encyclopedia/L/lungs.html
Summary: Content of Lung Cancer
Tutorial
∙Statistics in the United States
∙Anatomy of the lungs and respiratory
system
∙Lung cancer types
∙Lung cancer progression
∙Staging
∙Symptoms
∙Risk factors / risk reduction factors
∙Screening
∙Treatment
∙Clinical Trials
∙Current state of lung cancer research
∙References
www.physics.byu.edu
Summary: Lung Cancer Types
· How lung cancer is
classified
· Types of lung cancers
· Non-Small Cell Lung
Cancer (NSCLC)
· Types of NSCLC
· Small Cell Lung Cancer
(SCLC)
· Types of SCLC
www.999answers.com
Classification of lung cancer
↑ cancerous
tumor shown in
x-ray
· There are 2 major types of
lung cancers : non-small
cell (NSCLC) and small cell
(SCLC)
· These groups are further
divided
· Classification of the cancer
is done by the types of
cells it occurs in
· Cell types are defined by
the shape seen under a
microscope
Lung Cancer (2 Major Types)
↙
Non-small cell lung cancer
(NSCLC)
↓
↓
3 major types
↓
1.
2.
3.
Squamous cell
carcinoma
Adenocarcinoma
Large-cell
undifferentiated
carcinoma
↘
Small-cell lung cancer
(SCLC)
↓
4 minor types
↓
1.
2.
3.
4.
Pleomorphoic
Carcinoid tumor
Salivary gland
carcinoma
Unclassified
carcinoma
3 types
↓
1.
2.
3.
Small-cell carcinoma
Mixed small-cell / large-cell
carcinoma
Combined small-cell carcinoma
SCLC cells 
 NSCLC cells
www.lungblog.com
www.lungblog.com
Non-Small Cell Lung Cancer (NSCLC)
Non-small cell lung cancer
(NSCLC)
↓
↓
3 major types
4 minor types
↓
↓
1. Squamous cell carcinoma 1. pleomorphic
2. Adenocarcinoma
2. carcinoid tumor
3. Large cell undifferentiated 3. Salivary gland
carcinoma
carcinoma
4. unclassified
carcinoma
∙ 80% of lung cancers
are NSCLC
∙ 3 main subtypes of
NSCLC
∙ At least 4 other less
common types of
NSCLC
Squamous Cell Carcinoma
Non-small cell lung cancer
(NSCLC)
↓
↓
3 major types
4 minor types
↓
↓
1. Squamous cell carcinoma 1. pleomorphic
2. Adenocarcinoma
2. carcinoid tumor
3. Large cell undifferentiated 3. Salivary gland
carcinoma
carcinoma
4. unclassified
carcinoma
∙ 25% - 30% of all lung
cancers
∙ Also called
epidermoid cancer
∙ Found in the middle
of the lungs near
the bronchi
· Linked to smoking
Adenocarcinoma
Non-small cell lung cancer
(NSCLC)
↓
3 major types
↓
↓
4 minor types
↓
1. Squamous cell carcinoma 1. pleomorphic
2. Adenocarcinoma
2. carcinoid tumor
3. Large cell undifferentiated 3. Salivary gland
carcinoma
carcinoma
4. unclassified
carcinoma
∙ 40% of all lung cancers
∙ Also called
bronchiolalveaoar
adenocarcinoma
∙ Typically found in the
outer parts of the lung
· Begins in the cells that
line the alveoli
· Makes substances such
as mucus
· Have better prognosis
than those with other
lung cancer types
Large cell Undifferentiated Carcinoma
Non-small cell lung cancer
(NSCLC)
↓
3 major types
↓
↓
4 minor types
↓
1. Squamous cell carcinoma 1. pleomorphic
2. Adenocarcinoma
2. carcinoid tumor
3. Large cell undifferentiated 3. Salivary gland
carcinoma
carcinoma
4. unclassified
carcinoma
∙ 10% - 15% of all lung
cancers
∙ May begin in several
types of large cells
· May appear in any
part of the lung
· Grows and spreads
quickly
· Poor prognosis
4 Minor Types Of Non-Small Cell Lung
Cancer (NSCLC)
Non-small cell lung cancer
(NSCLC)
↓
↓
3 major types
4 minor types
↓
↓
1. Squamous cell carcinoma 1. pleomorphic
2. Adenocarcinoma
2. carcinoid tumor
3. Large cell undifferentiated 3. Salivary gland
carcinoma
carcinoma
4. unclassified
carcinoma
∙ All four types
account for < 5% of
all lung cancers
Small Cell Lung Cancer (SCLC)
Small cell lung cancer
(SCLC)
↓
3 Types
↓
1. Small cell carcinoma
2. Mixed small cell / large cell
carcinoma
3. Combined small cell carcinoma
· Accounts for 10-15% of all
lung cancers
· Almost always caused by
smoking
· Starts in the bronchi near the
center of the chest
· Grows and spreads rapidly
· Surgery must be combined
with other treatments
· Rarely cured by current
treatments
· Patient usually dies within 1-2
years
Small cell Carcinoma
SCLC
↓
3 types
↓
1. Small cell carcinoma
2. Mixed small cell / large cell
carcinoma
3. Combined small cell
carcinoma
· Also called oat cell carcinoma
or small cell
undifferentiated carcinoma
· 4-19% of small cell
carcinomas
· Less sensitive to chemo and
radiation therapy than small
cell carcinoma alone
· Made of small cell and
squamous cell lung cancer
cells or small cell and
adenocarcinoma cells
Lung Cancer (2 Major Types)
↙
Most common
Non-small cell lung cancer
80% all lung
(NSCLC) <5% all lung cancers
cancers
↓
↓
3 major types
↓
1.
Squamous cell
carcinoma
(Smoking)
2.
1.
2.
3.
Adenocarcinoma
(Better prognosis)
3.
4 minor types
↓
Large-cell
undifferentiated
carcinoma (Poor
Prognosis)
4.
Pleomorphoic
Carcinoid tumor
Salivary gland
carcinoma
Unclassified
carcinoma
↘
Almost always
caused by smoking
Small-cell lung cancer
(SCLC) 10%-15% all lung
↓ cancers
3 types
↓ 1-2 year survival
1.
2.
3.
Small-cell carcinoma
Mixed small-cell / large-cell
carcinoma
Combined small-cell carcinoma
Summary: Content of Lung Cancer
Tutorial
∙Statistics in the United States
∙Anatomy of the lungs and respiratory
system
∙Lung cancer types
∙Lung cancer progression
∙Staging
∙Symptoms
∙Risk factors / risk reduction factors
∙Screening
∙Treatment
∙Clinical Trials
∙Current state of lung cancer research
∙References
www.physics.byu.edu
Summary: Lung Cancer Progression
Begins at a
primary site
Spread to
near by
areas (lymph
nodes)
Metastasizes
to distant
areas in the
body
· Cancer
· Metastasis
Academic.evergreen.edu
Cancer
Cancerous lung tumor
http://science.nationalgeographic.com
· Lung cancer occurs when lung
cells begin to grow and
divide without control
∙ Lung cancer is caused by
mutations within the DNA
in the lung, mutations are
typically caused by
carcinogens
∙ Carcinogens are chemicals
that have been show to
cause mutations in DNA
that can result in damage to
“cancer genes”
Metastasis
lung cancer that has
metastasized to the brain
www.mayoclinic.org
· Metastasis occurs when
the cancer cells enter the
blood stream or
lymphatic system and
replace normal cells in
other tissues
· Lung cancer that has
spread to another organ
is still lung cancer
· Cancer that has spread to
the lungs from another
tissue is not lung cancer
Summary: Content of Lung Cancer
Tutorial
∙Statistics in the United States
∙Anatomy of the lungs and respiratory
system
∙Lung cancer types
∙Lung cancer progression
∙Staging
∙Symptoms
∙Risk factors / risk reduction factor
∙Screening
∙Treatment
∙Clinical Trials
∙Current state of lung cancer research
∙References
www.physics.byu.edu
Summary: Staging of Lung Cancer
· Staging of NSCLC
· T categories
· N categories
· M categories
· Stage grouping
· Staging of SCLC
Staging of NSCLC
· Staging is a standardized
way to describe the
extent to which the
cancer has spread
· The lung cancer type as
well as the stage
determines treatment as
well as prognosis
· NSCLC is staged using the
AJCC/TNM system
· Category: T category, N
category or M category
T, N, and M Categories; Stage Grouping
Stage Grouping
T: Tis- T4
N: N1-N4
M: M0-M1
T- T stands for tumor; describes
the size of the tumor and how
far it has spread in the lung
and to near by organs
N- N stands for spread to Lymph
Nodes (small bean like
structures that produce white
blood cells as well as filter
bacteria and other particles,
also called lymph glands)
M- stands for Metastasis
Stage Grouping
· Lower stage / group = better prognosis
Group
T,N,M categories
5 year survival %
0
Tis (Carcinoma in situ), N0, M0
IA
T1, N0, M0
62%
IB
T2, N0, M0
38%
IIA
T1, N1, M0
34%
IIB
T2, N1, M0 / T3, N0, M0
24%
IIIA
T1-2, N2, M0 / T3, N1-2, M0
13%
IIIB
T4, any N, M0 / any T, N3, M0
5%
IV
Any T, any N, M1
1%
Staging of SCLC
· 2 stage system
Limited stage- cancer is
contained to 1 lung and
the lymph nodes on the
same side
Extensive stage- cancer
has spread to other
lung, or lymph nodes on
the other side of the
chest, or to distant
organs
Summary: Content of Lung Cancer
Tutorial
∙Statistics in the United States
∙Anatomy of the lungs and respiratory
system
∙Lung cancer types
∙Lung cancer progression
∙Staging
∙Symptoms
∙Risk factors / risk reduction factors
∙Screening
∙Treatment
∙Clinical Trials
∙Current state of lung cancer research
∙References
www.physics.byu.edu
Summary: Symptoms
· Symptoms
· Early and late disease
symptoms
www.sgmc.ogr
Symptoms
∙ Most people do not
experience symptoms
until the cancer has
spread to far to be cured
∙ Many of the symptoms are
common to other
diseases, only a doctor
can determine if lung
cancer is the cause
∙ Symptoms are the same for
both NSCLC and SCLC
Possible Early and Late Disease
Symptoms
Possible Early Symptoms
Possible Late Symptoms
(metastasis)
∙ Cough that doesn’t go away
· Chest pain; aggravated by deep
breathing, coughing or
laughter
· Hoarseness
· Weight loss / appetite loss
· bloody / rust colored phlegm or
spit
· Reoccurring bronchitis /
pneumonia
·Wheezing
· Bone pain
· Neurological changes:
headache,
weakness/numbness of
limbs, dizziness, seizures
· Jaundice
· Visible masses from cancer
spreading to skin or lymph
nodes
Summary: Content of Lung Cancer
Tutorial
∙Statistics in the United States
∙Anatomy of the lungs and respiratory
system
∙Lung cancer types
∙Lung cancer progression
∙Staging
∙Symptoms
∙Risk factors / risk reduction factors
∙Screening
∙Treatment
∙Clinical Trials
∙Current state of lung cancer research
∙References
www.physics.byu.edu
Summary: Risk Factors / Risk
Reduction Factors
· Risk Factors
· Smoking and Lung
Cancer Statistics
Healthguide.howstuffworks.com
Risk Factors
Risk Factors
· Smoking
· Asbestos
∙ Radon gas (Test home for ↑
levels)
· High levels of arsenic in drinking
water
· Carcinogens found in the
workplace
· Radiation treatment to the
lungs/chest
·Personal / family history (usually
related to smoking)
·Air pollution
Radon Levels in the U.S.
Pink= ↑Radon levels southmetro-ppi.com
Yellow= ↓ Radon levels
static.howstuffworks.com
Smoking and Lung Cancer Statistics
Causes of Lung Cancer
Death
Smoking
90 %
80%
20%
10%
Lung
Cancer
Death
Men
Lung
Cancer
Death
Women
Other
· People who smoke are 10-20 X
more likely to die from lung
cancer
· 90% of lung cancer deaths in
men and 80% in women are
caused from smoking
· Cigarettes contain > 4000
chemicals, at least 43 of
which are carcinogenic
∙ Quitting smoking will ↓ risk for
lung cancer
∙ The more cigarettes smoked
and the longer a person
smokes ↑ risk for lung cancer
Summary: Content of Lung Cancer
Tutorial
∙Statistics in the United States
∙Anatomy of the lungs and respiratory
system
∙Lung cancer types
∙Lung cancer progression
∙Staging
∙Symptoms
∙Risk factors / risk reduction factors
∙Screening
∙Treatment
∙Clinical Trials
∙Current state of lung cancer research
∙References
www.physics.byu.edu
Summary: Screening
∙ Imaging Tests
∙ Chest x-ray, CT, MRI, and
PET scan
∙ Bone scan
∙ Screening sampling tissues or
cells
∙ Sputum cytology, Blood
counts/ blood count
chemistry
∙ Bronchoscopy,
Mediastinoscopy, ∙ Needles
Biopsy, Thoracentesis
Imaging tests
MRI
www.anaheimctpet.com
PET
MRI/PET
∙ Imaging tests are non-invasive
procedures
∙ Chest X-ray is often the first test
performed
∙ CT Scan takes many cross sectional
x-ray images and combines them
into a detailed image
∙ MRI uses radio waves and strong
magnets to produce a detailed
image
∙ PET uses a small amount radioactive
glucose injected in a
vein (Cancer cells absorb large
amounts of sugar)
∙ Bone Scan Similar to PET but bone
absorbs
radioactive substance
www.petctberkely.com
Screening Sampling Tissues or Cells
∙ Screening sampling tissues or
cells require a sample from
the area of the lung that
the cancer is found in
∙ The sample is examined for
cancer cells by a
pathologist
∙ One or more of the tests will
be used to confirm cancer
found from an imaging test
∙ Used to determine the
type of cancer, and if it
may have spread
∙ Often more invasive
Bronchoscopy ↑
 Biopsy
Farm1static.flickr.com
www.ucilungcenter.com
Sputum Cytology, Blood Counts/ Blood
Count Chemistry (CBC)
∙ Sputum cytology is
performed by sampling
phlegm that is collected
over a few days for cancer
cells
∙ CBC is often used after
treatment has begun
∙ CBC can detect high levels
of LDH, an indicator that
cancer has spread to the
liver and bones (poor
prognosis)
Human lung tissues that are stained
with florescent dye and placed under a
microscope
www.microscopyu.com
Bronchoscopy, Mediastinoscopy,
Needle Biopsy, Thoracentesis
∙ Bronchoscopy: Bronchoscope is
inserted through the mouth into
the bronchi to test for tumors and
blockages, other tips are often
placed
∙ Mediastinoscopy requires a small
incision to be made in the neck,
and a tube is then inserted behind
the sternum
∙ Needle Biopsy: Needle is inserted
into the lungs and a tissue sample
is taken
∙In Thoracentesis and Thoracoscopy a
needle is inserted between the
ribs to test if fluid build up in the
pleura is from cancer
 Bronchoscopy
www.daviddarling.info
www.blueshieldca.com
 Mediastinoscopy
Needle Biopsy 
www.nlm.nih.gov
drkawley.com
 Thoracentesis
Summary: Content of Lung Cancer
Tutorial
∙Statistics in the United States
∙Anatomy of the lungs and respiratory
system
∙Lung cancer types
∙Lung cancer progression
∙Staging
∙Symptoms
∙Risk factors / risk reduction factors
∙Screening
∙Treatment
∙Clinical Trials
∙Current state of lung cancer research
∙References
www.physics.byu.edu
Summary: Treatment
∙ Definition of
treatment types
∙ Treatment side effects
∙ Treatment for cancer
types
 NSCLC cells
Lung Cancer
↙
↘
Non Small Cell Lung
Cancer (NSCLC)
↓
↓
3 major types
4 minor types
3 types
↓
AJCC/TNM
staging system
SCLC cells 
Small Cell Lung Cancer
(SCLC)
↓
Limited and
extensive stage
Definitions of Treatment Types
∙ Surgery- A lobe of the lung may be removed (lobectomy), the entire
lung may be removed (pneumonectomy), or a potion of the lung
may be removed (segmentectomy), lymph nodes may also be
removed
∙ Radiation Therapy- High energy waves rays (X-rays) are targeted
toward the cancer either externally (external beam radiation
therapy) or internally through a bronchoscope (brachytherapy)
∙ Chemotherapy- Anticancer drugs are given intravenously or orally
over 21-28 day cycles for 6-8 cycles
∙ Targeted therapy- Newer drugs that specifically target cancer cells,
are usually given after chemo has failed
∙ Antiangiogenesis- drugs that block growth of new blood vessels ,
cause bleeding and can not be used for squamous cell cancer,
cancer metastasized to the brain , people coughing up blood, or
blood thinners
Treatment Side Effects
∙ Surgery- can only be performed on relatively healthy patients, pain, ↑ risk
pneumonia and bleeding (only used for NSCLC)
∙ Radiation- mild skin problems, nausea, vomiting, fatigue, and can increase
side effects of chemotherapy; used to treat primary lung cancer
∙ Chemotherapy- kill normal cells as well as cancer cells, nausea, vomiting, loss
of appetite, loss of hair, mouth sores, severe diarrhea, ↑ risk of
infection,↑ risk of bleeding/bruising and ↑ risk for fatigue; not used in
poor health. Platinum based drugs (cisplatin and carboplatin) are common
treatments, as well as combination therapies.
∙ Targeted therapy- skin rash and diarrhea
∙ Antiangiogenesis- bleeding; combined with chemo in advanced lung cancer
www-tc.pbs.org
Treatment for Cancer Types
Treatment
Good
health
Poor
health
metastasis
Surgery
X
Radiation
X
X
X
Chemo (drugs)
X
X
Targeted
X
Antiangiogenesis
X
Side
effects
NSCLC
SCLC
X
*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
*Surgery is rarely performed on patients with SCLC, only about 1 in 20 cases
SCLC treatment may also include Adjuvant Treatment, treatment such as radiation
to areas where cancer may not have been detected (brain) to prevent metastasis
Each X indicates the treatment is an option
Summary: Content of Lung Cancer
Tutorial
∙Statistics in the United States
∙Anatomy of the lungs and respiratory
system
∙Lung cancer types
∙Lung cancer progression
∙Staging
∙Symptoms
∙Risk factors / risk reduction factors
∙Screening
∙Treatment
∙Clinical Trials
∙Current state of lung cancer research
∙References
www.physics.byu.edu
Summary: Clinical Trials
Drug
Developed
Laboratory
Testing
Statistical
Analysis
Clinical Trials
( I, II, III,)
Submission
to FDA
Acceptance
∙ Definitions
Stage I, II, III, and IV
clinical trials
Clinical Trials
∙ Purpose is to test if a new and promising treatment will
be valuable to patients
∙ Treatments often have real benefits
Trial Stage
Purpose
I
How a new treatment is best administered and what is the highest dose
before side effects appear
II
To analyze if the drug works at the dosage found from stage I; side
effects are still being examined
III
Involves many people (>100), a control group (receiving only standard
treatment); if side effects are to great or one group is doing much
better the study will end
IV
After approval by the FDA, studies conducted to make sure the drug is
safe and effective
Summary: Content of Lung Cancer
Tutorial
∙Statistics in the United States
∙Anatomy of the lungs and respiratory
system
∙Lung cancer types
∙Lung cancer progression
∙Staging
∙Symptoms
∙Risk factors / risk reduction factors
∙Screening
∙Treatment
∙Clinical Trials
∙Current state of lung cancer research
∙References
www.physics.byu.edu
Summary: Current State of Lung
Cancer Research
∙ Cancer research
∙ Chemoprevention
∙ Biological Therapy
∙ New Combinations
jnci.oxfordjournals.org
Lung Cancer Research
Research type
Chemoprevention
Drugs that ↓ risk for developing lung cancer, or ↓ risk for lung
cancer reoccurring
*Biological Therapy/
Immunotherapy
Substances that ↑ the body’s own immune system to fight and
destroy cancer cells
New Combinations
New combinations of drugs or therapy types that may be more
effective in treating lung cancer
*Gene Therapy
Genes are inserted into the patient to give healthy copies of
damaged cancer causing genes, help to target cancer cells for
therapy, increase immune response, kill cancer cells, or to
inhibit the cancer cell’s ability to form new blood vessels
necessary for growth
*These are not yet in clinical trails
Summary: Content of Lung Cancer
Tutorial
∙Statistics in the United States
∙Anatomy of the lungs and respiratory
system
∙Lung cancer types
∙Lung cancer progression
∙Staging
∙Symptoms
∙Risk factors / risk reduction factors
∙Screening
∙Treatment
∙Clinical Trials
∙Current state of lung cancer research
∙References
www.physics.byu.edu
References
www.cancer.gov
www.cancer.org
www.seer.cancer.gov
genesdev.cshlp.org
hmg.oxfordjournals.org
Molecular Biology in Medicine; Timothy M. Cox, John Sinclair
Quick Facts: Lung Cancer What You Need to Know Now; American Cancer Society;
2007
Holland-Frie Manual of Cancer Medicine; Brown, Rini, Connell, Posner; 2005