Lung Cancer

I GEDE KETUT SAJINADIYASA

 Lung Cancer: Defined
 Uncontrolled growth of malignant cells in
one or both lungs and tracheo-bronchial
tree
 A result of repeated carcinogenic irritation
causing increased rates of cell replication
 Proliferation of abnormal cells leads to
hyperplasia, dysplasia or carcinoma in situ
 Incidence and Mortality
 Estimated new cases and deaths from lung
cancer (non-small cell and small cell
combined) in the United States in 2012
– New cases: 226,160.
– Deaths: 160,340.
 Lung cancer is the leading cause of cancer-
related mortality in the United States
 Most patients diagnosed with lung cancer
today already have advanced disease (40%
are stage IV, 30% are stage III)

American Cancer Society.: Cancer Facts and

Figures 2012
Estimated new cases (incidence) and deaths (mortality)
worldwide for the 15 most common cancers, 2000
Males Females
Lung
Breast
Colon/rectum
Stomach
Liver
Prostate
Cervix uteri
Oesophagus
Bladder
Non-Hodgkin’s lymphoma
Oral cavity
Leukaemia Incidence
Pancreas Mortality
Ovary
Kidney
1200 1000 800 600 400 200 0 200 400 600 800 1000 1200
Thousands
Parkin et al 2001
Worldwide mortality rates for the top
five cancer types
Cancer Type Annual Mortality

Lung 1.3 million

Stomach 803 000
Colorectal 639 000
Liver 610 000
Breast 519 000
World Health Organisation (2009)
 Risk Factors
 UNMODIFIABLE RISK FACTORS
– Gender
– Race
– Genetic Predisposition

 MODIFIABLE RISK FACTORS

– Smoking
– Environmental Tobacco Smoke (ETS)
– Occupational Exposure
 Risk Factors
 OTHER CAUSES OF LUNG
CANCER
– Air Pollution
– Diet
– Previous Lung Disease
Risk factor in lung cancer
Tobacco use is the leading cause
of lung cancer
80-90% of lung cancers are
related to smoking

Factor Relative risk

Non-smoker 1
Smoker, 1-2 pack/day 42
Ex-smoker 2 to 10
Passive smoke exposure 1,5 to 2

Asbestos exposure 5
Asbestos and tobacco 90

Harrish Patel & Catherine Gwilt, 2008

 Smoking Facts
 Tobacco use is the leading
cause of lung cancer
 87% of lung cancers are
related to smoking
 Risk related to:
– age of smoking onset
– amount smoked
– gender
– product smoked
Causative agents in cigarette smoke
Genes Commonly Altered in Lung
Cancer
Age-adjusted incidence of lung cancer
by race and ethnicity, United States,
1990–1995.
Occupational Human Lung
Carcinogens
Lung carcinogenesis
 Types of lung cancer
 Non-small-cell lung cancer (NSCLC) -75%
– Squamous cell carcinoma (25%)
– Adenocarcinoma (40%)
– Large-cell carcinoma (10%)

 Small-cell lung cancer (SCLC) -25%

Harrish Patel & Catherine Gwilt, 2008

The different types of NSCLC
Squamous Adenocarcin Large cell
cell oma. carcinoma
carcinoma
Male/female M>F F>M M>F
inciden
Location hilar peripheral Peripheral /
central
Histological keratin mucin -
stain
Growth rate slow medium rapid
Metastase late intermediate early

Harrish Patel & Catherine Gwilt, 2008

Types of lung cancer: small-cell lung
cancer (SCLC)
 Approximately 25% of all lung cancers
 Cellular classification
– small-cell carcinoma
– mixed small-cell/large-cell carcinoma
– combined small-cell carcinoma
 Occurs almost exclusively in smokers and is
more prevalent in women than men
 Lesions most commonly originate in central part
of chest
 Tendency to disseminate early
 Initially chemosensitive, becoming resistant
Major presenting symptoms of
lung cancer
Patients 100
(%)
80

60

40

20

0
Dyspnoea Cough Pain Loss of Haemoptysis
appetite

Baseline major presenting symptoms

Hollen et al 1999
Paraneoplastic syndromes

HPOA is hypertrophic pulmonary osteo-arthropathy.

SIADH is syndrome of inappropriate antidiuretic hormone secretion
 Diagnosis of Lung Cancer
 Histology
 Staging
 Performance status
Lung cancer diagnosis and staging
Physical examination Detect signs

Bronchoscopy Precise location of tumour, obtain biopsy

CT scan Detect chest wall invasion, mediastinal

lymphodenopathy, distant metastases

PET scan Lymph node staging

Laboratory analysis Detect changes in hormone production,

and haematological manifestations of lung cancer

Mediastinoscopy Visualise and sample mediastinal lymph nodes

MRI Evaluation of the brain

Bone scans Evaluation metastase to the bone

FNA, fine-needle aspirate; CT, computed tomography;

PET, positron emission tomography NCCN Guidelines 2000
BRONCHOSCOPY
Unit Broncoscopy
RSUP Sanglah
Percutaneous transthoracic needle aspiration using
computed tomographic guidance
TTB CT
Guidance
Transbronchial needle aspiration (TBNA)
Transbronchial needle aspiration (TBNA)
Thoracoscopy
Positron emission tomography (PET) scanning
Bone scan showing hypertrophic pulmonary osteoarthropathy
Mediastinoscopy and mediastinotomy
Thoracotomy
 BRONCHOSCOPY

FNAB
 NSCLC stages
Lymph nodes

Invasion of
chest wall
Metastasis
to distant
organs
Main
bronchus
Stage 0
Stage IA
Stage IIB
Stage IIIB
Contralateral Stage IV
lymph node
Stage groupings in 7th TNM classification
Stage T N M
Occult Tx N0 M0
0 Tis N0 M0
IA T1a,b N0 M0
IB T2a N0 M0
IIA T1a,b N1 M0
T2a N1 M
T2b N0 M0
IIB T2b N1 M0
T3 N0 M0
IIIA T1,T2 N2 M0
T3 N1,N2 M0
T4 N0,N1 M0
IIIB T4 N2 M0
Any T N3 M0
IV Any T Any N M1a, b
AJCC Cancer Staging Manual. 7th ed. 2010
 Definitions of TNM (1)
 TX = Primary tumor cannot be assessed, or tumor proven by the
presence of malignant cells in sputum or bronchial washings but not
visualized by imaging or bronchoscopy.
 Tis = Carcinoma in situ.
 T1a = Tumor ≤2 cm in greatest dimension.
 T1b = Tumor >2 cm but ≤3 in greatest dimension.
 T2a = Tumor >3 cm but ≤5 cm in greatest dimension
 T2b = Tumor >5 cm but ≤7 cm in greatest dimension.
 T3 = Tumor >7 cm or one that directly invades any of the following:
parietal pleural (PL3) chest wall (including superior sulcus tumors),
diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium.
Tumor in the main bronchus (<2 cm distal to the carinab but without
involvement of the carina). Associated atelectasis or obstructive
pneumonitis of the entire lung or separate tumor nodule(s) in the same
lobe.
 T4 = Tumor of any size that invades any of the following: mediastinum,
heart, great vessels, trachea, recurrent laryngeal nerve, esophagus,
vertebral body, carina, or separate tumor nodule(s) in a different
ipsilateral lobe.
AJCC Cancer Staging Manual. 7th ed. 2010
 Definitions of TNM (2)
 N0 = No regional lymph node metastasis.
 N1 = Metastasis in ipsilateral peribronchial and/or ipsilateral
hilar lymph nodes and intrapulmonary nodes, including
involvement by direct extension.
 N2 = Metastasis in ipsilateral mediastinal and/or subcarinal
lymph node.
 N3 = Metastasis in contralateral mediastinal, contralateral
hilar, ipsilateral or contralateral scalene, or supraclavicular
lymph node.
 M0 = No distant metastasis.
 M1a = Separate tumor nodule(s) in a contralateral lobe tumor
with pleural nodules or malignant pleural (or pericardial)
effusion.
 M1b = Distant metastasis.
AJCC Cancer Staging Manual. 7th ed. 2010
SCLC stages
Extensive
Tumour not confined
to hemithorax of
origin
Distant metastasis

Limited
Tumour confined to
hemithorax of origin
and/or the
mediastinum and
supraclavicular nodes

PDQ Guidelines 2000

 PERFORMANCE STATUS
 WHO: 0-4
 KARNOFSKY: 0-100%
 ECOG: 0-4
 KARNOFSKY PERFORMANCE SCALE

100 No evidence of disease

90 Minor signs or symptoms
80 Normal activity with effort
70 Fully able to care for self
60 Self care with some assistance
50 Required considerable help
40 Required special assistance
30 Severity disabled
20 Hospitalization is necessary
 WHO/ECOG (Eastern Cooperative Oncology
Group) Performance Scale
0 Fully active. Able to carry o all predisease
activities without restriction
1 Restricted in physically strenuous activity but
ambulatory and able to perform light work
2 Ambulatory and capable of all self-care but
unable to work. Up and about more than 50%
of waking hours.
3 Capable only limited self-care. Confined to
bed or chair more than 50% of waking hours
4 Completely disable. Cannot perform any self-
care. Continued to bed or chair
Standard Treatment Options for NSCLC
Stage Treatment Options 5-year
survival
Occult Surgery
0 Surgery
I Surgery + Radiation 58-73%
II Surgery, Neoadjuvant 36- 46%
chemotherapy, Adjuvant
chemotherapy , Radiation
therapy

Tufman A, Huber RM. ESR, 2010

Standard Treatment Options for NSCLC
Stage Treatment Options 5-year
survival
IIIA Chemotherapy combined with 24%
radiation therapy and/or
surgery
IIIB Sequential or concurrent 9%
chemotherapy and radiation
therapy
Chemotherapy followed by
surgery (for selected patients),
Radiation therapy alone
Tufman A, Huber RM. ESR, 2010
Standard Treatment Options for NSCLC
Stage Treatment Options 5-year
survival
IV Cytotoxic combination < 5%
chemotherapy (first line)
Combination chemotherapy
with bevacizumab or cetuximab

EGFR-Tyrosine kinase inhibitor

(first line for patients with EGFR
mutations)

Tufman A, Huber RM. ESR, 2010

 First-line chemotherapy for
advanced NSCLC
 Cisplatin-based regimens reduce risk of death by 27%
– ~10%  survival after 1 year1
Median
Response 1-year survival
ECOG trial2 rate (%) survival (%) (months)
Paclitaxel/cisplatin 21 31 7.8
Gemcitabine/cisplatin 22 36 8.1
Docetaxel/cisplatin 17 31 7.4
Paclitaxel/carboplatin 17 34 8.1
 Platinum-based doublet chemotherapy is standard of care
 Triplets not better than doublets in meta-analysis3
– one recent exception: paclitaxel/carboplatin ± gemcitabine4
1Non-Small Cell Lung Cancer Collaborative Group. Br Med J 1995;311:899–909
2Schiller JH, et al. N Engl J Med 2002;346:92–8
3Delbado C, et al. JAMA 2004;292:470–84
4Paccagnella A, et al. J Clin Oncol 2006;24:681–7
 Bevacizumab-based therapy is the first treatment to
increase OS in non-squamous NSCLC
beyond 1 year

2000s Platinum-based doublet + Bevacizumab

12.3 months

Platinum-based doublets:
1990s 8–10 months

Single-agent platinum:
1980s
6–8 months

1970s BSC:
2–5 months

0 2 4 6 8 10 12 14
Median survival (months)

Schiller, et al. NEJM 2002

Sandler, et al. NEJM 2006
SCLC: treatment options overview
 Limited-stage disease
– standard therapy
 surgery
 platinum-based combination chemotherapy
 thoracic irradiation
 prophylactic cranial irradiation (PCI) [for responders]
– new agents
 taxanes, eg paclitaxel and docetaxel
 topoisomerase I inhibitors, eg topotecan and irinotecan

 Extensive-stage disease
– combination chemotherapy +/- PCI
– radiotherapy + combination chemotherapy
SMOKING CESSATION
 Health Effects of Smoking
 Heart disease  Osteoporosis
 Lung disease – COPD, asthma  Wound healing
 Cancer  Anxiety
– Lung, ENT, pancreas  Miscarriage
– Cervix, colorectal  SIDS
– Skin (squamous cell)  Hearing loss
 Vascular disease - impotence  Rheumatoid arthritis
 Stroke  Macular degeneration
 Cataracts  Tooth decay
 Gum disease  Depression
 Dementia  Multiple sclerosis
 Early menopause
Smoking kills more people
each year than

 alcohol  homicide
 cocaine  suicide
 crack  car accidents
 heroin  fires
 AIDS
Health benefits after quitting
 cough, DOE resolve in weeks
 exercise tolerance improves rapidly
 bladder cancer: 50% reduction in 5 years
 lung cancer: 50% reduction in 10 years
 heart disease: 50% reduction in 1 year!
 No excess risk of heart disease by 10-15 years
 vascular disease: 50% reduction in 5 years
 mortality - same as never smokers by 10-15 yrs
Changes in relative risk (RR) for lung cancer after
cessation between former and
persistent smokers
Impact of smoking and smoking cessation on survival in men
Approach of Smoking Cessation
 5 A’s (Ask, Advise, Assess,
Assist, Arrange)
 5 R’s (Relevance, Risks, Rewards,
Roadblocks, Repetition)
Approach Model of Smoking Cessation

General
Population

Patient presents
to a health care
setting (clinic,
hospital, work site,
Relapse
others)

Ask – screen Assess Yes

Advise to Willingness Assist with Arrange
all patients for
Current Quit to quit quitting Follow up
tobacco use
Users
Never No Patient now
Use Former willing to
Promote Abstinent
Users quit
Primary motivation
Prevention to quit

Prevent
Relapse

Patient remains
unwilling
 Unwilling to quit
(5 R’s Approach.)
 Relevance :Encourage the smoker to identify why quitting is
personally relevant
 Risks :Ask the smoker to identify negative consequences of
continued tobacco use for them in both the short and long
term
 Rewards :Ask the smoker to identify and discuss specific
benefits of quitting
 Roadblocks :Assist the smoker to identify barriers and
specific impediments to quitting
 Repetition : Reinforce the motivational message at every
opportunity and reassure that repeated quit attempts are not
unusual
FDA-approved medications for smoking cessation
Transdermal NRT
Varenicline Tartrate
Thank you
Predictors of quit attempts and
cessation success
Fagerström test for nicotine dependence
(FTND)
 Earlier diagnosis
 Obstructive lung disease (chronic bronchitis and
emphysema)
 Genetic risk factors
 Sputum cytology
 Low-dose spiral computed tomography
 Positron emission tomography
 Laser-induced fluorescence endoscope (LIFE)
bronchoscopy

Edell 1997; Hirsch 2001

 LIFE bronchoscopy

White-light LIFE
bronchoscopy image bronchoscopy image
 Prevention
 Education and primary prevention
– avoidance of environmental carcinogens,
eg tobacco smoke

 Chemoprevention
– retinoids
– EGFR inhibitors
– selenium
– COX-2 inhibitors
– green tea
 Staging - TNM
 Tumor size:
– T1 < or = to 3cm
– T2 > 3cm
– T3 = local extension (parietal pleura,
chest wall or within 2cm of carina)
– T4 = spread to great vessels, trachea,
mediastinum, esophagus or malignant
effusion (nonresectable)
 Staging - TNM
 Lymph Node
– N0 = no involvement
– N1 = hilar nodes
– N2 = mediastinal nodes
– N3 = contralateral nodes or ipsilateral
supraclavicular (nonresectable)
 Staging Continued
 Stage IA - T1 N0 M0
 Stage IB - T2 N0 M0 (T >
3cm)
 Staging Continued
 Stage IIA - T1 N1 M0

 Stage IIB - T2 N1 M0

T3 N0 M0
 Staging Continued
 Stage IIIA - T3 N1 M0

T1-3 N2 M0

 Stage IIIB - Any T N3 M0

T4 Any N M0
 Staging Continued
Stage IV - Any T Any N M1
5-year survival by TNM status in
NSCLC
Stage TNM classification 5-year survival
(%)
IA T1N0M0 61
IB T2N0M0 38
IIA T1N1M0 34
IIB T2N1M0 or T3N0M0 24
IIIA T1-3N2M0 orT3N1M0 13
IIIB T4NanyM0 or TanyN3M0 5
IV TanyNanyM1 1

Mountain 1997
NSCLC: treatment options overview
Stage I
• Lobectomy or segment/wedge
resection
• Curative radiotherapy if surgery is
contraindicated
• Adjuvant chemotherapy
• Adjuvant radiotherapy
Stage II
• Lobectomy, pneumonectomy,
segment/wedge resection as
appropriate
• Curative radiotherapy if surgery
contraindicated
• Adjuvant chemotherapy
• Adjuvant radiotherapy

Stage IIIA Stage IV

• Surgery alone • Chemotherapy (platinum based),
• Chemotherapy + modest survival benefits
radiotherapy/neoadjuvant therapy • New chemotherapy agents
• Post-operative radiotherapy • External beam radiotherapy
• Radiotherapy alone (palliative relief)
Stage IIIB • Targeted agent
• Chemotherapy alone
• Chemotherapy + radiotherapy
• Radiotherapy alone
PDQ Guidelines 2000,Goldstraw et al 2007
 Advanced NSCLC:
new chemotherapy agents
 Platinum-based combination therapy gives
better response rates than monotherapy and
remains the ‘gold standard’ for first-line therapy
for advanced disease
 Paclitaxel, vinorelbine, docetaxel, gemcitabine
 In the past 3 decades, median survival in
NSCLC patients has only improved by
approximately 2 months

Corey Langer 2000; Breathnach et al 2001; Schiller et al 2002

Types of lung cancer: non-small-cell
lung cancer (NSCLC)
Squamous-cell carcinoma (~30%) Adenocarcinoma (30-50%)
• Most commonly found in men • Most common type of lung cancer
in women and non-smokers
• Closely correlated with smoking
(dose dependent) • Lesions are usually peripheral

• Tends to spread locally • Worldwide incidence increasing

• More readily detected in sputum
• Highly expressed genes encoding
proteins with detoxification/
anti-oxidant properties
• Highly expressed genes encoding
small-airway-associated and
immunologically related proteins
• K-ras mutations frequently reported
• Bronchoalveolar carcinoma is a
subtype

Large-cell carcinoma (10-25%)

• Very primitive, undifferentiated cells
• Lesions are usually peripheral
• High tendency to metastasise