RECENT ADVANCES IN
MANAGEMENT OF LUNG CANCER
Dr. P.K. Das
MD, DM (Medical Oncology, AIIMS)
Senior Consultant
Indraprastha Apollo Hospital
New Delhi
drpratapdas@gmail.com
Web site- www.drpkdas.com
Lung Cancer
Over View
• Epidemiology
• Etiology/Risk factors
• Diagnosis
• Histology
• Staging
• Various Treatment Options
• Complications
Worldwide incidence for lung cancer
 Lung cancer is the most common cancer in the world
Lung Cancer
•
Incidence
World
>1.3 million
Continent
% of World
Asia
49
Europe
28
North America
17
Central/South America
4
Africa
1
Lung cancer is the most common cause of cancer deaths in the
world
Kamangar et al. J Clin Oncol. 2006;24:2137-2150.
Lung Cancer Incidence – Geographical
Variation
Kamangar et al. J Clin Oncol. 2006;24:2137-2150.
Districtwise Minimum Age Adjusted Incidence Rate Per 100,000
LUNG - Males
© Copyright National Cancer Registry Programme 2001-2004
Districtwise Minimum Age Adjusted Incidence Rate Per 100,000
LUNG -Females
© Copyright National Cancer Registry Programme 2001-2004
Etiology
• Smoking (cigarette smoke has 300 chemicals, 40 of which
are carcinogenic) – 90 % patients are smokers
• Passive smoking/environmental tobacco smoke (ETS)/
second-hand tobacco smoke
• Asbestos
• Radiation
•
•
•
•
Radon
Air pollution
Lung injury/disease
Genetic factors ( EG F R, ras, p 5 3 )
Smoking
• Most lung cancers are caused by carcinogens and tumor
promoters ingested via cigarette smoking
• Smoking — active ↑ risk about 13 fold
ETS ↑ risk about 1.5 fold
• Cessation of smoking ↓ chance of developing lung cancer but
may never return to nonsmoker level
• Cigarette pack years – 2 packs/day for 2 0 years, ↑ 6 0 -7 0
fold risk
• Efforts to get people to stop smoking are mandatory
• Methods available for smoking cessation:
These methods are successful in
only 2 0%-25% of smokers at one
year (Preventing people from starting
to smoke may be more effective)
B e h a v ior t h era p y
Nicotine replacement ( g um, patc
h, sublingual spray & inhaler)
Lung Cancer Histology
Small-cell
20%
Squamous-cell
30%
Large-cell
10%
Adenocarcinoma
40%
Squamous cell &
SCLC are
decreasing in
incidence
Diagnosis
•Patient History
•Physical Examination
•Diagnostic Studies
Diagnosis of Lung Cancer
•History and Physical Examination
– Medical History
– Risk factor assessment
– Checking of airways, lymph nodes, lung sounds etc
•Diagnostic tests
– Routine lab tests like Complete Blood Counts, chest X-rays, Liver
function tests
– Non invasive tests – sputum cytology and imaging tests (CT, MRI, PET,
Bone Scan)
– Invasive tests – Bronchoscopy, Transbronchial FNA, Transthoracic
Percutaneous FNA, Mediastinoscopy, Mediastinotomy, etc
Clinical Manifestations
 A cough that does not go away
 Chest pain, often made worse by deep breathing
 Shoulder pain with numbness in some fingers; with or
without droopy eyelid (HORNER’S SYNDROME)
 Hoarseness
 Weight loss and loss of appetite
 Bloody or rust-colored sputum
 Shortness of breath
 Fever without a known reason
 Recurring infections such as bronchitis and pneumonia
 New onset of wheezing
 Headaches; change in vision or speech
 Seizures
Diagnostic Studies
– Imaging:
Used to visualize the interior of the body. Examples of such
studies include X-rays, Ultrasound, Computerized Tomography
(CT) scans, positron emission tomography (PET), and magnetic
resonance imaging (MRI)
– Endoscopy:
Involves use of a light on a flexible fiberoptic viewing device
(endoscope) to examine lining of the passages
Lung cancer presentation
The chest x-ray shows a shadow in
the left lung, which was later
diagnosed as lung cancer.
A CT scan of the lung shows a mass lesion
in the right lung. The mass turned out to be
lung cancer on examination of the needle
biopsy sample.
PET (Positron emission tomography)
 Computerized image of chemical
changes eg sugar metabolism that
take place in tumor tissue
 Patient injected with radioactive sugar
(FDG PET) and then scanned
 Uptake will happen in active tumor :
distinguish normal from abnormal
tissue
PET Image
Histologic Examination
Tissue Acquisition








Bronchoscopy
Biopsy
Core needle
Fine needle
Brush cytology
Incisional
Excisional
Other procedures
Microscopy
Grading
 G1
 G2
 G3, G4
Tissue Acquisition
Is done through biopsy – a procedure through which tissue or
fluid is removed from the body for examination.
Core needle biopsy:
– A procedure which uses a special needle to cut a core of tissue for
examination
Fine needle aspiration (FNAC):
– Is a cytologic procedure in which a needle is inserted into an organ
or body cavity and a small sample of fluid and cells is removed.
Brush Cytology:
– Brush cytology is a technique in which a very small brush, attached
to an endoscope, is used to rub off tumor cells for examination.
Often used for Pancreatic and lung cancers.
Lung Biopsy – Core needle
Lung Biopsy
CT Scan of the chest with a
biopsy needle extending into a lung
mass
The needle is oriented vertically
and goes into the mass (indicated
by red color).
The lung tissue is
black
the
and
bones
are
white. The patient is prone and the
heart is the large white structure at
the lower part of the chest.
Lung Cancer Subtypes:
• 1) Small Cell Lung Cancer
• 2) Non- Small Cell Lung Cancer
• a) Squamous
•
•
b) Non- Squamous
(i) Adenocarcinoma
(ii) Large Cell Carcinoma
Adenocarcinoma
 Cancer arising out of glandular
tissues
 Most frequent type diagnosed in
lung cancer (30 – 40%)
 Common in smokers and nonsmokers
 More common in women than in
men
 Usually arise in the peripheral
areas of lung and metastasize
quickly
 Bronchoalveolar
carcinoma
(BAC)
is
a
subtype
of
adenocarcinoma and is found
more in women and is
associated
with
scars
of
tuberculosis
 Early diagnosis is rare and
prognosis is poor
Large Cell




Account for approx. 15%
Progonosis same as adenocarcionoma
Both ( adeno and large) are known as Non-Squamous
Undifferentiated large cell, can be classified as poorly differentiated.
Squamous Cell
 Accounts for 30% of lung
cancers
 Strongly associated with
smoking
 Tend
to
be
centrally located
more
 Forms necrotic cavities,
that can be seen on Xrays
 Cell doubling rate is slow
and surgical resection
leads to a 30% 5 year
survival rate
 5 year survival rate of all
SCC is 5 – 7%
Small Cell Lung Cancer (SCLC)
– Comprises 15-20% of all lung cancers
– Spreads more aggressively than NSCLC
– Is more responsive to chemotherapy
– Frequently found in smokers or former
smokers
Small Cell Lung Cancer (SCLC)
Two stages: As per Veterans Administration
Lung Cancer study group (VALCG)

Limited stage

Extensive stage

TNM staging is Now the standard after 7th
Edition 2009
Small Cell Lung Cancer (SCLC) : Sites of
metastases
SITE
PERCENT

Liver
30

Bone
25

Bone marrow
20

Brain
10

Extrathoracic LN
5

Subcutaneous mass
5
Small Cell Lung Cancer (SCLC) :
Paraneoplastic syndromes

More common than in NSCLC

SIADH (syndrome of inappropriate antidiuretic
hormone) : 15% of cases

Hyponatremia (low serum sodium)

Cushing’s syndrome

Neurological syndrome

Peripheral neuropathy

Eaton lambert syndrome (proximal muscle weakness)
Step by Step Approach
– Advanced and Metastatic NSCLC
Metanalysis BMJ 1995
Pujol 2006
NSCLC: Strategies to overcome
chemotherapy‘s plateau
•
•
•
•
•
•
•
•
•
Novel antifolate (Alimta-Pemetrexed)
Monoclonal antibody-targeting VEGF (Avastin-Bevacizumab)
Monoclonal antibody-targeting EGFR (Erbitux-Cetuximab)
Small molecules targeting EGFR (Gefitinib, Erlotinib)
Small molecules targeting multi-TK‘s (Sorafenib, Sunitinib)
Immune modulation targeting TLR 9 (PF-3512676)
Vaccine targeting cancer associated MUC1-antigen (TG1410)
Gene guided therapy (ERCC1, RRM1)
Bisphosphonates (Zometa-Zoledronic acid)
1980’s - Advanced NSCLC
Does chemotherapy
prolong survival in
advanced stage disease?
Yes, it does!
Cisplatin based doublets do
Remaining issues
Toxicity
-Nausea
-Vomiting
-Myelosuppression
Median survival (months)
Central question in 1980’s
Cisplatin based
regimens
6-8
12
10
8
6
4
BSC
4-6
2
0
1970
1980
3rd Generation agents
Are platinum based
doublets with 3rd
Generation agents superior
to older doublets?
Yes, they are!
3rd Generation agents
Vinorelbine
Paclitaxel
Gemcitabine
Docetaxel
Median survival (months)
Central question in 1990’s
Platinum based
Cisplatin Doublets
based
(3rd generation)
regimens 8-10
6-8
12
10
8
6
BSC
4-6
4
2
0
1970
1980
1990
Mid-late 1990’s
- Advanced NSCLC
ECOG 1594
Central question
in mid-late 90’s
Coalition
Which of the new doublets
was the best ?
ASCO guideline
NCCN guideline
All of them have similar efficacy
and safety
Dominant regimens
in practice
US
Carboplatin based
regimens
EU
Cisplatin based
regimens
Late 1990’s and 2000’s - Advanced NSCLC
Central question
in late 90’s and 2000’s
Does the addition of a third
agent improve efficacy to a
platin- based doublet?
Yes or NO
Epidermal Growth Factor Receptor (EGFR)
Tyrosine Kinase Inhibitors (TKI)
Erlotinib
Gefitinib
Result: Negative
(TALENT, INTACT 1&2, TRIBUTE)
Vascular Endothelial
Growth Factor (VEGF) Antibody
(Anti-angiogenesis agent)
Targeted therapy
Bevacizumab (Avastin)
Target several new
specific targets unique
or largely unique to
malignant cells
Result:
Positive (ECOG4599)
PFS advantage but no OS advantage
(AVAIL)
2007 - Advanced NSCLC
Landmark Lilly Trial (Scagliotti et al) for the first time demonstrated a
survival advantage of treatment (Pemetrexed) by histology effect
Adeno
Large Cell
Squamous
NSCLC distribution by
stage and associated survival rates
NSCLC
Stage
Distribution
1
NSCLC
Stage
1-Year
2
Survival
5-Year
3
Survival
I
13%–24%
IA
IB
91%
72%
50%
43%
II
5%–10%
IIA
IIB
79%
59%
36%
25%
50%
III
31%–44%
IIIA
IIIB
37%
32%
19%
7%
IV
32%–39%
IV
20%
2%
1. Bulzebruck H, et al. Cancer. 1992;70:1102-1110. 2.Mountain CF. Chest. 1997:111;1710-1717. 3. Goldstraw P. Presented at the 12th World Conference on Lung Cancer; September 5,
2007; Seoul, Korea.
Importance of Adjuvant Therapy
 Three randomized phase III trials and the Lung
Adjuvant Cisplatin Evaluation meta-analysis have
shown a significant survival benefit for adjuvant
cisplatin-based chemotherapy for selected patients
with completely resected stage II and IIIA NSCLC
 Postoperative
adjuvant
cisplatin
based
chemotherapy now represents the standard of care
for the management of stage II to IIIA NSCLC
 Adjuvant cisplatin-based chemotherapy significantly
improves survival for patients with resected stage II
and IIIA NSCLC
CONVENTIONAL RADIATION THERAPY
XRT, is the medical use of ionizing radiation as part
of cancer treatment to control malignant cells
and also for some benign ds.
The treatment by radiation is when the tumour is
treated along with margin of safety with
conventional dose, fractionation regimen.
CONVENTIONAL RADIATION THERAPY
What improved the results of
conventional therapy?
1. Introduction of Mega Voltage Beam.
a) Linear Accelerator – 1950 U.K.
b) Cobalt Machine
- 1952 Canada
Marriage of computer science and medicine
2. Introduction of treatment planning
systems n CT in 70’s which led to better
planning and accuracy of radiation
dose delivery.
Overview-Major Milestones
3 DCRT
Teletherapy
COBALT & LINAC
IGRT
IMRT
DART
Tomotherapy
Gamma Knife
Radiation
Therapy
Stereotactic radiotherapy
LINAC X Knife
Cyberknife
Novalis
Image Assisted Brachytherapy
Brachytherapy
Intraoperative
Brachytherapy
THEN
3D CRT, IMRT & IGRT
NOW
What is IMRT ?
Intensity Modulated Radiotherapy is a special form
of 3D-CRT in which non-uniform fluence is delivered
to the patient from any given position of the
treatment beam to optimize the composite dose
Distribution; which is calculated by an inverse
treatment planning process designed to meet
specified dosimetric objectives.
3D CRT, IMRT & IGRT
PET-CT Image fusion
PET provides functional
information to an
anatomical scan
Combined PET-CT Scanners
reduce setup discrepancies
1
Information from PET can help modify PTV volumes
Non-Small Cell Carcinoma
Soft tissue window
Soft Tissue Window
Lung window
Lung Window
Green outline: CT only
Siemens medical
Solutions that help
Courtesy of Universitaets-Klinikum Essen
3D CRT, IMRT & IGRT
FDG - PET
Red outline: CT & FDG
IGRT-Image Guided Radiotherapy
DART-Dynamic Adaptive Radiotherapy
 Devising precise methods of delineating targets– MULTIMODALITY IMAGING
 Target Localization for verification by on-board imaging (OBI)
& changing the set up accordingly
 Minimizing the uncertainty due to intra-treatment motion (4D
RT- Respiratory Gating)

 DYNAMIC ADAPTIVE RADIOTHERAPY
Two components:
 Adapt to tumor motion (IGRT)
 Adapt to tumor / organ deformation and volume change.
3D CRT, IMRT & IGRT
3D-CRT & IMRT: Treatment Delivery &
Verification
5. Take Portal images
6. Match with DRRs
in EPID software
7. Final Treatment Execution
3D CRT, IMRT & IGRT
High Tech Radiotherapy Machines
Helical Tomotherapy
Cyber Knife
Gamma Knife
Novalis Tx
PRECISION-A Way Forward
State Of Art Technology-NOVALIS TX
3D CRT, IMRT & IGRT
NOVALIS Tx- Precision Radiotherapy and
Radiosurgery
 Novalis Tx, Newest generation LINAC
 Novalis Tx machine utilizes X-rays that are targeted
at the tumor to destroy the growth of cell without
pain and discomfort.
 The Novalis TX offers the advanced definition of
“multileaf collimator” (HDMLC 120). Precision 2.5
mm
3D CRT, IMRT & IGRT
The Novalis TX linear accelerator can deliver
radiation in many ways
 Image Guided Radiation Therapy (IGRT)
 Intensity Modulated Radiation Therapy (IMRT)
 EXAC TRAC Adaptive Gating
 Frameless Stereotactic Radiosurgery using High
definition micro MLC (HDMLC)
 Stereotactic Whole body radiation ( SBRT)
3D CRT, IMRT & IGRT
NOVALIS- Respiratory Gating
 Method where on-off status of treatment beam is controlled by
signals produced whenever breathing signal falls in the preset
gating window
 Instead of enlarging PTV to encompass the range of motion,
treatment delivered only during part of the respiratory cycle.
3D CRT, IMRT & IGRT
Novalis Tx- Rapid Arc
 The Powerful Treatment with Novalis Tx –
 Platform can deliver it quickly with the rapid arc
Technology, so that patients spend little time
immobilized on the treatment table. Fast treatments are
easier and accurate.
3D CRT, IMRT & IGRT
NOVALIS Tx
 For treatment precision – sharp, precise beams
 Beam Shaper: 2.5 mm HD120® high-definition beam
shaper
 Gantry Precision: Mechanical accuracy throughout with
0.5 mm isocentric precision
 Clinical Accuracy: Submillimeter accuracy technically &
clinically demonstrated
3D CRT, IMRT & IGRT
NOVALIS Tx
 For treatment power – powerful linac and advanced
treatment techniques
 High Dosing Delivery: Up to 1000 MU / minute dose rate
 Linac MV Power: 6 MV and HighX (10-20MV) power
 Flexible MV Control: RapidArc SRS/SBRS speed with
power
3D CRT, IMRT & IGRT
NOVALIS Tx
 For tissue targeting precision - sophisticated
imaging technologies
 Stereo X-ray Targeting: Includes ExacTrac X-Ray 6D
and Snap verification
 Cone Beam CT: Includes On-Board Imager® for 3D soft
tissue target confirmation for SBRS
 MV Portal Vision™ and Fluoroscopy: Helps you "see
what you treat while you treat" in real time
 Adaptive Gating: Includes ExacTrac X-Ray 6D for
treating tumors that move with respiration
 Robotic Couch: Corrects patient positioning in 6D,
including pitch, roll and yaw
 For ease of use - intelligent & intuitive software
3D CRT, IMRT & IGRT
Novalis treats-RT, SRS, FSRS, IMRT, IGRT

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











Acoustic Neuromas
Arteriovenous Malformation(AVM)
Brain metastasis/Glioma
Craniopharyngioma
Spine Tumors/Metastasis
Liver tumors/ Metastasis
Meningioma of skull base
Parkinson,s Disease
Paediatric Bone Tumours
Pituitary Adenomas
Prostate Cancer/Metastasis
Recurrent Brain Tumors
Spine Tumors/Metastasis
Trigeminal Neuralgia
3D CRT, IMRT & IGRT
BRIGHT FUTURE AHEAD…..
 Technology with lot of promises and great potentials
 Turning the promises and potentials into clinical
gains
– adequate infrastructure
– manpower & expertise
– Designed Depts
– understanding the limitations
3D CRT, IMRT & IGRT
RT in NSCLC: Stage Wise
 Stage: I : Surgery the mainstay; SBRT
 Stage II: Surgery the mainstay; SBRT
 Stage III: Surgery + RT, CT + RT
 Stage IV: Palliative RT

Pts. presenting with
Painful bone mets
Impending cord compression.
Brain mets
SVC obstruction/ bulky mediastinal mass
Hemoptysis
 ? Prophylactic cranial irradiation
CyberKnife
CyberKnife: Unique Properties
 Highly precise treatment delivery
 Motion management method
 Tumor tracking
 Dose painting
 Excellent dose distribution
 Fractionation schedule
 No rigid fixation
Thank You
Thank You